The ESC Textbook of

Intensive and Acute

Cardiovascular Care
EUROPEAN SOCIETY OF CARDIOLOGY PUBLICATIONS
The ESC Textbook of Cardiovascular Medicine (Third Edition)
Edited by A. John Camm, Thomas F. Lüscher, Gerald Maurer, and Patrick W. Serruys
The ESC Textbook of Preventive Cardiology
Edited by Stephan Gielen, Guy De Backer, Massimo Piepoli, and David Wood
The EHRA Book of Pacemaker, ICD, and CRT Troubleshooting: Case-​based learning
with multiple choice questions
Edited by Harran Burri, Carsten Israel, and Jean-​Claude Deharo
The EACVI Echo Handbook
Edited by Patrizio Lancellotti and Bernard Cosyns
The ESC Handbook of Preventive Cardiology: Putting prevention into practice
Edited by Catriona Jennings, Ian Graham, and Stephan Gielen
The EACVI Textbook of Echocardiography (Second Edition)
Edited by Patrizio Lancellotti, José Luis Zamorano, Gilbert Habib, and Luigi Badano
The EHRA Book of Interventional Electrophysiology: Case-​based learning with
multiple choice questions
Edited by Hein Heidbuchel, Matthias Duytschaever, and Harran Burri
The ESC Textbook of Vascular Biology
Edited by Robert Krams and Magnus Bäck
The ESC Textbook of Cardiovascular Development
Edited by José Maria Pérez-​Pomares and Robert Kelly
The EACVI Textbook of Cardiovascular Magnetic Resonance
Edited by Massimo Lombardi, Sven Plein, Steffen Petersen, Chiara Bucciarelli-​Ducci,
Emanuela R. Valsangiacomo Buechel, Cristina Basso, and Victor Ferrari
The ESC Textbook of Sports Cardiology
Edited by Antonio Pelliccia, Hein Heidbuchel, Domenico Corrado, Mats Börjesson, and
Sanjay Sharma
The ESC Handbook of Cardiac Rehabilitation
Edited by Ana Abreu, Jean-​Paul Schmid, and Massimo Piepoli
The ESC Textbook of Intensive and Acute Cardiovascular Care (Third Edition)
Edited by Marco Tubaro, Pascal Vranckx, Eric Bonnefoy-Cudraz, Susanna Price, and Christiaan Vrints

FORTHCOMING
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Edited by José Luis Zamorano, Jeroen Bax, Juhani Knuuti, Patrizio Lancellotti, Bogdan
Popescu, Fausto Pinto, and Udo Sechtem
The ESC Textbook of
Intensive
and Acute
Cardiovascular
Care
THIRD EDITION

EDITORS
Marco Tubaro
Pascal Vranckx

CO-​E DITORS
Eric Bonnefoy-Cudraz 
Susanna Price 
Christiaan Vrints

1
3
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Second Edition published in 2015
Third Edition published in 2021
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 Preface

Intensive cardiac care (procedures) saves lives and reduce car- ACVC has expanded the recommended treatment from a pre-
diac disability in acute cardiac patients. This treatment is to be vious focus on in-hospital intensive care, with emphasis on the
delivered by specially trained and accredited cardiologists, nurses intensive cardiac care units (ICCUs), to intensive and acute car-
and paramedics working in specially designed and equipped fa- diovascular care wherever it is needed (including pre-hospital,
cilities. The urgent nature of some acute cardiac presentations ambulances, emergency rooms, ICCUs, wards, operating theaters,
dictates the need to apply acute cardiac care as early as possible, etc.). This is in accord with the realization of the need for a con-
at the prehospital and or emergency room scenario. Prompt and tinuum mode of treatment and the incorporation of the specific
accurate diagnosis, meticulous monitoring and urgent treat- groups under the ACVC. Therefore, the effort for this new edition
ment are indicated in a wide variety of cardiovascular condi- of the ESC Textbook of Acute and Intensive Cardiovascular Care is
tions, including acute coronary syndromes, acute decompensated timely and highly appreciated.
heart failure, life-threatening rhythm disturbances, myocarditis, For simplicity and consecutiveness, the table of contents in
pulmonary embolism, infective endocarditis, as well as compli- the current edition has been maintained similar to that of the
cations of cardiac interventions and other acute maladies (i.e. second edition. However, the content has been improved and
infection, haemorrhage, trauma) whereby chronic heart disease updated and a new chapter (Chapter 50) is now fully dedicated
may jeopardize the short-term prognosis. to implanted cardiac support devices. A special mention is to be
The Association for Acute CardioVascular Care (ACVC) of dedicated to Chapter 3 on ‘Intensive Cardiovascular Care Units:
the European Society of Cardiology (ESC) has set out to pi- structure, organization and staffing’ which reflects the reality that
oneer this subspeciality of cardiology. The ESC Textbook of three levels of acute cardiac care may function in different hos-
Intensive and Acute Cardiovascular Care is a major asset. It is pitals. Some can apply only limited acute coronary care, while
the only textbook completely dedicated to the field of acute car- others can provide the full scope of advanced, comprehensive, in-
diovascular and intensive care. It contains all the basic neces- tensive, and acute cardiac care (level III).
sary comprehensive, yet practical information needed for the As in the previous editions, the print textbook is accompanied
optimal implementation of acute cardiac care. This includes by an expanded and more comprehensive online edition, which is
the recommended organization and function of the service, de- expected to be yearly updated.
tailed description of the laboratory tests, special cardiac evalu- The editors and authors of the third edition of the ESC Textbook
ation techniques, procedures, pharmacological and invasive of Intensive and Acute Cardiovascular Care should be congratu-
therapeutic interventions used for the practice of intensive car- lated on the completion of this major task. I am confident that this
diac care. A detailed description and recommendations for the endeavor will contribute to the daily conductance of acute cardiac
management of the various diseases in need for acute cardiac care and provide mandatory learning material for the education
care is also included. of cardiologists and allied staff training in the field.
Cardiology in general, and specifically the field of intensive car-
diac care, is constantly evolving. There is a constant new inflow of Professor Yonathan Hasin
information, introduction of updated evidence-based guidelines Founding chairperson of the Working Group on Acute Cardiac
and new and improved therapeutic techniques (including organ Care of the ESC
supportive therapy for the critically ill patients). Currently, the Ariel University Medical School
 Contents

Symbols and abbreviations  xi SECTION II

Contributors  xxix The pre-​hospital phase and the emergency
department 
Intensive and acute cardiovascular care: an
1
introduction  1 The emergency medical system  65
8
Eric Bonnefoy-Cudraz, Susanna Price, Marco Tubaro, Olivier Hoogmartens, Michiel Stiers, Koen Bronselaer,
Pascal Vranckx, and Christiaan Vrints and Marc Sabbe
Out-​of-​hospital cardiac arrest  76
9
Jerry P Nolan and Christian Hassager
SECTION I
Chest pain in the emergency department and the
10
Intensive and acute cardiovascular care  chest pain unit  88
Christiaan Vrints, Janina Stepinska, and Marc J Claeys
Training and certification in intensive and acute
2
cardiovascular care  5 Acute dyspnoea in the emergency
11
Susanna Price and Eric Bonnefoy-Cudraz department  103
Eleni Michou, Nikola Kozhuharov, Jasmin Martin, and
Intensive cardiovascular care units: structure,
3 Christian Mueller
organization, and staffing  11
Eric Bonnefoy-Cudraz and Tom Quinn
The heart team  25
4 SECTION III
Sergio Leonardi, Thomas Modine, and Stephan
Windecker Monitoring and investigations in the
intensive cardiovascular care unit 
Patient safety and clinical governance  33
5
Matthew Parkin and Tom Quinn
Pathophysiology and clinical assessment of the
12
Ethical issues in cardiac arrest and acute cardiac
6 cardiovascular system (including pulmonary
care: a European perspective  43 artery catheterization)  115
Jean-​Louis Vincent and Jacques Creteur Alessandro Sionis, Etienne Gayat, and
Alexandre Mebazaa
Quality of care assessment in acute
7
cardiac care  54 The respiratory system  127
13
Fiona Ecarnot and François Schiele Antoine Vieillard-​Baron
viii C onte n ts

Neurological assessment of the acute cardiac

14 Chest tubes  331
26
care patient  134 Giulio Maurizi, Camilla Vanni, and Erino Angelo Rendina
Mathieu van der Jagt, Jeroen JH Bunge, and
Renal support therapy  338
27
Fabio S Taccone
Claudio Ronco, Stefano Romagnoli, and Zaccaria Ricci
Monitoring of the kidneys, liver, and other
15
Percutaneous (short-​term) mechanical circulatory
28
vital organs  147
support  351
Karl Werdan, Brijesh Patel, Matthias Girndt, Henning
Holger Thiele and Pascal Vranckx
Ebelt, Jochen Schröder, and Sebastian Nuding
Nutrition support in acute cardiac care  360
29
Blood gas analysis: acid–​base, fluid, and
16
Michael P Casaer and Greet Van den Berghe
electrolyte disorders  165
Farah Shariff and Richard Paul Physiotherapy in critically ill patients  373
30
Rik Gosselink and Jean Roeseler
Interpretation and clinical use of chest
17
radiographs  181
Alexander Parkhomenko, Olga S Gurjeva, and
Tetyana Yalynska SECTION V
18.1 Echocardiography and thoracic ultrasound  201 The laboratory in intensive and acute
Frank A Flachskampf, Pavlos Myrianthefs, and cardiovascular care
Ruxandra Beyer
The use of biomarkers for acute cardiovascular
31
18.2 Echocardiography and thoracic ultrasound  218
Frank A Flachskampf, Pavlos Myrianthefs, and disease  387
Ruxandra Beyer Allan S Jaffe

Computerized tomography: coronary angiography

19 Biomarkers in acute coronary syndromes  400
32
Jasper Boeddinghaus, Thomas Nestelberger,
and cardiac imaging  224
Raphael Twerenbold, and Christian Mueller
Jeff M Smit, Mohammed El Mahdiui, Michiel A de Graaf,
Arthur JHA Scholte, Lucia Kroft, and Jeroen J Bax Biomarkers in acute heart failure  409
33
Rajiv Choudhary, Nicholas Wettersten, Kevin Shah, and
Cardiac magnetic resonance in the intensive and
20
Alan Maisel
cardiac care unit  246
Juerg Schwitter and Jens Bremerich Biomarkers of coagulation and thrombosis  425
34
Anne-​Mette Hvas, Erik L Grove, and
Steen Dalby Kristensen
SECTION IV Biomarkers of renal and hepatic failure  434
35
Mario Plebani, Monica Maria Mion, and
Procedures in the intensive cardiovascular
Martina Zaninotto
care unit 
Non-​invasive ventilation  267
21
Josep Masip, Kenneth Planas, and Arantxa Mas SECTION VI
Mechanical ventilation  284
22 Acute coronary syndromes
Luigi Camporota and Francesco Vasques
Atherosclerosis and thrombosis  447
36
Temporary pacing  306
23 Lina Badimon and Gemma Vilahur
Bulent Gorenek
The universal definition of myocardial
37
Ultrasound-​guided vascular access in
24 infarction  463
intensive/​acute cardiac care  314 Kristian Thygesen, Joseph S Alpert, Allan S Jaffe, and
Richard Paul Harvey D White
Pericardiocentesis  323
25 ST-​segment elevation myocardial infarction  479
38
Caterina C De Carlini and Stefano Maggiolini Borja Ibanez and Stefan James
 C on t e n ts ix

Fibrinolytic, antiplatelet, and anticoagulant drugs

39 Donor organ management  691
51
in acute coronary syndromes  494 Arne P Neyrinck, Patrick Ferdinande, Dirk Van
Sigrun Halvorsen, Giuseppe Gargiulo, Marco Valgimigli, Raemdonck, and Marc Van de Velde
and Kurt Huber
Palliative care in the intensive cardiovascular
52
Mechanical complications of myocardial
40 care unit  706
infarction  513 Jayne Wood
Elena Puerto and Héctor Bueno
Non-​ST-​segment elevation acute coronary
41
syndromes  531 SECTION VIII
Héctor Bueno and José A Barrabés Arrhythmias
Percutaneous coronary interventions in acute
42
coronary syndromes  549 Atrial fibrillation and supraventricular
53
Andreas Mitsis and Marco Valgimigli arrhythmias  719
Demosthenes G Katritsis and A John Camm
Coronary artery bypass graft surgery  565
43
Piroze M Davierwala and Michael A Borger Ventricular tachyarrhythmias  740
54
Paolo Della Bella, Dagmara Dilling, and Francesca Baratto
Sex considerations in acute coronary
44
syndromes  585 Pacemaker and ICDs: troubleshooting  755
55
Eva Swahn, Joakim Alfredsson, and Neasa Starr and Haran Burri
Sofia Sederholm Lawesson

SECTION IX
SECTION VII Specific acute cardiovascular conditions
Acute heart failure (including cardiogenic
Myocarditis and pericarditis  767
56
shock) Massimo Imazio and Stephane Heymans
Acute heart failure: epidemiology, classification,
45 Acute valve disease and endocarditis  778
57
and pathophysiology  603 Gregory Ducrocq, Franck Thuny, Bernard Iung,
Dimitrios Farmakis and Gerasimos Filippatos and Alec Vahanian

Acute heart failure: early pharmacological

46 Congenital heart disease in adults  795
58
therapy  617 Susanna Price, Brian F Keogh, and Lorna Swan
Kieran F Docherty, Jonathan R Dalzell, Mark C Petrie, and
Aortic emergencies  805
59
John JV McMurray
Marc Schepens and Eric Graulus
Low cardiac output states and cardiogenic
47
Cardiac complications in trauma  820
60
shock  633 Lydia Lam, Leslie Kobayashi, and Demetrios Demetriades
Holger Thiele and Suzanne de Waha-​Thiele
Cardiac emergencies in pregnancy  830
61
Non-​pharmacological therapy of acute heart
48 Mark Johnson and Jolien Roos-​Hesselink
failure: when drugs alone are not enough  651
Jeroen Dauw, Wilfried Mullens, Johan Vijgen, Pulmonary hypertension  839
62
and Pascal Vranckx Massimiliano Palazzini, Nazzareno Galiè, and
Alessandra Manes
Heart failure surgery and transplantation  664
49
Felix Schoenrath, Jan Klages, and Volkmar Falk Pulmonary embolism  849
63
Stavros Konstantinides, Marcin Kurzyna, and Adam
Implanted cardiac support devices  680
50 Torbicki
Andrew C Morley-​Smith, André R Simon, and
John Pepper
x C onte n ts

Infection, sepsis, and multiorgan dysfunction

70
SECTION X syndrome  945
Concomitant acute conditions Jean-​Louis Vincent

Acute respiratory failure and acute respiratory

64
Pain in the intensive cardiovascular care unit  956
71
Siân Jaggar and Helen Laycock
distress syndrome  863
Luciano Gattinoni, Mattia Busana, and Delirium in the intensive cardiovascular care unit  969
72
Eleonora Carlesso Stephen Keane, Kevin Clarkson, and John W McEvoy
Stroke  880
65 Special considerations in the immunosuppressed
73
Didier Leys, Solène Moulin, and Valeria Caso patient  979
Anne-​Sophie Moreau and Raphaël Favory
Acute kidney injury  895
66
Sofie A Gevaert, Eric Hoste, and John A Kellum Perioperative cardiac care of the high-​risk
74
Stress hyperglycaemia and endocrine
67 non-​cardiac patient  990
Martin Balik
emergencies  912
Jan Gunst, Yves Debaveye, and Greet Van den Berghe Perioperative management of the high-​risk
75
Bleeding and haemostasis disorders  926
68 surgical patient: cardiac surgery  1009
Pier Mannuccio Mannucci and Maddalena Lettino Marco Ranucci, Serenella Castelvecchio,
and Andrea Ballotta
Anaemia and transfusion  938
69
Pascal Vranckx, Davide Cao, Philippe Vandekerckhove,
and Roxana Mehran Index  1025
 Symbols and abbreviations

£ pound sterling ABC adenosine triphosphate-​binding cassette; airway,

$ dollar breathing, circulation
€ euro ABG arterial blood gas
° degree ABMS American Board of Medical Specialties
°C degree Celsius ABOARD Angioplasty to Blunt the Rise of Troponin in
% per cent Acute Coronary Syndromes Randomized
± plus or minus for an Immediate or Delayed Intervention
= equal to (trial)
> greater than ACCF American College of Cardiology
< less than Foundation
≥ equal to or greater than ACCOAST Comparison of Prasugrel at the Time of
≤ equal to or less than Percutaneous Coronary Intervention (PCI) or
α alpha as Pretreatment at the Time of Diagnosis in
β beta Patients with Non-​ST Elevation Myocardial
δ delta Infarction (trial)
γ gamma ACCP American College of Chest Physicians
κ kappa ACD active compression–​decompression
σ sigma ACE angiotensin-​converting  enzyme
Ω ohm ACEF age, creatinine, and ejection fraction (score)
π pi ACE-​I angiotensin-​converting enzyme inhibitor
τ tau ACGME Accreditation Council for Graduate Medical
® registered trademark Education
© copyright ACHD adult congenital heart disease
™ trademark ACLS advanced cardiac life support
Δ change ACP American College of Physicians
↑ increase ACPO acute cardiogenic pulmonary oedema
↓ decrease ACR albumin/​creatinine  ratio
→ leads to ACRIN American College of Radiology Imaging
3CPO Three Interventions in Cardiogenic Pulmonary Network-​Pennsylvania (trial)
Oedema (trial) ACS acute coronary syndrome
2D two-​dimensional ACT activated clotting time
3D three-​dimensional ACTH adrenocorticotrophic hormone
5-​FU 5-​fluorouracil ACTION Acute Coronary Treatment and Intervention
AAD antiarrhythmic drug Outcomes Network
AAR aspartate transaminase-​to-​alanine
transaminase ratio
xii Symb ols an d abbreviations

ACTION Registry–​GWTG Acute Coronary Treatment AKI acute kidney injury

and Intervention Outcomes AKIN Acute Kidney Injury Network
Network Registry—​Get With The ALARM-​HF Acute Heart Failure Global Survey
Guidelines of Standard Treatment (registry)
ACUITY Acute Catheterization and Urgent ALD adjustable loop diuretics
Intervention Triage Strategy (trial) ALI acute lung injury
ACVC Association for Acute ALS advanced life support
CardioVascular Care ALT alanine aminotransferase
ADA adenosine deaminase AMACING A MAastricht Contrast-​Induced
ADAM a disintegrin and Nephropathy Guideline (trial)
metalloproteinase AMI acute myocardial infarction
ADAPT 2-​Hour Accelerated Diagnostic AMP adenosine monophosphate
protocol to Assess Patients with AMPA α-​amino-​3-​hydroxy-​5-​methyl-​4-​
chest pain symptoms using isoxazole propionic acid
contemporary Troponins as the AMPK adenosine monophosphate-​
only biomarker (trial) activated protein kinase
ADCHF acutely decompensated chronic AMR antibody-​mediated rejection
heart failure ANC absolute neutrophil count
ADH antidiuretic hormone ANCA anti-​neutrophilic cytoplasmic
ADHERE Acute Decompensated HEart antibodies
Failure National REgistry ANP atrial natriuretic peptide
ADHF acute decompensated heart failure AP action potential; anteroposterior
ADM adrenomedullin APACE Advantageous Predictors of Acute
ADP accelerated diagnostic protocol; Coronary Syndromes Evaluation
adenosine diphosphate APACHE Acute Physiology and Chronic
ADQI Acute Dialysis Quality Health Evaluation
Initiative APC adaptive pressure control
ADSORB Acute Dissection: Stent graft OR APEX AMI Assessment of Pexelizumab in
Best medical therapy (trial) Acute Myocardial Infarction (trial)
AE adverse event APP abdominal perfusion pressure
AECC American-​European Consensus APPRAISE-​2 Apixaban for Prevention of Acute
Conference Ischemic Events 2 (trial)
AED automated external defibrillator; APPROACH Alberta Provincial Project for
antiepileptic drug Outcome Assessment in Coronary
AER albumin excretion rate Heart Disease (study)
AF atrial fibrillation APROCCHSS Activated Protein C and
AFE amniotic fluid embolism Corticosteroids for Human Septic
AG anion gap Shock (trial)
AGI acute gastrointestinal injury APRI aspartate transaminase-​to-​platelet
AHA American Heart Association ratio index
AHF acute heart failure aPTT activated partial
AHFS acute heart failure syndromes thromboplastin time
AHQR Agency for Healthcare Quality and AR aortic regurgitation
Research ARB angiotensin receptor blocker
AI asynchrony index; aortic ARC-​HBR Academic Research Consortium
insufficiency; adrenal insufficiency; for High Bleeding Risk
artificial intelligence ARDS acute respiratory distress
AIDS acquired immune deficiency syndrome
syndrome ARF acute respiratory failure; ascending
AIH amiodarone-​induced reticular formation
hyperthyroidism ARNI angiotensin receptor–​neprilysin
AIMS Australian Incident inhibitor
Monitoring System ARVC arrhythmogenic right ventricular
AIVR accelerated idioventricular rhythm cardiomyopathy
AKD acute kidney disease AS aortic stenosis
 Sym b ol s a n d a b b rev iat i on s xiii

ASCEND-​HF Acute Study of Clinical AVA aortic valve area

Effectiveness of Nesiritide in AVM arteriovenous malformation
Decompensated Heart Failure AVNRT atrioventricular nodal re-​entrant
(trial) tachycardia
ASIC acid-​sensing ion channel AVOID-​HF Aquapheresis versus Intravenous
ASPECT ASia Pacific Evaluation of Chest Diuretics and Hospitalizations for
pain Trial Heart Failure (trial)
ASSENT-​2 Assessment of the Safety and AVP arginine vasopressin
Efficacy of a New Thrombolytic AVR aortic valve replacement
(trial) AVRT atrioventricular re-​entrant
AST aspartate aminotransferase tachycardia
ASV adaptative servoventilation BACH Biomarkers in Acute Heart Failure
AT atrial tachycardia (trial)
ATACH II Antihypertensive Treatment of BARC Bleeding Academic Research
Acute Cerebral Hemorrhage II Consortium
(trial) BART Blood Conservation Using
ATC automatic tube compensation; Antifibrinolytics in a
Antithrombotic Trialists’ Randomized Trial
Collaboration BATTLESCARRED NT-​proBNP-​Assisted Treatment
ATG antithymocyte globulin To Lessen Serial Cardiac
ATIII antithrombin III Readmissions and Death (trial)
ATLANTIC Administration of Ticagrelor BAV balloon aortic valvuloplasty
in the Cath Lab or in the BEST Randomized Comparison of
Ambulance for New ST Elevation Coronary Artery Bypass Surgery
Myocardial Infarction to Open the and Everolimus-​Eluting Stent
Coronary Artery Implantation in the Treatment of
ATLAS ACS 2 Anti-​Xa Therapy to Lower Patients with Multivessel Coronary
Cardiovascular Events in Addition Artery Disease (trial)
to Standard Therapy in Subjects bio-​ADM bioactive adrenomedullin
with Acute Coronary Syndrome BiPAP bilevel positive airway pressure
(trial) BIS bispectral index; Berlin
ATN acute tubular necrosis Initiative Study
ATOLL Acute Myocardial Infarction BITA bilateral internal thoracic artery
Treated with primary angioplasty BiVAD biventricular ventricular
and intravenous enoxaparin Or assist device
unfractionated heparin to Lower BLS basic life support
ischemic and bleeding events at BLS-​TOR basic life support termination of
short-​ and Long-​term follow-​up resuscitation
(trial) BMI body mass index
ATOMIC-​HF Acute Treatment with Omecamtiv BMS bare-​metal  stent
Mecarbil to Increase Contractility BNP B-​type natriuretic peptide
in Acute Heart Failure (trial) BOLD Beta-​agonists for Oxygenation in
ATP adenosine triphosphate Lung Donors (trial)
AUC area under the curve BPA balloon pulmonary angioplasty
AUF adjustable ultrafiltration bpm beats per minute
AUGUSTUS Open-​Label, 2 × 2 Factorial, BPS Behavioural Pain Scale
Randomized, Controlled Clinical BRIDGE Maintenance of Platelet
Trial to Evaluate the Safety of inihiBition With cangRelor
Apixaban vs Vitamin K Antagonist After dIscontinuation of
and Aspirin vs Aspirin Placebo in ThienopyriDines in Patients
Patients with Atrial Fibrillation Undergoing surGEry (trial)
and Acute Coronary Syndrome BRIGHT Bivalirudin in Acute Myocardial
and/​or Percutaneous Coronary Infarction versus Heparin and GPI
Intervention (trial) Plus Heparin (trial)
AV atrioventricular BSA body surface area
xiv Symb ols an d abbreviations

BTC bridge to transplantation candidacy cfDNA cell-​free deoxyribonucleic acid

BTD bridge to decision cGMP cyclic guanosine monophosphate
BTR bridge to recovery CHAMPION Cangrelor versus Standard Therapy
BTS British Thoracic Society to Achieve Optimal Management of
BTT bridge to transplantation Platelet Inhibition (trial)
BUN blood urea nitrogen CHAMPION PHOENIX Cangrelor versus Standard Therapy
BV biological variability to Achieve Optimal Management of
Ca2+ calcium ion Platelet Inhibition (trial)
CABG coronary artery bypass grafting CHANCE Clopidogrel in High-​Risk
CAC coronary artery calcium/​calcification Patients with Acute Nondisabling
CAD coronary artery disease Cerebrovascular Events (trial)
CADASIL cerebral autosomal dominant CHD coronary heart disease; congenital
arteriopathy with subcortical infarcts heart disease
and leukoencephalopathy CI critical incident; confidence interval;
CAM-​ICU Confusion Assessment Method for cardiac index
the Intensive Care Unit CICU cardiac intensive care unit
cAMP cyclic adenosine monophosphate CIH cardiogenic ischaemic hepatitis
CANGRELOR CANgrelor and Crushed TICagrelor CIN contrast medium-​induced
in STEMI Patients Undergoing nephropathy
Primary Percutaneous Coronary CIRCI critical illness-​related corticosteroid
Intervention (trial) insufficiency
CANTOS Canakinumab Anti-​Inflammatory CK creatine kinase
Thrombosis Outcomes Study CKD chronic kidney disease
CANVAS CANagliflozin cardioVascular CKD-​EPI Chronic Kidney Disease
Assessment Study Epidemiology Collaboration
CAP community-​acquired pneumonia CK-​MB creatine kinase isoenzyme
CARP Coronary Artery Revascularization subunit MB
Prophylaxis (trial) CL compliance of the lung
CARRESS-​HF Cardiorenal Rescue Study in Acute Cl–​ chloride ion
Decompensated Heart Failure (trial) CLARITY Clopidogrel as Adjunctive
cART combination antiretroviral therapies Reperfusion Therapy
CAS carotid angioplasty and stenting CLOTS Clots in Legs Or sTockings after
CASTLE-​AF Catheter Ablation versus Standard Stroke (trial)
Conventional Therapy in Patients cm centimetre
with Left Ventricular Dysfunction CM contrast medium
and Atrial Fibrillation (trial) CME continuing medical education
CAV cardiac allograft vasculopathy cmH2O centimetre of water
CAVH continuous arteriovenous CMR cardiac magnetic resonance
haemofiltration CMV continuous mandatory ventilation;
CAVHD continuous arteriovenous cytomegalovirus
haemodiafiltration c-​MyC cardiac myosin-​binding protein C
CBF cerebral blood flow CNS central nervous system
CBV cerebral blood volume CNST Clinical Negligence Scheme for Trusts
CC core curriculum CO2 carbon dioxide
CCB calcium channel blocker CoA coarctation of the aorta
CCSS Critical Care Safety Study COCATS 4-​TF 13 Core Cardiovascular Training
CCTA coronary computerized tomography Statement 4 by Task Force 13
angiography COGENT Clopidogrel and the Optimization of
CCU coronary care unit; critical care unit Gastrointestinal Events Trial
CCW compliance of the chest wall COMET Carvedilol Or Metoprolol
CD cluster of differentiation European Trial
CE cholesterol ester COMFORTABLE AMI Comparison of Biolimus Eluted from
CEA carotid endarterectomy an Erodible Stent Coating with Bare-​
CEC Clinical Event Committee Metal Stents in Acute ST-​Elevation
cEEG continuous electroencephalogram Myocardial Infarction (trial)
 Sym b ol s a n d a b b rev iat i on s xv

COMMIT ClOpidogrel and Metoprolol in CSD cardiac sympathetic denervation

Myocardial Infarction Trial CSF cerebrospinal fluid
COMPARE-​ACUTE Comparison Between FFR CSS Clinical SYNTAX score
Guided Revascularization Versus CT computerized tomography
Conventional Strategy in Acute CTA computerized tomography
STEMI Patients With Multivessel angiography
disease (trial) CTCA computerized tomography coronary
COPD chronic obstructive pulmonary angiography
disease CTEPH chronic thromboembolic pulmonary
COPERNICUS Carvedilol Prospective Randomized hypertension
Cumulative Survival (trial) cTn cardiac troponin
COX cyclo-​oxygenase cTnI cardiac troponin I
CP chest pain cTnT cardiac troponin T
CPAP continuous positive airway pressure CTP computerized tomography perfusion
CPAP/​PS continuous positive airway pressure/​ CTPA computerized tomography
pressure support ventilation pulmonary angiography
CPB cardiopulmonary bypass CTR cardiothoracic ratio
CPC Cerebral Performance Category CULPRIT-​SHOCK Culprit Lesion Only PCI versus
(score) Multivessel PCI in Cardiogenic Shock
CpcPH combined post-​capillary pulmonary CUORE Continuous Ultrafiltration for
hypertension cOngestive heaRt failure (trial)
CPM continuous passive motion; central CURE Clopidogrel in Unstable Angina to
pontine myelinolysis Prevent Recurrent Events (trial)
CPOT Critical Care Pain Observation Tool CUS compression ultrasonography
CPP coronary perfusion pressure; cerebral CV coefficient of variation
perfusion pressure CVA cerebrovascular accident
CPR cardiopulmonary resuscitation CVC central venous catheter
CPU chest pain unit CVD cardiovascular disease
CPVT catecholaminergic polymorphic CvLPRIT Complete Versus Lesion-​Only
ventricular tachycardia Primary PCI trial
CQC Care Quality Commission CVP central venous pressure
CR cardiac rupture CVR cerebral vascular resistance
CRBSI catheter-​related bloodstream CVST cerebral venous and sinus
infection thrombosis
CrCl creatinine clearance CVVH continuous veno-​venous
CRISP-​AMI Counterpulsation to Reduce Infarct haemofiltration
Size Pre-​PCI Acute Myocardial CVVHD continuous veno-​venous
Infarction (trial) haemodialysis
CRM crew resource management CVVHDF continuous veno-​venous
CRP C-​reactive protein haemodiafiltration
CRRT continuous renal replacement therapy CXR chest  X-​ray
CRS compliance of the respiratory system DAG diacylglycerol
CRS cardiorenal syndrome DahLIA Dexmedetomidine to Lessen ICU
CRT cardiac resynchronization treatment Agitation (trial)
CRT-​D cardiac resynchronization treatment DANAMI DANish Study of Optimal Acute
defibrillator Treatment of Patients With ST-​
CRT-​P cardiac resynchronization treatment elevation Myocardial Infarction
pacemaker (trial)
CRUSADE Can Rapid Risk Stratification of DANAMI 3-​DEFER Third DANish Study of Optimal
Unstable Angina Patients Suppress Acute Treatment of Patients with
Adverse Outcomes with Early ST-​segment Elevation Myocardial
Implementation of the ACC/​AHA Infarction: DEFERred stent
Guideline (registry) implantation in connection with
CS cardiogenic shock primary PCI
xvi Symb ols an d abbreviations

DANAMI-​3–​PRIMULTI Third DANish Study of Optimal DOSE-​AHF Diuretic Optimization Strategy

Acute Treatment of Patients Evaluation in Acute Decompensated
With STEMI: PRImary PCI in Heart Failure (trial); Determining
MULTIvessel Disease Optimal Dose and Duration of
DAPT dual antiplatelet therapy Diuretic Treatment in People With
DAWN DWI or CTP Assessment with Acute Heart Failure (trial)
Clinical Mismatch in the Triage of DSE dobutamine stress echocardiography
Wake-​Up and Late Presenting Strokes DSM Diagnostic and Statistical Manual of
Undergoing Neurointervention Mental Disorders
with Trevo DSM-​V Diagnostic and Statistical Manual of
DBD donation/​donor after brain death Mental Disorders, fifth edition
DC dendritic cell; direct current DT destination therapy
DCD donation/​donor after DTI direct thrombin inhibitor
circulatory death dTT dilute thrombin time
DCM dilated cardiomyopathy DVT deep vein thrombosis
DDAVP 1-​deamino-​8-​d-​arginine-​vasopressin DWI diffusion-​weighted imaging
DECCA Delirium Epidemiology in Critical EACTA European Association of
Care (study) Cardiothoracic Anaesthesiology
DECLARE-​TIMI58 Dapagliflozin Effect on EACTS European Association of Cardio-​
Cardiovascular Events–​Thrombolysis Thoracic Surgery
in Myocardial Infarction 58 (trial) EACVI European Association of
DECREASE-​2 Dutch Echocardiographic Cardiac Cardiovascular Imaging
Risk Evaluation Applying Stress EAdi electrical activity of the diaphragm
Echocardiography-​2 (trial) EARLY-​ACS Early Glycoprotein IIb/​IIIa Inhibition
DEFUSE 3 Endovascular Therapy Following in Non-​ST-​Segment Elevation Acute
Imaging Evaluation for Ischemic Coronary Syndrome (trial)
Stroke 3 (trial) EARLY-​BAMI Early-​Beta blocker Administration
DELIVER Dapagliflozin Evaluation to Improve before reperfusion primary PCI in
the LIVEs of Patients With PReserved patients with ST-​elevation Myocardial
Ejection Fraction Heart Failure (trial) Infarction (trial)
DES drug-​eluting  stent EAST Eastern Association for the Surgery
DESTINY II Decompressive Surgery for the of Trauma
Treatment of Malignant Infarction of EBCT electron beam computerized
the Middle Cerebral Artery II (trial) tomography
DEXACET Dexmedetomidine and IV EBM evidence-​based medicine
Acetaminophen for the Prevention EBV Epstein–​Barr  virus
of Postoperative Delirium Following ECCO2R extracorporeal carbon dioxide
Cardiac Surgery (trial) removal
DEXCOM Dexmedetomidine Compared to ECF extracellular fluid
Morphine (trial) ECG electrocardiogram
DG diastolic gradient ECLS extracorporeal life support
DIC disseminated intravascular coagulation ECM extracellular matrix
DIPOM Diabetic Postoperative Mortality and ECMO extracorporeal membrane
Morbidity (trial) oxygenation
DKA diabetic ketoacidosis ECOS extracorporeal organ support
dL decilitre eCPR extracorporeal CPR
DNA deoxyribonucleic nucleic acid ECS-​PSC European Society of Cardiology
DNACPR do-​not-​attempt-​cardiopulmonary-​ position statement criteria
resuscitation ED emergency department
DNAR do-​not-​attempt-​resuscitation EDACS Emergency Department Assessment
DO2 myocardial oxygen supply of Chest Pain Score Accelerated
DOAC direct oral anticoagulant Diagnostic Pathway
DOSE Diuretic Optimization Strategies EDD extended daily dialysis
Evaluation (trial) EDTA ethylenediaminetetraacetic acid
 Sym b ol s a n d a b b rev iat i on s xvii

EEG electroencephalography ESCAPE Evaluation Study of Congestive

EES everolimus-​eluting  stent Heart Failure and Pulmonary Artery
EF ejection fraction Catheterization Effectiveness (trial)
eGFR estimated glomerular filtration rate ESCeL European Society of Cardiology
EHRA European Heart Rhythm Association e-​Learning
EIT electrical impedance tomography ESICM European Society of Intensive Care
®
ELF Enhanced Liver Fibrosis Test® Medicine
ELISA Early or Late Intervention in unStable ESKD end-​stage kidney disease
Angina (trial) ESPEN European Society for Clinical
EMA European Medicines Agency Nutrition and Metabolism
EMB endomyocardial biopsy ESPVR end-​systolic pressure–​volume
EMD emergency medical dispatching relationship
EMI electromagnetic interference ESR erythrocyte sedimentation rate
EMPA-​REG OUTCOME Empagliflozin Cardiovascular ET-​1 endothelin-​1
Outcome Event Trial in Type 2 ETT endotracheal tube
Diabetes Mellitus Patients–​Removing EU European Union
Excess Glucose EUNetPaS European Network for Patient Safety
EMPA-​RESPONSE Effects of Empagliflozin on Clinical EUROMAX European Ambulance Acute Coronary
Outcomes in Patients With Acute Syndrome Angiography (trial)
Decompensated Heart Failure (trial) EuroSCORE European System for Cardiac
EMS emergency medical services/​system; Operative Risk Evaluation
electrical muscle stimulation EUROSTAR European Collaborators on Stent
EMT emergency medical technician Graft Techniques for Thoracic Aortic
EN enteral nutrition Aneurysm and Dissection Repair
ENCHANTED Enhanced Control of Hypertension EV extracellular vesicle
and Thrombolysis Stroke Study EVEREST Endovascular Valve Edge-​to-​Edge
eNOS endothelial nitric oxide synthase Repair Study; Efficacy of Vasopressin
ENTRUST-​AF Edoxaban-​Based Antithrombotic Antagonism in Heart Failure
Regimen in Patients With Atrial Outcome Study With Tolvaptan
Fibrillation (trial) (trial)
EoLC end-​of-​life  care EVLP ex vivo lung perfusion
EOLCS End of Life Care Strategy EVLW extravascular lung water
EORP EURObservational Research Program EVT endovascular thrombectomy
EORTC/​MSG European Organization for Research EXAMINATION clinical Evaluation of the Xience-​
and Treatment of Cancer/​Invasive V stent in Acute Myocardial
Fungal Infections Cooperative Group INfArcTION (trial)
and the National Institute of Allergy EXPIRA Thrombectomy With EXPort
and Infectious Diseases Mycoses Catheter in Infarct-​Related Artery
Study Group During Primary Percutaneous
EP emergency medicine physician; Coronary Intervention (trial)
evoked potential EXTEND Extending the Time for Thrombolysis
EPA entrustable professional activity in Emergency Neurological Deficits
EPaNIC Early Parenteral Nutrition (trial)
Completing Enteral Nutrition in ExTRACT-​TIMI 25 Enoxaparin and Thrombolysis
Adult Critically Ill Patients (trial) Reperfusion for Acute Myocardial
EPAP expiratory positive airway pressure Infarction Treatment–​Thrombolysis
ePCR extracorporeal membrane oxygenation in Myocardial Infarction 25
cardiopulmonary resuscitation F French; factor
ERC European Resuscitation Council FABULOS-​PRO Facilitation through Aggrastat By
EROA effective regurgitant orifice area drOpping or shortening Infusion
ERTP early releasable troponin pool Line in patients with ST-​segment
ES electrical storm elevation myocardial infarction
ESA erythropoietin-​stimulating  agent compared to or on top of PRasugrel
ESC European Society of Cardiology given at loading dOse (trial)
xviii Symb ols an d abbreviations

FAME FFR vs Angiography for Multivessel GICS Gastrointestinal Complication Score

evaluation (trial) GIF gastrointestinal failure
FANTASTIC Full ANTicoagulation versus ASpirin and GIK glucose–​insulin–​potassium
TIClopidine (trial) GISSI Gruppo Italiano per lo Studio della
FAS full age spectrum Sopravvivenza nell’Infarto Miocardico
FAST focused assessment with sonography GLASSY GLOBAL LEADERS Adjudication
for trauma Sub-​Study
FAST-​MI French registry of Acute ST-​elevation or GLS global longitudinal strain
non-​ST-​elevation Myocardial Infarction GP glycoprotein
FBI fast, broad, irregular GPI glycoprotein IIb/​IIIa inhibitor
FDA Food and Drug Administration GRACE Global Registry of Acute
18
FDG-​PET F-​fluorodeoxyglucose positron emission Coronary Events
tomography GRC Global Risk Classification
FEV1 forced expiratory volume in 1 second GRV gastric residual volume
FFR fractional flow reserve GUIDE-​IT Guiding Evidence Based Therapy Using
FFRct fractional flow reserve measured by Biomarker Intensified Treatment in Heart
coronary computerized tomography Failure (study)
angiography GUSTO Global Utilization of Streptokinase
FIMR functional ischaemic muscle rupture/​ and Tissue Plasminogen Activator for
mitral regurgitation Occluded Coronary Arteries (trial)
FiO2 fraction of inspired oxygen h hour
FL fibrinolysis H+ hydrogen ion
FLAIR fluid-​attenuated inversion recovery HAART highly active antiretroviral therapy
FMC first medical contact Hb haemoglobin
FMEA failure modes and effects analysis HBD heart-​beating  donor
FO-​BAL fibreoptic bronchoscopy with HBV hepatitis B virus
bronchoalveolar lavage HCM hypertrophic cardiomyopathy
FOUR Full Outline of UnResponsiveness (score) HCO3–​ carbonate ion
FPR false positive ratio H2CO3 carbonic acid
FRC functional residual capacity HCV hepatitis C virus
FRISC Fast Revascularisation in InStability in HDL high-​density lipoprotein
Coronary disease (score/​trial) HEAT-​PPCI How Effective Are Antithrombotic
FUTURA OASIS-​8 Fondaparinux with UnfracTionated Therapies in Primary PCI (trial)
heparin dUring Revascularization in HEMS helicopter emergency medical services
Acute coronary syndromes (trial) HEPA high-​efficiency particulate air
FWR free wall rupture HES hydroxyethyl starch
g gram HF haemofiltration
G gauge HFA Heart Failure Association
GABA gamma-​aminobutyric  acid HFD high-​flux dialysis
GALACTIC-​HF Global Approach to Lowering Adverse HFmrEF heart failure with mid-​range left
Cardiac outcomes Through Improving ventricular ejection fraction
Contractility in Heart Failure (trial) HFNC high-​flow nasal cannula
GBD Global Burden of Diseases, Injuries, and HFOV high-​frequency oscillatory ventilation
Risk Factors (study) HFpEF heart failure with preserved left
GCS Glasgow Coma Scale ventricular ejection fraction
GDF-​15 growth differentiation factor-​15 HFrEF heart failure with reduced left ventricular
GDMT guideline-​directed medical treatment ejection fraction
GEMINI ACS 1 Safety of Rivaroxaban Versus HFSS Heart Failure Survival Score
Acetylsalicylic Acid in Addition to H-​Hb protonated haemoglobin
Either Clopidogrel or Ticagrelor Therapy HHS hyperglycaemic hyperosmolar state
in Participants With Acute Coronary HHV6 human herpesvirus 6
Syndrome (trial) HIF hypoxia-​inducible  factor
GFR glomerular filtration rate HIPA heparin-​induced platelet activation
GGT gamma glutamyltransferase HIT heparin-​induced thrombocytopenia
GI gastrointestinal HIV human immunodeficiency virus
 Sym b ol s a n d a b b rev iat i on s xix

HOCM hypertrophic obstructive cardiomyopathy IGFBP insulin-​like growth factor-​binding

HORIZONS-​AMI Harmonizing Outcomes with protein
Revascularization and Stents in Acute IGFBP-​7 insulin-​like growth factor-​binding
Myocardial Infarction (trial) protein-​7
HPO42–​ hydrogen phosphate IgG immunoglobulin G
H2PO4–​ dihydrogen phosphate IgM immunoglobulin M
HR hazard ratio; hormonal resuscitation IHCA in-​hospital cardiac arrest
HSCT haematopoietic stem cell transplantation IHD intermittent haemodialysis; ischaemic
hs-​cTn high-​sensitivity cardiac troponin heart disease
hs-​cTnI high-​sensitivity cardiac troponin I IHI Institute for Healthcare Improvement
hs-​cTnT high-​sensitivity cardiac troponin T IIE ineffective inspiratory efforts
HSP-​27 heat shock protein 27 IL interleukin
hs-​Tn high-​sensitivity troponin ILCOR International Liaison Committee on
hs-​TnI high-​sensitivity troponin  I Resuscitation
hs-​TnT high-​sensitivity troponin  T IL-​2RA interleukin-​2 receptor antagonist
HTAD heritable thoracic aortic aneurysm/​ IM intramuscular
dissection IMACS International Society for Heart and Lung
HTx heart transplant Transplantation Mechanically Assisted
HU Hounsfield unit Circulatory Support
HVHF high-​volume haemofiltration IMCA Independent Mental Capacity Advocate
Hz hertz IMH intramural haematoma
IABP intra-​aortic balloon pump IMPROVE-​CHF Improved Management of Patients With
IABP-​SHOCK II Intra-​Aortic Balloon Pump in Congestive Heart Failure (study)
Cardiogenic Shock II (trial) IMPROVE-​IT Improved Reduction of Outcomes:
IACC intensive and acute cardiovascular care Vytorin Efficacy International Trial
IAH intra-​abdominal hypertension IMV intermittent mandatory ventilation
IAP intra-​abdominal pressure iNOS inducible nitric oxide synthase
IC indirect calorimetry INR international normalized ratio
ICA invasive coronary angiography INSTEAD INvestigation of STEnt grafts in patients
ICAM-​1 intercellular adhesion molecule 1 with type B Aortic Dissection (trial)
ICCU intensive cardiovascular care unit INTERACT 2 Intensive Blood Pressure Reduction in
ICD implantable cardioverter–​defibrillator Acute Cerebral Hemorrhage Trial 2
ICDSC Intensive Care Delirium Screening INTERMACS Interagency Registry for Mechanically
Checklist Assisted Circulatory Support
ICF intracellular fluid IO intraosseous
ICG indocyanine green IoM Institute of Medicine
ICH intracranial haemorrhage IP3 inositol triphosphate
ICNARC Intensive Care National Audit and IPAH idiopathic pulmonary arterial
Research Centre hypertension
ICON-​RELOADED ICON: Re-​evaluation of Acute Diagnostic IPAP inspiratory positive airway pressure
Cut-​Offs in the Emergency Department IpcPH isolated post-​capillary pulmonary
(study) hypertension
ICP intracranial pressure IPPV intermittent positive pressure
ICU intensive care unit ventilation
ICU-​AW intensive care unit-​acquired weakness IPTW inverse probability of treatment weight
IDF incident dark field (imaging) IPV intrapulmonary percussive ventilation
IDSA Infectious Diseases Society of America IQR interquartile range
IE infective endocarditis IRA infarct-​related  artery
IFCC International Federation of Clinical IRAD International Registry of Acute Aortic
Chemistry and Laboratory Medicine Dissection
IFI invasive fungal infection IRI ischaemia and reperfusion injury
IFN interferon IS incentive spirometry; ischaemic stroke
iFR instantaneous wave-​free ratio ISAR Intracoronary Stenting and
Ig immunoglobulin Antithrombotic Regimen (trial)
xx Symb ols an d abbreviations

ISAR-​CABG Is Drug-​Eluting-​Stenting Associated with LDL low-​density lipoprotein

Improved Results in Coronary Artery LFA-​1 lymphocyte associated antigen-​1
Bypass Grafts (trial) LFABP liver fatty acid-​binding protein
ISAR-​COOL Intracoronary Stenting With LGE late gadolinium enhancement
Antithrombotic Regimen Cooling-​Off LGE-​CMR late gadolinium enhancement cardiac
(trial) magnetic resonance
ISAR-​REACT 4 Intracoronary Stenting and Antithrombotic LGE-​MRI late gadolinium enhancement magnetic
Regimen: Rapid Early Action for Coronary resonance imaging
Treatment 4 (trial) LiDCO lithium dilution cardiac output
ISDN isosorbide dinitrate LIDO Levosimendan Infusion versus Dobutamine
ISICEM International Symposium on Intensive Care (trial)
and Emergency Medicine LIMA left internal mammary artery
ISIS International Study of Infarct Survival LIS lung injury score
(trial) LITA left internal thoracic artery
ISMICS International Society of Minimally Invasive LMWH low-​molecular-​weight heparin
Coronary Surgery LOC loss of consciousness
ISS Injury Severity Score LoE level of evidence
ISTH International Society on Thrombosis and LOX1 lectin-​like oxidized low-​density lipoprotein
Haemostasis receptor 1
ITA internal thoracic artery Lp(a) lipoprotein (a)
ITD impedance threshold device LPS lipopolysaccharide
ITP intrathoracic pressure LQTS long QT syndrome
IU international unit LRP-​1 low-​density lipoprotein receptor-​related
IV intravenous protein 1
IVIG intravenous immunoglobulin LT laryngeal tube
I-​VT International Ventricular Tachycardia LUCAS Lund University Cardiac Arrest System
(score) LV left ventricular
IVUS intravascular ultrasound LVA left ventricular aneurysm
IVUS-​VH intravascular ultrasound virtual histology LVAD left ventricular assist device
J joule LVEDD left ventricular end-​diastolic diameter
JCAHO Joint Commission on Accreditation of LVEDP left ventricular end-​diastolic pressure
Healthcare Organizations LVEF left ventricular ejection fraction
JVP jugular venous pressure LVESD left ventricular end-​systolic diameter
K+ potassium ion LV-​ESV left ventricular end-​systolic volume
kcal kilocalorie LVOT left ventricular outflow tract
kDa kilodalton LVWR left ventricular wall rupture
KDIGO Kidney Disease: Improving Global m metre
Outcomes mA milli ampere
kg kilogram MAAVR minimal-​access aortic valve replacement
KIM 1 kidney injury molecule 1 MAC mitral annulus calcification
KLF4 kruppel-​like factor 4 MAC-​1 macrophage antigen 1
km kilometre MACCE major adverse cardiac and
kV kilovolt cerebrovascular event
Kw dissociation constant MACE major adverse cardiac event
L litre MACS Manchester Acute Coronary Syndromes
LA left atrial; left atrium MAP mean arterial pressure
LAD left anterior descending (artery) MAPSE mitral annular plane systolic excursion
LAP left atrial pressure MATRIX Minimizing Adverse Haemorrhagic Events
LAVA local abnormal ventricular activity by Transradial Access Site and Systemic
LAX long-​axis (view, ultrasound) Implementation of Angiox (trial)
LBBB left bundle branch block MATTIS Multicenter Aspirin and Ticlopidine Trial
LCX left circumflex after Intracoronary Stenting (trial)
LDB load-​distributing  band MaVS Metoprolol after Vascular Surgery (trial)
LDH lactate dehydrogenase MBG myocardial blush grade
 Sym b ol s a n d a b b rev iat i on s xxi

MC myxoedema coma; mechanical mmol millimole

complication MMP matrix metalloproteinase
MCEP medicine community educational MODS multiorgan dysfunction syndrome
programme MOF multiorgan failure
MCQ multiple choice question mol mole
MCS mechanical circulatory support MOMENTUM-​3 Multicenter Study of MagLev
M-​CSF macrophage colony-​stimulating Technology in Patients Undergoing
factor Mechanical Circulatory Support
MDRD Modified Diet in Renal Disease Therapy with HeartMate 3 (trial)
MELD Model for End-​Stage Liver Disease MONICA MoNItoring of trends and
MELD-​XI Model for End-​stage Liver Disease determinants in CArdiovascular
eXcluding INR disease
MENDS Maximizing Efficacy of Targeted mOsmol milliosmole
Sedation and Reducing Neurological MOST multiorgan support therapy
Dysfunction (trial) MP microparticle
MEq milli equivalent mPAP mean pulmonary arterial pressure
MESA Multi-​Ethnic Study of Atherosclerosis MPI myocardial perfusion imaging
METOCARD-​CNIC Effect of Metoprolol in MPO myeloperoxidase
Cardioprotection During an Acute MPR multiplanar reconstruction
Myocardial Infarction (trial) MPS myocardial perfusion scanning
MFI Microvascular Flow Index MR magnetic resonance; mitral
mg milligram regurgitation
Mg2+ magnesium ion MRA mineralocorticoid receptor antagonist
mGFR measured glomerular filtration rate MRC Medical Research Council
mGluR metabotropic glutamate receptor MRI magnetic resonance imaging
mGy milligray mRNA messenger ribonucleic acid
MHI manual hyperinflation MR-​proADM mid-​regional pro-​adrenomedullin
MHz mega hertz MR-​proANP mid-​regional pro-​atrial natriuretic
MI myocardial infarction peptide
MIC myocardial intervention centre mRS modified Rankin scale
MIDCAB minimally invasive direct coronary MRSA methicillin-​resistant
artery bypass Staphylococcus aureus
MIDEX Midazolam Compared to ms millisecond
Dexmedetomidine (trial) MS mitral stenosis
MI-​E mechanical insufflator–​exsufflator MSCT multi-​slice computerized tomography
min minute mSv milli sievert
MINAP Myocardial Ischaemia National Audit MTHFR methylenetetrahydrofolate reductase
Project mTOR mammalian target of rapamycin
MIND-​USA Modifying the Impact of ICU-​ mU milli unit
Associated Neurological Dysfunction–​ MULTISTRATEGY Multicentre Evaluation of Single High-​
USA (trial) Dose Bolus Tirofiban vs Abciximab
MINOCA myocardial infarction with non-​ With Sirolimus-​Eluting Stent or Bare
obstructive coronary arteries Metal Stent in Acute Myocardial
MIP maximum intensity projection Infarction Study
miRNA micro ribonucleic acid mV millivolt
mL millilitre MV minute ventilation
MLA minimal lumen area MVA mitral valve area
MLD minimal lumen diameter MVO microvascular obstruction
mm millimetre n number
MMF mycophenolate mofetil Na+ sodium ion
mmHg millimetre of mercury NAC N-​acetylcysteine
MMI methimazole NaCl sodium chloride
mmLDL minimally modified low-​density NAFLD non-​alcoholic fatty liver disease
lipoprotein NaHCO3 sodium bicarbonate
xxii Symb ols an d abbreviations

NASA National Aeronautics and Space NSTE-​ACS non-​ST-​segment elevation acute coronary
Administration syndrome
NASH non-​alcoholic steatohepatitis NSTEMI non-​ST-​segment elevation myocardial
NAVA neurally adjusted ventilatory assist infarction
NCC MERP National Coordinating Council on Medical NSVT non-​sustained ventricular tachycardia
Error Reporting and Prevention NT-​proBNP N-​terminal pro-​B-​type natriuretic
NCEPOD National Confidential Enquiry into peptide
Patient Outcome and Death NYHA New York Heart Association
NEFA non-​esterified fatty acid O2 oxygen
NEMS neuromuscular electrical stimulation OASIS Organization for the Assessment of
NET neutrophil extracellular trap Strategies for Ischemic Syndromes
NF nuclear factor OASIS-​5 Fifth Organization to Assess Strategies in
ng nanogram Acute Ischemic Syndromes (trial)
NG nasogastric OASIS 6 Organization for the Assessment of
NGAL neutrophil gelatinase-​associated lipocalin Strategies for Ischemic Syndromes 6
NH3 ammonia (trial)
NH4+ ammonium ion OAT Occluded Artery Trial
NHANES National Health and Nutrition OCT optical coherence tomography
Examination Survey O2ER oxygen extraction ratio
NHBD non-​heart-​beating  donor OFA omega-​3 fatty acid
NHS National Health Service OFR oxygen free radical
NHSLA National Health Service Litigation OH–​ hydroxide ion
Authority OHCA out-​of-​hospital cardiac  arrest
NICE National Institute for Health and Care OI oxygenation index
Excellence OMT optimal medical treatment
NICE-​SUGAR Normoglycemia in Intensive Care ONT Organización Nacional de Trasplantes
Evaluation–​Survival Using Glucose OPCABG off-​pump coronary artery bypass graft
Algorithm Regulation (trial) OPTIMA-​CC Study Comparing the Efficacy and
NIH National Institutes of Health Tolerability of Epinephrine and
NIPPV non-​invasive positive pressure ventilation Norepinephrine in Cardiogenic Shock
NIPSV non-​invasive pressure support ventilation OPTIME-​CHF Outcomes of a Prospective Trial of
NIRS near-​infrared spectroscopy Intravenous Milrinone for Exacerbations
NIS Nationwide Inpatient Sample of Chronic Heart Failure
NIST National Institute of Standards and OPTIMIZE-​HF Organized Program To Initiate Lifesaving
Technology Treatment In Hospitalized Patients With
NIV non-​invasive ventilation Heart Failure (registry)
NK natural killer OR odds ratio
NLRP3 NLR family pyrin domain-​containing 3 ORBI Observatoire Régional Breton sur
NMDA N-​methyl-​D-​aspartate l’Infarctus
nmol nanomole OSA obstructive sleep apnoea
NO nitric oxide OSCAR Oscillation in ARDS (trial)
NOAC non-​vitamin K antagonist oral OSCILLATE Oscillation for Acute Respiratory Distress
anticoagulant Syndrome Treated Early (trial)
NOMI non-​occlusive mesenteric ischaemia oxLDL oxidized low-​density lipoprotein
NORSTENT Norwegian Coronary Stent Trial P probability
NOS nitric oxide synthase PA posteroanterior
NP natriuretic peptide PAC pulmonary artery catheter/​
NPV negative predictive value; negative catheterization
pressure ventilation PaCO2 arterial partial pressure of carbon dioxide
NRCPR National Registry of Cardiopulmonary PACO2 alveolar pressure of carbon dioxide
Resuscitation PADIS Prevention and management of
NRLS National Reporting and Learning System pain, Agitation/​sedation, Delirium,
NRS numerical rating scale Immobility, and Sleep disruption
NSAID non-​steroidal anti-​inflammatory  drug PAF platelet-​activating  factor
NSE neuron-​specific enolase PAH pulmonary arterial hypertension
 Sym b ol s a n d a b b rev iat i on s xxiii

PAI-​1 plasminogen activator inhibitor type-​1 PE pulmonary embolus/​embolism

PAIRWAY airway pressure PEA pulseless electric activity
PALS Patient Advice and Liaison Service PEEP positive end-​expiratory pressure
PALV alveolar pressure PEEPi intrinsic positive end-​expiratory pressure
PAMI Primary Angioplasty in Myocardial PEGASUS-​TIMI 54
Prevention of Cardiovascular Events in
Infarction (trial) Patients with Prior Heart Attack Using
PAMP pathogen-​associated molecular pattern Ticagrelor Compared to Placebo on a
PaO2 arterial partial pressure of oxygen Background of Aspirin–​Thrombolysis in
PAO2 alveolar pressure of oxygen Myocardial Infarction 54
PAOP pulmonary artery occlusion pressure PER protein excretion rate
PAP pulmonary artery pressure PERT Pulmonary Embolism Response Team
PAPI pulmonary artery pulsatility index PESI Pulmonary Embolism Severity Index
PAR protease-​activated receptor PET positron emission tomography
PAR-​1 protease-​activated receptor  1 PFT platelet function test
PARAGON Platelet IIb/​IIIa Antagonism for the pg picogram
Reduction of Acute Coronary Syndrome PGI2 prostacyclin
Events in a Global Organization Network PH pulmonary hypertension; prolyl
(trial) hydroxylase
PARP-​1 poly(ADP-​ribose) polymerase  1 PH-​LHD pulmonary hypertension secondary to
PAU penetrating aortic ulcer left heart disease
PAV proportional assist ventilation PI protease inhibitor
PAWP pulmonary artery wedge pressure PICC peripherally inserted central catheter
PBW predicted body weight PiCCO pulse-​induced contour cardiac output
PCA patient-​controlled analgesia PIO2 inspired pressure of oxygen
PC-​ACV pressure-​controlled assist-​control PIONEER-​HF Comparison of Sacubitril–​Valsartan
ventilation versus Enalapril on Effect on NT-​proBNP
PC-​APRV pressure-​controlled airway pressure in Patients Stabilized from an Acute
release ventilation Heart Failure Episode (trial)
PCAS post-​cardiac arrest syndrome PIRRT prolonged intermittent renal replacement
PC-​BIPAP pressure-​controlled biphasic positive therapy
airway pressure PIS pulmonary interstitial syndrome
PCBS percutaneous cardiopulmonary bypass PLATO Study of Platelet Inhibition and Patient
support Outcomes (trial)
PCC prothrombin complex concentrate PLC phospholipase C
PC-​CMV pressure-​controlled continuous pLVAD percutaneous left ventricular assist
mechanical ventilation device
PCI percutaneous coronary intervention PM performance measure
PCI-​CURE Percutaneous Coronary Intervention-​ PMC percutaneous mitral commissurotomy
Clopidogrel in Unstable angina to PMI perioperative myocardial ischaemia
prevent Recurrent Events (trial) pmol picomole
PCOS polycystic ovary syndrome pmp patient per million (inhabitants)
PCR polymerase chain reaction PMR papillary muscle rupture
PCS pulse contour system; post-​cardiotomy PN parenteral nutrition
cardiogenic shock PO orally
PC-​SIMV pressure-​controlled synchronized pO2 partial oxygen pressure
intermittent mandatory ventilation POCT point-​of-​care  test
PCSK9 proprotein convertase subtilisin/​ POINT Platelet-​Oriented Inhibition in New TIA
kexin type 9 and Minor Ischemic Stroke (trial)
PCT procalcitonin POISE Perioperative Ischemic Evaluation (trial)
PCWP pulmonary capillary wedge pressure PP plasmapheresis
PD peritoneal dialysis PPCM peripartum cardiomyopathy
PDIRRT prolonged daily intermittent renal Ppeak airway peak pressure
replacement therapy PPI proton pump inhibitor
PDRICG plasma disappearance rate of PPL pleural pressure
indocyanine green PPLATEAU plateau pressure
xxiv Symb ols an d abbreviations

PPV positive predictive value; positive PWI perfusion-​weighted imaging

pressure ventilation PWR papillary wall rupture
PRAGUE PRimary Angioplasty in patients QCT quantitative computerized tomography
transferred from General community angiography
hospitals to specialized PTCA Units with QD dialysate flow
or without Emergency thrombolysis QI quality indicator
(trial) Qp pulmonary flow
PRAGUE-​18 Comparison of Prasugrel and Ticagrelor Qs systemic flow
in the Treatment of Acute Myocardial qSOFA quick SOFA
Infarction (trial) RAAS renin–​angiotensin–​aldosterone system;
PRAMI Preventive Angioplasty in Acute Richmond Agitation Sedation Scale
Myocardial Infarction (trial) RALT right anterolateral thoracotomy
PRECISE-​DAPT Predicting Bleeding Complication in RAS radiological 5-​point atelectasis score
Patients Undergoing Stent Implantation RBBB right bundle branch block
and Subsequent Dual Antiplatelet RBC red blood cell
Therapy (trial) RBF renal blood flow
PRECOMBAT Premier of Randomized Comparison RCA right coronary artery
of Bypass Surgery versus Angioplasty RCRI Revised Cardiac Risk Index
Using Sirolimus-​Eluting Stent in Patients RCT randomized controlled trial
with Left Main Coronary Artery Disease RCV reference change value
(trial) REDEEM Randomised Dabigatran Etexilate Dose
PRESERVE Prevention of Serious Adverse Events Finding Study in Patients With Acute
Following Angiography (trial) Coronary Syndromes (trial)
PRIDE Pro-​BNP Investigation of Dyspnea in the RELAX-​AHF Serelaxin, Recombinant Human Relaxin-​
Emergency Department (trial) 2, for Treatment of Acute Heart Failure
PRODEX Propofol Compared to Dexmedetomidine (trial)
(trial) REM rapid eye movement
PROTECT Placebo-​controlled Randomized Study REMATCH Randomized Evaluation of Mechanical
of the Selective A1 Adenosine Receptor Assistance for the Treatment of
Antagonist Rolofylline for Patients Congestive Heart Failure (trial)
Hospitalized with Acute Decompensated REPLACE-​2 Randomized Evaluation in PCI Linking
Heart Failure and Volume Over-​load to Angiomax to Reduced Clinical Events 2
Assess Treatment Effect on Congestion (trial)
and Renal Function (trial) RHC right heart catheterization
PRR pattern recognition receptor RI resistive index
PS pressure support ventilation RIFLE Risk of renal dysfunction, Injury to the
PSI patient safety incident kidney, Failure of kidney function, Loss
P-​SILI patient-​self-​induced lung  injury of kidney function, End-​stage kidney
PT prothrombin time disease
PTA percutaneous transluminal angioplasty RIFLE-​STEACS Radial Versus Femoral Randomized
PTCA percutaneous transluminal coronary Investigation in ST-​Elevation Acute
angioplasty Coronary Syndrome (trial)
PTLD post-​transplantation lymphoproliferative RITA right internal thoracic artery
disorder RITA 3 Randomized Intervention Trial of
PTU propylthiouracil Unstable Angina 3 (trial)
PURSUIT Platelet Glycoprotein IIb/​IIIa in Unstable RIVAL RadIal Vs femorAL access for coronary
Angina: Receptor Suppression Using intervention (trial)
Integrilin Therapy (trial) RNA ribonucleic acid
P/​V pressure/​volume ROC receiver operating characteristic
PVA patient–​ventilator asynchrony ROPAC Registry of Pregnancy and Cardiac
PVC premature ventricular contraction; disease
premature ventricular complex ROSC return of spontaneous circulation
PVR pulmonary vascular resistance; ROSE-​AHF Renal Optimization Strategies Evaluation
paravalvular regurgitation in Acute Heart Failure (trial)
pVT pulseless ventricular tachycardia rpm revolution per minute
 Sym b ol s a n d a b b rev iat i on s xxv

RR respiratory rhythm SIRS systemic inflammatory response syndrome

RRT renal replacement therapy SLEDD slow low-​efficiency extended daily dialysis
RSCD Regional Study of Care for the Dying SMUR emergency mobile resuscitation services
rSO2 regional oxygen saturation SNF systemic nephrogenic fibrosis
RT resuscitative thoracotomy SNP sodium nitroprusside
rtPA recombinant tissue plasminogen activator SOAP Sepsis Occurrence in Acutely Ill Patients
RT-​PCR real-​time polymerase chain reaction (trial)
RV right ventricular; right ventricle SOAP II Sepsis Occurrence in Acutely Ill Patients II
RVAD right ventricular assist device (trial)
RVEF right ventricular ejection fraction SOD superoxide dismutase
RVOT right ventricular outflow tract SOFA Sequential Organ Failure Assessment
RWPT R wave peak time (score)
s second SOLOIST-​WHF Effect of Sotagliflozin on Cardiovascular
SAH subarachnoid haemorrhage Events in Patients With Type 2 Diabetes
SALT San Antonio Lung Transplant Post Worsening Heart Failure (trial)
SaO2 arterial oxygen saturation S1P sphingosine-​1-​phosphate
SAPS Simplified Acute Physiology Score SPC specialist palliative care
SAT spontaneous awakening trial SPECT single-​photon emission computerized
SAVR surgical aortic valve replacement tomography
SAX short-​axis (view, ultrasound) sPESI simplified Pulmonary Embolism
SBP systolic blood pressure Severity Index
SBT spontaneous breathing trial SQTS short QT syndrome
SC subcutaneous SR scavenger receptor
SCAAR Swedish Coronary Angiography and SSEP somatosensory evoked potential
Angioplasty Register SSFP steady-​state free precession
SCAD spontaneous coronary artery dissection sST2 soluble suppression of tumorigenicity-​2
SCAI Society for Cardiovascular Angiography ST2 suppression of tumorigenicity 2
and Interventions STARRT-​AKI STandard versus Accelerated Initiation
SCD sudden cardiac death of Renal Replacement Therapy in Acute
SCr serum creatinine Kidney Injury (trial)
SCUF slow continuous ultrafiltration STARS Stent Anticoagulation Restenosis Study
ScvO2 central venous oxygen saturation; superior STARS-​BNP Systolic Heart Failure Treatment Supported
vena cava oxygenation saturation by BNP (trial)
SD standard deviation STE-​ACS ST elevation acute coronary syndrome
SDF sidestream dark field (imaging) STEMI ST-​segment elevation myocardial infarction
SDI sidestream dark field imaging STEMI-​RADIAL ST Elevation Myocardial Infarction treated
SE sentinel event by RADIAL or femoral approach (trial)
SEDCOM Safety and Efficacy of Dexmedetomidine STICH Surgical Treatment for Ischemic Heart
Compared with Midazolam (trial) Failure (trial); Surgical Trial in Spontaneous
SEES Sentinel Events Evaluation Study Intracerebral Haemorrhage (trial)
SFL Stent for Life (initiative) STICHES STICH Extension Study
SGA supraglottic airway STREAM Strategic Reperfusion Early after Myocardial
SGLT2 sodium–​glucose cotransporter 2 Infarction (trial)
SGOT serum glutamic-​oxaloacetic transaminase STS Society of Thoracic Surgeons
SHFM Seattle Heart Failure Model SUPPORT Study to Understand Prognoses and
SHOCK Should We Emergently Revascularize Preferences for Outcomes and Risks of
Occluded Coronaries for Cardiogenic Shock Treatment
(trial) SURVIVE Survival of Patients with Acute Heart
SHOCK-​COOL Mild Hypothermia in Cardiogenic Shock Failure in Need of Intravenous Inotropic
Complicating Myocardial Infarction (trial) Support (trial)
SIADH syndrome of inappropriate antidiuretic SV stroke volume
hormone SvO2 mixed venous oxygen saturation
SILI self-​inflicted lung injury SVR systemic vascular resistance
SIMV synchronized intermittent mandatory SVT supraventricular tachycardia
ventilation
xxvi Symb ols an d abbreviations

SYNTAX Synergy Between Percutaneous Coronary TNF tumour necrosis factor

Intervention with Taxus and Cardiac TNK-​tPA tenecteplase
Surgery (score/​trial) TOE transoesophageal echocardiography
T tesla TOF time-​of-​flight
T3 triiodothyronine tPA tissue plasminogen activator
T4 thyroxine TPE therapeutic plasma exchange
TACO transfusion-​associated circulatory TPG transpulmonary pressure gradient
overload TPP transpulmonary pressure
TACTICS TIMI 18 Treat Angina with Aggrastat and TR tricuspid regurgitation
Determine Cost of Therapy with an TRACER Thrombin Receptor Antagonist for
Invasive or Conservative Strategy)–​ Clinical Event Reduction in Acute
Thrombolysis in Myocardial Infarction Coronary Syndrome (trial)
18 (trial) TRA 2P-​TIMI 50 Thrombin Receptor Antagonist in
TAFI thrombin-​activatable fibrinolysis Secondary Prevention of Atherothrombotic
inhibitor Ischemic Events–​Thrombolysis in
TAG transluminal attenuation gradient Myocardial Infarction 50 (trial)
TAH total artificial heart TRALI transfusion-​related lung injury
TAO Treatment of Acute Coronary Syndrome TRANSITION Comparison of Pre-​and Post-​discharge
with Otamixaban (trial) Initiation of Sacubitril/​Valsartan Therapy
TAPAS Thrombus Aspiration during in HFrEF Patients After an Acute
Percutaneous Coronary Intervention in Decompensation Event (trial)
Acute Myocardial Infarction Study TREAT Ticagrelor in Patients With ST Elevation
TAPSE tricuspid annular plane systolic excursion Myocardial Infarction Treated With
TAR traumatic aortic rupture Pharmacological Thrombolysis (trial)
TAVI transcatheter aortic valve implantation TRICS Transfusion Requirements in Cardiac
TBW total body water Surgery (trial)
TCD transcranial Doppler TRILOGY Targeted Platelet Inhibition to Clarify the
TDI tissue Doppler imaging Optimal Strategy to Medically Manage
TdP torsades de pointes Acute Coronary Syndromes (trial)
TE expiratory time; thromboelastometry/​ TRIM transfusion-​induced immunomodulation
thromboelastography TRITON Trial to Assess Improvement in
TEA thoracic epidural analgesia Therapeutic Outcomes by Optimizing
TECOS Trial Evaluating Cardiovascular Platelet Inhibition with Prasugrel (trial)
Outcomes with Sitagliptin TRIUMPH Translational Initiative on Unique and
TENS transcutaneous electrical nerve novel strategies for Management of
stimulation Patients with Heart failure (study)
TEVAR thoracic endovascular aortic repair TROPICAL-​ACS Testing Responsiveness to Platelet
TF tissue factor Inhibition on Chronic Antiplatelet
TFPi tissue factor pathway inhibitor Treatment for Acute Coronary
TGF transforming growth factor Syndromes (trial)
TI inspiratory time TRP transient receptor potential
TIA transient ischaemic attack TRUE-​AHF TRial of Ularitide’s Efficacy and safety in
TICACOS Tight Calorie Control Study patients with Acute Heart Failure
TIMACS Timing of Intervention in Acute TRUST Triage Rule-​out Using high-​Sensitivity
Coronary Syndrome (trial) Troponin
TIME-​CHF Trial of Intensified vs Standard Medical TS thyroid storm
Therapy in Elderly Patients With TSAT transferrin saturation
Congestive Heart Failure (trial) TSH thyroid-​stimulating hormone
TIMI Thrombolysis in Myocardial Infarction TTE transthoracic echocardiography
TIMP tissue inhibitor of metalloproteinase TTM targeted temperature management
TITRe2 Transfusion Indication Threshold TTP thrombotic thrombocytopenic purpura
Reduction (trial) TUS thoracic ultrasound
TLR toll-​like receptor TXA2 thromboxane A2
TMP transmembrane pressure U unit
 Sym b ol s a n d a b b rev iat i on s xxvii

UA unstable angina VD dead space
UAG urine anion gap VDS verbal descriptor scale
UF ultrafiltration VEGF vascular endothelial
UFH unfractionated heparin growth factor
UK United Kingdom VF ventricular fibrillation
UK MINAP United Kingdom Myocardial VHD valvular heart disease
Ischaemia National Audit VHVHF very high-​volume
Project haemofiltration
UNOS United Network for Organ VILI ventilator-​induced lung
Sharing injury
URL upper reference limit ViR valve-​in-​ring
US United States; ultrasonography; VIRGO Variation in Recovery: Role of
ultrasound Gender on Outcomes of Young
V volt AMI Patients (trial)
VA ventricular arrhythmia ViV valve-​in-​valve
VAD ventricular assist device VKA vitamin K antagonist
VA-​ECMO veno-​arterial extracorporeal VO2 myocardial oxygen demand
membrane oxygenation V/​Q ventilation/​perfusion
VALIDATE-​SWEDEHEART Bivalirudin versus Heparin VRS verbal rating scale
in ST-​Segment and Non–​ST-​ VSD ventricular septal defect
Segment Elevation Myocardial VSMC vascular smooth muscle cell
Infarction in Patients on VSR ventricular septal rupture
Modern Antiplatelet Therapy VT tidal volume
in the Swedish Web System for VT ventricular tachycardia
Enhancement and Development VTE venous thromboembolism
of Evidence-​based Care in Heart VV-​ECMO veno-​venous extracorporeal
Disease Evaluated according membrane oxygenation
to Recommended Therapies vWF von Willebrand factor
Registry Trial VWR ventricular wall rupture
VAP ventilator-​associated W watt
pneumonia WCD wearable
VAS visual analogue scale cardioverter–​defibrillator
VASP vasodilator-​stimulated WHO World Health Organization
phosphoprotein WLST withdrawal of life-​sustaining
VASS-​T Vasopressin and Septic treatment
Shock Trial WOEST What is the Optimal
VC-​AC volume-​controlled assist-​ antiplatElet & Anticoagulant
control ventilation Therapy in Patients With
VCAM vascular cell adhesion molecule Oral Anticoagulation and
VC-​CMV volume-​controlled continuous Coronary StenTing (trial)
mechanical ventilation WPW Wolff–​Parkinson–​White
VC-​SIMV volume-​controlled (syndrome)
synchronized intermittent WRF worsening of renal function
mandatory ventilation WU Woods unit
 Contributors

Alfredsson, Joakim Borger, Michael A

Department of Cardiology, University Hospital, University Clinic for Cardiac Surgery, Heart Center, Leipzig,
Linköping, Sweden Germany
Alpert, Joseph S Bremerich, Jens
University of Arizona College of Medicine, Tucson, AZ, USA Department of Radiology, University Basel, Basel, Switzerland
Badimon, Lina Bronselaer, Koen
Program ICCC-​Institut Català de Ciències Cardiovasculars IR-​ Emergency Department, University Hospitals Leuven, Leuven,
Hospital de la Santa Creu i Sant Pau, Barcelona, Spain Belgium
Balik, Martin Bueno, Héctor
Department of Anaesthesia and Intensive Care, First Medical Cardiology Department, Hospital Universitario 12 de Octubre,
Faculty, General University Hospital, Charles University, Prague, Centro Nacional de Investigaciones Cardiovasculares, CIBER
Czech Republic Cardiovascular (CIBER-​CV), Madrid, Spain
Ballotta, Andrea Bunge, Jeroen JH
Department of Cardiothoracic Anaesthesia and Intensive Care, Departments of Intensive Care Adults and Cardiology, Erasmus
IRCCS Policlinico S Donato, Milan, Italy MC University Medical Center, Rotterdam, The Netherlands
Baratto, Francesca Burri, Haran
Arrhythmia Unit and Cardiac Electrophysiology, Ospedale San Cardiac Pacing Unit, Cardiology Department, University
Raffaele, Milan, Italy Hospital of Geneva, Switzerland
Barrabés, José A Busana, Mattia
Unidad Coronaria, Servicio de Cardiologia, Hospital Department of Anesthesiology, Emergency Medicine and
Universitari Vall d’Hebron, Barcelona, Spain Critical Care, University of Göttingen, Göttingen, Germany
Bax, Jeroen J Camm, A John
Department of Cardiology, Leiden University Medical Centre Department of Clinical Cardiology, St George’s Hospital,
(LUMC), Leiden, The Netherlands University of London, London, UK
Beyer, Ruxandra Camporota, Luigi
University of Cluj-​Napoca, Cluj-​Napoca, Romania Guy’s and St Thomas’ NHS Foundation Trust, St Thomas’
Hospital, London, UK
Boeddinghaus, Jasper
Cardiovascular Research Institute Basel (CRIB) and Department Cao, Davide
of Cardiology, University Hospital Basel, University of Basel, The Zena and Michael A. Wiener Cardiovascular Institute, Icahn
Switzerland School of Medicine at Mount Sinai, New York, USA
Bonnefoy-​Cudraz,  Eric Carlesso, Eleonora
Department of Acute Cardiovascular Care, University Hospital L Department of Pathophysiology and Transplantation, University
Pradel, Hospices Civils de Lyon, Lyon, France of Milan, Milan, Italy
xxx C ontribu tors

Casaer, Michael P Demetriades, Demetrios

Clinical Division and Laboratory of Intensive Care Medicine, Division of Trauma, Emergency Surgery, and Surgical Critical
Department of Cellular and Molecular Medicine, KU Leuven, Care, USC Medical Center, Los Angeles, CA, USA
Leuven, Belgium
Dilling, Dagmara
Caso, Valeria Department of Cardiology and Electrophysiology, Jessa
University of Perugia Stroke Unit, Perugia, Italy Ziekenhuis, Hasselt, Belgium
Castelvecchio, Serenella Docherty, Kieran F
Department of Cardiothoracic Anaesthesia and Intensive Care, Institute of Cardiovascular and Medical Sciences, University of
IRCCS Policlinico S Donato, Milan, Italy Glasgow, Glasgow, UK
Choudhary, Rajiv Ducrocq, Gregory
VA Medical Center, 3350 La Jolla Village Drive, San Diego, CA, USA Université de Paris, AP-​HP, French Alliance for Cardiovascular
Trials (FACT), INSERM U1148, Paris, France
Claeys, Marc J
Department of Cardiology, University Hospital Antwerp, Ebelt, Henning
Belgium Department of Internal Medicine III, Heart Center, Martin-​
Luther-​University Halle-​Wittenberg, University Hospital Halle/​
Clarkson, Kevin
Saale, Halle/​Saale, Germany
Department of Anaesthesia and Critical Care Medicine,
University Hospital Galway, National University of Ireland Ecarnot, Fiona
Galway School of Medicine, Galway, Ireland Department of Cardiology, University Hospital Besançon and
EA3920, University of Franche-​Comté, Besançon, France
Creteur, Jacques
Department of Intensive Care, Erasme University Hospital, El Mahdiui, Mohammed
Université Libre de Bruxelles, Brussels, Belgium Department of Cardiology, Leiden University Medical Center
(LUMC), Leiden, The Netherlands
Dalzell, Jonathan R
Scottish National Advanced Heart Failure Service, Golden Falk, Volkmar
Jubilee National Hospital, Glasgow, UK Klinik für Herz-​Thorax-​Gefässchirurgie, Deutsches
Herzzentrum Berlin, Germany
Dauw, Jeroen
Department of Cardiology, Ziekenhuis Oost-​Limburg, Genk, Farmakis, Dimitrios
Belgium University of Cyprus Medical School, Nicosia, Cyprus
Davierwala, Piroze M Favory, Raphaël
University Clinic for Cardiac Surgery, Heart Center, Leipzig, Intensive Care Department, Université de Lille, Inserm, CHU
Germany Lille, U995, Lille Inflammation Research International Center
(LIRIC), Lille, France
De Carlini, Caterina C
Cardiology Unit, SL Mandic Hospital, Merate (Lecco), Italy Ferdinande, Patrick
Department of Microbiology, Immunology and Transplantation,
De Graaf, Michiel A
Laboratory of Abdominal Transplantation, KU Leuven, Leuven,
Department of Cardiology, Leiden University Medical Center
Belgium
(LUMC), Leiden, The Netherlands
Filippatos, Gerasimos
De Waha-​Thiele, Suzanne
Heart Failure Unit, Department of Cardiology, Attikon
German Center for Cardiovascular Research (DZHK), partner
University Hospital, National and Kapodistrian University of
site Hamburg/​Kiel/​Lübeck, and University Heart Center Lübeck,
Athens Medical School, Athens, Greece
University Hospital Schleswig-​Holstein, Lübeck, Germany
Flachskampf, Frank A
Debaveye, Yves
Department of Medical Sciences, Uppsala University,
Clinical Division and Laboratory of Intensive Care Medicine,
Uppsala, Sweden
Department of Cellular and Molecular Medicine, KU Leuven,
Leuven, Belgium Galiè, Nazzareno
Department of Experimental, Diagnostic and Specialty
Della Bella, Paolo
Medicine-DIMES, Alma Mater Studiorum, University of
Arrhythmology Department, IRCCS San Raffaele Hospital,
Bologna, Bologna, Italy
Milan, Italy
 C on t ri bu tor s xxxi

Gargiulo, Giuseppe Hoogmartens, Olivier

Department of Advanced Biomedical Sciences, Federico II Leuven Institute for Healthcare Policy, Leuven University,
University of Naples, Naples, Italy Leuven, Belgium
Gattinoni, Luciano Hoste, Eric
Department of Anesthesiology, Emergency Medicine and Intensive Care Unit and Transplant Center, Ghent University
Critical Care, University of Göttingen, Göttingen, Germany Hospital, Ghent, Belgium
Gayat, Etienne Huber, Kurt
Department of Anesthesiology and Critical Care, Hôpital Department of Cardiology, Wilhelminenhospital,
Lariboisière (AP-HP), Paris, France; Inserm U942 MASCOT, Montleartstrabe 37, 1160 Wien, Austria
Paris, France; Université de Paris, Paris, France
Hvas, Anne-​Mette
Gevaert, Sofie A Department of Clinical Biochemistry, Aarhus University
Coronary Care Unit, Department of Cardiology, Ghent Hospital, Aarhus, Denmark
University Hospital, Ghent, Belgium
Ibanez, Borja
Girndt, Matthias Clinical Research Department, Centro Nacional de
Department of Internal Medicine III, Heart Center, Martin-​ Investigaciones Cardiovasculares Carlos III (CNIC), Spain
Luther-​University Halle-​Wittenberg, University Hospital Halle/​
Imazio, Massimo
Saale, Halle/​Saale, Germany
University Cardiology, AOU Città della Salute e della Scienza di
Gorenek, Bulent Torino, Torino, Italy
Eskisehir Osmangazi University Cardiology Department,
Iung, Bernard
Eskisehir, Turkey
Hôpital Bichat, APHP, Paris, Université de Paris and INSERM
Gosselink, Rik 1148, Paris, France
Department Rehabilitation Sciences, Faculty Movement and
Jaffe, Allan S
Rehabilitation Sciences, University Hospitals Leuven, Leuven,
Mayo Clinic, Rochester, MN, USA
Belgium
Jaggar, Siân
Graulus, Eric
Royal Brompton & Harefield NHS Foundation Trust,
AZ Sint-​Jan, Department of Cardiac Surgery, Brugge, Belgium
London, UK
Grove, Erik L
James, Stefan
Department of Cardiology, Aarhus University Hospital, Aarhus,
Department of Medical Sciences and Uppsala Clinical Research
Denmark
Center, Uppsala University, Uppsala, Sweden
Gunst, Jan
Johnson, Mark
Clinical Division and Laboratory of Intensive Care Medicine,
Department of Clinical Obstetrics, Imperial College, Chelsea
Department of Cellular and Molecular Medicine, KU Leuven,
and Westminster Hospital, London, UK
Leuven, Belgium
Katritsis, Demosthenes G
Gurjeva, Olga S
Department of Cardiology, Hygeia Hospital, Athens, Greece
Emergency Cardiology Department, National Scientific Center
‘MD Strazhesko Institute of Cardiology’, Kyiv, Ukraine Keane, Stephen
Department of Cardiology, University Hospital Galway, National
Halvorsen, Sigrun
University of Ireland Galway School of Medicine, Galway,
Department of Cardiology, Oslo University Hospital Ulleval, and
Ireland
University of Oslo, Oslo, Norway
Kellum, John A
Hassager, Christian
Center of Critical Care Nephrology, Department of Critical Care
The Heart Centre, Rigshospitalet, Copenhagen, Denmark
Medicine, Pittsburgh University, Pittsburgh, PA, USA
Heymans, Stephane
Keogh, Brian F
Department of Cardiology, Maastricht University Medical
Royal Brompton Hospital & Harefield NHS Foundation Trust,
Centre (MUMC), Cardiovascular Research Institute Maastricht
London, UK
(CARIM), Maastricht, The Netherlands
xxxii C ontribu tors

Klages, Jan Mannucci, Pier Mannuccio

Institute of Anesthesiology, German Heart Centre Berlin, Berlin, IRCCS Ca’ Granda Maggiore Policlinico Hospital Foundation,
Germany Milan, Italy
Kobayashi, Leslie Martin, Jasmin
Division of Trauma, Surgical Critical Care, Burns, and Acute Cardiovascular Research Institute Basel (CRIB) and Department
Care Surgery, Department of Surgery, University of California of Cardiology, University Hospital Basel, University of Basel,
San Diego Health, San Diego, CA, USA Basel, Switzerland
Konstantinides, Stavros Mas, Arantxa
Centre for Thrombosis and Haemostasis, University Medical Intensive Care Department, Consorci Sanitari Integral,
Centre Mainz, Germany and Department of Cardiology, University of Barcelona, Barcelona, Spain
Democritus University of Thrace, Greece
Masip, Josep
Kozhuharov, Nikola Intensive Care Department, Consorci Sanitari Integral,
Cardiovascular Research Institute Basel (CRIB) and Department University of Barcelona, Barcelona, Spain
of Cardiology, University Hospital Basel, University of Basel,
Maurizi, Giulio
Basel, Switzerland
Department of Thoracic Surgery, Sapienza University of Rome,
Kristensen, Steen Dalby Sant’Andrea Hospital, Rome, Italy
Department of Cardiology, Aarhus University Hospital, Aarhus,
McEvoy, John W
Denmark
Department of Cardiology, University Hospital Galway, National
Kroft, Lucia University of Ireland Galway School of Medicine, Galway,
Department of Radiology, Leiden University Medical Center Ireland
(LUMC), Leiden, The Netherlands
McMurray, John JV
Kurzyna, Marcin Institute of Cardiovascular and Medical Sciences, University of
Department of Pulmonary Circulation, Thromboembolic Glasgow, Glasgow, UK
Disease and Cardiology, Center for Postgraduate Medical
Mebazaa, Alexandre
Education, ECZ-Otwock, Poland
Department of Anesthesiology and Critical Care, Hôpital
Lam, Lydia Lariboisière (AP-HP), Paris, France; Inserm U942 MASCOT,
USC School of Medicine, Los Angeles, CA, USA Paris, France; Université de Paris, Paris, France
Laycock, Helen Mehran, Roxana
Department of Anaesthetics and Pain Medicine, Great Ormond The Zena and Michael A. Wiener Cardiovascular Institute, Icahn
Street Hospital, London, UK School of Medicine at Mount Sinai, New York, USA
Leonardi, Sergio Michou, Eleni
University of Pavia, Coronary Care Unit, Fondazione IRCCS Cardiovascular Research Institute Basel (CRIB) and Department
Policlinico S Matteo, Pavia, Italy of Cardiology, University Hospital Basel, University of Basel,
Basel, Switzerland
Lettino, Maddalena
Cardiovascular Department, San Gerardo Hospital, Monza, Italy Mion, Monica Maria
Department of Laboratory Medicine, University-​Hospital,
Leys, Didier
Padova, Italy
University of Lille, Inserm U1172, Lille, France
Mitsis, Andreas
Maggiolini, Stefano
Department of Cardiology, Inselspital, Bern University Hospital,
Cardiology Unit, SL Mandic Hospital, Merate (Lecco), Italy
Bern, Switzerland
Maisel, Alan
Modine, Thomas
Department of Medicine, Division of Cardiology, University of
Centre Hospitalier Regional et Universitaire de Lille, Lille,
California, San Diego, La Jolla, CA, USA
France
Manes, Alessandra
Moreau, Anne-​Sophie
Cardiovascular and Thoracic Department, Bologna University
Intensive Care Department, Université de Lille, Inserm, CHU
Hospital, Bologna, Italy
Lille, U995, Lille Inflammation Research International Center
(LIRIC), Lille, France
 C on t ri bu tor s xxxiii

Morley-​Smith, Andrew C Pepper, John

St Bartholomew’s Hospital, London, UK Royal Brompton and Harefield NHS Foundation Trust,
London, UK
Moulin, Solène
Centre Hospitalier Universitaire de Reims, Reims, France Petrie, Mark C
Institute of Cardiovascular and Medical Sciences, University of
Mueller, Christian
Glasgow, Glasgow, UK and Scottish National Advanced Heart
Cardiovascular Research Institute Basel (CRIB) and Department
Failure Service, Golden Jubilee National Hospital, Glasgow, UK
of Cardiology, University Hospital Basel, University of Basel,
Basel, Switzerland Planas, Kenneth
Intensive Care Department, Consorci Sanitari Integral,
Mullens, Wilfried
University of Barcelona, Barcelona, Spain
Department of Cardiology, Ziekenhuis Oost-​Limburg, Genk,
Belgium Plebani, Mario
Department of Laboratory Medicine, University-​Hospital of
Myrianthefs, Pavlos
Padova, Padova, Italy
National & Kapodistrian University of Athens ‘Agioi Anargyroi’
Hospital Nea Kifisia, Athens, Greece Price, Susanna
Royal Brompton Hospital & Harefield NHS Foundation Trust,
Nestelberger, Thomas
London, UK
Cardiovascular Research Institute Basel (CRIB) and Department
of Cardiology, University Hospital Basel, University of Basel, Puerto, Elena
Basel, Switzerland Cardiology Department, Instituto de Investigación imas12,
Hospital Universitario 12 de Octubre, Madrid, Spain
Neyrinck, Arne P
Department of Anesthesiology, University Hospitals Leuven, Quinn, Tom
Leuven, Belgium Emergency, Cardiovascular, and Critical Care Research Group,
Joint Faculty, Kingston University & St George’s, University of
Nolan, Jerry P
London, London, UK
Department of Anaesthesia and Intensive Care Medicine, Royal
United Hospital, Bath, UK Ranucci, Marco
Department of Cardiothoracic Anaesthesia and Intensive Care,
Nuding, Sebastian
IRCCS Policlinico S Donato, Milan, Italy
Department of Internal Medicine III, Heart Center, Martin-​
Luther-​University Halle-​Wittenberg, University Hospital Halle/​ Rendina, Erino Angelo
Saale, Halle/​Saale, Germany Department of Thoracic Surgery, Sapienza University of Rome,
Sant’Andrea Hospital, Rome, Italy
Palazzini, Massimiliano
Department of Experimental, Diagnostic and Specialty Ricci, Zaccaria
Medicine-DIMES, Alma Mater Studiorum, University of Pediatric Cardiac Intensive Care Unit, Department of Pediatric
Bologna, Bologna, Italy Cardiac Surgery, Bambino Gesù Children’s Hospital, Rome, Italy
Parkhomenko, Alexander Roeseler, Jean
Emergency Cardiology Department, National Scientific Center Cliniques Universitaires St Luc, Département de Médecine
‘MD Strazhesko Institute of Cardiology’, Kyiv, Ukraine Aiguë, Service des Soins Intensifs, Brussels, Belgium
Parkin, Matthew Romagnoli, Stefano
Adult Critical Care Unit, Barts Heart Centre, St Bartholomew’s Department of Anesthesiology and Intensive Care, Azienda
Hospital, London, UK Ospedaliero-​Universitaria Careggi, Florence, Italy
Patel, Brijesh Ronco, Claudio
Department of Intensive Care, Royal Brompton & Harefield Department of Nephrology Dialysis and Transplantation, San
Adult Intensive Care Units, London, UK Bortolo Hospital, Vicenza, Italy
Paul, Richard Roos-​Hesselink,  Jolien
NIHR Respiratory Biomedical Research Unit at the Royal Erasmus Medical Center, Rotterdam, The Netherlands
Brompton and Harefield NHS Foundation Trust and Imperial
Sabbe, Marc
College London, London, UK
Emergency Department, University Hospitals Leuven, Leuven,
Belgium
xxxiv C ontribu tors

Schepens, Marc Swahn, Eva
AZ Sint-​Jan, Department of Cardiac Surgery, Brugge, Belgium Department of Cardiology, University Hospital,
Linköping, Sweden
Schiele, François
Department of Cardiology, University Hospital Besançon and Swan, Lorna
EA3920, University of Franche-​Comté, Besançon, France Division of Cardiology, Peter Munk Cardiac Centre; Toronto
Congenital Cardiac Centre for Adults, University of Toronto,
Schoenrath, Felix
Toronto ON, Canada
Department of Cardiothoracic and Vascular Surgery, German
Heart Centre, Berlin, Germany Taccone, Fabio S
Department of Intensive Care, Hôpital Erasme, Brussels,
Scholte, Arthur JHA
Belgium
Department of Cardiology, Leiden University Medical Center
(LUMC), Leiden, The Netherlands Thiele, Holger
Heart Center Leipzig at University of Leipzig, Department of
Schröder, Jochen
Internal Medicine/​Cardiology, Leipzig, Germany
Department of Internal Medicine III, Heart Center, Martin-​
Luther-​University Halle-​Wittenberg, University Hospital Halle/​ Thuny, Franck
Saale, Halle/​Saale, Germany Aix-Marseille University, Assistance Publique-Hôpitaux de
Marseille, Mediterranean University Cardio-Oncology Center,
Schwitter, Juerg
Unit of Heart Failure and Valvular Heart Diseases, Department
Cardiac MR Centre of the CHUV, University Hospital Lausanne
of Cardiology, Hôpital Nord, Marseille, France
and University of Lausanne FBM, Lausanne, Switzerland
Thygesen, Kristian
Sederholm Lawesson, Sofia
Department of Cardiology, Aarhus University Hospital,
Department of Cardiology, University Hospital,
Denmark
Linköping, Sweden
Torbicki, Adam
Shah, Kevin
Department of Pulmonary Circulation, Thromboembolic
Department of Medicine, Division of Cardiology, University of
Disease and Cardiology, Center for Postgraduate Medical
Utah, Salt Lake City, Utah, USA
Education, ECZ-Otwock, Poland
Shariff, Farah
Tubaro, Marco
NIHR Respiratory Biomedical Research Unit at the Royal
Intensive Cardiac Care Unit, San Filippo Neri Hospital,
Brompton and Harefield NHS Foundation Trust and Imperial
Rome, Italy
College London, London, UK
Twerenbold, Raphael
Simon, André R
Cardiovascular Research Institute Basel (CRIB) and Department
Royal Brompton and Harefield NHS Foundation Trust,
of Cardiology, University Hospital Basel, University of Basel,
London, UK
Basel, Switzerland
Sionis, Alessandro
Vahanian, Alec
Hospital de la Santa Creu i Sant Pau IIB Sant Pau, Carrer de Sant
Department of Cardiology, Bichat Claude Bernard Hospital,
Quintí, 89, 08041 Barcelona, Spain
Assistance Publique Hôpitaux de Paris, Paris, France
Smit, Jeff M
Valgimigli, Marco
Department of Cardiology, Leiden University Medical Centre
Department of Cardiology, Inselspital, Bern University Hospital,
(LUMC), Leiden, The Netherlands
Bern, Switzerland
Starr, Neasa
Van De Velde, Marc
Cardiac Pacing Unit, Cardiology Department, University
Department of Anesthesiology, Leuven University Hospital,
Hospital of Geneva, Geneva, Switzerland
Leuven, Belgium
Stepinska, Janina
Van Den Berghe, Greet
Institute of Cardiology, Warsaw, Poland
Clinical Division and Laboratory of Intensive Care Medicine,
Stiers, Michiel Department of Cellular and Molecular Medicine, KU Leuven,
Emergency Department, University Hospitals Leuven, Leuven, Leuven, Belgium
Belgium
Van Der Jagt, Mathieu
Department of Intensive Care Adults, Erasmus MC University
Medical Center, Rotterdam, The Netherlands
 C on t ri bu tor s xxxv

Van Raemdonck, Dirk Vrints, Christiaan

Department of Thoracic Surgery, University Hospitals Leuven, Department of Cardiology, Antwerp University Hospital and
Leuven, Belgium University of Antwerp, Antwerp, Belgium
Vandekerckhove, Philippe Werdan, Karl
Belgian Red Cross-​Flanders, Mechelen, Belgium and Department of Internal Medicine III, Heart Center, Martin-​
Department of Public Health and Primary Care, University of Luther-​University Halle-​Wittenberg, University Hospital Halle/​
Leuven, Leuven, Belgium Saale, Halle/​Saale, Germany
Vanni, Camilla Wettersten, Nicholas
Department of Thoracic Surgery, Sapienza University of Rome, Department of Medicine, Division of Cardiology, University of
Sant’Andrea Hospital, Rome, Italy California, San Diego, La Jolla, CA, USA
Vasques, Francesco White, Harvey D
Guy’s and St Thomas’ NHS Foundation Trust, St Thomas’ Green Lane Cardiovascular Service, Auckland City Hospital and
Hospital, London, UK University of Auckland, Auckland, New Zealand
Vieillard-​Baron, Antoine Windecker, Stephan
Intensive Care Unit, University Hospital Ambroise Paré, Department of Cardiology, Inselspital, Bern University Hospital,
Boulogne-​Billancourt,  France Bern, Switzerland
Vijgen, Johan Wood, Jayne
Department of Cardiology, Jessa Ziekenhuis, Hasselt, Belgium Symptom Control and Palliative Care Team, The Royal Marsden
NHS Foundation Trust, London, UK
Vilahur, Gemma
Program ICCC-​Institut Català de Ciències Cardiovasculars IR-​ Yalynska, Tetyana
Hospital de la Santa Creu i Sant Pau, Barcelona, Spain Ukranian Children’s Cardiac Centre (UCCC), Kyiv, Ukraine
Vincent, Jean-​Louis Zaninotto, Martina
Department of Intensive Care, Erasme University Hospital, Department of Laboratory Medicine, University-​Hospital,
Université Libre de Bruxelles, Brussels, Belgium Padova, Italy
Vranckx, Pascal
Cardiac ITU, Virga Jesse Ziekenhuis, Hasselt, Belgium
CHAPTER 1

Intensive and acute

cardiovascular care:
an introduction
Eric Bonnefoy-Cudraz, Susanna Price, Marco
Tubaro, Pascal Vranckx, and Christiaan Vrints

Cardiovascular diseases (CVDs) are a major cause of premature death worldwide and an
important cause of loss of disability-​adjusted life years [1]‌. For most types of CVD, early
diagnosis (within minutes) and intervention are independent drivers of patient outcome.
Clinicians must be properly trained and centres appropriately equipped in order to deal
with these critically ill cardiac patients [2].
Desmond Julian was the first to suggest the concept of the coronary care unit (CCU) to
the British Cardiothoracic Society in 1961 [3]‌—​an innovation widely recognized as one
of the great developments in cardiology. In 1962, he set up the first CCU for the moni-
toring of patients with acute myocardial infarction (AMI) in Sydney (Australia), and in
1964 he established the first European CCU in Edinburgh. A few years later, Killip and
Kimball demonstrated that ‘aggressive’ pharmacological therapy in a CCU could signifi-
cantly reduce mortality (from 28% to 7%) in AMI patients without shock [4]. Since the
inception of the intensive cardiovascular care unit (ICCU) in the early 1960s, the pa-
tient mix has drastically evolved [2, 3]. Due to the ageing population, growing medical
complexity of treated patients, and improved survival from complex cardiovascular and
medical conditions, patients with advanced cardiac disease complicated by severe non-​
cardiovascular comorbidities [e.g. sepsis or kidney injury in a patient on extracorporeal
membrane oxygenation (ECMO)] have become increasingly common in the ICCU
[5–​7]. In concert, due to advances in procedural techniques, patients with severe non-​
cardiovascular illness complicated by secondary cardiovascular comorbidities [e.g. type
II myocardial infarction (MI) or septic cardiomyopathy] are also growing in prevalence
in the ICCU environment. Hospitalizations complicated by multiorgan failure (MOF) are
frequent, while patient admissions with isolated primary cardiac dysfunction [e.g. acute
coronary syndrome (ACS), arrhythmias] are becoming less common [2].
As a result, this environment led to the emergence of the cardiac intensivist, who
should be trained in intensive care medicine and emergency medicine, as well as internal
medicine and cardiology [2, 5, 7, 8].
The actual intensive and acute cardiovascular care (IACC) model makes the patient
the centre of care, with continuous management by a core team of acute cardiovascular
physicians and nurses—​all in collaboration with cardiologists, cardiovascular surgeons,
and affiliated health care workers [2]‌. Strategic planning of a patient’s diagnosis and man-
agement over the course of a hospitalization is grounded in multidisciplinary discus-
sion, giving patients the benefit of not only the full spectrum of a hospital’s resources (an
additive benefit), but also the wisdom of multidisciplinary deliberation (a multiplicative
benefit greater than the sum of its parts) [9].
2 CHAPTER 1   In ten sive and acu te cardiovas cu l a r ca re: a n i n trodu cti on

The Association for Acute CardioVascular Care (ACVC) of the pharmacological and non-​pharmacological treatments. The other
European Society of Cardiology (ESC) has been at the forefront main cardiovascular acute conditions are grouped in Section IX.
of establishing best practice in acute cardiac and intensive care, Last, but not least, Section X is dedicated to the many concomi-
first as a working group and subsequently, from 2012 onwards, tant acute non-​cardiovascular conditions that contribute to the
as an association. The ACVC promotes research and education patient case mix in the ICCU. The acute and intensive manage-
and spreads knowledge of new and emerging science in the field ment of this variety of acute illnesses requires deep and, at the
of acute cardiac care. The ESC Textbook of IACC, third edition, same time, wide clinical training in all aspects of critical care.
follows the IACC training core curriculum (CC) and is designed The ESC Textbook of Intensive and Acute Cardiovascular Care,
to be used as a text of teaching and a guide for learning. The chap- third edition, contains in total two brand new chapters: Chapter 47
ters also serve as the basis for the European Society of Cardiology (Low cardiac output states and cardiogenic shock) and Chapter 55
e-​Learning (ESCeL) teaching modules. It is sufficiently large in (Pacemakers and ICDs: troubleshooting). More than one-​third of
scope to provide an overview of important areas related to acute all chapters have benefited from a major revision.
cardiovascular care and makes it relevant to both trainees and As in the previous editions, each chapter has been written by
non-​trainees in cardiology, emergency and intensive care medi- a real expert in the field and is in line with the ESC guidelines
cine, and beyond. and the CC in IACC; multiple choice questions (MCQs) on many
Section I focuses on the definition, structure, organization, and of the chapters are available for continuing medical education
function of ICCUs and on ethical issues and quality of care. (CME). A  particular asset of this textbook is the online edition
Section II addresses the pre-​hospital and immediate in-​hospital (available at: M oxfordmedicine.com/ESCIACC3e). Purchasers of
[emergency department (ED)] emergency cardiac care. the print, as well as of the online-​only bundle, can access the on-
In Sections II–​V, patient monitoring, diagnosis, and specific line material via an access code. The online version contains all
procedures are described. Laboratory medicine is widely used the material from the printed book, as well as many more figures
in IACC, both for prompt diagnosis of acute conditions and for and tables, an extended reference list for each chapter, and original
prognostic stratification, which frequently drives patient alloca- material like photos and videos, to better illustrate diagnostic and
tion and treatment strategies. therapeutic techniques and procedures in IACC.
ACS, acute decompensated heart failure (ADHF), and serious We believe that this textbook will be very useful in establishing a
arrhythmias deserve a whole section each, being the three most common basis of knowledge and a uniform and improved quality
important groups of cardiac diseases managed in ICCUs (Sections of care in all European countries and beyond, for the benefit and
VI–​VIII). These entities are dealt with in great detail, including improved care of our patients. Enjoy reading!

References
1. Roth GA, Johnson C, Abajobir A, et al. Global, regional, and national 6. Katz JN, Shah BR, Volz EM, et  al. Evolution of the coronary care
burden of cardiovascular diseases for 10 causes, 1990 to 2015. J Am unit:  clinical characteristics and temporal trends in healthcare de-
Coll Cardiol 2017;70:1–​25. livery and outcomes. Crit Care Med 2010;38:375–​81.
2. Bonnefoy-​Cudraz E, Bueno H, Casella G, et  al. Editor’s Choice—​ 7. Morrow DA, Fang JC, Fintel DJ, et al. Evolution of critical care car-
Acute Cardiovascular Care Association Position Paper on Intensive diology: transformation of the cardiovascular intensive care unit and
Cardiovascular Care Units:  an update on their definition, struc- the emerging need for new medical staffing and training models:  a
ture, organisation and function. Eur Heart J Acute Cardiovasc Care scientific statement from the American Heart Association. Circulation
2018;7:80–​95. 2012;126:1408–​28.
3. Julian DG. Treatment of cardiac arrest in acute myocardial ischaemia 8. Walker DM, West NE, Ray SG. From coronary care unit to acute
and infarction. Lancet 1961;2:840–​4. cardiac care unit:  the evolving role of specialist cardiac care. Heart
4. Killip T, 3rd, Kimball JT. Treatment of myocardial infarction in a cor- 2012;98:350–​2.
onary care unit. A two year experience with 250 patients. Am J Cardiol 9. Dudzinski DM, Januzzi JL, Jr. The evolving medical complexity of the
1967;20:457–​64. modern cardiac intensive care unit. J Am Coll Cardiol 2017;69:2008–​10.
5. Katz JN, Minder M, Olenchock B, et al. The genesis, maturation, and
future of critical care cardiology. J Am Coll Cardiol 2016;68:67–​79.
 SECTION 1

Intensive and acute

cardiovascular care

2 Training and certification in intensive and acute cardiovascular care  5

Susanna Price and Eric Bonnefoy-Cudraz
3 Intensive cardiovascular care units: structure, organization, and staffing  11
Eric Bonnefoy-Cudraz and Tom Quinn
4 The heart team  25
Sergio Leonardi, Thomas Modine, and Stephan Windecker
5 Patient safety and clinical governance  33
Matthew Parkin and Tom Quinn
6 Ethical issues in cardiac arrest and acute cardiac care: a European perspective  43
Jean-​Louis Vincent and Jacques Creteur
7 Quality of care assessment in acute cardiac care  54
Fiona Ecarnot and François Schiele
 CHAPTER 2

Training and certification

in intensive and acute
cardiovascular care
Susanna Price and Eric Bonnefoy-Cudraz

Contents
Summary  5 Summary
Introduction  5 Acute cardiovascular care is now a complex and technical subspecialty of cardi-
Training in acute cardiovascular care  6 ology. Specific training in acute cardiovascular care is warranted, in addition to
First step  6 skills acquired during the initial phase of cardiology training. Data are available
Second step  6
Third step  6 that show that this training brings benefits to patients and improves their outcome.
Curricula in acute cardiovascular care  7 The Association for Acute CardioVascular Care (ACVC) of the European Society
Competency-​based training  7 of Cardiology (ESC) offers a comprehensive postgraduate programme in acute
Simulation for training in acute cardiovascular care. This programme is in line with the three levels of expertise
cardiovascular care  7
described for intensive cardiac care unit organization. A curriculum focused on
Acute cardiovascular care EPA in the
initial training is also available through the American College of Cardiology. Both
ESC core curriculum for the general
cardiologist  7 curricula are competency-​based. Teaching practical knowledge and skills through
The ESC-​ACVC acute cardiovascular care simulation should be integrated throughout training in acute cardiovascular care.
curriculum  7 To measure specific and overall achievement in competencies, different and com-
The American College of Cardiology plementary tools are available. Diffusion of the certification process, like the one
COCATS 4-​TF 13  8 provided by the ESC-​ACVC, is important for acute cardiovascular care to be rec-
Assessment of competencies  8 ognized as a cardiology subspecialty.
Certification in acute cardiovascular care  9
Personal perspective  9
References  10

Introduction
Acute cardiovascular care is now a well-​defined, complex field. A typical ICCU is a col-
laboratively managed multidisciplinary unit, admitting a wide range of patients with
acute cardiovascular conditions and comorbidities [1–​3]. Acute cardiovascular con-
ditions managed in ICCUs, such as acute heart failure (AHF) or ACS, are most often
the acute expression of a CVD that will require long-​term follow-​up in a specialized
cardiovascular setting. In addition to managing patients’ immediate presenting clin-
ical issues and prevention of adverse events (AEs), ICCUs should contribute to the
initiation of secondary prevention strategies. Care requirement for a given patient is a
dynamic process that may change rapidly, depending on the success or failure of ini-
tial management strategies. Many cardiologists working in ICCUs have gained ex-
pertise and skills over time with experiential learning. Some have relevant additional
training in other subspecialties of cardiology, in general critical care, or in acute car-
diac care. As with other critical care specialties [4]‌, there is evidence that a specialized
environment for the initial management of acutely ill cardiovascular patients is re-
lated to better in-​hospital and long-​term outcomes [5–​7]. Therefore, patients deserve
6 CHAPTER 2   Train ing and certif ication i n  i n ten si ve a n d acu te ca rdi ovas cu l a r  ca re

to be managed by appropriately trained physicians in the spe- Beyond a common basis that provides the minimal expertise
cialty, and beyond their general cardiology education, physicians needed to manage level 1 patients and work in level I ICCUs, add-
working in an ICCU must have specific training in acute cardio- itional training will allow for additional expertise and technical
vascular care [7]. skills to care for more demanding acute cardiovascular patients
Cardiovascular societies should provide curricula that set managed in higher-​level ICCUs [8–​12].
standards for training in acute cardiovascular care. Providing
frameworks for certification is also of importance for acute First step
cardiovascular care to evolve as a subspecialty of cardiology. The first step (Step 1) refers to the essentials in acute cardiovascular
care that should be common to all cardiologists. There is the need
of a common basis in knowledge and skills in acute cardiovascular
Training in acute cardiovascular care care shared by all cardiologists. It enables them to approach the
critically ill cardiac patient in a systematic fashion, understand the
Training in acute cardiovascular care should provide cardio-
range of acute cardiovascular conditions and therapeutic options,
logists the appropriate knowledge and technical skills for man-
and ensure appropriate referral is made where required. Therefore,
aging confidently acute cardiovascular patients. In line with
this level of training should be done during the fellowship, as is
intensive care societies, the ESC has recently proposed a grading
advocated in the ESC general cardiology CC and the American
of ICCUs in three levels, according to the monitoring and care
College of Cardiology Core Cardiovascular Training Statement 4
requirements of the patients they manage [8]‌. The three levels are
by Task Force 13 (COCATS 4-​TF 13).
presented in E Table 2.1.
Not all physicians will have to master the techniques required
Second step
to work in the most demanding ICCUs. A  one-​size-​fits-​all ap-
proach is not adapted to the challenges of training in acute car- This second step (Step 2) will provide for specific expertise in ad-
diovascular care. Expertise and technical skills should match vanced acute cardiovascular care. This level of training should be
the ICCU gradation. A  stepwise approach in training is more sanctioned by a qualifying examination that measures specific
appropriate. It should encompass the full spectra of expertise knowledge, skills, and competence. It supposes additional training
needed to manage acute cardiovascular patients for a given level after a fellowship, especially in some aspects of critical care. The
of ICCU, as well as accompany the cardiologist during all his/her full ESC-​ACVC CC, complete with the practical assessment, fulfils
professional life. this prerequisite [13]. Some university diplomas also do.
For the sake of clarity and effectiveness, in line with the
available curricula, training materials, and ICCU organiza- Third step
tion, training in acute cardiovascular care will be presented The third step (Step 3) draws as much from acute cardiology as
following a three-​step approach, each step with increasing ex- from critical care [7]‌. It focuses on complete autonomy and ad-
pertise. E Table 2.2 presents technical competencies for each vanced expertise in specific fields, i.e. ventilator management,
step. This approach is a little arbitrary because the actual level multiorgan dysfunction management, end-​of-​life care (EoLC),
of acuity and risk of a patient is not always known immediately. and assist devices. This level of expertise might be reached
Moreover, the response to initial treatment might dramatic- through advanced training in acute cardiovascular care and
ally change the expertise needed for managing an acute clinical additional education in critical care on top of what is already
condition. required in Step 2 [8–​10, 14].

Table 2.1  Level of intensive cardiac care units according to the ESC

Level I ◆ Level I ICCUs are designed to manage patients with cardiovascular conditions demanding level 1 care, i.e. cardiovascular conditions requiring
careful cardiac rhythm and non-​invasive haemodynamic monitoring, as well as some specific treatments (vasoactive drugs, non-​invasive bi-​level
positive airway pressure or continuous positive airway pressure, chest tube insertion, and monitoring)
These units mainly focus on the care of patients with ACS, congestive heart failure without shock (or rapidly improving patients with low cardiac
◆
output), or complex, not life-​threatening arrhythmias. These units may also offer specific monitoring to patients post-​structural and endovascular
interventions
Level II Level
◆ II ICCUs are designed to manage level 1 and level 2 patients
◆ Level 2 patients refers to those with acute cardiovascular conditions whose risk requires central venous access and/​or an arterial line for
monitoring central venous pressure and arterial pressure, respectively, and/​or sampling of central venous or arterial blood, as well as continuous
infusion of multiple cardioactive drugs (because of low cardiovascular output or compromised organ perfusion)
Additional relevant interventions considered as level 2 include temporary transvenous pacing, percutaneous cardiac assist device (intra-​aortic
◆
balloon pump or percutaneous axial pump), and pericardiocentesis. Level II ICCUs should provide initial evaluation and management of severe or
high-​risk patients with congestive heart failure and/​or low cardiac output complicating acute or chronic cardiac conditions
Level III ◆ Level III ICCUs are designed to care for level 3 patients who have acute cardiac conditions that are severe enough to require, or be at high risk of
needing, invasive mechanical ventilation, renal replacement therapy, extracorporeal life support, emergent heart surgery, or surgical cardiovascular
assistance
Source data from Bonnefoy-​Cudraz E, Bueno H, Casella G, et al. Editor’s Choice—​Acute Cardiovascular Care Association Position Paper on Intensive Cardiovascular Care Units: An
update on their definition, structure, organisation and function. Eur Heart J Acute Cardiovasc Care 2018;7(1):80–​95. doi:10.1177/​2048872617724269.
 The ES C- ACVC acu te ca rdi ovas cu l a r ca re c urri c ulum 7

Table 2.2  Techniques with expected full competency according to training step

Step 1 training Step 2 training Step 3 training

All non-​invasive clinical parameter monitoring
◆ All invasive haemodynamic monitoring
◆ Extracorporeal life support
◆
24/​7 echocardiography and thoracic ultrasound
◆ Ultrasound-​guided central venous line insertion
◆ Mechanical circulatory support expertise (left
◆
Direct current cardioversion
◆ Pericardiocentesis
◆ ventricular assist device, biventricular ventricular
Non-​invasive ventilation
◆ Transvenous temporary pacing
◆ assist device)
Transcutaneous temporary pacing
◆ Transoesophageal echocardiography
◆ Renal replacement therapy
◆
Chest tubes
◆ Pulmonary artery catheterization/​right heart
◆ Mechanical ventilation
◆
catheterization
Percutaneous circulatory support (intra-​aortic
◆
balloon pump, Impella®)
Targeted temperature management
◆

Curricula in acute cardiovascular care that create a realistic environment—​are now well defined and be-
coming largely available [20, 21]. Beyond procedural skills, there
The ESC and American College of Cardiology provide curricula
is strong evidence that simulation is effective in teaching commu-
on Step 1 training in acute cardiovascular care [12,  13]. These
nication and teamworking skills that are so important in acute
curricula use a well-​defined, competency-​based framework that
cardiovascular care [22].
comprehensively describes individual aspects of training in the
Simulation-​based training and education should be integrated
subspecialty and presents the requirements for training institu-
throughout the acute cardiovascular care programme and must
tions and trainers. The ESC-​ACVC presents a specific curriculum
be consistent with the curriculum vision and end-​of-​programme
for Step 2 training in acute cardiovascular care that is associated
outcomes [23]. Therefore, it is important to review the end-​of-​
with a certification process and defines the minimum require-
programme outcomes and map the simulation courses to the curric-
ments to qualify as a cardiovascular intensivist.
ulum. This allows for simulation training to coincide with the level
of the learner and to precisely determine how the simulation courses
are expected to contribute to the overall development of trainees
Competency-​based training graduating from the acute cardiovascular care curriculum [21].
Training in acute cardiovascular care is well suited for competency-​
based curricula [15]. Competency-​based education states that a
trainee is ready to graduate from the training programme only after Acute cardiovascular care EPA
mastering the knowledge (core competencies) and specific skills (or in the ESC core curriculum for the
actions, decisions, and activities) called ‘entrustable professional
activities’, or EPAs, of a specialty [16, 17]. In theory, a curriculum general cardiologist
based on learning objectives permits flexibility in the duration of A general cardiologist should be able to work and take night-​time
training, allowing for personalized and/​or adjusted training path- duties in a level I ICCU. Training in acute cardiovascular care of such
ways. Competency-​based curricula allow to insert competencies a physician is described in the Acute Cardiovascular Care section
drawn from curricula of other specialties. This is of interest in acute of the ESC General Cardiology Core Curriculum. It consists in the
cardiovascular care where many fields imply cross-​sectional know- following EPAs:
ledge and multidisciplinary collaboration [18]. As EPAs are observ-
◆ Managing pharmacologic agents.
able and measurable, this allows formal and objective assessment.
◆ Advanced diagnostic and therapeutic techniques in the ICCU.
However, this training model is demanding. It requires gen-
erating a comprehensive list of EPAs, disciplined and rigorous ◆ Acute complications of chronic cardiac conditions and patients
with complications of invasive cardiovascular procedures.
assessment/​self-​assessment, and potentially difficult and compre-
hensive evaluation by the faculty. EPAs can be relatively difficult ◆ Cardiac patients in the context of critical illness and organ
to define and even more difficult to assess. That is why it might dysfunction.
be interesting to base this training on available training materials ◆ Patients with haemodynamic instability and shock.
like the ones provided by the ESC-​ACVC. It also emphasizes multidisciplinary teamwork skills and coord-
ination of care in the ICCU, as well as participating in decision-​
making and end-​of-​life issues.
Simulation for training in acute
cardiovascular care
The ESC-​ACVC acute cardiovascular
Clinical hours can be substituted, in part, with simulation [19].
The simulation world has expanded. Components of a successful
care curriculum
simulation programme—​faculty members trained in simulation The ESC-​ACVC curriculum concerns primarily cardiologists who
pedagogy, experts providing debriefing, and simulation settings have already completed advanced training in cardiology to the
8 CHAPTER 2   Train ing and certif ication i n  i n ten si ve a n d acu te ca rdi ovas cu l a r  ca re

level required for certification as a cardiologist at a national level. Specialties (ABMS). This allows for consistencies between training
It is relevant to those board-​certified or country-​recognized cardi- for acute cardiovascular care and other training recommendations
ologists who wish to be certified in acute cardiac care. Therefore, provided by the American College of Cardiology. These general
it is Steps 2 to 3 training that presents the range of knowledge, competencies are:  (1) medical knowledge; (2)  patient care and
skills, behaviours, and attitudes required to independently manage procedural skills; (3)  practice-​based learning and improvement;
cardiovascular emergencies and critically ill cardiac patients and (4) systems-​based practice; (5) interpersonal and communication
their comorbidities in level II and level III ICCUs. It emphasizes skills; and (6) professionalism (see E Box 2.1) [25].
the importance of a step-​up and step-​down strategy from the ICCU For each competency and domain, the document provides
and teamworking. Beyond recommendations for training of those milestones with the stage of fellowship training by which a trainee
intending to be expert in acute cardiac care, it provides a framework should achieve the designated level. Contrary to the ESC-​ACVC
for continuing education of those already practising in the area. curriculum, there are no specific guidelines for advanced training
The ESC-​ACVC curriculum is divided into around 20 acute in acute cardiovascular care beyond suggesting an additional
cardiovascular critical care topics. Each topic presents a list 3–​6 months of clinical training within the 3-​year cardiovascular
of objectives, knowledge, skills, behaviour, and attitude. The medicine fellowship.
curriculum is closely related to ESC teaching resources. The
ESC-​ACVC’s ESC Textbook of Intensive and Acute Cardiovascular
Care maps the knowledge, skills, and professional domains of the Assessment of competencies
subspecialty. Therefore, it is at the core of the theoretical know-
ledge required in the curriculum. Other learning tools available For the practical part of the training, there is a consensus that
for training are the current ESC guidelines, the ESCeL pro- learning outcomes are preferred to recommendations based
gramme, and other teaching materials from the different and rele- solely on the amount of time spent in a department and/​or
vant associations and working groups of the ESC. on the number of procedures performed [24]. In Europe,
The ESC-​ACVC curriculum puts special emphasis on practical practical training in acute cardiovascular care also depends
training. Beyond a precise description of skills and behaviours, it upon the training pathways in cardiology already in place
asks for rotations in specific environments that will provide a car- throughout the ESC member states.
diologist with the competencies to work in a level II or III ICCU. As in many medical fields, statements on what is practical com-
The first part covers 9  months in general cardiology training petencies achievement are mainly based on expert experience and
(3 months in general intensive care, 6 months in an ICCU), with opinion [26]. The methods and tools used to assess competency
on-​call/​night-​time/​weekend duties with the equivalent of at least in acute cardiovascular care training are in line with those recom-
1 night per week for at least 3 years. This will give the physician mended in acute and critical care [27].
in training the autonomy in managing patients in a level II ICCU. Assessment and validation processes need to be under
Additional training of 12 months post-​residency as a junior at- the control of the programme director or his/​her equivalent
tending physician [6 months in a level II or III ICCU, 6 months [12,  13]. They are responsible for confirming experience and
in a post-​operative cardiovascular intensive care unit (ICU) or
general medical critical care ICU] will allow the physician to be Box 2.1  ACGME core competencies
fully in charge of a level II ICCU and contribute confidently to the
management of patients in a level III ICCU. ◆ Patient care—​that is compassionate, appropriate, and effective
for treating health problems and promoting health
Medical knowledge—​about established and evolving biomed-
◆

ical, clinical, and cognate (e.g. epidemiological and social–​

The American College of Cardiology behavioural) sciences and application of this knowledge to
COCATS 4-​TF 13 patient care
The American College of Cardiology states that the essentials in Practice-​based learning and improvement—​that involve
◆

investigation and evaluation of a fellow’s patient care,

acute cardiovascular care should be integrated in the cardiovascular
self-​appraisal, and assimilation of scientific evidence and im-
disease fellowship training programme [3 years in the United States
provements in patient care
(US)]. The COCATS 4-​TF 13 is a competencies-​based curriculum
Interpersonal and communication skills—​that result in ef-
◆
in acute cardiovascular care that focuses on Step 1 competencies.
fective information exchange and teaming with patients, their
The minimum duration of practical training is 8 weeks in ICCUs
families, and other health professionals
over the course of the first 24 months of training. Many knowledge
Professionalism—​as manifested by a commitment to carrying
◆
and skills relevant to acute cardiovascular care will be acquired
out professional responsibilities, adherence to ethical prin-
through other rotations, especially in electrophysiology, cardiac
ciples, and sensitivity to a diverse patient population
catheterization, imaging, and heart failure. As in most documents
Systems-​based practice—​as manifested by actions that demon-
◆
on training provided by the American College of Cardiology [24],
strate an awareness of, and a responsiveness to, the larger con-
training in acute cardiovascular care addresses the six general com-
text and system of health care and the ability to effectively call
petencies promulgated by the Accreditation Council for Graduate
on system resources to provide care that is of optimal value
Medical Education (ACGME)/​ American Board of Medical
 Per s ona l  pe r spe c t i v e 9

The full ESC-​ACVC certification process provides an example of

Box 2.2 Evaluation tools
a Step 2 certification in acute cardiovascular care. Certification con-
Direct observation by instructors
◆ sists of two parts: (1) demonstration of theoretical knowledge; and
In-​training examinations
◆ (2) demonstration of competence. The first part is validated through
Case logbooks
◆ an MCQ-​based exam. The second part, which is demonstration of
Conferences
◆ competence, is validated through a logbook confirming the pro-
Case presentations
◆ cedures undertaken and countersigned by the trainee’s educational
Multisource evaluations
◆
supervisor (or equivalent) to confirm they have met the required
levels of competence. It should also show that the required training
Trainee portfolios
◆
programme (9 or 21 months) has been undertaken and evidence of
Simulation
◆
ongoing training and assessment during the training period. The
whole certification is presented in detail [30]. The ESC-​ACVC certi-
fication is prestigious and, in some cases, nationally recognized. That
competence and for reviewing the overall progress of individual it does not yet confer recognized additional privilege is mainly related
trainees. The clearer and more precise the process, the easier it to the absence of a recognized acute cardiovascular care subspecialty
will be for the programme director to assume this role. Defining in most European countries. The ESC-​ACVC certification provides
representative curricular milestones during training will help in important standards of knowledge and skills in acute cardiovascular
identifying trainees and areas that require additional focused care and a clear roadmap to reach these standards. Such standards
attention. should help national cardiology societies to promote training and
Most curricula state that trainees should maintain records of education in acute cardiovascular care, thereby improving the quality
participation and advancement in the form of a logbook that of care and outcomes of patients with acute CVD.
summarizes predefined pertinent information. Some evaluation Level III ICCUs are highly specialized cardiovascular critical care
tools that may be part of this logbook are presented in E Box 2.2. units. Physicians managing patients in such environments should
Competency to perform procedures should be based on evalu- demonstrate advanced expertise in acute cardiovascular care, as well
ation by a supervising physician [28]. as competencies in critical care. There is evidence that these specific
There are some controversies on the need of defining the competencies improve patient care [5]‌. Provided full practical training
number of procedures required to achieve technical competen- (21  months) has been validated, the ESC-​ACVC certification is the
cies [12, 13, 24]. The number of procedures performed (as well as nearest to Step 3 training, drawing from both critical care and acute
the length of exposure) are uncertain proxies of proficiency and cardiovascular care. Other options are available at national levels. Some
outcome. When they exist, these numbers are based on consensus universities provide a diploma after validating the specific training in
about the educational needs and progress of typical trainees and acute cardiovascular care they organize [11]. A  dual certification in
are intended as general guidance, not absolute thresholds. In cardiology and critical care is possible in some European countries and
some cases (e.g. central venous access, echocardiography), more the US [9, 10, 14, 31, 32]. The training consists of a full curriculum in
robust evidence exists [29]. cardiology and at least 12 additional months in critical care, allowing
Procedural volume targets are not provided by the American the certification process of both specialties to be validated.
College of Cardiology, but it suggests anyway the completion of
a logbook. The ESC-​ACVC curriculum does not provide specific
numbers either but suggests the numbers of procedures are made Personal perspective
available for those preparing for the acute cardiovascular care cer-
tification exam as a guidance. ◆ How many physicians will be willing to focus their prac-
tice in this field, and will it justify the development and
multiplication of national programmes?
Certification in acute ◆ Moreover, there is a large gender disparity in this field
(only 3.3% of dual-​certified critical care cardiologists
cardiovascular care are women) [7]‌. It has been suggested that improved
Ideally, any curriculum in acute cardiovascular care should lead mentorship for women considering critical care cardi-
to a process of formal certification. ology and ongoing diversity task force implementation
Step 1 training that is part of the fellowship, as with the will aid in closing the gender gap [7, 33].
COCATS 4-​TF 13 curriculum or the ESC general cardiology CC, Lifelong education in acute cardiovascular care.
◆

does not suppose formal dedicated certification.

10 CHAPTER 2   Train ing and certif ication i n  i n ten si ve a n d acu te ca rdi ovas cu l a r  ca re

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4. Wilcox ME, Chong CAKY, Niven DJ, et al. Do intensivist staffing pat- Care Med 2016;42:147–​63.
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5. Na SJ, Chung CR, Jeon K, et al. Association between presence of a benefits? Trends Cardiovasc Med 2017;27:163–​70.
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 CHAPTER 3

Intensive cardiovascular
care units: structure,
organization, and staffing
Eric Bonnefoy-Cudraz and Tom Quinn

Contents
Summary  11 Summary
Introduction  11 The nature and complexity of acute cardiovascular care have changed markedly
Grading of the level of acute cardiovascular since the early days of the coronary care unit, introduced in the 1960s to prevent
care  12
and treat life-​threatening arrhythmias associated with acute myocardial infarction.
The three levels of ICCU  12 In the present day, the patient population is older and has more multimorbidity,
Level I ICCU (first level; enhanced
cardiovascular care units)  17 which comprises a range of conditions, alongside critical cardiovascular disease,
Level II ICCU (intermediate; cardiovascular and associated multiple organ failure, requiring increasingly sophisticated man-
high dependency units)  17 agement. To reflect this, the Association for Acute CardioVascular Care of the
Level III ICCU (highest level; cardiovascular
critical care units)  17 European Society of Cardiology published a comprehensive update of recom-
Structure and equipment  17 mendations in 2018, developed by a multinational working group of experts. These
Level I ICCU  17 recommendations, which inform this chapter, address the definition, structure, or-
Level II ICCU  19
Level III ICCU  19
ganization, and function of the contemporary intensive cardiovascular care unit
Premises  19 (ICCU).
Number of beds  19 Reflecting the modern case mix, three levels of acuity of care are described and the
Clinical governance and continuous corresponding requirements for ICCU organization defined. Recommendations
improvement  19 on ICCU staffing (medical, nursing, and allied professions), equipment, and archi-
The ICCU team  19 tecture are presented, alongside considerations of the role of the ICCU within the
Nurses and advanced nurse wider hospital and cardiovascular care network.
practitioners  20
ICCU medical staff and cardiovascular
intensivists  20
On-​duty physicians  20
Interaction with other specialties  20
ICCU—​part of a regional network  21 Introduction
Telemedicine  21 ICCUs are physically and administratively identified hospital units dedicated to, and
Personal perspective  21 specialized in, the management of acute cardiovascular conditions. They serve as the
References  23 primary site of care in that hospital for patients with these conditions [1, 2]. They have a
well-​defined organizational model, providing 24/​7 expertise in acute cardiovascular care,
in close cooperation with cardiovascular and non-​cardiovascular specialties both in and
out of the hospital.
12 CHAPTER 3   In ten sive cardiovascu l ar ca re u n i ts :  stru ctu re, org a n i z ati on , a n d  sta f f i n g

The traditional CCU has largely disappeared. Nowadays, an mortality rate and hospital length of stay [13,  14]. In addition,
ICCU delivers acute cardiovascular care in a wide variety of acute it enhances the networking between tertiary/​university and dis-
cardiovascular conditions [3,  4]. These conditions rarely exist trict/​
community hospitals and associated emergency medical
alone but are complicated by additional acute or chronic non-​ services, facilitating an efficient use of resources [15].
cardiovascular comorbidities in the context of a rapidly changing Applying this process to acute cardiovascular care has the full
demographic with increasing numbers of elderly patients. spectrum of acute cardiovascular conditions classified according
There is evidence that a specialized cardiovascular environ- to risk and levels of care required. The Association for Acute
ment for the initial management of cardiovascular patients is CardioVascular Care (ACVC) of the ESC has suggested a strati-
closely related to in-​hospital and long-​term patient follow-​up fication into three levels of care [16]. Level 1 refers to patients
and outcome [5–​7]. Many acute cardiovascular conditions, such with acute cardiovascular pathologies whose needs cannot be met
as AHF or ACS, are the acute expression of a CVD that will through care provided by a general cardiology ward because they
require long-​ term follow-​ up in a specialized cardiovascular are at risk of their condition deteriorating, demand special ex-
setting. pertise or additional facilities, or need a higher level of observa-
A one-​ size-​
fits-​
all-​
ICCU organizational model is not rele- tion. Level 2 refers to patients who require advanced observation
vant. Even if all ICCUs were to have specific technical capabil- and monitoring or treatment. Lastly, level 3 refers to patients with
ities and specialized medical/​ nursing and allied professional acute cardiovascular conditions commanding a level of care or
staff, all ICCUs will not have to manage the full range of acute intervention that is equivalent to critical care.
cardiovascular conditions. Further, organizational models will E Table 3.1 presents the monitoring and techniques, the re-
also depend on external factors like the type of hospital (large, quirement of which for managing a patient contributes to the
tertiary, and/​or university versus community hospitals) and his- grading of his/​her acute cardiovascular condition. E Table 3.2
torical and regulatory constraints. presents the classification of common acute cardiovascular
conditions.
Of note, care requirement for a given patient is a dynamic pro-
Grading of the level of acute cess that may change rapidly, depending on the success or failure
of initial management strategies. A favourable response to initial
cardiovascular care treatment will allow stabilization and rapid improvement of the
Acute cardiovascular patients will present with different levels of clinical condition. If not, demand in care may rapidly increase to
acuity and requirements for care [3, 4, 8, 9]. The level of care (in much higher levels than those initially provided or to institution
terms of nurses, physicians, allied professionals, techniques, and of palliative care or EoLC where appropriate.
environment) to manage a given acute cardiovascular condition
may be defined and graded. This grading system was originally
developed for trauma centres and then extended to most spe-
cialties of critical care [10–​12]. In this setting, it contributes to
The three levels of ICCU
a better understanding of patient management, a more efficient The level of an ICCU is directly related to its case mix, i.e. the
allocation of resources, and improvements in outcome, including levels of acuity and requirements for care of the most severe

Table 3.1  Techniques which contribute to defining the level of care for acute cardiovascular conditions

Level 1 acute cardiovascular conditions Level 2 acute cardiovascular conditions Level 3 acute cardiovascular conditions
◆ Need for continuous observation based on ◆ Need for central venous line for monitoring of Need for invasive mechanical ventilator support
◆
clinical condition central venous pressure Need for RRT for acute condition
◆
Need for observation because of serious risk of
◆ Need for arterial line for monitoring arterial
◆ Need for TTM
◆
aspiration pneumonia pressure and/​or sampling of arterial blood Need for surgically implanted mechanical
◆
Need for continuous O2 therapy because of
◆ Need for central venous access:
◆ circulatory support
clinical hypoxaemia To deliver titrated fluids to treat hypovolaemia
● Need for ECLS
◆
Need for frequent daily respiratory
◆
For boluses or continuous infusion of IV drugs
●
physiotherapy to treat/​prevent respiratory failure Need for single IV vasoactive drug to support or
◆
Need for bi-​level positive airway pressure or
◆
control arterial pressure, cardiovascular output, or
continuous positive airway pressure (CPAP) organ perfusion
Need for chest drain monitoring
◆
Need for temporary cardiovascular pacemaker
◆
Need for intravenous (IV) rhythm-​controlling
◆
Need for percutaneous cardiac assist device (e.g.
◆
drug(s) to support or control supraventricular IABP, axial pumps)
arrhythmias Need for pericardiocentesis or myocardial biopsies
◆
Table 3.2  Grading the demand of care for some common acute cardiovascular diseases
Overall Specific Specific Specific Non-​invasive Central Arterial Clinical NIV or Invasive Central IV Percutaneous ECLS IV rhythm Temporary OTHER
demand in monitoring: monitoring: monitoring: haemo­ venous line hypoxaemia CPAP mechanical venous vasoactive cardiac assist controlling pacemaker
care low risk intermediate high risk dynamic line for requiring ventilator access for drugs device (e.g. drug(s)/​
risk monitoring CVP continuous support continuous IABP, axial cardioversion
O2 infusion of pumps)
drugs
ACUTE CONDITIONS acting as modifier
AHF with Level 2 RRT
hypoperfusion as
dominant clinical
expression
AHF with venous Level 1
congestion as
dominant clinical
expression
Acute renal failure Level 2 RRT
with oliguria
Condition Level 2
(e.g. sepsis, RV
dysfunction)
requiring IV
vasopressor
Acute pulmonary Level 2
oedema with low
arterial pressure
CS Level 3 RRT
Cardiac arrest with Level 3 Hypothermia
coma
Ventricular Level 1
tachyarrhythmia
with no
haemodynamic
complication
Cardiac Level 2
arrhythmias with
heart failure
VT/​VF electrical Level 3
storm
ACUTE CORONARY SYNDROME
Uncomplicated Level 1
STEMI after initial
cath lab admission
and successful
reperfusion

(continued )
Table 3.2 Continued

Overall Specific Specific Specific Non-​invasive Central Arterial Clinical NIV or Invasive Central IV Percutaneous ECLS IV rhythm Temporary OTHER
demand in monitoring: monitoring: monitoring: haemo­ venous line hypoxaemia CPAP mechanical venous vasoactive cardiac assist controlling pacemaker
care low risk intermediate high risk dynamic line for requiring ventilator access for drugs device (e.g. drug(s)/​
risk monitoring CVP continuous support continuous IABP, axial cardioversion
O2 infusion of pumps)
drugs

Uncomplicated-​ Level 1
type NSTEMI
before transfer to
the cath lab
NSTEMI type 2—​ Level 1
no complication
Ischaemic Level 2
complication
of PCI
Acute ST-​segment Level 2
elevation AMI,
with no or
unsuccessful
reperfusion
High-​risk NSTEMI Level 2
before PCI
NSTEMI/​STEMI Level 2
complicated by
congestive heart
failure—​no shock
ACUTE CARDIOVASCULAR PATHOLOGIES
AHF with Level 1
pulmonary
oedema and high
systolic arterial
pressure
Third-​degree AVB Level 1
with heart failure
AF or Level 1
supraventricular
arrhythmias with
heart failure
Myopericarditis—​ Level 1
uncomplicated
Myocarditis Level 1
or peripartum
cardiomyopathy,
with no/​minimal
EF alteration
Peripartum MCP Level 2
or myocarditis with
reduced EF with no
symptoms of AHF
Primary pulmonary Level 2
hypertension with
right heart failure
PE—​not high risk Level 1
High-​risk PE at Level 2
risk of or requiring
thrombolysis
Heart transplant Level 3
patient with
suspected acute
rejection and LV
dysfunction
Free wall rupture Level 3
after MI
Non-​complicated Level 2
type B dissection
Type A aortic Level 3
dissection
Cardiac Level 2 Pericardiocentesis
tamponade
Prosthetic valve Level 3
thrombosis
without heart
failure
Acute endocarditis Level 3
with heart failure
Acute aortic Level 3
regurgitation with
heart failure
Mitral stenosis—​ Level 1
complicated
Aortic stenosis Level 2
with heart
failure—​initial
management
Acute mitral Level 2
regurgitation with
heart failure—​
initial management

(continued )
Table 3.2 Continued

Overall Specific Specific Specific Non-​invasive Central Arterial Clinical NIV or Invasive Central IV Percutaneous ECLS IV rhythm Temporary OTHER
demand in monitoring: monitoring: monitoring: haemo­ venous line hypoxaemia CPAP mechanical venous vasoactive cardiac assist controlling pacemaker
care low risk intermediate high risk dynamic line for requiring ventilator access for drugs device (e.g. drug(s)/​
risk monitoring CVP continuous support continuous IABP, axial cardioversion
O2 infusion of pumps)
drugs

All conditions Level 3

considered as
level 2 care
that does not
respond rapidly to
treatment, stabilize,
or improve
Patients with Level 1
post-​structural
or endovascular
interventions

AF, atrial fibrillation; AHF, acute heart failure; AMI, acute myocardial infarction; AVB, atrioventricular block; CPAP, continuous positive airway pressure; CS, cardiogenic shock; CVP, central venous pressure; ECLS, extracorporeal life support; EF,
ejection fraction; IABP, intra-​aortic balloon pump; IV, intravenous; LV, left ventricular; MI, myocardial infarction; NIV, non-invasive ventilation; NSTEMI, non-​ST-​segment elevation myocardial infarction; PCI, percutaneous coronary intervention; PE,
pulmonary embolism; RRT, renal replacement therapy; RV, right ventricular; STEMI, ST-​segment elevation myocardial infarction; VF, ventricular fibrillation; VT, ventricular tachycardia.
 Stru ctu re a n d   e qui p m e n t 17

patients it commonly manages (see E Figure 3.1). Most recent cardiac conditions. Level II ICCUs require immediate access to
position papers present three levels of ICCU, each implying a dif- a 24/​7 coronary interventional catheter laboratory. With round-​
ferent organization [16–​19]. the-​clock service for PCI, level II ICCUs will usually form the hub
The level and organization of an ICCU will be linked to the of a STEMI network. A general critical care unit must be present
structure and range of services provided by the host hospital. on the same site as the ICCU, and intensivists should be available
However, there is no obligatory relationship between the level of 24/​7 for consultation, co-​management of complex patients, and
an ICCU and the overall capabilities of the hospital. Beyond hos- urgent support [10].
pital size and technical capabilities, many parameters will con-
tribute to the case mix of an ICCU:  geographical distribution; Level III ICCU (highest level; cardiovascular
history of acute cardiovascular care development; and interaction critical care units)
with other specialties such as general critical care, cardiothoracic Level III ICCUs are designed to care for level 3 patients who have
intensive care, internal medicine, and emergency medicine. acute cardiac conditions that are severe enough to require, or be
at high risk of requiring, invasive mechanical ventilation, RRT,
Level I ICCU (first level; enhanced ECLS, emergency cardiac surgery, or surgical cardiovascular
cardiovascular care units) assistance.
Level I  ICCUs are designed to manage patients with cardio-
vascular conditions demanding level 1 care. They mainly focus
on the care of patients with ACS, congestive heart failure without Structure and equipment
shock (or rapidly improving patients with low cardiac output), or
complex, not life-​threatening arrhythmias. A  level I  ICCU will Whatever the functional organization of a hospital, ICCUs have
offer specialized cardiovascular care in different hospital settings. the responsibility to provide services and personnel that ensure
In community hospitals, they will offer first-​line management of optimal patient care according to their case mix and level. There
many acute cardiovascular conditions. In hospitals with higher is a large consensus among recommendation and position papers
technical capabilities, level I ICCUs may also admit patients fol- that all ICCUs must have appropriate diagnostic facilities avail-
lowing PCI for ACS or post-​structural or endovascular interven- able to inform delivery of pharmacological and invasive treat-
tions. They might act as step-​down units for level II or III ICCUs, ment according to the current guidelines [16–​19]. A summary of
sharing management and resources. suggested equipment is presented in E Tables  3.3 and 3.4. All
equipment must conform to the relevant safety standards and
Level II ICCU (intermediate; cardiovascular be regularly serviced. All staff members must be appropriately
high dependency units) trained, competent, and familiar with the use of equipment [10].
Level II ICCUs are designed to manage level 1 and level 2 pa-
tients. Level II ICCUs should provide initial evaluation and man- Level I ICCU
agement of severely ill or high-​risk patients with congestive heart A level I  ICCU will be fully equipped for the needs of level 1
failure and/​or low cardiac output complicating acute or chronic patients. Accordingly, level I  ICCUs should provide all types

Acute cardiac care

Intensity of care

Prehospital
care
Acute cardiovascular pathologies
→ demand in intensive care
Non-intensive cardiovascular
care Level 1 Level 2 Level 3

Case mix,
hospital type, capability, and
organization

Intensive cardiovascular care units

Cardiology ward
Levels I to III

Figure 3.1  From demand in care for acute cardiac conditions to the level of ICCUs. All ICCUs provide a higher degree of care in relation to other cardiology
units up to a telemetry cardiovascular ward. The grade of intensive cardiovascular care refers to both the quantity and expertise of medical and paramedical
care being provided for management of a given cardiovascular condition. A given ICCU will present a case mix of acute cardiovascular patients with conditions
needing different intensities of care. The level of expertise and technical requirements of an ICCU will depend on this case mix, along with external factors,
mainly the hospital’s type, capability, and organization.
18 CHAPTER 3   In ten sive cardiovascu l ar ca re u n i ts :  stru ctu re, org a n i z ati on , a n d  sta f f i n g

Table 3.3  Levels of ICCUs: technical capabilities and expertise of the ICCU and its hospital

Technical capabilities and expertise of the ICCU

Level I ICCU: basic cardiovascular intensive Level II ICCU: advanced cardiovascular Level III ICCU: cardiovascular critical care
care intensive care
All non-​invasive clinical parameter monitoring
◆ As in level I ICCU, plus: As in level II ICCU, plus:
24/​7 echocardiography and thoracic ultrasound
◆ Ultrasound-​guided central venous line insertion
◆ ECLS
◆
Direct current cardioversion
◆ Pericardiocentesis
◆ Mechanical circulatory support expertise (LVAD,
◆
NIV
◆ Transvenous temporary pacing
◆ bi-ventricular assist device)
Transcutaneous temporary pacing
◆ Transoesophageal echocardiography
◆ RRT
◆
Chest tubes
◆ Pulmonary artery catheterization/​right heart
◆ Mechanical ventilation
◆
Nutrition support
◆ catheterization
Physiotherapy on ward
◆ Percutaneous circulatory support (IABP, Impella®)
◆
TTM (in many centres)
◆

Technical capabilities and expertise that should be available in hospital

Level I ICCU Level II ICCU Level III ICCU
ED
◆ As in level I ICCU, plus: As in level II ICCU, plus:
CT scanner
◆ 24/​7  PCI
◆ Comprehensive cardiovascular surgery
◆
Transoesophageal echocardiography
◆ Pacing and cardiovascular resynchronization
◆ (coronary artery bypass graft surgery; surgical
Palliative care programme
◆ therapy programme management of acute disorder of the aorta,
Ultrasound-​guided central venous line insertion
◆ Implantable cardioverter–​defibrillator
◆ valves, and any other cardiovascular structure)
X-​ray system for fluoroscopy in the vicinity of
◆ programme Interventional vascular radiology, including
◆
the unit Ablation therapy programme
◆ expertise in complicated aortic dissection,
24/​7 chest radiographs
◆ Renal support therapy
◆ embolization, and neuro-​interventional
24/​7 computerized tomography angiography
◆ Cardiovascular magnetic resonance
◆ radiology
24/​7 blood gas analysis
◆ Post-​cardiovascular arrest treatment
◆ Any percutaneous structural heart intervention,
◆
24/​7 biomarkers: ACS
◆ Neuromonitoring for prognostic evaluation
◆ valvuloplasty, and transcatheter aortic valve
24/​7 biomarkers: AHF
◆ Endomyocardial biopsy
◆ implantation
24/​7 biomarkers: coagulation and thrombosis
◆ Donor organ and transplantation programme
◆
24/​7 biomarkers: renal and hepatic function/​
◆
failure

Table 3.4  Suggested monitoring and equipment according to ICCU level

Level I ICCU Level II ICCU Level III ICCU

At least two ECG channels
◆ Same as level I ICCU, plus: Same as level II ICCU, plus all techniques and
Non-​invasive blood pressure monitor
◆ Additional ECG channels
◆ equipment that place this unit on par with a
At least one invasive pressure channel
◆ Invasive haemodynamic channels
◆ general critical care unit, including:
Pulse oximeters
◆ End-​tidal  CO2
◆ Specific additional monitoring
◆
Electronic prescribing and chart access (advisable)
◆ Non-​invasive cardiovascular output
◆ Haemodialysis/​haemofiltration machine
◆
Nurse station to be used for central monitoring
◆ Non-​invasive thermometers
◆ Mechanical ventilators
◆
of at least one ECG lead from each patient, and Mechanical ventilators
◆ And more specifically:
relevant haemodynamic and respiratory data should Mobile echocardiography machine, including
◆ ECLS
◆
continuously be present on a central screen transoesophageal echocardiography probe, Hypothermia maintenance devices
◆
Slave monitors to enable monitoring of patients from
◆ vascular probe
different sites in the unit At least one echography device for ultrasound
◆
Working stations for retrospective analysis of
◆ guidance for central venous line
index events Percutaneous circulatory assist devices (IABP,
◆
Volumetric pump/​automatic syringes
◆ percutaneous axial pump)
CPAP delivery systems to use with face mask
◆ X-​ray system for fluoroscopy in the unit
◆
At least one mechanical ventilator for the unit with
◆ Haemodialysis/​haemofiltration machine
◆
NIV capacity through the nephrology department
Biphasic defibrillators
◆ (advisable)
At least one external pacemaker for the unit
◆ Hypothermia maintenance devices (advisable)
◆
Temporary VVI pacemakers and at least one DDD for
◆
the unit advisable
Mobile echocardiography machine
◆
Glucose level measurement kits
◆
If blood chemistry tests cannot come back from the
◆
central lab within 5 minutes: blood clot meter (ACT),
blood chemical marker kits, blood gas and electrolyte
analyser, multiparametric blood analyser
 The I C C U  t e a m 19

of non-​invasive monitoring, have the expertise and the means number of beds in an ICCU is not clearly defined either and is
to administer NIV for respiratory failure and inotropes for low often constrained by staffing regulatory requirements. Due to its
cardiovascular output, and provide immediate resuscitation of specific function and staffing, it is reasonable to advise a level II
cardiovascular arrest. ICCU to have at least six beds.
Possible formulae for calculation of level II ICCU beds are [1]‌:
Level II ICCU ◆ For every 100 000 inhabitants: 4–​5 ICCU beds.
All invasive and non-​invasive monitoring should be available in ◆ For every 100 000 visits per year in the ED: ten ICCU beds.
a level II ICCU. Advanced techniques, including invasive venti-
For any ICCU, additional factors to be considered when
lation or institution of percutaneous mechanical circulatory sup-
devising the number of beds required in a hospital include [25]:
port, should be available and staff trained in their use, even if
patients will subsequently be transferred rapidly to a higher-​level ◆ Acute beds in the hospital (medical and surgical).
unit. Percutaneous circulatory support (IABPs, percutaneous ◆ Previously calculated occupancy of wards, high dependency
axial pumps) should be available. In many centres, level II ICCUs units, and critical care units and target occupancy of the ICCU.
will manage patients following resuscitation from cardiac arrest, ◆ History of inability to admit patients due to lack of ICCU capacity.
including provision of targeted temperature management. ◆ Number and location of other high-​care areas in the hospital or
in other hospitals in the surrounding catchment area.
Level III ICCU ◆ Number of on-​site operating theatres.
A level III ICCU should be fully equipped for the needs of level ◆ Presence of specialist services which may require cardiovas-
3 patients. Level III ICCUs should have all forms of invasive and cular support.
non-​invasive monitoring capabilities, as well as invasive venti- ◆ Ability to transfer patients to an off-​site location.
lation and RRT. These units should be able to manage patients
receiving ECLS. Advanced technologies, such as mechanical cir-
culatory assist devices, should also be available. Clinical governance and continuous
Level III ICCUs require a hospital environment that pro-
vides specific and highly specialized professionals required at
improvement
times for the support of patients with advanced and severe acute ICCUs must operate within established frameworks for clinical
cardiovascular conditions. Immediate access to interventional governance that comply with local, regional, and national re-
cardiology, anaesthesiology, and cardiovascular surgical support quirements [26]. Within each unit, a lead for clinical governance
is required. and quality improvement should be designated. Uniform proto-
cols and processes may reduce mortality and are recommended
[27, 28]. An audit programme, including assessment of compli-
Premises ance with guidelines (local, national, international) and quality
indicators (e.g. out-​of-​hours transfer, readmission, morbidity, and
Recent documents in cardiology [1, 20] and general critical care mortality versus risk stratification, nosocomial infection rates),
[21–​24] provide detailed information on the specific design and should be implemented. Data collection on bed occupancy, diag-
engineering requirements applicable to level II or III ICCUs. Some nosis, mortality, and morbidity is recommended. Measurement
facilities should be provided in all level II ICCUs: single (isola- of additional relevant quality indicators is required, and, where
tion) rooms, a central nurse station, a procedure room with X-​ray possible, data should be submitted to local or national databases
and equipment for invasive monitoring, space for staff facilities, [29,  30] and participation in relevant national or international
including restrooms, catering facilities, changing rooms, en-​suite registries [31] encouraged. Benchmarking against approved
overnight accommodation for on-​call (on-​duty) staff, and edu- standards and outcomes is recommended, as well as participation
cation and training facilities. It is important when designing an in regional/​national critical care networks.
ICCU to anticipate support facilities for relatives and carers and Data collection and clinical governance strategies should be sus-
the patient’s right to privacy and dignity, and strategies for noise tainable, with appropriate administrative and technological sup-
reduction and maximizing natural light. Most countries have spe- port. Institutions should provide the adequate technical means and
cific national standards for ‘high-​end’ ICU provision, to which financing for any ICCU to provide high-​quality clinical governance.
level III ICCUs must comply.

The ICCU team
Number of beds Since the functional level of an ICCU must be tailored to the level
There is no definitive formula for the number of ICCU beds of care of the most demanding or severe patients that it is required
needed in a hospital. It is, of course, important for the number to to manage, so should be the expertise of physicians, nurses, and
be commensurate with the workload and case mix. The minimum allied professionals.
20 CHAPTER 3   In ten sive cardiovascu l ar ca re u n i ts :  stru ctu re, org a n i z ati on , a n d  sta f f i n g

With an organization based on cardiac intensivist-​directed framework for this education. Cardiologists working in ICCUs
care, an ICCU will deliver the best care for acute cardiovascular should at least have the competences required by the CC. Beyond
patients [7]‌. The wider ICCU team comprises a range of allied level I ICCU, all physicians must have specialized skills in critical
professionals, including (but not limited to) respiratory physio- care. To qualify as a cardiovascular intensivist, the ESC-​ACVC
therapists, pharmacists, dietitians, psychologists, cardiac sci- suggests a minimum of 12 months of full-​time training after com-
entists, and perfusionists, alongside physicians from clinical pletion of the core cardiology training.
pharmacology, palliative care, and infectious diseases. All ICCUs should be coordinated by a cardiology director. He/​
The ICCU should be under the full medical responsibility of a she should be appropriately trained and qualified in acute cardio-
dedicated cardiovascular team (closed unit). The situation where vascular care and ICCU management [1, 9].
the non-​ICCU physician admitting the patient retains responsi- According to the ESC-​ACVC, a level I  ICCU should be dir-
bility for orchestrating and implementing care for this patient (open ected and managed by cardiologists and a level 2 ICCU must be
unit) is not compatible with the objectives of a modern ICCU [22, directed and managed by cardiovascular intensivists. In a level
32, 33]. The ICCU team must liaise with patients’ primary phys- 3 ICCU, the director of the unit and the core team of cardiolo-
icians to include them in important discussions such as the appro- gists should all be cardiovascular intensivists. General critical care
priateness of high-​risk procedures and end-​of-​life decisions [2, 17]. physicians working collaboratively with cardiologists can be an
alternative option. For most aspects of staffing and organization,
level III ICCUs should follow the relevant national rules that
apply for general critical care units in their country.
Nurses and advanced nurse There is no clear recommendation for the senior physician or
practitioners consultant-​to-​patient ratio [1, 10]. It is acknowledged, however,
that requirements for senior physicians to provide direct clinical
High-​quality nursing is the cornerstone of acute cardiovascular
care in ICCUs vary greatly, with additional support provided by
care. The nurse:patient ratio and the quality of nurse education
fellows and specialized nurses.
and clinical experience have a direct impact on the quality of pa-
tient outcomes [34–​37].
More specifically, in acute cardiovascular care, the nurses’ ex-
pertise extends also to monitoring rhythm disturbances, evalu- On-​duty physicians
ating the potential for complications, especially after interventional
In any ICCU, continuity of medical cover must be provided 24/​7.
procedures or deterioration, and coordinating the communication
A level I  ICCU should provide round-​the-​clock echocardio-
within the ICCU interdisciplinary team [35–​ 39]. ICCU nurses
graphy and expertise for acute cardiovascular conditions in
should have a specialist post-​ registration qualification in acute
its hospital and the on-​duty physician should have the corres-
cardiovascular care and clinical expertise in this area. The ESC-​
ponding expertise. In a level II ICCU, the on-​duty physician
ACVC recommends advanced nurse practitioners to be part of
should be a cardiovascular intensivist based in the unit. The dir-
the ICCU team. Additional education (Master’s degree or other
ector of the unit may approve provision of night cover by other
postgraduate education) allows them to undertake specialist roles,
cardiologists competent in the emergency techniques required in
which have been associated with improved efficiency and better pa-
a level II ICCU.
tient satisfaction and long-​term outcomes [34, 40].
Night shifts could potentially be covered by fellows or residents
All ICCUs should have a nursing team leader with managerial
trained in acute cardiovascular care and techniques needed for
responsibility (level I ICCU) or a nursing director (level II and III
the corresponding ICCU level. In that case, an attending member
ICCUs).
of the ICCU team must be available on call for senior consult-
Even if there are national regulatory requirements for
ation and assistance [1, 30]. A recent study in general critical care
nurse:patient ratios in different levels of ICCU, the nurse:patients
reported that adding a night-​time intensivist to an ICU already
ratio should be related to the level of care that patients are needing.
staffed with physicians in training at night appeared to offer no or
The ESC-​ACVC recommends a minimum ratio of one nurse to
marginal improvements in outcomes [41, 42].
four level 1 patients, a nurse:patients ratio of 1:2 to 1:3 for patients
In level III ICCUs, the organization of on-​site 24/​7 continuity
with level 2 acute cardiovascular conditions, and a ratio of 1:1 or
of care should follow the national regulations applicable in the
1:2 for patients with level 3 acute cardiovascular conditions.
country for general critical care units [10]. On-​duty phys-
icians should have both advanced acute cardiovascular care
and critical care expertise that is required for working in a level
ICCU medical staff and III ICCU.
cardiovascular intensivists
To ensure high standards in ICCU patient management, for-
malized education in acute cardiovascular care should be avail-
Interaction with other specialties
able in any national health care system. The ESC-​ACVC CC for The close relationship between the ICCU and other subspecialties
acute cardiovascular care provides guidance with a well-​defined of cardiology and other medical specialties is pivotal to running
 Per s ona l  pe r spe c t i v e 21

an excellent unit. Beyond collaborating closely with different

subspecialties of cardiology, the specialized ICCU staff must also Telemedicine
establish close relationships with non-​ cardiovascular special-
Level II and III ICCUs should behave as a hub for emergency con-
ties [43]. Typically specialists who collaborate on a regular basis
sultations and should be organized to provide expert opinion on
with the ICCU team are cardiovascular surgeons, cardiovascular
patients with acute cardiovascular conditions in hospitals without
anaesthesiologists, critical care physicians, nephrologists, infec-
cardiology or PCI facilities. This can be achieved through secure
tious disease specialists, clinical pharmacologists, palliative care
video-​conferencing, with visualization of cardiovascular examin-
teams, and emergency physicians for the pre-​cardiology part of
ations such as coronary angiography or echocardiography [55].
patient management [44, 45]. Frequently, the initial, sometimes
Such programmes can streamline the transfer of patients for
lifesaving, interventions do not demand a multidisciplinary ex-
higher-​intensity care and help reduce costs. Telemedicine should
pertise; however, following stabilization, a wider multidisciplinary
be seen as a delivery tool or system in support of acute cardio-
and multiprofessional team will be required to plan, coordinate,
vascular care [56]. Video-​conferencing, secure transmission of
and manage patients’ care [46].
images and other data, and CME should all be part of an ICCU’s
In many institutions, ‘heart teams’ combining relevant spe-
way of working and interaction with colleagues elsewhere. Video-​
cialties are held weekly or more frequently, especially for heart
conferencing equipment should be available for the ICCU team
failure, coronary revascularization, extracorporeal support, and
and should be located as near as possible to the unit [57].
infective endocarditis [47]. ICCU patients with complex issues
Health care organizations should establish a budget that en-
should be discussed during the relevant multidisciplinary spe-
compasses the cost of implementation, which may include items
cialist meetings, as well as the ICCU multidisciplinary team
such as staff education programmes, hardware, software, and
meetings.
their upgrades and replacements.
Patients admitted to current ICCUs have increasingly advanced
and complex medical conditions, and palliative care is an integral
component of their care. Palliative care education and training
must be a standard among clinicians who are involved in cardio-
Personal perspective
vascular intensive care [48, 49]. Acute cardiovascular care is facing many challenges. The
Care of acute cardiovascular patients extends beyond the organization of ICCUs in three levels (as summarized in
ICCU. The ICCU team should provide acute cardiovascular care E Table 3.5) in close relation to intensity of care is not ar-
consults to inpatients with a potential need for ICCU admission. bitrary but essential to face these challenges and eventually
In critical care, outreach services have had a positive impact on ensure optimal quality in care.
patient outcomes [50].
◆ A firstchallenge corresponds to the fast evolution in the
type of pathologies managed in ICCUs. Initially designed
to secure and support the management of MI, ICCUs have
ICCU—​part of a regional network seen their recruitment evolve into different forms of AHF,
rhythm disorders, and the recognition and treatment of
The ESC-​ACVC recommends that all ICCUs participate in a
acute non-​cardiac conditions in cardiac patients. This
formalized regional network of acute cardiovascular care. These
evolution has been neither programmed nor anticipated.
networks should follow the ‘hub and spoke’ model developed so
Remaining clearly cardiologic in relation to their nature
successfully for STEMI [9, 51, 52], with each level referring acute
and/​or their background, these pathologies are more in-
cardiovascular patients to higher-​level ICCUs when escalation is
tricate and complex. They require more attention during
required [9]‌. Developing ICCUs as part of a network, rather than
ICCU stay, more extensive and often multidisciplinary
as isolated units serving a limited area, facilitates good coverage
expertise, and, at the end, insertion of patient follow-​up
of the population and optimizes the management of acute cardio-
in a precise cardiologic setting. Managing patients with
vascular patients across an entire region [53].
these conditions is becoming always more specialized.
The benefits observed in STEMI networks rely on the devel-
◆ A  second challenge is the evolution of cardiology.
opment of a well-​established transfer protocol, shortening delays
The components of the specialty of cardiology (e.g.
and standardizing procedures between centres [49, 51]. The op-
rhythmology, interventional cardiology, heart failure)
timal ICCU network configuration for a region should be collect-
have also evolved considerably in the last 20  years and
ively and consensually organized and precisely define the clinical
have become highly technical and specific. These highly
conditions that meet the criteria for transfer, transfer modalities,
specialized cardiologists are less apt and less inclined to
and treatment protocols before and during transfer and also en-
participate directly in ICCUs’ activity. Therefore, special-
sure communication between participating parties and on-​time
ization of the ICCU medical team is made necessary not
information on bed availability, as well as return policy [54]. It
only by evolution of pathologies, but also by evolution of
should also address any potential legal or financial challenges (e.g.
the cardiology specialty.
reimbursement of transfer).
22 CHAPTER 3   In ten sive cardiovascu l ar ca re u n i ts :  stru ctu re, org a n i z ati on , a n d  sta f f i n g

Table 3.5  Intensive cardiovascular care units: summary

Level I ICCU Level II ICCU Level III ICCU

Population Level 1 cardiovascular conditions (see Level 1 and 2 patients (see % Table 3.2); severe Mainly level 3 patients, some level 2 patients;
and disease % Table 3.2), monitoring of patients post-​ or high-​risk patients with congestive heart failure acute cardiac conditions needing invasive
structural and endovascular interventions and/​or low cardiac output complicating acute or mechanical ventilation, RRT, ECLS, emergent
(see % Table 3.2 and text) chronic cardiac conditions heart surgery, or surgical cardiovascular
assistance
Technology ◆ All non-​invasive clinical parameter All invasive and non-​invasive cardiovascular
◆ ◆ All advanced invasive and non-​invasive
and therapy monitoring monitoring cardiovascular monitoring
in ICCU ◆ 24/​7 echocardiography and thoracic ◆ Idem level I ICCU, plus: ultrasound-​guided Idem level II ICCU, plus: ECLS; mechanical
◆
ultrasound; direct current cardioversion; central venous line insertion; transvenous circulatory support; RRT; mechanical
NIV; transcutaneous temporary pacing temporary pacing; transoesophageal ventilation
echocardiography; pulmonary artery
catheterization/​right heart catheterization;
percutaneous circulatory support; X-​ray system
for fluoroscopy
Hospital ◆ ED; CT scanner; transoesophageal echo; ◆ 24/​7 coronary interventional cath lab; hub centre ◆ Tertiary or university hospital
X-​ray system for fluoroscopy of an STEMI network ◆ Idem for level II ICCU, plus: percutaneous
Idem for level I ICCU, plus; pacing; cardiovascular
◆ structural heart intervention;
resynchronization therapy; implantable endomyocardial biopsy; donor organ and
cardioverter–​defibrillator programme; ablation transplantation programme; interventional
therapy; renal support therapy; scanner and vascular radiology; comprehensive
cardiac magnetic resonance cardiovascular surgery
Level of Head: cardiologist
◆ Head: cardiovascular intensivist
◆ ◆ Head: cardiovascular intensivist or co-​
competence ◆
Team: cardiologists Team: cardiovascular intensivists
◆ directorship with a general critical care
On site: intensivist consultation 24/​7
◆ On site: intensivist consultation 24/​7
◆ specialist
Team: cardiovascular intensivists with
◆
additional education in critical care; may
include general intensivists with additional
education in cardiology
Education Recommended: written exam towards ◆
◆ Required: specific national curriculum for acute ◆ Idem level II ICCU, plus: specific curriculum
programmes ESC-​ACC certification for individuals; cardiovascular care or ESC-​ACVC curriculum for for general critical care training
should master all techniques required in cardiovascular intensivist Residents and fellow cardiovascular
◆
level I ICCU ◆ Residents or fellow cardiovascular intensive care intensive care; critical care
Residents or fellow in cardiology
◆

On-​duty ◆ Cardiologists with level I ICCU expertise; ◆

Cardiovascular intensivists; trained cardiologists; ◆ Should have all the requirements and
physicians if approved by the unit’s director, physicians advanced in their cardiovascular expertise for working in a level III ICCU
trained residents or other physicians, intensivist training, provided availability of a
provided availability of an on-​call cardiovascular intensivist or an interventional
member of the ICCU team cardiologist
Nursing/​ ◆ Nursing director (could be shared with ◆ Nursing director Nursing director
◆
other regular ward) Dedicated nurses: nurse-​to-​patient ratio 1:2 or
◆ Dedicated nurses: nurse-​to-​patient ratio
◆
personnel Dedicated nurses: nurse-​to-​patient ratio
◆ 1:3 for level 2 acute cardiovascular conditions 1:2 or 1:1 for level 3 acute cardiovascular
1:4 for level 1 patients conditions
Research ◆ Encouraged to be part of outcome ◆ Encouraged to conduct clinical research ◆ Strong commitment to perform clinical
research research

◆ The number of cardiologists in training is limited and ◆ The regulatory aspects are finally essential. Acute
only a small proportion can be trained as cardiovascular cardiovascular care is a young, and unfortunately in-
intensivists. This is one reason why the ESC-​ACVC re- sufficiently known, specialty. To adjust to changes
commends that specialization in acute cardiovascular in intensive care cardiology, recognition of acute
care be gradual and follows the organization of ICCUs cardiovascular care as a subspecialty and its posi-
into three levels (see E Chapter 2). This is also why set- tioning in relation to other intensive specialties, with
ting up networks is essential. Networks allow all patients the possible establishment of bridges, is an urgent and
to access the necessary expertise. important step.
 Re f e re n c e s 23

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 CHAPTER 4

The heart team
Sergio Leonardi, Thomas Modine, and
Stephan Windecker

Contents
Summary  25 Summary
Introduction  25 Modern cardiovascular medicine is complex, dynamic, and interactive. Therefore,
General considerations on heart teams  26 a multidisciplinary dialogue between different cardiovascular specialists is re-
Definition and composition  26 quired to deliver optimal patient care. This requirement has led to the concept
Function  26
Indications  26 of teams of different specialists caring for patients with complex cardiovascular
Considerations for optimal interaction  26 diseases—​hence the concept of ‘heart teams’. These teams are particularly valuable
Heart teams in patients with complex when complex and/​or rapid decision-​making is essential. This chapter is intended
coronary artery disease requiring
revascularization  27 to provide conceptual and practical considerations for the composition, structure,
Indications  27 and function of multidisciplinary teams involved in the treatment of complex car-
Non-​urgent (elective) indications diovascular diseases; to discuss strategies for clear and transparent patient com-
(patients with stable CAD or stabilized
munication and promotion of a patient-​centric approach; and to provide guidance
NSTE-​ACS)  27
Urgent or emergent indications  27 on optimal implementation of the heart team concept in patients requiring myo-
Patient communication strategies  27 cardial revascularization of a broad spectrum of complex coronary artery disease,
Roles and responsibilities of team
components  28 from stable angina to acute coronary syndrome patients with mechanical compli-
Considerations on decision-​making and cations and haemodynamic instability.
optimal mode of revascularization  28
Optimal use (and potential limitations) of
scores of anatomical complexity  28
PCI: anatomical and procedural
considerations  29
CABG: anatomical and procedural
considerations  29
Completeness of revascularization  29 Introduction
Conduit selection  30
Final decision-​making considerations  30 There is increasing emphasis on multidisciplinary decision-​making by clinical practice
Conclusion  31 guidelines in different patient populations [1–​5]. Team-​based care has relevant potential
References  31 merits and is often advocated to optimize patient care. By bridging together specialists
of different expertise, this approach may promote interdisciplinary dialogue, as well as
continuity of care, with the goal of offering a balanced and complementary approach to
the care of patients. On the other hand, multidisciplinary decision-​making may increase
logistical complexity, may cause diagnostic and treatment delays, and has therefore been
criticized  [6]‌.
Despite being consistently recommended as the favoured decision-​making approach
by European and American guidelines [1–​5] and proving to be beneficial and consistent
in diverse patient populations [7–​9], heart teams still remain poorly implemented [10].
The substantial variation in coronary artery bypass grafting (CABG)-​to-​PCI ratios across
countries, as well as different geographical locations within the same country, cannot be
solely explained by different geographical patterns of CAD and may be driven by local
expertise, reimbursement, and economic considerations and likely reflect variability in
multidisciplinary decision-​making and specialty bias [11]. Several strategies to optimal
heart team utilization have been proposed, including optimization of logistical, profes-
sional, and interdisciplinary barriers [12–​14].
26 CHAPTER 4   The heart  t eam

In this chapter, we will discuss composition, structure, and Considerations for optimal interaction

function of heart teams, attempting to provide conceptual and Interaction between components defines heart teams. It is there-
practical considerations for multidisciplinary decision-​making in fore essential to discuss requisites for balanced relationships be-
patients with complex CVD; discuss strategies for patient com- tween members, detail their structure, and reflect on strategies for
munication and promotion of a patient-​centric approach; and optimal interaction.
provide guidance on optimal implementation of the heart team First, a written institutional protocol is a preliminary step in
concept in the historical first and still one of the most important this regard and, as recommended by current guidelines, should
settings, i.e. patients with complex CAD requiring myocardial be produced [1]‌. The local protocol should be agreed upon des-
revascularization. ignated representatives of each component and include clear
decisional pathways (especially for urgent or emergent situations)
based, whenever possible, on relevant guidelines and scientific
General considerations on heart evidence, clear instructions indicating criteria for selecting pa-
tients that should be presented on heart team round-​tables, feasi-
teams bility considerations, and local expertise. The protocol should be
Definition and composition regularly revised, as new evidence emerges or local facilities/​ex-
pertise evolve and indicate how often planned meetings should
The heart team is defined as a group of different specialists
be convened. It should also indicate the modality of unplanned
that optimally interact to provide a balanced, unbiased, timely,
meetings when rapid decision-​making is required. According to
and—​whenever possible—​evidence-​based decision-​making to
current guidelines, institutional protocols should also be estab-
patients with complex heart diseases. The types of specialists
lished in institutions without on-​site cardiac surgery where cardi-
involved depend on the disease of interest:  anaesthesiologists,
ology departments should team up with a referral cardiac surgery
cardiac surgeons, and interventional cardiologists for patients
unit [1].
with complex CAD and/​or valvular heart disease (VHD) [1]‌; in-
Second, the responsibilities and area of expertise of each com-
vasive electrophysiologists and specialized surgeons in patients
ponent should be clearly outlined in the local protocol. While
with complex arrhythmias [3]; and infectious disease special-
team-​based decisions should be informed by, and do not rely
ists for patients with complicated endocarditis [2]. Clinical (i.e.
solely on, scores [1]‌, the use of validated risk scores, such as
non-invasive) cardiologists (typically the treating physicians) are
the Synergy Between Percutaneous Coronary Intervention
always part of heart teams and are generally responsible for syn-
with Taxus and Cardiac Surgery (SYNTAX) scores, the Society
thesizing the discussion and communicating with the patient.
of Thoracic Surgeons (STS) scores, and EuroScore II, has po-
Other specialists may be needed, depending on specific concomi-
tential advantages and may help delineate an explicit risk as-
tant conditions or patients’ comorbidities such as geriatricians for
sessment [15, 16]. Actionable (i.e. which provide a risk/​benefit
elderly patients.
stratification algorithm to inform decision-​making on the pref-
erable therapeutic option) scores should be favoured. A limita-
Function tion is inclusion of relevant comorbidities (such as advanced
Indications dementia or frailty) that are currently not part of most scores.
A heart team is usually indicated when important decisions These should be reported in writing and considered for the final
that intersect multiple specialties are being undertaken, typic- decision-​making.
ally requiring percutaneous or surgical interventions. Examples Last, but not least, the management of disagreements among
include the choice of the mode of myocardial revascularization members should be addressed. In general, different opinions
(surgical or percutaneous) in patients with complex CAD [1]‌; should be viewed as an opportunity, not as a barrier, for decision-​
management of patients with severe VHD; management of pa- making. Concerns and observations by any component should
tients with atrial fibrillation (AF) and failed rhythm control be adequately discussed, analysed, and documented. As a gen-
therapy who require interventional or surgical AF ablation [3]; eral rule, the team component with the highest expertise in the
and the indication and timing of surgery in patients with com- area of disagreement should take the final decision. For example,
plicated endocarditis [2]. in case of disagreement on the assessment of surgical risk, such
As timing may be crucial in acute settings, it is essential that as low predicted risk based on score, but perceived higher risk
urgent/​emergent diagnostic or therapeutic decisions, as well as based on other comorbidities, the opinion of the cardiac anaes-
specialists to be contacted, are coordinated in advance as much thesiologist and surgeon should weighed relatively more than
as possible, with predefined and clear communication channels that of the clinical cardiologist or interventional cardiologist. If
to minimize delays. In these settings, it is helpful to define, in a after extensive discussion, major disagreements on patient man-
written institutional heart team protocol, simple decision path- agement persist, these should be transparently communicated to
ways based on actionable steps, as well as local feasibility and ex- the patient—​ideally together and by the entire team. Eventually,
pertise considerations to streamline the process of care, including transparent communication is necessary to inform and share
common ‘real-​world’ scenarios. decision-​making with the patient in non-​urgent settings.
Heart teams in patients with complex coronary artery disease requiring revascularization 27

surgery (and/​or PCI) and may not require formal heart team
Heart teams in patients with meetings. These factors should be jointly discussed by heart team
complex coronary artery disease member representatives and listed in the written institutional
protocol to minimize inappropriate heart team meetings and pos-
requiring revascularization sible treatment delays.
The concept of the heart team was first proposed by the Task Force
of ESC/​EACTS 2010 Myocardial Revascularization Guidelines Non-​urgent (elective) indications (patients with stable
and subsequently developed for patients with complex CAD to CAD or stabilized NSTE-​ACS)
jointly decide the optimal mode of revascularization, i.e. surgical A heart team is usually recommended for elective patients with
or percutaneous [17]. In this section, we provide practical guid- complex CAD. Complex CAD involves at least one of three ana-
ance to implement the heart team for these patients and specif- tomical settings: (1) significant involvement of the proximal left
ically discuss indications, patient communication strategies, and anterior descending (LAD) artery (≥50% of luminal diameter
specific considerations on decision-​making regarding the optimal narrowing, as assessed visually by coronary angiography in the
mode of revascularization (see E Figure 4.1). ‘worst view’ angiographic projection); (2)  significant distal left
main stenosis; and (3)  three-​vessel disease. In the last two set-
Indications tings, calculation of the SYNTAX score is recommended and
Multidisciplinary decision-​making is not required in all patients should be routinely performed [1]‌.
undergoing coronary revascularization but should be considered
in patients with complex and stable CAD (elective patients) or
Urgent or emergent indications
stabilized non-​ST elevation acute coronary syndrome (NSTE-​ In an urgent or emergent situation, such as unstable NSTE-​ACS
ACS) [1, 18]. (or ACS patients with persistent ST elevation) and complex CAD,
This latter group includes patients admitted for ACS, but a culprit-​lesion PCI is generally indicated. In patients with re-
without evidence of recurrent myocardial ischaemia (symptoms sidual multivessel CAD who may benefit from a surgical com-
or dynamic ST changes on the ECG), as well as haemodynamic pletion of revascularization (e.g. residual involvement of the
(AHF or cardiogenic shock) and/​or electrical instability (cardiac proximal LAD or significant left main stenosis), heart team dis-
arrest or sustained ventricular arrhythmias) [1, 19]. cussion should occur after clinical stabilization, also considering
A separate setting (urgent or emergent indications) is com- hybrid revascularization.
posed by patients with unstable ACS, including ST elevation Uncommon, but clinically important, scenarios include mech-
acute coronary syndrome (STE-​ACS), or patients experiencing anical complications of AMI. In these situations, urgent CABG
mechanical complications. with concomitant surgical correction should be generally con-
While heart teams should ideally take place in all stable patients sidered. To streamline decision-​making processes, it is advis-
with complex CAD, there may be situations—​very elderly pa- able to include in the written institutional protocol predefined
tients or those with reduced life expectancy, advanced dementia, decisional steps, as a formal heart team meeting may delay
and other substantial comorbidities—​that are unfavourable for lifesaving care.
Specifically, all ACS patients presenting with cardiogenic shock,
a new (or presumably new) loud systolic murmur, or flash pul-
monary oedema should routinely undergo emergency echocar-
General
practitioner diography to diagnose a possible mechanical complication while
(Interventional) awaiting coronary angiography [20, 21]. In these situations, heart
Intensivist cardiologist team discussion is important to optimize the timing for surgery,
Heart team rather than to discuss therapeutic options. In some very high-​risk
Family patients with post-​infarct ventricular septal defect (VSD), multi-
Imaging
disciplinary discussion may include the option of haemodynamic
Geriatrician Patient
specialist stabilization (by ECMO or axial left ventricular–​aorta pumps) or
percutaneous VSD closure. In an urgent or emergent situation of
a conscious patient, communication should be kept as simple as
possible and only verbal consent should be considered.
Cardiac surgeon Anaesthesiologist
Other Patient communication strategies
specialist
In elective patients, communication about the possibility—​and
mode—​of myocardial revascularization should start when first
Figure 4.1  Composition of the heart team to decide on myocardial
revascularization in patients with complex CAD. Green box: comprises the consenting for coronary angiography. This is the first important
core members of the heart team. Yellow box: represents facultative members opportunity to illustrate therapeutic options that include medical
to be consulted for heart team meetings. therapy and myocardial revascularization, with discussion of the
28 CHAPTER 4   The heart  t eam

pros and cons of percutaneous and surgical revascularization. If aspect such as indications for mechanical circulatory support in
the patient, after adequate consent, expresses a clear preference patients undergoing high-​risk PCI).
for one of the options, this should be reported in writing in the The primary responsibility of the cardiac surgeon is to provide
clinical chart and considered for decision-​making at the time of an opinion on feasibility, anticipate completeness and complexity
angiography. of surgical revascularization, and describe the general procedural
Deciding on the mode of coronary revascularization at the time aspects.
of coronary angiography in elective patients (i.e. stable CAD or The main responsibility of the anaesthesiologist is to assess sur-
stabilized NSTE-​ACS) with complex CAD is generally discour- gical risk in tandem with the cardiac surgeon and potential meas-
aged. For the same reason, ad hoc PCI in these patients should be ures to reduce this risk.
generally avoided.
The proportion of patients who refuse one type of Considerations on decision-​making and
revascularization might be influenced by the way this is com- optimal mode of revascularization
municated. For this reason, patients who refuse CABG or PCI The rationale for revascularization is provided not only by the
might be monitored and reported for quality purposes (see E presence of severe coronary lesions, but also by an underlying vi-
Table 4.1). able myocardium. In patients with normal systolic function, it can
To optimize and share decision-​making on the mode of cor- be generally assumed that the ischaemic myocardium is viable
onary revascularization, it is advisable that the heart team reaches and should be revascularized. Patients with systolic dysfunction,
a consensus on the recommended mode of revascularization especially if severe, may need further testing. Markedly depressed
before discussing with the patient. Providing separate opinions left ventricular (LV) function in patients with ischaemic car-
has the potential to generate biased perception and confusion diomyopathy, but with preserved viability, may be reversed by
(especially in challenging cases or when conflicting evidence revascularization [22, 23]. In this setting, advanced imaging, such
is present) and may compromise patient trust and optimal as cardiac magnetic resonance imaging (MRI), single-​photon
decision-​making. emission computerized tomography (SPECT), or echocardiog-
raphy, may be very helpful. Cardiac MRI is nowadays the gold
Roles and responsibilities of team components standard to assess myocardial scarring as evidence of non-​viable
The main responsibilities of the clinical cardiologist are to lead tissue. SPECT can estimate resting perfusion, stress-​induced is-
patient communication (both at the time of coronary angio- chaemia, scarring, and cardiac function.
graphy and subsequently after team decision), assess the clinical
indications for revascularization (ischaemic threshold and con- Optimal use (and potential limitations)
sequences of ischaemia on quality of life, presence of myocardial of scores of anatomical complexity
viability) and potential concomitant indications for surgery (such The calculation of the Synergy Between Percutaneous Coronary
as VHD), and define the clinical profile, including risk factors for Intervention with Taxus and Cardiac Surgery (SYNTAX) score is
CAD (such as diabetes), as well as relevant comorbidities, espe- currently recommended in patients with complex CAD to quan-
cially if not included in risk scores (such as advanced dementia), tify anatomical complexity [Class I, level of evidence (LoE) B][1].
and medications compliance [such as contraindications to ad- The SYNTAX score is a comprehensive anatomical assessment
equate dual antiplatelet therapy (DAPT)]. of CAD complexity. In brief, each coronary lesion with ≥50% of
The main responsibilities of the interventional cardiologist are luminal stenosis in vessels ≥1.5  mm is included on the basis of
to quantify the anatomical complexity and functional severity of the modified American Heart Association (AHA) coronary tree
CAD, anticipate the completeness and complexity of percutan- segment classification and independently scored considering the
eous revascularization (including anticipated contrast medium presence of bifurcations/​trifurcations, ostial location, chronic oc-
volume), and describe the general procedural aspects (including clusion, vessel tortuosity, calcification, length, and thrombus for-
number and type of stent, anticipated DAPT duration, and other mation. The score of each lesion is added to obtain the patient’s

Table 4.1  Potential tools for heart team implementation in stable or stabilized patients with complex coronary artery disease

Indicator Reporting method Comments

1. Written institutional protocol Presence: yes/​no This should be an agreed representative of each component locally and include feasibility
considerations
2. Anatomical assessment of coronary severity Proportion SYNTAX score
3. Assessment of surgical risk Proportion STS score favoured over EuroScore II
4. Heart team discussion performed Proportion This should be written in the patient record and include, at a minimum, the clinical
cardiologist, interventional cardiologist, and cardiac surgeon
Heart teams in patients with complex coronary artery disease requiring revascularization 29

final SYNTAX Score, with higher scores indicative of increasingly In multivessel-​disease patients with high SYNTAX scores, if
complex coronary disease. After being derived from the SYNTAX surgery is deemed contraindicated by the heart team (e.g. due
trial, the score has been validated in different patient populations to comorbidities or poor quality of distal vessels for grafting
[24, 25]. There are, however, several independent observations of purposes), PCI can be accomplished using standard of care
substantial interindividual variability in calculating the SYNTAX techniques. Contemporary techniques include intracoronary
score [26–​28]. The scoring of bifurcation and trifurcation le- haemodynamic assessment and intracoronary imaging to avoid
sions and the presence of small-​vessel disease remain the main unnecessary stenting. Calcified or resistant lesions can be suc-
source of inconsistency [26]. In one study, the interobserver vari- cessfully dilated by means of rotational atherectomy, lithotripsy,
ability of a group of interventional cardiologists with an average or use of high-​pressure, non-​compliant balloons [36]. Chronic
of 7.5  years of experience was poor and improved only slightly total occlusions can be approached by dedicated operators, with
after core laboratory team revision. This may have important high rates of success, through anterograde or retrograde tech-
implications for the adoption of the SYNTAX score in clinical niques [37]. In cases of complex procedures in patients at risk
decision-​making  [26]. of haemodynamic instability (or performed in patients who are
The residual SYNTAX score was developed to quantitatively haemodynamically unstable), mechanical circulatory support
assess the degree and complexity of residual stenoses, based on may improve procedure safety. In heart team discussions, a key
recalculating the SYNTAX score after PCI [29]. The intention of criterion for considering PCI as an alternative to surgery should
this index is to quantitatively assess the angiographic complete- be the ability to achieve the same level of complete functional
ness of revascularization. High residual SYNTAX scores have revascularization.
been associated with worse outcomes in patients undergoing
angiography-​guided PCI [30,  31]. Hence the anticipated com- CABG: anatomical and procedural considerations
pleteness of revascularization by PCI or CABG should be con- Similarly to PCI, specific considerations relevant to CABG
sidered and prioritized for final decision-​making (Class IIa, LoE feasibility can be raised, and the anticipated completeness of
B)  [1]‌. revascularization and conduit selection may require discussion
In addition, the functional significance of a lesion, based on by the entire team. For example, venous grafts are less durable
fractional flow reserve (FFR) or instantaneous wave-​free ratio than arterial ones and mammal and radial artery harvesting
(iFR), is an important determinant of future adverse cardiac as well as Y-​ type anastomoses for bypass surgery requires
events in patients undergoing PCI [32–​34]. expertise.
In conclusion, the calculation of the SYNTAX score should
be performed by experienced operators and—​ ideally—​
Completeness of revascularization
independently confirmed by both the interventional cardiologist For both CABG and PCI, there is no universally accepted defin-
and the cardiac surgeon. Functional assessment of coronary le- ition of complete anatomical revascularization. In the SYNTAX
sions (invasive or non-​invasive) should be routinely considered trial, anatomical complete revascularization was defined as PCI
to guide revascularization in stable patients in cases of lesions ofor bypass of all epicardial vessels with a diameter exceeding
intermediate-​grade stenosis (i.e. 50–​90% by visual assessment) or ≥1.5 mm and a luminal reduction of ≥50% in at least one angio-
without documented ischaemia. If functional assessment is not (or graphic view, while other studies have used other definitions [16].
cannot be) performed, the residual SYNTAX score can be helpful Two large meta-​analyses, including both randomized and ob-
to verify if revascularization is anatomically complete (<8). servational studies, showed a significant reduction in long-​term
mortality, MI, and repeat myocardial revascularization in pa-
PCI: anatomical and procedural considerations tients with complete revascularization, independently of whether
In approaching complex CAD by means of PCI, the heart team CABG or PCI was used [38].
has to consider in diverse anatomical and procedural consider- The 2018 ESC-​ EACTS myocardial revascularization guide-
ations. In stable patients, PCI of ostial and mid-​shaft left main lines recommend that completeness of revascularization should
disease is generally a straightforward procedure in high-​volume be prioritized when choosing between CABG and PCI in pa-
institutions by expert operators. Multivessel disease may present tients with multivessel disease (Class IIa, LoE B) [1]‌. As of now,
either with single, relatively short lesions or with complex, long, complete revascularization has been reported to be more often
and calcified disease located along the three main epicardial ves- achieved after CABG than after PCI. In a recent meta-​analysis
sels, including chronic total occlusions. Complex PCI procedures including 3212 patients from three randomized trials, complete
may also require higher contrast medium volumes, and thereby revascularization was accomplished in 57.2% of patients with PCI
carry a higher risk of acute kidney injury (AKI). In a meta-​ and 66.8% of those with CABG [39]. In the SYNTAX trial, 52.8%
analysis of 11 trials comparing PCI [with bare-​metal stent (BMS) of the PCI arm and 66.9% of the CABG arm received complete
or first-​or second-​generation drug-​eluting stent (DES)] with anatomical revascularization [16]. The FAME study showed that
CABG, surgery had a mortality benefit over PCI in patients with a more restrictive selection of target lesions based on functional
multivessel disease, particularly those with diabetes and higher guidance resulted in improved long-​term outcomes, compared
coronary complexity [35]. with angiography-​guided PCI [32].
30 CHAPTER 4   The heart  t eam

Conduit selection radial artery grafting include poor function of the ulnar artery
Conduit availability and selection in CABG are an important (positive Allen test), lack of local expertise, and patient char-
consideration to anticipate completeness and durability of myo- acteristics. Hybrid procedures, defined as consecutive or com-
cardial revascularization. In general, the anticipated conduit to bined surgical and percutaneous revascularization, may be
be used should be considered during the multidisciplinary dis- considered in specific patient subsets at experienced centres.
cussion. Indeed, if complete revascularization cannot be achieved For this type of revascularization, multidisciplinary decision-​
due to lack of conduits, this may influence the choice between making is particularly advantageous.
PCI and CABG.
Radial artery grafting is now recommended with a Class I in-
Final decision-​making considerations
dication over saphenous vein grafts in patients with severe sten- Current guidelines delineate specific aspects to consider in
osis [1]‌, particularly in younger patients (<75  years), female decision-​making that favour CABG or PCI (see E Figure 4.2)
patients, and patients without renal insufficiency [40]. However, and provide recommendations in patients with acceptable sur-
as of now, radial artery grafting has been insufficiently adopted gical risk [1]‌. The definition of acceptable surgical risk is indi-
(Class  I, LoE B) [41]. If the patient lacks sufficient graft ma- cated (‘for example, absence of previous cardiac surgery, severe
terial due to previous excision of the saphenous vein or poor morbidities, frailty, or immobility precluding CABG’ [1]). In gen-
vein quality and/​or has widespread peripheral atherosclerosis eral, a 30-​day mortality risk of <2–​3%, preferably assessed using
involving the radial or ulnar arteries, conduits option selection the STS score, may be considered as guidance to define low risk
may be limited; as when contraindications for vein harvesting in conjunction with other relevant patient-​related comorbidities
exist, i.e. due to leg ulcers. Reasons that may limit the use of not included in the risk scores. However, the terms acceptable and

PCI CABG

Left internal thoracic

artery to left anterior
descending

Left coronary artery Right internal thoracic

artery or radial artery
Circumflex
Right coronary
coronary artery
artery
Left anterior Sequential anastomosis
descending to obtuse marginal
coronary 1 and 3
Distal right artery
coronary
artery

FAVOURS PCI FAVOURS CABG

Clinical characteristics Clinical characteristics

Presence of severe comorbidity (not adequately reflected Diabetes
by scores) Reduced LV function (EF ≤35%)
Advanced age/frailty/reduced life expectancy Contraindication to DAPT
Restricted mobility and conditions that affect the Recurrent diffuse in-stent restenosis
rehabilitation process
Anatomical and technical aspects
Anatomical and technical aspects
MVD with SYNTAX score ≥23
MVD with SYNTAX score 0–22 Anatomy likely resulting in incomplete revascularization
Anatomy likely resulting in incomplete revascularization with PCI
with CABG due to poor quality or missing conduits Severely calcified coronary artery lesions limiting lesion
Severe chest deformation or scoliosis expansion
Sequelae of chest radiation
Porcelain aortaª Need for concomitant interventions
Ascending aortic pathology with indication for surgery
Concomitant cardiac surgery

Figure 4.2  Considerations for decision-​making regarding complex CAD revascularization by the heart team. CABG, coronary artery bypass grafting; DAPT,
dual antiplatelet therapy; EF, ejection fraction; MVD, multivessel coronary artery disease; PCI, percutaneous coronary intervention; SYNTAX, Synergy between
Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery. a Consider no-​touch off-​pump CABG in case of porcelain aorta.
Reproduced from Sousa-​Uva M, Neumann FJ, Ahlsson A, et al. 2018 ESC/​EACTS Guidelines on myocardial revascularization. Eur J Cardiothorac Surg 2019;55:4–​90 with permission
from Oxford University Press.
 Re f e re n c e s 31

low surgical risk have different implications. An ‘acceptable’ risk three-​vessel disease and low SYNTAX scores (0–​22) and (2) PCI
is related to the alternative treatment option (such as PCI or op- favoured over CABG in patients with one-​or two-​vessel CAD
timal medical therapy in patients considered for CABG) and in- without proximal LAD involvement. The LoE is generally higher
cludes patient preference, while low risk is an absolute concept, for recommendations supporting CABG over PCI [1]‌.
mostly related to explicit risk assessment by score. Heart teams are particularly valuable in complex decisions such
Clinically, the presence of diabetes, LV systolic dysfunction, as when factors favouring both PCI and CABG are present. In
high bleeding risk contraindicating appropriate DAPT, high ana- these instances, it is important that the team comprehensively
tomical CAD complexity, and concomitant indication for valve lists and optimally quantifies each factor that may affect decision-​
or other concomitant procedures are considerations that favour making in order to precisely assess the risk of mortality and mor-
CABG over PCI. Conversely, the presence of severe comorbid- bidity and appropriately inform patients about the decision.
ities, especially if not included in risk scores, such as frailty, that
may affect the rehabilitation process favours PCI.
There are two anatomical settings with a strong recommen- Conclusion
dation preference for one mode of myocardial revascularization
in stable patients, i.e. Class I versus Class III—​both with CABG In patients with complex CVD, multidisciplinary decision-​
favoured over PCI: (1) left main disease with high SYNTAX scores making may promote evidence-​based care, reduce specialty bias,
(≥33) and (2)  three-​vessel disease with intermediate or high and help patients make informed decisions. We discuss strategies
SYNTAX scores (≥22), with or without diabetes; and two settings to implement ‘heart teams’ in patients with complex CVD and
where there is a recommendation preference, i.e. Class  I  versus promote a patient-​centric approach that may ultimately help in
Class IIb: (1) CABG favoured over PCI in diabetic patients with translating these considerations into clinical practice.

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 CHAPTER 5

Patient safety and clinical

governance
Matthew Parkin and Tom Quinn

Contents
Summary  33
Summary
Clinical governance  33 Clinical governance appeared as a concept in the United Kingdom (UK) in the
Assessment of clinical governance  34 late 1990s, following scandals in which patients were harmed as a consequence
Patient safety  35 of health care failures. Further international research estimates that one in ten in-
Why do things go wrong in health care?  35 patients suffer harm as a result of their health care, leading to death in some cases.
Errors and harm in acute cardiovascular
care  36
Clinical governance is a framework centred around the domains of patient safety,
Hazard identification  37 clinical effectiveness, and patient experience, underpinned by effective teamwork,
Reporting and escalating incidents  37 leadership, and communication. Its aim is to ensure consistent, reliable, high-​
Responding to incidence  38 quality care delivered by competent individuals in a safe environment.
Duty of candour  38 Understanding why things go wrong in health care is key to finding solutions to
Patient safety organization  38 ensure patient safety. Health care is an increasingly high-​risk activity at organiza-
Improving patient safety  38
Designs for safety  38
tional, departmental, and individual levels, and hazard identification and manage-
Checklists  38 ment are important. Recent recognition of human factors as contributing to many
Simulation training  38 adverse events has facilitated the exploration of how health care professionals func-
Leadership, teamwork, human factors, and
non-​technical skills  39 tion within the context of a high-​pressure, unpredictable environment. Lessons
Quality improvement  39 from non-​health care industries have changed focus from blaming individuals for
Conclusion  39 errors to understanding systems and how they can promote or mitigate failure.
Personal perspective  39
Further reading  40
References  40

Clinical governance
Clinical governance is an international concept, although it was introduced into the
National Health Service (NHS) in the UK in the 1990s as part of the UK government’s
aim to create a ‘modern (health) service delivering high-​quality care for all’ [1]‌. In their
BMJ publication in 1998, Scally and Donaldson [2] defined clinical governance as ‘a
system through which NHS organisations are accountable for continuously improving
the quality of their services and safeguarding high standards of care by creating an en-
vironment in which excellence in clinical care will flourish’. The aim is to optimize the
delivery of high-​quality patient-​centred care and encourage and support staff to deliver
evidence-​based medicine (EBM) in a safe environment, with an emphasis on learning
from mistakes with an open culture and robust accountability. The concept was originally
organized around ‘seven pillars’ [3] (see E Box 5.1)
These concepts emerged in response to three significant events reflecting poor quality
of care in the UK:
1. The Bristol Royal Infirmary Inquiry into paediatric cardiac surgery [4]‌between 1984
and 1995 showed that a third of children treated had received substandard care, due
34 CHAPTER 5   Patie nt saf et y and clinical g overna n ce

evidence, in the most cost-​effective way. McGlynn et  al. [11]

Box 5.1  Seven pillars of clinical governance
found that patients in the US only receive 50% of recommended
1. Clinical effectiveness—​a measure of the extent to which a care. There is a requirement to continually audit against best
health care intervention works practice to ensure consistently high standards of care, together
2 . Risk management effectiveness—​considering and managing with the promotion of continued education and training and
risks to patients, staff, and organizations professional development.
3 . Patient experience—​ensuring the service is patient-​centred 2. Patient experience:  the patient should be placed at the centre
4 . Communication effectiveness—​ensuring effective communi- of health care provision. Every aspect of the patient experi-
cation within organizations and with patients and the public ence during a hospital stay, from basic needs (including nu-
5 . Resource effectiveness—​ensuring all resources are used opti- trition and hydration) to involvement in treatment (ensuring
mally for the benefit of patients clear communication and provision of information, as well as
6 . Strategic effectiveness—​planning and developing services, addressing complaints effectively), should be monitored and
reflecting local needs measured.
7 . Learning effectiveness—​continued professional develop- 3. Patient safety:  patient safety concerns are universal.
ment for staff, including learning teamwork, leadership, and Approximately 10% of hospital admissions are associated with
communication skills
patient harm. Don Berwick [12] in 2003 stated that we should
‘place the quality of patient care, especially patient safety, above
to poor teamwork, leadership, and failure to promptly identify all other aims’. Strategies to improve safety include incident re-
and address problems. porting, effective risk management systems, patient alert sys-
tems, and safeguarding procedures, as well as ensuring a safe
2. The Royal Liverpool Children’s Inquiry [5]‌in 1999 relating to environment. However, there is a view that patient safety is
the retention and disposal of organs and tissue at post-​mortem more about culture and attitudes to care and its delivery within
found evidence of inadequate consent and communication a systematic framework.
with parents.
During a 2013 review by Sir Bruce Keogh, a cardiac surgeon,
3. The Shipman Inquiry into the actions of a British general prac- into 14 hospitals in England, immediate action was taken to
titioner found to be a serial killer, estimated to have killed up close operating theatres and change staffing levels. The review
to 250 patients [6]‌. The first of six reports looked at ways to found patient experience, safety, workforce, clinical and oper-
safeguard patients from ‘the actions of a homicidal doctor’. ational effectiveness and governance, and leadership all needed
Health care failures are not restricted to the UK. In Paris, in to improve [13].
2005, a scandal emerged relating to the illegal retention of still-
born infants and fetuses without parental knowledge or permis-
sion [7]‌. More recently, in Germany, in 2012, it emerged that liver Assessment of clinical governance
transplant surgeons had been fraudulently manipulating test re-
sults, making patients appear sicker than they were, to expedite A clinical governance framework represents a significant step to-
transplants [8]. wards improving care for patients. In England, the CQC moni-
Following the subsequent publication of the Department of tors, inspects, and regulates services that provide health and social
Health document An Organisation With a Memory [9]‌, two gov- care, making sure they comply with standards of care that place
ernmental organizations were set up to promote universal safe, an emphasis on safety, outcomes, and user experiences. The CQC
high-​quality care across the NHS: reviews and monitors compliance with the standards set and has
◆ The National Institute for Health and Care Excellence (NICE), the power to enforce fines, warnings, or even close services if they
which develops national evidence-​based guidance. have concerns about standards of care.
In the UK, NHS Resolution is the body which handles all clin-
◆ The Care Quality Commission (CQC), which is the health care ical negligence claims within the NHS. It has developed a strin-
regulator in the UK. gent risk management programme, aimed at raising standards
The High Quality Care for All:  NHS Next Stage Review Final and reducing litigation rates. The Clinical Negligence Scheme
Report was published in 2010 by Lord Darzi, a surgeon [10], based for Trusts (CNST) has been established in a way such that con-
on the principal areas central to the delivery of optimal care: tributions by health care providers are based on the assessment
◆ To help people stay healthy. of compliance with risk management standards, including areas
◆ To empower patients. such as staff induction, training, and competence and clinical in-
cident reporting. The Joint Commission in the US is a similar or-
◆ To provide the most effective treatments.
ganization. It accredits health care organizations across America,
◆ To keep patients as safe as possible.
and some states have come to require this as a condition of licence
Darzi defined three components of safe, high-​quality care. and to receive Medicaid reimbursement. The organization states
1. Clinical effectiveness:  this requires health care professionals its aim is ‘to continuously improve health care for the public, in
and organizations to deliver the best care, based on the latest collaboration with other stakeholders, by evaluating health care
 Patie n t   sa f et y 35

organizations and inspiring them to excel in providing safe and

Box 5.2  Definitions
effective care of the highest quality and value’ [14].
◆ Clinical governance: a framework to ensure high-​quality care,
centred around the domains of patient safety, clinical effect-
iveness, and patient experience [2]‌.
Patient safety
Whistleblowing: raising concerns that are harming the ser-
◆
The concepts of medical error and patient safety are not new. In vice an organization delivers or commissions [21].
1863, Florence Nightingale wrote: ‘ . . . the very first requirement Duty of candour: to be open and honest with patients and/​or
◆
in a Hospital that it should do the sick no harm’ [15]. families when something goes wrong which could have led,
In the last two decades, the acknowledgement and recognition or did lead to, harm [22].
of unnecessary morbidity and mortality of patients in health care A ‘patient safety incident’ (PSI) is defined as ‘any unintended
◆
have been brought to the forefront of health care professionals’ event caused by the health care that either did or could have
agenda worldwide. In 1999, the Institute of Medicine (IoM) pub- led to patient harm’ [23].
lished a report To Err is Human [16], based on two studies as- A ‘critical incident’ (CI) is defined as ‘an unplanned event or
◆
sessing the incidence of AEs in hospitals in Colorado and Utah series of events and circumstances that may result in an un-
[17] and New York [18]. An AE was defined by the authors [18] desirable consequence’ [24].
as ‘an injury that was caused by medical management (rather An ‘adverse event’ (AE) is an incident that results in ‘unin-
◆
than the underlying disease) and that prolonged the hospital- tended injury to patients’ [24].
ization, produced a disability at the time of discharge, or both’. A ‘sentinel event’ (SE) is defined by the Joint Commission as
◆
This landmark study found medical errors and AEs occurred ‘an unexpected occurrence involving death or serious phys-
in approximately 3% of all admissions, with 7–​12% leading to ical or psychological injury, or the risk thereof ’ [25].
death. Extrapolation suggested that medical error was the eighth A ‘serious incident’ is defined as an event ‘where the potential
◆
leading cause of death in the US, with an estimated total national for learning is so great, or the consequences to patients, fam-
cost of errors of $17–​19 billion annually. Subsequently, the UK ilies and carers, staff or organization are so significant, that
Department of Health report An Organization With a Memory they warrant using additional resources to mount a compre-
[9]‌stated that AEs causing harm occur in approximately 10% of hensive response’ [26].
admissions, which, when extrapolated across the NHS, cost an
estimated £2 billion per annum in hospital admissions alone.
Improving patient safety has therefore become the priority for working environment. Reason [29] emphasizes the importance
health care at international, national, and local levels, with efforts of distinguishing between ‘active failures’ and ‘latent conditions’.
focused on identifying the causes of errors and harm and finding An active failure is an unsafe act performed by a person at the
ways to prevent them. ‘sharp end’ and has immediate consequences, e.g. a pilot turning
The European Commission is currently financially supporting off the wrong engine or a cardiologist incorrectly removing a
a number of projects and studies into patient safety. The European pacing wire in a pacing-​dependent patient. Active failures occur
Network for Patient Safety (EUNetPaS) established a network of in a specific context and can be precipitated by latent conditions
health care professionals, patient groups, institutions, and re- (factors that stem from management or design decisions made
searchers to collaborate on patient safety. Other examples include at an earlier time), e.g. the warning system in the cockpit design
implementing strategic bundles for infection prevention and may be misleading or the cardiologist may be working too hard,
management (IMPLEMENT), looking at the most effective way leading to fatigue as a result of organizational pressure to meet
of implementing such bundles [19]. targets.
Specifically for ICUs, the European Society of Intensive Care The anatomy of PSIs is explained in Reason’s ‘Swiss cheese’
Medicine (ESICM) released indicators to improve safety and model [30] which illustrates how hazards are ubiquitous, but
quality of care for critically ill patients in 2012 [20]. defences prevent incidents from occurring, e.g. noticing that a
patient is listed for a procedure on the wrong side prior to inter-
Why do things go wrong in health care? vention. However, on occasions, a series of minor errors and
It is important to understand the various terms in use which failures occur simultaneously or in sequence, resulting in a ca-
overlap to some extent and overall refer to anything that does tastrophe. Even a seemingly robust system can be prone to error
or could cause patient harm. Various definitions are provided in and paradoxically create dangers, as people are lulled into a false
E Box 5.2. sense of security from the routine. Reason emphasizes that some
The Harvard Medical Practice Study [18, 27] found that almost PSIs are the result of decisions made at managerial or organiza-
half of all AEs were associated with surgery; 27.6% were due to tional level, e.g. in the design of a piece of equipment or the way
negligent care, and the most common non-​operative AEs were a service is run. Potential effects of decisions taken remotely may
drug errors. not always be apparent at the time they are made by the people
Vincent [28] argues that the causes of errors should be con- who make them. Vincent et al. [31] have modified Reason’s ‘Swiss
sidered in context and that staff are influenced both by the task cheese’ model to identify contributory factors to PSIs (also see
and the team with which they are working within the wider E Box 5.3), which can be used as a framework for analysing CIs.
36 CHAPTER 5   Patie nt saf et y and clinical g overna n ce

comorbidities. In a study of the frequency of potential errors

Box 5.3  Contributory factors in patient safety incidents
and AEs in the ICU, Gallesio [39] noted an increased AE rate,
◆ Patient factors: compared with the general ward setting, due to an approximately
Clinical condition, physical factors, social factors, psycho-
● 10-​fold increased rate of patient interventions. Two studies—​the
logical/​mental factors, interpersonal relationships Critical Care Safety Study (CCSS) in the US [40] and the Sentinel
Staff factors:
◆ Events Evaluation Study (SEES) in Europe [41]—​attempted to
Physical issues, psychological, social/​domestic, personality,
● quantify the rate of error in the critical care setting. The CCSS
and cognitive factors found an approximate daily rate of 0.8 AEs and 1.5 serious errors
Team factors:
◆ for a ten-​bedded unit, while the SEES found an error rate of
Role congruence, support, leadership
●
38.8 AEs per 100 patient days. Emergencies (i.e. cardiac arrest)
Task factors:
◆
are particularly prone to errors and AEs. Studies [40,  42] have
shown higher rates of AEs during emergency resuscitation, com-
Guidelines, decision aids, policies, protocols, task design
●
pared with the general hospital population (2–​4 times higher),
Communication factors:
◆
attributed to:
Verbal, non-​verbal, written, management
●

◆ An increased rate of patient interventions.

Working condition factors:
◆

Time, workload, physical design, administration

●
◆ The time-​critical nature of care.
Equipment factors:
◆
◆ The need for rapid decision-​making.
Displays, integrity, position usability, ergonomics
●
◆ Teams of individuals who may have never previously worked
Education and training factors:
◆
together.
Competence, supervision availability, accessibility
● Reporting of PSIs in health care is poor [23, 43, 44], more so
Organizational factors:
◆ when they occur in a cardiac arrest situation, since the team
perception is that the outcome is unlikely to be successful. Few
Strategy, structure, culture
●
publications detail AEs during resuscitation, but Andersen et al.
Source data from National Patient Safety Agency (NPSA) contributory fac-
tors framework. [45] published findings of a search of the Danish Patient Safety
Database, where, of 122 incidents, four main themes of causative
factors were identified (see E Figure 5.1).
In 2012, Ornato [46] published results from the US National
The shift towards a culture of prevention and learning and Registry of Cardiopulmonary Resuscitation (NRCPR) database,
‘no blame’ culture seems to be on the forefront of organizations looking at errors reported during resuscitation. Of 118 387 resus-
throughout the world to improve patient safety. The World Health citations, in an 8-​year period, 28.7% had one or more errors re-
Organization (WHO) in Patient Safety: Making Health Care Safer ported, associated with a decreased rate of return of spontaneous
reinforces the need to reduce the fear around reporting to allow to circulation (ROSC), survival to 24 hours, and survival to hospital
progress and learning from errors [32]. The NHS’s A Just Culture discharge. He concluded:
has a guide for managers to treat staff involved in incidents in
‘Resuscitation training should be targeted to emphasise avoiding the
a consistent, constructive, and fair way [33]. In the US, Wachter
types of errors having the greatest impact on survival (e.g. delays in
recognizes the need for the ‘no blame’ approach as the only hope initial defibrillation and medication administration and adherence
to engage physicians in patient safety efforts [34]. A narrative re- to ACLS protocols). An increasing body of evidence indicates that
view of the literature into safety culture in intensive care inter-
nationally and in Australia found that the challenge was in the
different perceptions of safety culture between ICUs, unit and 122 incidents
hospital management, and professional groups [35].
The WHO recognizes that staffing levels will have an impact on pa- Alerting Human Equipment Physical
tient safety [32]. There is clear evidence that having the right people resuscitation performance issues environment
in the right place reduces mortality within the ICU [36]. Research team 26% 18% 32% 11%
on workforce moral distress and impact of working in such a highly
Lack of
stressful environment shows an emotional cost on nurses [37] and equipment 11%
a negative impact on work–​life balance [38], with the concern that
these lead to mistakes, burnout, and/​or leaving the profession. Equipment
malfunction 16%
Errors and harm in acute cardiovascular care
In critical care medicine, including acute cardiovascular care, pa- Inability to use
equipment 5%
tients are particularly susceptible to the effects of error, as they
undergo multiple interventions requiring advanced technology Figure 5.1  Causative factors of critical incidents related to cardiac arrest
and complex team interactions, while unwell with multiple from the Danish Patient Safety Database.
 Rep orti n g a n d es ca l ati n g   i n c i de n ts 37

effective leadership and teamwork rather than just individual know- using the National Coordinating Council on Medical Error
ledge, skills, and attitudes are required to optimise outcomes and Reporting and Prevention (NCC MERP) index. This informa-
minimise errors in a variety of medical emergencies.’ tion is measured over time (producing a harm rate per 100 bed
days) and used to identify areas for further improvement [47].

Hazard identification
Reporting and escalating incidents
Safe health care systems require a systematic approach to iden-
tifying and analysing how things may go, or have gone, wrong. There are numerous ways for health care professionals to raise
These can be proactive or reactive processes (see E Figure 5.2). concerns about care. These include Patient Advice and Liaison
A selection of these are discussed in more detail below: Service (PALS), incident reporting, and whistleblowing. These
three are discussed below.
◆ Patient safety walkrounds: visits by members of the executive
team to clinical areas to discuss safety issues with frontline staff. ◆ Patients raising concerns and complaining:  PALS within the
This approach was developed by the Institute for Healthcare NHS offers confidential advice, support, and information on
Improvement (IHI) in the US (available from: M http://​www. health-​related matters. They provide a valuable point of con-
ihi.org) in order to: tact for patients, their relatives, and carers for health-​related
Increase awareness of safety issues among all clinical staff.
● questions, raising and resolving concerns, advice on com-
Make safety a priority for leaders by spending time pro-
● plaints procedures, and signposting to other support groups
moting a safety culture in the organization. outside the NHS [48]. In Australia, the Health Complaints
Educate staff about safety concepts such as incident reporting.
● Commissioner is a statutory impartial and independent body
Obtain and act on information gathered that identifies areas
●
that helps resolve complaints and educates health services and
for improvement. patients about their rights and responsibilities [49].
Build effective communication and working relationships
●
◆ Incident reporting:  incident reporting systems were established
with the aim of identifying what was going wrong, so that lessons
with frontline staff; walkrounds are now standard in many
could be learnt and systems put in place to prevent recurrence. All
hospitals, and evidence is appearing that important safety
health care organizations should promote PSI reporting and have
issues are identified and dealt with using this approach.
a system for reporting and reviewing AEs. A  number of large-​
◆ Case note review (trigger tool): the trigger tool was developed by scale reporting systems exist such as the Veteran Affairs system in
the IHI in the US to measure harm events in hospitals. Using the US, the National Reporting and Learning System (NRLS) in
a paper-​based proforma for a retrospective case note review, it the UK, and the Australian Incident Monitoring System (AIMS).
uses a system of triggers to identify possible harm events in ran- Centralizing reporting systems facilitates analysis and dissemin-
domly selected sets of case records. It focuses on harm events, as ation of safety issues nationally, additionally allowing the identifi-
opposed to AEs, and does not seek to determine preventability. cation of important, but infrequently occurring, events. It is widely
Once a harm event is identified, then the severity is assessed acknowledged that reporting of CIs and AEs is poor (7–​15% of
AEs) [23, 43, 44]. Reasons identified include: staff not thinking an
incident is worthy to report, fear of blame and disciplinary action,
Safety walkrounds
or the feeling that reporting has no effect, so ‘why bother?’. For a
reporting system to be successful, it is essential for information to
Case note review be fed back promptly to staff to ensure lessons are learnt and safety
solutions are implemented. In 2015, it was suggested that patient
PROACTIVE External reviews safety incidences were underreported [50]; this was due to 74% of
PSIs reported in the NHS occurring in hospitals and 1% in pri-
Risk assessments mary care [51], with 90% of NHS patient interactions occurring
in primary care [50]. The WHO acknowledges that this is a real
In situ simulation barrier to progress and learning from errors [32].
HAZARD
IDENTIFICATION ◆ Whistleblowing: this is the act of raising concerns that are harming
the service an organization delivers or commissions without
AE reporting
the fear of retribution [21]. In the UK, the release of Freedom
to Speak Up in 2016 highlights the legal and policy framework
Morbidity and mortality
review for implementation [21]. There are numerous international ex-
REACTIVE amples of whistleblowing; these include the Mid Staffordshire
Complaints and claims NHS Foundation Trust Public Inquiry where Robert Francis QC
investigated substandard care [52]. A  few examples of unsafe
Clinical audit findings include delay in addressing shortages of skilled nursing
staff and failure of the board to tighten its accountability and
Figure 5.2  Proactive and reactive methods of hazard identification. governance structure [52].
38 CHAPTER 5   Patie nt saf et y and clinical g overna n ce

between designers, researchers, health care practitioners, and

Responding to incidence NHS agencies, with the single aim of reducing error and harm.
This includes simple process changes such as the ‘daily goals’ sheet
Duty of candour [56], which increases the understanding by team members of the
With high-​profile cases of health care organizations’ attempt to therapy goals for ICU patients from 10% to 95%, as well as re-
regain the trust of the public, a move to a more transparent cul- duces the average length of stay from 2.2 to 1.1 days.
ture is needed. In the UK, the General Medical Council and the
Nursing and Midwifery Council released guidance as a standard Checklists
of professional conduct. Duty of candour is being honest and The Federal Aviation Administration defines checklists as ‘a
open with patients, colleagues, and the employer when things go formal list used to identify, schedule, compare or verify a group
wrong, apologizing, finding a remedy or support, and explaining of elements or . . . used as a visual or oral aid that enables the user
the short-​and long-​term effects of what has happened [22]. to overcome the limitations of short-​term human memory’ [57].
Despite their obvious utility, their introduction to health care has
Patient safety organization been slow. In 2001, Pronovost et al. [58] created a checklist based
There are numerous examples of patient safety organization. These on an evidence-​based bundle of care for central venous cath-
include the National Confidential Enquiry into Patient Outcome eter (CVC) insertion, aimed at reducing catheter-​related blood-
and Death (NCEPOD). The NCEPOD reviews the management stream infections (CRBSIs) by ensuring a reliable application of
of patients by undertaking confidential surveys and research to the bundle elements. Within 3 months, the CRBSI rate fell from
learn, maintain, and improve standards. Its reports include Time 2.7 (mean 8.7) per 1000 catheter days to 0 (mean 2.3). This simple
to Intervene, a review into in-​hospital cardiac arrest care, and Just intervention was estimated to have saved $175 million in health
Say Sepsis, a review into sepsis care [53]. care costs and over 1500 lives.
In Australia, the Australian Patient Safety Foundation Inc, Implementation of the WHO Surgical Safety Checklist resulted
a non-​profit independent organization, carries out research to in a reduction in surgical mortality of nearly 50% [59]. The check-
promote patient safety. Reports by them include the Emergency list involves a list of items that must be checked before anaesthesia
Medicine Events Register from 2017 [54]. (sign in), immediately before incision (time out), and before
leaving the operating theatre (sign out). This helps the team to
Improving patient safety focus on the operation and to promote teamwork and reduce au-
There are many ways in which patient safety can be improved, thority gradients. Its use is now mandatory for all operations in
including error reduction strategies, developed from a funda- the UK but has not yet been successfully deployed as routine in
mental knowledge of human behaviour and psychology (see the cardiac catheterization laboratory, although their potential
E Box 5.4). utility is clear [60]. The AHA has published a scientific statement
on patient safety in the cardiac operating room, indicating that
Designs for safety the use of checklists should be considered mandatory [61].
The Department of Health published a report in 2004 entitled The WHO safe surgery checklist [62] is world renowned.
Design for Patient Safety [55], recommending the collaboration A  quality improvement project in the UK looked at the use of a
checklist for the cardiac catheterization laboratory. This quality
improvement project found a reduction in turnaround time and
Box 5.4  Human factors: error reduction strategies reported complications [63]. The use of a checklist for invasive
procedures has been advised by the Intensive Care Society for per-
Design for safety
◆
cutaneous tracheostomy, intubation, central line insertion, bronch-
Automate carefully
◆
oscopy, and chest drain and nasogastric (NG) tube insertion [64].
◆ The way we think (cognition strategies):
Avoid reliance on memory
● Simulation training
Simplify
●
A simulator has been described as ‘a device that attempts to re-
Standardize
●
create characteristics of the real world’ [65]. Simulations can be
Safer labels and signs
● delivered via low-​fidelity ‘part-​task’ simulators in fully immersive
The things we do (behavioural strategies):
◆ environments, such as the simulated operating theatre, or via in
Use constraints/​forcing functions
● situ simulations in the clinical environment. Simulation can en-
Use protocols and checklists
● hance learning through feedback and repeated practice and im-
Improve information access
● prove quality of care [66]. In situ simulation delivers training to
The way we feel about our work (emotional strategies):
◆
an entire ‘real’ team in a realistic setting, enabling training and
assessment of non-​technical teamworking skills, as well as pro-
Promote effective team functioning
●

viding opportunities to risk-​assess the clinical environment for

Reduce number of, and structure, handovers
●
latent threats such as missing equipment [66].
 Per s ona l  pe r spe c t i v e 39

Leadership, teamwork, human factors, and awareness is especially important in areas where information flow
non-​technical skills can be high and poor decisions can lead to serious consequences.
Experience from high-​reliability industries demonstrates that, by
Communication failure is a leading cause of patient harm [16], taking account of human factors and behaviour when designing fa-
and while team members require the technical skills to per- cilities, processes, and equipment, the impact of human error may be
form a task, non-​technical skills are also necessary. These are mitigated [78]. One technique to proactively identify potential failure
‘the cognitive, social, and personal resource skills that com- points is failure modes and effects analysis (FMEA) which considers
plement technical skills, and contribute to safe and efficient the potential failures of a system and their likelihood and impact,
task performance’ [67] and include interpersonal skills, such thereby allowing strategies to reduce failure. FMEA is a recent add-
as communication, cooperation, and leadership, and cogni- ition to health care safety, but in 2001, the Joint Commission on
tive skills such as situation awareness and decision-​making Accreditation of Healthcare Organizations (JCAHO) selected FMEA
[68–​71]. as a method to improve patient safety standards [79]. By using a ‘sys-
Our understanding of non-​technical skills mostly derives from tems approach’ to safety, industries have been able to significantly
aviation. A series of airline accidents in the 1970s, in which no reduce AEs. By improving the system components and their inter-
primary technical fault was found, highlighted the importance action, overall safety can be improved, and this strategy is increas-
of these skills, as illustrated by a crash in Tenerife in 1977, in ingly employed to improve patient safety in health care [31, 80].
which 583 people died. Analysis of the accident revealed prob-
lems with communication, team coordination, decision-​making, Quality improvement
and leadership [72]. In 1979, the National Aeronautics and Space
Quality improvement has no agreed definition. The King’s Fund
Administration (NASA) initiated research to identify exactly
defines quality improvement as a systematic use of methods and
which skills were important and found that they were all skills
tools to try to continuously improve quality of care and outcomes
that pilots knew were traits of a good pilot but were never formally
for patients [81]. There are numerous methods and tools. The IHI
taught. Crew resource management (CRM) courses were devel-
use the Model for Improvement, combining ‘what are we trying
oped to teach leadership, decision-​making, situation awareness,
to accomplish?’, ‘how will we know that the change is an improve-
and communication skills and to flatten the hierarchy within the
ment?’, and ‘what change can we make that will result in improve-
cockpit [73]. A comparative review between aviation and health
ment?’ with the ‘plan, do, study, act’ cycle [82].
care and its implications for patient safety found that while health
There is no evidence that one tool is superior to another; it
care can learn from aviation, the lessons need to be nuanced to
is the process of having a systematic, but dynamic, approach to
health care [74].
quality improvement and applying this consistently that is im-
Non-​technical skills have been undervalued in health care;
portant, rather than the method used [83].
however, since reports highlighting their importance in the
levels of error and harm and failure (particularly in the emer-
gency setting), greater interest is being shown in providing
teaching and training to all health care staff in human fac- Conclusion
tors, leadership, and teamwork [9,  16]. A  major contributor
Acute cardiovascular care is an area of cardiology where, by
to health care failures is the professional authority gradient
virtue of the severity and acuity of illness of the patients and
[75]. In some areas of health care, a steep hierarchy remains,
the high number of emergency procedures, patient safety may
despite evidence [69,  76] demonstrating that better commu-
be compromised. Increasing understanding and awareness
nication in multidisciplinary teams improves coordination
of error in health care will lead to fundamental changes in the
of patient care and reduces mortality and average patients’
way that clinicians practise, both as individuals and as part of a
length of stay.
multidisciplinary team.
Cognitive psychology indicates that it is impossible for the
human brain to process everything simultaneously, and there-
fore, we focus on some things more than on others, depending
on experience and specific cues in the environment. Endsley [77]
Personal perspective
found that, in 88% of aviation accidents in which human factors Increasing national and international focus on patient
were implicated, the lack of situation awareness was a major causal safety and clinical governance makes these topics manda-
factor. A  hypothetical example from the cardiac catheterization tory for any clinician in every specialty. Greater complexity
laboratory is when the cardiology team is performing a complex of care delivery to patients with multiple comorbidities
endovascular procedure that is more challenging and technic- makes health care a high-​risk activity. There is a balance to
ally demanding than anticipated. The patient becomes haemo- be struck between checklists and non-​technical skills, when
dynamically unstable due to continued and unnoticed blood loss appropriate and safe staffing has a significant bearing on
from the femoral puncture site, but this is not recognized due to patient safety. Appropriate workforce planning and appro-
the intense focus on the imaging and technical challenges of the priate investigations and handling of PSIs will play an im-
intervention, and a cardiac arrest occurs which could have been portant role for the future.
prevented, had there been better situation awareness. Situation
40 CHAPTER 5   Patie nt saf et y and clinical g overna n ce

Further reading
Brennan TA, Leape LL, Laird NM, et al. Incidence of adverse events and Gawande A. Better—​ A Surgeon’s Notes on Performance. Profile
negligence in hospitalised patients. Results of the Harvard Medical Books: London; 2008.
Practice Study. N Engl J Med 1991;324:370–​6. Gawande A. The Checklist Manifesto:  How to Get Things Right. Profile
Department of Health. An organisation with a memory. 2000. Available Books: London; 2010.
from: M http://​webarchive.nationalarchives.gov.uk/​+/​www.dh.gov.uk/ Haxby E, Hunter D, Jaggar S (editors). An Introduction to Clinical
​ e n/​ P ublicationsandstatistics/​ p ublications/​ p ublicationspolicy Governance and Patient Safety. Oxford University Press: Oxford;
andguidance/​browsable/​dh_​4098184. 2010.
Department of Health. Building a safer NHS for patients:  implementing an Morath JM, Turnbull JE. To do no harm: ensuring patient safety in health
organisation with a memory. 2001. Available from: M https://​webarchive. care organizations. San Francisco: Jossey-​Bass; 2005.
nationalarchives.gov.uk/​20070402203945/​http://​www.dh.gov.uk/​en/​ Vincent C. Analysis of clinical incidents: a window in the system not a
Publicationsandstatistics/​Publications/​PublicationsPolicyAndGuidance/​ search for root causes. Qual Saf Health Care 2004;13:242–​43.
DH_​4006525. Vincent C, Neale G, Woloshynowych M. Adverse events in
Department of Health (National Audit Office). A safer place for British hospitals:  preliminary retrospective record review. BMJ
patients:  learning to improve patient safety. 2005. Available from: 2001;322:517–​19.
M http://​www.nao.org.uk/​wp-​content/​uploads/​2005/​11/​0506456.pdf. Weingart S, Wilson RM, Gibberd R, Harrison B. Epidemiology of medical
Gawande A. Complications—​A Surgeon’s Notes on an Imperfect Science. error. BMJ 2000;320:774–​7.
Profile Books: London; 2002.

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 CHAPTER 6

Ethical issues in cardiac

arrest and acute cardiac
care: a European
perspective
Jean-​Louis Vincent and Jacques Creteur

Contents
Summary  43 Summary
Introduction  43
Acute cardiac syndromes are common and responsible for considerable mortality
Overview of the ethical principles  44 and morbidity. Decision-​making in such patients can be difficult clinically but
Beneficence  44
Non-​maleficence  44 can also be complex and challenging from an ethical perspective. This chapter re-
Autonomy  44 views some of the ethical problems, including organ donation and withholding/​
Distributive justice  44 withdrawing, that can occur in the acutely ill adult cardiac patient, starting with
Overview of specific ethical issues in cardiac
a brief look at the ethical principles that should guide our decision-​making: ben-
arrest and acute cardiac care  44
Family presence during cardiopulmonary eficence, non-​maleficence, autonomy, and distributive justice. The role of advance
resuscitation  44 directives and considerations related to family presence during cardiopulmonary
Advance directives  45 resuscitation will also be discussed. With the increasing incidence and prevalence
Do-​not-​attempt-​resuscitation orders  45
Withholding/​withdrawing  46 of coronary artery disease worldwide, the number of patients with cardiac arrest
Withholding/​withdrawing and requiring acute cardiac care is going to increase and doctors will be increas-
cardiopulmonary resuscitation  46
Withholding/​withdrawing life-​sustaining ingly faced with difficult ethical decisions associated with these patients. Open dis-
therapies  46 cussion and debate about these issues and good communication among patients,
Specific case of extracorporeal membrane family members, and members of the health care team are essential to ensure that
oxygenation  48
Organ donation  48 all patients receive the best possible end-​of-​life care.
International differences in approaches to
ethical issues  49
Personal perspective  49
Further reading  50
References  51
Introduction
ACS are common and responsible for considerable mortality and morbidity. Precise esti-
mates of the incidence of out-​of-​hospital cardiac arrests are difficult to make, as many go
unreported, but estimates for patients treated by the emergency medical system (EMS)
vary from 43 to 108/​100 000 population/​year [1–​3]. Patients who have an out-​of-​hospital
cardiac arrest will frequently be treated by bystanders or EMS teams who have no prior
knowledge of the patient’s background, quality of life, or personal wishes regarding end-​
of-​life management. Prognostication in such patients is generally very difficult, and the
time window for effective treatment is short, so that immediate measures are usually
started with the plan to re-​evaluate the situation later. In the immediate urgency of the
event, it can be easy to overlook (or postpone) the ethical issues associated with initiating
and continuing cardiopulmonary resuscitation (CPR) and, more recently, extracorporeal
44 CHAPTER 6   Ethic a l issu es in cardiac arrest a n d acu te ca rdiac ca re: a Eu ropea n perspe c t i v e

CPR. Yet guidelines exist to assist with such situations [4, 5], both on themselves and others. Patients may choose an approach that
for the EMS teams first on the scene and for hospital staff once differs from that of the attending physician or care team, and their
the patient is admitted. Here, we will review some of the often decision needs to be respected wherever possible. However, the
complex and challenging ethical decisions that can occur in the principle of autonomy can conflict with other principles, if the
acutely ill adult cardiac patient, starting with a brief look at the decision involves something that physicians believe may harm
ethical principles that should guide our decision-​making. the patient or is not in their best interest. In the acute cardiac ar-
rest situation, it is often difficult, or impossible, to apply the prin-
ciple of patient autonomy, unless a do-​not-​attempt-​resuscitation
Overview of the ethical principles (DNAR) order has already been discussed with, and approved by,
the individual.
All ethical decision-​making within medicine should be guided
by the four key principles of medical ethics:  beneficence, non-​ Distributive justice
maleficence, autonomy, and distributive justice [6]‌. Application The principle of distributive justice relates to the equitable distri-
of these principles is not always straightforward, and the rela- bution of health care resources across society, such that all patients
tive weight of each principle may differ in different situations. have similar chances of receiving the treatments and care they
Importantly too, cultural, religious, legal, and economic factors need. Distributive justice tries to balance treatment decisions, so
may all influence the ways in which each of the principles are in- that those who will benefit the most are treated. Importantly, dis-
terpreted and applied. Temporal changes in individual and global tributive justice involves a calculation as to what will benefit other
values and needs may also affect the relative importance of each patients and society as a whole, and not necessarily just the indi-
principle; for example, patient autonomy now carries more weight vidual patient. For example, administering life-​sustaining treat-
than previously and distributive justice is increasingly relevant as ment to a patient who has no hope of survival uses resources that
financial constraints increase. could be better used in an individual who has some chance of re-
covering a meaningful life and therefore goes against the principle
Beneficence of distributive justice.
The principle of beneficence concerns acting in a way that will
ultimately benefit the patient or be in the patient’s best interest.
This is perhaps the most commonly used ethical principle. In the
cardiac arrest situation, application of the principle of benefi- Overview of specific ethical issues in
cence will generally lead to the initiation of CPR but could lead to cardiac arrest and acute cardiac care
withholding CPR if it is considered there is no chance of a mean-
ingful survival. Beneficence may, at first glance, appear relatively Family presence during cardiopulmonary
straightforward but can be complicated, especially in acutely ill resuscitation
patients who are unknown to the medical team.
Decisions about whether family members should be allowed to
be present during CPR continue to generate considerable debate.
Non-​maleficence Importantly, in a cardiac arrest situation, the patient is uncon-
Non-​maleficence—​primum non nocere, i.e. first do no harm—​ scious and his/​her wishes cannot be taken into consideration.
forms part of the Hippocratic oath. Again, application of the prin- Hence, the ethical principle of autonomy is not applicable; dis-
ciple is not always easy, because the definition of ‘harm’ may vary tributive justice is also of little relevance here. Some would argue
in different situations; for example, many effective medical treat- that allowing family members to remain present is not of benefit
ments have harmful, or potentially harmful, adverse effects, but to the patient, because it is easier to work under stressful emer-
their benefits will outweigh their harmful effects, such that the gency conditions when family members are not present; others
principle of beneficence will prevail over that of non-​maleficence. would suggest that having family members present is of benefit,
Importantly, harm refers not only to suffering, but also to loss of especially for the patient who later recovers, as it helps patients
dignity. In end-​of-​life decision-​making, providing life-​supportive come to terms with their near-​death experience. In the case of
treatment simply to prolong life may thus be seen as causing more non-​survival, being present during resuscitation can help reassure
harm than benefit; in such situations, allowing a patient to die can the family member that everything that could have been done was
sometimes be a way of ‘doing no harm’. done and can provide a chance to say goodbye, but at the potential
cost of an increased risk of post-​traumatic stress. Clearly, some
Autonomy individuals will not want to be present and they should certainly
Derived from the Greek word autonomia, meaning independence, not be urged to stay. Surveys have suggested that as many as 75%
the principle of autonomy reflects the right of each individual to of relatives would wish to be present [7]‌, although the percentage
make their own decisions. Importantly, to be able to follow this of medical staff who are in favour of this approach is lower. A pro-
principle, the patient must be competent and sufficiently well in- spective study in France reported that family members who were
formed of all the options and the effects of any possible decision present during CPR had fewer post-​traumatic stress symptoms
 Ov erview of   specif ic eth i ca l i s su es i n ca rdiac a rrest a n d acu te ca rdiac   c a re 45

than family members who were not present and that the pres- for the physician, although a carefully written, informed advance
ence of family members did not interfere with the effectiveness directive must be respected, the lack of an advance directive does
or duration of the CPR [8]. Although some have raised fears of not mean that the patient should receive maximum, even futile,
increased medicolegal claims if families are present during CPR, therapy.
this study did not support this suggestion [8]. Cultural and re- Importantly, the legal validity of different types of advance
ligious backgrounds and beliefs will influence the approach to directive varies in different countries [15–​17]. Within Europe,
this issue. As with much of medical ethics, this is an area where written advance directives are legally binding in many countries
attitudes have changed over the years as these issues have been (e.g. the UK, Austria, Spain, Hungary, Belgium, the Netherlands,
more openly discussed. The AHA guidelines for CPR and emer- Germany, Portugal, Switzerland, Finland), whereas in others, they
gency cardiovascular care recommend (grade IIa, LoE C) that are considered more as advisory documents (e.g. France, Italy) or
select family members should be offered the opportunity to be no legislation is yet in place (e.g. Norway, Poland, Sweden, Greece,
present during resuscitation [9]. The European Resuscitation Serbia, Slovakia, Bulgaria, Lithuania, Turkey). Importantly, even
Council (ERC) guidelines also recommend that relatives should when considered legally binding, certain criteria need to be met
be offered the choice to be present during a resuscitation attempt by the directive and/​or patient in order for the binding nature
[5]. Importantly, unlike staff members, most family members to be upheld; for example, in the UK and Ireland, documents in
will not have witnessed a resuscitation event. If they are present which treatment is refused are legally binding, but not documents
during CPR, it is therefore essential that some explanation is that request treatment be given. In several countries (e.g. Austria,
given regarding what is happening and, whatever the outcome, Hungary), there is a time limit, such that older advance directives
some form of debriefing is provided afterwards to address any are no longer considered valid. In some countries, the advance
questions and help deal with any emotions raised during what directive must be countersigned by a physician stating that the
will have been a stressful event for them [10]. patient was competent to make such a directive (e.g. Hungary)
or by a lawyer (e.g. Austria), and in many countries, there is a
proviso that complying with the advance directive be in the ‘best
Advance directives interests of the patient’. These issues are being hotly debated
Advance directives are oral, written, or videoed documents across Europe, and indeed worldwide, as governments try to find
stating the type of medical care that a patient wishes to have at an appropriate balance between patient autonomy and the more
a point in the future, should a certain set of circumstances be paternalistic physician approach to end-​of-​life decision-​making.
met. As such, advance directives reflect the ethical principle of Although calls have been made for a general European policy on
autonomy and help to ensure it is respected, even when a pa- this issue [15], the sociocultural, religious, and legal backgrounds
tient is no longer able to communicate his/​her wishes. There are of the countries involved are too different for this to be likely in
many types of advance directive, the simplest and most widely the near future.
used being the do-​not-​attempt-​resuscitation (DNAR) order (see
E Do-​not-​attempt-​resuscitation orders, p. 45). A patient can re- Do-​not-​attempt-​resuscitation orders
quest a DNAR order or the physician can propose one, which The DNAR order was a topic of controversy for many years but is
the patient can refuse or accept. Living wills contain more de- now generally accepted as a valid means of indicating a patient’s
tailed, specific directions about a greater spectrum of interven- wishes, should the need for resuscitation arise. Importantly, the
tions than just resuscitation, and durable powers of attorney or DNAR order is exactly what it says and refers only to ‘resusci-
health care proxy forms specify a ‘surrogate’ who can make med- tation’, and not to other medical treatments or life-​sustaining
ical treatment decisions for the individual in case of incapacity. therapies. The DNAR order evolved out of an increasing belief by
Such surrogates can be particularly helpful when end-​of-​life de- physicians that CPR was not necessarily of benefit to all patients;
cisions need to be made, e.g. in the case of a patient with poor indeed, many adopted the practice of subtly marking a patient’s
neurological recovery after cardiac arrest. Living wills and power notes to indicate when resuscitation should not be attempted.
of attorney orders are increasingly common, and it is now es- Emphasis on patient autonomy led to widespread introduction of
timated that about one-​third of US adults have established one DNAR orders, and increasingly patients are asking for such orders
[11]; these percentages vary across countries and with age, re- to be recorded, rather than waiting for the subject to be raised by
ligious and cultural backgrounds, and comorbidity [12,  13]. the medical staff. It is widely considered that such orders should
Importantly, although considered a notable advance in terms of be officially documented on a form designed for that purpose or
respecting patient autonomy, living wills and advance directives clearly written in the patient’s notes and that oral orders are not
have several limitations, including the often vague terminology acceptable [5, 9]. Nevertheless, in some countries, oral DNAR or-
used and the limitation of the directive to the conditions and ders are preferred to written ones, by fear of possible legal im-
interventions listed within it, as it is impossible to list every pos- plications [18]. This is particularly true in countries with strong
sible outcome—​how does the physician act if the patient does religious influences, e.g. in the South of Europe. For the out-​of-​
not fall into the categories described [14]? There is also a chance hospital cardiac arrest situation, DNAR orders are often not avail-
that the patient will change their mind when actually faced with able, but the use of CPR should be discussed with all hospitalized
one of the situations discussed in their advance directive. And, patients at potential risk of cardiac arrest and decisions reviewed
46 CHAPTER 6   Ethic a l issu es in cardiac arrest a n d acu te ca rdiac ca re: a Eu ropea n perspe c t i v e

at regular intervals [9, 19]. Patients must be fully informed about The AHA guidelines recommend its use in adult out-​of-​hospital
the implications of such decisions and what aspects of ‘resuscita- cardiac arrest where ALS is not available (grade I, LoE A) [9]. It is
tion’ are/​are not included; studies have suggested, however, that less widely applied in many places in Europe where medicalized
this may not be the case [20]. The presence of a DNAR order may ambulances usually intervene.
also subtly influence the non-​resuscitation treatment a patient is For in-​hospital cardiac arrest, guidelines state that CPR should
given. Moreover, ‘partial’ DNAR orders can be confusing and may be started in all patients, unless there is a written DNAR order
not necessarily lead to management that is of greatest benefit to or objective evidence of irreversible death [4]‌. European guide-
the patient [21]. Despite the widespread use of these orders, fur- lines state that CPR should not be attempted if it will be obviously
ther open discussion and improved communication are needed futile [7], but the definition of ‘futile’ can be difficult and varies
to clarify some of the potential limitations and improve interpret- according to cultural, religious, and personal beliefs. There are
ation and application. no independent predictors for non-​survival that have been ad-
equately validated on prospective patient populations, and phys-
icians have to rely on personal judgement and an awareness of
Withholding/​withdrawing
risk factors for death such as comorbidities and extreme age. (See
Withholding/​withdrawing cardiopulmonary resuscitation also E Chapter 6.)
If a written DNAR order is available, the decision to withhold
CPR is relatively easy to take. In other situations, whether and Withholding/​withdrawing life-​sustaining therapies
when CPR should be withheld or withdrawn is less clear. For Importantly, as mentioned earlier, the DNAR order does not cover
each individual, decisions need to be based on a balance between other interventions, such as intubation and mechanical ventila-
the potential benefits and harm that CPR could place on the pa- tion, renal support, and inotropes and vasopressor drugs, which
tient, family, and health care providers [5]‌. However, in an out-​ are frequently used post-​cardiac arrest in the CCU or ICU. Many
of-​hospital cardiac arrest, these factors are very difficult to assess of these life-​supporting interventions are withdrawn once it be-
reliably and rapidly, and in general, CPR is considered the default comes clear that there is no reasonable expectation of the patient
action [22]. Nevertheless, there are some patients in whom CPR surviving and continuing therapy is considered futile, i.e. there
should not be considered in this situation and it may be that, will be no beneficial effect in terms of quality of life or duration;
by making CPR the default, many patients actually receive an there may be a physiological effect, but this will not correspond
intervention that is against their best interests and indeed causes to benefit for the patient. Good communication among the health
harm, making it ethically unjustifiable [22]. The AHA guidelines care team, the patient (if possible), and the patient’s relative(s) is
suggest several situations for out-​of-​hospital cardiac arrest in essential in this situation to make it clear that no benefit will be
which it may be appropriate to withhold CPR, including situ- gained from starting or continuing the therapy in question; al-
ations where performing CPR would put the rescuer at risk of though modern medicine can do much in terms of saving lives,
serious injury or death or where there are obvious clinical signs there are times when nature must be allowed to play its role. The
of irreversible death (e.g. decapitation, decomposition) [4]. The decision that an intervention is futile in a particular patient is
British Medical Association, Resuscitation Council (UK), and clearly a medical one; whether and when that decision is acted on
the Royal College of Nursing [23] and other groups have devel- and treatment withheld/​withdrawn may be influenced by specific
oped relatively complex clinical frameworks to help health care circumstances related to the patient, physician, local cultures, and
workers determine whether or not CPR should be started (see laws—​however, health care providers should never feel obliged to
E Figure 6.1), but in the acute situation, simply deciding provide futile treatment when there is a sound medical consensus
whether a patient is likely to survive CPR or not may be suffi- that it will be ineffective [9]‌.
cient to guide the initial decision [24]. The majority of deaths in the ICU are now preceded by a de-
Once started, CPR should be continued until circulation is re- cision to limit treatment in some way [29–​32]. As with the other
stored, the criteria of obvious irreversible death are met, or the ethical issues discussed, such decisions are influenced by many
patient meets predefined criteria for termination of resuscita- factors, including personal beliefs and experience, cultural and
tion [9]‌. Several rules for termination of resuscitation after out-​ religious influences, and peer and family pressure. Most ethi-
of-​hospital cardiac arrest have been developed. In the absence cists and medical societies agree that there is no ethical or moral
of advanced life support (ALS), the basic life support (BLS) ter- distinction between withholding or withdrawing life-​sustaining
mination of resuscitation (BLS-​TOR) rule is the best known and treatments [9, 33–​35], but this is not a universal opinion [36, 37].
most widely validated. The BLS-​TOR rule includes three simple It is very important to accept the concept that life support should
criteria: (1) cardiac arrest not witnessed by EMS personnel; (2) no be withdrawn in futile cases, both for the individual (otherwise
ROSC after three full rounds of CPR; and (3) no automatic ex- doctors may hesitate to start full support, and therefore not give
ternal defibrillator (AED) shock delivered [25]. The rule has a patients the best possible chance) and for society (keeping pa-
specificity of 90.2% for recommending transport of survivors to tients with no hope of meaningful survival in the ICU is against
the ED and a positive predictive value (PPV) for death of 99.5% the principle of distributive justice). Of course, many phys-
when termination is recommended [25], and has been validated icians find it harder to withdraw than to withhold a therapy,
in Canada [25], the US [26], Scandinavia [27], and Japan [28]. although it should be remembered that patients die because of
 Ov erview of   specif ic eth i ca l i s su es i n ca rdiac a rrest a n d acu te ca rdiac   c a re 47

Is cardiac or respiratory It is not necessary to discuss CPR with the patient unless they
arrest a clear possibility express a wish to discuss it.
for the patient? No
If a DNACPR decision is made on clear clinical grounds that CPR
Yes would not be successful, there should be a presumption in favour of
informing the patient of the decision and explaining the reason for
it (see section 5). Those close to the patient should also be informed
and offered explanation, unless a patient’s wish for confidentiality
Is there a realistic chance prevents this.
that CPR could be
successful? Where the patient lacks capacity and has a welfare attorney or court-
No appointed deputy, or guardian, this representative should be informed
of the decision not to attempt CPR and the reasons for it, as part of the
Yes ongoing discussion about the patient’s care.
Where the patient lacks capacity, the decision should be explained to
those close to the patient without delay. If this is not done immediately,
the reasons why it was not practicable or appropriate must be
Does the patient lack documented (see section 5).
capacity AND have an
advance decision If the decision is not accepted by the patient, their representative, or
specifically refusing CPR those close to them, a second opinion should be offered.
OR have an appointed
attorney, deputy, or If a patient has made an advance decision refusing CPR, and the criteria
guardian? for applicability and validity are met, this must be respected.
Yes If an attorney, deputy, or guardian has been appointed, they must be
consulted (see sections 9.1 and 10).
No

Discussion with those close to the patient must be used to guide a

Does the patient lack
decision in the patient’s best interests (see section 10). When the
capacity?
patient is a child or young person, those with parental responsibility
Yes
should be involved in the decision where appropriate, unless the
No child objects (see section 11).

Is the patient willing to Respect and document their refusal (see section 6.3). Discussion
discuss his/her wishes with those close to the patient may be used to guide a decision in the
regarding CPR? No patient’s best interests, unless confidentiality restrictions prevent this.

Yes

The patient must be

involved in deciding If cardiorespiratory arrest occurs in the absence of a recorded
whether or not CPR will decision, there should be an initial presumption in favour of
be attempted in the event attempting CPR.
of cardiorespiratory Anticipatory decisions about CPR are an important part of
arrest. high-quality health care for people at risk of death or
cardiorespiratory arrest.
Decisions about CPR are sensitive and complex and should be
undertaken by experienced members of the health care team
with appropriate competence.
Decisions about CPR require sensitive and effective
communication with patients and those close to patients.
Decisions about CPR must be documented fully and carefully.
Decisions should be reviewed with appropriate frequency and
when circumstances change.
Advice should be sought if there is uncertainty.

Figure 6.1  Decision-​making framework for performing CPR in out-​of-​hospital cardiac arrest: guidance from the British Medical Association, the Resuscitation
Council (UK), and the Royal College of Nursing. Sections refer to the published text available from: M https://www.resus.org.uk/sites/default/files/2020-
05/20160123%20Decisions%20Relating%20to%20CPR%20-%202016.pdf​.

the unfavourable progression of their disease process, and not [38–​40]. Good communication with the relatives is vitally im-
because of the decision to withdraw or withhold therapy. In the portant in such a ‘trial’ to ensure that the nature and time limits
ICU situation, there may be a place for a time-​limited ICU or life-​ of the test are clearly understood and that no false hope is given.
sustaining therapy trial in which certain therapies are tested to see With the large numbers of deaths now associated with an end-​
if the patient responds, but once the predefined ‘test period’ has of-​life decision, improving the process by which life-​sustaining
concluded and there is no response, then therapy is withdrawn treatments are withheld or withdrawn is an important aspect of
48 CHAPTER 6   Ethic a l issu es in cardiac arrest a n d acu te ca rdiac ca re: a Eu ropea n perspe c t i v e

improving the quality of care in the ICU [33]; guidelines have When CPR is unsuccessful, the outcome is clear, whereas once
been published to help physicians with the practical aspects of ECMO has been commenced, it becomes a life-​sustaining inter-
withdrawal [33, 39]. Good communication among medical staff vention and the ethical issues associated with withdrawal must
and with patients (where possible) and family members and be considered (as discussed in E Withholding/​withdrawing
careful documentation of any discussions, decisions, plans, and life-​sustaining therapies, p. 46). Finally, issues surrounding the
outcomes are essential components [31, 33, 34]. Ensuring the pa- potential use of eCPR and ECMO as a means of maintaining
tient dies comfortably and with dignity is crucial. Monitoring is organ viability in patients in whom there is no hope of survival
unlikely to provide useful information, once a decision has been need to be elucidated [51].
made to withdraw, and may be distressing and confusing, espe-
cially for relatives, so monitoring equipment should ideally be re- Organ donation
moved [33, 39]. Faced with shortages in the numbers of suitable organs for donation
Withdrawal of any intervention is usually performed slowly [52], all physicians working with patients at risk of dying should be
when sudden cessation would be distressing to the patient, e.g. in familiar with local and regional plans for organ donation and pro-
the case of mechanical ventilation, in which terminal ventilator curement. In the ICU, organ donation should be considered a key
discontinuation, with transition from full ventilatory support to component of end-​of-​life decision-​making. All ICU admissions
T-​piece or extubation, over 10–​20 minutes, is recommended [31]. and/​or their families should be asked about advance directives and
Withdrawal should also not be so abrupt that it risks distressing organ donation, so that preferences are known, should death occur.
the relatives. In some centres, and it is a general rule in Belgium Different religious and cultural beliefs related to death, dying, and
[34], the doses of analgo-​sedative agents are increased to shorten the dead will influence the rates of organ donation [53–​55].
the dying process. Specifically designed withdrawal of life support Donation after brain death is the most common form of organ
protocols may be of use in some units [41], and consultation with donation, but organ donation is increasingly performed after
palliative care teams has sometimes been found to be helpful [42], circulatory determination of death [donation after circulatory
although this should not be the rule. death (DCD)], also previously called non-​heart-​beating dona-
Increasing numbers of patients now have implanted cardiac tion (this terminology is no longer used). There are two types
pacemakers and antiarrhythmia devices, including implantable of DCD. In uncontrolled DCD, ECMO is started with the only
cardioverter–​defibrillators (ICDs) and ventricular assist devices aim being to preserve the organs to be transplanted. In con-
(VADs). These are effectively life-​sustaining therapies, and the trolled DCD, life-​supporting therapy is withdrawn in a planned
same ethical principles apply to removing or deactivating these manner in the operating room and organs harvested shortly after
devices as to other interventions [43, 44]. cardiopulmonary arrest (Maastricht type III donors [56, 57]). In
some centres, including ours, major sedation with muscle par-
Specific case of extracorporeal membrane alysis is used to shorten the agonal phase and ensure better organ
oxygenation preservation. In Belgium, 34% of deceased donors were DCD in
In recent years, use of ECMO in the acute cardiac patient has 2015 [58]; in the UK, between March 2017 and March 2018, 24%
increased considerably [45, 46]. ECMO and extracorporeal CPR of all donors were DCD [52]. This approach can increase the
(eCPR) can provide circulatory support and thus offer the pa- number of organ donors, which is important because demand
tient additional time for interventions to correct underlying still exceeds supply, but raises separate ethical issues related to
causes of cardiac arrest or failure [4, 47,  48]. The most recent consent and preparation of the donor occurring before death
AHA guidelines recommend that eCPR could be considered for [59, 60]. The duration of cardiac arrest necessary for death to be
cardiac arrest patients with a potentially reversible cause of car- declared and organ procurement started has also raised debate
diac arrest (Class  IIb, LoE C-​LD) [4]‌. However, this technique [61]. Moreover, some have suggested that decisions to withdraw
raises new ethical questions [47–​49]. Before starting eCPR or therapy from a critically ill patient may be biased, consciously or
ECMO, it is essential that the goal of therapy is clearly defined not, by the potential of obtaining organs by DCD [62]. Another
and potentially achievable [48,  50]. When considering use of controversial issue is whether, once a patient has been accepted
eCPR, strict criteria are needed to decide which patients should for DCD, it is acceptable to administer interventions with the
receive it [50]. As it becomes more widely available, discussions purpose of improving the viability of the organs and avoiding
will be needed to determine whether consent for eCPR should a useless agonal period. Indeed, once the decision for DCD has
be presumed when no specific DNR order is available, as is the been made, although some time can be taken to help families
case for conventional CPR. Although eCPR has been associated make a decision, it does seem reasonable to optimize the con-
with greater rates of good neurological outcomes at 6  months dition of the donor organs to ensure maximum benefit for the
than conventional CPR, it has also been associated with higher future recipient(s) [63–​65].
rates of vegetative state. The risk therefore is that eCPR could Obviously, the DCD approach is applicable only if the organs
prolong suffering, compared to conventional CPR, without are of sufficient quality, e.g. probably not for patients in shock or
changing the outcome [50]. Given that eCPR is a more extreme with severe heart failure, but primarily after cardiac arrest when
intervention than CPR, a standard DNR order should preclude the haemodynamic status is satisfactory and in the absence of any
its use, but do we need a specific ‘do not ECMO’ order [48]? contraindication to organ transplantation.
 Per s ona l  pe r spe c t i v e 49

The DCD approach is supported by many of the large med- countries, there were marked differences in attitudes to various
ical organizations [59,  66], although there are marked differ- clinical scenarios and ethical questions [18]. For example, whereas
ences among countries regarding the legislation surrounding the vast majority of physicians in Northern and Central Europe,
organ donation, the ways in which it is practised, and attitudes of North America, and Australia said that they would be likely to
health care providers towards different types of donation [67, 68]. apply written DNAR orders in a patient with severe post-​anoxic
Whichever type of donation is used, clearly defined protocols for lesions after an initial cardiopulmonary arrest, oral orders were
the withdrawal of life-​sustaining therapies are needed [59,  69]. preferred in Southern Europe, Turkey, and Brazil; one-​third of the
Families should also be able to say goodbye to their loved ones; Japanese respondents said they would not apply DNAR orders. The
this may be difficult when a patient is transferred to the operating degree of involvement of family members in end-​of-​life decision-​
room for DCD, although, in some cases, relatives have been in- making also varies considerably, generally being more frequent in
vited to the operating room to be present during the final with- Northern Europe and the US than in southern European coun-
drawal process [70]. (See also E Chapter 51.) tries, which still have a more paternalistic approach [80].

International differences Personal perspective

in approaches to ethical issues With the increasing incidence and prevalence of CAD
worldwide, perhaps particularly noticeable in the developing
An individual’s attitude to ethical dilemmas will be influenced world, the number of patients with cardiac arrest and re-
by multiple factors, including cultural, religious, and educa- quiring acute cardiac care is also going to increase. The eth-
tional backgrounds; age, training, and prior experience; legal ical issues surrounding end-​ of-​
life decision-​
making and
attitudes and peer pressure; and current trends. It is therefore death are being talked about more openly than ever before,
not surprising that there are marked national and international as widespread access to media and the Internet, including
differences in attitudes towards many of the ethical issues sur- the social media, helps to spread information and harness
rounding acute cardiac care and end-​of-​life decisions in critically debate. Advance directives will become more widespread
ill patients [18, 30, 71–​78]. Although there are some differences and more widely accepted by health care staff, as the current
in legislation regarding withdrawal/​withholding and precise pro- focus on patient autonomy continues to grow. As societies
cesses for organ donation within Europe, the major reasons for become increasingly multicultural and multiracial, some of
international differences relate more to individual characteristics the marked international differences will become less ap-
than to legal aspects. parent, but recognition and understanding of potential dif-
In the Ethicus prospective observational study of 31  417 pa- ferences at an individual level will be even more important.
tients admitted to 37 ICUs in 17 European countries [30], which Good communication with patient, family, and other mem-
was conducted in 1999/​2000, withdrawal of therapy was reported bers of the health care team is essential to ensure the best
as being more common in northern (Denmark, Finland, Ireland, possible end-of-life-care. Where there is doubt or disagree-
Netherlands, Sweden, and the UK) than in southern (Greece, ment among the health care team or with family members
Israel, Italy, Portugal, Spain, and Turkey) European countries. In related to end-​of-​life decisions or care, some believe that an
an analysis of the SAPS 3 database, which included data on 14 488 ethics consult may be of value [81, 82]. End-​of-​life care and
patients from 282 ICUs in seven different geographical regions, communication skills need to be included in medical and
the percentage of deaths that occurred after an end-​of-​life decision intensivist training curricula [33]. With continuing short-
ranged from 26% in Central and South America to 48% in Central ages of donor organs, organ donation will become a more
and Western Europe [77]. More recently, in an analysis of a data- ‘everyday’ part of end-of-life-care but must never become so
base of more than 9500 patients from countries around the world, routine that due consideration and compassion for the dying
the percentage of hospital non-​survivors with a withhold/​with- patient’s family are forgotten. Guidelines for DCD need to be
draw decision ranged from 10% in South Asia to 21% in Eastern standardized to help maximize donor organ supply without
Europe, 49% in Western Europe, and 65% in North America [71]. conflicts with any of the four ethical principles. The WHO,
In a systematic review that included 56 studies from almost 1000 the Transplantation Society, and the Spanish Organización
ICUs in over 30 countries, in addition to the substantial variability Nacional de Trasplantes (ONT) have developed a so-​called
in the withdrawal of life-​sustaining treatment among and within ‘critical pathway’ for deceased donation (see E Figure 6.2)
countries, there were also considerable differences among individ- to help provide some uniformity in practice and to encourage
uals in the same centre [73]. Religious backgrounds and beliefs consideration of donation in appropriate patients [83].
play a key role in these international differences. For example, in Attitudes to ethical issues are changing, but the four
the Ethicus study, if the physician was Jewish, Greek Orthodox, or key principles—​beneficence, non-​maleficence, patient au-
Muslim, they were more likely to withhold than to withdraw life-​ tonomy, and distributive justice—​remain as relevant as
sustaining therapy, whereas if they were Catholic or Protestant, or ever, and although they cannot dictate clinical actions, they
had no religious affiliation, they were more likely to withdraw [79]. should be used to guide end-​of-​life decision-​making.
In a questionnaire regarding end-​of-​life practice in the ICU in 21
50 CHAPTER 6   Ethic a l issu es in cardiac arrest a n d acu te ca rdiac ca re: a Eu ropea n perspe c t i v e

Critical pathways for organ donation*

Possible deceased organ donor

A patient with a devastating brain injury or lesion or a patient with circulatory failure
and apparently medically suitable for organ donation

Donation after circulatory death (DCD) Treating physician to

Donation after brain death (DBD)
identify/refer a potential donor

Potential DCD donor Potential DBD donor

A. A person whose circulatory and A person whose clinical condition
Reasons why a potential donor
respiratory functions have ceased is suspected to fulfil brain death
does not become a utilized donor
and resuscitative measures are not criteria.
to be attempted or continued.
System
or
• Failure to identify/refer a potential or
B. A person in whom the cessation of eligible donor
circulatory and respiratory functions • Brain death diagnosis not confirmed
is anticipated to occur within a time (e.g. does not fulfil criteria) or
frame that will enable organ completed (e.g. lack of technical
recovery. resources or clinician to make diagnosis
or perform confirmatory tests)
• Circulatory death not declared within
Eligible DCD donor the appropriate time frame Eligible DBD donor
• Logistical problems (e.g. no recovery
A medically suitable person who has learn) A medically suitable person who
been declared dead based on the • Lack of appropriate recipient (e.g. child, has been declared dead based on
irreversible absence of circulatory and blood type, serology positive) neurologic criteria as stipulated by
respiratory functions as stipulated by the law of the relevant jurisdiction.
the law of the relevant jurisdiction,
within a time frame that enables Donor/organ
organ recovery. • Medical unsuitability (e.g. serology
positive, neoplasia)
• Haemodynamic instability/unanticipated
Actual DCD donor cardiac arrest Actual DBD donor
• Anatomical, histological, and/or
A consented eligible donor: functional abnormalities of organs A consented eligible donor:
A. In whom an operative incision was • Organs damaged during recovery A. In whom an operative incision
made with the intent of organ • Inadequate perfusion of organs or was made with the intent of
recovery for the purpose of thrombosis organ recovery for the purpose
transplantation. of transplantation.
or or
B. From whom at least one organ was Permission B. From whom at least one organ
recovered for the purpose of • Expressed intent of deceased not to was recovered for the purpose
transplantation. be donor of transplantation.
• Relative’s refusal of permission for organ
donation
Utilized DCD donor • Refusal by coroner or other judicial Utilized DBD donor
officer to allow donation for forensic
An actual donor from whom at least reasons An actual donor from whom at
one organ was transplanted. least one organ was transplanted.

* The ‘dead donor rule’ must be respected i.e. patients may only become donors after death and the recovery of organs must not
cause a donor’s death.

Figure 6.2  The WHO critical pathway for deceased organ donation.

Reproduced from Dominguez-​Gil B, Delmonico FL, Shaheen FA, Matesanz R, O’Connor K, Minina M, et al. The critical pathway for deceased donation: reportable uniformity in the
approach to deceased donation. Transpl Int 2011;24:373-​8 with permission from John Wiley & Sons.

Further reading
Bossaert LL, Perkins GD, Askitopoulou H, et  al. European Downar J, Delaney JW, Hawryluck L, Kenny L. Guidelines for
Resuscitation Council Guidelines for Resuscitation 2015 sustaining measures. Intensive Care Med
the withdrawal of life-​
Section 11. The ethics of resuscitation and end-​of-​life decisions. 2016;42:1003–​17.
Resuscitation 2015;95:302–​11. Lobo SM, Barros de Simoni FH, Jakob SM, et  al.; ICON investigators.
Curtis JR, Vincent JL. Ethics and end-​of-​life care for adults in the Decision-​making on withholding or withdrawing life-​support in the
intensive care unit. Lancet 2010;376:1347–​53. ICU: a worldwide perspective. Chest 2017;152:321–​9.
 Re f e re n c e s 51

Morrison LJ, Kierzek G, Diekema DS, et al. Part 3: ethics: 2010 American Truog RD, Campbell ML, Curtis JR, et  al. Recommendations for end-​
Heart Association Guidelines for cardiopulmonary resuscitation of-​
life care in the intensive care unit:  a consensus statement by
and emergency cardiovascular care. Circulation 2010;122(18 Suppl the American College of Critical Care Medicine. Crit Care Med
3):S665–​75. 2008;36:953–​63.

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 CHAPTER 7

Quality of care assessment

in acute cardiac care
Fiona Ecarnot and François Schiele

Contents
Summary  54 Summary
Introduction  54 This chapter will describe the use of performance measures and quality measures
Measuring process  55 in the assessment of the quality of care delivered to patients with acute cardiovas-
Measuring outcomes  56 cular disease. It gives a brief recap of the major landmarks in the development of
Composite performance measures  56 the use of performance measures and goes on to explain the different approaches
Linear combinations  57 to measuring processes of care and outcomes. The utility and construction of com-
Regression-​based composite performance
measures  57 posite measures are also described.
Logical combinations  57
Unobserved composite (incommensurable
measurement scales)  57
Challenges in the implementation of
composite performance measures  57
Evaluation and validation of composite
performance measures  57
Temporal changes  58
Introduction
A composite of composites: the solution to
quality measurement in acute coronary The concept of measuring quality of care was first introduced in 1966 by Avedis
syndromes?  58 Donabedian who proposed an assessment of quality that would encompass structure,
Conclusion  58 process, and outcome. Structure refers to the material conditions in which care is dis-
Personal perspective  58 pensed, including premises, caregiving staff, technical facilities, and funding. Process
Further reading  58 examines the range of actions necessary to dispense care, including diagnostic proced-
References  60 ures, treatment, prevention, or education. Outcome includes not only the concepts of
survival and event-​free survival, but also other elements measuring well-​being or quality
of life. Outcomes evaluate the patient’s health as a result of the quality of care. In recent
years, this concept has been expanded to include another domain, namely the patient’s ex-
perience, based on the patient’s feedback. It includes various aspects such as the patient’s
perception of the quality of care, but also of the quality of explanations they received
about the disease and its treatment. The final objective of measuring quality of care is to
improve any deficient aspects, compare quality of care between centres, and ultimately
improve quality of care dispensed to patients.
The assessment of quality of care remained a theory without practical application until
the early 2000s when a report published by the IoM in 2001 revived the debate by calling
attention to the wide gap between the actual performance of the American health care
system and what it could potentially achieve. Since then, the assessment of quality of care
has progressively been organized and implemented, particularly in the field of cardiology
for clinical situations such as heart failure or the acute phase of MI.
There has been intense activity in the application of quality of care measures in the
context of AMI, especially in the US. Since the 2000s, there have been a number of joint
publications by the ACC and the AHA addressing methods for defining performance
measures (PMs) (in 2001 and 2005), and individual indicators were first proposed in
2006 for the evaluation of quality of care in the context of MI.
 M easu ri n g   pro c e s s 55

real-​life practice. As compared to the initial set, certain PMs

Measuring process were removed, such as prescription of β-​blockers at admission,
in particular, in response to the results of the COMMIT study
Although the ultimate goal of quality care is undoubtedly to
[7]. Other indicators were modified such as initiation of lipid-​
achieve the best possible clinical outcome for the patient, the
lowering therapy at discharge if LDL cholesterol level was >1 g/​L.
measure of processes of care is often preferred as a means to as-
This was transformed into prescription of a statin at discharge,
sess quality of care. Indeed, processes of care are often chosen, be-
regardless of the LDL cholesterol level, in accordance with the
cause they are directly linked to clinical outcome but present the
most recent guidelines at the time. Other indicators were added
advantage of being easier to measure, specifically attributable to a
such as measure of LV ejection fraction (LVEF), which did not
department or group of physicians, and lastly they highlight de-
appear at all in the initial set of PMs. In addition to this modified
ficiencies in particular aspects of the management and therefore
set of PMs, a number of test measures were introduced, focusing
are actionable. Conversely, measuring processes of care also has
mainly on the use of anticoagulations. The main aim of these test
several disadvantages, notably the fact that many tenets of good
measures was to detect excess doses of heparin, enoxaparin, or
clinical practice are not suitable for translation into good quality
glycoprotein IIb/​IIIa inhibitors [8].
indicators (QIs).
As regards reperfusion times and strategies in STEMI, time
Quality assessment based on measures of process requires the
from admission to initiation of fibrinolysis, time to instrumental
use of PMs. PMs are individual indicators of the quality of dis-
reperfusion (door-​to-​balloon), and the percentage of patients
crete processes of care and can be used for public reporting or for
treated by fibrinolysis within 30 minutes, or by primary angio-
the comparison of quality of care between centres. PMs are cre-
plasty within 90 minutes, were all maintained. In addition, several
ated from individual QIs, which are themselves developed on the
new PMs were added such as the rate of patients transferred to
basis of international guidelines for clinical practice, usually those
a centre with catheterization facilities after thrombolytic therapy
with a grade I recommendation [1]‌. Although it seems logical that
and time from arrival in the first admission unit to primary
strict adherence to guidelines should indicate a high standard of
angioplasty in patients transferred from other centres and in non-​
care, it does not necessarily follow that an individual recommen-
transferred patients.
dation, even with a high grade of recommendation and level of
In the latest update of the ACC/​AHA PMs for use in pa-
evidence, constitutes a good QI.
tients with STEMI and NSTEMI, published in 2017, the Task
Indeed, these two terms are not exactly synonymous, in that
Force proposed 17  ‘Performance Measures’ and seven ‘Quality
a recommendation for management is supposed to be applied
Improvement Measures’ [9]‌ . The document distinguishes be-
using clinical judgement and taking the patient’s characteristics
tween quality measures and PMs, indicating that quality meas-
into account. Conversely, a QI is intended for use as a categor-
ures are metrics that may be useful for local quality improvement
ical (usually a percentage) measure of good or poor quality care.
but are not yet appropriate for public reporting or pay for per-
Whereas guidelines often admit to a certain degree of uncertainty,
formance programmes (which are the main uses of PMs). In this
QIs are transformed into a binary variable. Furthermore, guide-
update, some PMs were withdrawn due to consistently high levels
lines are formulated to guide and advise, whereas recording of QIs
achieved (smoking cessation counselling), because they were non-​
is often mandatory, with a view to benchmarking, classification,
concordant with recent guidelines (LDL cholesterol assessment),
or even financial incentives or penalties [2]‌. In view of these po-
or because they covered only limited aspects of medications (anti-
tential pitfalls in converting guidelines into QIs, the methodology
coagulant dosing). Other PMs were revised for consistency with
for the definition and selection of QIs has been the subject of im-
the guidelines (e.g. statin use or P2Y12 inhibitor at discharge),
mense research, with publications by the ACC-​AHA in 2005 [3]
and four new PMs were introduced.
and updated in 2010 [4].
In 2016, the ESC-​ACVC published a set of QIs for the manage-
The first set of PMs for the management of AMI with or
ment of AMI [10]. As compared with previously published QIs,
without ST-​segment elevation was published by the ACC-​AHA
those prepared by the ACVC not only take into account current
in 2006 [5]‌and comprised a series of 11 measures, including pre-
medications and treatment strategies, but also go beyond simple
scription of aspirin at admission and discharge, prescription of
measurement of acute and discharge treatments, to cover the full
β-​blockers at admission and discharge, measure of low-​density
spectrum of the patient pathway, from access to care to patient sat-
lipoprotein (LDL) cholesterol level, lipid-​lowering therapy in pa-
isfaction. They also include a clearly defined composite indicator
tients with LDL cholesterol levels above 1 g/​L, and prescription of
to summarize multiple indicators in one metric. The ACVC QIs
an angiotensin-​converting enzyme inhibitor (ACE-​I) in the case
cover seven main domains of care, namely: (1) facility and rapidity
of LV dysfunction.
of management, by evaluating centre organization based on direct,
Three other PMs were listed, relating to reperfusion in STEMI,
simple, and rapid access to care; (2) use of an invasive strategy in
as well as the time to reperfusion by fibrinolysis or primary angio-
cases of STEMI (including assessment of times to reperfusion)
plasty, plus one PM relating to counselling for smoking cessation.
or NSTEMI; (3) evaluation of the thrombotic and haemorrhagic
An update of these PMs was published in 2008 [6]‌, justified
risks; (4)  guidelines-​compliant use of antithrombotic therapy,
by new scientific evidence and changes in guidelines, but also
including antiplatelet agents; (5) discharge treatment, considering,
by the initial experience of applying the previous set of PMs in
56 CHAPTER 7   Qualit y of   care assessment i n  acu te ca rdiac ca re

in particular, certain aspects of discharge treatment where there AMI, irrespective of good quality care. Second, the use of mortality
remains significant room for improvement such as high-​intensity as an indicator could discourage certain centres from accepting
statins, ACE-​Is, and β-​blockers in cases of LV dysfunction; (6) pa- high-​risk patients. Third, adjustment for characteristics related to
tient satisfaction and feedback regarding quality of care, including severity is not sufficient to eliminate all the potential biases, and
the quality of information about the disease and its treatment, re- obviously adjustment is limited to the clinical characteristics at ad-
spect during hospitalization, and quality of information provided mission and cannot take treatment into account [4]‌. Despite these
at discharge; and (7) at least one indicator from each of these do- drawbacks, 30-​day mortality remains widely used as a PM, and
mains is included in a composite indicator, calculated using the it is recommended to adjust on a well-​established risk score. In
opportunity-​based method, to summarize the overall quality in- the context of ACS, the Global Registry of Acute Coronary Events
formation in one metric. (GRACE) score is one such score, but in this case, we are faced
Although, in principle, QIs require specific registries in order with the need to record the multiple variables that compose the
to be recorded and analysed adequately, it is nonetheless pos- score, with the associated risk of limiting the sample size when
sible to apply these new QIs to existing national registries, e.g. there are missing data for any of the component variables. Finally,
the French Registry of Acute ST-​Elevation or Non-​ST-​Elevation in the event of a 30-​day mortality rate of <10%, it becomes neces-
Myocardial Infarction (FAST-​MI) [11] or the United Kingdom sary to record adjusted mortality over long periods in each centre
Myocardial Ischaemia National Audit Project (UK MINAP) data- in order to perform any analysis, since an event rate that is too
base [12]. Results of attempts to apply QIs to existing databases low could lead to biased estimates of percentages in low-​volume
show that although all QIs cannot be calculated, since the regis- centres. This phenomenon has been termed the ‘zero mortality
tries were non-​specific and therefore do not necessarily contain paradox’, with low or zero mortality observed in surgery centres
all the required information, more than half of QIs can be cal- with a low volume of activity, whereas mortality rates were found
culated and the value of the composite indicator is significantly to be much higher when observed over a longer period [15].
associated with survival.
Lastly, in 2017, the ESC guidelines for STEMI [13] included a
slightly modified version of the ACVC QI set, keeping the main Composite performance measures
architecture in seven domains of care and including a composite QI.
In 2020, the ESC-​ACVC QIs will be updated, with the same Individual PMs remain difficult for physicians to interpret, do
overall design, notably the separation into seven domains and, not yield an accurate reflection of the overall quality of care, and
for each domain, the definition of the Main and Secondary QIs. do not allow comparison between centres. Composite measures
The domains themselves have been kept unchanged, as have represent a multifaceted approach that compensates for these
several QIs. Instead of the 20 QIs in the 2017 set, the Working drawbacks. A composite measure is a combination of at least two
Group has selected 26 QIs for the present update, i.e. 13 Main, ten individual PMs to give one final score, which summarizes sev-
Secondary, two Composite, and one Outcome QI. Three QIs from eral dimensions of performance and thus facilitates comparison.
the original set have been withdrawn; six are new, and most of the Composite measures also have other theoretical advantages; in
others have been modified according to new evidence, changes in particular, they widen the scope of measurement and incorp-
guidelines, the perception of clinical interest, and the results of QI orate a higher number of quality measures. Lastly, they can also
application for quality assessment in existing registries. be used for comparison between centres and for public reporting
of performance, and they are also suitable for use in pay-​for-​
performance systems. On the other hand, composite indicators
suffer from a lack of transparency due to the loss of individual
Measuring outcomes data, and consequently, it is no longer possible to identify, from
Measuring outcomes as an intrinsic reflection of the quality of a single composite measure, the specific domains where there is
care would appear to be the best option and is by far the favourite room for improvement. Finally, there are many different tech-
option of physicians. However, the major disadvantage of this ap- niques for calculating composite scores, and the chosen approach
proach is that patient outcome is only very partially determined must be clearly explained, as it has a considerable influence on
by the quality of care and depends to a much greater degree on the results [16].
the patient’s comorbidities. Furthermore, when mortality rate is The first stage in the development of a composite PM is to de-
used as an indicator, problems with the statistical analysis arise fine as clearly as possible the domain in which the quality of care
when the mortality rate is low or moderate [14]. Physical status is to be assessed. On the basis of this definition, the most suitable
and quality of life are not generally used as QIs in the context individual PMs for inclusion in the composite and the mathemat-
of ACS, although they are widely implemented as PMs in other ical model for its calculation can be selected.
contexts such as stable angina or heart failure. On the contrary, The individual PMs to be included in the composite can com-
30-​day mortality has been used since 2007 in certain sets of PMs prise measures of process or outcome indicators such as mortality,
for AMI, and in acute pneumonia since 2008. morbidity, or quality of life. Measures of structure, such as volume
While 30-​day mortality is certainly the most easily interpretable of activity, available facilities and resources, and organization of
QI, it suffers from three major limitations. First, death can occur in the medical teams, can also be included.
 C o m p o si te perfor m a n ce   m e asure s 57

The selection of the individual PMs must be coherent. In con- example of this method is the STS score used in cardiac surgery;
structing a composite, selecting individual PMs that are cor- to obtain a composite score in four separate domains (adjusted
related is debatable, since they are supposed to reflect different mortality, adjusted morbidity, surgical technique, and preopera-
dimensions of the same concept. In the context of STEMI, for tive use of medications), rescaling with the incommensurable
example, a composite indicator could include indicators relating measurement scale makes it possible to attribute an equal weight
to reperfusion and secondary prevention, thus reflecting several to each dimension.
dimensions of overall quality of care.
Different mathematical models are available for the construc- Challenges in the implementation of composite
tion of composite indicators. The most frequently used methods performance measures
are as follows.
It is usually necessary to recalibrate a composite score in order
for it to be implementable in practice. Most often, the composite
Linear combinations is transformed into categories, which are easier to interpret. For
◆ The mathematical sum of all individual PMs, allocating one example, a composite score, based on medical prescription at
point per PM. discharge after AMI (i.e. appropriate prescription of aspirin,
◆ Budget allocation process: weights are assigned to different indi- P2Y12 inhibitor, β-​blocker, ACE-​I, and statin), can be calcu-
vidual PMs to achieve an overall sum of 100. This makes it pos- lated using the all-​or-​none method. Measurement in a large
sible to attribute a greater weight to certain PMs, with the weight number of centres makes it possible to compute a mean with
to be assigned to each PM decided by expert consensus. an associated 95% confidence interval (CI) for each centre. In
◆ Opportunity-​based scoring: used when one or more individual this format, the result is difficult to interpret. However, an easier
PMs are not applicable in all patients/​centres. For example, a format to interpret is benchmarking by classifying all centres
composite indicator for STEMI could include criteria relating according to the mean or by creating three different categories.
to reperfusion by angioplasty that would not be applicable in Categories are usually easier to interpret and can be created,
centres that do not have catheterization laboratory facilities. based on the 95% CI for each centre, in comparison with the
In this case, an opportunity score makes it possible to measure overall (e.g. national) average. Accordingly, three categories can
quality of care in centres, both with and without angioplasty be created, namely centres whose performance is within the na-
facilities. tional average, centres whose performance is better than the
national average, and centres whose performance is below the
Regression-​based composite performance national average.
measures
This is the gold standard method but requires a measure of out-
Evaluation and validation of composite
come. In this situation, individual PMs are selected, based on lo- performance measures
gistic or Bayesian regression and it is also possible to attribute a Irrespective of the methods chosen to select the component PMs
weight to each individual PM, according to its impact on outcome. and to calculate the composite measure, it is important that the
composite yield results that are in accordance with the intended
Logical combinations measure and its intended interpretation. This can be verified by
investigating the performance of the composite when the indi-
Logical combinations, such as the ‘all-​or-​none’ or ‘any-​or-​none’
vidual components vary. It is indeed of fundamental importance
methods, are often used in measuring quality of care. The ‘all-​or-​
to check that a change in one of the component PMs satisfac-
none’ approach consists of the attribution of 1 point for the com-
torily influences the composite. If there is too strong a correlation
posite when all individual PMs score, and zero if one or more
between one of the individual items and the overall composite
individual PMs are absent. This method is appropriate to iden-
score, this suggests that a variation in this individual item would
tify centres with a very high quality of care. The ‘any-​or-​none’
have too strong an impact on the composite. Conversely, if the
method, on the contrary, assigns one point for the composite if at
influence of any individual item on the composite is too weak,
least one of the individual PMs is present. This method is appro-
then this item needs to have its weight reinforced in the model.
priate in assessing processes to avoid and is useful for the identi-
Sensitivity analysis can also be conducted to perform simulations
fication of poor performers.
of the composite’s behaviour when the weight of the individual
items changes.
Unobserved composite (incommensurable The validity of the measure can be estimated according to the
measurement scales) American College of Physicians (ACP) scale [17]: (1) importance
This technique is used when the different constituent elements (clinical impact of the measure); (2) appropriate care (under-​or
of the composite are based on different scales of measure and overuse); (3) evidence support; (4) measure specification (clarity
when it is not desirable or feasible to attribute different weights of the definition of the numerator and denominator, reliability of
to one individual component, as compared to another, e.g. by div- the measure); and (5) feasibility of the measure (e.g. taking into
iding each measure by its own standard deviation (SD). A salient account the experience of previous assessment).
58 CHAPTER 7   Qualit y of   care assessment i n  acu te ca rdiac ca re

The validity of the composite should be verified in terms of A composite of composites: the solution to quality
clinical outcome of the patients. This was done, for example, in measurement in acute coronary syndromes?
the CRUSADE (Can Rapid Risk Stratification of Unstable Angina
Patients Suppress Adverse Outcomes with Early Implementation To date, no PM, be it individual or composite, has been acknow-
of the ACC/​AHA Guideline) registry. A composite PM was cal- ledged as the preferred indicator for the measure of quality of care
culated as a linear combination of nine individual PMs (four at in the context of MI. It will likely be necessary to combine several
admission and five at discharge) and was compared to in-​hospital PMs relating to processes for treatment within the first 24 hours,
mortality by quartiles in patients admitted for NSTEMI [18]. In including reperfusion, but also times to reperfusion, a composite
a further example, a composite indicator, calculated as a linear PM covering treatment at discharge, and an outcome measure ad-
combination of six measures during hospitalization, was valid- justed for risk. A composite measure that could summarize in one
ated by quartiles in terms of 1-​year mortality, adjusted for quar- single score the five aspects proposed by Weston [23], with repeated
tiles of the GRACE risk score [19]. In this study, the composite measures over several years, could be the answer to this challenge.
indicator classed by quartiles showed a strong correlation with
mortality.
Lastly, the reliability and accuracy of the composite should be Conclusion
optimized by computing a composite in which the variability due
Quality assessment has become an essential component of im-
to chance is as low as possible. Any variations in the composite
proved knowledge in the field of ACS. Nowadays, it would be in-
score should reflect true variations in the quality that the com-
conceivable not to assess the impact of management strategies and
posite is supposed to be measuring.
new medications such as they are used in the real world. The use of
QIs or PMs is likely the best approach for this purpose. However,
Temporal changes
only large registries make it possible to assess QI or PMs, provided
When campaigns to assess quality of care are repeated over time that the indicators have been defined, bearing in mind issues re-
in the same centres, it becomes possible to assess temporal trends lating to data recording through registries, and provided that the
in the quality of prescription and care. Accordingly, spectacular registries include the relevant variables needed to assess quality.
improvements in times to reperfusion (door-​to-​balloon time)
were reported to occur between 2005 and 2010 in the US [20].
Similarly, over longer periods, a significant increase in the use of
aspirin, β-​blockers, ACE-​Is, and lipid-​lowering drugs has been Personal perspective
reported in patients admitted for ACS [21]. In parallel to these Measuring the quality of care calls for a specific method-
changes in management, significant reductions in mortality have ology, combining measures of structure, process, and out-
been reported in the same clinical situation. In the EHS ACS 3, come. Composite indicators are a combination of several
over a relatively short period of 2 years, there was a reduction in measures into one metric that can be used for temporal or
reperfusion times, a significant increase in the use of guideline-​ between-​centre comparisons and to evaluate improvement
recommended therapies, and, in parallel, a reduction in in-​ in the quality of care.
hospital mortality [22].

Further reading
Aissaoui N, Puymirat E, Tabone X, et al. Improved outcome of cardiogenic admission during out of hours (insight into the AMIS Plus Registry).
shock at the acute stage of myocardial infarction:  a report from the Am J Cardiol 2008;101:422–​7.
USIK 1995, USIC 2000, and FAST-​MI French nationwide registries. Bonow RO, Masoudi FA, Rumsfeld JS, et al. ACC/​AHA classification of
Eur Heart J 2012;33:2535–​43. care metrics:  performance measures and quality metrics:  a report of
Aros F, Heras M, Vila J, et  al. [Reduction in 28  days and 6  months of the American College of Cardiology/​American Heart Association Task
acute myocardial infarction mortality from 1995 to 2005. Data Force on Performance Measures. Am Coll Cardiol 2008;52:2113–​17.
from PRIAMHO I, II and MASCARA registries]. Rev Esp Cardiol Danchin N, Blanchard D, Steg PG, et al. Impact of prehospital thrombolysis
2011;64:972–​80. for acute myocardial infarction on 1-​year outcome: Results from the
Ben-​Dor I, Hasdai D, Behar S, et al. Prognostic implications of increased French Nationwide USIC 2000 Registry. Circulation 2004;110:1909–​15.
cardiac biomarkers and ST segment depression in non-​ST elevation Danchin N, Coste P, Ferrieres J, et  al. Comparison of thrombolysis
acute coronary syndromes: lessons from the acute coronary syndrome followed by broad use of percutaneous coronary intervention with
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 Fu rth e r re a di n g 59

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 SECTION II

The pre-​hospital phase

and the emergency
department

8 The emergency medical system  65

Olivier Hoogmartens, Michiel Stiers, Koen Bronselaer, and Marc Sabbe
9 Out-​of-​hospital cardiac arrest   76
Jerry P Nolan and Christian Hassager
10 Chest pain in the emergency department and the chest pain unit   88
Christiaan Vrints, Janina Stepinska, and Marc J Claeys
11 Acute dyspnoea in the emergency department   103
Eleni Michou, Nikola Kozhuharov, Jasmin Martin, and Christian Mueller
 CHAPTER 8

The emergency medical

system
Olivier Hoogmartens, Michiel Stiers,
Koen Bronselaer, and Marc Sabbe

Contents
Summary  65 Summary
Introduction: the emergency medical The mission of the emergency medical services is to promote and support a highly
system defined  65
reliable system that provides high-quality and state-​of-the-art emergency medical
EMS goals defined  66 care, including ambulance services, to anyone who is victim of a sudden injury
Structure or chain of emergency or illness, at any time and any location. A  medical emergency has five different
medical care  66
Population  66
phases, namely: population awareness and behaviour, occurrence of the problem
The caller  67 and its detection, alarming of trained responders and help rendered by bystanders
The EMS dispatching system  67 and trained pre-​hospital providers, transport to the nearest or most appropriate
Bystander immediate life support  68
Pre-​hospital resources  68 hospital, and, if necessary, admission or transfer to a tertiary care centre which
The one-​level rescue system  68 provides a high degree of subspecialty expertise. In order to meet these goals,
The tiered systems  68 emergency medical services must work aligned with local state officials, fire and
Pre-​hospital drug administration  68
The vector for medical teams  69 rescue departments, other ambulance providers, hospitals, and other agencies to
Patient transport  69 foster a high-​performance network. The term emergency medical service evolved
The receiving facility  69
to reflect a change from a straightforward system of ambulances providing nothing
Legal regulations and funding of EMS
organizations  69 but transportation to a complex network in which high-​quality medical care is
Legislation in relation to EMS systems in given from the moment the call is received, on-​scene with the patient, and during
Europe  69 transportation. Medical supervision and/​or participation of emergency medi-
Funding  70
cine physicians (EPs) in the emergency medical service systems contribute to the
Teaching  70
The population  70
quality of medical care. This emergency medical services network must be cap-
The dispatching  70 able of responding instantly and maintaining efficacy around the clock, with well-​
Pre-​hospital resources  70 trained, well-​equipped personnel, linked through a strong communication system.
Research in pre-​hospital care  70 Research plays a pivotal role in defining the necessary resources and in continu-
Trial specifics in out-​of-​hospital emergency
research  71 ously improving the delivery of high-​quality care. This chapter gives an overview
Informed consent  71 of the different aspects of emergency medical services and calls for high-​quality
Reference treatment in randomized research in pre-​hospital emergency care in a true partnership between cardiolo-
controlled trials  71
Re-​evaluation of priorities  71 gists and EPs.
The variety in EMS systems  71
Operational cardiac examples  72
Time-​sensitive conditions  72
The right patient at the right time to the
right hospital  72
Collaboration models  72
Improvement  72 Introduction: the emergency medical
Personal perspective  73
Further reading  74
system defined
References  74 Most European countries have a system for pre-​hospital emergency medical services
(EMS), which is a component of the emergency health care system [1]‌. EMS provide
66 CHAPTER 8   The e mergency medical syst em

treatment to those in need of urgent medical care, with the goal From a historical perspective, the initial focus was on the acute
of effectively treating the presenting conditions or arranging for care of trauma patients [5]‌. Removal at the incident scene was
timely removal to the next point of appropriate care, most likely important and included technical rescue operations such as ex-
an ED at a hospital. Time-​sensitive, life-​threatening illnesses and trication, rescue out of buildings, and water rescue. Subsequently,
injuries are among the leading causes of morbidity and mortality. critically ill patients came into the picture and in the late 1990s,
However, professional standards, organizational structures, and one began to recognize the importance of high-​performance EMS
coordination vary widely across the European Union (EU). systems through implementation and evaluation of system-​and
EMS also encompass the role of transporting patients from one community-​level interventions for the improvement of the health
medical facility to another, usually to facilitate the provision of status of a population [6].
higher-​level or more specialized care (‘upgrade’). On the other
hand, EMS also facilitate, in some countries, the transfer of pa-
tients from a specialized facility to a local hospital or nursing
home when they no longer require the services of that specialized
Structure or chain of emergency
hospital, such as following successful cardiac catheterization due medical care
to an MI (‘downgrade’). In such services, EMS are not summoned The EMS system can be conceptualized in different ways—​one of
by members of the public, but by clinical professionals (e.g. phys- which is by response area (e.g. urban, suburban, rural, or mixed)
icians or nurses) in the referring facility. However, for patients in or by identifying the organizational type or provider of the EMS
need of urgent care, recognition of the urgency and availability system (e.g. community non-​profit agency, fire-​based agency,
of an emergency number to alarm and to activate a professional governmental services-​ based agency, hospital agency, private
response is crucial. non-​hospital-​based agency). Another way is by describing poten-
A crucial decision in pre-​hospital care is whether the patient tial stakeholders (users, providers, and government) or by map-
should be immediately taken to a hospital or whether advanced ping processes. In this paragraph, we have deliberately chosen to
care resources should be taken to the patient. The ‘scoop and run’ describe the following links from the chain of emergency med-
approach is a pure transport modality, whereas the ‘stay and play’ ical care:  population, callers, dispatching system, bystander im-
approach is exemplified by the French and Belgian emergency mediate life support, pre-​hospital resources, and hospitals. One
mobile resuscitation services (SMUR) or the German ‘Notarzt’ could bundle them in the community and professional response
system (pre-​hospital emergency physician). Traditionally, it was (see E Figure 8.1).
sometimes simplified to the Anglo-​Saxon or Germano-​French
system. The discussion will remain on which approach will ultim-
ately lead to better outcomes for a specific pathology in a given
Population
EMS system. For penetrating trauma, a scoop and run approach The population covered by the EMS system can be described
saves lives [2]‌. Whereas early pre-​hospital treatment of AHF im- in population characteristics (e.g. population density, average
proved outcome significantly [3]. income), health indices (e.g. life expectancy, infant mortality
Although each EMS system shares common grounds, it is rate, maternal mortality rate), or leading causes of death (e.g.
of extreme importance to recognize the existing differences. heart disease, cancer, cerebrovascular disease). It is important
EMS are provided by a variety of individuals, using a variety of to describe these population characteristics to allow meaningful
methods. To some extent, these will be determined by each in- comparisons between EMS systems or to produce strategies
dividual country. Beyond the national model of care, the type of to improve pre-​hospital care. Socio-​demographic characteris-
EMS will be decided by local jurisdictions and medical author- tics are important in general health care, and even more so for
ities, based upon the needs of the community and the economic potential EMS users. There may be considerable variability in
resources to support it. As there is no unique EMS standard socio-​demographic characteristics between countries, but also
in the EU, it is thus complex to benchmark EMS systems and between regions within one country. In addition, patients with
to identify universal and meaningful outcome indicators for specific socio-​demographic characteristics may not want to ac-
comparison  [4]‌. cess the EMS system and may use alternative ways to enter the
health care system in case of an acute event. On the other hand,
today patients increasingly keep track of their fitness and health
data with wearable technology. These devices range from activity
EMS goals defined trackers and augmented-​reality glasses to smart clothing, which
The basic goal is that, for patients in need of urgent care, the tracks steps, heart rate, and/​or physical activity. People wearing
therapeutic-​free interval remains as short as possible and all inter- these devices generate health data just by their daily routine.
ventions at the scene or during transportation must reduce mor- Machine learning and data-​mining techniques will allow to pre-
tality, morbidity, or invalidity. Before treatment, medical history dict and prevent life-​threatening cardiac events by detecting
taking, clinical examination, and diagnostic tests, e.g. standard changes in clinical patterns of their normal everyday life. These
12-​lead electrocardiogram (ECG), should be performed to fur- changes may alert a caller or even generate an EMS alert on its
ther distinguish between differential diagnoses. own  [7]‌.
 Stru ctu re or cha i n of em erg en cy m e di c a l   c a re 67

Community response Professional response

Awareness Access Emergency Emergency

Receiving facility
and and medical dispatch medical services
behaviour reaction

Population Recognition of Call Educational level Nearest

characteristics urgency prioritization emergency
Transport vector department
European Appropriate
Smart technology emergency response Telemedicine Nearest hospital
number and
Pre-arrival advanced Most appropriate
Bystander Preliminary instructions notification care facility
empowerment interventions

Figure 8.1  Chain of emergency medical care.

The caller recognition of all specific conditions reported to the dispatching

centre. EMD also includes: provision of accurate instructions to
The caller is a person or device that alarms the EMS system and
the caller before pre-​hospital care providers arrive (e.g. telephone-​
judges that a potential patient is in need of emergency medical
assisted CPR); attribution of the right pre-​hospital team to the
care. The caller, with or without any relationship with the potential
right patient; selection of the most appropriate hospital for defini-
patient, can be the patient him-​/h ​ erself, a family member, a lay-
tive medical care; and, in case of disaster, necessary coordination
person, a medical professional, or a medical device such as wear-
(see E Table 8.1).
able technology. Two elements may trigger the caller to contact
For the EU, 112 is the emergency telephone number which
the EMS system—​recognition of the urgency and the confidence
allows European citizens to contact the emergency services
that the EMS system will provide an adequate response. To im-
in all member states. However, there is still an ongoing debate
prove community awareness and increase public understanding
about whether the dispatching response on a 112 call should be
of their vital role in recognition of an urgent critical condition
discipline-​specific or be provided through a centralized reception,
is a long-​lasting educational task. This subject is often neglected
regardless of the type of request (e.g. medical, police, firefighters).
in educational programmes, but critical to improve outcome of
The system with a universal centralized call-​taker has advantages
pre-​hospital care. The general population is not knowledgeable
concerning the optimal management of all calls. However, this
about typical symptoms of common diseases needing urgent care.
can take time and potentially vital seconds can be lost. In general,
Many non-​medically trained people (i.e. laypeople) do not recog-
there are two types of EMD systems. Common to both systems is
nize the key symptoms of common cardiovascular emergencies
that the trained dispatcher allocates each call to one of the listed
such as ACS and stroke [8]‌. We can hope that further evolution of
chief complaints. While one system focuses on codes and scripted
the above-​mentioned wearable technology will support this early
questions to put to the caller, the other system relies on the ex-
recognition of an urgency or emergency.
perience of the dispatcher to conduct the interview. The essential
To induce sufficient confidence in an EMS system is an even
more difficult task. In countries with an efficient EMS system, pa-
tients are still too often brought to the hospital by using alterna- Table 8.1  Functions of the EMD
tive ways of transportation [9]‌. Factors influencing an individual
caller are multifaceted, but it is imperative to recognize and ad- To call prioritization by: Determining the level of urgency
dress these factors if the system is not alerted frequently for clear Ranking the level in view of all calls
indications. Selection of an appropriate response
Provision of pre-​ambulance arrival
The EMS dispatching system instructions in first-​aid and scene
Calls to the EMS system should be transferred as soon as pos- management
sible to a trained dispatcher able to make a layered response using Communication with the pre-​hospital
an appropriate emergency dispatch system. This response focuses team at the scene
on the allocation of appropriate human resources and equipment Communication with receiving
to anyone who urgently asks for medical help. Consequently, the hospitals
accuracy of emergency medical dispatching (EMD) implies that Coordination if more than one team
the level of care dispatched matches the level of acuity and in is dispatched or in case of disaster
68 CHAPTER 8   The e mergency medical syst em

elements, which have been identified, are: use of standard proto- tomorrow. Laypeople who witness an event can provide essential
cols; the need for medical supervision; an audit of operations; and first aid. A large Swedish study provided the evidence that CPR
training of dispatchers [10]. performed before arrival of the EMS team improved survival fol-
Two pivotal elements in medical dispatching are the available lowing cardiac arrest [13]. But also laypersons in the vicinity of
means and medical needs. The case mix of incoming calls differs the event can be alerted to provide CPR or bring an AED [14]. As
significantly between countries, but also between regions within discussed later, one could consider these ‘certified’ laypeople as an
countries. Even an abuse of the unique number to obtain infor- extra tier within the EMS system.
mation can be significant and distracting from the real urgent
calls. The available means depend on the qualification of the team Pre-​hospital resources
and the number of teams available. In some countries, regulation From an organizational perspective, we can recognize a one-​level
exists that defines the minimum number of available teams per rescue system, a two-​tiered system, and a three-​tiered system.
100 000 inhabitants. However, fluctuation of available teams be-
tween day and night and week or weekend may be significant and The one-​level rescue system
possibly jeopardize appropriate medical dispatching. The case The one-​level system comprises mainly basic first aid skills and
mix of incoming calls and the (specific) teams available are fac- makes medical dispatching almost unnecessary. However, the
tors to be studied in each medical dispatching centre. competences considered as basic first aid skills differ significantly
Besides these determinant elements, the analytic capacities of from one country to another. The duration of training varies
the dispatcher are overestimated. In general, the caller commu- enormously. Those who advocate the ‘scope and run’ concept are
nicates under stress, providing limited information in any given in favour of this system; however, a tiered system has proven to be
language. To standardize the responses and help the dispatcher, more effective and efficient [11, 15].
predetermined decision-​making algorithms are defined and can
help to determine the most appropriate response. Medical regu- The tiered systems
lation, as in France, is an option to improve EMD. However, the In the tiered systems, different education and skill levels exist.
impact of medical regulation on improvement of the health status A  small proportion of calls require pre-​hospital advanced care
of a population has never been proven. interventions, including advanced airway management, son-
In modern medical dispatching, a computerized system assisting ography, advanced coronary life support, or inotropic drug
the call-​taker, recording responses, supporting decision-​making, support. These tiered systems can generally be categorized as
and providing information for audit and quality assurance is con- either a physician-​led system or a pre-​hospital specialists-​led
sidered essential [10,  11]. Computer-​aided medical dispatching system [emergency medical technicians (EMTs) or paramedics,
is becoming standard practice. Today, smart technology can also with or without EMS physician oversight]. For calls without
support emergency medical dispatchers through image-​based life-​
threatening characteristics, an ambulance with an EMT
interfaces, which are a lot faster than making phone calls or using crew is sent. For time-​sensitive, critical conditions, a second re-
traditional mapping software. And as reports from a caller are sponse with paramedics is dispatched. Training of paramedics
sent through the system, it offers options to exchange additional ranges from 2-​to 4-​year training. However, the most common
information like images or video footage from the scene. At the tiered system in Europe is a medicalized second or third level.
same time as the dispatcher is handling the call, intelligent soft- Training of physicians can vary, from different basic specialties
ware can identify important patterns in the ongoing conversation up to specific training in emergency medicine [16, 17]. An inter-
and provides real-​time decision support [12]. New dispatching mediate medicalized tiered system can work with nurses, with
technologies, as mentioned earlier, can be helpful. However, at all or without specific pre-​hospital training. Variations in systems
times, medical dispatching remains a complex human decision-​ and training of pre-​hospital care providers result in a great di-
taking process. versity of medicalized or advanced pre-​hospital care. Beside the
level of training, variations in the providers’ origin (independent
ambulance service, firefighters, Red Cross, hospital-​based, etc.)
Bystander immediate life support and their professional or voluntary status make the complexity of
Several digital health innovations have been developed to enable pre-​hospital care even more colourful. The usefulness of a tiered
patients and laypeople improve clinical outcomes by supporting system has been debated, but there is evidence that extended
EMS in their battle against time. When patients suffer from a procedural capacity and decision-​making do benefit many pa-
time-​sensitive critical condition, each minute waiting for treat- tient groups [18].
ment significantly reduces the chance of survival. This includes
cardiac arrest patients. Wearable technology, smartphone appli- Pre-​hospital drug administration
cations, and integrated technological advances will shift emer- Drug administration in the pre-​hospital setting is allowed in
gency medical care, from within the hospital since the late 1960s many European countries—​however, only for physicians. Other
to professional pre-​hospital management of the patient in the EMS professionals can deliver pharmacological therapy solely
years thereafter, to save lives in the community by empowering on the basis of advanced prescriptive medical orders, approved
bystanders today and through the use of artificial intelligence protocols, or teleconsultation. In addition, wide differences
 L eg a l reg u l ati on s a n d fu n di n g of EM S  org a n i z at i on s 69

among countries and services exist on the availability of drugs in part of a community non-​profit agency, a governmental service-​
ambulances and also for early management of ACS patients. based agency, a hospital agency, or a private non-​hospital-​based
agency. It is important to identify that an EMS system in a par-
The vector for medical teams ticular country does not always fit the needs of another country.
The vector used to transport medical teams varies, from ambu- The majority of European countries have a government-​
lances, light vehicles, helicopters, i.e. helicopter emergency med- controlled EMS system or a private-​based agency. Both gov-
ical services (HEMS), and fixed-​wing aircrafts to marine medical ernmental and private-​ based systems have advantages and
rescue. The quality of pre-​hospital care is not driven by the vector, disadvantages. Implementation of a unique emergency call
but rather by the procedural skills required for rescuing, stabil- number (112) implicitly endorses the use of an integrated system
izing, and treating patients and the decision-​making capacities in each member state, structured to serve the goal of providing
beyond the rigid pre-​hospital protocols of the crew [15]. A sys- timely and adequate medical rescue and treatment to those in
tematic review on adherence to guidelines and protocols in the need of urgent medical care.
pre-​hospital and emergency settings, however, revealed that Moreover, the system can be a separate or a combined organ-
professionals’ adherence to guidelines demonstrated a wide ization of safety and security services (e.g. police, fire brigade,
variation [19]. civil protection, etc.). From a purely technical and management
perspective, a combined system is more efficient, but increased
Patient transport
effectiveness has not been proven yet. As modern technology
Transporting a patient from the scene to the most appropriate makes medical, or even security, dispatching more complicated,
care facility is gaining importance. After all, identifying the right a tendency is observed to abandon these combined organizations
hospital for the right patient does not mean that there is only one and continue with purely medical dispatching.
bed available but encompasses transporting the patient to the EMS systems are regulated, in the large majority of member
closest hospital where specialized definite care can be provided. states, by a set of laws and regulations and typically contain the
Dispatching a patient with an STEMI to a hospital without PCI topics outlined in E Table 8.2. It is important to highlight that
facilities proved to result in worsened outcome [20]. In add- the majority of EU member states envisage minimum standards
ition, a recent publication demonstrated an improved diagnostic of care and equipment, as well as a set of minimum qualifications
accuracy of physician-​ staffed emergency medical teams over for EMS professionals.
time [21].
Legislation in relation to EMS systems in Europe
The receiving facility
Considering the relatively young history of EMS and the develop-
The final step in the pre-​hospital chain is normally the receiving ment of EMS systems throughout Europe, it is not surprising that
facility (i.e. the hospital). In different countries, comparable with some countries do not yet have comprehensive laws specifically
the tiered EMS services, there exists a tiered system for EDs and dealing with the establishment, organization, and regulation of an
hospitals. This tiered system either can be based on regulations EMS system. In addition, given the relationship that EMS shares
with specific infrastructural and human resource requirements with other emergency services (e.g. police, fire brigade, civil pro-
or can purely be based on practical implications due to available tection, etc.), it might be more appropriate to consider a broader
resources. However, a well-​organized and staffed ED that has the spectrum of legislative acts that involve the delivery of emergency
capacity to deliver uninterrupted emergency care 24 hours a day, medical care. Adoption and adherence to minimum standards
7 days a week basis is crucial. This includes full-​time (24/​7) access could form the basis for effective harmonization of the quality
to specialized care such as trauma surgery, interventional cardi- of emergency care delivered throughout Europe. However, there
ology, and radiology.
Thus, the complete set of out-​of-​hospital and in-​hospital emer-
gencies constitutes the wider EMS. And the different steps as Table 8.2  Regulations by national laws
described earlier are often considered as a chain. As always, the
strength of a chain depends on the weakest link. One of the dif- Emergency number One or more numbers, 112
ficulties is to balance investments between the different links in Dispatching Separate or combined organization
these EMS systems [22]. Ambulance vehicles Equipment and visibility
Staff Minimal requirements of qualification and
training

Legal regulations and funding Hospitals Free access for all

of EMS organizations Minimal structural and process requirements

Financing mechanisms Out-​of-​pocket payments
In general, the EMS status of each European member state de- Individual private insurance
pends on its specific geographic, political, cultural, linguistic, his- Employment-​based insurance
Government financing
torical, and medical settings. In addition, the EMS system can be
70 CHAPTER 8   The e mergency medical syst em

is still a long way to go towards a uniform European legislation education programmes in primary or secondary schools. As
and policy. Today, the limited European regulations about EMS mentioned previously, modern technology may assist in recog-
relate to the minimal regulations about ambulance standards and nizing potential emergencies.
equipment [23, 24].
The dispatching
Funding Core competencies and fundamental skills for EMD include: the
The legislative framework in the majority of EU member states ability to operate a variety of communications equipment,
implies secured funding mechanisms for EMS. However, finan- including radio consoles, telephones, and computer systems;
cing may be very different from country to country and, in some high tolerance when dealing with high work load, coping with
countries, even from region to region [25]. Emergency care is work pressure, and handling various stressful situations or chal-
provided to all persons by EU member states through direct or lenges; excellent communication skills with people in various
indirect purchasing of services, using various financing mechan- emotional states; and good knowledge of different (regional) lan-
isms, most commonly by pooling resources from the state budget guages. Finally, good judgement skills in order to best match re-
and other sources (e.g. national health insurance institutions). sources to the medical needs based on the information obtained
This reflects the fact that EMS coordination is considered to be from the caller and minimal medical knowledge (e.g. to help
a key responsibility of public authorities, in particular, the role callers manage emergency situations while they are waiting for
of dispatching [23]. All EU member states proclaimed ‘free ac- professional help to arrive) are essential [26]. EMS dispatchers
cess to in-​hospital emergency care for all’, including uninsured may be asked to distinguish between callers with an immediate
or unidentified persons. In reality, some countries or regions, or need for EMS and those who may safely use alternative services.
even individual hospitals, invoice patients for emergency care Overtriage will lead to less efficiency, but undertriage can result
(e.g. ambulance services). However, co-​payment for emergency in a patient safety problem.
care is waived in the event of life-​threatening conditions. Co-​
payment issues are important, as they may induce underuse of Pre-​hospital resources
the EMS system and the establishment of alternative care sys- In Europe, the training required for (para-​) medical staff to work
tems. On the other hand, if the system is fully covered by health in EMS is not standardized. Against this background and aiming
care insurance, the EMS system is often overused for non-​urgent for the highest quality of emergency medical care, the following
medical demands and includes the risk that the availability of an minimal goals for training and education can be set:
appropriate team for a real emergency is affected. In addition,
◆ All professionals providing pre-​hospital emergency care, i.e.
exposure of all teams to real emergencies is diluted, and thus
physicians, nurses, and paramedics, should possess a broad
sufficient exposure is also an important component to maintain
knowledge base and advanced skills, including surgical pro-
quality of care.
cedures, trauma resuscitation, advanced cardiac life support
(ACLS), and advanced airway management.
◆ Emergency medicine (para-​) medical staff should acquire and
Teaching maintain knowledge and skills required for prevention, diag-
nosis, and management of acute and urgent aspects of illnesses
There are three groups that benefit from a specific and adapted
and injuries (e.g. basic and continuing educational programmes)
teaching programme: the population; the dispatcher; and the pre-​
[16].
hospital resources.
Emergency medicine (para-​) medical staff should acquire and
◆

update knowledge on other emergency services (e.g. police,

The population fire brigade, civil protection, etc.), structures and procedures,
Out-​of-​hospital emergencies occur frequently, and laypersons including communication. Conversely, emergency medicine
are often the first to respond to these events. Emergency medi- (para-​) medical staff should endorse continuous training for
cine community educational programmes (MCEPs) may en- non-​medical EMS providers.
hance layperson preparedness for medical emergencies. The
first and difficult task of MCEPs is to educate potential callers
to recognize a potential medical emergency. The second task is Research in pre-​hospital care
to teach the caller how to timely and most efficiently alarm the
EMS system in stress or crisis situations. The third task is to teach In the field of pre-​ hospital care, the paucity of high-​quality
how to focus on the critical information needed by the EMD to evidence-​based research to support policies and practice is not-
determine an appropriate course of actions. There are different able. In the early days of EMS, most clinical practices were not
strategies to enhance layperson preparedness for medical emer- tested in the field. Treatments and diagnostic modalities were ex-
gencies. The two most used teaching approaches are general trapolated from the hospital to the pre-​hospital setting, despite
public messages using standard media (including ‘new’ media tremendous differences in environments, or they were adopted
such as Twitter, Facebook, etc.) or implementation in standard based on limited testing in a controlled setting. Pre-​hospital
 Resea rch i n  pre- ho spi ta l   c a re 71

professionals can no longer afford this approach. Thus, the main [30]. For all other patients, written consent is required in EMS re-
goals of research in the pre-​hospital area are to: search, despite the delays to treatment that this will usually entail.
1. Foster delivery of high-​quality care in the field, by integrating It should be evident that trials involving the EMS system seek to
best research evidence, clinical expertise, and patient values. assess the effects of time-​critical treatments for life-​threatening
disorders such as STEMI, stroke, severe haemorrhage, or respira-
2. Help reduce purely empirical medical behaviour—​the vast ma-
tory distress. As such, consent rituals by themselves may delay
jority of current daily pre-​hospital interventions have never
the start of a trial treatment, such that the treatment effect could
been subjected to scientific scrutiny.
be reduced or obscured. Moreover, the vast majority of EMS pro-
3. Achieve knowledge transition in out-​of-​hospital emergency viders are committed to provide timely, comprehensive care to
care. acutely ill patients, regardless of their eligibility for research par-
Effective and timely incorporation of research-​based evidence ticipation. In addition, there must be reasonable evidence that
into emergency medical care has the potential to improve survival the studied therapy has the potential to provide real and direct
and good quality of life and be cost-​effective [27]. benefit. Furthermore, these studies must follow the highest eth-
ical standards and undergo rigorous independent reviews to en-
Trial specifics in out-​of-​hospital sure that these standards are met. Before any patient is enrolled,
the community must be consulted and made aware that informed
emergency research consent cannot be obtained for most study participants before the
Traditional patient-​oriented trial designs can be implemented in study is started, as required by law. The legal representatives and,
pre-​hospital trial designs (e.g. observational and randomized). In in a later stage, the surviving patient need to be informed as soon
an observational trial design, events are monitored and analysed as possible to still meet the highest possible ethical standards and
without an attempt to manipulate or alter the outcome. While this to provide the patient full rights as a study patient. However, the
design is simple and suitable in the pre-​hospital setting, it cannot European Parliament has debated a revision to the Clinical Trials
define cause and effect relationships and should be considered as Directive (2001/​20/​EC) and it is encouraging that emergency re-
being hypothesis-​generating. These studies are important in the search is included, as it was not in the previous Directive [31, 32].
cycle of research, as the problem or current status must be defined
before proposing changes. Pre-​ hospital research particularly Reference treatment in randomized controlled trials
lends itself to observational studies, since events during a study Some treatment modalities in pre-​hospital emergency care are
are sporadic, beyond control, and unpredictable. Within observa- based on limited evidence and expert opinions. To establish a
tional studies, we can use a cross-​sectional design, providing data group with placebo treatment will never be ethically accepted,
on the prevalence of an outcome or other variables within a popu- because one could state that the patient is denied treatment that
lation. A longitudinal design can better determine a cause–​effect is accepted to be effective. Thus, the use of existing therapy as a
relationship. In contrast, case-​control studies identify subjects, control group remains.
based on the presence or absence of the outcome, and look back
to see what differences could account for this outcome occurring, Re-​evaluation of priorities
whereas cohort studies identify subjects without the outcome and The constant re-​evaluation of priorities and the necessity for
then expose them to a treatment. In the specific setting of EMS, clinical care to take precedence over research make conducting
a randomized design is often hampered by a lack of control over clinical studies difficult. Study protocols that either facilitate or,
events and variables. Confounders may cloud or boost differences at most, minimally impact on patient care are more likely to be
noted after treatment [28]. successfully completed in the pre-​hospital setting. Studies that in-
Conducting research in the pre-​hospital arena faces important volve EMS resource utilization in excess of typical pre-​hospital
imminent design challenges. These are not always fully appre- care are more likely to encounter obstacles or fail.
ciated by those not regularly working in this environment. In
addition, ethical, legal, and practical aspects also limit the estab-
The variety in EMS systems
lishment of high-​quality pre-​hospital research [29]. What may be beneficial in an urban system can be of no effect, or
even be harmful, in a rural EMS system. Extrapolation of study
Informed consent findings from one EMS system to another system should be done
A major challenge in out-​of-​hospital EMS research is the issue with critical caution.
around informed consent. For research involving people who An important challenge is to maintain accuracy and consist-
are incapable of giving informed consent, the Declaration of ency in the interpretation of clinical endpoints across geographic
Helsinki states that, if no patient representative is available and areas and over the course of a trial. Selection of appropriate clin-
the research cannot be delayed, the study may proceed without ical endpoints and standardization of definitions for single and
informed consent, provided that the specific reasons for involving composite clinical endpoints in pre-​hospital care trials are essen-
patients with a disorder that renders them unable to give in- tial prerequisites for quality in emergency care outcome research.
formed consent have been stated in the research protocol and Conversely, variability in endpoint definitions creates a barrier to
that the study has been approved by a research ethics committee the understanding of results across clinical trials or the pooling of
72 CHAPTER 8   The e mergency medical syst em

therapy [8, 37]. In addition, early administration of specific medi-

Box 8.1  Six Ds: outcome categories in pre-​hospital
outcome research cation has also been demonstrated to be beneficial in patients
with STEMI. Depending on the time intervals of transporta-
Reduction
◆ of death—​survival tion, pre-​hospital administration of these drugs can make a large
Reduction of disease
◆ difference [35].
Reduction of disability
◆

Minimizing discomfort
◆ The right patient at the right time to the
Minimizing dissatisfaction
◆ right hospital
Destitution (cost-​effectiveness)
◆
This is a well-​known adagio in trauma care, namely that a severely
injured victim is transported preferably to a level 1 trauma centre.
Considering the need for early reperfusion strategies in ACS pa-
results for the detection of rare safety signals. Emergency care re-
tients, these patients should be transported not only to a hospital
search metrics should be measurable, explicitly defining the mul-
with PCI facilities, but also to one with 24/​24 availability of per-
tiple stakeholders involved.
sonnel to perform this intervention [20].
EMS outcome research has been defined as the six Ds outcome
categories (see E Box 8.1) [33]. Further, reduction of mortality,
morbidity, and invalidity, as well as human and economic factors,
Collaboration models
are considered. Although these six Ds outcome categories seem Collaboration in clinical research requires partnership/​involve-
simple and logical, some problems remain. Identification of the ment by a group of clinicians/​scientists in the development, im-
most appropriate timing for endpoint assessment is one (arrival at plementation, evaluation, and publication of a research project.
the hospital, discharge from the ED or hospital, etc.). To improve Critical to the research process is an in-​depth knowledge of both
pre-​hospital research, specific guidelines have helped to improve the clinical condition being studied and the research question.
the quality of the research (see E Boxes 8.1 and 8.2) [27]. Likewise, planning a clinical study requires an in-​depth under-
standing of care at all stages of the chain of emergency care.
Involvement of emergency medicine physicians (EPs)
working in the pre-​hospital setting in cardiology studies may
Operational cardiac examples create a win–​win situation. Both cardiologists and EPs gain a
Time-​sensitive conditions better understanding of the challenges and opportunities at
their respective stages of care. On the one hand, most cardiolo-
Many patients die of a heart attack or stroke without even reaching
gists are not aware of these challenges and opportunities. On
the hospital [34]. Many physicians working in a hospital are not
the other hand, EMS staff may gain more current knowledge re-
aware of these facts. It takes time to convince these physicians
garding advances in caring for patients with the condition being
(and policymakers) of the need to improve the emergency med-
studied. In addition, EMS staff can be crucial to patient recruit-
ical care offered to patients before they reach the hospital and to
ment and early treatment. The impact of study protocols (e.g.
promote pre-​hospital research on what happens during that crit-
obtaining consent, early pre-​hospital blood sampling or other
ical time frame.
tests, and managing complications) is best assessed by EMS
The clinical outcome in patients with STEMI is largely de-
personnel. Ideally, the EP should be listed as a co-​investigator
pendent on the time to reperfusion [35]. As longer time from
and be involved in pre-​hospital and ED planning and the design
symptom onset to reperfusion therapy has been associated with
phase of the study. Authorship credit should follow, according to
decreased myocardial reperfusion, and thus increased morbidity
the standard authorship requirements. This collaborative model
and mortality, efforts have been made in reducing the ischaemic
for conducting pre-​hospital research was exemplified in the
time. Several studies have presented the benefit of pre-​hospital
STREAM study [35]. Such arrangements may well assist EPs in
ECG in decreasing the door-​to-​balloon time [36]. Transmission
enhancing academic productivity and improving links between
via wireless technology is becoming more and more standard pre-​
different research groups within an institution and beyond [38].
hospital practice and should serve to decrease time to arrival in
the angioplasty suite, ultimately decreasing time to reperfusion
Improvement
Rapid growth in information technology and telecommunica-
Box 8.2  Specific pre-​hospital research guidelines tions has enabled technologies to support advanced services.
Use standardized forms for specific clinical problems.
◆
For instance, telemedicine helps eliminate distance barriers (e.g.
distal rural communities) and facilitates collaborative real-​time
Establish a national clearing house for the collection of data.
◆
patient management. It allows prompt access and real-​time inter-
Create a standing panel of EMS researchers to identify rele-
◆
action with remote, specialized health care providers.
vant outcomes and evaluate interventions.
In the diagnostic stage, more electronic devices are implanted
Improve the conduct, reporting, and dissemination of high-​
◆
in patients or ‘at-​home’ point of care will be used. In addition,
quality outcome research.
positioning systems can indicate exactly the location of the
 Per s ona l  pe r spe c t i v e 73

patient and pre-​hospital team. These opportunities can pro-

vide even more timely treatment of acutely ill patients. On the Further professionalization of the EMS system, in con-
other hand, comparable with anti-​theft alarm systems, many junction with evolution of technology, will provide a boost
false-​positive alarms may be created, resulting in inappropriate of scientific and technical opportunities to improve the im-
EMS use. mediate care of all acutely ill and injured patients. A large
In the therapeutic stage, long-​distance expert advice, decision-​ focus existed in the last decennia on trauma care. ACS,
taking, or prescription can change the EMS organization stroke, or early sepsis will be the diseases of interest for pre-​
dramatically. hospital care providers.
Furthermore, health care providers are being offered a wide High-​quality research in pre-​hospital emergency care is still
range of smartphone applications and digital platforms which pro- immature. Pre-​hospital care as yet has no strong academic
vide them with clinical decision support at the point of care. These tradition, but has large patient volumes, highly engaged teams,
systems will also track health care providers’ exposure to critical and outcomes are linked to adequate responses provided by
conditions and give individualized feedback. In case there is a need EMS. In this growing field of health sciences, demonstrating
for training due to a lack of sufficient clinical experience or due to an impact in practice is fundamental to the continued attrac-
under-​performance, the software will point out shortages and ad- tion of research funding and building of research skills and
just personalized continuing medical education programmes. culture, and thus high-​quality evidence-​based research, to
improve future pre-​hospital policies and practice.
Pre-​hospital care providers also need to strengthen their
Personal perspective communication and collaboration with first-​line health care
providers. Technical evolution will create the opportunity
The need for greater awareness of the public of 112 as the to use the same dispatching system for urgent and non-​
European emergency number is still necessary. However, urgent calls. The European EC directive 2007/​698/​EG on
raising public awareness is a difficult and long-​lasting effort. ‘the number for non-​emergency medical questions and as-
Changing the behaviour of 112 callers requires a well-​ sistance’ has to be implemented. Integration of these calls
prepared and well-​planned behaviour-​changing programme. within the 112 centre may be safe, effective, and efficient
After implementation of such a programme, monitoring the (see E Figure 8.2) [39].
changes in behaviour for potential adjustments of the pro- Finally, the hospital gatekeeping task of an ED could be
gramme is essential. In addition, technological opportunities at an earlier stage, namely pre-​hospital. A study on patients
to alert the Emergency Medical Dispatch centre create not with AMI demonstrated that such efforts were associated
only opportunities, but also threats. with a reduction in delays and mortality of 60% [40].

Non-urgent care Non-urgent

planned care

Medical dispatching
General
practitioner
consultation
EU non-emergency number Computer-aided dispatching
General practitioner
at home
Geographic decision
support system
BLS ambulance

EU emergency number Artificial intelligence

ALS ambulance or
helicopter

Physician-manned
Urgent care ambulance or
helicopter

Figure 8.2  EMD as a hub to access appropriate medical care.

74 CHAPTER 8   The e mergency medical syst em

Further reading
Brophy JR. Leadership Essentials For Emergency Medical Services Huber K, Goldstein P, Danchin N, Fox KAA. Network models for large
(Continuing Education), first edition. Jones and Bartlett Publishers: cities: the European experience. Heart 2010;96:164–​9.
Sudbury, MA; 2009. Huber K, Goldstein P, Danchin N, et  al. Enhancing the efficacy of
Evans BE, Dyar JT. Management of EMS, first edition. Pearson: London; delivering reperfusion therapy:  a European and North American
2009. experience with ST-​segment elevation myocardial infarction networks.
Fox KA, Huber K. A European perspective on improving acute systems Am Heart J 2013;165:123–​32.
of care in STEMI: we know what we do, but how can we do it? Nat Clin Kübler-​Ross E. On Death and Dying: What the dying have to teach doctors,
Pract Cardiovasc Med 2008;5:708–​14. nurses, clergy and their own families. Scribner: New York, NY; 2014.
Hazzard K. A Thousand Naked Strangers: A Paramedic’s Wild Ride to the Le Baudour C, Bergeron JD, Wesley K. Emergency Medical Responder: First
Edge and Back. Scribner: New York, NY; 2016. on Scene, eleventh edition. Pearson: London; 2018.

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 CHAPTER 9

Out-​of-​hospital cardiac
arrest
Jerry P Nolan and Christian Hassager

Contents
Summary  76
Summary
Introduction  76 Cardiac arrest is the most extreme of medical emergencies. If the victim is to
Epidemiology and outcomes from have any chance of high-​quality neurological recovery, cardiac arrest must be
cardiac arrest  76 diagnosed quickly, followed by summoning for help, as basic life support (chest
Basic life support  77 compressions and ventilations) is started. In most cases, the initial rhythm will
High-​quality cardiopulmonary be shockable, but this has often deteriorated to a non-​shockable rhythm by the
resuscitation  77
Advanced life support  77 time a monitor and/​or defibrillator is applied. While basic life support will sustain
Defibrillation  77 some oxygen delivery to the heart and brain and will help to slow the rate of de-
Adrenaline  77 terioration in these vital organs, it is important to achieve restoration of spontan-
Antiarrhythmic drugs  77
Mechanical devices  78
eous circulation as soon as possible (by defibrillation if the rhythm is shockable).
Airway management  79 Once return of spontaneous circulation is achieved, the quality of post-​cardiac
Reversible causes and role of arrest management will influence the patient’s final neurological and cardiological
echocardiography  79
Extracorporeal CPR  79 outcome. These interventions aim to restore myocardial function and minimize
Post-​cardiac arrest syndrome  80 neurological injury.
Post-​cardiac arrest brain injury  80
Post-​cardiac arrest myocardial
dysfunction  80
Systemic ischaemia/​reperfusion response  80
Persisting precipitating pathology  80
Airway and breathing with controlled
reoxygenation  80
Circulation  81
Introduction
Disability—​optimizing neurological
recovery  81
Recovery from cardiac arrest depends on an intact chain of survival: early recognition
Sedation  81 and call for help; early CPR; early defibrillation; and post-​resuscitation care. All four links
Control of seizures  81 in the chain must be strong if a good neurological outcome is to be achieved. This chapter
Glucose control  82
Targeted temperature management  82 will address the key components to high-​quality CPR and the treatment that is delivered
Prognostication  82 once ROSC is achieved.
Clinical examination  83
Electrophysiology  83
Biomarkers  83
Imaging  83
Multimodal approach to prognostication  83
Epidemiology and outcomes from cardiac arrest
Organ donation  84 The annual incidence of EMS-​treated out-​of-​hospital cardiopulmonary arrests (OHCAs)
Conclusion  84 for all rhythms in the US is 73 per 100 000 population [1]‌; similar incidences have been
Personal perspective  84 cited in Europe, but the precise incidence varies between regions. The incidence of ven-
Further reading  84 tricular fibrillation (VF) as the first documented rhythm after cardiac arrest is declining;
References  84 it was approximately 25% among EMS-​treated arrests of cardiac aetiology, documented
in a Danish registry [2]. Survival to hospital discharge is 8–​10% for all-​rhythm cardiac
arrests and around 30–​40% for VF cardiac arrests [2, 3].
 A dva n ced l if e   supp ort 77

Bystander CPR increases survival by 2–​3 times [4, 5], and use are continued as the defibrillator is charged; the compressions
of text message alerts sent to volunteer first responders is an ef- are paused to enable a 150–​200 J shock to be delivered. Chest
fective method of increasing bystander CPR rates [6]‌. compressions are resumed immediately, without reassessing the
rhythm; they are continued for 2 minutes, before pausing to as-
sess the rhythm. If VF/​pVT persists, another shock (150–​200 J bi-
Basic life support phasic) is delivered. Health care providers must practise efficient
coordination between CPR and shock delivery. A shock is more
Basic life support (BLS) and advanced life support (ALS) together likely to be successful if the pre-​shock pause is short (<5 seconds).
form a continuum of CPR. The keys steps are that cardiorespira-
tory arrest is recognized immediately, help is summoned, and Adrenaline
CPR (chest compressions and ventilations) is started immedi- Adrenaline 1 mg is injected after the third shock and subse-
ately and, if indicated, defibrillation attempted as soon as pos- quently every 3–​5 minutes, until ROSC is achieved. If the initial
sible (ideally, within 3 minutes of collapse). The ERC guidelines rhythm is non-​shockable [asystole or pulseless electrical activity
for layperson CPR indicate that, once cardiac arrest is diagnosed (PEA)], chest compressions are resumed and adrenaline 1 mg
(unresponsive and not breathing normally), chest compressions is injected immediately and repeated every 3–​5 minutes. If IV
are started at a rate of 100–​120 per minute and a depth of 5–​6 cm, access cannot be established within the first 2 minutes of resus-
allowing full recoil between each compression [7]‌. If the by- citation, consider gaining intraosseous (IO) access. This is faster
stander is trained and willing, two rescue breaths are given after than attempted central venous access and IO delivery of resus-
every 30 compressions (compression:ventilation ratio of 30:2). citation drugs will achieve adequate plasma concentrations. An
Compression-​only CPR is recommended if the bystander is un- observational study with ROSC as the primary endpoint con-
trained in standard CPR or is unwilling or unable to give rescue cluded that IO access was non-​inferior to IV access [12]. The α-​
breaths. The compression-​only technique is also preferred for adrenergic effects of adrenaline increase coronary and cerebral
dispatcher-​assisted telephone CPR [8]. perfusion pressure, and two placebo-​ controlled randomized
clinical trials have documented that adrenaline increases the
High-​quality cardiopulmonary resuscitation rate of ROSC by three times, compared with placebo [13,  14].
During CPR, perfusion of the brain and myocardium is, at best, Only the most recent of these two randomized controlled trials
25% of normal; successful ROSC is more likely, the higher the (RCTs) was adequately powered for long-​term survival and this
coronary perfusion pressure (CPP). Chest compressions in- showed a significantly higher 30-​day survival among those re-
crease the amplitude and frequency of the VF waveform and ceiving adrenaline versus placebo [13]; however, there was no
increase the likelihood that attempted defibrillation will be statistically significant difference in favourable neurological sur-
successful. According to the AHA, five critical components de- vival. Although not statistically different, adrenaline resulted in
fine high-​quality CPR: minimizing interruptions in chest com- increased neurologically unfavourable survivors, compared with
pressions; providing compressions of adequate rate and depth; placebo. Although this RCT does not address the pathophysi-
avoiding leaning between compressions; and avoiding exces- ology behind the higher number of survivors with neurological
sive ventilation [9]‌. Once an advanced airway [tracheal tube deficit in the adrenaline group, it is likely that the heart is more
or supraglottic airway (SGA)] has been inserted, ventilation is resilient to hypoxic–​ischaemic injury and injection of adrenaline
provided at ten breaths per minute, without interrupting chest may achieve ROSC at times when the brain has already sustained
compressions. Use of feedback devices [such as modified defib- severe and irreversible damage.
rillators that incorporate accelerometers (compression rate and
depth) and measure changes in transthoracic impedance (venti- Antiarrhythmic drugs
lation rate)] improve the quality of CPR and may improve out- Evidence from two RCTs (the ARREST and ROC-​ALPS trials)
come [10, 11]. comparing amiodarone with placebo for OHCAs, showed, with
very low certainty, no statistically significant difference in sur-
vival to hospital discharge with good neurological outcome, sur-
Advanced life support vival to hospital discharge, or ROSC [15, 16]. However, experts
have raised concerns that both studies may have been underpow-
The ERC ALS algorithm (see E Figure 9.1) provides a simple ered to detect a clinically meaningful treatment effect [17]. Based
structure for the interventions used in an attempt to achieve  ROSC. on expert consensus, amiodarone 300 mg is given by bolus injec-
tion after the third shock. On current evidence, there is no clear
Defibrillation difference in the effect of lidocaine, compared with amiodarone,
Chest compressions are continued while defibrillator elec- in shock-​refractory cardiac arrest; thus, lidocaine can be given
trodes are applied to the chest. If the rhythm is shockable [VF as an alternative to amiodarone [17]. The benefit of giving mag-
or pulseless ventricular tachycardia (pVT)], chest compressions nesium routinely during cardiac arrest is unproven. Magnesium
78 CHAPTER 9   Ou t- of-h ospital cardiac arrest

Advanced life support

Unresponsive and
not breathing normally?

Call resuscitation team

CPR 30:2
Attach defibrillator/monitor
Minimize interruptions

Assess rhythm

Shockable Non-shockable
(VF/pulseless VT) (PEA/asystole)

1 shock Return of
minimize spontaneous
interruptions circulation

Immediately resume IMMEDIATE POST- Immediately resume

CPR for 2 min CARDIAC ARREST CPR for 2 min
Minimize interruptions TREATMENT Minimize interruptions
• Use ABCDE approach
• Aim for SaO2 of 94–98%
• Aim for normal PaCO2
• 12-lead ECG
• Treat precipitating cause
• Targeted temperature
management

DURING CPR TREAT REVERSIBLE CAUSES

• Ensure high-quality chest compressions Hypoxia Thrombosis—coronary or pulmonary
• Minimize interruptions to compressions Hypovolaemia Tension pneumothorax
• Give oxygen Hypo-/hyperkalaemia/metabolic Tamponade—cardiac
• Use waveform capnography Hypothermia/hyperthermia Toxins
• Continuous compressions when advanced airway
in place CONSIDER
• Vascular access (intravenous or intraosseous) • Ultrasound imaging
• Give adrenaline every 3–5 min • Mechanical chest compressions to facilitate transfer/treatment
• Give amiodarone after 3 shocks • Coronary angiography and percutaneous coronary intervention
• Extracorporeal CPR

Figure 9.1  The 2015 European Resuscitation Council advanced life support algorithm.
Reproduced from Soar J, Nolan JP, Bottiger BW, et al. European Resuscitation Council Guidelines for Resuscitation 2015: Section 3. Adult advanced life support. Resuscitation 2015;
95: 100–​147 with permission from Elsevier.

sulfate 2 g IV is given for refractory VF if there is any suspicion of resuscitation attempts where rescuer fatigue may impair the ef-
hypomagnesaemia. fectiveness of manual chest compression.
The Lund University Cardiac Arrest System (LUCAS) is a gas-​
Mechanical devices driven sternal compression device that incorporates a suction
Several CPR techniques and devices may improve haemo- cup for active compression–​decompression (ACD)-​CPR. One
dynamics or short-​ term survival when used by well-​ trained pragmatic RCT comparing LUCAS-​CPR with standard CPR in
providers in selected cases. Although mechanical devices are OHCA documented no difference in outcome overall, but among
used routinely in only a few centres, they are used occasionally those with shockable rhythms, the outcome was worse in the
to support patients undergoing primary PCI and for prolonged LUCAS group [18].
 A dva n ced l if e   supp ort 79

The load-​distributing band (LDB) is a circumferential chest ◆ Minimize the risk of hypoxia by ensuring that the patient’s
compression device comprising a battery-​powered constricting lungs are ventilated adequately with 100% oxygen (O2).
band and a backboard. A  large pre-​hospital RCT comparing ◆ PEA caused by hypovolaemia is usually due to severe haemor-
LDB-​CPR with high-​quality manual CPR showed no difference rhage. Restore intravascular volume rapidly with fluid, coupled
in hospital survival between the two groups [19]. with urgent surgery to stop the haemorrhage.
An impedance threshold device (ITD) is a valve that limits air ◆ Hyperkalaemia, hypokalaemia, hypocalcaemia, acidaemia, and
entry into the lungs, as the chest recoils during the compression other metabolic disorders are detected by biochemical tests or
release phase; this decreases the intrathoracic pressure and in- suggested by the patient’s medical history, e.g. renal failure. IV
creases venous return to the heart. Prospective randomized trials calcium chloride is indicated in the presence of hyperkalaemia,
indicate no difference in long-​term outcome when an ITD is used hypocalcaemia, and calcium channel-​blocking drug overdose.
with standard CPR, but one study has documented higher long-​ ◆ Suspect hypothermia in a drowning incident.
term survival rates, compared with standard CPR, when the ITD ◆ A tension pneumothorax may be the primary cause of PEA and
is combined with ACD-​CPR [20]. may follow attempts at CVC insertion. Decompress rapidly by
needle thoracocentesis or urgent thoracostomy, and then insert
Airway management a chest drain.
Conventionally, airway opening and ventilation are considered ◆ Rapid transthoracic echocardiography (TTE) with minimal
essential during CPR, and advanced airway techniques are per- interruption to chest compressions can be used to identify a
ceived as the ‘gold standard’. Several observational studies have pericardial effusion causing cardiac tamponade. Cardiac arrest
documented an association between use of bag–​mask ventilation after penetrating chest trauma is highly suggestive of tamponade
and better outcome, in comparison with use of either an SGA or a and is an indication for resuscitative thoracotomy.
tracheal tube, but these studies have a high risk of selection bias. ◆ In the absence of a specific history, accidental or deliberate inges-
Three randomized clinical trials involving airway management tion of therapeutic or toxic substances may be revealed only by
in OHCA were published in 2018 [21–​23]. A  non-​inferiority laboratory investigations.
trial of bag–​mask ventilation versus tracheal intubation (CAAM ◆ The most common cause of thromboembolic or mechanical
study) found no difference in favourable functional outcome at circulatory obstruction is massive pulmonary embolism (PE).
day 28 and was deemed inconclusive [21]. A  cluster random- If cardiac arrest is likely to be caused by PE, consider giving
ized trial of the laryngeal tube (LT) versus tracheal intubation a fibrinolytic drug immediately. Case reports indicate that
(PART) reported better 72-​hour survival with the LT [22], but ROSC can be achieved as long as 90 minutes after giving a
a cluster randomized trial of the i-​gel versus tracheal intubation thrombolytic drug.
(AIRWAYS-​2) documented no difference in functional outcome Ultrasound (US) imaging during cardiac arrest provides infor-
between the groups at hospital discharge [23]. mation that may help to identify reversible causes of cardiac ar-
The ideal airway management strategy during CPR remains rest, e.g. cardiac tamponade, PE, ischaemia (regional wall motion
unclear. In practice, there is often a progression in complexity of abnormality), aortic dissection, hypovolaemia, pneumothorax.
airway management, from no intervention (compression-​only Integration of US into ALS requires considerable training to en-
CPR), mouth-​to-​mouth, and bag–​mask ventilation, through to sure that interruptions to chest compressions are minimized.
SGA devices and tracheal intubation. The best airway strategy is A subxiphoid probe position is recommended. Placement of the
likely to vary, depending on the time point in the resuscitation probe just before chest compressions are paused for a planned
process and the skill set of the attending rescuer. A key message rhythm assessment enables a well-​trained operator to obtain
is to ensure high-​quality chest compressions and minimize any views within 10 seconds.
interruptions for airway intervention.
Waveform capnography is the most sensitive and specific way Extracorporeal CPR
to confirm and continuously monitor the position of a tracheal
OHCA patients with apparently good prognostic factors in whom
tube in victims of cardiac arrest and should supplement clinical
ROSC cannot be achieved may be considered for immediate
assessment. Several studies have indicated that exhaled carbon
eCPR with ECMO and mechanical circulatory support with can-
dioxide (CO2) is detected reliably during CPR, except after pro-
nulation of the femoral vein and artery. Cohort studies indicate
longed cardiac arrest (>30 minutes) when pulmonary flow may be
that among patients without ROSC after OHCA, overall survival
negligible. Existing portable monitors make initial capnographic
after eCPR is only about 20–​30% (with wide variation); further-
confirmation and continuous monitoring of tracheal tube pos-
more, many of the surviving patients will have poor neurological
ition feasible in almost all settings where intubation is performed,
outcomes. A recent systematic review by the International Liaison
including out of hospital, ED, and in-​hospital locations.
Committee on Resuscitation (ILCOR) concluded that there was
inconclusive evidence to either support or refute the use of eCPR
Reversible causes and role of echocardiography for OHCA and that the certainty of evidence across studies is very
Potential causes or aggravating factors for which specific treat- low [25]. There are no randomized studies on this issue yet, but
ment exists are sought during any cardiac arrest [24]. some are ongoing.
80 CHAPTER 9   Ou t- of-h ospital cardiac arrest

In a large series of patients admitted to ICU after OHCA, shock

Post-​cardiac arrest syndrome [defined as the need for continuous adrenaline or noradren-
aline infusion to maintain a mean arterial pressure (MAP) of
Data from the UK Intensive Care National Audit and Research
>60  mmHg for >6 hours] was present in 68% of patients [33].
Centre (ICNARC) indicate that approximately 8664 patients each
In another series of OHCA patients, cardiac index values de-
year are admitted to UK ICUs after cardiac arrest; survivors of
creased to a nadir 8 hours after ROSC but then returned gradually
cardiac arrest account for 12.2% of all mechanically ventilated
to normal by 72 hours [46]. Targeted temperature management
admissions to UK ICUs [26]. Interventions applied after ROSC
increases systemic vascular resistance (SVR) and decreases the
impact significantly on the quality of survival. There is consid-
heart rate, resulting in further decrease in cardiac index by about
erable variation in post-​cardiac arrest treatment and patient out-
30% when targeting 33°C [47].
come between hospitals [27]. Approximately 40–​60% of patients
admitted to an ICU after cardiac arrest will survive to hospital
discharge, and most of these will have a good neurological out-
Systemic ischaemia/​reperfusion response
come [26, 28, 29]. Outcomes may be improved if these patients Total systemic ischaemia occurs during cardiac arrest and is only
are treated in ‘cardiac arrest centres’ that offer a comprehensive partly reversed by CPR (which achieves a cardiac output of only
package of care that includes PCI, therapeutic hypothermia, and 25% of normal). After ROSC, myocardial dysfunction and micro-
a high-​quality neurology service [30]. The ERC and ESCIM pub- circulatory failure will prolong the period of inadequate tissue
lished guidelines on post-​resuscitation care in 2015 [31]. O2 delivery. Restoration of tissue oxygenation generates reactive
Systemic ischaemia during cardiac arrest and the subsequent O2 species and reperfusion injury, causing MOF and increased
reperfusion response after ROSC causes post-​cardiac arrest syn- risk of infection [48]. This condition resembles sepsis, with high
drome (PCAS) [32]. The severity of PCAS is determined by the concentrations of inflammatory mediators [49] and activation of
cause and duration of the cardiac arrest and has four key clinical coagulation and fibrinolysis [50]. Clinical manifestations of this
components: systemic ischaemic–​reperfusion response include intravascular
volume depletion, impaired vasoregulation, impaired O2 delivery
◆ Post-​ cardiac arrest brain injury—​ manifests as coma and
and utilization, and increased susceptibility to infection [51].
seizures.
◆ Post-​cardiac arrest myocardial dysfunction—​typically improves Persisting precipitating pathology
after 48–​72 hours.
The most common cause of OHCA among those surviving to
Systemic ischaemia/​
◆ reperfusion response—​ tissue reperfusion
can cause programmed cell death (apoptosis), affecting all organ ICU is ischaemic heart disease, and many of these cases will be
systems and resulting in a systemic inflammatory response syn- associated with AMI [52]. Following an STEMI, urgent coronary
drome (SIRS)-​like syndrome. reperfusion is essential. Other precipitating causes will also need
◆ Persisting precipitating pathology—​ CAD being the most treatment [24]:
common precipitating cause after OHCA. ◆ CVD (AMI/​ACS, cardiomyopathy).
◆ Respiratory disease [chronic obstructive pulmonary disease
Post-​cardiac arrest brain injury (COPD), asthma].
In patients surviving to ICU admission, but subsequently dying Central nervous system (CNS) disease [cerebrovascular accident
◆

in hospital, brain injury [or withdrawal of life-​sustaining treat- (CVA)].

ment (WLST) because of brain injury] is the cause of death in ◆ Thromboembolic disease (PE).
more than two-​thirds of cases after OHCA [33] and in approxi- ◆ Toxicological (overdose, poisoning).
mately 25% after in-​ hospital cardiac arrest (IHCA) [34,  35]. ◆ Infection (sepsis, pneumonia).
Clinical manifestations of post-​cardiac arrest brain injury include ◆ Hypovolaemia.
coma, seizures, myoclonus, varying degrees of neurocognitive
dysfunction, and brain death [36]. After resuscitation, ischaemic Post-​cardiac arrest care is started immediately after ROSC has
cell death (by necrosis, apoptosis, or auto-​phagocytosis) can be been achieved, irrespective of location. An ‘ABCDE’ (Airway,
delayed for hours to up to 4 days [37], which provides a thera- Breathing, Circulation, Disability, Exposure) systems approach is
peutic window for neuroprotective strategies. Several factors can used to identify and treat physiological abnormalities and organ
exacerbate post-​cardiac arrest brain injury: endothelial swelling, injury.
leucocyte adherence to the endothelium, and red blood cell
(RBC) sludging, collectively causing the ‘no reflow’ phenomenon Airway and breathing with controlled
[38]; hypotension (cerebral autoregulation is impaired) [39, 40]; reoxygenation
hyperoxia [41]; hypocapnia [42]; pyrexia [43]; hyperglycaemia After ROSC is achieved, patients who remain comatose or agi-
[26]; blood glucose variability [44]; and seizures [45]. tated with a decreased conscious level and those with breathing
difficulties will require sedation, tracheal intubation, and mech-
Post-​cardiac arrest myocardial dysfunction anical ventilation. At the time of ROSC and for an undefined
Post-​cardiac arrest myocardial dysfunction is a significant cause period afterwards, hyperoxaemia increases the formation of re-
of morbidity and mortality after both IHCA and OHCA [34, 35]. active O2 species and increases post-​ischaemic oxidative injury
 P o st- ca rdiac a rrest   sy n dro m e 81

and cellular death [41, 53]. An analysis of a large North American may be high initially, the release of inflammatory cytokines as-
ICU database documented an association between hyperoxia at sociated with PCAS causes vasodilatation [32]. Treatment with
the time of the first blood gas analysis and a poor outcome [54]; fluids, inotropes, and vasopressors is guided by blood pressure,
however, this was refuted in a study of a large Australian and New heart rate, urine output, rate of plasma lactate clearance, central
Zealand ICU database which showed that, after adjustment for venous O2 saturations, and cardiac output monitoring (typically
sickness severity, for inspired oxygen fraction (FiO2) and for rele- non-​invasive). Given the possibility of cerebral hypoperfusion
vant covariates, arterial oxygen pressure (PaO2) was no longer in the post-​ cardiac arrest patient, guidelines have suggested
predictive of hospital mortality [55]. A prospective cohort study maintaining an MAP of >65–​70  mmHg [31], but observational
measured PaO2 at 1 and 6 hours after ICU admission and on data indicate an association between higher MAP values and a
multivariable analysis showed that a 1-​hour longer duration of better neurological outcome [64]. It is likely that patients will re-
hyperoxia exposure was associated with a 3% increase in risk of quire individual titration of blood pressure [40], although in a re-
poor neurological outcome (relative risk, 1.03; 95% CI, 1.02–​1.05) cent study, targeting a higher MAP in post-​cardiac arrest patients
[41]. There are several weaknesses of these observational studies, improved cerebral oxygenation but did not improve the extent of
the most important being that they completely missed the period anoxic brain damage or neurological outcome [65].
immediately after ROSC (until ICU admission), which is when Patients who survive a cardiac arrest caused by VF/​pVT and
hyperoxia is most likely to cause harm. Ongoing prospective who have no evidence of a disease that can be treated effectively
controlled trials may provide the data needed to inform clin- (e.g. coronary revascularization) are considered for an ICD before
ical practice [56]. In the meantime, current guidance is to ad- leaving hospital.
just the inspired O2 concentration immediately after ROSC to
achieve normal arterial O2 saturation (94–​98%) when it can be Disability—​optimizing neurological recovery
measured reliably by pulse oximetry or arterial blood gas (ABG)
Approximately 4% of OHCAs have a neurological cause, e.g.
analysis [57].
subarachnoid haemorrhage (SAH) [66]; however, unless there
Ventilation is adjusted to achieve normocapnia and monitored
is a neurological or respiratory prodrome—​ in which case,
using end-​tidal CO2 with waveform capnography and ABGs.
brain and chest computerized tomography (CT) is a priority,
Avoid hyperventilation, which will cause cerebral vasoconstric-
the OHCA patient should be considered for immediate cor-
tion and possible cerebral ischaemia [42]. Other observational
onary angiography. CT scanning is undertaken secondarily in
studies of post-​cardiac arrest ICU patients have shown an associ-
those patients in whom no culprit lesion is found on immediate
ation between hypocapnia and a higher risk-​adjusted in-​hospital
angiography [66].
mortality [57]. However, a randomized trial targeting low-​normal
Strategies for improving neurological outcome in the comatose
or high-​normal arterial carbon dioxide tension (PaCO2) and
post-​cardiac arrest patient include controlled reoxygenation and
normoxia or moderate hyperoxia after OHCA using markers of
ventilation, maintenance of an adequate cerebral perfusion pres-
cerebral and cardiac injury as endpoints was neutral [58].
sure, adequate sedation, control of seizures and glucose, and tar-
geted temperature management (TTM).
Circulation
Early reperfusion therapy is indicated for STEMI, and this is Sedation
achieved most effectively with primary PCI, as long as a STEMI During treatment with therapeutic hypothermia, use of sed-
diagnosis-​to-​balloon time of <120 minutes can be achieved; if ation reduces O2 consumption, prevents shivering, and facilitates
not, fibrinolysis (thrombolysis) may be preferable [59]. An early cooling [67]. Clearance of many drugs is reduced by about one-​
post-​resuscitation 12-​lead ECG is less reliable for diagnosing third at 34°C [68], and use of short-​acting sedatives and opioids
acute coronary occlusion than it is in non-​arrest patients [60]; (e.g. propofol, alfentanil, remifentanil) will enable earlier neuro-
for this reason, immediate coronary artery angiography should logical assessment after rewarming.
be considered in all OHCA patients without an obvious non-​
cardiac cause of arrest, regardless of ECG changes. About 20–​30% Control of seizures
of patients without an obvious non-​cardiac cause for their car- Seizures or myoclonus occur in about 20–​30% of those who re-
diac arrest and no evidence of STEMI on their initial 12-​lead ECG main comatose and are cooled after cardiac arrest [45, 69,  70].
will have a coronary lesion on angiography that is amenable to Many of these cases will have non-​convulsive status epilepticus,
stenting, but not all are acute plaque ruptures [61]. One random- which may require electroencephalography (EEG) for reliable de-
ized clinical trial involving 552 comatose resuscitated OHCA pa- tection. To ensure seizures are not missed, consider continuous
tients without STEMI on their ECG did not show any benefit of EEG monitoring in patients receiving neuromuscular-​blocking
immediate coronary artery angiography [62]. drugs. Seizures are associated with a fourfold increase in mor-
After cardiac arrest, patients often have haemodynamic in- tality, but good neurological recovery has been documented in
stability and arrhythmias associated with reversible myocardial up to 17% of those with seizures [45,  69]. Treat seizures with
dysfunction. Echocardiography often shows global impairment levetiracetam, sodium valproate, benzodiazepines, propofol, or a
with both systolic and diastolic dysfunction [63]. Although SVR barbiturate.
82 CHAPTER 9   Ou t- of-h ospital cardiac arrest

Glucose control ◆ Cold water immersion.

Both hyperglycaemia and hypoglycaemia after ROSC are asso- ◆ Intravascular heat exchanger (catheter with balloons with circu-
ciated with a poor neurological outcome [26,  69]. Expert con- lating fluid or a metal catheter), placed usually in the femoral,
sensus is that blood glucose should be maintained between 4 and jugular, or subclavian veins.
10 mmol/​L. ◆ Cardiopulmonary bypass, e.g. during ECLS.
Intravascular cooling systems provide tight temperature con-
Targeted temperature management
trol via a cooling catheter in a large vein (usually femoral), with
Pyrexia is common in the first 72 hours after a cardiac arrest and is feedback from a temperature probe in the bladder or oesophagus,
associated with worse outcome [71]. Mild hypothermia improves but there is no evidence that they produce better neurological
the outcome after a period of global cerebral hypoxia–​ischaemia, outcome than external cooling systems [83]. Initial cooling is fa-
although the evidence for this is confined to OHCA caused by cilitated by concomitant neuromuscular blockade, with sedation
shockable rhythms [72–​75]. Cooling suppresses many of the path- to prevent shivering. Continuous infusion of neuromuscular-​
ways associated with ischaemia–​ reperfusion injury, including blocking drugs is usually unnecessary. Magnesium (e.g. 5 g IV
apoptosis (programmed cell death) and the harmful release of ex- over 5 hours) will help to reduce the shivering threshold. Although
citatory amino acids and free radicals [74, 76]. Hypothermia also current guidelines suggest cooling is maintained for 12–​24 hours,
decreases cerebral O2 requirements (6% for each 1°C reduction in some experts are using longer periods of hypothermia (at least 24
temperature), but this is not a primary mechanism for its impact hours and sometimes up to 72 hours), especially when there has
on outcome. been a long duration of cardiac arrest. In one RCT, TTM at 33°C
TTM originally comprised induction of hypothermia, main- for 48 hours, compared with 24 hours, did not improve 6-​month
tenance at 32–​34°C, rewarming while preventing hyperthermia, neurological outcome; however, some experts suggest that this
and maintaining normothermia until the patient recovers con- study was insufficiently powered to detect a meaningful clinical
sciousness [77]. A  large RCT in which post-​arrest patients had difference [84]. Rewarming is controlled at 0.25–​0.5°C per hour
their temperature controlled for 24 hours at either 33°C or 36°C and rebound hyperthermia avoided.
found no difference in survival or neurological outcome [78]. As There are several physiological responses to mild hypothermia
a result of this trial, many clinicians have elected to use a target and some complications, including:
temperature of 36°C for TTM in post-​cardiac arrest patients. The
◆ Shivering.
ILCOR published an advisory statement on TTM in 2015 [79],
and these guidelines were incorporated into the 2015 ERC-​ESICM ◆ Dysrhythmias—​particularly bradycardia.
Guidelines for post-​resuscitation care [31]. The current recom- ◆ Increased peripheral vascular resistance.
mendations are to maintain a constant temperature between 32°C ◆ Diuresis.
and 36°C for at least 24 hours. Most clinicians use TTM for coma- ◆ Electrolyte abnormalities:
tose post-​cardiac arrest patients of any initial rhythm and for both Hypophosphataemia.
●

IHCA and OHCA. Hypokalaemia.

●

Methods for inducing and maintaining hypothermia include Hypomagnesaemia.

●

[80]: Hypocalcaemia.
●

◆ Infusion of 30 mL/​k g of 4°C 0.9% sodium chloride or ◆ Decreased insulin sensitivity and insulin secretion—
Hartmann’s solution—​decreases core temperature by approxi- ​hyperglycaemia.
mately 1.5°C. This was thought to be well tolerated, even in pa- ◆ Impaired coagulation and increased bleeding.
tients with post-​cardiac arrest myocardial dysfunction, but a ◆ Impairment of the immune system—​increased infection rates,
recent study showed that the incidence of pulmonary oedema e.g. pneumonia [85].
on the first chest X-​ray (CXR) and the rate of re-​arrest was ◆ Increased plasma amylase concentration.
higher among pre-​hospital post-​cardiac arrest patients infused
◆ Delayed drug clearance.
with such fluid, compared with a control group not given pre-​
hospital fluid [81]. Severe sepsis (hypothermia depresses immune function) and
◆ Intranasal cooling by evaporating perfluorocarbon through pre-​existing coagulopathy (use of fibrinolysis is not a contraindi-
intranasal cannulae, although a recent RCT has shown no benefit cation) are the main contraindications to TTM.
with this technique [82].
◆ Simple ice packs and/​or wet towels (inexpensive but may be
more time-​consuming for nursing staff; may result in greater Prognostication
temperature fluctuations).
In patients remaining comatose after cardiac arrest, reliable pre-
◆ Cooling blankets or pads. diction of a poor neurological outcome [Cerebral Performance
◆ Water-​or air-​circulating blankets. Category (CPC) score of 3, 4, or 5 (see E Box 9.1)] will enable
◆ Water-​circulating gel-​coated  pads. withdrawal of futile therapy and will inform discussion with
 Pro g n o st i c at i on 83

Box 9.1  The Cerebral Performance Category scale Electrophysiology

Somatosensory evoked potentials (SSEPs), involving electrical
1. Good cerebral performance (normal life):
stimulation of the median nerve at the wrist and recording of the
Conscious, alert, and able to work and lead a normal life.
N20 response over the contralateral sensory cerebral cortex, can
May have minor psychological or neurologic deficits (mild
provide valuable prognostic information. When recorded after
dysphasia, non-​incapacitating hemiparesis, or minor cranial
return to normothermia, the bilateral absence of N20 responses
nerve abnormalities).
has high specificity, but low sensitivity, for predicting a poor
2 . Moderate cerebral disability (disabled, but independent):
outcome [36].
Conscious; sufficient cerebral function for part-​time work in
In most centres, the EEG is recorded over a 30-​minute period,
sheltered environment or independent activities of daily life
but some specialist neurological centres will record the EEG con-
(dress, travel by public transportation, food preparation). May
tinuously [95, 96]. EEG reactivity is assessed using sound (speech
have hemiplegia, seizures, ataxia, dysarthria, dysphasia, or
or a loud clap), pain, or tracheal suction. The absence of EEG
permanent memory or mental changes.
background reactivity is a strong predictor of a poor outcome
3. Severe cerebral disability (conscious, but disabled and dependent):
[97]. Status epilepticus in post-​cardiac arrest patients includes
Conscious; dependent on others for daily support (in an in-
several clinical or EEG variants, with different implications on
stitution or at home with exceptional family effort). Has at
prognosis, making it essential to obtain expert neurological ad-
least limited cognition. This category includes a wide range of
vice. Instead of focusing on isolated signs on the EEG, an inte-
cerebral abnormalities, from patients who are ambulatory but
grated analysis is recommended. In a subanalysis of a TTM trial,
have severe memory disturbances or dementia precluding in-
dependent existence to those who are paralysed and can com- a highly malignant EEG after rewarming reliably predicted poor
municate only with their eyes, as in the locked-​in syndrome. outcome in half of patients, without false predictions [98].
4 . Coma/​vegetative state (unconscious):
Biomarkers
Unconscious, unaware of surroundings, no cognition. No
verbal or psychological interaction with the environment. Several protein biomarkers of brain injury measured in blood
5 . Brain death (certified brain-​dead or dead by traditional 24–​72 hours after OHCA (such as neuron-​specific enolase [99],
criteria). protein S-​100B [100], the axonal injury marker tau [101], and the
neurofilament light chain [102]) correlate well with the neuro-
logical outcome. However, as yet, there are no universally ac-
cepted cut-​off values for these assays. Biomarkers should not be
families [86]. Predicting outcome in patients remaining comatose
used in isolation but may be an important component of multi-
after cardiac arrest is challenging, and guidance is changing rapidly
modal prognostication.
as more data become available [86–​92]. An important limitation of
virtually all prognostication studies is self-​fulfilling prophecy, i.e.
at least some of the results of prognostic tests were used to make
Imaging
withdrawal decisions. A multimodal approach is therefore recom- Hypoxic–​ischaemic brain injury may appear on CT as loss of
mended [87, 92]. grey–​white differentiation (visible within 24 hours of cardiac ar-
rest, but rarely within 1 hour of cardiac arrest), indicating cere-
Clinical examination bral oedema [103]. MRI is more sensitive for the detection of
hypoxic–​ischaemic brain injury but is more difficult to acquire in
An absent or extensor motor response to pain at day 3 (pre-
critically ill patients. These imaging modalities have insufficient
viously considered a reliable predictor of poor outcome) has a
specificity to be used alone for prognostication but are used as
relatively high false-​positive rate, and it is not recommended as
part of a multimodal approach [87, 103–​105].
an early predictor of outcome in patients resuscitated from car-
diac arrest. Bilateral absence of pupillary light reflex at 72 hours
from cardiac arrest predicts poor outcome with high specificity,
Multimodal approach to prognostication
but low sensitivity. Use of pupillometry increases the sensitivity The current consensus is for a combination of neurological exam-
because the speed of pupillary response to a standardized light ination and electrophysiological investigations for prognosti-
stimulus is measured [93]. The absence of corneal reflexes is a cation in the comatose post-​cardiac arrest patient [87, 92, 105].
less reliable predictor. Generalized and prolonged myoclonus Reliable neurological examination, CT and MRI imaging, and
lasting more than 30 minutes (status myoclonus) is associated EEG should be available for all post-​cardiac arrest patients treated
with a very poor prognosis, although good neurological re- in an ICU. Biomarkers may be included. Delayed clearance of sed-
covery is possible in a subgroup that have a continuous back- ation and modification of neurological recovery by hypothermia
ground EEG [94]. Seizure activity that arises after rewarming means that, in most cases, prognostication should be delayed
and stopping of sedative drugs may still be compatible with a until at least 72 hours after return to normothermia and at least
good recovery [87]. 24 after stopping sedation [87].
84 CHAPTER 9   Ou t- of-h ospital cardiac arrest

result in MOF. Interventions in this phase aim to restore myocar-

Organ donation dial function and minimize neurological injury. Accurate prog-
nostication to enable potential withdrawal of lifesaving treatment
Approximately 13% of patients who achieve sustained ROSC after
is challenging and is being increasingly delayed beyond 3  days
cardiac arrest fulfil the criteria for brain death and can be con-
after return to normothermia.
sidered for organ donation [106].

Conclusion Personal perspective
In recent years, increasing attention has been applied to the
A successful outcome from OHCA depends on an intact and ef-
prevention of cardiac arrest, but if cardiac arrest occurs,
ficient chain of survival. Immediate activation of the EMS is crit-
provision of high-​quality CPR is a high priority. Whether
ically important. While BLS will sustain some O2 delivery to the
any drugs given during cardiac arrest provide long-​term
heart and brain and will help to slow the rate of deterioration in
benefit is still debatable. Immediate coronary angiography
these vital organs, it is important to achieve ROSC as soon as
should be considered in most OHCA survivors. There is
possible. Once ROSC is achieved, the quality of post-​cardiac ar-
still consensus on the use of TTM at 33–​36°C for 12–​24
rest management will influence the patient’s final neurological
hours in comatose patients.
outcome. Many of these patients will develop PCAS, which may

Further reading
Kirkegaard H, Taccone FS, Skrifvars M, Soreide E. Postresuscita­ focus on targeted temperature management. Anesthesiology 2019;
tion care after out-​of-​hospital cardiac arrest:  clinical update and 131:186–​208.

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 CHAPTER 10

Chest pain in the

emergency department
and the chest pain unit
Christiaan Vrints, Janina Stepinska,
and Marc J Claeys

Contents
Summary  88 Summary
Definition  88 The diagnosis and assessment of acute chest pain remain challenging. Inappropriate
Epidemiology  89 discharge of patients with unrecognized life-​threatening acute cardiovascular dis-
Clinical assessment of patients presenting ease, such as acute myocardial infarction or acute aortic syndromes, from the
with acute chest pain  89
hospital can result in potentially avoidable death. By contrast, routine hospital ad-
Diagnostic testing  91 mission of patients with non-​significant chest pain can lead to unnecessary inves-
Electrocardiogram  91
Cardiac troponin testing  95 tigations and interventions, with associated potential harm and increased health
Echocardiography  96 care costs. As only a small minority of patients presenting with acute chest pain
Chest X-​ray  96 will ultimately be diagnosed with an acute coronary syndrome or another life-​
Computerized tomography  96
Ultrasonography (other than threatening acute cardiovascular syndrome, it is essential to use rapid and straight-
echocardiography)  97 forward diagnostic methods that allow accurate identification of high-​risk chest
Further predischarge testing  98
Role of chest pain units  98 pain patients and safe and early discharge of low-​risk patients in order to avoid con-
Conclusion  98 gestion in the emergency department. Triage and diagnosis of patients presenting
References  99 with acute chest pain should rely on careful history taking, judicious interpretation
of the 12-​lead ECG on presentation, and use of rapid rule-​in/​rule-​out diagnostic
algorithms of acute myocardial infarction using high-​sensitivity cardiac troponin
assays for the detection of myocardial cell necrosis. Chest pain units are organiza-
tional short-​stay units with specific management protocols designed to facilitate
and optimize the diagnosis of patients presenting with chest pain. Implementation
of chest pain units has resulted in increased adherence to guidelines and improved
clinical outcome.

Definition
Acute chest pain is the perception of non-​traumatic pain or other thoracic discomfort
occurring within the past 24 hours, localized anteriorly between the base of the nose
and the umbilicus and posteriorly between the occiput and the twelfth vertebra [1]‌.
Descriptors include a range of features, including stabbing or burning and also pressure,
tightness, or heartburn.
Acute chest pain can be caused by an extensive variety of disorders (see E Table 10.1),
ranging from life-​threatening syndromes like ACS, acute aortic diseases, and PE to relatively
 Clinical asse s sm en t of pati en ts presen ti n g w i th acu te c h e st   pa i n 89

Table 10.1  Causes of chest pain

Primary cardiovascular Primary non-​cardiovascular

◆ ACS: Oesophageal spasm, oesophagitis, gastro-​oesophageal reflux
◆

STEMI
● Peptic ulcer disease, cholecystitis, pancreatitis
◆

NSTE-​ACS
●
Pneumonia, bronchitis, acute asthma
◆
Pleuritis, pleural effusion, pneumothorax
◆
NSTEMI
●
PE, severe pulmonary hypertension
◆
Unstable angina
●
Thoracic trauma
◆
Acute pericarditis, pericardial effusion
◆
Costochondritis, rib fracture
◆
Acute myocarditis
◆
Cervical/​thoracic vertebral or discal damage
◆
Severe hypertensive crisis
◆
Herpes zoster
◆
Stress cardiomyopathy (Takotsubo syndrome)
◆
Psychogenic
◆
Tachyarrhythmias
◆
Hypertrophic cardiomyopathy, aortic stenosis
◆
Severe AHF
◆
Acute aortic syndrome (dissection, haematoma)
◆
PE, pulmonary infarction
◆

Reproduced from Bueno H. Non-​ST-​segment elevation acute coronary syndromes. In: Bueno H, Vranckx P, eds. The Acute Cardiovascular Care
Association Clinical Decision-​Making Toolkit, 2018 Edition. ESC Editions, Nice 2018 with permission from European Society of Cardiology.

harmless conditions. There are significant gender differences in EPs therefore face a significant challenge to rapidly and accur-
epidemiology, pathophysiology, clinical presentation, response to ately identify the small group of patients who require hospital-
therapy, and clinical outcome of acute chest pain syndromes [2]‌. ization for acute management and the larger group with more
Microvascular disease more commonly causes anginal symptoms benign conditions who can be safely discharged from the ED.
in women, and Takotsubo syndrome is almost ten times more fre-
quently observed in women than in men [3]. An underdiagnosed
cause of ACS that predominantly occurs in women is spontaneous
coronary artery dissection [4]. Clinical assessment of patients
presenting with acute chest pain
The triage of chest pain patients in the ED depends on careful his-
Epidemiology tory taking, physical examination, recording and interpretation of
Acute chest pain is one of the most frequent reasons to attend the a 12-​lead ECG within 10 minutes of arrival, and measurement of
ED, accounting for approximately 10% of non-​injury related visits cardiac biomarkers [13].
[6–​11]. The incidence of chest pain-​related visits to the ED is 8–​19 Identifying patients who need urgent transfer to the catheter-
per 1000 person-​years [6, 10, 11], being higher in urban than in ization laboratory has very high priority and should be done
rural hospitals, with a mean age of 52–​61 years and 49–​57% male within minutes after admission. Immediate PCI (<2 hours) is re-
[6, 7, 9–​11]. In current practice, about half of the patients pre- commended in STEMI patients [14] and in some NSTE-​ACS pa-
senting with chest pain can be discharged from the ED without tients with at least one of the very high-​risk criteria [13]:
further hospitalization [9, 10]. The vast majority of these patients ◆ Haemodynamic instability or cardiogenic shock (CS).
(83%) have a non-​cardiac cause of their chest pain (unspecified ◆ Recurrent or ongoing chest pain refractory to medical treatment.
chest pain in 48% and other non-​cardiac causes in 35%) [10]. Of ◆ Life-​threatening arrhythmias or cardiac arrest.
the patients admitted to the hospital, only about 25% (range 12.2–​ ◆ Mechanical complications of MI.
59.1%) have a final diagnosis of an ACS [9–​11]. Another 25% of
◆ AHF with refractory angina or ST-​segment deviation.
the patients will be discharged with a diagnosis of angina pec-
toris (3.5–​6.6%) or with other non-​ischaemic cardiac problems ◆ Recurrent dynamic ST-​segment or T-​wave changes, particu-
(10–​19%). In the remaining half of the admitted patients, the final larly with intermittent ST-​segment elevation.
diagnosis will be unspecified chest pain (26%) or a non-​cardiac However, in the case of a haemodynamically unstable patient,
cause (27%) [10]. Acute vascular emergencies and PE constitute initial haemodynamic stabilization (e.g. CS management, drugs,
only a tiny minority (2–​3%) of the patients [11]. intubation, mechanical ventilation) may be necessary before the
Approximately 2% of chest pain patients with an ACS are mis- invasive procedure.
takenly discharged from the ED, which is associated with a two- Although clinical judgement and bedside examination allow
fold increase in 30-​day morbidity and mortality [12]. Of patients the identification of a small high-​risk group with clinical features
presenting to the ED without diagnosis-​specific symptoms, AMI (see E Table 10.2) highly suggestive of an NSTE-​ACS mandating
was the final diagnosis in 1.6% [9]‌. The absence of typical chest an early invasive coronary strategy, the findings will remain in-
pain therefore does not exclude an ACS. conclusive in many low-​risk patients. To avoid inadvertent early
90 CHAPTER 10   C hest pain in  th e emergency depa rtm en t a n d the chest pa i n  u n i t

Table 10.2  High-​risk criteria for chest pain suggestive of ACS troponin (cTn) measurements [22, 23]. Between 10% and 20% of
the patients presenting with chest pain in the ED were classified
Symptoms Prolonged ongoing chest pain (≥20 minutes)
as low risk with >99% sensitivity and a negative predictive value
History Prior PCI in the last 6 months (NPV) of almost 100%. In a randomized trial that compared the
Prior CABG
ADAPT protocol with a standard-​care pathway (cTn test on ar-
Clinical findings Pulmonary oedema most likely due to ischaemia rival at hospital, prolonged observation, and a second cTn test 6–​
Hypotension
12 hours after onset of pain), use of the ADAPT pathway resulted
Tachycardia
New mitral regurgitation murmur in an almost doubling of the proportion of patients with chest
AHF Killip class >1 pain discharged early [24]. In a retrospective analysis on the ori-
New systolic murmur at Erb’s point ginal ADAPT cohort, a modified ADAPT pathway using a TIMI
ECG Dynamic ST changes >0.5 mm during chest pain score of 0 or 1 and a high-​sensitivity, instead of a contemporary
New or presumably new bundle branch block non-​high-​sensitivity, cTn assay allowed to identify 40% of pa-
Sustained ventricular tachycardia tients as low risk with >99% sensitivity and NPV. This was further
High-​degree atrioventricular block
corroborated in a prospectively studied APACE (Advantageous
Biomarkers Elevated cTn Predictors of Acute Coronary Syndromes Evaluation) cohort [25].
Score GRACE risk score ≥140 The TRUST (Triage Rule-​out Using high-​Sensitivity Troponin)
HEART score ≥7 accelerated diagnostic protocol (ADP) pathway based on a modi-
PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft; ECG, fied Goldman risk score, a non-​ischaemic ECG, and a single
electrocardiogram; GRACE, Global Registry of Acute Coronary Events; HEART, History, high-​sensitivity cTn (hs-​cTn) assay measured on presentation
ECG, Age, Risk factors, and Troponin.
also allowed to classify 40% of the patients as low risk, similarly
to ADAPT and APACE, with very high sensitivity and NPV [26].
discharge from the ED, these patients need prolonged clinical The HEART score was specifically developed for unselected
observation following an accelerated diagnostic pathway, com- patients with chest pain presenting at the ED [27]. The HEART
prising serial ECG recordings and cardiac injury biomarker score (see E Figure 10.1) differs from the TIMI and other risk
measurements obtained over 1–​3 hours to accurately diagnose stratification tools, as it also includes clinical suspicion by the
(rule in) or exclude (rule out) an ACS. Most often, this is carried physician and the presence of multiple coronary risk factors in
out in an observation unit in the ED or a dedicated chest pain its calculation. Moreover, as it is mainly based on simple clin-
unit (CPU), within or close to the ED [15]. A negative accelerated ical parameters, it can be easily calculated at the bedside. The
diagnostic evaluation allows early discharge, whereas patients HEART score represents the patients’ risk of developing a major
with a diagnosis of AMI are admitted to an ECG monitoring unit adverse cardiac event (MACE) within 6 weeks after initial pres-
and referred for early coronary angiography. entation. The HEART score has been tested and validated in nu-
Clinical risk stratification tools may help clinicians to integrate merous studies performed in Europe [28–​30], the US [31, 32],
symptoms, ECG, and biomarker findings in risk stratification of and the Asia-​Pacific [27, 33]. Overall a HEART score of ≤3 al-
chest pain patients. These tools have been incorporated in accel- lowed to identify 35–​46% of low-​risk patients with very high
erated diagnostic pathways that facilitate fast triage and safe early sensitivity and NPV [34]. Patients with HEART scores of ≥7
discharge of low-​risk chest pain patients [16, 17]. are a very high-​risk subgroup, with >50% of MACEs within 6
The guidelines on NSTE-​ACS recommend the use of the TIMI weeks [28], who therefore should be admitted immediately to
(Thrombolysis In Myocardial Infarction) and GRACE risk strati- an ICCU. The HEART score was initially validated for use in
fication tools mainly to assess the prognosis of patients with conjunction with contemporary cTn assays. The HEART score
ACS and to identify patients who may benefit from intensive based on the results of hs-​cTn assays should therefore be used
antithrombotic therapy and an early invasive strategy [13, 18]. with caution, as the troponin-​related points may vary with the
Both the TIMI and GRACE risk stratification tools were initially assay used. However, in two retrospective cohort studies in
validated in patients already diagnosed with an ACS [19, 20]. In which hs-​cTn assays were used, application of the HEART score
a validation study in chest pain patients presenting in the ED, a resulted in the identification of 31.6–​37.2% of low-​risk patients
modified TIMI score correlated well with 30-​day clinical outcome with a sensitivity of 93.7–​100% and an NPV of 98.3–​100%, re-
but failed to optimally risk-​stratify the patients [21]. As patients sults that are very similar to those observed in earlier validation
with the lowest risk defined by a TIMI score of 0 had a 1.7% in- studies [26, 29].
cidence of AEs, it was concluded that the TIMI risk score should The North American Chest Pain Rule was 100% sensitive for a
not be used in isolation to guide which ED chest pain patients can cardiac event within 30 days and classified 18% of patients as low
be discharged safely. risk who may be suitable for discharge [35].
The ASPECT (ASia Pacific Evaluation of Chest pain Trial) The Vancouver Chest Pain Rule for detection of low-​risk pa-
and ADAPT (2-​Hour Accelerated Diagnostic protocol to Assess tients is based on clinical assessment of the ECG, cardiac history,
Patients with chest pain symptoms using contemporary Troponins nitrate use, age, pain characteristics, and a single measurement of
as the only biomarker) trials combined a modified TIMI risk score troponin at 2 hours after presentation. Using either contemporary
with ECG findings and 0-​hour and 2-​hour contemporary cardiac or high-​ sensitivity troponin assays, the rule allows detecting
 Diag n o st i c   t e st i n g 91

HEART score 6-week MACE

50
2 = highly suspicious
History 1 = moderately suspicious
0 = slightly or non-suspicious 40
2 = significant ST-depression
ECG 1 = non-specific repolarization disturbance
0 = normal 30
2 = ≥65 years

%
Age 1 = ≥45 to <65 years
0 = <45 years 20
2 = ≥3 or history of atherosclerotic disease
Risk factors 1 = 1 or 2
0 = no risk factors known 10

2 = ≥3x upper limit

Troponin 1 = 1x to 3x upper limit
0 = ≤ upper limit 0
≤3 4–6 ≥7
LOW RISK HEART score ≤3 HEART score

Figure 10.1  Calculation of the HEART score and incidence of 6-​week MACE according to the HEART score, as tested in a large population of patients
presenting with chest pain in the ED [28].
Reproduced from Backus BE, Six AJ, Kelder JC, et al. A prospective validation of the HEART score for chest pain patients at the emergency department. Int J Cardiol 2013;168(3):2153–​
8 with permission from Elsevier.

13–​20% of low-​risk patients who are eligible for early discharge on ADAPT, EDACS, and HEART scores have the strongest sci-
with a sensitivity of 95–​98% and an NPV of about 98% [36, 37]. entific evidence supporting their use. However, none of the risk
The Manchester Acute Coronary Syndromes (MACS) clinical scores and diagnostic pathways are foolproof, and this knowledge
decision rule includes measurement on a single sample of heart-​ may incite physicians to decide for additional observation and
type fatty acid-​binding protein and high-​sensitivity troponin T downstream testing in spite of a low-​risk score result. There is
blood concentrations, besides clinical and ECG parameters [38]. increasing interest in shared decision-​making that involves edu-
The biomarker concentrations are entered as continuous variables cating patients and their families on their health problems and
into a formula that allows calculating the 30-​day risk of MACEs. risks and discussing the diagnostic and treatment options. In the
The measurement of two biomarkers and the need to use a com- Chest Pain Choice Trial, a single-​centre RCT, sharing the deci-
puter are a significant limitation for the wide adoption of this sion using a graphical decision aid increased the knowledge of
clinical decision rule. patients who decided less frequently to be admitted to the obser-
The Emergency Department Assessment of Chest Pain Score vation unit for cardiac stress testing [46].
Accelerated Diagnostic Pathway (EDACS-​ADP) is a combin- The utility of clinical risk stratification tools is decreasing since
ation of an easily countable risk score (EDACS) based on clin- the advent of diagnostic pathways using hs-​cTn assays that allow
ical variables with an accelerated diagnostic pathway based on a very accurate and fast diagnosis of AMI.
0-​and 2-​hour troponin measurements using contemporary as-
says, that has been derived and validated in Australian [39] and
North American [40] patient cohorts. EDACS-​ADP allowed clas-
sifying >40% of patients at low risk with very high sensitivity. In Diagnostic testing
a randomized clinical trial, EDACS-​ADP was as equally effective Electrocardiogram
as ADAPT-​ADP in detecting low-​risk patients who could be dis-
charged <6 hours without an adverse outcome [41]. The 12-​lead ECG within 10 minutes of first medical contact
In summary, several decision aids, with or without clin- (FMC) is pivotal in the decision pathway for the evaluation and
ical markers, have been derived, validated, and incorporated in management of patients presenting with acute chest pain.
ADPs that allow detecting low-​risk chest pain patients eligible for In addition to the STEMI ECG criteria [13, 47], emergency cor-
early discharge [16, 17, 42]. In comparison studies, the HEART onary angiography should also be considered with the following
score outperforms the TIMI and GRACE risk scores in the iden- ECG findings:
tification of high-​and low-​risk patients in developing MACE ◆ A complete left bundle branch block (LBBB) with clinical sus-
[43,  44]. Compared to the modified HEART score, the original picion of ongoing myocardial ischaemia.
EDACS and simplified EDAC scores performed equally well in ◆ When persistent ischaemic symptoms occur in the presence of
a large retrospective study [45]. The diagnostic pathways based right bundle branch block (RBBB).
92 CHAPTER 10   C hest pain in  th e emergency depa rtm en t a n d the chest pa i n  u n i t

◆ Continuous ventricular pacing with clinical suspicion of ongoing ischaemia. When in doubt, posterior ECG leads V7–​V9 should
myocardial ischaemia. be obtained [57, 58].
◆ Isolated ST-​segment depression ≥0.05 mV in leads V1–​V3, sug- The presence of diffuse ST-​segment depression in all leads with
gesting an acute posterior MI. coexisting ST-​segment elevation in aVR is a marker of extensive
◆ ST-​segment elevation in aVR and ST-​segment depression >0.1 myocardial ischaemia often caused by left main stem stenosis
mV in ≥8 surface leads, suggesting extensive myocardial is- (see EFigure 10.3) or severe three-​vessel disease and should also
chaemia due to severe multivessel disease or left main coronary trigger an urgent transfer to the catheterization laboratory.
artery obstruction. Instead of showing a typical precordial ST-​segment elevation,
◆ ‘Hyperacute’ tall T-​waves in patients presenting early after some patients with a proximal LAD occlusion show an atypical
onset of symptoms with an otherwise non-​diagnostic ECG. ‘De Winter’ pattern (see E Figure 10.4) with 1-​to 3-​mm J-​point
Although the prevalence of AMI is high (80%) in patients depression in leads V1–​V6 followed by an upsloping ST-​segment
presenting with acute chest pain and ST-​segment elevation, the and tall, positive symmetrical T-​waves [59].
specificity of the 12-​lead ECG is not perfect, which may lead to Isolated ST-​segment depression and/​or T-​wave inversion in
false activation of the cardiac catheterization laboratory [48–​50]. aVL may be a forewarning sign of impending inferior MI with RV
A  cross-​sectional survey showed that significant disagreements involvement [60–​63]. Registration of right precordial leads can be
occur among physicians regarding interpreting ECGs suggestive helpful in this situation.
of STEMI [51]. The overall sensitivity to identify by ECG inter- Although there are many non-​ischaemic causes of T-​wave in-
pretation ‘true’ ST-​segment elevation MIs was 65%, and the spe- version, the presence of abnormally inverted T-​waves of ≥2 mm
cificity 79% [51]. Other conditions which may mimic STEMI in two or more leads in patients presenting with chest pain most
should always be considered in the differential diagnosis (see often points at the presence of a tight coronary artery stenosis in
E Box 10.1) [52–​54]. one of the major coronary vessels. Depending on the time interval
Possible pitfalls in the ECG diagnosis of AMI that should not between the onset of symptoms and the ECG recording, the
be missed are posterior AMI, extensive LV ischaemia due to left T-​waves may show a biphasic terminal inversion (early after an-
main stem, proximal LAD coronary artery, or severe three-​vessel gina) or a symmetrical and sometimes deep T-​wave inversion
disease, or an imminent inferior MI with right ventricular (RV) (later after the chest pain has subsided) in ECG leads linked to the
involvement [54–​56]. In these situations, a typical ST-​segment perfusion territory of one of the major coronary arteries or its side
elevation infarction pattern is not always observed, but emer- branches. Similar ischaemic T-​wave inversions also occur after
gency coronary angiography and reperfusion are also indicated successful reperfusion of an occluded coronary artery, indicating
in these conditions. that these regional T-​wave inversions in patients presenting with
A posterior MI (see E Figure 10.2) should be immediately chest pain are the result of prolonged, but transient, ischaemia
suspected if ST-​segment depressions are observed exclusively due to spasm or a thrombotic occlusion followed by spontaneous
in V1–​V3, with concomitant tall R-​waves and upright T-​waves. reperfusion with minimal or limited subendocardial necrosis.
This pattern should not be mistaken for anterior subendocardial The presence in a patient presenting with chest pain of inverted
T-​waves with preserved R-​waves in the right and middle precor-
dial leads in association with tight stenosis in the proximal LAD
artery is known as Wellens’ syndrome [64,  65] (see E Figure
Box 10.1  Common causes of non-​ischaemic ST-​segment elevation 10.5). Without revascularization, patients showing this syndrome
[52–​54] frequently develop an anterior wall STEMI. Similarly to this syn-
drome, inverted T-​waves in the inferior leads may occur after an
Left
◆ ventricular hypertrophy (LVH) anginal pain attack in association with severe unstable stenosis
◆ Conduction defect [LBBB and non-​specific intraventricular in a dominant right coronary artery, whereas tall T-​waves in the
conduction delay (IVCD)] right precordial leads (mirroring inverted T-​waves at the pos-
Early repolarization pattern (notched J-​point mainly in
◆
terior wall) may develop in patients with stenosis in the circum-
anterolateral leads) flex artery.
Normal variant of ST-​segment elevation (non-​ischaemic ST-​
◆ Only a tiny number of patients presenting with acute chest pain
segment elevation, mainly in V2–​V3) to the ED show a typical STEMI ECG pattern. The vast majority
Old MI/​aneurysm
◆ of patients show either a completely normal ECG (40–​60% of pa-
Takotsubo cardiomyopathy (apical ballooning syndrome)
◆ tients) or atypical non-​ischaemic ECG changes [48, 66–​69]. The
Pericarditis
◆ 30-​day mortality and infarction rates in these patients are very
Brugada syndrome
◆ low and vary between 2% and 4%, depending on the presence of
Wolff–​Parkinson–​White syndrome (pre-​excitation)
◆ known CAD. Most of the studies relating ECG findings on admis-
Hypercalcaemia
◆ sion with clinical outcome have been performed in the era before
Hyperkalaemia
◆
the introduction of the first universal definition of MI [70]. In a
more recent study of a large cohort of patients presenting with
 Diag n o st i c   t e st i n g 93

Scapula

I aVR V1 V4

II aVL V2 V5

V8
III aVF V3 V6

V9

Figure 10.2  Acute true posterior myocardial infarction [72]. Note ST-​segment depression and tall negative T-​waves in V1–​V3 (mirror image of ST-​segment
elevation and tall T-​waves that could be recorded by electrodes on the posterior surface of the heart). Recording of the precordial leads V8 and V9 shows indeed
ST-​segment elevation and tall T-​waves, allowing to make a diagnosis of STEMI of the posterior wall.

I V1

II V2

III V3

aVR V4

aVL V5

aVF V6

Figure 10.3  A 12-​lead ECG recorded during severe anginal pain in a patient with a tight left main coronary artery stenosis. There is marked ST-​segment
depression in all leads, except in aVR and aVL where ST-​segment elevation is observed.
94 CHAPTER 10   C hest pain in  th e emergency depa rtm en t a n d the chest pa i n  u n i t

I aVR V1 V4

II aVL V2 V5

III aVF V3 V6

Figure 10.4  A 12-​lead ECG recorded on admission in a 72-​year-​old man with ongoing constrictive anginal pain. The QRS complex shows an atypical
intraventricular conduction abnormality (QRS complex with notch) and junctional ST-​segment depression, followed by tall, symmetrical T-​waves in the right
precordial leads. Coronary angiography showed a totally occluded proximal LAD artery. This is a typical ‘De Winter’ pattern that can be observed during the
early hours of acute anterior transmural myocardial ischaemia [59].

acute chest pain in which the diagnosis of MI was based on the to be old had a 30-​day odds ratio (OR) for MACE 24 times higher
most recent criteria, almost 60% of patients showed a normal ad- than patients with a normal ECG on admission. These find-
mission ECG with a very low infarction rate [69, 71]. Conversely, ings support the recommendation to perform early coronary
patients with ischaemic ECG changes or signs of MI not known angiography (<72 hours) in patients presenting with chest pain

On admission Severe angina Day 1 post-PCI type A Day 2 post-PCI type B

V1 V1 V1 V1

V2 V2 V2 V2

V3 V3 V3 V3

V4 V4 V4 V4

V5 V5 V5 V5

V6 V6 V6 V6

If recurrent ischaemia: pseudo-normalization

Figure 10.5  Typical sequence of dynamic ECG changes in a patient presenting with unstable anginal pain symptoms caused by severe proximal LAD stenosis.
The ECG on admission showed an almost normal repolarization pattern. Later on, the patient developed severe angina with ST-​segment elevation and tall T-​
waves in the precordial leads. The patient was urgently transferred to the catheterization laboratory and primary PCI was performed. Upon reperfusion, the ST-​
segment elevation and tall T-​waves disappeared and the patient developed biphasic terminal negative T-​waves in the precordial leads (type A Wellens’ pattern).
The next day, the T-​waves were symmetrically negative (Wellens’ type B pattern). If recurrent ischaemia were to occur, one would see flipping over of the
negative T-​waves (pseudo-​normalization), eventually followed by a new ST-​segment elevation with tall T-​waves.
 Diag n o st i c   t e st i n g 95

suspected for an NSTE-​ACS and with ischaemic changes on the at presentation [75–​80]. Although hs-​cTn assays quantify the
admission ECG [13]. Although the incidence of AMI is very low, amount of cardiomyocyte damage, they need to be interpreted
it is not nil, and therefore, a normal admission ECG should not be as quantitative variables, and not in a binary (negative/​positive)
used alone to rule out an ACS. fashion. The higher the cTn level, the higher the likelihood for the
Patients with ischaemic T-​waves as part of Wellens’ or a re- presence of MI.
lated syndrome may show pseudo-​normalization of the T-​waves The latest ESC NSTE-​ACS guidelines give a IA recommenda-
during a recurrent episode of myocardial ischaemia. One should tion for the use of hs-​cTn as the standard biomarker for clinical
not miss these dynamic T-​wave changes, as they indicate that practice, and a IB recommendation for the application of two
the acute coronary lesion in the culprit artery remains unstable main novel algorithms with cardiac biomarkers for the manage-
despite anginal and antithrombotic therapy and is jeopardizing ment of patients with acute chest pain in the ED [13]. In patients
the regional myocardial perfusion. Observation of these dy- presenting with suspected NSTE-​ACS, it is recommended to use
namic T-​wave changes should prompt a decision to conduct an the 0-​hour/​3-​hour ESC algorithm (see E Figure 10.6). As an
early invasive strategy to prevent the development of an extensive alternative, the 0-​hour/​1-​hour ESC algorithm is recommended
transmural MI. when hs-​cTn assays with a validated algorithm are available (see
In order not to miss these critical dynamic ECG changes, it is E Figure 10.7).
essential to repeat the ECG recording at least 10 minutes after the In the 0-​hour/​3-​hour ESC algorithm, MI is ruled out if con-
first ECG recording, even if the first ECG recording on admission centrations of hs-​cTn remain in the normal range (below the
was entirely inconspicuous, and last but not least, every time a respective 99th percentile) in the blood sample drawn at presen-
patient shows recurrent chest pain symptoms. tation and 3 hours later and if the patient fulfils two additional
requirements—​to be pain-​free and to be at low risk of in-​hospital
Cardiac troponin testing mortality, as quantified by a GRACE score below 140 [13]. In pa-
Clinical assessment, combined with an ECG, is not sufficient to tients presenting >6 hours after the onset of chest pain, in whom
diagnose or exclude MI in all patients presenting with acute chest chest pain onset can be reliably quantified, one single blood
pain, and therefore, the additional measurement of cTnT or cTnI sample at presentation is considered sufficient. Patients are ruled
on serial blood samples is crucial [13, 70, 71, 73]. in if they have a clearly elevated hs-​cTn blood concentration at
cTnT and cTnI are structural proteins unique to the heart. The presentation or if the 3-​hour sample shows a relevant change. This
cTn complex is immobilized on the thin filament of the contractile approach has been recommended by the ESC guidelines since
apparatus and plays a critical role in the regulation of excitation–​ 2011 and is the standard of care in many institutions worldwide
contraction coupling in the heart. In MI, cTnI and cTnT are re- (see E Figure 10.6). Its use regarding ruling out of MI seems to
leased from necrotic myocardium both as intact proteins and as be safe for all hs-​cTn assays [81]. The exact performance of ruling
degradation products [74]. in cannot be quantified, as no precise definitions of its rule-​in cut-​
hs-​cTn assays allow the precise quantification of cardiomyocyte off levels are given.
injury around the 99th percentile, substantially increasing the In the 0-​hour/​1-​hour ESC algorithm, the concept of the 0-​
accuracy of MI diagnosis based on the blood sample obtained hour/​1-​hour ESC algorithm (see E Figure 10.7) is based

Acute chest pain: suspected NSTEMI

Admission hs-cTn < ULN Admission hs-cTn > ULN

Highly abnormal hs-cTn and clinical presentation

Pain >6 hours Pain <6 hours

Re-test hs-cTn at 3 hours

hs-cTn no change hs-cTn Δ change hs-cTn no change

1 value > ULN

Pain-free, GRACE <140 Work-up

differential diagnoses excluded differential diagnoses

Discharge stress testing Invasive management

Figure 10.6  The ESC 0-​hour/​3-​hour rule-​out and rule-​in algorithm of NSTE-​ACS using hs-​cTn assays [13]. ULN, upper limit of normal.
96 CHAPTER 10   C hest pain in  th e emergency depa rtm en t a n d the chest pa i n  u n i t

Acute chest pain: suspected NSTEMI

0-hour hs-cTn 0h hs-cTn lowB 0-hour hs-cTn highD

very or and Other or
lowA* no 0-1 hour ∆C 0-1 hour ∆ +++E

Rule-out Observe Rule-in

Discharge ED or CPU ICCU or CCU

Outpatient follow-up hs-cTn 3 hours Coronary
Echocardiography angiography
Functional imaging (invasive)
Coronary angiography
(invasive or CCTA)

Figure 10.7  The ESC 0-​hour/​1-​hour rule-​out and rule-​in algorithm using hs-​cTn assays in patients presenting with suspected NSTEMI to the ED. * If chest pain
onset >3 hours. For three additional hs-​cTnI assays, a 0-​hour/​1-​hour algorithm has been derived and validated and the respective manuscripts are currently
undergoing peer review.

exclusively on information provided by hs-​cTn blood concen- Echocardiography

trations on blood samples taken on admission and 1 hour later.
Echocardiography should be routinely available in the ED or CPU,
The decision points derived and validated for each assay are
and performed by a trained staff [91]. It is not required where a
assay-​specific [13, 82–​87]. The 0-​hour/​1-​hour ESC algorithm
non-​cardiac diagnosis is obvious or in whom the probability of
obviates the need for formal use of clinical scores and allows
an acute cardiovascular cause is considered very low. TTE is in-
safe rule-​out of MI, even in patients with mild, non-​specific
dicated in patients with acute chest pain and: (1) a diagnosis or a
ECG abnormalities.
high clinical suspicion of an ACS; (2) haemodynamic instability;
The diagnostic algorithms using hs-​cTn assays have substan-
(3)  AHF; (4)  suspicion of acute aortic syndromes, myocarditis,
tially improved the efficiency of triage of chest pain patients
or pericarditis; and (5) underlying cardiac disease such as aortic
in the ED. The increased sensitivity of hs-​cTn assays abridges
valve stenosis and hypertrophic cardiomyopathy. Although it is
the troponin blind period early after onset of MI and allows
reasonable for individual risk stratification during the hospital
marked shortening of the time interval to the second blood
stay, echocardiography is not recommended in haemodynam-
sample needed to demonstrate a significant rise of the bio-
ically stable, normotensive patients with suspected PE [92].
marker. The 0-​hour/​1-​hour ESC algorithm is as effective as the
Transoesophageal echocardiography (TOE) may be indicated
0-​hour/​3-​hour ESC in ruling in and ruling out AMI with a very
when TTE is non-​diagnostic. In cases of suspected aortic dissec-
high NPV [88]. Moreover, it allows to detect—​1 hour earlier—​
tion, TOE is more sensitive than TTE [93]. Echocardiographic
a greater number of patients eligible for early discharge than
signs suggestive of myocardial ischaemia or necrosis include: (1)
the previously widely used ADPs using contemporary cTn as-
segmental wall motion abnormalities; (2)  impaired myocardial
says (ADAPT-​ADP) that included the additional calculation
perfusion detected by contrast echocardiography; and (3)  re-
of a clinical low-​risk score (see E Figure 10.8). Institutional
duced regional function using strain and strain rate imaging [91].
standard operational procedures for the diagnosis of acute
chest pain based on the 0-​hour/​1-​hour ESC algorithm will
Chest  X-​ray
therefore not only increase patients’ safety, but also markedly
shorten the duration of stay in the ED, which may lead to im- A CXR is often performed in the evaluation of patients attending
portant cost savings. the ED. In one large study, a quarter of such patients showed sig-
The 0-​hour/​3-​hour and 0-​hour/​1-​hour ESC algorithms have nificant findings:  cardiomegaly, pneumonia, and pulmonary
inflexible rules for the timing of troponin resampling and cut-​ oedema [94]. When there is a high clinical suspicion of acute life-​
off levels for the diagnosis of MI that clinically is not always ap- threatening conditions other than an ACS (pericardial effusion,
plicable. An international consortium has recently developed and acute aortic dissection, PE, pneumothorax, or pneumonia), a CXR
validated a risk assessment tool that integrates hs-​cTn concentra- is indicated and should be available, preferably within 30 minutes.
tions at ED presentation, the dynamic change in concentration
during serial sampling, and the time between obtaining samples Computerized tomography
that allows, in a more flexible way, to determine the probability of Coronary computerized tomography angiography (CCTA) has
MI and 30-​day outcomes [90]. been proposed as a rapid and accurate diagnostic technique to
 Diag n o st i c   t e st i n g 97

HEART Undetectable ESC 0-hour/1-hour ADAPT-ADP ADAPT-ADP ESC 0-hour/3-hour

≤3 hs-cTn algorithm TIMI = 0 TIMI ≤1 algorithm
C cTn hs-cTn

98.1 98 100 100 98.4 99.5 99.3 99.7 99.7 99.7 98.4
100
92.4

80

63.7
60
52
%

40
40
28

19 20
20 16 17.3

0
0 0 1 2 2 3
Decision based on blood samples obtained × hours after presentation to the ED

Rule-in ACS Low-risk or rule-out ACS Sensitivity Negative predictive value

Figure 10.8  Comparison of the performance in ruling in and ruling out AMI or identifying low-​risk chest pain patients with various risk stratification scores
and/​or diagnostic pathways either using contemporary (C cTn) or hs-​cTn assays [16, 89]. The 0-​hour/​1-​hour ESC algorithm is very effective in ruling in and
ruling-​out AMI with a very high NPV.

rule out obstructive CAD, given its very high NPV [95, 96]. Three high-​risk PE, i.e. those presenting with shock or hypotension or
multicentre studies have evaluated the feasibility, safety, and diag- those with a high clinical probability of PE.
nostic accuracy of early CCTA, compared to usual care, in the The high accuracy of CTA in the diagnosis of PE and acute
triage of chest pain patients in the ED [97–​99]. A meta-​analysis aortic dissection and the utility of CCTA in excluding CAD have
showed that a diagnostic strategy using early CCTA is as safe as led to the development of a triple rule-​out scan protocol, allowing
usual care of chest pain patients in the ED and results in a signifi- the simultaneous assessment of all three causes of acute chest
cant reduction of cost and length of hospital stay [100]. pain with a single scan [105]. Even with modern scanners, which
However, in a recent multicentre study that compared early offer a wider coverage and a greater temporal resolution, this
CCTA with standard optimal care diagnostic protocols based on necessitates a longer scanning time and an increased contrast
the use of hs-​cTn assays, early CCTA failed to identify more pa- volume. In a recent registry, a triple rule-​out protocol was associ-
tients with significant CAD requiring coronary revascularization, ated with a slightly higher yield of PE and acute aortic dissection
shorten hospital stay, or allow for more direct discharge from the than CCTA, specifically in patients presenting in the ED [103].
ED [101]. Selective use of CCTA may be considered in the 20% of
chest pain patients in whom a diagnosis of NSTE-​ACS cannot be Ultrasonography (other than
reliably ruled out or ruled in by the ECG and hs-​cTn diagnostic echocardiography)
algorithms [13, 102]. Ultrasonography (US) can help in the management of acute chest
Computerized tomography angiography (CTA) of the aorta pain, in particular when evaluating possible non-​cardiac causes.
plays a central role in the diagnosis, risk stratification, and man- Lung US is useful to detect pleural effusion or pneumothorax. The
agement of acute aortic syndromes. In most patients with sus- CXR may miss the diagnosis when the volume of fluid or air is
pected acute aortic dissection, CTA is the preferred initial small, while US has a higher sensitivity and specificity (>90%).
imaging modality [93]. Typical findings in pleural effusion are the ‘quad and sinusoid
Pulmonary CTA allows the detection of PE and adequate visu- signs’, while the ‘seashore sign’ (lung sliding) and ‘stratosphere
alization of the pulmonary arteries down to at least the segmental (barcode) sign’ suggest pneumothorax [104]. Lung US is also im-
level [103,  104]. Pulmonary CTA is the second-​line test in pa- portant in detecting B-​lines or ‘comets’, which indicate the amount
tients with suspected non-​high-​risk PE and an elevated D-​dimer of extravascular lung water and correlate with AHF that can be as-
level, whereas it is the first-​line test in patients with suspected sociated with acute ischaemic chest pain. When gastrointestinal
98 CHAPTER 10   C hest pain in  th e emergency depa rtm en t a n d the chest pa i n  u n i t

(GI) causes of chest pain are suspected (e.g. cholecystitis, biliary

Box 10.2  Physical and technical requirements of a CPU
colic, pancreatitis), abdominal US is appropriate.
Two to four monitoring beds
◆
Further predischarge testing One examination room
◆
Exercise ECG or non-​invasive stress testing has been recom- One waiting room
◆
mended in low-​risk patients as the final confirmatory test before Continuous heart rhythm monitoring, preferably centralized
◆
safe discharge from the ED [18, 106]. Routine use of predischarge Continuous non-​invasive blood pressure monitoring
◆
ischaemia testing may, however, lead to a longer length of stay in
External defibrillator with transcutaneous pacing modality
◆
the ED or observation units, more downstream invasive angio-
Non-​invasive ventilation equipment available <30 minutes
◆
graphy and revascularization procedures, more radiation ex-
Transport monitoring/​ventilating systems available <30 min-
◆
posure, and greater costs without any improvement in clinical
utes if needed
outcome [107–​110]. Use of the HEART score may aid in identi-
Echocardiographic equipment available <30 minutes
◆
fying patients in whom predischarge testing should be considered
[31,  32]. In the HEART pathway implementation trial, patients Pulse oximetry
◆

with a HEART score of ≤3 in whom an ACS was excluded by Full blood gas analysis available <15 minutes if needed
◆

serial troponin testing could be safely discharged without fur- 24-​hour emergency biology laboratory with turnaround time
◆

ther testing [111]. Based on these studies, it is proposed to limit of <90 minutes
predischarge exercise testing and cardiac imaging to patients with
a HEART score of >3 (see E Figure 10.8).
supervision of the unit by a cardiologist, and the presence of cer-
tified CPU nurses.
Role of chest pain units To ensure maximal benefits from the CPU concept, regular
CPUs are organizational short-​stay units with specific manage- training (once a year) for all staff members is a prerequisite. Such
ment protocols designed to facilitate and optimize the diagnosis training should include teaching and practical assessment of the
of patients presenting with chest pain in whom the diagnosis is implementation of the process of care for chest pain patients and
still uncertain after an initial clinical assessment and who are at also training in performing and interpreting diagnostic tests such
too high risk to be discharged immediately from the ED. as 12-​lead ECG, biomarkers, and non-​invasive tests.
Clinical studies, mainly from the US and the UK, have demon-
strated that CPUs manage their patients as effectively as inpatient
admission, but in a shorter time and at a lower cost [112–​114].
In Germany, an almost complete network of 244 certified CPUs
Conclusion
has been established [115]. In Europe, many hospitals have devel- The diagnosis and management of patients presenting with chest
oped some elements of CPU care, although sometimes without pain to the ED depends on careful history taking, physical exam-
establishing a formal CPU [116, 117]. ination, recording and expert interpretation of a 12-​lead ECG
Clinical observation in a certified CPU results in enhanced within 10 minutes of arrival, and measurement of cardiac bio-
quality of care of chest pain patients—​adherence to guidelines markers. This process has considerably improved through the im-
is better [118] and clinical outcome of patients with ACS is im- plementation of new diagnostic clinical algorithms using hs-​cTn
proved [119]. Furthermore, admission to the CPU offers a favour- assays. These new diagnostic algorithms allow a more effective
able moment to instruct patients about a heart-​healthy lifestyle and rapid triage of chest pain patients, as an AMI can be diag-
while they are undergoing a diagnostic evaluation to rule out nosed (rule-​in) or excluded (rule-​out) in three of four patients,
myocardial ischaemia [120]. based on the measurement of hs-​cTn on admission and 1 hour
A recent position paper of the ESC-​ACVC describes the op- later. Up to half of the patients are eligible for early discharge if dif-
timal organizational structure and the physical and technical re- ferential diagnoses are excluded. Although the new hs-​cTn-​based
quirements of a CPU either close to the ED or as an integral part diagnostic algorithms obviate the use of clinical risk stratification
of the ED (see E Box 10.2) [15]. Different requirements are sug- scores, a HEART score of ≤3 has been proposed to be added as
gested for standard or advanced CPUs. A standard CPU should an additional criterion for the decision on early discharge, as this
be supervised by a cardiologist, which can be in co-​direction with score predicts a very low MACE risk during early follow-​up. The
an EP, and should be staffed by a specialist or fellow in training for remaining group of patients in whom the diagnosis is unclear
internal or emergency medicine. The medical staff should be as- should remain in the ED, CPU, or observation unit until further
sisted by at least one certified emergency, CPU, or CCU nurse per ECG monitoring, repeated hs-​cTn measurement, bedside echo-
four beds. A higher level of accreditation requires the permanent cardiography, and additional CCTA or ischaemia testing allow to
presence of a specialist in cardiology or emergency medicine, the clarify the diagnosis (see E Figure 10.9).
 Re f e re n c e s 99

Acute chest pain: suspected ACS

History taking - clinical examination - ECG <10’ - hs-cTn on admission – HEART score

ECG normal ECG normal ECG ST ↓ or T ↓

and and and/or
hs-cTn <LoD* hs-cTn <ULN hs-cTn >ULN

hs-cTn at 1 hour

hs-cTn hs-cTn hs-cTn

no 0–1 hour ∆ 0–1 hour ∆ ? 0–1 hour ∆ +++

Ischaemic ECG ∆
Observe and/or
TTE wall motion ∆
Pain-free and hs-cTn at 3 hours and/or
HEART ≤3 and hs-cTn 0–1–3 hour ∆ +
Differential
diagnoses hs-cTn
excluded no 0–3 hour ∆
Diagnosis ? HEART >3

Discharge CCTA/ischaemia testing Invasive strategy

Figure 10.9  Management of chest pain within the ED [1]‌. TTE, transthoracic echocardiography. * If chest pain onset >3 hours.

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 CHAPTER 11

Acute dyspnoea in the

emergency department
Eleni Michou, Nikola Kozhuharov,
Jasmin Martin, and Christian Mueller

Contents
Summary  103
Summary
Definition and epidemiology  103 Acute dyspnoea is a very common symptom in the acute cardiac care setting. In
Pathophysiology of dyspnoea  104 contrast to current beliefs, acute dyspnoea, as the leading symptom in the emer-
Prevalence of the most common disorders gency department, is associated with about twice the mortality risk, compared to
underlying acute dyspnoea  104 acute chest pain. Rapid and accurate identification of the cause of dyspnoea is crit-
Triage and initial management  104 ical to the initiation of specific and effective treatment. In most patients, a rapid and
From symptoms to diagnosis  105 accurate diagnosis in the emergency department can be achieved by a combination
Cardiac cause: acute heart failure  105 of vital signs, including pulse oximetry, detailed patient history, physical examin-
Symptoms and signs  105
Electrocardiogram  105 ation, blood tests, including B-​type natriuretic peptide or N-​terminal pro-​B-​type
Chest radiograph and lung natriuretic peptide, venous blood gases, and C-​reactive protein in all patients, and
ultrasound  105 D-​dimers in selected patients, electrocardiograms, chest X-​ray, and pleural and/​or
Natriuretic peptides  106
Case report  108 lung ultrasound. It is key to remember that the prevalence of acute heart failure
Echocardiography  108 in unselected patients with acute dyspnoea is about 50%. Therefore, a high aware-
Pneumonia  109
Obstructive pulmonary disease (chronic ness for the presence of acute heart failure is mandatory. Acute heart failure, pneu-
obstructive pulmonary disease/​ monia, obstructive pulmonary diseases (chronic obstructive pulmonary disease
asthma)  109 and asthma), pulmonary embolism, and anxiety disorders represent >90% of all
Pulmonary embolism  109
Uncommon, but important, causes of cases with acute dyspnoea in the emergency department. In about 10–​15%, two
dyspnoea  109 acute causes (e.g. acute heart failure and pneumonia) may be present and require
Upper airway disease  109
Poisoning  109
combined treatment. Transthoracic echocardiography should be immediately per-
Neuromuscular disease  110 formed in all patients with acute dyspnoea and shock, and in those patients in
Risk stratification  110 whom the diagnosis remains uncertain, even after initial work-​up.
End of life  110
Personal perspective  110
Further reading  110
References  111

Definition and epidemiology
Dyspnoea is the perception of an inability to breathe comfortably. Acute dyspnoea is the
term used whenever dyspnoea is severe enough to require presentation to the ED, irre-
spective of whether the dyspnoea is new or simply worsened from that experienced pre-
viously. Acute dyspnoea is a very common symptom in acute cardiac care. In contrast to
current belief, acute dyspnoea as the leading symptom in the ED is associated with about
twice the risk of mortality, compared to acute chest pain (CP) [1]‌. The chief complaint
of dyspnoea or shortness of breath makes up 3–​5% of, or >10 million, visits to the ED in
Europe and the US. Among the greater than 30 possible diagnoses that may be respon-
sible for acute dyspnoea, AHF is very common and therefore particularly important [1].
104 CHAPTER 11   Ac u te dyspnoea in  th e emerg en cy  depa rtm en t

Currently, >15  million patients have heart failure in North pneumonia or bronchitis (20%), exacerbation of COPD or asthma
America and Europe, with nearly 2 million new cases every year (20%), PE (5–​10%), anxiety disorders (5%), and other causes such
[2]‌. Diagnostic uncertainty delays the initiation of adequate treat- as malignancy, interstitial lung disease, upper airway obstruction,
ment and increases morbidity, hospitalization rates, and costs. or anaemia (5–​10%). In about 10–​15% of patients, two disorders
Considering the high prevalence of dyspnoea and the enormous will be present at the same time (e.g. AHF and pneumonia).
number of resulting hospitalizations, rehospitalizations, and We estimate the prevalence of AHF in other health care set-
deaths, and thus the high costs associated with these patients, an tings as follows:  primary care, 30%; ICU, 50%; and CCU, 85%
optimal diagnostic assessment and risk stratification, with widely [2–​5,  9–​24].
and rapidly available tools, are highly desirable.

Triage and initial management

Pathophysiology of dyspnoea It is important to stress that immediate assessment of vital signs,
Dyspnoea is a complex syndrome, and the pathophysiological including O2 saturation, and application of supplemental O2 are
mechanisms are still poorly understood. A  mismatch between mandatory. Airway, breathing, and circulation (ABC approach)
efferent signals to the respiratory muscles and the afferent feed- are the primary focus when beginning the management of the pa-
back from mechanoreceptors and chemoreceptors of the lung and tient with acute dyspnoea. Once these parameters are stabilized,
chest wall seems to play a major role [3–​5]. further clinical investigation and treatment can proceed. In cases
In 1963, Campbell and Howell postulated the association be- of severe respiratory failure, immediate unspecific treatment,
tween dyspnoea and the structures of the CNS in the theory of including NIV or intubation, must precede further diagnostic
‘length–​ tension inappropriateness’. According to their theory, measures. The severity of respiratory failure and the response to
dyspnoea arises from a disturbance in the relation between the the initial measures of bed rest, upright positioning, and supple-
force or tension generated by respiratory muscles and the re- mental O2 need to be carefully monitored, particularly within the
sulting changes in muscle length and lung volume. The theory first minutes, to decide whether the patient needs NIV, intub-
has been generated to include information about the mismatch ation, and transfer to an ICU (see E Figure 11.1) [25].
between respiratory motor command and afferent feedback. The first contact with the patient may be at the patient’s home.
Experimental data are also consistent with the concept of afferent It is important to check all medications or devices, such as in-
mismatch  [6–​8]. halers, as they may be the only source regarding the previous
The current understanding of dyspnoea still assumes a mis- medical history in an acute dyspnoeic patient unable to speak.
match between central respiratory motor activity and incoming In many European countries, ambulances are staffed with EPs
afferent information from respiratory mechanoreceptors, which trained in intubation. In these circumstances, a number of pa-
are localized in the airways, lungs, and chest wall structures or tients with severe respiratory failure arrive intubated and under
chemoreceptors. Changes in ABGs and acid–​base metabolism are analgo-​sedation at the hospital. Giving the hospital team early
observed by peripheral chemoreceptors in the aorta and carotid information about the patient’s cardiorespiratory condition will
sinus, or alternatively by the brainstem. allow the timely preparation of a ventilator in the ICU (‘fore-
There seems to be an excessive or abnormal activity of the warned is forearmed’). Furthermore, if it has not been possible to
respiratory centre in the medulla oblongata [6]‌. This activity is definitely secure the airway in a critically ill patient before arrival
caused by stimuli from different structures and their abnormal-
ities, such as respiratory muscle abnormality, abnormal ventilator
impedance, abnormal breathing patterns, and blood gas abnor-
malities, which are important at the onset of dyspnoea [3]. Initial management
Oxygen saturation, blood pressure, heart rate, respiratory
rate, temperature

Prevalence of the most common 4–6 L O2/minute (aim: oxygen saturation >90%)

disorders underlying acute  Insert venous cannula and observe the patient

dyspnoea If these criteria persist for >30 minutes despite treatment,

consider admission to intensive care unit
AHF is the most common disorder responsible for acute dyspnoea Respiratory rate >35/minute Systolic blood pressure <90 mmHg
in patients treated in acute cardiac care settings (see E Figure Oxygen saturation <85% Heart rate >120 bpm
11.1) (also see E Chapter 45). However, it is important to note
Diagnostic test
that the prevalence of AHF is influenced substantially by the spe-
ECG CXR Full blood count BNP
cifics of the local health care setting. In an ED setting of unselected
Venous blood gases
patients with acute dyspnoea, the prevalence of AHF is about
50% [2, 9–​16]. Other common causes of acute dyspnoea include Figure 11.1  Initial management of patients with acute dyspnoea.
 Fro m sym p to m s to   diag n o si s 105

at hospital, it is mandatory to get expert support to the ED before

the ambulance arrives.
Lung HISTORY Heart

From symptoms to diagnosis History of heart failure

While the clinical diagnosis of AHF and other common causes of
dyspnoea may be straightforward in about half of the patients, it History of asthma/COPD
remains challenging in the remainder, resulting in delays in the
initiation of adequate treatment, and increases morbidity, hospi- Orthopnoea/paroxysmal nocturnal dyspnoea
talization rates, and costs. Therefore, a systematic approach using
a predefined set of simple, inexpensive, and non-​invasive inves- Relief after expectoration
tigations complementing clinical assessment is mandatory in all
patients with acute dyspnoea. Fortunately, the widespread use Yellow/green sputum
of natriuretic peptides (NPs) has substantially reduced the per-
centage of patients with diagnostic uncertainty [1, 2, 9, 14–​16]. Chest pain
Detailed patient history and physical examination remain the
basis for the diagnosis of patients with acute dyspnoea. Palpitations
A history of dyspnoea in the past caused by any of the above-​
mentioned diseases commonly resulting in acute dyspnoea in- Nocturia
creases the likelihood that the current episode is a relapse. For
example, in patients with a history of heart failure, the likelihood
Peripheral oedema
ratio for AHF is about 5!
Current evidence regarding the diagnostic performance of
Weight gain
symptoms, signs, and other individual diagnostic tests is largely
based on studies performed in the ED setting. As patient char-
acteristics, the severity of dyspnoea, the incidence of AHF, and
physician experience differ considerably between the ED and, for Figure 11.2  Use of symptoms to differentiate cardiac from pulmonary
causes of acute dyspnoea. The less central the position of the box, the more
example, the private practice or the ICU, these findings should helpful the symptom.
only cautiously be applied to other settings.

Cardiac cause: acute heart failure

While the term AHF is sometimes used synonymously with Electrocardiogram
‘cardiac causes’ of acute dyspnoea, it is important to highlight A 12-​lead ECG should be performed in every patient with acute
two cardiac causes that require a different approach to ‘regular’ dyspnoea within 5 minutes, as it may identify STEMI as the cause
AHF: AMI and tachyarrhythmia. of acute dyspnoea [2]‌. ECG changes are common in patients with
Acute dyspnoea may be the presenting symptom of AMI, par- AHF (see E Table 11.2). However, an abnormal ECG has little
ticularly in women and the elderly. predictive value for the presence of AHF as the main cause of
acute dyspnoea. If the ECG is completely normal, AHF, especially
Symptoms and signs with LV systolic dysfunction, is unlikely [27].
It is currently unclear whether the exact wording used by the pa- In patients with AHF, the ECG may help immediately in iden-
tient to describe dyspnoea may help differentiate the cause. Most tifying common causes of the acute decompensation such as
symptoms are rather unspecific. E Figure 11.2 shows symptoms tachycardic AF, ventricular tachycardia (VT), or STEMI. This is
and E Figure 11.3 shows signs that help differentiate cardiac from of major importance, as specific treatments are available for these
pulmonary causes of acute dyspnoea [23, 26]. Most classical clinical triggers.
signs associated with AHF are not very sensitive (see E Table 11.1)
[23, 26]. Chest radiograph and lung ultrasound
The presence of paroxysmal nocturnal dyspnoea, orthopnoea, Chest radiography is an established, easily available, non-​
nocturia, peripheral oedema, and weight gain increases the like- invasive, and inexpensive method, which should be part of the
lihood of AHF. initial work-​up in all patients with dyspnoea (see E Chapter 17).
Signs of AHF on physical examination are not very sensitive, Whenever possible, chest radiographs should be obtained in the
although rather specific. Therefore, the absence of lower ex- erect position in two planes. The chest radiograph quantifies the
tremity oedema should not disregard the presence of AHF, while cardiac size and shape and directly visualizes pulmonary conges-
the presence of, for example, two signs (jugular venous distension tion. Findings of cardiomegaly, cephalization, interstitial oedema,
and bilateral basal rales) makes AHF very likely. including peribronchial cuffing, septal lines, and hilar blurring,
106 CHAPTER 11   Ac u te dyspnoea in  th e emerg en cy  depa rtm en t

the relatively short examination duration, and the non-​invasive

Lung Heart nature of this technique make it an attractive point-​of-​care tool.
Quantification of B-​lines (vertical artefacts that result from an in-
SIGNS
crease in interstitial density) seems useful in the diagnosis, moni-
toring, and risk assessment of patients with suspected AHF [30].
Use of accessory respiratory muscles Moreover, pleural effusions can be detected rapidly by US and
Pursed-lip breathing
represent specific treatment targets by drainage.

Barrel chest Natriuretic peptides

NPs, including B-​type natriuretic peptide (BNP), N-​terminal
Allergies pro-​B type natriuretic peptide (NT-​proBNP), and mid-​regional
pro-​ atrial natriuretic peptide (MR-​ proANP) are considered
Wheezing/prolonged expirium
quantitative markers of haemodynamic cardiac stress and HF
Rales
(see E Chapter 33). The clinical introduction of NPs constitutes
the most important advance in the management of patients with
Fever acute dyspnoea in the last decades. BNP is a 32-​amino acid poly-
peptide that is co-​secreted with the inactive NT-​proBNP from the
Third heart sound (if age >40 years) left and right cardiac ventricles, in response to ventricular volume
expansion and pressure overload [19].
Holosystolic mitral murmur
Recent data suggest that LV end-​ diastolic wall stress and
Jugular venous distension wall stiffness may be the predominant triggers of BNP and NT-​
proBNP synthesis and release. NPs are released into blood in re-
Peripheral oedema lation to disease severity and correspond to the New York Heart
Association (NYHA) functional classification system. The NP
level can be used to quantify the severity of heart failure, reflecting
Figure 11.3  Use of signs to differentiate cardiac from pulmonary causes of
acute dyspnoea. The less central the position of the box, the more helpful the combined haemodynamic consequences of systolic and dia-
the sign. stolic LV dysfunction, as well as VHD and RV dysfunction [19].
The clinical importance of a specific disease marker is related
to the overall importance of the disease or the biological signal it
pleural effusions, or alveolar oedema, suggest the presence of
quantifies, the availability of alternative methods to reliably diag-
AHF (see E Figure 11.4) [28–​31].
nose the disease and quantify disease severity, and, of course, the
It is important to note that up to 20% of patients with AHF
performance of the marker. NPs, as quantitative markers of car-
may have no radiographic signs of congestion. On the other
diac stress and heart failure, owe their enormous clinical import-
hand, bronchitis and pneumonia may mimic many of the radio-
ance to the fact that heart failure is a major public health problem,
graphic findings of congestion. Therefore, all radiographic find-
the uncertainty in the clinical diagnosis and management of heart
ings need to be co-​assessed to form an overall impression, which
failure, and their excellent diagnostic and prognostic utility.
can then have moderate to high accuracy in the diagnosis of acute
Two important principles underlie the clinical use of NPs. First,
dyspnoea.
the NP level is not a standalone test. It is always of greatest value
Recently, lung US has emerged as an additional, or even alter-
when it complements the physician’s clinical skills, along with
native, imaging modality in patients presenting with acute dys-
other available diagnostic tools e.g. estimated glomerular filtra-
pnoea [30]. Based on the interpretation of US artefacts, specific
tion rate (eGFR). Second, NP levels should be interpreted and
structure appearances, and their distribution, lung US allows
used as continuous variables in order to make full use of the bio-
for a rapid point-​of-​care evaluation of a number of conditions,
logical information provided by the measurement.
including pulmonary oedema and consolidation, as well as
NPs have consistently shown very high accuracy in the diag-
pleural effusion and pneumothorax [30]. The ease of learning,
nosis of heart failure in patients presenting with acute dyspnoea
to the ED. NP levels are very high in patients with dyspnoea due
Table 11.1  Sensitivity of findings on physical examination in the to heart failure, and low in patients with other causes of dyspnoea
diagnosis of AHF [11–​13, 17, 19, 21].
Numerous diagnostic studies including patients presenting
Findings Sensitivity (%)
with dyspnoea have validated NPs against a gold standard diag-
Third heart sound 5 nosis of AHF and have shown convincingly that NPs have a very
Jugular venous distension 50 high diagnostic accuracy [11, 12, 17–​24]. The higher the NP
Lower extremity oedema 60 level, the higher the probability that dyspnoea is caused by AHF.
Rales 60–​70 Overall, all clinically available NPs (BNP, NT-​proBNP, and rarely
 Fro m sym p to m s to   diag n o si s 107

Table 11.2  Common ECG abnormalities in heart failure

Abnormality Cause Clinical implication

Sinus tachycardia Decompensated heart failure, anaemia, fever, Clinical assessment, laboratory investigation
hyperthyroidism
Sinus bradycardia β-​blockade, digoxin, ivabradine, antiarrhythmics, Evaluate drug therapy, laboratory investigation
hypothyroidism, sick sinus syndrome
Atrial tachycardia/​flutter/​fibrillation Hyperthyroidism, infection, mitral valve diseases, Slow AV conduction, medical conversion, electroversion,
decompensated heart failure, infarction catheter ablation, anticoagulation
Ventricular arrhythmias Ischaemia, infarction, cardiomyopathy, Laboratory investigation, exercise test, perfusion studies,
myocarditis, hypokalaemia, hypomagnesaemia, coronary angiography, electrophysiology testing, ICD
digitalis overdose
Ischaemia/​infarction CAD Echocardiography, troponins, coronary angiography,
revascularization
Q-​waves Infarction, hypertrophic cardiomyopathy, LBBB, Echocardiography, coronary angiography, ICD
pre-​excitation
LV hypertrophy Hypertension, aortic valve disease, hypertrophic Echocardiography/​Doppler
cardiomyopathy
Atrioventricular (AV) block Infarction, drug toxicity, myocarditis, sarcoidosis, Evaluate drug therapy, pacemaker, systemic disease
Lyme disease
Microvoltage Obesity, emphysema, pericardial effusion, Echocardiography, CXR
amyloidosis
QRS length >120 ms or LBBB morphology Electrical and mechanical dyssynchrony Echocardiography, cardiac resynchronization treatment
(CRT) (CRT pacemaker, CRT defibrillator)
Reproduced from Dickstein K, Cohen-​Solal A, Filippatos G, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the
Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the
ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM) [published correction appears in Eur Heart J 2010 Apr;12(4):416. Dosage error in article text]
[published correction appears in Eur Heart J 2010 Mar;31(5):624. Dosage error in article text]. Eur Heart J 2008;29(19):2388–​2442 doi:10.1093/​eurheartj/​ehn309 with permission from
Oxford University Press.

MR-​proANP) seem to have similar accuracy in the diagnosis of presenting with dyspnoea, BNP levels <100 pg/​mL strongly argue
AHF [19, 21]. against AHF [11–​13, 17, 19, 21]. On the other hand, BNP levels
The clinical impact of using the diagnostic and prognostic in- >400 pg/​mL have a very high specificity and PPV for AHF. Similar
formation provided by BNP or NT-​proBNP was demonstrated cut-​off values apply for NT-​proBNP (see E Table 11.3). In pa-
also in several randomized controlled studies [13, 22, 32–​34]. In tients with NP levels above the upper cut-​off level, and therefore
the BASEL study, the BNP group showed a significant reduction with substantial cardiac haemodynamic stress, we can be quite
in time to adequate therapy, admission rate, and time to discharge. certain that AHF is the predominant cause of dyspnoea, and it
Hence, if we diagnose the cause of dyspnoea earlier and with is imperative to promptly initiate appropriate treatment such as
greater accuracy, we can initiate appropriate treatment earlier; nitrates, diuretics, and ACE-​Is. It is important to remember that
patients would improve more rapidly and would be able to be dis- NPs are also secreted from the right ventricle (RV). Therefore, se-
charged sooner from the hospital. These findings were confirmed vere PE with resulting RV stretch will also result in NP secretion
by two additional randomized controlled studies [22, 33]. Thus, and should always be included in the differential diagnosis of ele-
data from three large randomized controlled studies consistently vated NP levels.
demonstrated that the additional use of NPs improves medical The vast majority of patients with acute dyspnoea will present
and economic outcomes in patients with dyspnoea. Accordingly, with either low or high NP levels. However, about 25% of patients
the use of NPs is supported by a class I recommendation in cur- will present with NP levels in the grey zone. These patients need
rent guidelines [1]‌. further clinical evaluation for a correct diagnosis. NT-​proBNP
Easily applicable algorithms for the interpretation of NPs by and BNP levels need to be adjusted in obese patients. In addition,
applying specific cut-​off levels have been developed (see E Table BNP levels need to be adjusted in those with severe kidney dis-
11.3). It is important to see that NPs are quantitative variables ease but do not have to be adjusted for gender or age [19]. When
and should always be used in conjunction with other clinical using NT-​proBNP, the use of an age-​adjusted upper cut-​off level
information. largely obviates the need for further adjustments for renal func-
As NPs are quantitative markers of heart failure, the use of tion [18]. For patients presenting with NP levels in the grey zone,
cut-​off levels is only the second best approach. Yet, in the busy other diagnostic tools, including CT scans and bedside echocar-
emergency room, NP decision limits can be helpful. In a patient diography, have particular additional value.
108 CHAPTER 11   Ac u te dyspnoea in  th e emerg en cy  depa rtm en t

Case report
A 76-​year-​old male patient presented to the ED with acute dys-
pnoea over 24 hours. The patient reported a history of exercise-​
induced dyspnoea, but he emphasized that it was the first time he
experienced dyspnoea at rest. His past medical history included
CAD, persistent AF, and COPD. At presentation, the patient was
tachypnoeic, with a body temperature of up to 38.5°C, a heart rate
of 60 bpm, a blood pressure of 120/​80 mmHg, and an O2 saturation
on room air of 94%. Clinical examination revealed prolonged expir-
ation and wheezing and mild pre-​existing bilateral ankle oedema.
Neither a third heart sound nor a heart murmur could be auscul-
tated, while the jugular venous pressure (JVP) could not be reliably
assessed. The ECG confirmed the already known AF without any
other relevant changes, compared to the previous ECG.
Initial assessment suggested an infective exacerbation of
COPD, while measurement of BNP clearly identified AHF as the
predominant cause of his acute dyspnoea. BNP concentration was
substantially elevated at 1000 ng/​L. This value documents mas-
sively increased intracardiac filling pressures and thus makes a
cardiac aetiology of acute respiratory distress very likely. In this
case, AHF complicated an infection in a patient with known
COPD. Loop diuretic therapy was initiated to relieve congestion
and fluid overload, together with a prompt cardiological evalu-
ation, including echocardiography, to select further management
and identify the underlying structural heart disease.
This case should show:
1. Fever and a systemic infection are not only common causes
of exacerbated COPD, but also the most common triggers
of AHF.
2. An obstructive auscultation finding (such as wheezing) is
equally likely to be an expression of pulmonary congestion (in
the sense of cardiac asthma) in patients with pre-​existing heart
disease, and not only a sign of obstructive pulmonary disease.
3. BNP or NT-​proBNP play an important role in the diagnostic
evaluation of patients with dyspnoea whenever HF is included
in the differential diagnosis.

Echocardiography
TTE with tissue Doppler imaging (TDI) should be performed
immediately in all patients with acute dyspnoea and shock, and
in those patients in whom the diagnosis remains uncertain after
Figure 11.4  Chest radiograph during various stages of AHF, showing
the initial work-​up (see E Chapter 18.2) [27]. In patients diag-
different radiographic findings and degrees of congestion. nosed with AHF, echocardiography is critical to determining the
(A) Close-​up view of a posteroanterior radiograph revealing clearly visible underlying structural heart disease. In most of these cases, echo-
bronchial walls (arrows) without blurring of the margins (no peribronchial cardiography can be deferred safely, until dyspnoea has improved
cuffing). Hilar vessels (arrowheads) are sharply outlined (no hilar changes). sufficiently to allow the patient to remain in the supine position
Redistribution of flow is present.
(B) Close-​up view of a posteroanterior radiograph from the same patient with
for some time (usually on day 2 of hospitalization).
increasing signs of congestion. Prominent thickening of bronchial walls (plain Routine assessment includes determination of atrial and ven-
arrows), with partially indistinct outlines (peribronchial cuffing), as well as tricular size, ventricular wall thickness, regional and global LV
hilar enlargement, together with blurred vascular margins. Septal lines (tailed and RV function, including TDI, valvular structure and function,
arrows) appear between indistinct vessels in the basal region. possible pericardial pathology, and mechanical complications of
(C) Close-​up view of an anteroposterior radiograph obtained in the supine
position. There is now complete loss of the bronchial interface (arrows,
MI. About 50% of patients with AHF will be found to have heart
peribronchial cuffing). The density and size of the hila have further increased failure with preserved LVEF; therefore, a detailed evaluation of
(arrowheads), and the margins of hilar vessels are indeterminable. Alveolar LV diastolic function, including TDI, as well as global longitu-
oedema is present (asterisks). dinal strain (GLS), is critical. In addition, increased left atrial
 Fro m sym p to m s to   diag n o si s 109

Table 11.3  Cut-​off levels for NT-​proBNP and BNP in acute dyspnoea

Cut-​off levels (ng/​L)*

NT-​proBNP BNP
Age <50 Age 50–​75 Age >75 Age <50 Age 50–​75 Age >75
AHF unlikely <300 <100
Sensitivity ~95%#
AHF possible 300–​450 300–​900 300–​1800 100–​400
AHF likely >450 >900 >1800 >400
Specificity ~90%**
* In obesity (BMI ≥30 kg/​m2): multiply concentration by 2 [40].
#
Negative likelihood ratio = 0.1.
** Positive likelihood ratio = 8 [11, 18, 41, 42].
AHF, acute heart failure; BMI, body mass index; BNP, B-​type natriuretic peptide; NT-​proBNP, N-​terminal pro-​B-​type natriuretic peptide.
ESICM. Eur Heart J. 2008 Oct;29(19):2388–​2442.

(LA) volume is a relevant and valuable indicator of heart failure not be withheld from patients with COPD. The target O2 satur-
in patients with preserved LVEF. ation in these patients is 90–​92%.

Pneumonia Pulmonary embolism
Pulmonary infections, such as severe bronchitis or pneu- Risk factors for PE include a history of deep vein thrombosis
monia, can cause shortness of breath and hypoxia. Productive (DVT) or PE, prolonged immobilization, recent trauma or sur-
cough, fever, and pleuritic CP are common, but indiscrim- gery (particularly orthopaedic), pregnancy, malignancy, stroke
inate, signs. A  chest radiograph is generally necessary for or paresis, and a personal or family history of hypercoagulability.
diagnosis. It is important to remember that small infiltrations Presentation varies widely, but dyspnoea at rest and tachypnoea
may not be seen on standard chest radiographs but become are the most common signs. A sizeable minority of patients have
only visible by CT scanning. Another important caveat is the no known risk factors at the time of diagnosis. Other embolic
fact that C-​reactive protein (CRP) and procalcitonin (PCT), phenomena include fat embolism, especially after a long bone
both valuable markers indicating possible systemic bacterial fracture, and amniotic fluid embolism (AFE). Once PE is sus-
infection, require at least 6–​12 hours from the onset of in- pected, the diagnostic work-​up combines clinical assessment by a
fection to reach clearly elevated concentrations in peripheral prediction rule, D-​dimer measurement, and CTA in patients with
blood. Patients who present very early, e.g. after an episode an elevated D-​dimer level or a high clinical probability of PE [38].
of possible bacteraemia, indicated by shivering, often have (See also E Chapter 63.)
normal concentrations of CRP and PCT at presentation, while
serial sampling at 24 hours often shows a substantial eleva- Uncommon, but important, causes
tion. Therefore, in the appropriate clinical setting, antibiotic of dyspnoea
therapy should be initiated early in the ED, as none of the Upper airway disease
currently available tools provide a high enough NPV for the
Any disease that results in a narrowing of the upper airways may
presence of bacterial pneumonia. At 24 hours, however, anti-
result in acute dyspnoea, often accompanied by an inspiratory
biotic therapy can be stopped safely in patients with persistent
stridor. These include tracheal foreign objects, such as food, den-
low concentrations of CRP or PCT [35–​37]. Pneumonia is a
tures, and medication tablets, angio-​oedema, anaphylaxis, and
common trigger of AHF in elderly patients. In addition, AHF
infections.
commonly develops as a complication in elderly patients hos-
pitalized with pneumonia. Poisoning
Along with other presenting symptoms, poisoning should also
Obstructive pulmonary disease (chronic always be considered in the differential diagnosis of patients
obstructive pulmonary disease/​asthma) with acute dyspnoea. Several toxins, including carbon mon-
Exacerbations of COPD almost invariably present with acute oxide, can cause derangements in respiratory function, leading
shortness of breath. Most often, a viral or bacterial respiratory in- to acute dyspnoea.
fection exacerbates the patient’s underlying disease. PEs may be Carbon monoxide is a potentially lethal toxin that impairs
responsible for up to 25% of apparent COPD exacerbations and O2 metabolism, leading to tachypnoea and acute dyspnoea.
should be suspected when the patient has no signs of acute infec- Extrapulmonary symptoms include altered mental status, head-
tion or fails to improve with standard COPD treatment. O2 must ache, malaise, and chest discomfort.
110 CHAPTER 11   Ac u te dyspnoea in  th e emerg en cy  depa rtm en t

Organophosphate poisoning causes an increase in airway se-

cretions and bronchospasm. End of life
Salicylate overdose leads to stimulation of the medullary re-
Acute dyspnoea may occur at the end of life in patients with
spiratory centre, causing hyperventilation and respiratory al-
various cancers, chronic lung disease, and chronic terminal HF
kalosis initially, followed by metabolic acidosis. Additional
(see E Chapter  52). Although the details of palliative care go
symptoms include tinnitus, vertigo, vomiting, diarrhoea, and, in
far beyond the scope of this chapter, it is important to stress that
more severe cases, mental status changes.
patient management in an end-​of-​life situation should, of course,
Diabetic ketoacidosis (DKA) can cause tachypnoea and acute
be very different from the management of other patients. Ideally,
dyspnoea from involuntary respiratory correction of metabolic
patients and their relatives should be prepared for this scenario in
acidosis. Additional symptoms include polyuria, polydipsia, and
advance, to ensure that the health care professionals involved in
progressive weakness.
the acute dyspnoea episode are immediately aware of the end-​of-​
Anaemia may result in dyspnoea due to reduced O2-​carrying
life situation. Clinical assessment should search for easily treatable
capacity of blood. Usually, other symptoms, including fatigue,
causes, like upper airway obstruction due to secretions, that could
predominate.
be resolved potentially, e.g. by tracheal suctioning. Even in a pal-
Neuromuscular disease liative end-​of-​life situation, it is often well justified to follow the
standard simple and non-​invasive diagnostic approach outlined
Neuromuscular diseases, such as Guillain–​ Barré syndrome
previously, as cause-​specific treatment, like nitrates and diuretics
or myasthenia gravis, may lead to weakness of the respiratory
for AHF or antibiotics for pneumonia, will substantially alleviate
muscles and acute respiratory failure (ARF).
dyspnoea. As the end of life is often a period, rather than a time
point, these measures should, whenever possible, be tailored ac-
cording to the patient’s wish. Close physical contact with family
Risk stratification members and continuous IV infusion of morphine might be con-
Risk stratification of patients with acute dyspnoea presenting to the sidered helpful in terminal patients (see also E Chapter 6).
ED is challenging, as the range and urgency of the causes of breath-
lessness are vast. Assessment of vital signs, particularly including
respiratory rate, always should be the first step. Monitoring of O2 sat- Personal perspective
uration and blood pressure also helps the clinician to determine the
The introduction of rapid testing for NPs has significantly
initial response to therapy. Recent evidence shows that these easy-​
improved the clinical management of patients presenting
to-​measure values are important factors in the risk stratification of
with acute dyspnoea. These tools will continue to be used
these patients. Currently, biomarkers, such as serum creatinine, BNP,
more widely also in settings outside the ED, including pri-
NT-​proBNP, MR-​proANP, mid-​regional pro-​adrenomedullin (MR-​
vate practice and the ambulance service. More accurate de-
proADM), hs-​cTn, copeptin, and suppression of tumourigenicity 2
tection of heart failure as the cause of dyspnoea in other
(ST2), have been proven helpful in the risk stratification of patients
settings will help to provide important additional treatment
presenting with acute dyspnoea to the ED [39].
options to thousands of patients every year.

Further reading
American Thoracic Society. Dyspnea. Mechanisms, assessment, and manage­ Ponikowski P, Voors AA, Anker SD, et  al. 2016 ESC Guidelines
ment: a consensus statement. Am J Respir Crit Care Med 1999; 159:321–​40. for the diagnosis and treatment of acute and chronic heart
Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid measurement of B-​ failure:  the Task Force for the diagnosis and treatment of acute
type natriuretic peptide in the emergency diagnosis of heart failure. N and chronic heart failure of the European Society of Cardiology
Engl J Med 2002;347:161–​7. (ESC). Developed with the special contribution of the Heart
Maisel A, Mueller C, Adams K, Jr, et al. State of the art: using natriuretic Failure Association (HFA) of the ESC. Eur Heart J 2016;37:
peptide levels in clinical practice. Eur J Heart Fail 2008;10:824–​39. 2129–​200.
McCullough PA, Nowak RM, McCord J, et al. B-​type natriuretic peptide Schuetz P, Christ-​Crain M, Thomann R, et al.; ProHOSP Study Group.
and clinical judgment in emergency diagnosis of heart failure: analysis Effect of procalcitonin-​based guidelines vs standard guidelines on
from Breathing Not Properly (BNP) Multinational Study. Circulation antibiotic use in lower respiratory tract infections:  the ProHOSP
2002;106:416–​22. randomized controlled trial. JAMA 2009;302:1059–​66.
Mueller C, Scholer A, Laule-​Kilian K, et  al. Use of B-​type natriuretic Studler U, Kretzschmar M, Christ M, et al. Accuracy of chest radiographs
peptide in the evaluation and management of acute dyspnea. N Engl in the emergency diagnosis of heart failure. Eur Radiol 2008;8:
J Med 2004;350:647–​53. 1644–​52.
Platz E, Lewis EF, Uno H, et  al. Detection and prognostic value of Wang CS, FitzGerald JM, Schulzer M, Mak E, Ayas NT. Does this
pulmonary congestion by lung ultrasound in ambulatory heart failure dyspneic patient in the emergency department have congestive heart
patients. Eur Heart J 2016;37:1244–​51. failure? JAMA 2005;294:1944–​56.
 Re f e re n c e s 111

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 SECTION III

Monitoring and
investigations in the
intensive cardiovascular
care unit

12 Pathophysiology and clinical assessment of the cardiovascular system

(including pulmonary artery catheterization)  115
Alessandro Sionis, Etienne Gayat, and Alexandre Mebazaa
13 The respiratory system  127
Antoine Vieillard-​Baron
14 Neurological assessment of the acute cardiac care patient  134
Mathieu van der Jagt, Jeroen JH Bunge, and Fabio S Taccone
15 Monitoring of the kidneys, liver, and other vital organs  147
Karl Werdan, Brijesh Patel, Matthias Girndt, Henning Ebelt, Jochen Schröder, and
Sebastian Nuding
16 Blood gas analysis: acid–​base, fluid, and electrolyte disorders  165
Farah Shariff and Richard Paul
17 Interpretation and clinical use of chest radiographs  181
Alexander Parkhomenko, Olga S Gurjeva, and Tetyana Yalynska
18.1  Echocardiography and thoracic ultrasound  201
Frank A Flachskampf, Pavlos Myrianthefs, and Ruxandra Beyer
18.2  Echocardiography and thoracic ultrasound  218
Frank A Flachskampf, Pavlos Myrianthefs, and Ruxandra Beyer
19 Computerized tomography: coronary angiography and cardiac imaging  224
Jeff M Smit, Mohammed El Mahdiui, Michiel A de Graaf, Arthur JHA Scholte,
Lucia Kroft, and Jeroen J Bax
20 Cardiac magnetic resonance in the intensive and cardiac care unit  246
Juerg Schwitter and Jens Bremerich
 CHAPTER 12

Pathophysiology and
clinical assessment of the
cardiovascular system
(including pulmonary
artery catheterization)
Alessandro Sionis, Etienne Gayat, and
Alexandre Mebazaa

Contents
Summary  115 Summary
Introduction  116 The underlying pathophysiological derangements of the cardiovascular system
Left ventricular diastolic dysfunction  116 in many medical conditions are often complex. Acute circulatory dysfunction
Pathophysiology  116 can be related broadly to a cardiogenic cause leading to acute heart failure or be
Cardiac catheterization  116
Myocyte energy imbalance  117 secondary to hypovolaemia or vascular dysfunction (e.g. sepsis). Different mech-
Contraction–​relaxation coupling  117 anisms may be involved, including left ventricular diastolic and/​or systolic dys-
Afterload reserve  117
An alternative concept: end-​systolic function and/​or right ventricular dysfunction. Many aspects of left ventricular
volume dependency  117 function are explained by considering ventricular pressure–​volume characteris-
How to assess left ventricular diastolic tics. Epidemiological studies show that clinical signs at admission, morbidity, and
function in clinical practice  117
Left ventricular systolic dysfunction  117 mortality differ between the main scenarios of acute heart failure: left ventricular
Pathophysiology  117 diastolic dysfunction, left ventricular systolic dysfunction, right ventricular dys-
Clinical assessment  119 function, and cardiogenic shock. Although echocardiography is usually the first
Investigations  119
investigation used to assess the mechanism of cardiac dysfunction, in selected
Cardiogenic shock  119
cases (in particular, in cases of refractory shock secondary to both vascular and
Pathophysiology  119
Clinical assessment  119 heart dysfunction or in cases of refractory haemodynamic instability associated
Investigations  120 with severe hypoxaemia), the pulmonary artery catheter can help to assess and
Right ventricular failure  120 monitor the cardiovascular status and evaluate response to treatments.
Pathophysiology  120
Right ventricular systolic impairment  120
Effect of an increase in right ventricular
afterload  120
Effect of an increase in right ventricular
volume  120
Ventricular interdependence  121
The vicious cycle of auto-​aggravation  121
Consequences of systemic venous Pericardial diseases  122 The particular case of right ventricular
congestion  121 Pathophysiology  123 failure  123
Assessment of right ventricular function  121 Clinical assessment  123 Conclusion  124
Vascular dysfunction  122 Use of pulmonary artery catheter in acute Personal perspective  124
Pulmonary hypertension  122 heart failure  123 Further reading  125
Pathophysiology  122 Recommendations/​indications for heart
Clinical assessment  122 failure  123 References  125
116 CHAPTER 12   Pathoph ysiol o gy and clinica l as ses sm en t of the ca rdi ovas cu l a r syst e m

Introduction 120

Thorough clinical assessment and understanding of the patho-

LV pressure (mmHg)
physiology of the multiple medical conditions that can affect the 80
cardiovascular system are essential skills for any physician dealing
Decreased
with acute and critically ill patients. compliance
The most severe alteration in the cardiovascular system occurs in 40 Normal
shock, a clinical condition with characteristic symptoms and signs compliance
related to an imbalance between O2 supply and demand leading to
tissue hypoxia. Severe alteration in the cardiovascular system may LV volume (mL)
lead to impairment in systemic blood pressure, stroke volume, and
end-​organ function. Derangements in cardiovascular system func- Figure 12.1  Relationship between pressure and volume in the LV during
a cardiac cycle. The dashed lines correspond to the end-​diastolic pressure–​
tion can have a cardiogenic cause leading to AHF or be secondary volume relationship. The red line corresponds to a normal heart, and the
to hypovolaemia or sepsis, with anaphylactic and neurogenic aeti- blue line to a heart suffering from diastolic dysfunction. As shown by the
ologies occurring less frequently. The initial evaluation should be graph, the pressure remaining in the LV for the same end-​diastolic volume is
focused on the assessment of the four most frequent causes (brady- increased in the case of altered compliance.
cardia, hypovolaemia, myocardial dysfunction, and/​or vascular
dysfunction) in order to ascertain which is primarily involved.
10  mmHg in control patients) [2]‌. Systolic and diastolic func-
If both heart rate and volaemia are adequate, haemodynamic
tions are best described using the LV pressure/​volume relation-
instability may be related to myocardial and/​or vascular dysfunc-
ship, represented graphically as pressure/​volume (P/​V) loops (see
tion. Note that prolonged myocardial dysfunction may lead to as-
E Figure 12.1).
sociated vascular dysfunction.
Diastole begins upon closure of the aortic valve and lasts until
This chapter describes the pathophysiology and assessment
closure of the mitral valve and can be divided into two phases.
of the four most frequent mechanisms and clinical scenarios of
The first corresponds to LV pressure decline at constant volume,
AHF, including:
called isovolumic relaxation, which lasts from closure of the
◆ AHF with pulmonary oedema (related to diastolic dysfunction). aortic valve to opening of the mitral valve. The second, called
◆ AHF with low stroke volume, often related to decompensated auxotonic relaxation, corresponds to LV chamber filling and lasts
chronic heart failure (related to LV systolic dysfunction). until closure of the mitral valve. LV filling mainly depends on
◆ Cardiogenic shock (CS). the pressure gradient between the left atrium (LA) and the LV,
◆ AHF with predominant RV. which is mainly influenced by passive chamber properties (com-
pliance), active relaxation, and at end-​diastole by atrial contrac-
Vascular dysfunction, pulmonary hypertension (PH), pericar-
tion. Thus, impairment in LV compliance (which decreases the
dial diseases, and the role of the pulmonary artery catheter (PAC)
LA–​LV pressure gradient) or loss of atrial contraction directly re-
are also briefly discussed.
duces diastolic filling. Structural modifications (e.g. myocardial
hypertrophy, fibrosis) mainly affect the passive phase of diastole
and are more likely to develop chronically, whereas functional
Left ventricular diastolic dysfunction factors (e.g. ischaemia, sepsis) adversely affect active relaxation
LV diastolic dysfunction refers to abnormalities of diastolic disten- during early diastole. Consequently, for a given LV end-​diastolic
sibility, filling, or relaxation, regardless of whether LVEF is normal volume, LV end-​diastolic pressure is increased and may result in
or abnormal and whether or not the patient is symptomatic [1]‌. pulmonary congestion (see E Figure 12.1).
Kawaguchi et  al. [3]‌demonstrated that in heart failure with
Pathophysiology preserved LVEF, the diastolic portion of the P/​V loop, although
apparently normal at rest, became altered on exertion.
LV diastolic dysfunction can be defined as inability of the LV
Zile et  al. conducted a multicentre prospective study using
chamber to fill at low atrial pressures. This can result either from
cardiac catheterization and echocardiography to assess LV dia-
impairment in LV compliance (passive mechanism) or from al-
stolic properties in 47 patients suffering from heart failure with
teration in LV relaxation (active relaxation). Of these two com-
diastolic dysfunction and ten normal controls [4]‌. The authors
ponents, ‘relaxation’ is usually the first to be altered in cases of
demonstrated that an insight into the respective roles of active re-
LV diastolic dysfunction and can occur abruptly, especially in the
laxation and compliance could be gained using a detailed analysis
context of anaesthesia or critical care.
of the LV diastolic pressure curve. The following measurements
Cardiac catheterization are of particular interest:
Diastolic heart failure is characterized by an elevated LV end-​ ◆ τ, the time constant of isovolumic relaxation.
diastolic pressure (16–​26  mmHg) in 92% of patients (versus ◆ Pmin, the minimal LV pressure (P) after opening of the mitral valve.
 L eft ven tri cu l a r systol i c dysf un c t i on 117

◆ Ppre-​A, the LV pressure just before atrial contraction. Table 12.1  Differences between systolic and diastolic dysfunction
◆ LV end-​diastolic pressure, just after atrial contraction. Systolic dysfunction Diastolic dysfunction
These authors showed that in diastolic heart failure patients, Dyspnoea Chronic Mainly transient
in contrast to normal subjects, isovolumic relaxation was incom-
Heart rate Increased Increased
plete at the time of Pmin. Thus, τ was prolonged and Pmin increased,
resulting in a positive correlation between τ and Pmin. Incomplete MR Present Rare
relaxation accounted for 7 ± 1 mmHg of the measured increase in S3/​S4 gallop S3 > S4 Mainly S4
Pmin. Among these patients, LV compliance was also significantly Rales Present Present
altered, as supported by an increase in LV end-​diastolic pressure, Peripheral oedema Present Rare
despite a reduced LV end-​diastolic volume.
Cardiomegaly Constant Variable
Myocyte energy imbalance Abnormal ECG Constant Variable
Relaxation can be defined as ‘the time period during which the LVEF Reduced >40%
myocardium loses its ability to generate force and shortens and LV dilatation Nearly constant Absent
returns to an unstressed length and force’ [5]‌. It corresponds to BNP/​NT-​proBNP Markedly increased May be only mildly
the dissociation of actin–​myosin cross-​bridges that begins during increased
the early phase of LV ejection, before aortic valve closure [6].
BNP, B-​type natriuretic peptide; LVEF, left ventricular ejection fraction; MR, mitral
Thus, diastolic dysfunction involves phenomena that occur not regurgitation; NT-​proBNP, N-​terminal natriuretic peptide.
only during diastole, but also earlier in the cardiac cycle, at the
time of calcium (Ca2+) uptake by the sarcoplasmic reticulum [7].
Since relaxation is an energy-​ consuming process, it is ad- on LV end-​systolic volume than on afterload, namely LV systolic
versely affected by myocardial ischaemia. Ischaemia precludes pressure [16]. Indeed, recoiling forces are generated when the LV
optimal Ca2+ exchanges between the cytosol and the sarco- contracts below its equilibrium volume (usually slightly higher
plasmic reticulum and is rapidly associated with impairment in than LV end-​systolic volume), and therefore recoiling forces act
LV relaxation [8]‌. during early diastole. Thus, since a healthy heart is able to respond
to increased afterload without any change in its LV end-​systolic
Contraction–​relaxation coupling volume, relaxation remains unaffected. On the contrary, in failing
As a consequence of the close relation between relaxation and dilated ventricles, LV end-​systolic volume might exceed the equi-
contraction, LV relaxation is greatly affected by the lack of homo- librium volume, which deprives the LV of recoiling forces and de-
geneity in LV contraction. Both LV segmental coordination and creases the rate of isovolumic relaxation.
atrioventricular (AV) synchronization are essential to guaran-
teeing efficient relaxation [9,  10]. The loss of atrial contraction How to assess left ventricular diastolic
associated with AF not only alters LV filling, but also results in a function in clinical practice
slowing of myocardial relaxation.
E Table 12.1 shows the major differences between systolic and
Several other factors known to alter contractile function,
diastolic dysfunction, in terms of symptoms, physical examin-
including changes in afterload and use of inotropes, markedly af-
ation, ECG abnormalities, and radiographic findings. Diagnostic
fect relaxation. On the other hand, the effect of preload variations
criteria for heart failure with preserved (HFpEF) or mid-​range
on relaxation is still a matter of debate.
(HFmrEF) ejection fraction are also proposed in E Box 12.1.
In a failing heart, an increase in afterload induces a delay in
Echocardiography plays a major role in the diagnosis of dia-
the onset of relaxation and an increase in the time constant of
stolic dysfunction. Specific findings are detailed elsewhere. NPs,
isovolumic relaxation [11].
either BNP or NT-​proBNP, have shown high sensitivity for the
Afterload reserve diagnosis of AHF. Normal values of NPs in patients presenting
with suspected AHF make the diagnosis unlikely [17]. It is im-
The afterload reserve is the ability of the normal LV to respond
portant to keep in mind that NPs may be unexpectedly low in
to afterload elevation without changes in LV end-​systolic volume
some patients with preserved LV systolic function presenting
and LV pressure decline [12]. Ventricles with altered contractile
with acute hypertensive (‘flash’) pulmonary oedema [18].
function consistently show a decreased afterload reserve [13–​15].
In such ventricles, even a small afterload elevation will markedly
deteriorate LV relaxation parameters and increase LV systolic and
diastolic volumes. Left ventricular systolic dysfunction
An alternative concept: end-​systolic volume Pathophysiology
dependency LV systolic dysfunction refers to impaired ventricular contract-
Chemla et al. proposed an alternative approach based on the sug- ility (inotropy). In HF with reduced left ventricular ejection frac-
gestion that, at constant heart rate, relaxation might depend more tion (HFrEF), loss of cardiac inotropy results in a decrease in
118 CHAPTER 12   Pathoph ysiol o gy and clinica l as ses sm en t of the ca rdi ovas cu l a r syst e m

200
Box 12.1  Diagnostic criteria of diastolic dysfunction in patients ESPVR
with HFpEF and HFmrEF
Increased
150 afterload
Criteria

LV pressure
◆ Presence of symptoms and signs of heart failure
100 c
AND
Normal or mid-​range LVEF (echocardiography)
◆ Stroke
volume Increased
AND 50
d b preload
Elevated BNP or NT-​proBNP
◆

AND 0
a
Objective evidence of underlying cardiac functional and
◆ 0 50 100
ESV EDV
structural alterations (echocardiography or CMR imaging) LV volume
AND
Figure 12.2  Left ventricular pressure–​volume relationships. A cardiac cycle
In case of uncertainty, a stress test or invasive measurement
◆
is illustrated by the loop labelled ‘a’, ‘b’, ‘c’, and ‘d’. ESPVR, end-​systolic pressure–​
of elevated LV filling pressure may be needed to confirm the volume relationship; LV, left ventricular.
diagnosis (echocardiography or right heart catheterization in Reproduced from Walley KR. Left ventricular function: time-​varying elastance and left
selected cases) ventricular aortic coupling. Critical Care (2016)20:270. Creative Commons Attribution
4.0 International License (http://​creativecommons.org/​licenses/​by/​4.0/​.
BNP, B-​type natriuretic peptide; CMR, cardiac magnetic resonance imaging;
HFpEF, heart failure with preserved left ventricular ejection fraction;
HFmrEF, heart failure with mid-​range left ventricular ejection fraction;
LVEF, left ventricular ejection fraction; NT-​proBNP, N-​terminal natriuretic straight line—​ the end-​ systolic pressure–​ volume relationship
peptide. (ESPVR) (see E Figure 12.2). The slope of this line is the time-​
varying elastance, defined as the change in pressure over time or
ΔP/​ΔV (note that compliance is the inverse of elastance, expressed
stroke volume and a compensatory rise in preload [often meas- as ΔV/​ΔP). Ventricular systole is best defined by time-​varying
ured as ventricular end-​diastolic pressure or pulmonary capillary elastance in [20–​21]. Consequently, if preload is increased (or de-
wedge pressure (PCWP)]. The rise in preload is considered com- creased), so that end-​diastolic volume is increased (or decreased),
pensatory, because it activates the Frank–​Starling mechanism to the subsequent stroke volume is increased (or decreased) to the
help maintain the stroke volume despite the loss of inotropy. If the same extent, so that the end-​ systolic pressure–​volume point
preload did not rise, the decline in stroke volume would be even still lies on the same ESPVR. Importantly, for energetically effi-
greater for a given loss of inotropy. Depending on the precipi- cient systolic ejection, ventricular elastance is matched to aortic
tating cause of heart failure, there will be LV hypertrophy, dilata- elastance. If ventricular elastance is less than arterial elastance, as
tion, or a combination of the two. (See also E Chapter 45.) in HFrEF, then energy is wasted as potential mechanical work.
Loss of intrinsic inotropy is associated with an increase in end-​ It is important to realize that AHF may or may not be followed
systolic volume. There is also an increase in end-​diastolic volume by ventricular remodelling. Indeed, in the case of AHF resulting
(compensatory increase in preload), but this increase is not as from a large anterior MI occurring in a previously healthy heart,
great as the increase in end-​systolic volume. Therefore, the net a large portion of the anterior wall becomes functionally inactive
effect is a decrease in stroke volume. Because stroke volume de- within seconds and the rest of the ventricular myocardium is sud-
creases and end-​diastolic volume increases, there is a substantial denly exposed to an increase in its haemodynamic load; it has to
reduction in ejection fraction (EF). perform the work of the whole ventricle, including the ischaemic/​
The reason for preload rising as inotropy declines is related to infarcted area, under very unfavourable biological conditions
the increased end-​systolic volume. Indeed, in the failing heart, called ‘biomechanical stress’. In this case, AHF simply results
at the beginning of diastole, there is already a ‘high’ end-​systolic from acute dysfunction of the cardiac pump as a whole, with an
volume. The venous return is added to this, leading to an increase associated hyperfunction of the remote area that tries to compen-
in end-​diastolic volume and pressure. Thus, an important and sate for the loss of function of the ischaemic/​infarcted myocardial
deleterious consequence of systolic dysfunction is the rise in end-​ area. Another example of this situation of AHF with no previous
diastolic pressure. This can lead to pulmonary congestion and cardiac remodelling is acute mitral regurgitation (MR) due to
oedema. chordae rupture.
Another important determinant of LV systole is the interplay In the case of AHF occurring as a decompensation of a chronic-
between the LV and the arterial (e.g. aortic) system, namely LV–​ ally failing heart, cardiac myocytes have been remodelled through
aortic coupling, which is a key determinant of global cardiovas- years of biomechanical stress resulting from the originating dis-
cular performance [19, 20]. Sagawa et al. showed that during the ease. In such a situation, the heart is obviously placed in an un-
ejection phase in a given P/​V loop, the end-​systolic volume points favourable situation when, being previously weakened by a long
for different afterload conditions all fall along an approximately process of detrimental remodelling, it is unable to compensate for
 Ca rdi o g e n i c   sh o c k 119

the, often mild, insult at the origin of the acute decompensation of medical conditions [24]. CS mortality is extremely high and
(e.g. an episode of paroxysmal AF). remains the most common cause of death in hospitalized patients
with AMI [25, 26].
Clinical assessment In this setting, CS usually results from an extensive acute in-
The aetiology of LV dysfunction is diverse, but the leading cause farction, although a smaller infarction in a patient with previously
is currently CAD. A previous history of MI makes the diagnosis compromised LV function may also precipitate shock. CS can also
of AHF more likely. Other causes of heart failure include long-​ be caused by mechanical complications of infarction such as acute
standing hypertension and alcohol excess. A smaller proportion MR, rupture of the interventricular septum or rupture of the free
of patients have VHD. In these patients, symptoms and signs wall, or by a large RV infarction.
develop gradually, over days or weeks, and pulmonary and sys-
temic congestion (jugular venous distension, pulmonary rales, Pathophysiology
and peripheral oedema) is usually present. They usually have a CS pathophysiology is complex and has evolved over the past
reduced LVEF. Despite high LV filling pressures, they may present 20 years from a classic model based on the severe depression of
with variable degrees of pulmonary congestion (clinical and/​or myocardial contractility to a model that takes into account the
radiographic) and some may only have minimal pulmonary derangements of the entire circulatory system [25].
congestion. In general, there is a profound depression of myocardial con-
In Western Europe, the five most frequent causes of AHF tractility, resulting in a potentially deleterious spiral of reduced
are ischaemia, arrhythmia, infection, hypertension, and non-​ cardiac output, low blood pressure, and further coronary is-
compliance with medication, and precipitating factors are inde- chaemia, followed by additional reductions in contractility.
pendently associated with 90-​day mortality [22]. Indeed, myocardial perfusion, which depends on the pressure
gradient between the coronary arteries and the LV and on the
Investigations duration of diastole, is compromised by hypotension and tachy-
An ECG can provide very useful information. LV systolic dys- cardia, exacerbating ischaemia. Increased ventricular diastolic
function was found to be unlikely in a primary care population if pressures caused by pump failure further reduce CPP, and the
there was no major abnormality on the ECG (sensitivity 9%, NPV additional wall stress elevates myocardial O2 requirements, fur-
98%) [23]. Thus, in patients with breathlessness and a normal ther worsening ischaemia. This classic paradigm also includes
ECG, the clinical context needs to be carefully assessed and alter- compensatory systemic vasoconstriction, which has an additional
native causes might be considered first, although patients must be adverse impact, resulting in increased afterload. This relatively
investigated further (e.g. with echocardiography) if heart failure simple pathological concept has been enriched by evidence dem-
is still thought to be the likely diagnosis. onstrating that CS can cause severe derangements in the entire
A chest radiograph may provide useful information. circulatory system, with microcirculation involvement playing a
Cardiomegaly may be present—​ cardiothoracic ratio (CTR) major role. Additionally, SIRS develops in many patients with CS
>0.50. It may also show pulmonary congestion or another ex- without evidence of sepsis and is associated with decreased SVR,
planation for breathlessness. All patients in whom the diagnosis impaired inotropy, and end-​organ damage [27, 28]. Endothelial
of heart failure cannot be excluded require an assessment of and inducible nitric oxide (NO) synthase may play a major role in
LV function. Patients in whom the diagnosis of heart failure is the production of high NO levels, along with peroxynitrite, which
secure may also be considered for an assessment of LV function has a negative inotropic effect and is cardiotoxic. Other inflam-
as an indicator of prognosis. Echocardiography is the most fre- matory mediators, such as interleukins (ILs) and tumour necrosis
quently used investigation but may not be possible for technical factor (TNF), can also contribute to systemic vasodilatation and
reasons, and alternative investigations may be necessary. AF have been associated with mortality in CS.
also makes the assessment of LV function less reliable. Some pa-
tients may have had an alternative method to estimate LV func- Clinical assessment
tion in secondary care, e.g. gated heart scan, LV angiography The initial diagnosis of CS is based on the recognition of symptoms
during coronary angiography. and signs of congestion and hypoperfusion (see E Table  12.2).
Patients with shock are usually cyanotic and can have cool skin
and mottled extremities. Cerebral hypoperfusion may cloud the
sensorium. Pulses are rapid and faint and may be irregular in
Cardiogenic shock the presence of arrhythmias. Jugular venous distension and pul-
(See also E Chapter 47.) monary rales are usually present, although their absence does
CS occurs when the heart is unable to deliver enough blood to not exclude the diagnosis. The precordial heave, resulting from
maintain adequate tissue perfusion, and therefore oxygenation. LV dyskinesis, may be palpable. Heart sounds may be distant,
It is one of the most challenging emergencies for the intensivist. and third or fourth heart sounds are usually present. A  sys-
The leading cause of CS is AMI, responsible for up to 80% of tolic murmur of MR or VSD may be heard, but these complica-
cases, with the remaining 20% of CS cases due to a broad range tions may occur without an audible murmur. Documentation of
120 CHAPTER 12   Pathoph ysiol o gy and clinica l as ses sm en t of the ca rdi ovas cu l a r syst e m

Table 12.2  Clinical diagnosis of cardiogenic shock

Box 12.2  Causes of right ventricular failure
Persistent hypotension SBP <90 mmHg for ≥30 minutes Acute left ventricular failure
◆
AND OR catecholamines to maintain SBP
>90 mmHg Right ventricular ischaemia/​infarction
◆

Symptoms and signs of elevated Orthopnoea, paroxysmal nocturnal Acute pulmonary embolism
◆

or normal filling pressures dyspnoea, pulmonary rales (bilateral), S3 Exacerbation of chronic lung disease and/​or hypoxia
◆
AND Acute lung injury or respiratory distress syndrome
◆

Symptoms and signs of Cold sweated extremities, oliguria, Sepsis

◆
abnormal organ perfusion mental confusion, dizziness, narrow pulse Chronic pulmonary hypertension (groups 1–​5)
◆
AND pressure, urine output <0.5 mL/​kg/​hour
Pericardial disease (tamponade)
◆
Elevated blood lactate Lactate >2 mmol/​L
Arrhythmias (supraventricular or ventricular tachycardia)
◆
SBP, systolic blood pressure; S3, third heart sound. Congenital heart disease (e.g. atrial or ventricular septal de-
◆

fect, Ebstein’s anomaly)

myocardial dysfunction and exclusion of alternative causes of Valvulopathies (e.g. tricuspid valve regurgitation, pulmonary
◆

hypotension allow for the diagnosis of CS. valve stenosis)

Cardiomyopathies (e.g. arrhythmogenic right ventricular dys-
◆

Investigations plasia, familial, idiopathic)

An ECG should be performed immediately. Other initial diag- Myocarditis or other inflammatory diseases
◆

nostic tests should include a chest radiograph and measurement Cardiac surgery (e.g. cardiac transplant or left ventricular as-
◆

of ABGs, including blood lactate [29], electrolytes, full blood sist device implantation)
count, and cardiac biomarkers (see E Chapter 17). Haematological disorders (e.g. acute chest syndrome in
◆

Echocardiography is an excellent tool for confirming the diag- sickle-​cell disease)

nosis of CS and for sorting through the differential diagnosis and
should be performed as early as possible (see E Chapters 18.1
and 18.2). underfilled LV [31]. These changes in RV mechanics lead to a de-
Invasive haemodynamic monitoring, usually with a PAC, pressed right-​sided output, a decreased LV preload, and subse-
can confirm the diagnosis of CS and exclude volume depletion quently a reduced overall cardiac output [32].
and is also used to guide management and optimize therapy in
refractory cases. Effect of an increase in right ventricular afterload
As described previously, increased PAP alters both coronary
perfusion and ventricular function of the RV. In a patient with
Right ventricular failure pulmonary hypertension, the RV dilates to maintain the stroke
volume, though the EF is reduced and peristaltic contraction is
RV failure is a complex syndrome that results from many causes lost, causing an accelerated worsening in RV failure.
(see E Box 12.2). Its prevalence is difficult to estimate, but its The increased afterload also prolongs the isovolumic contrac-
predominant causes (i.e. LV dysfunction, PE, and AMI) are tion phase and ejection time, and therefore the increased myo-
common. Pathophysiologic changes in right heart failure vary ac- cardial O2 consumption. In addition, RCA perfusion only occurs
cording to the underlying cause. in diastole.
Accordingly, in a patient with a further increase in PAP and a
Pathophysiology decrease in RCA perfusion, it is important to rapidly reduce the
RV mechanics and function are altered in the setting of either RV afterload to improve the O2 supply/​demand balance in the RV
pressure or volume overload. Various mechanisms are involved, and maintain RV function.
including decreased RV contractility, increased RV pressure, and Of note, in patients with acute respiratory distress syndrome
increased RV volume (see E Figure 12.3) [30]. (ARDS), circulating vasoconstrictors, increased sympathetic
tone, microvascular obstruction, and hypoxic vasoconstriction
Right ventricular systolic impairment all increase RV afterload. In addition, mechanical ventilation also
This condition occurs most often in cases of RV ischaemia and increases RV afterload.
infarction. Usually, RV infarction is due to proximal occlusion
of the right coronary artery (RCA). In this condition, the RV is Effect of an increase in right ventricular volume
unable to contract against a normal pulmonary artery pressure Volume overload is common during RV failure, and volume
(PAP). Accordingly, RV ischaemia rapidly leads to RV dilatation, loading may further dilate the RV, increase tricuspid regurgi-
with a concomitant rise in RV diastolic pressure. Such elevation tation (TR), and consequently worsen hepatic and renal con-
causes a shift of the interventricular septum towards an already gestion and RV failure. Accordingly, volume management is
 Ri g ht ven tri cu l a r   fa i lure 121

RV pressure
↑ RV wall tension
overload

Tricuspid regurgitation
RV dilatation
Pulmonary regurgitation

↑ Oxygen demand
↓ Contractility Arrhythmia,
RV volume overload
RV dysfunction RV ischaemia,
injury, inflammation
↓ Coronary perfusion
Altered systolic or
↑ Right atrial pressure
↓ RV output diastolic ventricular
↑ Central venous pressure
interdependence

↓ LV preload
↓ Cardiac output
Hypotension
Shock
Systemic Organ dysfunction
congestion or failure

Figure 12.3  Pathophysiology of acute right ventricular failure. LV, left ventricular; RV, right ventricular.
Reproduced from Veli-​Pekka Harjola, Alexandre Mebazaa, Jelena Celutkien, Dominique Bettex, Hector Bueno, Ovidiu Chioncel et al. Contemporary management of acute right
ventricular failure: a statement from the Heart Failure Association and theWorking Group on Pulmonary Circulation and Right Ventricular Function of the European Society of
Cardiology. Eur J Heart Fail (2016) 18, 226–​241 with permission from John Wiley and Sons.

a difficult, but important, task in the treatment of RV failure. events occurs, self-​worsening RV dysfunction. This is unique to
Physiologically, volume loading may be useful in increasing the RV and is rarely seen in isolated LV failure. A sudden increase,
preload, but in the large majority of patients with RV failure, although modest, in RV afterload (inhaled NO withdrawal, for
this compensatory mechanism is potentially limited beyond a instance) on an ischaemic RV immediately dilates the ventricle,
mean PAP of 30 mmHg [33], and therefore, caution is warranted induces TR, and decreases cardiac output.
when considering volume loading in any patient with suspected
Consequences of systemic venous congestion
RV failure.
The liver and kidneys are tied in inextensible capsules. In the case
Ventricular interdependence of venous congestion, intraorgan pressure of the liver and kidneys
There is a high degree of ventricular interdependence due to rapidly increases, leading to lower organ perfusion pressure and
the role of the interventricular septum in the contraction of higher sensitivity to ischaemia when cardiac output is reduced
both ventricles, which is pronounced because of the presence (see E Chapter 45).
of the pericardium [34]. Indeed, increases in the end-​diastolic Congestion in liver sinusoids collapses the bile ducts, leading to
volume of the LV are transmitted to the RV by movement of the cholestasis [35, 36]. Centrolobular necrosis occurs when a mech-
interventricular septum towards the right cavity, increasing the anism of reduced O2 supply is associated with passive venous con-
end-​diastolic pressure of the RV. Similarly, when the RV end-​ gestion. This causes hypoxic hepatitis (formerly known as ‘shock
diastolic volume is increased, the interventricular septum shifts liver’), characterized by intense hepatic cytolysis [37]. In kidneys,
towards the left cavity during diastole due to restrictions imposed venous congestion in the Bowman’s capsule increases interstitial
by the pericardium on the RV as the cavity volume increases. This pressure which compresses the tubules, impairing the GFR (38–​40).
leftward shift impairs the function of the LV due to the reduction This mechanism is thought to be the most predominant factor,
in LV volume, decreasing both LV filling and compliance, mani- leading to renal failure, rather than a low cardiac output, when RV
fested as increased LV muscle stiffness. failure is present.

The vicious cycle of auto-​aggravation Assessment of right ventricular function

Compared to the LV, RV failure progresses quickly from com- The sensitivity of conventional chest radiography techniques in
pensated to end-​stage heart failure because of a vicious cycle of identifying changes in RV structure is limited by the unusual
auto-​aggravation. Auto-​aggravation implies that after an initial shape of the RV and the unpredictable manner in which it dilates
injury (change in loading or pressure condition), a cascade of (see E Chapter 17).
122 CHAPTER 12   Pathoph ysiol o gy and clinica l as ses sm en t of the ca rdi ovas cu l a r syst e m

Inferential diagnosis may be possible by the identification of

other radiographic changes such as the state of the pulmonary Pulmonary hypertension
circulation and the position of the heart in the chest. Changes in
PH is defined as a resting mean pulmonary arterial pressure
the LV may be apparent on a chest radiograph, resulting from the
(mPAP) of >20  mmHg measured by right heart catheterization
decreased LV preload as a consequence of RV failure.
(RHC) [41]. PH is currently classified into five groups, based on
Liver congestion causes cholestasis with elevated alkaline phos-
the underlying aetiology, with the term pulmonary arterial hyper-
phatase and direct bilirubin levels [35]. When associated with
tension (PAH) reserved for group 1 PH.
compromised O2 delivery to the liver, cytolytic hepatitis can
PH secondary to left heart disease (PH-​LHD) can be seen in
occur, with increases in transaminases (up to 100-​fold the upper
HFrEF, HFmrEF, and HFpEF; it is the most common form of PH
limit of normal) and total bilirubin [37]. This hypoxic hepatitis
and is classified as group 2 PH. Of note, PH-​LHD can be fur-
can lead to acute liver failure, with low prothrombin time (PT)
ther sub-​classified into isolated post-​capillary PH and combined
and elevated lactate levels, sometimes misdiagnosed as viral or
post-​and precapillary PH in which pulmonary vascular disease
toxic hepatitis (whereas this level of cytolysis is unlikely in non-​
is superimposed with passive elevation of mPAP caused by eleva-
hypoxic causes).
tion of LV filling pressures.
Echocardiography is an alternative, more accessible tech-
nique for the diagnosis of RV failure and for intermittent re- Pathophysiology
petitive follow-​up of the dynamics of therapeutic responses
(see E Chapters 18.1 and 18.2). Its advantage is that a qualitative In the majority of patients with PH-​LHD, the elevation in mPAP
conclusion can be reached instantaneously. When RV failure is can be considered a manifestation of HF, with a normal pulmonary
secondary to an increase in afterload, the isovolaemic contrac- vascular response, though early remodelling of pulmonary ar-
tion phase and ejection time are prolonged and increases in PAP terioles and veins can still be present [42, 43]. Increased left heart
and flow are accelerated. Echocardiography also provides infor- filling pressures can also reduce pulmonary arterial compliance,
mation about the mechanisms of RV failure such as pericardial promoting ‘stiff ’ pulmonary vasculature. This can lead to enhanced
effusion, with or without tamponade, tricuspid insufficiency, pulmonary wave reflections during systole and an elevated pulsatile
PEs, or RV ischaemia and the resulting acute cor pulmonale. load on the RV [42–​44]. Functional MR and loss of LA compliance
Additionally, echocardiography enables the simultaneous evalu- are additional haemodynamic insults that can promote LA hyper-
ation of LV function, a possible component of the RV failure. tension that transmits back to the pulmonary vasculature.
Because of the geometry and location of the RV, the accuracy The subset of patients with PH-​LHD with combined post-​and
and necessity of determining the exact RV dimensions remain precapillary PH develop pulmonary vascular disease secondary to
questionable and an experienced intensive care physician fa- vasoconstriction and pathologic remodelling of the pulmonary vas-
miliar with performing and evaluating echocardiography is es- culature, generating an elevation in mPAP that is ‘disproportionate’
sential. Although serial echocardiographic evaluations can be to that generated by the transmission of increased left-​sided filling
performed, in many cases, continuous information provided by pressures alone. Chronic contraction of the right heart against this
the PAC may be valuable. increased resistive afterload can ultimately lead to maladaptive
hypertrophy, dilatation, and subsequent contractile failure [45].

Clinical assessment
Vascular dysfunction Patients with PH-​ LHD typically present with symptoms and
An artery is not a cylindrical tube of constant diameter. In reality, signs of both left-​and right-​sided heart failure. Differential
an artery is a viscoelastic tube consisting of three layers (intima, diagnosis with other groups of PH and distinguishing between
media, and adventitia), with its diameter varying with a pul- isolated post-​
capillary and combined post-​and precapillary
sating system. In addition, the arterial system will propagate pres- PH-​LHD can be challenging. Initial investigations should be fo-
sure, flow, and diameter waves, generated by ejection from the cused on establishing the diagnosis of PH-​LHD and its mech-
ventricle, at a given velocity, which is largely determined by the anisms. Echocardiography is nowadays the mainstay for the
elastic properties of the arterial wall. evaluation of patients with suspected PH-​LHD. RHC may be
There are two kinds of vascular dysfunction. The first consists necessary in order to confirm the diagnosis and evaluate for the
of an increase in arterial stiffness due to atherosclerosis, leading presence of precapillary PH.
to a chronic increase in LV afterload and eventually to an im-
pairment of organ perfusion. The second consists of a decrease
in arterial resistance, leading to vasoplegia and low blood pres-
sure. The latter is an acute phenomenon whose main cause is the
Pericardial diseases
systemic release of vasoactive substance. Severe sepsis and septic The pericardium is a thin, double-​layered fibroblastic sac that
shock are the usual causes of vasoplegia, which can also be asso- surrounds the heart. It normally contains only a small amount
ciated with AHF. of pericardial fluid. By virtue of their anatomic and functional
 U se of pu l mona ry a rtery catheter i n  acu te hea rt   fa i lure 123

interactions, medical conditions affecting the pericardium almost selected, with CS patients being clearly underrepresented [49–​
invariably will affect the heart and the cardiovascular system. Thus, 51]. However, many physicians still consider the PAC as a useful
whenever larger amounts of fluid accumulate (pericardial effusion) monitoring device when indications are rationalized, team
or changes in its elastic properties (pericardial constriction) occur, trained, and measurements, interpretations, and therapeutic ac-
one of three major pericardial syndromes will develop:  pericar- tions correct [52]. Indeed, an increase in the use of the PAC in
dial tamponade, constrictive pericarditis, or effusive–​constrictive heart failure patients has been recently reported [53]. The PAC
pericarditis. provides the physician with haemodynamic parameters (cardiac
output; right atrial, pulmonary, and pulmonary artery occlusion
Pathophysiology pressures; and possibly RV volumes) and also with tissue perfu-
Pericardial tamponade is characterized by a sudden or progressive sion variables (venous O2 saturation, O2 extraction, and venous
accumulation of fluid in the pericardial cavity that results in an in- CO2 pressure). These PAC-​derived parameters are briefly sum-
crease in pericardial pressure and compression of cardiac vessels marized in E Table 12.3.
and chambers. The resulting compromise in venous return also
leads to a reduction in end-​diastolic volumes. Once the pericardial
Recommendations/​indications for heart failure
pressure overcomes the diastolic pressures, expansion of the RV According to the ESC guidelines [17] published in 2016, the
during diastole is limited by the rigid pericardium. This phenom- PAC may be considered only in a subset of the most complex pa-
enon generates a shift of the interventricular septum towards the tients ‘who, despite pharmacological treatment present refractory
already underfilled LV, further reducing LV compliance [46]. symptoms (particularly with hypotension and hypoperfusion)’
In constrictive pericarditis, a thickened and inelastic peri- (Class IIb, LoE C).
cardium prevents transmission of the physiologic inspiratory Current American College of Cardiology Foundation (ACCF)/​
decrease in intrathoracic pressure to the heart. The rigid peri- AHA heart failure guidelines recommend limiting the use of the
cardium also represents an obstacle to venous return and diastolic PAC to patients with ‘respiratory distress or impaired systemic
filling. As the severity of constriction increases, a progressive re- perfusion when clinical assessment is inadequate’ (Class  I, LoE
duction in ventricular and stroke volumes is seen [47]. C) and discourage its use in routine management of heart failure
Effusive–​constrictive pericarditis is characterized by an under- (Class III, LoE B) [54].
lying constrictive physiology with a coexisting pericardial ef- Experts have stated that direct measurement of haemodynamic
fusion, often with cardiac tamponade. This usually results in a parameters can be helpful in patients for whom physical examin-
mixed haemodynamic picture with features of both constrictive ation is limited or discordant with symptoms. It may be particu-
pericarditis and cardiac tamponade. larly useful for determining the contribution of heart failure to a
complex clinical picture such as sepsis, acute renal failure, or ACS
Clinical assessment in the setting of chronic heart failure. Another common setting
Differential diagnosis of pericardial syndromes can be challen- where PAC insertion may be helpful is the evaluation of dyspnoea
ging, especially when the patient presents with features of both and elevated right heart pressures in patients with concomitant
effusion and constriction. pulmonary and cardiac disease.
Clinical examination is notable for symptoms and signs of ele-
vated right heart pressures (e.g. increased JVP). Pulsus paradoxus
The particular case of right ventricular failure
(a drop of >10 mmHg in arterial pressure during inspiration) and Recent data show that, in patients with PH, evaluations of PAP
Kussmaul’s sign (JVP increase during inspiration) can be present and cardiac output using echocardiography are inaccurate [55–​
but are also unspecific findings. In constrictive pericarditis, a 57]. In right heart failure, catheterization of the pulmonary artery
pericardial knock may be audible. is more invasive than echocardiography but is useful to evaluate
Definite diagnosis is largely based on echocardiographic find- RV function and to confirm the presence of RV failure in patients
ings. Other investigations such as MRI and RHC may be neces- in ICU [58]. The PAC measures both mixed venous O2 saturation
sary in selected cases. and intravascular pressures or pressure changes in the RV, as well
as PAP and PCWP. Despite difficulties in the interpretation of
mean intravascular pressure values, the tracings showing changes
in pressure and flow enable the assessment of the impact of treat-
Use of pulmonary artery catheter ment on RV function. This cautious interpretation accounts for
in acute heart failure the almost constant reflux due to tricuspid insufficiency, which
can be observed by central venous and right atrial pressure
The use of the PAC has been challenged over the last decade.
changes. Such regurgitation could be used as a hallmark for RV
Many RCTs failed to demonstrate an outcome benefit in pa-
failure and as a marker for treatment efficacy.
tients having a therapeutic strategy based on PAC data [48].
If a CVC or PAC is in place, haemodynamic parameters that can
Nonetheless, several factors may explain these findings,
aid in the diagnosis of RV failure include an increase in right atrial
including the fact that in these trials, patients were highly
pressure and a decrease in arterial blood pressure, cardiac output,
124 CHAPTER 12   Pathoph ysiol o gy and clinica l as ses sm en t of the ca rdi ovas cu l a r syst e m

Table 12.3  Pulmonary artery catheter-​derived measurements

Method Normal values Clinical value

RAP Direct 0–​7 mmHg Measure of RV preload; evaluation of AHF,
shock, and PH
RVP Direct Systolic: 15–​25 mmHg; diastolic: 3–​12 mmHg Evaluation of AHF, shock, and PH
PAP Direct Systolic: 15–​28 mmHg; diastolic: 5–​16 mmHg; Evaluation of AHF, shock, and PH
mean: 4–​12 mmHg
PAOP Direct 10–​22 mmHg; mean: 16 mmHg Obtained after inflating the distal balloon
of the PAC; it reflects LAP and LVEDP;
evaluation of AHF and shock
CO/​CI Direct: thermodilution (intermittent or 2.8–​4.2 L/​minute/​m2 Gold standard tool for measuring cardiac
continuous) output; evaluation of AHF, shock, and PH
PAPi Indirect: PAPi: PAPS–PAPD /PVC >0.9 Marker of severe RV dysfunction
SvO2 Direct: intermittent or continuous 60–​80% Measures the balance between O2 delivery
and consumption (directly related to
O2 extraction ratio; OER = VO2/​DO2);
evaluation of shock
SVR/​SVRI Indirect: SVR = 80 × (MAP –​ CVP)/​CO 900–​1400 dyn·s/​cm5 Measure of LV afterload; evaluation of shock
5
PVR/​PVRI Indirect: PVR = 80 × (mean PAP –​PAOP)/​CO 150–​250 dyn·s/​cm Measure of RV afterload; evaluation of PH
2
SV/​SVI Indirect: SVI = CI/​heart rate 30–​65 (mL/​m /​beat) Variation in SV/​SVI can be used to assess
fluid responsiveness
CPO/​CPOI Indirect: CPO = (MAP · CO)/451 >0.6 W Prognostic value in CS
DO2 Indirect: DO2 = CI × 13.4 × haemoglobin Approximately 1000 mL/​minute Assessment of tissue perfusion; evaluation
concentration × arterial O2 saturation of shock
VO2 Indirect: VO2 = CI × 13.4 × haemoglobin Approximately 250 mL/​minute Assessment of tissue perfusion; evaluation
concentration × (arterial O2 saturation –​ of shock
venous O2 saturation)
AHF, acute heart failure; CO/​CI, cardiac output and CO index; CPO/​CPOI, cardiac power output and CPO index; CS, cardiogenic shock; DO2, oxygen delivery; LAP, left atrial pressure; LV, left
ventricular; LVEDP, left ventricular end-​diastolic pressure; MAP, mean arterial pressure; O2, oxygen; OER, oxygen extraction ratio; PAC, pulmonary artery catheter; PAOP, pulmonary artery
occlusion pressure; PAP, pulmonary arterial pressure; PH, pulmonary hypertension; PVR/​PVRI, pulmonary vascular resistance and PVR index; RAP, right atrial pressure; RV, right ventricular;
RVP, right ventricular pressure; SvO2, mixed venous oxygen saturation; SVR/​SVRI, systemic vascular resistance and SVR index; SV/​SVI, stroke volume and SV index; VO2, oxygen uptake.

and mixed venous O2 saturation (see E Figure 12.4), despite usu- dramatic increase in right atrial pressure, with no change in cardiac
ally preserved PAP and PCWP. For difficult cases, a technique output. This test should not be used in patients who are in acute RV
often cited in the literature for the diagnosis of RV failure involves failure, as there is a risk of severe aggravation of tricuspid insuffi-
the administration of 250 mL of crystalloids or colloids over 10 ciency and organ congestion after volume loading.
minutes [59]. If the patient is suffering from RV failure, all of the
above haemodynamic parameters would worsen, including a

Conclusion
• Analgesia, sedation
• Shivering
• Myorelaxation
• Pain, stress Understanding the pathophysiological principles of the multiple
• Mechanical ventilation
• Hypothermia
• Hyperthermia medical conditions that can affect the cardiovascular system is
imperative in the acute and critical care settings. Indeed, prompt
• Right-to-left shunt identification of the underlying mechanisms will lead to an ap-
• Hypoxaemia propriate therapeutic strategy.
• Fever
VO2 • High (2,3-DPG)
SvO2 = SaO2 - • Acidosis
CO . Hb . OP • Hypercapnia Personal perspective
This chapter illustrates the importance of prompt identifica-
• Myocardial ischaemia
• Hypovolaemia
tion of the pathophysiological mechanisms related to med-
• Tamponade • Bleeding ical conditions affecting the cardiovascular system and the
• Massive pulmonary embolism • Haemodilution challenge of maintaining an appropriate balance between
the need for invasive and non-​invasive investigations.
Figure 12.4  Main factors influencing mixed venous O2 saturation. OP,
oxyphoric power of haemoglobin.
 REFERENCES 125

Further reading
Aurigemma GP, Gaasch WH. Clinical practice. Diastolic heart failure. N (HFA) of the European Society of Cardiology (ESC). Eur J Heart Fail
Engl J Med 2004;351:1097–​1105. 2018;20:1081–​99.
Harjola VP, Mebazaa A, Čelutkienė J, et al. Contemporary management Sanfilippo F, Scolletta S, Morelli A, Vieillard-​Baron A. Practical approach
of acute right ventricular failure: a statement from the Heart Failure to diastolic dysfunction in light of the new guidelines and clinical
Association and the Working Group on Pulmonary Circulation and applications in the operating room and in the intensive care. Ann
Right Ventricular Function of the European Society of Cardiology. Eur Intensive Care 2018;8:100.
J Heart Fail 2016;18:226–​41. van Diepen S, Katz JN, Albert NM, et al. Contemporary Management of
Harjola VP, Parissis J, Brunner-​La Rocca HP, et  al. Comprehensive in-​ Cardiogenic Shock: A Scientific Statement From the American Heart
hospital monitoring in acute heart failure:  applications for clinical Association. Circulation 2017;136:e232–​68.
practice and future directions for research. A  statement from the Walley KR. Left ventricular function:  time-​varying elastance and left
Acute Heart Failure Committee of the Heart Failure Association ventricular aortic coupling. Crit Care 2016;20:270.

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 CHAPTER 13

The respiratory system
Antoine Vieillard-​Baron

Contents
Summary  127 Summary
Introduction  127 The respiratory system is key to the management of patients with respiratory, as
Definitions—​physiological reminders  127 well as haemodynamic, compromise and should be monitored. The ventilator is
Blood gas exchange  127 more than just a machine that delivers gas; it is a true respiratory system moni-
Alveolar ventilation and dead space  128
Main causes of acute hypoxaemia  128 toring device, allowing the measurement of airway pressures and intrinsic positive
Airway pressures and respiratory end-​expiratory pressure and the plotting of pressure/​volume curves. For effective
mechanics  128
Heart–​lung interactions  129 and reliable monitoring, it is necessary to keep in mind the physiology such as
What can and should be monitored at the alveolar gas equation, heart–​lung interactions, the equation of movement, etc.
the bedside?  129 Monitoring the respiratory system enables adaptation of not only respiratory man-
Conclusion  131 agement, but also haemodynamic management.
Personal perspective  132
Further reading  132
References  132

Introduction
A textbook on intensive and acute cardiac care should describe most of the mechanisms
responsible for haemodynamic compromise such as AHF with its many aetiologies [1]‌.
However, the respiratory system status appears key to the management of such failure,
first because many causes of heart failure lead to pulmonary congestion, and so to re-
spiratory failure; second because changes in respiratory system properties may impact
on the haemodynamics; and finally because mechanical ventilation, when required, may
have beneficial, but also deleterious, effects on cardiac function [2].
Cardiologists and intensivists have to be fully conversant with heart–​lung interactions,
with how their knowledge helps to understand changes in haemodynamics related to
changes in ventilatory settings or respiratory mechanics, and with how monitoring of the
respiratory system is usable at the bedside. (See also E Chapters 21, 22, 62, 63, and 64.)

Definitions—​physiological reminders
Blood gas exchange
Blood gas exchanges occur passively through the alveolar–​capillary membrane, ac-
cording to the gradient in gas concentration between the capillary blood and the alveoli.
This gradient is mediated, in part, by the equilibrium between O2 and CO2 in the alveoli,
depending on the alveolar gas equation (see E Figure 13.1):

PAO2 = PIO2 − 1.2 × PACO2

(where PAO2 is the alveolar pressure of O2, PACO2 the alveolar pressure of CO2, and PIO2
the inspired pressure of O2, calculated as FiO2 × (760 –​47) where FiO2 is the fraction
128 CHAPTER 13   The respiratory  syst em

PIO2 Main causes of acute hypoxaemia

Hypoxaemia may occur if there is a mismatch between ventila-
PvO2 40 mmHg PaO2 100 mmHg tion and perfusion, with V/​Q <1. This is described as a shunt ef-
PAO2 fect, also called venous admixture. It occurs in many situations,
PvCO2 45 mmHg O2
PaCO2 40 mmHg
including pulmonary oedema, of whatever cause, pneumonia, and
PE. Interestingly, in these situations, changes in cardiac output,
PA CO2 PV
as induced by treatment, may change blood gases. For instance,
Q
PaO2 was reported to be in the normal range at admission in pa-
V/Q tients with massive PE, whereas the increase in cardiac output in-
=1 duced by dobutamine was secondarily responsible for its fall [5]‌.
RV LV
Conversely, low cardiac output induces an increase in peripheral
O2 extraction, and so low O2 venous saturation, leading to a sharp
PAO2 = PIO2 – 1.2 PACO2 fall in PaO2 which may be partially corrected after improvement
in O2 transport. This is why it is not rare for intensivists to note
Figure 13.1  Schematic representation of blood gas exchange mechanisms.
an increase in O2 saturation after blood volume expansion in
Oxygenation of blood depends on the alveolar gas equation and the V/​Q
ratio, whereas decarboxylation depends on alveolar ventilation. PA, hypovolaemia.
pulmonary artery; PaCO2, CO2 arterial pressure; PACO2, CO2 pressure in the The second cause of acute hypoxaemia, as explained previously,
alveoli; PaO2, O2 arterial pressure; PAO2, O2 pressure in the alveoli; PIO2, O2 is alveolar hypoventilation. This induces an increase in PaCO2,
inspired pressure; PV, pulmonary vein; PvCO2, CO2 venous pressure; PvO2, and so a decrease in PaO2. Alveolar hypoventilation may be due
O2 venous pressure; LV, left ventricle; RV, right ventricle; V/​Q, ventilation/​
first to excessive alveolar dead space, as occurs in many situations
perfusion ratio.
such as acute exacerbation of COPD, or second due to a decrease
in minute ventilation, as in comatose patients and in some cases
of drug poisoning. Even if not classic, alveolar hypoventilation
of inspired O2, 760  mmHg is the atmospheric pressure, and has also been reported in severe cardiogenic pulmonary oedema,
47 mmHg is the part of the inspired gas that is transformed into especially in older patients. Increasing FiO2 easily corrects PaO2
water.) but does not change, and may even mask and worsen alveolar
Moreover, PACO2 is directly proportional to CO2 consumption hypoventilation, with deleterious consequences. The only way to
and inversely proportional to alveolar ventilation. Differences be- improve the patient’s condition is to correct the hypoventilation.
tween PAO2 and arterial pressure of O2 (PaO2) are, in part, ex-
plained by the ventilation/​perfusion (V/​Q) ratio. In a ‘perfect’ Airway pressures and respiratory mechanics
lung, i.e. a lung where V/​Q = 1, PaO2 is close to PAO2.
There are, in fact, three pressures: pleural pressure (PPL), alveolar
Then, in room air, oxygenation directly depends on alveolar
pressure (PALV), and transpulmonary pressure (TPP) (see sum-
ventilation. A  decrease in alveolar ventilation will increase
mary in E Figure 13.2). In a spontaneously breathing patient, PPL
PACO2, and so decrease PAO2. Under O2, it is the FiO2 that mainly
is negative throughout the respiratory cycle, whereas it is positive
determines the level of oxygenation. This explains why lung func-
tion must be evaluated using the PaO2/​FiO2 ratio. A patient with
a ‘perfect’ lung has a ratio close to 500 mmHg, whereas acute lung Spontaneous ventilation Mechanical ventilation
injury (ALI), and more recently ARDS [3]‌, is defined as a ratio PALV
below 300 mmHg. Exp Insp Exp
0
Insp

Alveolar ventilation and dead space

Dead space (VD) is defined as the volume of gas not usable for PPL
Exp
blood gas exchanges. The total dead space is also called the 0
Insp
physiological dead space and is the sum of the alveolar dead Insp
space (part of the lungs with V/​Q >1) and the anatomical dead Exp
space (trachea, bronchi, etc.). Alveolar ventilation (L/​min) is
thus the difference between minute ventilation (tidal volume VT
× respiratory rate) and the physiological dead space and finally
TPP
determines PaCO2. In healthy subjects, in the supine position, Insp Exp Insp Exp
the anatomical dead space has been reported as between 100 and 0
120 mL, and the physiological dead space around 150 mL [4]‌.
Figure 13.2  Airway pressures in spontaneous ventilation and in mechanical
But dead space can also be expressed as a fraction of the tidal ventilation during inspiration (Insp) and expiration (Exp). PALV, alveolar
volume (VD/​VT). pressure; PPL, pleural pressure; TPP, transpulmonary pressure.
 W hat ca n a n d shou l d b e mon i tored at th e b e d si de ? 129

during tidal ventilation in a mechanically ventilated patient and systemic venous return (see E Figure 13.3) [6, 7]. This can ex-
also sometimes during expiration, depending on the positive end-​ plain the deleterious effect of PEEP in hypovolaemic patients or
expiratory pressure (PEEP). Changes in PPL (ΔPPL) are related to the beneficial effects of the same PEEP in a patient with cardio­
changes in VT, according to the compliance of the chest wall (CCW): genic pulmonary oedema. What is true for therapeutic PEEP
was also described for intrinsic PEEP. Some studies have sug-
C CW = VT /∆PPL gested that a positive PPL will help a failed LV to act by decreasing
its afterload [8, 9].
PALV is nil at end-​expiration and at end-​inspiration in a spon- An increase in TPP, due to severe alteration in CL, will induce
taneously breathing patient (see E Figure 13.2). In a mechanic- systolic overload of the RV [10]. This was especially described in
ally ventilated patient, airway pressure (PAIRWAY) depends first on patients ventilated for severe ARDS [11] (see E Chapter 64).
PEEP, second on the resistive part of the pressure (Q × R), and
finally on the static part of the pressure (VT/​CRS). It is expressed
by the equation of movement:
What can and should be monitored
PAIRWAY = PEEP + (Q + R ) + VT /C RS at the bedside?
(where Q is the inspiratory flow, R the resistance to flow, and CRS In general, monitoring of the respiratory system is limited in
the compliance of the respiratory system, i.e. lung + chest wall.) spontaneously breathing patients, whereas many tools are avail-
When the flow is nil, during a pause, PAIRWAY represents PALV. At able in mechanically ventilated patients to evaluate the properties
end-​inspiration, this is the plateau pressure (PPLATEAU), which de- of the respiratory system. In the first situation, the main aim of
pends on VT and CRS. In normal subjects, PALV at end-​expiration monitoring will be to identify patients and situations requiring
is nil. It can become positive either if a ‘therapeutic’ PEEP is ap- invasive or non-​invasive mechanical ventilation. In the second
plied or if dynamic hyperinflation is occurring, leading to an situation, the aims of monitoring will be to optimize respiratory
intrinsic PEEP. settings (VT, respiratory rate, PEEP, etc.) to avoid excessive airway
Finally, TPP is the distending pressure of the lung, calculated as pressures, to limit the deleterious effect of PPV on cardiac func-
PALV –​ PPL. Changes in TPP (ΔTPP) are related to changes in VT, tion, and finally to optimize respiratory management.
according to the compliance of the lung (CL): The first requirement of monitoring the respiratory system is
the correct interpretation of clinical signs of respiratory failure.
C L = VT /∆TPP These include polypnoea, cyanosis, tachycardia, and intercostal,
suprasternal, or supraclavicular recession. O2 saturation can be
Any decrease in lung compliance will induce an increase in non-​invasively monitored by plethysmography (SpO2), but some
TPP for a given lung volume. differences have been reported between SpO2 and SaO2, and the
signal is not always optimal when shock is associated. Physicians
Heart–​lung interactions have to look for, in particular, signs suggesting hypercapnia, be-
Briefly, any changes in respiratory mechanics, or passing from cause they may require specific management such as application
spontaneous ventilation to mechanical ventilation, will act on of non-​invasive mechanical ventilation. These include sweating,
cardiac function by modifying the different airway pressures (see flapping tremor, and decrease in consciousness. Blood gas ana-
E Figure 13.2) [2]‌. lysis will confirm the clinical evaluation (see E Chapter 16). In
An increase in PPL, due to a decrease in CCW, as in obese pa- exacerbations of COPD, uncompensated respiratory acidosis will
tients, or due to positive pressure ventilation (PPV), will decrease indicate the need for non-​invasive mechanical ventilation [12].

ZEEP PEEP 5

SVC

Exp Insp Exp Insp

Figure 13.3  TOE in a mechanically ventilated patient, at zero end-​expiratory pressure (ZEEP) and 5 cmH2O PEEP. Two-​dimensional view of the superior vena
cava (SVC), associated with the time–​motion study, demonstrates collapse of the vessel during tidal ventilation in PEEP conditions, reflecting a decrease in
systemic venous return. Exp, expiration; Insp, inspiration.
130 CHAPTER 13   The respiratory  syst em

(a) FiO2 0.7 12/01/09 12/01/09

14:57 15:21
PEEP 5 ZEEP

70.0

pH 7.46 7.50
PaCO2 41 38
PaO2 64 101

(b)

FiO2 0.7 13/01/09 13/01/09

15:24 16:20

PEEP 5 ZEEPTEL

pH 7.44 7.41
PaCO2 41 45
PaO2 108 57

Figure 13.4  CXR and blood gas analysis at ZEEP and PEEP (5 cmH2O) in a patient at day 1 (panel A) and at day 2 (panel B). At day 1, the CXR showed
unilateral injury of the lung. PEEP removal induced an increase in PaO2 and a decrease in PaCO2, reflecting overdistension of the lung related to PEEP. At day 2,
lung injury was bilateral. PEEP injury induced a decrease in PaO2 and an increase in PaCO2, reflecting derecruitment of the lung.

Monitoring of blood gases, in accordance with the CXR, may also and pneumothorax [16]. Strict limitation of PPLATEAU has been
help to clarify the effect of PEEP in a patient mechanically venti- shown to save lives, especially in ARDS [17] and acute asthma
lated for ALI, as illustrated in E Figure 13.4. [18]. However, a recent large multicentre international study re-
Monitoring of PPLATEAU is crucial in a sedated mechanically ven- ported that PPLATEAU was not very well monitored in ventilated
tilated patient (see E Figure 13.5) (see E Chapter 22). It is used patients, even with ARDS [19]. A PPLATEAU below 30 cmH2O, and
as a surrogate for TPP but overestimates it [13]. TPP is not avail- much better if below 27  cmH2O, limits lung overdistension and
able in clinical practice, because PPL is difficult to record since it PH and their effects on the RV [21]. However, respirators are
requires placement of a balloon in the oesophagus [14], while re- not equipped with an alarm for PPLATEAU, but only for peak pres-
cent research suggested its feasibility and usefulness [15]. PPLATEAU sure, i.e. the pressure reached before the end-​inspiratory pause
has been reported to be strongly related to the risk of barotrauma (see E Figure 13.5) (see E Chapter 22). As recalled previously

(a) 60 (b) 60
Ppeak
Ppeak
PPLATEAU
PPLATEAU
Paw Paw
cmH2O cmH2O

4 8 12 16 20 4 8 12 16 20

Figure 13.5  Recording of airway pressure from the respirator trace in a patient ventilated with a respiratory rate of 15 cycles/​min (panel A) and 30 cycles/​min
(panel B). End-​expiratory occlusion (arrow) unmasked intrinsic PEEP at high respiratory rate, which caused an increase in airway peak pressure (Ppeak) and plateau
pressure (PPLATEAU).
 C on c lusi on 131

(a) VT (b) VT (c) VT

(litres) (litres) (litres)
1.2 1.2 1.2

0.8 0.8 0.8

0.4 0.4 0.4

0 0 0
0 10 20 0 10 20 0 10 20

Figure 13.6  Quasi-​static pressure/​volume loop of the respiratory system in three different mechanically ventilated patients. The loop was built by limiting the
flow to below 9 L/​min during inspiration and expiration to neglect the resistive part of the pressure. In patient (A), the compliance of the system was normal, as
shown by the slope of the relationship during inspiration (dashed line). In patient (B), the compliance of the respiratory system was decreased, but the potential
for lung recruitment was high, as suggested by the hysteresis between the inspiratory and the expiratory curves. In patient (C), the compliance was severely
decreased and the potential for recruitment very low, as suggested by the absence of significant hysteresis between the two curves.

with the equation of movement, a peak pressure alarm may re- overdistension and recruitment [28]. A lung CT scan of a patient
flect: (1) an abrupt increase in intrinsic PEEP (does the patient have ventilated for severe ARDS is given as an example in E Figure 13.7
an expiratory flow limitation?); (2) an increase in flow resistance [is (see E Chapter  64). Whether lung US can non-​invasively give
the endotracheal tube (ETT) partially occluded?]; and (3) a deteri- similar information remains to be confirmed [29, 30].
oration of lung mechanics (does the patient have pneumothorax?
Does the patient have abrupt-​onset pulmonary oedema?). Intrinsic
PEEP may be easily detected by performing an end-​expiratory
pause, as shown in E Figure 13.5.
Conclusion
Recording of expiratory CO2 is possible, especially in intubated The respiratory system is key to the management of patients with
patients, by sensors positioned between the proximal end of the respiratory, and also haemodynamic, compromise. According to
ETT and the Y piece of the ventilator. Mean expiratory (PECO2) its properties, it may act differently on cardiac function. Because
and end-​tidal (PetCO2) CO2 can thus be monitored, allowing cal- the most severely compromised patients in the ICCU are mech-
culation of the physiological dead space (VDphysiol/​VT = 1 –​  PECO2/​ anically ventilated, it is mandatory for intensivists to under-
PaCO2) and the alveolar dead space (VDalv/​VT = 1 –​ PetCO2/​PaCO2). stand fully that any change in ventilatory settings will also affect
A decrease in VD/​VT reflects improvement in respiratory mech- haemodynamics. It is clinically possible to monitor the respira-
anics and subsequently in the patient’s status. This is true in acute tory system. The ventilator is more than just a machine that de-
exacerbations of COPD or in acute asthma where a decrease in livers gas; it is a true respiratory system monitoring device able
VD/​VT reflects a decrease in expiratory flow limitation, and also to evaluate Ppeak, PPLATEAU, intrinsic PEEP, and expiratory flow
in ARDS where a decrease in VD/​VT mostly reflects a decrease in limitation (see E Chapter 22).
lung overdistension. It has been suggested that, in these patients,
even a slight decrease in PaCO2 reflects functional lung recruit-
ment induced by some procedures, such as prone positioning
[21], and that this decrease [22] as the use of prone position [23]
is associated with a better prognosis.
The P/​V loop of the respiratory system has long been proposed
as a means of evaluating respiratory mechanics [24]. Whereas
the curve is linear during inspiration in patients without lung in-
jury (see E Figure 13.6), it includes a lower and an upper inflec-
tion point in ARDS (see E Figure 13.6). The P/​V loop pattern
has been proposed for assessing the ‘recruitability’ of the system
[25, 26] (see E Figure 13.6). However, this loop is difficult to
use at the bedside.
Finally, a few words should be said about lung CT scanning.
Although unavailable at the time at the bedside, many studies have
demonstrated its utility in ARDS in assessing the ‘recruitability’ of Figure 13.7  Lung CT scan in a ventilated patient with severe ARDS related
the lung [27] and in evaluating the effect of PEEP in terms of lung to extensive pneumonia.
132 CHAPTER 13   The respiratory  syst em

Personal perspective
Because most ICCU patients are mechanically ventilated, with ARDS or acute asthma, show that a rigorous ap-
respiratory management, and therefore respiratory moni- proach to ventilation can save lives. Such studies should be
toring, is critical. Respirators are too often considered used to increase intensivists’ awareness of the importance
as simple machines that deliver gas, whereas they can of limiting PPLATEAU, avoiding intrinsic PEEP, and adapting
be used as a true monitoring device. A  serious effort respiratory settings to respiratory mechanics. In the fu-
has to be made to train intensivists better to understand ture, new methods will be available at the bedside for all
how to monitor the respiratory system and why. Recent intensivists such as perhaps CT scanning and less ‘aggres-
studies in severely compromised patients, such as those sive’ lung US.

Further reading
Brochard L, Mancebo J, Wysocki M, et  al. Noninvasive ventilation for The Task Force on Acute Heart Failure of the European Society of
acute exacerbations of chronic obstructive pulmonary disease. N Engl Cardiology. Guidelines on the diagnosis and treatment of acute heart
J Med 1995;333:817–​22. failure. Eur Heart J 2005;26:1115–​40.
No authors listed. Ventilation with lower tidal volumes as compared with Vieillard-​Baron A, Prin S, Chergui K, Page B, Beauchet A, Jardin F. Early
traditional tidal volumes for acute lung injury and the acute respiratory patterns of static pressure-​volume loops in ARDS and their relations
distress syndrome. The Acute Respiratory Distress Syndrome Network. with PEEP-​induced recruitment. Intensive Care Med 2003;29:1929–​35.
N Engl J Med 2000;342:1301–​8. Whittenberger JL, McGregor M, Berglund E, Borst HG. Influence of
Scharf SM, Caldini P, Ingram RH. Cardiovascular effect of increasing state of inflation of the lung on pulmonary vascular resistance. J Appl
airway pressure in the dog. Am J Physiol 1977; 232:35–​43. Physiol 1960;15:878–​82.

References
1. The Task Force on Acute Heart Failure of the European Society of 13. Terragni PP, Rosboch G, Tealdi A, et al. Tidal hyperinflation during
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 CHAPTER 14

Neurological assessment
of the acute cardiac
care patient
Mathieu van der Jagt, Jeroen JH Bunge, and
Fabio S Taccone

Contents
Summary  134 Summary
Introduction  134 Recognizing neurological conditions, as well as their initial diagnostic work-​up
General clinical neurological evaluation  135 and first steps in management, should be part of the competence of doctors and
Quick clinical neurological evaluation at the nurses caring for these patients. In this chapter, we have aimed to convey the back-
bedside  135
Level of consciousness  135 ground and practical tips on the neurological clinical examination, as can be per-
Cognition  136 formed by non-​neurologists. Further, we have summarized the ancillary tests that
Brainstem function  136
Motor function  137 are currently in use by most critical and acute care facilities caring for acute cardiac
Neurological phenotypes in acute patients. The focus is on practical information that can be applied in everyday clin-
cardiac care: diagnosis and acute ical practice, and this is based both on clinical practice experience by the authors
management  137 and on scientific evidence, when available.
Syncope  137
Delirium and encephalopathy  138
We will provide a concise review of clinical knowledge and essential professional
Stroke  138 skills to facilitate the management of patients with neurological complications re-
Seizures and myoclonus  138 lated to acute cardiac conditions within the setting of intensive and acute cardio-
Coma  139
Post-​anoxic coma  139 vascular care. We will review clinical approaches to neurological assessment and
Neurological complications in review the most common phenotypes of neurological disorders in these patients,
extracorporeal and cardiac assist and their work-​up, diagnostic challenges, and prognosis.
devices  140
Neuromonitoring: who, when, and
how?  140
Standard of care: neuromonitoring
modalities  140
Electroencephalography  140
Somatosensory evoked potentials Introduction
(SSEPs)  140
Imaging of the brain  141 It is vital to recognize neurological conditions in the acute cardiac patients, because some
Computerized tomography  141
Magnetic resonance imaging  141
of these may be reversible upon prompt recognition, they may bear important prognostic
Neuromonitoring modalities: what other implication, or they may be informative on the evolution of a cardiac condition or even
options?  141 point at an underlying diagnosis (e.g. endocarditis). This chapter aims to help readers
Monitoring cerebral perfusion and
oxygenation  141
Near-​infrared spectroscopy  142
Case vignette  142
Brain ultrasound  142 SSEP  144 Conclusion  144
Other modalities  142 CT  144
Personal perspective  145
Neuroprognostication  143 MRI  144
Clinical neurological examination  143 Biomarkers  144 References  145
EEG  143 Pupillometry  144
 G en er a l cl i n i ca l n eu rol o g i ca l eva luat i on 135

acquire the knowledge needed to recognize and handle urgent managed in cardiac/​cardiothoracic critical care units (CCUs) will
neurological conditions in cardiac patients in the acute setting of be sedated, daily ‘spontaneous awakening trials’ (SATs) are essen-
an emergency room or cardiac care/​ICU. We will provide the ‘first tial to facilitate regular neurological evaluations. It is important
steps’ in management, rather than being exhaustive, aimed for to note that current practices are moving away from routine sed-
non-​neurologists. We will provide the reader with practical and, ation towards a state of being ‘comfortably awake’ [1]‌, acknow-
whenever possible, evidence-​based information that is applicable ledging that circumstances can still call for targeted sedation, e.g.
in everyday clinical practice in acute cardiac care. in the case of an agitated patient on ECLS. When sedation is in-
Neurological monitoring starts with clinical neurological assess- deed needed, short-​acting sedatives, rather than continuous IV
ment, which is—​in essence—​the best neurological monitor, since benzodiazepines, are preferred. A  SAT entails daily stopping of
it aims to evaluate the actual function of the brain. It is important all sedatives and, when the patient has no pain, all narcotics, with
to recognize that all other (technical) neuromonitoring modalities the aim to both evaluate the neurological function and facilitate
generally monitor only a specific part or aspect of cerebral func- spontaneous breathing trials (SBTs), which, combined with SATs,
tioning and, as such, are more limited regarding the information have been shown to improve ICU outcomes. SATs and SBTs are
they provide. Therefore, a key principle in neurological assessment part of modern ICU management aimed at maximizing brain
of cardiac patients (which applies to all patients with neurological functioning during critical illness, instead of ‘putting the brain to
conditions) is that clinical examination should always be the first sleep’. This modern approach is now the principle underlying the
step of the assessment, with additional neuromonitoring mo- latest ABCDEF bundle (Assess, prevent, and manage pain; Both
dalities being used only for confirmation (e.g. of prognosis) or SATs and SBTs; Choice of analgesia and sedation; Delirium: as-
diagnostic evaluation (the reason for neurological worsening) or sess, prevent, and manage; Early mobility and exercise; Family en-
when clinical examination is impeded (e.g. when the patient is gagement and empowerment) and the clinical practice guidelines
sedated). for the Prevention and management of pain, Agitation/​sedation,
Delirium, Immobility, and Sleep disruption (PADIS) in adult pa-
tients in the ICU [1].
General clinical neurological Level of consciousness
evaluation The Glasgow Coma Scale (GCS) should be considered a baseline
The first basic rule in neurological assessment of the acute cardiac competence of every physician and ICU nurse [2]‌. Newer tools,
patient is that neurological functioning should not be impeded at such as the Full Outline of UnResponsiveness (FOUR) score, have
all, meaning that any (new) neurological impairment, be it con- been adopted by some centres, but widespread use of such alterna-
sciousness, cognition, or motor functioning, and however subtle, tive tools has not surpassed that of the GCS. Although the initial
requires prompt evaluation. This includes even mild impairments use of the GCS was in traumatic brain injury patients to allow for
of attention or delirium. structured follow-​up of consciousness over time, its use has be-
A second basic rule is that a brief global neurological examin- come much more widespread, including all kinds of neurological
ation will likely uncover most of the neurological conditions that conditions and other alterations of consciousness (e.g. metabolic
can occur in acute cardiac patients. encephalopathy). The GCS assesses arousal (reaction to stimulus)
and also partly awareness (cognitive performance), which are
Quick clinical neurological evaluation the two components of consciousness. Arousal originates from
at the bedside the ascending reticular formation (ARF) in the dorsal regions of
(See E Figure 14.1.) the brainstem (pons) and its ascending neuronal circuits to both
A quick neurological evaluation is essential in every patient thalami bilaterally. Awareness relates to the ‘contents’ of the con-
portraying any neurological deficit but may also be advised on scious mind (originating from the cortex) [3]. Consequently, for
a daily basis in every patient at high risk of neurological compli- intact consciousness, both need to be present. Well-​known ex-
cations (e.g. endocarditis). Since a proportion of patients being amples of coma due to ARF or thalamic lesions are basilar artery
thrombosis or compression of the brainstem, e.g. due to cerebellar
haemorrhage. Examples of coma due to hemispheric and cortical
disruption include post-​anoxic coma due to persistent vegetative
state, or metabolic causes such as deep hypoglycaemia.
Consciousness: The GCS (https://www.glasgowcomascale.org/) consists of
Glasgow coma scale
-arousal three components—​ eyes (E), motor (M), and verbal (V)—​
-awareness Delirium screening
and the score ranges from 3 (deep, unresponsive coma) to
15 (fully alert). Assessment of the GCS score always starts
Brainstem reflexes Motor responses with calling the patient’s name out loud and, if no response fol-
lows, shaking the patient (without eliciting pain), followed
Figure 14.1  Brief neurological evaluation. finally by a pain stimulus. The painful stimulus can be one
136 CHAPTER 14   N eurol o gical assessment of the acu te ca rdiac ca re pati en t

of several: pressing the supraorbital ridge where the supraorbital Cognition

nerve exits in a small groove (medial orbital rim), pressing the
A good way to screen for acute changes in cognition is the rou-
nailbeds, and rubbing the sternum with the knuckles (not suitable
tine use of validated bedside screening tools for delirium in
for post-​cardiac surgery patients!). However, formally the supra-
acute and critically ill patients. These tools assess awareness,
orbital ridge stimulus should be used for the GCS-​M score. The
rather than arousal, for which the GCS is more suitable. These
other stimuli can be used to elicit arousal and evaluate the GCS-​E
tools have been based on the Diagnostic and Statistical Manual
and V components. Further, regarding the GCS-​M: 2 (extension)
of Mental Disorders (DSM) criteria for delirium. Two of these
means extension and endorotation/​pronation of the arms; 3 (ab-
tools have been recommended for the critical care setting in the
normal flexion) means any flexing response in the elbow, with
latest PADIS guidelines [1]‌: the Confusion Assessment Method
two of the following: concomitant extension or endorotation of
for the ICU (CAM-​ ICU) and the Intensive Care Delirium
the legs, flexion of fingers 2–​5 over the thumb, variable exten-
Screening Checklist (ICDSC). Explanations of their contents and
sion or endorotation of the arm, flexion in the wrist; 4 (flexion;
use are readily available on excellent supporting websites (e.g.
withdrawal) means a flexing response in the elbow without the
M https://​www.nice.org.uk/​guidance/​cg103 or M https://​www.
characteristics previously described under 3; 5 (localizing) means
icudelirium.org). Routine delirium testing in critically ill pa-
that the patient brings his hand towards the hand of the clin-
tients has an added value since it has been shown that hypoactive
ical investigator, above the level of the shoulders; and M6 (fol-
delirium often remains unrecognized, in spite of burdening the
lows commands) means execution of commands by the clinician,
patient and adverse prognostic implication [4]. Furthermore, de-
which may be either a ‘thumbs up’ or making a fist/​squeezing the
lirium portends a worse prognosis [5].
investigator’s hand or finger on request. Some patients may have
The CAM-​ICU involves a strict set of criteria and bedside
a grasp reflex mimicking a squeeze, and to differentiate from pur-
cognitive tests and tests on attention that should be assessed in
poseful behaviour in case of doubt, the command ‘let go of the
a strict order to decide whether the test is positive (indicating
finger’ can be added to confirm M6. Likewise, when eliciting a
delirium) or not [6]‌. However, the consequence is, for example,
painful response through pressing the nailbed as an alternative to
that a patient may have delusions, but not be assessed as posi-
the supraorbital ridge, M5 can be scored when the patient crosses
tive for delirium, since delusions and hallucinations are not part
the midline towards the stimulus with the other arm (only reliable
of the CAM-​ICU. In contrast, the ICDSC is a more graded test
if no paralysis is present contralaterally).
indicating whether more or less delirium symptoms are present,
Importantly, although the M-​score component of the GCS is
with ICDSC scores of 4 or more indicating delirium, scores of 1–​3
drafted as a continuum from 1 to 6, it should be acknowledged
indicating ‘subsyndromal delirium’, and a score of 0 indicating no
that M4 can be compatible with the persistent vegetative state,
delirium [1]. Therefore, the ICDSC has a better resolution, ren-
whereas a clear M5 will very often develop into an M6. Therefore,
dering this screening tool more suitable for follow-​up over time
M4 may be regarded as a double-​edged score—​it may signify an
and for subtle signs of delirium. For both, it is essential that they
intermediate score on the way to M5 and then probably M6, but
should be assessed ‘as is’, meaning that interpretations about the
it may also be a final situation, with M4 as a persisting maximum
role of sedation for the delirium symptoms should not be in-
GCS-​M score, compatible with the vegetative state.
cluded in the assessment. This can be understood because seda-
However, in spite of the widespread use of the GCS, its
tive drugs can contribute to delirium symptoms or even cause
application is certainly not without any flaws; for example,
them, but on the other hand, sedation can also uncover under-
deafness, blindness, or non-​ cerebral neurological deficits
lying delirium. The so-​ called ‘sedation-​
related delirium’ will
(e.g. ICU-​acquired weakness) may falsely impede the GCS-​
subside when sedatives are withdrawn, whereas ‘true delirium’
M score and underestimate the GCS score as a measure of
will persist [7]. Distinguishing these two forms of ‘delirium’ is
brain function. Especially in critically ill patients who have
important because of their prognostic implications—​sedation-​
been in the ICU for more than a week, such ‘false negatives’
related delirium does not increase mortality risk, in contrast to
regarding GCS-​M may facilitate self-​f ulfilling prophecies re-
‘true’ delirium. Especially in the acute cardiac and cardiovascular
garding prognosis and may therefore be hazardous. Further,
acutely and critically ill, screening for delirium, as the ‘canary in
aphasia may impede even perfectly alert patients after a stroke
the coal mine’ (warning sign), is an essential part of general and
from following commands and therefore may score M5 as a
neurological assessment in daily practice.
maximum, which does not mean that their consciousness
is decreased because of decreased GCS. Also, the GCS does
Brainstem function
not include brainstem reflexes, which the FOUR score does,
which may be regarded as a limitation. Finally, it is important Brainstem dysfunction can uncover many clues with regard to
to annotate the GCS score components in the medical file, underlying pathologies of the brain and has an important local-
when the interpretation is not straightforward (which often is izing value. Brainstem reflexes disappear when the reflex pathway
the case), e.g. ‘M5, due to aphasia, and otherwise alert’ or ‘M1 from afferent to central/​nucleus and subsequently the efferent
with arms, due to cervical cord lesion, but M6 with eyelids, pathway back to the target organ (eye, face, etc.) has been dam-
closing them on command’. aged. Also, the brainstem reflexes as described below follow a
 N eurol o gical ph enot ypes in  acu te ca rdiac ca re:  diag n o si s a n d acu te m a nag e m e n t 137

rostro-​caudal sequence. Therefore, compression from the hemi- ◆ Strength: usually this is measured using the Medical Research
sphere towards the brainstem will damage the pupillary response Council (MRC) scale, ranging from 0 (no muscle contraction)
first, thereafter the corneal reflex, etc., and this will be different to 5 (normal muscle strength). This can be tested against the
when there is a pathologic condition lower in the brainstem. strength of the investigator and may include at least flexion,
Pupillary reflexes:  isocore (same-​sized) pupillary response to extension at the elbow and wrist, and flexion/​extension at the
light is normal. Absence of any response signifies bilateral im- hip, knee, and ankle. Asymmetry more often points to a CNS
pairment of both the optic (II) nerve (afferent), or its tract, and lesion, whereas symmetric paresis may point to a peripheral
the oculomotor (III) nerve (efferent) and/​or its nucleus in the nervous system condition or spinal cord lesion.
brainstem. Often, inexperienced operators document isocore, for ◆ Coordination: ask the patient to point at your finger and at their
responsive, large or very small pupils, but these may be normal own nose, back and forth. Another test is to ask the patient to
variants. Any clear differences in size (anisocoria) between the put their heel on their knee and slide down their tibia. Ataxia will
two pupils should alert the clinician for pathology of the brain- be evident when movements overshoot their targets, resulting in
stem and impending neurological deterioration, independent tremulous movements in an attempt to correct this. Abnormal
from its cause, especially if this is accompanied by a decreased coordination generally points at cerebellar pathology, although
GCS score. Causes may be an expanding space-​occupying lesion, it can also point at peripheral nerve pathology.
e.g. intracerebral haemorrhage (ICH) with oculomotor nerve ◆ Muscle tone:  spasticity (subacutely after a CNS lesion) can
compression, or a basilar artery thrombosis, with ischaemia of be discerned from rigidity (basal ganglia disorders, meaning
the brainstem, both of which would require immediate manage- hypokinetic rigid syndromes, such as Parkinson’s disease, but
ment. However, a perfectly alert patient with very mild anisocoria also seen as a side effect of antipsychotic drugs such as halo-
may just signify ‘physiological’ anisocoria. Commercially avail- peridol) or flaccid muscles (typical in the acute phase of a central
able pupillometers are becoming popular and are more sensitive, lesion or in peripheral lesions).
compared with the human eye, in the assessment of pupillary ◆ Tendon reflexes: reflexes at the biceps and knee are most easily
responses. elicited. Asymmetry points to a central lesion. This requires
Corneal reflexes:  similar to pupillary reflexes, but absence of some practice to perform well and reliably. Brisk reflexes occur
corneal reflexes suggests an unfavourable outcome and indicates with central lesions, and low or absent reflexes with peripheral
damage to the trigeminal (V) nerve, or the facial (VII) nerve, or lesions. However, absent reflexes may be non-​pathologic.
one of their brainstem nuclei. As for abnormal pupillary reflexes, ◆ Skilfulness: usually tested with up-​speed alternating movements
this may be caused, among others, by intracranial space-​occupying and comparing asymmetries between the left and right sides, e.g.
lesions, local ischaemia, or post-​anoxic brain damage. The corneal supining/​pronating the palm of the hand (turning movement) as
quickly as possible (or tapping with the foot)—​any asymmetry,
reflex is tested preferably by instillation of drops of water, rather
however subtle, may point to a central lesion.
than by eliciting the reflex using a cotton bud or gauze, since this
has been shown to have a small risk of corneal abrasion.
Other brainstem reflexes:  a ‘quickscan’ of the other brainstem
reflexes involves assessment of eye movements in all directions Neurological phenotypes in acute
(the patient is asked to follow his gaze left–​right and up–​down by cardiac care: diagnosis and
moving an object, e.g. pencil—​divergence of the eyes will indicate
partial muscular paresis of the eye through nerves III, trochlear
acute management
(IV), abducens (VI); symmetric grimacing or laughing on re- Syncope
quest (facial motor functions by nerve VII); gag reflex or cough
Syncope is defined as a transient loss of consciousness (LOC) due
in unconscious patients [through manipulation of the ETT or
to cerebral hypoperfusion, characterized by a rapid onset, a short
suctioning through the tube—​glossopharyngeal (IX) and vagus
duration, and a spontaneous, complete recovery. Main causes in-
(X) nerves]; sticking out the tongue [hypoglossal (XII) nerve XII].
clude reflex or orthostatic syncope or cardiac causes. The first steps
Caloric and oculocephalic reflex testing is usually reserved for the
in suspected syncope should include a detailed history (of current
specific setting of suspected brain death.
and previous episodes), physical examination, ECG, and assessing
the need for further diagnostic evaluation thereafter. For further
Motor function (cardiac) work-​up and risk stratification of syncope, we refer to
A quickscan of motor functions and their (a)symmetry is inform- the 2018 ESC guidelines on diagnosis and management of syncope
ative to detect hemiparesis and differentiate between a CNS and [8]‌. Alternative diagnoses that have to be considered in the case of
a peripheral nervous system problem which has important diag- transient LOC are epilepsy or a psychogenic origin. Finally, rare
nostic relevance. Lesions leading to contralateral disability in- causes include subclavian steal syndrome, vertebrobasilar tran-
clude hemispheric and brainstem lesions, whereas cerebellar and sient ischaemic attack (TIA), or SAH. Important features that plea
spinal cord lesions cause ipsilateral loss of function. Motor func- against (cardiac or reflex) syncope are: longer duration of LOC,
tion that can be easily tested at the bedside includes: gradual onset of decreased consciousness, and LOC accompanied
138 CHAPTER 14   N eurol o gical assessment of the acu te ca rdiac ca re pati en t

by headache or neurological focal signs. Signs suggestive of epi- Stroke

leptic seizures, rather than syncope, are: lack of a trigger, lack of
(See also E Chapter 65.)
anamnestic light-​headedness preceding LOC, duration of LOC
Stroke is an umbrella term for an acute cerebrovascular at-
of several minutes, tongue bite at the side of the tongue, no full
tack, generally evident from focal neurological signs with intact
alertness for <10 seconds after an attack, and 20–​100 myoclonic
consciousness (in anterior cerebral circulation ischaemic stroke,
jerks with extremities (rather than <10). Urinary incontinence,
which is the most common), focal neurological deficit with or
contrary to common belief, is not particularly helpful to differen-
without decreased consciousness (ICH), or brainstem and other
tiate syncope from epilepsy.
focal neurological deficits often with decreased consciousness.
Ischaemic stroke (IS) may occur due to a variety of causes in car-
Delirium and encephalopathy
diac patients. Since a timely diagnosis and intervention can pre-
(See also E Chapter 72.) vent its devastating consequences, due to the current possibility
Encephalopathy is an umbrella term that indicates any to perform endovascular thrombectomy (EVT), it is key to be
global disease of the brain that alters brain function [9,  10]. alert for this complication and to act promptly when neurological
Encephalopathy may be caused by infection, metabolic causes deficits become manifest. Many cases of stroke in a cardiac care
(e.g. uraemic, hepatic), toxic substances or drugs, e.g. seda- unit are procedure-​related, most of them ischaemic from embolic
tives, and many other causes [10]. Altered mental state is the events. Although rare, any intervention where catheters or can-
key phenomenology. Especially in metabolic causes, subtle nulae are used in the heart or ascending aorta can provoke an
motor signs, such as myoclonus, may be present and any IS. The incidence of stroke after PCI is 0.3%, and radial access
type of cognitive changes may accompany encephalopathy. is associated with an even lower risk of periprocedural stroke
Delirium is a specific type of encephalopathy where conscious- [11]. Incidences of stroke after transcatheter aortic valve implant-
ness and responsiveness are intact, but attention and cogni- ation (TAVI) have been reported to be as low as 0.6% in low-​risk
tion are disturbed. Coma signifies decreased consciousness patients to >6% in high-​risk patients [12]. Embolic protection
and unresponsiveness and thus excludes a bedside diagnosis devices may decrease the rate of intra-​procedural stroke [13].
of delirium (i.e. delirium and coma are mutually exclusive). Post-​operative stroke is a feared complication of cardiac surgery
Therefore, in essence, the brain function status of ICU patients as well and may manifest only when sedatives are ceased post-​
can be described as either normal, delirious, or comatose (see operatively, often too late for interventions. In recent large trials,
E Figure 14.2). the incidence of stroke after CABG was 1.4% and 2.4% in low-​risk
The first steps in the assessment of encephalopathy are to dif- patients undergoing aortic valve replacement [12, 14]. Apart from
ferentiate delirium from coma and to search for underlying periprocedural embolic events, emboli could originate from left-​
causes. The PADIS guidelines contain recommendations to deal sided endocarditis or from an LV or LA thrombus. ICH may be a
with delirium. Management may involve halting any sedatives or primary event or secondary due to haemorrhagic transformation,
other drugs that may impact on consciousness, especially benzo- which is more common in the acute cardiac patient due to the
diazepines, but other drugs need to be evaluated for potential frequent need for anticoagulation, compared with other settings.
causality such as (cephalosporin) antibiotics. Regarding the use As first steps, after clinical suspicion of new-​onset stroke (new,
of antipsychotics, strong evidence is lacking to support the rou- usually unilateral neurological deficit), urgent CT scanning (with
tine use of any of these drugs for ICU delirium. However, specific CTA) should be performed to distinguish haemorrhagic stroke
symptoms associated with delirium may justify pharmacological from IS and evaluate the presence of anterior cerebral arterial oc-
treatment, e.g. haloperidol for hallucinations or α2-​agonists or clusion suitable for EVT. The time frame from the onset of stroke
short-​acting gamma-​aminobutyric acid (GABA) agonists (e.g. symptoms to successful EVT is 6 hours (proven for anterior cere-
propofol) for agitation. bral circulation stroke and currently under investigation for pos-
terior circulation stroke), and in selected cases even beyond that
period [15]. Starting anticoagulants has to be weighed against the
Alert and oriented risk of haemorrhagic transformation of (large) infarcted areas,
and and anticoagulation is generally not advised within 6 days after
cognition intact
moderate or severe stroke [16].
Yes No
No brain
Encephalopathy
Seizures and myoclonus
dysfunction
Seizures are transient occurrences of signs and symptoms due
Responsive Unresponsive to abnormal excessive or synchronized neuronal activity in the
brain, often due to underlying abnormalities or disease processes
Delirium Coma
of the brain. Seizures can be focal (possibly without LOC) or gen-
eralized (with LOC) in onset and have a predominant motoric
Figure 14.2  Terminology of brain dysfunction.
 N eurol o gical ph enot ypes in  acu te ca rdiac ca re:  diag n o si s a n d acu te m a nag e m e n t 139

symptomatology (e.g. tonic—​muscle tightening, clonic—​jerking to be able to halt sedation and assess the actual level of conscious-
movements) or a non-​motor presentation (e.g. autonomic, be- ness, without residual sedation.
havioural, cognitive, sensory). Although primarily a clinical diag-
nosis, seizures are often assessed with EEG, which assesses mainly Coma
electrical activity in the cerebral cortex where seizures are gen- Coma signifies a state of unresponsiveness and is generally defined
erally thought to originate. Clinically, seizures may elicit a surge as a GCS score of ≤8 or GCS-​M score of ≤5 [2]‌. Consciousness re-
of (motoric) signs, from subtle to more intense, and then fading quires all of the following: (1) an intact ARF in the dorsal brain-
out again, accompanied by rhythmic motor activity, and this typ- stem; (2) an ascending tract from the ARF through the thalamic
ical time-​course is an important feature differentiating seizures nuclei; and (3) the brain hemispheres/​cortex [3, 19]. Terminologies
from other paroxysmal attacks. Myoclonus is characterized by pertinent to the acute cardiac care patient and that can be under-
sudden, brief, involuntary jerks of a muscle or group of muscles, stood from the previous brain pathological–​anatomical relations
which often are less rhythmic than in seizures. Their occurrence include:  persistent vegetative state (unresponsive state/​ coma,
has historically been regarded as prognostically bad after car- which may include a gradual return of eye opening during day-
diac arrest, but this picture has met more nuance in recent years, time and an intact autonomic reserve and airway reflexes, due to
since patients may awaken in spite of the presence of myoclonus. severe and global cortical disruption or widespread bilateral dis-
Negative myoclonus is sudden interruption of muscle activity, connection of cortical tracts, most often encountered after cardiac
such as in asterixis (flapping tremor of the hand when the wrist is arrest or severe brain injury), minimally conscious state (similar to
extended), which is commonly seen in toxic–​metabolic enceph- vegetative state, but with some signs of responsiveness), locked-​
alopathies. Myoclonus can be epileptic but is often thought to ori- in syndrome (intact consciousness, but total paralysis, except for
ginate from deeper brain layers, compared with seizures, such as vertical eye movements, due to disruption of the ventral bundle
the brainstem. Importantly, 100% differentiation based on clinical of central motor neurons in the brainstem, leaving the structures
signs can be difficult, and in such cases, EEG may help to rule out necessary for consciousness intact—​the patient is ‘locked-​in’ in
seizure activity. their own body, given the near-​total paralysis, with an inability
The first steps in the assessment of seizures generally is imaging to communicate, except for vertical eye movements; most often
to detect the underlying cause. In cardiac patients, seizures may caused by basilar artery IS).
be the first sign of new-​onset cerebral pathology such as stroke.
Apart from structural causes, electrolyte or other metabolic de- Post-​anoxic coma
rangements may cause seizures, as well as many medications, Of all out-​of-​hospital cardiac arrest patients who reach the hos-
notably tranexamic acid (0.7%), in which case seizures have been pital following ROSC after resuscitation, around half will regain
associated with a higher risk of stroke or death [17]. Seizures that consciousness nowadays after sedation associated with TTM has
do not show a tendency to subside within minutes should be been halted. Initial coma results from global anoxia due to circu-
treated with benzodiazepines (midazolam, lorazepam). Seizures latory arrest, and reversibility depends on the extent and duration
persisting for 5 minutes or more should be regarded as signi- of the circulatory arrest/​ischaemia and the quality of the resusci-
fying ‘status epilepticus’ and treated aggressively [18]. EEG can tation. The cortex and other areas in the brain with a high density
be necessary to differentiate seizures from myoclonus in patients of nerve cells, such as the basal ganglia (i.e. the grey matter, rather
with decreased consciousness, e.g. after cardiac arrest. Both seiz- than the white matter, representing the axons of the neurons),
ures and myoclonus may be managed with antiepileptic drugs are especially susceptible to ischaemic damage, and likewise the
(AEDs) (typically, valproate and levetiracetam are good first brain hemispheres in general are more susceptible than the brain-
choices). EEG is also indicated when a patient does not recover stem. Although many prognostic factors for awakening have been
after a seizure and the imaging results do not explain persistent identified (e.g. duration until ROSC, initial rhythm, age, etc.), no
coma, to rule out non-​convulsive status epilepticus (continuous single parameter in and of itself has 100% specificity to predict
epileptic activity causing decreased consciousness, with no or persistent coma [20]. It is important to note that residual or low-​
minimal motor signs). Discerning seizures from myoclonus can dose sedation or other confounding factors that normally cause
have prognostic implications, since the first may be treatable and encephalopathy and moderately decreased consciousness (e.g.
treatment of seizures may subsequently result in recovery from uraemic or hepatic encephalopathy) may prolong deep coma in
a comatose state. Furthermore, treating seizures or myoclonus is the setting of post-​anoxic coma, due to higher susceptibility of the
very important because continuous brisk motor (seizure or myo- post-​hypoxic brain to such toxins.
clonus) activity requiring sedation in intubated patients impedes The first steps in the management of post-​anoxic comatose pa-
straightforward neurological assessment. Thus, severe myoclonus tients admitted to the cardiac ICU is TTM targeted between 32°C
not responding to initial AEDs and necessitating sedation for the and 36°C, (analgo-​)sedation, and adequate management of PCAS,
intubated patient often requires higher dosing of AEDs and com- including avoidance of both hypo-​and hyperoxia, hypotension,
binations (two or more) to abolish brisk myoclonic jerks, in order infection prevention, etc., according to current guidelines [21].
140 CHAPTER 14   N eurol o gical assessment of the acu te ca rdiac ca re pati en t

depth of 1–​2 cm only. Amplitude is expressed in microvolts, nor-

Neurological complications mally ranging from 10 to 200 microvolts. The frequency spectrum
in extracorporeal and cardiac of the EEG is categorized as follows: delta <4 Hz; theta 4–​8 Hz;
alpha 8–​13 Hz; and beta >13 Hz. In awake, relaxed adults, with
assist devices the eyes closed, the alpha rhythm predominates. The beta rhythm
In veno-​arterial ECMO-​treated patients, neurological complica- supervenes when the subject is stimulated (e.g. when the eyes are
tions (mainly consisting of IS and ICH) occur in between 5% and opened). Theta and delta waves are seen during normal sleep or
8% of patients, with slightly higher rates reported in eCPR settings sedation. Normally, some theta activity is detectable in awake pa-
[22, 23]. ICH portends a higher mortality rate, whereas this seems tients, but persistent delta activity is considered abnormal. Visual
less so for IS. Risk factors have been identified for ICH and in- online interpretation of the raw EEG is confounded by many
clude low platelets (<80 × 109/​L), female sex, central cannulation, sources of electrical artefacts, including body movements, ECG
and rapid CO2 change at ECMO start. Because patients on veno-​ monitors, and nearby electrical devices. Cortical dysfunction is
arterial ECMO may be sedated, non-​invasive neuromonitoring generally associated with slowing of EEG frequency and a decrease
may be worthwhile to identify neurological complications, since in amplitude of the recorded signal, similar to that produced by
they, especially IS, may be reversible nowadays with timely EVT cerebral ischaemia. EEG activity is very sensitive to cerebral is-
upon prompt identification. In the case of ICH, consideration chaemia, and EEG is able to detect ischaemia instantly upon oc-
should be given to rapid weaning from ECMO, discussions with currence, before infarction (tissue death) occurs. Observation of
the treatment team and family members on prognosis, neurosur- reactivity of the electrical activity to stimulus and spontaneous
gical management, and optimizing coagulation [24]. For left ven- variability in the patterns of EEG activity are associated with im-
tricular assist devices (LVADs), a risk of stroke (both IS/​ICH) has proved outcome in comatose patients, compared with those with
been significant (10% after 6  months and 15–​19% after 12 and a fixed pattern. Continuous EEG monitoring (cEEG) offers ad-
24 months when all assist devices are taken together), but signifi- vantages, compared to intermittent EEG monitoring, due to the
cant improvements have occurred with newer LVADs (HeartMate possibility to detect non-​clinical seizures, which are frequently
3™), with a reported stroke risk of 6% per year [25]. reported in any critical care patient. The introduction of future
computerized algorithms for cEEG monitoring may render this
monitoring even more feasible, as it should allow readily the in-
terpretation of any epileptic activity or asymmetries present in the
Neuromonitoring: who, when, raw EEG tracing without the need for specific expertise.
and how?
Somatosensory evoked potentials
This section summarizes the most important pathophysiological
The major value of evoked potential (EP) monitoring is that these
aspects underlying the available monitors and gives a practical
signals are very resistant to alterations by pharmacological agents
overview of clinical applications.
such as sedatives [26]. However, it is important to note that whereas
the presence of the EP signal seems very resistant, the amplitude
Standard of care: neuromonitoring modalities
of the signal may be decreased, theoretically increasing the risk of
Electroencephalography false negatives. However, in general, absent EPs can still be attrib-
The main indications of EEG in the acute cardiac patient are uted correctly to a genuine functional derangement. Under condi-
excluding seizure activity and prognostication [26]. tions of cerebral hypoxia, evoked responses have until quite recently
EEG to exclude the presence of (non-​convulsive) seizure activity been regarded as a more sensitive marker of irreversible hypoxic
is indicated in these circumstances: (1) patient not awakening after cellular damage than the EEG. However, more recently, several
a discrete epileptic seizure which may be due to persistent non-​ malignant EEG patterns with zero false-​positive rate have been
convulsive seizures or non-​convulsive status epilepticus; (2) un- reported (meaning that the presence of the unfavourable pattern
explained unresponsiveness/​coma, including not awakening after has an almost 100% predictive value for death or persistent vegeta-
halting sedation, especially when subtle signs indicating possible tive state or severe disability, comparable to that of an absent SSEP
seizure activity are present (such as nystagmus, subtle twitches of signal) [28]. Measurement and recording of EPs require computer-​
muscles anywhere in body, and incidental myoclonus); (3) moni- assisted analysis, because the amplitude of the EP signal is so low
toring of treatment effectiveness in the case of status epilepticus that it cannot be differentiated from background EEG activity.
(which then involves continuous EEG monitoring for a prolonged Computer analysis is facilitated by the fact that EP signals occur at
period of time); and (4) differentiating epileptic myoclonic jerks a predictable interval after a standardized stimulus, so averaging of
from non-​epileptic myoclonic jerks [26]. EEG as a prognostic in- many responses can be performed. The information derived from
vestigation is indicated mainly in post-​anoxic coma patients who the interpretation of an EP response includes the post-​stimulus la-
fail to regain consciousness after TTM and when sedatives have tency (in milliseconds) and the peak amplitude (in microvolts) of
been interrupted [20, 27]. the various waveforms in the tracing. Abnormalities are classified
The standard EEG is the summation of electrical activity gener- as an absence of certain waveforms, prolonged latency, or reduced
ated in the pyramidal cells of the cerebral cortex. The EEG signal amplitude. Several neural pathways lend themselves to EP moni-
recorded at the scalp represents the activity of cortical cells to a toring, but the most commonly used in clinical practice is the SSEP.
 N eu ro mon i tori n g moda l i ti es : w hat othe r op t i on s ? 141

Imaging of the brain outcome after cerebral insults. However, this qualitative assess-
Neuroimaging provides a non-​invasive, reliable method of as- ment is not very reliable when it is evaluated by the human eye.
sessing structural brain injury. Computer algorithms seem necessary to quantitatively assess
the prognostic value of the grey-​to-​white matter ratio for clin-
Computerized tomography ical use, and the prognostic value reportedly varies [29,  30].
CT scanning is one of the most frequently used tests for neuro- On the other hand, when there is complete filling of the intra-
logical deterioration. cranial space by brain tissue with darkened (hypodense) brain
In terms of indications, CT allows the immediate detection of tissue on CT, without any grey–​white matter (grey-​scaled)
the presence of a localized ICH or SAH. Therefore, in a patient differentiation, it is generally safe to say that the chance of
with a focal neurological deficit with or without decreased con- recovery has been reduced to zero (the situation described ac-
sciousness, an immediate CT of the brain should be performed to tually constitutes impending or actual brain herniation and
rule out an ICH or SAH. When an acute focal neurological deficit subsequent brain death).
is accompanied by a ‘normal’ CT (which is often not the case since
Magnetic resonance imaging
the experienced rater—​either a neurologist or a radiologist—​will
often see subtle changes indicating ischaemia, which will be less MRI is based on magnetism which differs between different tissue
evident to less experienced clinical observers), the diagnosis in types, explaining the high spatial resolution of this imaging mo-
principle is an ‘IS’, which should nowadays be accompanied by a dality. Since sensitivity of CT is inferior to that of MRI due to
CTA to assess for the presence of an arterial occlusion, to be able lower resolution and the possibility of MRI to change the imaging
to perform acute EVT [15]. Early signs of ischaemia can often mode to evaluate different target tissues (e.g. fat, fluid), MRI can
be seen on an early CT, but it requires experience to recognize help to understand what is going on in several scenarios where
such changes. Acute IS of large hemispheric areas, e.g including CT is inadequate—​multiple small embolic infarcts due to endocar-
the entire anterior circulation due to carotid artery occlusion or ditis or in so-​called ‘strategic’ locations such as the thalamus with
dissection, or IS of the posterior circulation are more often ac- small infarcts impacting hugely on consciousness; evaluation of is-
companied by decreased consciousness. Another, sometimes chaemic white matter changes not visible on CT, or, less commonly,
overlooked, indication for brain CT next to a suspicion of stroke meningitis with visible thickening of the meninges surrounding
is post-​cardiac arrest coma in a patient without evident CAD. the brain; or multiple small metastases which may not be visible
Such patients require brain CT scanning to rule out neurological on CT but may cause recurring seizures and persistent coma.
diagnoses, especially aneurysmal SAH, and CTA when focal Furthermore, MRI may have a good predictive value in combin-
brainstem deficits are present indicating a posterior circulation ation with prognostic machine learning, due to its ability to show
stroke. If CT is normal and CAD absent, primary rhythm disturb- widespread ischaemic white matter lesions not visible on CT [31].
ances, e.g. due to genetic causes or previously unrecognized car- However, compared with CT, MRI poses practical barriers for crit-
diomyopathy, become more probable. Another indication for CT ically ill patients.
on admission after cardiac arrest (and coma) is suspicion of head
trauma, which should not be omitted in the case of a bystander-​
reported head trauma at the moment of arrest or other signs of
Neuromonitoring modalities:
external injury cranial to the shoulder level. what other options?
A normal CT scan of the brain shows a clear difference be-
This part helps the reader understand the principles of other
tween the white matter, with its high lipid content, and the
neuromonitoring modalities, to get a basic grasp of the potential
grey matter with its high water content. After global cerebral
value or pitfalls for clinical practice.
anoxia (e.g. following cardiac arrest), inadequate production
of adenosine triphosphate (ATP) that accompanies global is-
Monitoring cerebral perfusion
chaemia results in an overall increase in water content (cyto-
toxic oedema). Furthermore, a delayed form of brain swelling
and oxygenation
can occur which is related to ischaemia–​reperfusion injury. The adequacy of cerebral perfusion is usually monitored as a de-
Initially, the cerebral blood vessels collapse, resulting in a de- rived value, rather than as a directly measured parameter, because
creased intracranial volume. If systemic hypotension is cor- of the complexity of cerebral blood flow (CBF) measurements. In
rected, this results in distension of the deep medullary veins. order to optimally interpret any monitoring parameter on cere-
As a result, the white matter becomes distended with blood bral perfusion, a basic knowledge of the physiological regulation
and appears denser on unenhanced CT scans. Therefore, a loss of cerebral perfusion is required. CBF is determined by cerebral
of distinction between the grey and white matter after car- perfusion pressure to resistance:
diac arrest could result from a combination of decreased grey
matter intensity, due to cytotoxic oedema, and increased white CBF = CPP/CVR
matter intensity, due to distension of the medullary draining [where CPP is the cerebral perfusion pressure, which is the math-
veins. It has been a general impression that a reduced distinc- ematical difference between MAP and intracranial pressure
tion between the grey and white matter on CT predicts poor (ICP); and CVR is the cerebral vascular resistance.)
142 CHAPTER 14   N eurol o gical assessment of the acu te ca rdiac ca re pati en t

In humans, cerebral autoregulation adjusts CVR automatically blood flow deterioration, i.e. it is a more sensitive tool for very
and continuously, such that global CBF remains constant over large changes in blood flow and it has been used and validated
a wide range of MAP, from 50 to 150  mmHg. In the presence with more established tools to quantify cerebral autoregulation.
of any acute brain injury, such as intracranial bleeding, stroke, NIRS might be useful to monitor gross decreases in cerebral per-
or post-​resuscitation status, however, autoregulation may be re- fusion in at-​risk patients, e.g. in ECMO patients on deep sedation.
gionally or globally impaired, resulting in pressure-​passive CBF Some data indicate that rSO2 might correlate with systemic vari-
regulation and implying the need for meticulous control of MAP. ables after cardiac arrest, but further studies are needed to deter-
In these conditions, every decrease (or increase) in MAP will in- mine whether NIRS-​guided systemic management may improve
duce a reciprocal decrease (or increase) in CBF, thereby reaching outcome [35]. Likewise, admission rSO2 may have prognostic
critical thresholds (for cerebral ischaemia in cases of severe ar- value after cardiac arrest, with a threshold of 40%, but the added
terial hypotension or for severe cerebral hyperaemia with the values of this finding for established prognostic modalities such as
ensuing risk of blood–​brain barrier disruption in cases of severe SSEP are unclear [36].
arterial hypertension). In the absence of critical vascular sten-
osis, CVR is determined by cerebral autoregulation, the level of Case vignette
neural activity, blood viscosity, and arterial CO2 (PaCO2) and ar- A patient with total respiratory insufficiency due to pulmonary
terial O2 tensions (PaO2). Acute incremental changes in PaCO2 fibrosis and right-​sided heart failure awaiting lung transplant-
cause corresponding directional changes in CBF, in the order of a ation while on VA-​ECMO was transplanted and VA-​ECMO was
4% change in CBF per 1 mmHg change in PaCO2. If the intracra- removed. The arterial cannula of the ECMO was in the right sub-
nial compliance is reduced, as in the presence of an intracerebral clavian artery. Post-​operatively, the patient was sedated for some
bleed, any increase in CBF may be accompanied by a rise in cere- time due to the need for mechanical ventilation. When sedation
bral blood volume (CBV). Conversely, alterations in PaO2 cause was stopped on post-​operative day 1, the patient did not awake
opposite changes in CBF. CBF increases abruptly as PaO2 falls and developed anisocoria, and CT showed a large area of right
below 40 mmHg, whereas a rise in PaO2 from the normoxic to hemispheric brain infarction, probably due to embolic stroke and
the hyperoxic range results in a 15% decrease in CBF. This is possibly related to decannulation of the ECMO cannula on the
offset by a corresponding increase in arterial O2 content. Thus, same side. NIRS monitoring could have helped to identify the
monitoring of ABG tensions enhances the interpretation of embolic stroke earlier.
changes in other parameters. Continuous assessment of cerebral
autoregulation can be done using variable techniques (e.g. using Brain ultrasound
US or cerebral oximetry), both with and without the use of an Optic nerve sheath diameter, which can be assessed by US, has
ICP monitor, but has up to now been confined mainly to the re- been reported to correlate with prognosis after cardiac arrest and
search setting [32]. Finally, care should also be taken to render coma and may, after further validation studies, become an add-
the patient euvolaemic, since both hypo-​and hypervolaemia ition to the prognostic armamentarium at the ICU. Transcranial
(and subsequent venous congestion) may induce further brain Doppler (TCD) is well known for its ability to detect microemboli
damage, especially in the acute phase after cardiac arrest [33]. to the brain which may be relevant in patients on ECMO [36].
Further applications include assessment of autoregulation,
Near-​infrared spectroscopy vessel patency, and non-​invasive imaging of the brain—​US can
Near-​infrared spectroscopy (NIRS) constitutes an easy-​to-​use, identify different types of stroke (ICH versus IS) at the bedside
non-​invasive technique based on light absorbance at wavelengths as a screening tool or a midline shift due to a cerebral space-​
of 680–​1000 nm, which is absorbed by oxy-​and deoxyhaemoglobin occupying lesion. However, as with many monitoring tools in in-
chromophores (but also by cytochrome oxidase, which is the ter- tensive care, evidence that its use impacts on patient outcome is
minal enzyme of the respiratory chain) but penetrates (skull) bone absent. Further, application of brain US and its various specific
and skin easily, and indicates the level of mixed arterial and venous possibilities requires training and experience, rendering it rather
cerebral oxygen saturation [regional oxygen saturation (rSO2)]. It difficult for non-​expert health care providers to use on a routine
is quite well established for brain monitoring in cardiac and ca- basis [36].
rotid artery surgery and paediatric/​neonatal ICU settings, but less
so for adult ICU [34]. Barriers hampering its widespread use and Other modalities
increasing difficult interpretation include extracranial contamin- ICP monitoring is generally not indicated in acute cardiac patients,
ation by the skin of the forehead, not reflecting one-​on-​one the unless they acquire a neurological condition that would other-
CBF, and wide inter-​and intra-​individual variability of the satur- wise require such monitoring. When CT shows brain swelling
ation within physiological (non-​pathological) boundaries (thus, in the acute phase after resuscitation in a comatose patient, ICP
pathological thresholds of saturation from NIRS are ill charac- monitoring is neither indicated nor of proven benefit, since such
terized). NIRS performs better in identifying total or very severe (massive) swelling usually indicates a dismal prognosis.
 N eu ropro g n o st i c at i on 143

motor responses, bilateral loss of pupillary light responses re-

Neuroprognostication mains a robust indicator of poor outcome, independent of the
application of TTM. It is, however, of key importance that any
(See E Figure 14.3 [20, 38].)
confounders that may impact on motor or pupillary responses
Monitoring the brain function in the acute cardiac care patient
are excluded. In case of doubt and especially when using
is mainly applied to comatose patients admitted after cardiac
benzodiazepine-​based sedation during TTM, excluding residual
arrest. For prognostic evaluation, no differentiation is made be-
sedation by assessing residual blood or urine metabolites is es-
tween OHCA and IHCA, although the latter has a worse prog-
sential since the post-​anoxic brain may be particularly sensitive
nosis. The degree of hypoxic–​ischaemic brain damage, caused by
to even very low levels of residual sedation. Before any ancil-
insufficient flow during cardiac arrest and CPR, and the ensuing
lary tests to assess prognosis are done, an unconfounded neuro-
global reperfusion injury after ROSC, are widely considered as
logical assessment should always be performed first. Of note, a
the determining factors for brain injury. Over the past decade,
GCS score that is slowly improving every day requires observa-
outcome substantially ameliorated due to improvements in ALS,
tion and continued re-​evaluation, rather than ancillary testing
emergency coronary interventions, implementation of TTM, and
to confirm poor prognosis! Furthermore, a grimace that can be
intensive care management with haemodynamic targets aimed
consistently elicited upon a painful stimulus should cast serious
at optimization of (extra-​) cerebral perfusion. Despite these im-
doubt on a perceived poor prognosis, including non-​awakening
provements in post-​resuscitation care, about 50% of patients suc-
in due time.
cessfully resuscitated out of hospital and admitted to the ICCU
still die or end up with a poor neurological prognosis. Following
cardiac arrest, it is of utmost importance to distinguish as early EEG
as possible between delayed awakening or prolonged coma and EEG signals directly reflect synaptic activity in cortical neurons
irreversible neurologic injury. Recently, a sequential algorithm and therefore provide valuable insights into the degree of neur-
on neuroprognostication after cardiac arrest has been adopted onal injury in the post-​ischaemic brain of cardiac arrest patients
by international guidelines that includes four main modalities [20, 26]. The interpretation of a routine EEG should cover three
which—​whenever possible—​should be used in conjunction with main aspects: (1) background activity; (2) EEG reactivity; and
each other, i.e. clinical examination, electrophysiology, blood bio- (3)  the presence of epileptiform features or status epilepticus
markers, and brain imaging [38]. [27]. These features should ideally be assessed in both the early
and late stages following cardiac arrest, implying that EEG re-
Clinical neurological examination cordings should be initiated as soon as possible after hospital
admission. In the context of neuroprognostication, studies
Clinical neurological examination is still the gold standard to
demonstrated that the highest predictive power of EEG lies
assist with neuroprognostication. A  clinical examination in-
within 12–​24 hours after ROSC. Multiple EEG background pat-
cludes the assessment of motor responses to pain and brainstem
terns can be classified as malign and are strongly indicative of
reflexes, in particular pupillary light responses. In contrast to

Box 1
<M3 (GCS) and
EEG with malignant pattern**
TTM (0–24h)
OR
Sedation
Bilateral absent SSEP
OR
Exclude
Large unresponsive pupils:
confounders*
POOR PROGNOSIS
and assess Box 2
GCS NO BOX1 FEATURES and <M3 (GCS) and two or more of:
(24–72h) • Diffuse oedema or clearly diminished grey-white matter
differentiation <7 days
Exclude • Early status myoclonus (<48h of admission)
confounders* • High NSE levels
POOR PROGNOSIS likely
and assess
Consider limiting treatment based on multidisciplinary discussions
GCS
and family consultations
(>72h)
*See text for explanation
**See text: EEG is valid from 12h of TTM and independently of sedation

Figure 14.3  Prognostication after cardiac arrest in patients with persistent coma after halting sedation. Red text (BOX 1): prognostic factors with very high
reliability to predict poor prognosis. Blue text (BOX 2): prognostic factors which, combined, yield high reliability for poor prognosis (however, with less certainty
than variables in BOX 1).
144 CHAPTER 14   N eurol o gical assessment of the acu te ca rdiac ca re pati en t

a lack of neurological recovery, i.e. the presence of low-​voltage MRI

(<20 microvolts) or flat EEG at 12–​24 hours, burst suppression
Compared to CT, diffusion-​ weighted imaging of the brain
patterns with generalized epileptiform discharges, and the ap-
(DWI) is considered to be a more appropriate and robust
pearance of a suppression-​burst pattern with identical bursts.
imaging option to visualize hypoxic–​ischaemic cerebral lesions
On the contrary, a normal-​voltage EEG background with con-
after cardiac arrest, and therefore might serve as a prognostic
tinuous activity from 12 hours following cardiac arrest is asso-
adjunct. The majority of studies assessed the prognostic power
ciated with a high likelihood of attaining a good neurological
of DWI based on the calculation of apparent diffusion coeffi-
outcome [20, 38]. Status epilepticus (defined as prolonged peri-
cient values reflecting the degree of diffusion of water mol-
odic or rhythmic epileptiform discharges) after cardiac arrest is
ecules in brain tissue. Two large retrospective multicentre trials
observed in about 30% of patients and is an independent pre-
recently reported an FPR for poor outcome lying between 7%
dictor of poor outcome. However, epileptiform EEG patterns
and 9%, based on different DWI findings. Nonetheless, the in-
are not obligate predictors of dismal prognosis [false positive
sufficient power of available prognostication studies—​which are
ratio (FPR) 9%]. Post-​anoxic status epilepticus, if diagnosed
based on a limited sample size and are mostly retrospective in
and treated early, can be compatible with good recovery, at
nature—​clarifies why a brain MRI is still considered as optional
least in a subset of patients. One of the limitations of the EEG
within the process of neuroprognostication. In clinical practice,
is that a single conventional EEG is only a snapshot of what is
guidelines now recommend its use only in those patients who
occurring in the brain during a limited amount of time (usu-
remain persistently comatose (i.e. >5–​7 days after cardiac arrest)
ally 20–​30 minutes). The obvious application for cEEG moni-
without obvious poor outcome signs based on other prognostic
toring is in seizure detection in the sedated, paralysed patient.
markers [31, 38].
cEEG may be preferable if treatment of seizures is initiated to
monitor the effect of AEDs and the eventual need for further Biomarkers
drug titration.
The best studied biomarker after cardiac arrest is non-​specific
SSEP enolase (NSE). NSE is a glycolytic enzyme found mainly in
neurons and neuroectodermal cells. High serum levels have been
It has been repeatedly shown that bilaterally absent cortical re-
reported with malignant tumours such as neuroblastomas and
sponses (N20) on SSEP are almost 100% predictive of poor out-
small cell carcinoma of the lung. Studies have shown that NSE
come when performed at 24–​72 hours after an arrest (but in
is a marker for severity of neuronal cell injury in many types of
practice, because of residual sedation, application of SSEP after
brain injuries. In a substudy of the TTM trial, thresholds between
48 hours is generally more appropriate) [26, 38]. It is important to
30 and 50 ng/​mL at 48–​72 hours after the arrest were strongly
note that persistent GCS-​M4 scoring can be compatible with ab-
correlated with a poor prognosis with tight FPRs (<3%) and tem-
sent SSEP. Although false negatives have been reported, this may
perature had no impact [39]. Besides, serial NSE sampling be-
or may not be explained by technical or human error in assessing
tween 24 and 72 hours seemed to improve prognostic accuracy
the SSEP and, in any case, argues against using SSEP as a ‘limita-
[40]. One of the major limitations regarding the use of NSE as
tion of care’ test per se, without using other robust (clinical) pre-
a prognostic marker is the large variability in laboratory as-
dictors of poor outcome.
says. To summarize, whether a cut-​off NSE value exists beyond
which neurological recovery is impossible remains to be eluci-
CT
dated. For now, NSE should be used as a valuable adjunct within
Early CT scanning of the brain is commonly used to rule out an the process of early neuroprognostication after cardiac arrest in
unexpected intracerebral cause of coma in patients who remain the context of multimodality monitoring. Like NSE, S-​100B and
unconscious after cardiac arrest. In fact, admission of a comatose others (e.g. neurofilament light chain [41]) seem useful but need
cardiac arrest patient, where the cause of the arrest is ambiguous, further study.
should always be followed by a brain CT scan in order to rule out
any cerebral pathology. Besides, recent studies showed that a brain Pupillometry
CT scan performed within 24–​48 hours after the arrest predicts Pupillometry can be regarded as another ‘biomarker’ that
poor neurological outcome accurately, although the reported sen- seems promising to predict poor outcome in the setting of
sitivity was rather poor. The main CT finding of global cerebral multimodality monitoring after cardiac arrest, with reported
anoxia after cardiac arrest is cerebral swelling, which appears as 100% specificity [42].
a marked reduction in the interface between the grey and white
matter (quantified as the ratio between grey and white matter dens-
ities). A GWR ranging between 1.12 and 1.22 has been associated
with a lower likelihood for a good outcome (FPR 0%). Nonetheless, Conclusion
current guidelines state that further research is mandatory to sup- Neuromonitoring and neurological assessment of the acute
port CT imaging as a prognostic instrument [29, 30, 38]. cardiac care patient should rely heavily and primarily on
 REFERENCES 145

clinical evaluation at the bedside. Established diagnostic tools

are imaging (mainly CT), EEG, SSEP, and potentially biomarkers
Personal perspective
(NSE). More advanced neuromonitoring techniques are avail- Clinical neurological examination should be given atten-
able but have only been truly established in the setting of post-​ tion in the daily rounds, also by the non-​neurologist, given
anoxic coma, with the aim to estimate prognosis more accurately. the importance of early diagnosis of neurological compli-
Advanced neuromonitoring should generally be used only when cations. Early detection facilitates diagnostic, therapeutic,
a clear rationale to their use and clear therapeutic consequences and prognostic information that may have clear relevance
are available, but implementation issues are often barriers to for the quality of care. Acute cardiac patients deserve a
widespread use. holistic view from their health care providers, including
neurological assessment.

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 CHAPTER 15

Monitoring of the kidneys,

liver, and other vital organs
Karl Werdan, Brijesh Patel, Matthias Girndt,
Henning Ebelt, Jochen Schröder, and
Sebastian Nuding

Contents
Summary  147 Summary
Introduction  147 The prognosis of critically ill cardiac patients in the critical care unit and intensive
The kidneys  148 cardiac care unit depends not only on the underlying cardiac disease, but also on
Clinical monitoring of acute kidney injury  148 the development of secondary organ complications and failures. Therefore, close
Clinical staging of acute kidney injury  149
Renal imaging techniques  149 monitoring of vital organs is mandatory in all critically ill cardiac patients to detect
Monitoring of kidney function in cardiac the development of non-​cardiac organ failure as early as possible.
disease  149
Acute heart failure with cardiorenal
syndrome  149
Cardiogenic shock complicating myocardial
infarction  150
Advanced heart failure supported by left
ventricular assist device  151
The liver  151 Introduction
Clinical staging of hepatic
encephalopathy  151 Intensive care deals with patients whose clinical condition may change rapidly and
Biomarkers of liver dysfunction  152 whose illnesses create substantial risk for death or major morbidity. It utilizes pro-
The LiMON monitor  152
Radiographic evaluation  152
cedures and therapies that similarly may have high morbidity and cause rapid, major
Liver biopsy  152 physiologic changes in the patient. In this context, monitoring is a vital and critical part
Monitoring the liver in specific of intensive care.
conditions  152
Monitoring of liver function in severe Severe cardiac disease not only affects the heart, but also impairs other vital or-
sepsis  152 gans of the cardiac patient, including the kidneys, liver, and GI tract. Furthermore,
Monitoring of liver function in cardiac AHF and CS impair systemic microcirculation and may trigger the development
disease  152
The gastrointestinal tract  153 of multiorgan dysfunction syndrome (MODS) and sepsis, with concurrent global
Clinical monitoring of gastrointestinal microcirculatory dysfunction. Therefore, these organ functions and pathophysio-
failure  153 logical states have to be carefully monitored in cardiac patients on the critical care
Clinical staging of gastrointestinal failure  154
Gastrointestinal dysfunction in specific
unit (CCU) and ICCU.
conditions  154
Impaired splanchnic perfusion  154
Splanchnic blood flow under specific
therapeutic interventions  154
Intra-​abdominal hypertension  154
Monitoring of gut dysfunction in cardiac
patients  154
Sepsis: quick SOFA (qSOFA)  155 Personal perspective  159
Monitoring of severity of disease, sepsis, Sepsis: procalcitonin (PCT)  156
disseminated intravascular coagulation, Further reading  161
DIC score  158
and microcirculation  155 Monitoring of microcirculation in cardiac References  161
Severity of disease  155 patients  158 Additional online material  164
Sepsis  155 Mechanical cardiopulmonary support and
qSOFA, PCT, and DIC scores  155 microcirculation  159
148 CHAPTER 15   Mon itoring of  t h e kidneys, l i ver, a n d other vi ta l  org a n s

The kidneys Box 15.1  Clinical measures and biomarkers for the identification

of AKI in critically ill patients
Although, in critically ill patients, the kidney is often just one of The recommended use in critically ill patients is indicated in
a number of failing organ systems, the presence of acute kidney italics.
injury (AKI) confers a disproportionate disadvantage in terms of Overhydration.
◆
survival and leads to an increased risk of developing ‘non-​renal’ Oliguria/​anuria/​polyuria.
◆
complications such as bleeding and sepsis [1]‌. The kidney is the
Electrolyte disturbances (e.g. hyperkalaemia).
◆
main emunctory of waste products, as well as the principal regu-
↑ serum creatinine and serum urea nitrogen.
◆
lator of volume and electrolyte composition of body fluids. To
perform these functions, the kidney produces and subsequently Urinalysis (protein +; glucose +; sediment: leucocytes, RBCs,
◆

cylinders).
excretes urine. In addition, the kidney plays a critical role in the
modulation of arterial pressure, RBC production, and skeletal Creatinine clearance [6]‌.
◆

growth/​structure by secreting humoral factors. Calculation of eGFR [7, 8].

◆

The incidence of AKI in post-​cardiac surgery patients varies GFR by clearance of inulin, 99mDTPA, or iohexol.
◆

from 1% post-​ coronary vascularization to over 30% post-​ Serum cystatin C.

◆

ventricular assist device insertion [2]‌. Definitions of AKI have Urine or plasma NGAL.
◆

changed over recent years through an amalgamation from RBF by selective arteriography, Doppler ultrasonography, or
◆
RIFLE (Risk of renal dysfunction, Injury to the kidney, Failure radionuclide scanning.
of kidney function, Loss of kidney function, End-​stage kidney RIFLE criteria [3]‌: risk → injury → failure → loss (RRT >4
◆
disease, 2004) [3] to AKIN (the Acute Kidney Injury Network weeks) → end-​stage disease (RRT >3 months).
criteria, 2007) [4], through to a merger of RIFLE and AKIN in AKIN criteria (see E Table 15.1).
◆
the most recent KDIGO (Kidney Disease:  Improving Global KDIGO criteria (merger of RIFLE and AKIN).
◆
Outcomes, 2012) guidelines [5]. AKI is defined by using any of eGFR, estimated glomerular filtration rate; GFR, glomerular filtration rate;
the following criteria: NGAL, neutrophil gelatinase-​associated lipocalin; RBF, renal blood flow;
RRT, renal replacement therapy.
◆ A rise in serum creatinine of >0.3 mg/​dL or 26 micromoles/​L
or greater within 48 hours.
◆ A 50% or greater rise in serum creatinine known or presumed to
Since GFR cannot easily be measured directly, endogenous cre-
have occurred within the past 7 days.
atinine clearance is used as a surrogate.
◆ A fall in urine output to <0.5 mL/​kg/​hour for >6 hours in adults
Yet, a 50% reduction in GFR might keep the serum creatinine
and >8 hours in children and young people.
level within the normal range, despite doubling it (e.g. a base-
◆ A  25% or greater fall in estimated glomerular filtration rate line serum creatinine of 0.7 mg/​dL increases to 1.4 mg/​dL in
(eGFR) in children and young people within the past 7 days. response to a 50% fall in GFR). This calculation assumes a con-
A number of clinical symptoms and signs (e.g. biomarkers) are stant rate of creatinine production and sufficient time to reach a
in use for the monitoring of renal function (see E Box 15.1). (See new steady state where the rates of production and elimination
also E Chapter 35.) are identical. A number of alternative markers of renal function
have been proposed, such as neutrophil gelatinase-​associated
Clinical monitoring of acute kidney injury lipocalin (NGAL), KIM-​1, IL-​18, and cystatin C, but none are
The deterioration of renal function may be discovered by a meas-
ured decrease in urine output. Often, it is diagnosed on the basis
of blood tests for substances normally eliminated by the kidney—​ 1000
urea and creatinine. Furthermore, it has been shown that an in-
Serum creatinine (micromoles/L)

crease in serum creatinine of >0.3 mg/​dL (>26.5 micromoles/​L) 800

was independently associated with mortality [9]‌. Similarly, pa-
tients undergoing cardiac surgery showing a post-​operative in- 600
crease in serum creatinine of >0.5 mg/​dL (>44.2 micromoles/​L),
400
but also those with a decrease of >0.3 mg/​dL (>26.5 micromoles/​
L), have worse survival [10].
200
However, the evaluation of renal function by serial assessment
of serum creatinine or urea demonstrates major limitations. For 0
instance, it takes about 24 hours for the creatinine level to rise, 0 50 100 150
even if both kidneys have ceased to function—​daily increase of CreaCl (mL/min)
about 0.9–​2.9 mg/​dL (79–​256 micromoles/​L). Moreover, as indi- Figure 15.1  Relationship between creatinine clearance (CreaCl) and serum
cated when GFR falls, serum creatinine rises (see E Figure 15.1). creatinine.
 T h e   k i dn eys 149

Table 15.1  Classification/​staging system for acute kidney injury

Stagea Serum creatinine criteria (changes within 48 hours) Urine output criteria
c
1 Increase ≥0.3 mg/​dL (≥26.5 micromoles/​L) or increase ≥1.5–​1.9-​fold from baseline <0.5 mL/​kg/​hour for >6 and <12 hours
2 Increase >2–​3-​fold from baselinec <0.5 mL/​kg/​hour for >12 hours
b c
3 Increase >3-​fold from baseline or ≥4.0 mg/​dL (≥354 micromoles/​L), with an acute <0.3 mL/​kg/​hour for ≥24 hours or anuria for ≥12 hours
increase of at least 0.5 mg/​dL (44 micromoles/​L)
a
Only one criterion—​either creatinine or urine output—​has to be fulfilled to qualify for a stage.
b
Given the wide variation in indications and timing of initiation of RRT, patients who receive RRT are considered to have met the criterion for stage 3, irrespective of the stage in
which they are at the time of RRT.
c
If the baseline creatinine value is unknown and no chronic kidney disease is found in the history, a normal baseline serum creatinine value can be assumed and calculated from the
Modified Diet in Renal Disease (MDRD) formula (eGFR before acute disease, 75 mL/​min/​1.73 m2).
Reproduced from Mehta RL, Kellum JA, Shah SV, et al. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007;11(2):R31.
doi:10.1186/​cc5713 with permission from Springer Nature.

currently established enough to replace creatinine as a marker of correlate with mortality [4]‌: 18.5% in AKIN-​1, 28.1% in AKIN-​2,
renal function. For a detailed discussion on biomarkers of kidney and 32.6% in AKIN-​3.
injury, see E Chapter 35. Alternatively, endogenous creatinine
clearance can be monitored by a 2-​hour clearance [6]‌. Again, Renal imaging techniques
stable kidney function is a prerequisite for the estimation of GFR Monitoring of renal function can require the use of one or more
[7, 8]. renal imaging techniques, including US, CT, MRI, radionuclide
imaging, and angiography. Doppler US is the simplest readily
Clinical staging of acute kidney injury available technique; it allows the evaluation of renal vessels (e.g.
Monitoring of the changes of both serum creatinine and urine in renovascular disease) and their flow, and colour Doppler US
output over time already allows for a more sensitive assessment provides a pictorial view of the renal circulation. US is a harmless
of renal function than single measurements (see E Table 15.1). technique that does not require any preparation and is devoid of
Urine output should be evaluated only after clinical exclusion of contraindications.
dehydration. AKI may be diagnosed early when there is rapid re- The renal arterial resistive index (RI) is a sonographic index to
duction in kidney function, as measured by serum creatinine or assess for renal arterial disease and directly reveals and quantifies
based on a rapid reduction in urine output, termed oliguria. The modifications in renal vascular resistance. It is measured as (peak
RIFLE classification [3]‌is based on serial measurements of serum systolic velocity –​end-​diastolic velocity)/​(peak systolic velocity)
creatinine and urine output over up to 7 days and describes three and has a normal value of 0.60–​0.70. This index may be able to
severity levels of renal impairment—​‘risk’, ‘injury’, and ‘failure’—​ detect reversibility of AKI in critically ill patients but requires fur-
in combination with the consequences of ‘loss of function’ and ther validation [11].
‘end-​stage disease’. The RIFLE classification was recently refined Direct quantification of renal blood flow (RBF) is rarely indi-
and published as the AKIN classification with stages AKIN-​1 to cated. Selective arteriography or radionuclide scanning can be
AKIN-​3 [4] (see E Table 15.1) (see also E Chapter 66). Stages used; the gold standard method of para-​aminohippurate clear-
AKIN-​1 to AKIN-​3 are defined by specified increases in serum ance is not applicable in clinical practice. Arteriography will
creatinine or decreases in spontaneous urine output within 48 rarely be used, particularly due to concerns associated with the
hours of an acute insult. Ensuring the patient is in a balanced fluid application of contrast media, and radionuclide scanning is not
state is a prerequisite for calculation of the AKIN stage. However, readily available in many centres.
severe dehydration can mimic a ‘pseudo-​increase’ of serum cre-
atinine. In daily practice, the AKIN classification is more manage- Monitoring of kidney function in cardiac
able than the RIFLE classification and should be the classification disease
of choice for monitoring acute kidney dysfunction in the critically
Every third critically ill patient (37.1%) has one of AKIN-​1 to
ill patient.
AKIN-​3 stages (AKIN-​1, 18.1%; AKIN-​2, 10.1%; AKIN-​3, 8.9%)
Detection of the ‘pre-​failure’ stages is of utmost importance.
[4]‌, which constitutes 5% of CCU patients, 15.4–​19.2% of cardiac
Even relatively mild renal injury, best described by the AKIN cri-
surgery patients, and 51.8–​67.2% of unselected ICCU patients [12].
teria (see E Box 15.1 and Table 15.1), drastically impairs the
patient’s prognosis. However, the criteria for AKIN stages still do
not allow an early diagnosis of renal injury. Patients who need Acute heart failure with cardiorenal
RRT are classified as AKIN-​3. The AKIN criteria can also be ap- syndrome
plied to patients with ‘acute-​on-​chronic’ renal failure if serum Patients with severe heart failure often have renal impairment
creatinine or GFR before the renal insult is known; the diag- [13], with its degree, as measured by GFR, being an independent
nosis can be difficult if this information is missing. AKIN stages and potent predictor of cardio-​ renovascular outcome [14].
150 CHAPTER 15   Mon itoring of  t h e kidneys, l i ver, a n d other vi ta l  org a n s

Cardiorenal syndrome (CRS) I in AHF, which induces rapid de- with no congestion, had no higher mortality (HR 1.04, 95% CI
terioration of renal function, mainly occurs in patients with se- 0.62–​1.73, P = 0.8822) than patients with no congestion and no
vere impairment of LV systolic dysfunction and often indicates worsening renal function. In contrast, patients with congestion
the transition to terminal heart failure [15]. In CS, CRS I is pre- and worsening renal function had a HR of 2.44 (95% CI 1.24–​
sent in about 70% of patients [16]. As the detection of CRS I has 4.81, P = 0.0097), while the HR for patients with congestion, but
therapeutic consequences [15], monitoring of evolving AKI is of with no worsening of renal function, was 1.35 (95% CI 0.52–​3.5,
the utmost importance. P  =  0.5324). Whether or not worsening of renal function is an
In AHF with systolic blood pressure >125  mmHg, worsening independent, or ‘only’ a dependent, risk factor, the prevention of
renal function, defined by serum creatinine increase of ≥0.3 mg/​dL renal dysfunction in AHF should be an important goal of AHF
(27 micromoles/​L) or cystatin C increase of ≥0.3 mg/​L (22 nmol/​L) treatment (see also E Chapter 48).
at day 2, occurs in about 15–​20% and is associated with an in-
creased 180-​day all-​cause mortality [17] (see E Figure 15.2)
[creatinine: hazard ratio (HR) 1.76, 95% CI 1.11–​2.82, P = 0.016; Cardiogenic shock complicating
cystatin-​C: HR 2.10, 95% CI 1.38–​3.20, P = 0.0004). myocardial infarction
The role of worsening renal function as an independent de- AKI occurs within the first 3 days in 55% of shock patients [19].
terminant of outcomes in patients with AHF has, however, AKI risk factors are age over 75 years, LVEF of 40% or less, and use
been questioned [18]. In a series with 599 consecutive patients of mechanical ventilation. Patients developing AKI have a longer
with AHF, those patients with worsening renal function, but hospital stay, a more complicated clinical course, and a significantly

(a) Troponin T (b) Cystatin C (c) AST

0.20 <20% increase 0.20 <20 nmol/L increase (0.3 mg/L) 0.20 <20% increase
≥20% increase ≥20 nmol/L increase (0.3 mg/L) ≥20% increase
0.15 0.15 0.15
Cumulative risk

Cumulative risk
Cumulative risk

0.10 0.10 0.10

0.05 0.05 0.05

1.80 (1.16, 2.78) 2.10 (1.38, 3.20) 1.66 (0.92, 3.00)
P = 0.0076 P = 0.0004 P = 0.0987
0 0 0
0 20 40 60 80 100 120140 160180 0 20 40 60 80 100 120140 160180 0 20 40 60 80 100 120140 160180
Study day Study day Study day
Number at risk: Number at risk: Number at risk:
<20% increase 825 810 799 790 782 775 771 762 750 654 <20 nmol/L increase 869 851 841 834 826 819 815 804 798 687 <20% increase 906 882 872 861 852 845 841 830 827 718
≥20% increase 231 219 218 216 210 207 204 200 199 174 ≥20 nmol/L increase 212 202 199 194 187 184 181 179 179 160 ≥20% increase 99 96 95 95 92 89 87 87 86 71

(d) ALT (e) NT-proBNP (f) Worsening heart failure

0.20 <20% increase 0.20 <30% decrease 0.20 No WHF to day 5
≥20% increase ≥30% decrease WHF to day 5
0.15 0.15 0.15
Cumulative risk

Cumulative risk

Cumulative risk

0.10 0.10 0.10

0.05 0.05 0.05

1.96 (1.13, 3.40) 0.47 (0.31, 0.69) 1.90 (1.11, 3.22)
P = 0.0152 P = 0.0001 P = 0.0164
0 0 0
0 20 40 60 80 100 120140 160180 0 20 40 60 80 100 120140 160180 0 20 40 60 80 100 120140 160180
Study day Study day Study day
Number at risk: Number at risk: Number at risk:
<20% increase 970 946 935 924 914 907 901 889 885 767 <30% decrease 395 376 372 365 357 351 349 341 339 288 No WHF to day 5 1058 1030 1018 1010 994 985 977 964 959 834
≥20% increase 99 94 92 91 88 85 84 84 83 69 ≥30% decrease 686 677 666 663 656 652 647 642 638 559 WHF to day 5 103 98 97 92 88 88 88 88 87 73

Figure 15.2  Changes in markers of organ dysfunction, damage, and congestion, and 180-​day all-​cause mortality in the RELAX-​AHF (Relaxin in Acute Heart
Failure) study. The 180-​day all-​cause mortality of patients with AHF is presented in those patients, with and without a specified increase in organ-​specific
biomarkers from baseline to day 2. (A) <20% increase versus ≥20% (22% of patients) increase in troponin T. (B) <22 nmol/​L versus ≥22 nmol/​L (20% of patients)
increase in cystatin C. (C) <20% versus ≥20% (10% of patients) increase in serum AST. (D) <20% versus ≥20% (9% of patients) increase in serum ALT. (E) <30%
(30% of patients) versus ≥30% decrease in NT-​proBNP. (F) No worsening heart failure versus worsening heart failure (9% of patients) by day 5. ALT, alanine
aminotransferase; AST, aspartate aminotransferase; NT-​proBNP, N-​terminal pro-​brain B-​type natriuretic peptide; WHF, worsening heart failure.
Reproduced from Metra M, Cotter G, Davison B, et al, for the RELAX-​AHF Investigators. Effect of Serelaxin on Cardiac, Renal, and Hepatic Biomarkers in the Relaxin in Acute Heart
Failure (RELAX-​AHF) Development Program. J Am Coll Cardiol 2013; 61(2): 196–​206 with permission from Elsevier.
 The liver 151

Table 15.2  Predictors of 12-​month mortality in the IABP-​SHOCK grounds, creatinine should be preferred, since it is much less in-
II trial fluenced by changes in nutritional state and catabolism than urea.
(See also E Chapter 28.)
Predictor HR (95% CI) P-​value
Age, per 10 years 1.25 (1.12–​1.39) <0.0001
History of stroke 2.00 (1.37–​2.93) 0.0004
The liver
Baseline serum lactate, per 10 mmol/​L 1.24 (1.10–​1.39) 0.001
Adequate liver function is essential for the survival of critically ill
Baseline creatinine, per 100 micromoles/​L 1.23 (1.08–​1.40) 0.002
patients. Global aspects of liver function are well appreciated: bile
Altered mental status 1.57 (1.15–​2.16) 0.005
production, protein synthesis, glucose homeostasis, and fat pro-
Oliguria (<30 mL/​hour) 1.40 (1.08–​1.82) 0.01 duction. Recognition of hepatic dysfunction can be problematic.
pH <7.36 at admission 1.35 (1.02–​1.79) 0.04 Often patients with compensated liver disease are not identified,
LBBB 1.41 (1.01–​1.98) 0.04 until additional stress, such as infection or haemorrhage, results
in hepatic decompensation.
LBBB, left bundle branch block.
Reproduced from Thiele H, Zeymer U, Neumann FJ, et al. Intra-​aortic balloon An elevated serum bilirubin concentration of >2 mg/​dL within
counterpulsation in acute myocardial infarction complicated by cardiogenic shock 48 hours of admission, without a history of liver disease, occurs
(IABP-​SHOCK II): final 12 month results of a randomised, open-​label trial. Lancet
in 11% of critically ill patients and is an independent risk factor
2013;382(9905):1638–​1645. doi:10.1016/​S0140-​6736(13)61783-​3 with permission
from Elsevier. for poor prognosis [26], with a longer median ICU stay and an
increased hospital mortality (30.4% versus 16.4%; P <0.001). Pre-​
higher mortality rate (50% versus 2.2%; relative risk 12.3). In these existing liver cirrhosis even doubles the mortality risk in patients
shock patients, as studied in the TRIUMPH trial [20], a reduced with ICU-​acquired pneumonia [27].
creatinine clearance is one of the three most important predictors
of mortality, besides reduced systolic blood pressure and vaso- Clinical staging of hepatic encephalopathy
pressor support [21]; for every 10 mL/​minute increment of re- Hepatic encephalopathy can be classified in four stages, depending
duced creatinine clearance, the 30-​day mortality is lowered by 23%. on clinical severity (see E Table 15.3). It is likely mediated, in
In comparison, a 10 mmHg increase of systolic blood pressure at part, by the pathway of the receptor for GABA, via which barbit-
shock confirmation reduces the 30-​day mortality risk by 35%. urates and benzodiazepines produce their effects. It may be ex-
One of the largest trials yet concerning CS complicating acerbated by anaesthetic agents, analgesics, and anxiolytics that
MI—​ the IABP-​ SHOCK II trial with 600 patients included are commonly used in the CCU.
[22]—​has identified several predictors of 12-​month mortality
(see E Table 15.2), with baseline creatinine and oliguria being
two markers of acute kidney failure, out of eight markers, valid-
ated by multivariate analysis [23]. Table 15.3  Clinical stages of hepatic encephalopathy
Finally, by analysing the results of 1600 patients from the
Stage Clinical features
SHOCK trial and registry and from the TRIUMPH trial, the fol-
lowing mortality risk factors have been identified by multivariate I Short attention span
Nightmares
analysis [24]: Poor night-​time sleep with daytime sleepiness
◆ Age. Restlessness
◆ Anoxic brain damage. Depression
Aimless wandering
◆ End-​organ hypoperfusion. Anxiety
◆ Stroke work. Irritability
◆ LVEF. II Drowsiness
◆ Systolic blood pressure and vasopressor support. Obvious personality changes
Gross impairment of ability to do mental tasks
◆ Creatinine clearance. Slowed response
Taking all findings together, the importance of acute kidney Disobedience
Sullenness
failure as an important risk marker, or even as a risk factor, for the Disorientation for time and place
worse outcome of CS is clearly evident.
III Bizarre behaviour
Occasional fits of rage
Advanced heart failure supported by left Marked confusion
ventricular assist device Incomprehensible speech
Paranoia and anger
Serum creatinine and blood urea nitrogen can be used to monitor
improvement of renal organ function [25]. From theoretical IV Coma
152 CHAPTER 15   Mon itoring of  t h e kidneys, l i ver, a n d other vi ta l  org a n s

Biomarkers of liver dysfunction biliary scan, radionucleotide liver/​spleen scan). A detailed discus-

sion is beyond the scope of this chapter.
A detailed review is provided in E Chapter 35. Batteries of bio-
chemical tests are routine in the evaluation of critically ill patients,
Liver biopsy
but they reflect liver function minimally. Nevertheless, many valu-
able inferences can be drawn from these tests. When looking for In the case of acute liver failure, histological data (end-​stage liver
the ‘ideal’ marker, one has to bear in mind which of the specific disease; viral infections) will rarely change therapy [32]. In add-
liver organ functions should be monitored (see E Table 15.4). ition, percutaneous biopsy in an unstable, coagulopathic patient
Tests of hepatic reserve are increasingly important to define the may be deemed too risky; if a biopsy is really necessary, a retro-
viability of donated liver allografts for transplantation and to ad- grade biopsy technique via the inferior vena cava is preferable.
dress the potential impact of major hepatic resections. In patients
with acute liver failure, the brain is exposed to high levels of am-
Monitoring the liver in specific conditions
monia (NH3), which has a neurotoxic effect. An arterial NH3 of Monitoring of liver function in severe sepsis
≥124 micromoles/​L was found to have a sensitivity of 78.6% and a Depending on the marker used, the incidence of liver dysfunc-
specificity of 76.3% as a predictor of death (P <0.001). NH3 levels tion in severe sepsis is found to be 42% (bilirubin >1.2 mg/​dL),
above this value had an OR of 10.9 as a predictor of death (95% CI 11% (bilirubin >2 mg/​dL) [31], 31% (bilirubin >2 mg/​dL) [29],
5.9–​284.0)  [28]. or 74% (PDGICG <16%/​min), and the incidence of severe liver
dysfunction—​as defined by a sequential organ failure assessment
The LiMON monitor (SOFA) subscore for the liver item of 3 or more (bilirubin ≥6 mg/​
The LiMON (Pulsion Medical Systems Ltd) is a non-​invasive dL)—​is 8% [30].
monitor of global liver function. It utilizes the measurement of Conventional markers for liver injury [ALT:  area under the
the plasma disappearance rate of indocyanine green (PDRICG). curve (AUC) 0.48, P  =  0.084; bilirubin:  AUC 0.43, P  =  0.412]
ICG elimination is measured as PDRICG (%/​min), retention rate fail to predict outcome, whereas PDGICG of <8%/​ min (AUC
(R15, %), or blood clearance (CB, mL/​min) and represents the 0.81, P = 0.006), as a complex estimate of perfusion, energy me-
so-​called global liver function, a combination of functional re- tabolism, and transporter function, predicts death with a sensi-
serve of intact hepatocytes and liver perfusion [29]. ICG is tivity of 81% and a specificity of 70% [30] (see E Figure 15.3).
almost exclusively eliminated by the liver, without biotransform- Furthermore, in patients with septic shock, impaired PDRICG is
ation, and does not undergo enterohepatic recirculation. As the associated with the need for RRT and a longer ICU stay.
liver is part of the splanchnic circulation, PDR can be used for
Monitoring of liver function in cardiac disease
the indirect evaluation of liver and splanchnic perfusion. In par-
ticular, repeated measurements with rapid changes in repeated AHF, severe hypotension, and CS can trigger hypoxic hepatitis
LiMON measurements are most likely to reflect changes in [33] where the clinical presentation ranges from asymptom-
splanchnic perfusion. A PDRICG of <16%/​min is assumed to be atic cases to acute liver failure. A  striking increase in serum
pathological [30]. Two-​thirds of surgical intensive care patients aminotransferases, as well as in lactate dehydrogenase (LDH),
qualified for advanced haemodynamic monitoring exhibit re- is typical for hypoxic hepatitis, while jaundice is severe only
duced PDRICG values, accompanied with a significantly increased in cases developing acute liver failure. However, long-​lasting
mortality [31]. hyperbilirubinaemia can occur due to bilirubin tightly bound
to albumin. A rapid decline in serum aminotransferases occurs
Radiographic evaluation once cardiac failure is corrected. Otherwise, an international
normalized ratio (INR) value of >2 is an independent risk factor
Radiography is an essential component of the evaluation of a
for mortality [34]. In patients with AHF (see also E Chapter 45),
patient suspected of having liver disease. Studies can be divided
a ≥20% increase in alanine transaminase (ALT) and aspartate
into those providing a guide to structural distortion (e.g. US, CT)
transaminase (AST) within the first 48 hours increases the 180-​
and those having a functional component (e.g. cholangiography,
day mortality risk by 66% (HR 1.66, 95% CI 0.92–​3.00, P = 0.099)
and 96% (HR 1.96, 95% CI 1.13–​3.40, P = 0.025), respectively
(see E Figure 15.2) [17]. Analysis of the ASCEND-​HF cohort
Table 15.4  Monitoring of hepatic function (enrolment within 24 hours of hospitalization for heart failure or
within 48 hours of a diagnosis of AHF if hospitalized for another
Measure Organ function/​dysfunction
cause) showed in 4228 patients with liver function tests that 42%
AST ↑, ALT ↑ Hepatocellular injury had abnormal bilirubin, 22% had abnormal ALT, and 30% had
Cholinesterase ↓, prothrombin ratio ↓ Impaired synthetic function abnormal AST. Indeed, in multivariate analysis, increased total
CRP ↑, albumin ↓ Acute phase response bilirubin was associated with increased 30-​day mortality or HF
Bilirubin ↑, PDRICG ↓, NH3 ↑ Impaired excretory function rehospitalization (HR 1.17 per 1 mg/​dL increase) [35].
In a meta-​analysis of use of extracorporeal support in ACS, high
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRP, C-​reactive protein;
NH3, ammonia; PDRICG, plasma disappearance rate of indocyanine green. activated clotted time (ACT) was associated with an increased risk
 The g astroi n test i na l   t r ac t 153

(a) 1.0 (b) 1.0

0.8 0.8

0.6 0.6

Sensitivity
0.4 0.4

0.2 0.2 Cholinesterase

AST
ALT Prothrombin ratio
Reference line Reference line
0.0 0.0
0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0
(c) 1.0 (d) 1.0

0.8 0.8

0.6 0.6
Sensitivity

0.4 0.4

0.2 0.2
CRP
Albumin
Bilirubin
Reference line PDRICG
0.0 Reference line
0.0
0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0
1 - specificity 1 - specificity

Figure 15.3  Hepatic parameters in patients with severe sepsis. Relation of hepatic parameters indicative of (A) hepatocellular injury (AST, ALT), (B) synthetic
function (cholinesterase, prothrombin ratio), (C) acute phase response (C-​reactive protein, albumin), and (D) excretory function (bilirubin, PDRICG) to outcome,
as assessed by receiver operating characteristics in 48 patients with severe sepsis. ALT, alanine aminotransferase; AST, aspartate aminotransferase; PDRICG, plasma
disappearance rate of indocyanine green.
Reproduced from Kortgen A, Paxian M, Werth M, et al. Prospective assessment of hepatic function and mechanisms of dysfunction in the critically ill. Shock 2009;32(4):358–​365 with
permission from Wolters Kluwer.

of MOF, and this variable in relation to the severity of shock could Clinical monitoring of gastrointestinal failure
potentially be indicative of liver failure and coagulopathy [36].
In a retrospective analysis of 2588 adult medical and surgical ICU
In patients with advanced heart failure supported by an LVAD,
patients [39], about 10% had GIF, defined as at least one of the
serum ALT, AST, and bilirubin can be used to monitor improve-
following GI problems:
ment of hepatic organ function [25]. In particular, the model for
end-​stage liver disease (MELD) score (used predominantly for ◆ Food intolerance: inability to feed the patient via an NG tube due
prognostication and prioritization for receipt of liver transplant) to vomiting or residue. Vomiting (emesis) is the occurrence of
is predictive of outcome following LVAD implantation [37, 38]. any visible regurgitation of gastric content, irrespective of the
amount. Gastric residual volume could be considered high if a
single volume exceeds 200 mL.
◆ GI haemorrhage:  GI bleeding is any bleeding into the GI tract
The gastrointestinal tract lumen, confirmed by the macroscopic presence of blood in
vomited fluids, gastric aspirate, or stool. The following ICU pa-
The human GI tract has many functions, including facilitating di-
tient groups are prone to GI haemorrhage [40]:
gestion to absorb nutrients and water, barrier control to modu-
Patients with ≥3 accompanying diseases (OR 8.9).
●
late the absorption of intraluminal microbes (and their products),
Patients with coexisting liver disease (OR 7.6).
●
and endocrine and immune functions. Perfusion, secretion, mo-
tility, and a coordinated gut–​microbiome interaction are pre- Patients with RRT (OR 6.9).
●

requisites for adequate function. Acute GI dysfunction and failure Patients with accompanying coagulopathy (OR 4.3).
●

have been increasingly recognized in critically ill patients and are Patients with pre-​existing antacid medication.
●

important determinants of outcome. Increased mortality (43.7% Patients with a higher organ failure score (OR 1.4).
●

versus 5.3%), as well as longer ICU stay (10 days versus 2 days) ◆ Paralysis of lower GI tract (paralytic ileus): inability of the bowel
and longer duration of mechanical ventilation (8  days versus to pass stool due to impaired peristalsis. Clinical signs in-
1 day), accompanies GI failure (GIF) [39]. clude absence of stool for 3 or more consecutive days, without
154 CHAPTER 15   Mon itoring of  t h e kidneys, l i ver, a n d other vi ta l  org a n s

mechanical obstruction. Bowel sounds may or may not be pre- vasoconstriction due to sympathetic overdrive, shifting blood flow
sent on cautious auscultation. to vital organs [42]. The clinical picture varies from mild transient
colitis to the development of extensive gangrene. Blood flow to the
Clinical staging of gastrointestinal failure liver is usually less impaired [43, 44]. Further impairment of mu-
Acute GI injury (AGI) is malfunctioning of the GI tract in critic- cosal microcirculation and disruption of the intestinal barrier re-
ally ill patients due to their acute illness. According to severity, the sult from venous congestion due to right heart failure, with elevated
following grades of AGI can be distinguished [41]: venous pressure, splanchnic congestion, and mucosal oedema [45].
1. AGI grade I (risk of developing GI dysfunction or failure): the Splanchnic blood flow under specific
function of the GI tract is partially impaired, expressed as GI therapeutic interventions
symptoms related to a known cause and perceived as transient.
◆ Enteral feeding increases blood flow in the superior mesenteric
Examples include post-​ operative nausea and/​ or vomiting
artery, and parenteral feeding decreases it [42].
during the first days after abdominal surgery, post-​operative
◆ Reversible bowel ischaemia (up to 40%) is induced by hypo-
absence of bowel sounds, and diminished bowel motility in the
thermic cardiopulmonary bypass [46, 47].
early phase of shock.
◆ PEEP values of up to 10 mbar does not cause deterioration in
2. AGI grade II (GI dysfunction): the GI tract is not able to per- hepato-​splanchnic flow [48].
form digestion and absorption adequately to satisfy the nutrient ◆ In patients with vasodilatory shock after cardiac surgery, even
and fluid requirements of the body. There are no changes in the low to moderate doses of vasopressin induce intestinal and gas-
patient’s general condition related to GI problems. Examples in- tric mucosal vasoconstriction [49].
clude gastroparesis with high gastric residuals or reflux, paralysis ◆ Noradrenaline has minimal impact on mesenteric blood flow,
of the lower GI tract, diarrhoea, intra-​abdominal hypertension although the combination of noradrenaline and dobutamine
(IAH) grade I [intra-​abdominal pressure (IAP) 12–​15 mmHg], increases splanchnic blood flow; vasopressin and adrenaline
and visible blood in gastric content or stool. Feeding intolerance both have negative effects on splanchnic blood flow [50]. In
is present if at least 20 kcal/​kg bodyweight/​day via the enteral pigs with endotoxaemic shock, the combination of dobutamine
route cannot be reached within 72 hours of feeding attempt. plus noradrenaline, but not levosimendan, maintains portal
3. AGI grade III (GIF):  loss of GI function where restoration blood flow [51, 52].
of GI function is not achieved despite interventions, and the Routine nursing procedures in ventilated ICU patients (airway
◆

general condition is not improving. Examples include, if des- suctioning, assessment of level of sedation, changing patient’s
pite treatment, refractory feeding intolerance with high gas- position) may also impair splanchnic perfusion [53].
tric residuals present, persisting GI paralysis, occurrence or
Intra-​abdominal hypertension
worsening of bowel dilatation, progression of IAH to grade II
(IAP 15–​20  mmHg), and low abdominal perfusion pressure As mentioned, the presence of any combination of the causes of
(APP) (below 60 mmHg). Feeding intolerance is present. enteral dysfunction described previously can induce significant
increases in the steady state pressure within the abdominal cavity
4. AGI grade IV (GIF with severe impact on distant organ func- (IAP). This is termed IAH and has been graded into four categories,
tion): AGI has progressed to become directly and immediately depending on the pressure monitored: grade I, IAP 12–​15 mmHg;
life-​threatening, with worsening of multiorgan dysfunction and grade II, IAP 16–​20  mmHg; grade III, IAP 21–​25  mmHg; and
shock (e.g. bowel ischaemia with necrosis, GI bleeding leading grade IV, IAP >25 mmHg [54, 55]. Increased IAP is common and
to haemorrhagic shock, Ogilvie’s syndrome, abdominal com- has significant physiological effects, including compromised renal,
partment syndrome requiring decompression). Abdominal liver, and splanchnic perfusion. Additionally, it can negatively im-
compartment syndrome is defined as a sustained (minimum of pact upon ventilation and, more importantly, affect cardiac pre-
two standardized measurements, performed 1–​6 hours apart) load, afterload, and contractility, all components of cardiac output
increase in IAP above 20 mmHg, with new-​onset organ failure. [56]. It can be monitored through the wall of any hollow viscus or
Most patients develop GIF during the first week of ICU stay. vascular structure which acts as a membrane to transduce pres-
A patient’s profile (emergency surgical or medical), high values of sure. Hence, the stomach, colon, bladder, and inferior vena cava
acute physiology and chronic health evaluation (APACHE) II and have been used. The most common method is through a Foley
SOFA scores, and use of catecholamines (OR 4.16) on admission catheter in the bladder, but this requires a standardized approach
are risk factors for the development of GIF [41]. Daily monitoring to measurement [57]. If accurate, this can prevent, detect early,
of GIF is strongly recommended. and guide the management of increased IAP through medical and
surgical management [55].
Gastrointestinal dysfunction in specific
conditions Monitoring of gut dysfunction in cardiac
Impaired splanchnic perfusion patients
In heart failure and shock, non-​occlusive mesenteric ischaemia is In general, GIF monitoring, i.e. monitoring for food intolerance,
the result of low-​flow states, as well as overwhelming splanchnic GI haemorrhage, and ileus, should be carried out routinely every
 Monitoring of  severi t y of di sease, sepsi s , DI C, a n d  m i cro c i rc ul at i on 155

day in all critically ill patients [41], including those with heart risk of death. In patients with CS complicating MI, the APACHE
disease. The incidence of GIF is 19.1% in medical emergency pa- II score as a marker of severity of disease/​MODS is a better pre-
tients and 5.7% in cardiac surgical patients. The development of dictor of death (AUC 0.85) than the cardiac index (AUC 0.771)
GIF increases the risk of death markedly in medical emergency (see E Figure 15.6) [63].
patients (OR 13.64), as well as in elective cardiac surgery patients
(OR 31.82) [39]. Sepsis
Enteral dysfunction plays an important role in patients with Sepsis nowadays is defined as life-​threatening organ dysfunction
chronic, as well as acute, heart failure. Reduced tissue perfu- caused by a dysregulated host response to infection. For clinical
sion in congestive heart failure results in non-​occlusive mesen- operationalization, organ dysfunction can be represented by an
teric ischaemia and impaired intestinal microcirculation, with increase in the SOFA score of 2 points or more [64]. Septic shock
the consequence of a disturbed intestinal mucosa showing in- is defined as a subset of sepsis with vasopressor requirement to
creased permeability to bacteria and their products, including maintain an MAP of 65 mmHg or greater and serum lactate level
lipopolysaccharide (LPS). As a result of entry into the blood- >2 mmol/​L (>18 mg/​dL) in the absence of hypovolaemia, leading
stream, higher LPS levels have been found in the hepatic veins to particularly profound circulatory, cellular, and metabolic ab-
than in the LV; this translocation of bacterial products, in turn, normalities, resulting in a hospital mortality of >40% [64]. Early
triggers a local, as well as systemic, inflammatory response and detection [65] and treatment [65] are crucial, and improvement in
sepsis [45]. Emerging literature also suggests that both acute and tissue perfusion and microcirculatory flow is essential. A detailed
chronic heart failure are associated with changes in the intestinal overview is provided in E Chapter 70. If sepsis/​septic shock oc-
microbiome and that such changes may relate to gut failure spe- curs in a critically ill cardiac patient, then a fall in SVR may point
cific to these clinical entities [58–​60]. to the development of septic cardiomyopathy (see E Figures 15.7,
15.8, and 15.9) [66], superposing the underlying heart disease and
further deteriorating outcome.
Monitoring of severity of disease,
sepsis, disseminated intravascular qSOFA, PCT, and DIC scores
Sepsis: quick SOFA (qSOFA)
coagulation, and microcirculation
In out-​of-​hospital, emergency department, or general hospital
(See E Figure 15.4.) ward settings, adult patients with suspected infection can be rap-
idly identified as being more likely to have poor outcomes typical
Severity of disease of sepsis if they have at least two of the following clinical criteria
The severity of disease of critically ill cardiac patients can be [64]: respiratory rate of 22/​min or greater, altered mentation, or
characterized by several validated scoring systems (see E systolic blood pressure of 100 mmHg or less. In severely ill cardiac
Figure 15.5) [61]. MODS and sepsis develop in 15–​20% of pa- patients, however, these signs are very often seen too and there-
tients with MI complicated by CS [62] and further increase the fore may not be very helpful in identifying the development of

220
200 32 31 23 20 19 APACHE II score
20 24 19 18 15 Sepsis score
180
Cardiac output SVR-rel. (%)

160
140
120
100
80
60
40
20
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14
Days

Figure 15.4  Case report: patient with pneumococcal sepsis—​reversibility of septic cardiomypathy. In this patient, the SVR-​related cardiac output as a
percentage of normal was determined daily during the course of pneumococcal sepsis, according to 17.12. In addition, the values of serial APACHE II score and
sepsis score (severe sepsis ≥12) monitoring are shown. In this patient, reversibility of septic cardiac impairment is an early and complete process.
Reproduced from Werdan K, Hettwer S, Bubel S, et al. [Septic circulatory shock and septic cardiomyopathy.] Internist 2009;50(7):799–​809 with permission from Springer Nature.
156 CHAPTER 15   Mon itoring of  t h e kidneys, l i ver, a n d other vi ta l  org a n s

(a) (a)
100

80

Percentage of patients (%)

60
Non-survivor
Survivor
40

20
(b)
0
0 1 2 3 4 5 6 7 8
(b)
100 Score 0–2

80 Score 3–4

Survival (%)
60

40 Score 5–6

(c)
20

Score 7–8
0
0 7 14 21 28
Day after admission

Figure 15.6  Prognostic relevance of coagulation abnormalities in ICU

patients with CVD. In 231 ICU patients with CVD (acute disturbed rhythm,
AHF, MI, CS, and resuscitation), coagulation abnormalities were measured
using a coagulation score (ISTH Overt DIC score). (A) The graph shows the
percentage of survivors and non-​survivors in the respective score category.
(B) Survival data (Cox regression analysis) depending on the score categories.
Reproduced from Angstwurm MWA, Dempfle CE, Spannagl M. New disseminated
intravascular coagulation score: A useful tool to predict mortality in comparison with
Acute Physiology and Chronic Health Evaluation and Logistic Organ Dysfunction scores.
Crit Care Med 2006;34:314–​320 with permission from Wolters Kluwer.

sepsis in severely ill cardiac patients. Therefore, the gold standard

of sepsis diagnosis [65]—​blood cultures—​should be drawn when-
ever suspicion of sepsis arises.

Sepsis: procalcitonin (PCT)
The sepsis biomarker of choice is PCT [67], with a half-​life of
about 24 hours. Under normal conditions, plasma PCT is below
0.1 ng/​mL, but in severe sepsis, levels can rise, starting within 2
Figure 15.5  Clinical aspects of DIC and purpura fulminans. (A) Dotted hours. Classification of PCT ranges may be helpful (see E Box
bleeding in an oedematous hand of a patient with septic shock. 15.2). Initial median PCT values have been described: 0.6 ng/​mL
(B) Disseminated ecchymoses in a 24-​year-​old woman with severe in cases of non-​infectious SIRS, 3.5 ng/​mL in sepsis, 6.2 ng/​mL in
meningococcal sepsis. (C) Purpura fulminans in a male patient with sepsis with organ failure (severe sepsis), and 21.3 ng/​mL in septic
pneumococcal septic shock. shock [67]. For a PCT cut-​off value of 1.1 ng/​mL, the sensitivity
Reproduced from Werdan K, Hettwer S, Bubel S, et al. [Septic circulatory shock and
septic cardiomyopathy.] Internist 2009;50(7):799–​809 with permission from Springer for discrimination between sepsis and non-​infectious SIRS is 97%,
Nature. with a specificity of 78% [67]. PCT monitoring every 4–​5 days in
 Monitoring of  severi t y of di sease, sepsi s , DI C, a n d  m i cro c i rc ul at i on 157

Skeletal muscle pO2

Relative GROUP I Relative GROUP III
frequency (%) frequency (%)
12.5 12.5
Patients with severe sepsis Patients with cardiogenic shock
10 (n = 39) 10 (n = 15)

7.5 7.5
Mean pO2 48 torr Mean pO2 22 torr
5 5

2.5 MpO2 2.5 MpO2

(torr) (torr)
0 00
0 10 20 30 40 50 60 70 80 90 100 10 20 30 40 50 60 70 80 90 100
Relative Relative
frequency (%) GROUP II frequency (%) CONTROL GROUP
12.5 12.5
Patients with limited infection Healthy volunteers
10 (n = 16) 10 (n = 10)

7.5 7.5
Mean pO2 28 torr Mean pO2 33 torr
5 5

2.5 MpO2 2.5 MpO2

(torr) (torr)
0 0
0 10 20 30 40 50 60 70 80 90 100 0 10 20 30 40 50 60 70 80 90 100

Figure 15.7  Partial pressure of oxygen (pO2) in skeletal muscle in healthy volunteers and in patients with severe sepsis, CS, and limited infection. pO2 was
measured with a Clark electrode in skeletal muscle. In patients with limited infection, mean pO2 was not significantly different to that in healthy volunteers, but
patients with CS had lower mean pO2 due to reduced O2 delivery. However, in patients with severe sepsis, pO2 was even higher than that of healthy volunteers
due to cytopathic hypoxia.
Reproduced from Boekstegers P, Weidenhöfer S, Kapsner T, Werdan K. Skeletal muscle partial pressure of oxygen in patients with sepsis. Crit Care Med 1994;22:640–​650 with
permission from Wolters Kluwer.

(a) (b) (c)

2 a

3
1

Sublingual
surface

Figure 15.8  Monitoring of blood flow of sublingual microcirculation in critically ill patients with the SDI technique. (A) Concept: 1, green light emitting diodes;
2, CCD camera; 3, magnifying optics. (B) SDI monitoring of arterioles in microcirculation. Magnification ×167. (C) Measuring instrument, with the tip—​protected
by a plastic tube—​placed on the sublingual mucosa. CCD, charge-​coupled device.
Reproduced from Werdan K, Hettwer S, Bubel S, et al. [Septic circulatory shock and septic cardiomyopathy.] Internist 2009;50(7):799–​809 with permission from Springer Nature.
158 CHAPTER 15   Mon itoring of  t h e kidneys, l i ver, a n d other vi ta l  org a n s

(a) (b)
100 +++ 60
95 +++
90
All vessels (%)

85 50
+++$

Absent flow (%)

80
75 40
70
65 30 +++
60
55
50 20
100 10
Large vessels (%)

95
0
90
85
80
60
75
50

Intermittent flow (%)

70
100 40 +++ +++
90
Small vessels (%)

80 +++ +++
70 30
60
50 20
40
30
20 10
10
0 0
Control Cardiac CS Control Cardiac CS
failure failure

Figure 15.9  Sublingual microcirculation of nine patients with AHF and 31 patients with CS, in comparison to that of 15 non-​compromised controls.
Measurements were carried out with the SDI technique (Cytoscan). Data are presented as box plots. (A) Proportion of perfused vessel per visual field.
(B) Proportion of small vessels with absent (top panel) or intermittent (lower panel) perfusion. ‘Large vessels’, >20 micrometres; ‘small vessels’, ≤20 micrometres.
+++, P <0.001 versus control patients. $, P <0.05 CS versus cardiac failure.
Reproduced from De Backer D, Creteuer J, Dubois M-​J, et al. Microvascular alterations in patients with acute severe heart failure and cardiogenic shock. Am Heart J 2004;147:91–​99
with permission from Elsevier.

manifest sepsis and septic shock may help to see a response to DIC problems are often not identified, though they are prognos-
therapy in the individual patient [65]. Conditions with haemo- tically relevant and can be quantified by a simple DIC score (see
dynamic impairment and endotoxin translocation from the gut, E Figure 15.11).
such as CS [68], polytrauma, and large surgical procedures, may
also trigger an increase in PCT. Especially in CS complicating MI, Monitoring of microcirculation
increased PCT levels are found [69–​71], with levels of around in cardiac patients
7 ng/​mL (median) described [71]. These high PCT levels in CS Low cardiac output of patients with severe heart disease like CS
patients—​often reflecting SIRS, but not sepsis—​are indicative of an severely impairs perfusion of vital organs, with the consequence
unfavourable prognosis [69–​71]. For diagnosing sepsis in CS pa- of development of MODS. Besides cytopathic hypoxia with high
tients, a value of 10 ng/​mL, instead of 2 ng/​mL (see E Box 15.2), tissue O2 partial pressure due to impaired mitochondrial O2 util-
has been recommended [70]. ization seen predominantly in septic shock (see E Figure 15.12)
DIC score [72], impairment of microcirculation (small vessels <100 micro-
metres:  arterioles, capillaries, venules) plays a dominant role in
Cogulation disorders—​ disseminated intravascular coagulation
this scenario [73, 74]. In an ICU population, 17% were reported to
(DIC) and bleeding—​are well-​accepted complications of sepsis
have an abnormal microvascular flow, being an independent addi-
(see E Figure 15.10). In critically ill patients with CVD, however,
tive predictor for in-​hospital mortality in tachycardic (heart rate
>90 bpm) ICU patients [75]. With several non-​invasvie methods
like the ‘sidestream dark field imaging’ (SDI), sublingual micro-
Box 15.2  Procalcitonin ranges in the monitoring of sepsis
circulation can be measured in the oral cavity, even in ventilated
PCT <0.5 ng/​mL: severe sepsis very unlikely.
◆ patients (see E Figure 15.13) (see also z Videos 15.1 and 15.2)
PCT >1.0–​2.0 ng/​mL: high risk of sepsis.
◆ [76, 77], and semi-​quantified in a reproducible manner, e.g. with
PCT >2.0 ng/​mL: diagnosis of sepsis highly probable.
◆ the ‘Microvascular Flow Index’ (MFI) (see E Table 15.5) [78].
PCT >10.0 ng/​mL: manifest severe sepsis or septic shock
◆
In AHF and CS, the proportion of perfused sublingual small
highly probable. vessels is reduced, more so in non-​survivors than in survivors
[79, 80]. Topical application of acetylcholine completely restores
 Monitoring of  severi t y of di sease, sepsi s , DI C, a n d  m i cro c i rc ul at i on 159

(a) (b)
100 1
90 0.9
p = 0.5
80 0.8
Observed mortality (%)

70 p = 0.01 0.7
60 0.6

Sensitivity
50 p = 0.6 0.5
40 0.4
30 p = 0.8 0.3 ICU
ICU
20 CCU 0.2 CCU
Line of identity Identity
10 p = 0.09 0.1
0 0
0 0.2 0.4 0.6 0.8 1 0 0.2 0.4 0.6 0.8 1
Risk of death 1 –Specifity

Figure 15.10  Predictability of mortality by SAPS II score in critically ill patients in the CCU and ICU. In 1587 patients (879 in the ICU, 708 in the CCU, with
77% having ACS), SAPS II score was determined within the first 24 hours. (A) Calibration curves—​score-​predicted versus observed mortality—​for ICU and
CCU groups. (B) ROC curves for ICU and CCU patients. AUC was 0.888 for ICU patients, and 0.908 for CCU patients (P = 0.5). AUC, area under the curve; CCU,
coronary care unit; ICU, intensive care unit; ROC, receiver operating characteristic.
Reproduced from Schuster H-​P, Schuster FP, Ritschel P, et al. The ability of the Simplified Acute Physiology Score (SAPS II) to predict outcome in coronary care patients. Intensive Care
Med 1997;23:1056–​1061 with permission from Springer Nature.

mucosal perfusion [80], highlighting the functional character of This becomes evident either from organ-​to-​organ cross-
vasoconstricted vessels, in agreement with the strongly attenuated talk, as seen in CRS of patients with AHF, or from MODS
parasympathetic tone in patients with shock and MODS [81]. In in patients with CS. Consequently, cardiologists should
contrast to sublingual microcirculation, cerebral microcircula- implement non-​cardiac organ monitoring tools and val-
tion is much less reduced in CS, highlighting the autoregulation idate their relevance for our cardiac patients. Tools, such
of this regional perfusion area [82, 83]. as the AKIN criteria, PDRICG, and GIF scores, are available
to monitor kidney, liver, and gut function better than we
Mechanical cardiopulmonary support usually do, but we also have to apply them in our cardiac
and microcirculation patients.
In patients with CS, ECMO and cardiac-​assist systems like the It is also necessary, as a critical care cardiologist, to
IABP and the Impella are in use to support the failing heart. rethink the concept of haemodynamic monitoring.
In case reports, the effects of these devices on microcirculation Macrohaemodynamic monitoring—​ blood pressure
have been described [85]. However, in the only prospective ran- monitoring—​alone is not enough and has not helped us
domized trial (the IABP-​SHOCK II trial), no beneficial effects to improve our patients’ prognosis in recent years. We
were achieved through using the IABP pump on microcircula- now have tools available to monitor microcirculation.
tion [86], in agreement with the neutral effect of this device on These techniques are admittedly still experimental and not
mortality. standard practice in the ICU, but they open up a new field
of understanding about the detrimental consequences of
cardiac failure on the tissue level of vital organs.
And finally, we have to accept that, in CS patients, evolving
Personal perspective MODS or sepsis can threaten the patient’s life, even more so
Many patients with cardiac disease in the CCU or ICCU than the underlying cardiac disease. Consequently, cardi-
not only have ‘cardiac’, but also ‘non-​cardiac’, problems—​ ologists should implement MODS and sepsis monitoring
reduced blood flow in vital organs impairs organ functions. in their routine ICU/​CCU programmes.
160 CHAPTER 15   Mon itoring of  t h e kidneys, l i ver, a n d other vi ta l  org a n s

(a) (b)

N-S 4

3.5 S
30

Cardiac index (L min–1 m–2)

3
APACHE II score

2.5
20 S
2

1.5
10 N-S
1 Cardiac index
APACHE II score
0.5

0 0
hours 0 24 48 72 96
0 24 48 72 96

(c) (d)
2000
BNP
1000
IL-6
1500 N-S

Interleukin (ng/mL)
S 3000
BNP (ng/mL)

1000
2000
N-S
500
1000
S

0 0
0 24 48 72 96 hours
0 24 48 72 96

(e) ROC curve

1.0
APACHE II
Cardiac index
0.8 BNP
IL-6

0.6
AUC
Sensitivity

APACHE II 0.850
0.4 Cardiac index 0.771
IL-6 0.769
ROC curve BNP 0.502
0.2

0.0
0.0 0.2 0.4 0.6 0.8 1.0
Specificity

Figure 15.11  What determines prognosis in patients with MI complicated by CS? Forty patients in the IABP-​SHOCK trial with MI complicated by CS and
early successful PCI treatment have been prospectively randomized for additional haemodynamic support with or without IABP. (A–​D) Serial biomarker
monitoring for the 27 survivors (S) and the 13 non-​survivors (N-​S) of the total group (with and without IABP) during the first 96 hours after starting treatment.
(A) The APACHE II score represents the severity of disease and MODS. (B) The cardiac index represents heart function. (C) Plasma BNP represents pump failure.
(D) Serum IL-​6 represents systemic inflammation. Mean APACHE II score at 0 hour was 18.1 for survivors and 29.9 for non-​survivors; within the next 96 hours,
the APACHE II score fell by 4.2 points in survivors and rose by 1.0 point in non-​survivors. The values for APACHE II and IL-​6 were significantly different at all time
points (P <0.05), and the cardiac index differed significantly at 24 hours (P <0.05). BNP levels, however, were not different between the groups. (E) ROC curve for
mortality of the described patient group calculated from the initial (0 hour) APACHE II score, cardiac index, plasma BNP, and IL-​6. AUC, area under the curve;
BNP, B-​type natriuretic peptide; IL-​6, interleukin-​6; ROC, receiver operating characteristic.
Reproduced from Prondzinsky R, Lemm H, Swyter M, et al. Intra-​aortic balloon counterpulsation in patients with acute myocardial infarction complicated by cardiogenic shock—​the
prospective, randomized IABP SHOCK trial for attenuation of multi-​organ dysfunction syndrome. Crit Care Med 2010;38:152–​160 with permission from Wolters Kluwer.
 REFERENCES 161

Clinical improvement
CO
(L/min)
ASPIRATION
LAVAGE
18

SVR
(dyn*s/cm–5)
100
RR 10
(mmHg) 800
DOPAMINE +
6
50 DOBUTAMINE
400 (mg/h)
10

200
100

15 10 DAY 13

Figure 15.12  Cardiovascular changes in a patient with Pseudomonas septic shock. For further comments, see text.
Reproduced from Werdan K, Hettwer S, Bubel S, et al. [Septic circulatory shock and septic cardiomyopathy.] Internist 2009;50(7):799–​809 with permission from Springer Nature.

20.0
18.0
16.0
14.0 Further reading
CO(L/min)

12.0
10.0
⇐** Bosetti F, Galis ZS, Bynoe MS, et  al. Small blood vessels big health
problems?’:  scientific recommendations of the National Institutes of
8.0 Health Workshop. J Am Heart Assoc 2016;5.pii:e004389.
6.0 Kidney Disease Improving Global Outcomes (KDIGO) Acute Kidney
4.0 ⇐*
Injury Work Group. KDIGO Clinical Practice Guideline for Acute
2.0 Kidney Injury. Kidney Int Suppl 2012;2:1–​138.
0 Samsky MD, Dunning A, DeVore AD, et  al. Liver function tests in
2000 1500 1000 500 0
patients with acute heart failure and associated outcomes:  insights
SVR (dyne cm–5 s)
from ASCEND-​HF. Eur J Heart Fail 2016;18:424–​32.
Figure 15.13  Correlation of CO and SVR in patients with severe sepsis and Reintam Blaser A, Malbrain MLNG, Starkopf J, et  al. Gastrointestinal
septic shock (N = 31). By correlating measured CO with the expected CO of function in intensive care patients:  terminology, definitions, and
a non-​failing heart (upper line, pink) for the respective SVR, the percentage management. Recommendations of the ESICM Working Group on
of expected CO in correlation with the respective SVR can be calculated. For Abdominal Problems. Intensive Care Med 2012;38:384–​94.
instance, the measured CO (blue) is 5 L/​min and the calculated SVR for the
respective determination is 500 dyne cm–​5 s; the expected CO value (for a
healthy heart) is 11 L/​min (pink); then the SVR-​related CO is 5/​11 × 100 = 45%
of normal. CO, cardiac output; SVR, systemic vascular resistance.
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164 CHAPTER 15   Mon itoring of  t h e kidneys, l i ver, a n d other vi ta l  org a n s

82. Wan Z, Ristagno G, Sun S, Li Y, Weil MH, Tang W. Preserved cere- 86. Jung C, Fuernau G, de Waha S, et  al. Intraaortic balloon

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14:193.
 CHAPTER 16

Blood gas analysis:

acid–​base, fluid, and
electrolyte disorders
Farah Shariff and Richard Paul

Contents
Summary  165 Summary
Blood gas analysis and acid–​base Maintenance of acid–​base homeostasis is necessary for normal cellular and organ
disorders  165
function. Outside of normal physiological pH, essential intracellular functions are
Maintenance of acid–​base balance in the
disrupted and extremes of pH are life-​threatening. Arterial blood gas analysis is the
human body  166
The buffer system  166 most common point-​of-​care test in the intensive cardiovascular care unit (ICCU)
Bicarbonate–​carbonic acid buffer  166 and is essential in the evaluation and monitoring of respiratory gas exchange, acid–​
Phosphate buffer  167 base status, and basic electrolyte concentrations. Water and electrolyte disorders
Protein buffers  167
The respiratory system  167 are common in the ICCU with patients presenting with either acute kidney in-
The renal system  167 jury or cardiac failure, or both. It is essential that these are promptly diagnosed
Arterial blood gas analysis  168 and treatment initiated to prevent metabolic decompensation. Therapeutic strat-
Anion gap  168
Respiratory acidosis  169
egies range from simple electrolyte substitution and fluid management, to extra-
Respiratory alkalosis  169 corporeal filtration of excess fluid and electrolytes. This chapter discusses these
Metabolic acidosis  169 systematically.
Metabolic alkalosis  169
Stepwise approach to arterial blood gas
analysis  169
Introduction to fluid and electrolyte
disorders  171
Water and volume disorders  171
Volume depletion  172
Blood gas analysis and acid–​base disorders
Volume excess  173
ABG analysis is the most common POCT in the ICCU. It is essential in the evaluation
Electrolytes and electrolyte disorders  173
Sodium disorders  173 and monitoring of respiratory gas exchange, acid–​base status, basic electrolyte concen-
Hyponatraemia  173 trations (serum [K+], [Na+], [Ca2+]), plasma glucose, and osmolality. It is a rapid way of
Management of mild to moderate being able to glean valuable information in a relatively short period of time.
hyponatraemia  174
Management of severe Any significant deviation from the human body’s normal pH range can lead to intracel-
hyponatraemia  174 lular metabolic derangement and reduced protein synthesis and transport activity, with
Treatment of syndrome of
inappropriate antidiuretic hormone
significant physiological and clinical sequelae (see E Table 16.1) [1]‌. pH derangement
secretion  174 can also reduce the effect of pharmacological agents, leading to treatment and recovery
The Furst formula  175
Management of hyponatraemia in renal
failure  175
Hypernatraemia  175
Potassium disorders  175
Hypokalaemia  175
Hyperkalaemia  176
Disorders of calcium and magnesium
balance  178
Treatment of hypocalcaemia  178 Conclusion  179 Further reading  179
Treatment of hypercalcaemia  178
Treatment of hypomagnesaemia  179 Personal perspective  179 References  180
166 CHAPTER 16   B l o od gas analysis: acid–base, flu i d, a n d el ectroly te di s order s

Table 16.1  Physiological effects of altering pH

Acidosis (decreased pH) Alkalosis (increased pH)

Increased: Increased:
Kreb’s cycle oxidation (muscles and renal cortex)
◆ Insulin-​induced glycolysis
◆
Gluconeogenesis (renal cortex)
◆ Lactate production
◆
Glycolysis
◆
Lipolysis
◆
2,3-​diphosphoglycerate concentration (oxyhaemoglobin dissociation
◆
curve shifted to the right)
Plasma [K+] as a result of reduced insulin secretion
◆

◆ PVR ◆ Responsiveness to catecholamines

Decreased: Decreased:
Hepatic glycogen stores
◆ Kreb’s cycle oxidation (muscles and renal cortex)
◆
Lactate production
◆ Gluconeogenesis (renal cortex)
◆
Insulin secretion and receptor binding
◆ 2,3-​diphosphoglycerate concentration (oxyhaemoglobin dissociation
◆
Pancreatic amylase secretion
◆ curve shifted to the left)
Pulmonary macrophage production
◆
Granulocyte function
◆
Immune response
◆

Mesenteric blood flow
◆ ◆ Vascular tone and resistance
Peripheral vascular resistance
◆
Responsiveness to catecholamines
◆
Threshold for VF
◆

PVR, pulmonary vascular resistance; VF, ventricular fibrillation.

Source data from Powers A. Acid-​Base Balance Critical care nursing of infants and children. 2nd ed. London; 2001. pp. 1–​13.

difficulties. Examples of important agents affected by changes in that pH homeostasis is maintained, acids produced by the body
pH include: must either be buffered (neutralized) or excreted. As H+ ions are
◆ Local anaesthetic agents. needed for so many chemical processes in the body, the majority
◆ Vasopressors. are buffered and recycled, rather than being permanently lost [2].
There are three main mechanisms by which buffering and excre-
◆ Inotropes.
tion are achieved:
◆ Neuromuscular-​blocking agents.
1. The buffer system.
Treatment relies predominantly on correcting the underlying
pathology, thus demanding prompt diagnosis and management 2. The respiratory system.
of the underlying aetiology using clinical and biochemical indi- 3. The renal system.
cators such as ABG analysis. Care should be taken to distinguish
respiratory and metabolic disorders, and acute from chronic The buffer system
conditions with any physiological compensation that may have This is the collective term for multiple buffer pairs, activated im-
occurred. mediately after the addition of an acid or alkali to prevent any
change in the body’s normal pH. As the pKa of a weak acid rep-
resents the pH at which equal quantities of the acid are in both
Maintenance of acid–​base balance the ionized and unionized form, the body’s most efficient buffers
will have pKas close to this normal pH to be able to buffer both
in the human body acids and bases. The most common buffers are the bicarbonate–​
The normal pH range in the human body is narrow (7.35–​7.45). carbonic acid, phosphate, and plasma protein buffer systems [3]‌.
Enzyme reactions, protein synthesis, and ion channels are exquis- Bicarbonate–​carbonic acid buffer
itely dependent on the surrounding pH, and values of <6.8 and
>7.8 are generally incompatible with life. Human metabolism This is responsible for over 50% of the buffering capacity of the
produces either volatile [e.g. bicarbonic acid (H2CO3)] or fixed body and is the main component of ECF buffering (80%). It is
acids (e.g. lactic and pyruvic acid). H2CO3 is the largest source particularly important due to its association with both of the other
of hydrogen ions (H+) in the human body and is a volatile (or re- main buffer systems (respiratory and renal). H2CO3 is a weak acid,
spiratory) acid, in that it dissociates into either H+ ions and bicar- in equilibrium with HCO3−, a weak base, in solution [3]‌.
bonate ions (HCO3−) or CO2 and water, with the respiratory acid
H2CO3  H + + HCO3 −
(CO2) subsequently being excreted by the lungs [2]‌. To ensure
 M a i n tena n ce of aci d –base ba l a n ce i n  the hum a n   b ody 167

When excess H+ ions are added to the system, the equilibrium When blood reaches the pulmonary capillaries, the presence
shifts to the left, with the formation of H2CO3 by the reaction of of a high O2 concentration favours O2 binding and promotes the
H+ ions with HCO3−. When H+ ions are removed from the re- loss of H+ ions from H-​Hb. Reduced haemoglobin is converted
action [or excess base added, e.g. hydroxide ions (OH−)], the to oxyhaemoglobin, and H+ ions are released and buffered by
equilibrium shifts to the right, with the dissociation of H2CO3 to the bicarbonate–​carbonic acid system to form CO2 and water.
release H+ ions. Therefore, when a small quantity of H+ ions is Aqueous CO2 follows a concentration gradient into blood, across
added or removed from blood or extracellular fluid (ECF), the the alveolar membrane, and into the alveolar space where it is
equilibrium is able to shift to maintain a relatively constant pH. eliminated during ventilation [3]‌. This is part of the Bohr effect,
The buffering capacity of this system is further enhanced by its whereby an increase in partial pressure of CO2 in blood or acid-
coupling with the renal and respiratory systems, which can con- osis is associated with a lower affinity of haemoglobin for O2 [4].
trol the concentration of HCO3− and H2CO3 through the elimin- This facilitates O2 transport via haemoglobin from the lungs and
ation of HCO3− and CO2, respectively. its subsequent offloading to metabolically active tissues to meet
their O2 demand [2].
Phosphate buffer
This system has a very low concentration and acts as an intracel- The respiratory system
lular buffer; it also works within RBCs and the renal tubules to
Ventilation plays a major role in pH homeostasis by eliminating
regulate pH. Phosphoric acid is a triprotic weak acid, with three
or conserving CO2. The addition of H+ ions to blood activates the
possible dissociations, each with different pKas [2]‌. At the pH
bicarbonate–​carbonic acid buffer system, increasing H2CO3 con-
of the human body, the predominant buffer pair is dihydrogen
centration. This subsequently dissociates into CO2 and water, and
phosphate (H2PO4−) as the weak acid, and hydrogen phosphate
excess CO2 then diffuses passively into the alveoli of the lungs and
(HPO42–​) as the weak base. The equilibrium formed by these two
is eliminated. Peripheral chemoreceptors in the carotid and aortic
ions in solution is:
bodies and central chemoreceptors in the medulla oblongata are
H2PO4 −  H+ +HPO4 2 − stimulated by free H+ ions, CO2 in plasma, and CO2 in the cere-
brospinal fluid, respectively, to increase the respiratory rate and
The pKa of H2PO4− is 7.21, making the phosphate buffer system tidal volume, leading to greater minute ventilation and increased
an ideal buffer in the human body. CO2 elimination [5]‌. If the HCO3− concentration is increased
Protein buffers (metabolic alkalosis), the CO2 concentration increases to buffer
the excess HCO3− (respiratory compensation). High HCO3− con-
Protein buffers in blood include both haemoglobin and plasma
centration therefore inhibits central and peripheral chemorecep-
proteins. The plasma protein buffering system is the most abun-
tors, resulting in reduced minute ventilation (rate × tidal volume)
dant intracellular and ECF buffering pair but is responsible for
and reduced CO2 elimination [5]. Therefore, by controlling CO2
only 15% of the body’s buffering capacity. Proteins can act as both
concentration of blood, the respiratory system is capable of com-
acid and base buffers, depending on the pH of the solution in
pensating for pH changes due to metabolic derangement. This
which they are, as both their free carboxyl (acid) and free amine
system is quicker than the other major buffer systems, occurring
(base) groups dissociate in solution. At the normal pH of blood
in just minutes.
(7.34), proteins tend to act as weak acids [1]‌.
Haemoglobin and oxyhaemoglobin are the second most abun-
dant buffer pair. While haemoglobin is found intracellularly, it is The renal system
classed as an ECF buffer, as erythrocytes are confined to the ECF. In contrast to the passive elimination of CO2 by the respiratory
As oxygenated blood passes through an organ’s capillary network, system, the kidneys actively regulate acid–​base balance through
two main processes occur: several mechanisms:
1. CO2 from the cells enters erythrocytes and combines with 1. Reabsorption of HCO3− for use in the bicarbonate–​carbonic
water to form H2CO3 by the action of carbonic anhydrase. acid buffer system.
2. Oxyhaemoglobin gives up its bound O2 to the cells, producing 2. Excretion of fixed acids [e.g. ammonium (NH4+) and titratable
reduced haemoglobin (negatively charged). acids] which also results in HCO3− production.
In the RBC, H2CO3 dissociates into H+ and HCO3−. The HCO3− The proximal tubule contributes to acid–​base balance by reab-
ions diffuse into plasma in exchange for chloride (Cl−) ions (the sorbing HCO3− from the urine and the production of NH4+. In
chloride shift) to retain electroneutrality, and reduced haemoglobin response to a low pH, H+ ions are secreted into the urine either
attracts H+ ions (binding them more readily than oxyhaemo- in exchange for Na+ ions via the Na+–​H+ antiporter or by using
globin). This results in the formation of protonated haemoglobin the H+–​ ATPase active transport systems. HCO3− is simultan-
(H-​Hb), which is a weaker acid than H2CO3 [3]‌. The formation of eously reabsorbed in exchange for Na+ ions [6]‌. The overall ef-
the weaker acid results in a lower concentration of H+ ions in the fect is that HCO3− and Na+ ions are reabsorbed from the tubular
erythrocyte (buffering) [2]. lumen in exchange for H+ ions being secreted into the urine [3].
168 CHAPTER 16   B l o od gas analysis: acid–base, flu i d, a n d el ectroly te di s order s

The reabsorbed Na+ and HCO3− ions form sodium bicarbonate Table 16.2  Unmeasured anions and cations contributing to the AG
(NaHCO3) in the tubule cells, which is then useable as a buffer.
Unmeasured anions (mEq/​L) Unmeasured cations (mEq/​L)
The reactions occur in reverse for increases in pH, leading to a
net excretion of HCO3− ions [7]. Phosphate (HPO42–​/​H2PO4−) is Protein (albumin) 15.0 Ca2+ 5.0
a major titratable acid buffer. Excretion of titratable acids is de- Organic acids 5.0 K+ 4.5
pendent on the quantity of phosphate excreted by the kidneys, on Phosphates 2.0 Mg 2+
1.5
intake (e.g. diet), and on phosphate resorption from bone. The rate
Sulfates 1.0
of increase in phosphate is slow and cannot respond quickly to
Total: 23.0 Total: 11.0
an increased acid load; however, NH4+ production can. NH4+ is
produced by the proximal tubular cells from glutamine, in a reac-
tion catalysed by glutaminase that also produces α-​ketoglutarate
normal circumstances, the majority of the gap is made up of nega-
[7]. NH4+ is then secreted into the tubular lumen but reabsorbed
tively charged proteins; however, in complex or mixed metabolic
within the medulla (medullary recycling), during which time it
acidotic conditions, acid anions (e.g. lactate, acetoacetate, and sul-
dissociates to ammonia (NH3) and H+ ions [6]. NH3 then diffuses
fate) may be produced that are not measured by usual laboratory
into the collecting duct where it combines with free H+ ions to
methods [9]‌. The H+ ions produced by these acids are buffered by
form NH4+, which is then excreted in the urine. In acidotic states,
HCO3−, reducing the concentration of the measured anions that,
this process can be amplified. Therefore, excess H+ secretion by
in turn, increases the proportion of these unmeasured anions, and
H+–​ATPase pumps in distal convoluted tubular cells, in response
the gap increases. The predominant unmeasured extracellular
to an acid load, leads to greater NH3 diffusion into the tubules and
cations are K+, Ca2+, and magnesium (Mg2+), so the AG can be
its combination with H+ to form NH4+, and hence greater excre-
affected by increases or decreases in unmeasured cations or anions
tion of free H+ ions. HCO3− is simultaneously produced in the
(see E Table 16.2).
proximal tubules by the metabolism of α-​ketoglutarate and is then
The anion gap is calculated from the following formula:
transferred to the systemic circulation, demonstrating one of the
most important functions of the kidney with regard to acid–​base
balance [7]. As a result of H+ and NH4+ excretion, urine usually has ( ) (
AG =  Na +  + K +  − Cl −  + HCO3 −  )
a pH of approximately 6. Therefore, a particularly low urinary pH
It is now accepted that the formula can be stated without [K+],
(high urine acidity) is a good indicator of renal compensation for
which, under normal circumstances, is very low, leaving the
systemic acidosis; however, as all mechanisms are via active trans-
formula as:
portation, compensation is slow, taking days, rather than minutes.
(
AG =  Na +  − Cl −  + HCO3 −  )
Arterial blood gas analysis A normal AG is <11 mEq/​L, and a high gap usually indicates
metabolic acidosis. Using the AG can help to differentiate between
The interdependence between pH, HCO3− concentration, and HCO3− loss and consumption (e.g. a renal from a non-​renal cause
PaCO2 is the basis for understanding and interpreting acid–​base of metabolic acidosis). An AG acidosis is also present, regardless
balance. These factors enable the differentiation of respiratory from of the pH or [HCO3−], when the AG is >20 mEq/​L [9]‌. Causes of
non-​respiratory acid–​base disturbances, but not metabolic disturb- alterations in the AG are shown in E Table 16.3.
ances, as any change in PaCO2 also causes a change in HCO3− con-
centration. To overcome these limitations, successive investigations
led to the introduction of ‘standard bicarbonate’ and ‘buffer base
Table 16.3  Causes of alterations in the plasma AG
[6]‌, followed by the concept of ‘base excess’ (the concentration of
H+ ions required to return the pH of blood to 7.4) [8]. Conversely, Increased AG Decreased AG
‘base deficit’ defines the amount of strong base that must be added Methanol Decreased unmeasured anions:
to restore normal pH to blood, assuming the blood sample is fully Uraemia Hypoalbuminaemia
oxygenated, at a temperature of 37°C, and PaCO2 is maintained at Diabetic ketoacidosis
40 mmHg. Base excess and HCO3− concentration will inform the Paraldehyde Increased unmeasured cations:
clinician of the degree of acidosis/​alkalosis (with or without pH Inborn metabolism errors/​idiopathic Lithium toxicity
change) but is not able to distinguish the underlying cause (HCO3− Lactic acidosis Hypercalcaemia,
Ethanol toxicity hypermagnesaemia
loss or consumption, unmeasured anions, etc.) [8]. Calculations of
Salicylate toxicity Myeloma
the anion gap (AG) can help with this differentiation. (hypergammaglobulinaemia)
Others: Drugs:
Anion gap Dehydration Iodide
The AG represents the concentration of all unmeasured an- Penicillin Bromide
ions subtracted from unmeasured cations in the plasma. Under Alkalosis (moderately increased AG) Polymyxin B
 Stepw i se a pproach to  a rteria l b l o od g as   a na lysi s 169

Normal AG acidosis results from a net increase in [Cl−], sec- Table 16.4  Physiological effects of hypercarbia by system
ondary to a loss of HCO3−. This is known as hyperchloraemic
Respiratory:
metabolic acidosis and is most commonly associated with:
Increased
◆ rate of ventilation
◆ GI HCO3− loss (diarrhoea, ileus, pancreatic fistula, villous
adenoma). ◆ Increased depth of ventilation
Renal HCO3− loss (AKI, proximal and distal renal tubular acid-
◆ ◆ Increased PAPs
osis, carbonic anhydrase inhibitors). ◆ Severe hypoxaemia (PCO2 >100 mmHg)
◆ Isotonic (0.9%) saline infusion. ◆ Respiratory depression (PCO2 >100 mmHg)
However, in critically ill patients, the usefulness of the AG in Cardiovascular:
interpreting acid–​base disturbances is limited by the tendency for ◆ Vasodilatation and arterial dilatation
these patients to be hypoalbuminaemic. This leads to a reduction
Tachycardia
◆
in the baseline AG [10].
◆ Hypertension (from autonomic stimulation)
Respiratory acidosis ◆ Increased cardiac output
This is caused by an increase in arterial PaCO2 (hypercarbia) and may ◆ Increased myocardial contractility (with acidosis, this is reduced)
be secondary to hypoventilation, poor CO2 clearance from damaged ◆ Arrhythmias
lung parenchyma and alveolar membrane integrity, or increased
◆ Increased coronary blood flow
metabolism with increased CO2 production (e.g. sepsis, burns).
Overfeeding critical care patients, either enterally or parenterally is CNS:
a rare, but important, cause of increased CO2 production [1]‌. ◆ Increased CBF
Hypercarbia causes significant physiological changes. At low ◆ Increased ICP
levels, there is generalized cardiovascular, respiratory, and auto- ◆ Respiratory stimulation
nomic stimulation. However, as PaCO2 rises, this reverses to
Autonomic
◆ stimulation
organ depression, the most important of which is the central ner-
◆ CO2 narcosis
vous system (CNS), leading to drowsiness, respiratory depres-
sion, and eventually coma [2]‌. An alveolar PACO2 of >100 mmHg ◆ CNS depression/​confusion/​coma
is incompatible with life when a patient is breathing room air, due Endocrine:
to associated severe hypoxaemia that will result from the high ◆ Release of adrenaline and noradrenaline
partial pressure of CO2 in the alveolus. Other effects are shown
in ETable 16.4. Over a period of days, metabolic compensation
In intensive care, one of the most common causes is chronic diur-
occurs (increased [HCO3−] via renal excretion of H+).
etic use. Loop diuretics block the Na+–​K+–​2Cl− cotransport system
Respiratory alkalosis in the thick ascending limb of the loop of Henle to inhibit Na+ and
Increased minute ventilation, by increasing either the rate or the Cl− reabsorption [11]. The decrease in Cl− reabsorption increases
depth of ventilation, will result in reduced PaCO2 and respira- the luminal electronegativity of the distal tubules, leading to a com-
tory alkalosis. Without a ‘mixed’ acid–​base disorder, a resultant pensatory influx of H+ and K+ ions into the urine and over time, an
metabolic compensation with decreased [HCO3−] production increase in blood pH. Due to both cations being lost in the urine,
and reabsorption by the kidney will occur over several days [3]‌. this is termed hypokalaemic metabolic alkalosis [12].
E Table 16.5 lists the common causes. A simple acid–​base disturbance is where only one primary de-
rangement is present and responsible for the altered pH. When more
Metabolic acidosis than one system is responsible for the disturbance, it is characterized
HCO3− loss or reduced HCO3− production through renal dysfunc- as mixed. Respiratory compensation occurs within minutes and is
tion or the build-​up of fixed acids through increased production/​ completed within 24 hours; however, renal compensation starts
reduced excretion leads to metabolic acidosis. Respiratory compen- within 6 hours, taking 4–​5 days to be complete [12]. E Table 16.6
sation occurs through hyperventilation to reduce PaCO2. A clin- demonstrates the biochemical changes that are seen on ABG ana-
ical example of this is diabetic ketoacidosis (DKA) where the body lysis in acute and chronic respiratory and metabolic disturbances.
attempts to counteract the pH change from acidic ketone bodies
(acetone, acetoacetate, and β-​hydroxybutyrate) by increasing the
depth and rate of respiration (Kussmaul breathing) [9]‌. Stepwise approach to arterial blood
Metabolic alkalosis gas analysis
Increased [HCO3−] through either HCO3− gain or H+ ion loss causes In order to correctly interpret the acid–​base disturbance, it is ad-
raised blood pH. This is usually slow and accompanied by respiratory visable to use a consistent approach (see E Figure 16.1). Normal
compensation, with an increase in PaCO2 through hypoventilation. values are shown in E Table 16.7.
170 CHAPTER 16   B l o od gas analysis: acid–base, flu i d, a n d el ectroly te di s order s

Table 16.5  Acid–​base disorders: pathophysiology, compensatory mechanisms, and common causes

Disturbance Pathophysiology Compensation PaCO2 HCO3–​ Common causes

Respiratory CO2 retention Production of HCO 3
–​
Primary ↑ Compensatory ↑ Reduced MV
acidosis Pulmonary oedema
COPD exacerbation
Pneumonia
Opiate overdose
Respiratory CO2 removal HCO3–​ removal Primary ↓ Compensatory ↓ Hypoxaemia
alkalosis (↓ H+ excretion) Increased MV (pain/​anxiety)
Salicylate intoxication
Liver failure
PE
Sepsis
Metabolic HCO3–​ removal CO2 removal Compensatory ↓ Primary ↓ Acute renal failure
acidosis (hyperventilation) Acute liver failure
Lactic acidosis
DKA
Hypovolaemia
Shock (all causes)
Metabolic HCO3–​ retention CO2 retention Compensatory ↑ Primary ↑ Vomiting (acute and chronic)
alkalosis (hypoventilation) Diuretic therapy
Hyperaldosteronism (e.g. Cushing’s,
Bartter’s, Conn’s)
Severe hypokalaemia
COPD, chronic obstructive pulmonary disease; DKA, diabetic ketoacidosis; MV, minute ventilation; PE, pulmonary embolism.

◆ Is the pH normal? ● If PaCO2 and [HCO3−] change in the opposite direction, then
If the pH is <7.35, then acidaemia is present; if it is >7.45,
● the primary disorder is mixed.
alkalaemia predominates. If it is normal, there is either no If the trend of change in PaCO2 and [HCO3−] is the same, the
●

disturbance or a compensated or mixed state exists. one with the greatest percentage difference from normal is
◆ Is the primary disturbance respiratory or metabolic? the dominant disorder (as compensation is not perfect).
In relation to the pH change: ◆ If the primary disturbance is respiratory, is it acute or chronic?
If PaCO2 is altered, the primary disturbance is respiratory.
● If PaCO2 is high, it is important to gauge its chronicity by exam-
If [HCO3−] is altered, the primary disturbance is metabolic.
● ining the ratio between the change in [H+] and PaCO2 from their
If both are abnormal, then the directional change should be
● reference values:
compared (see E Figure 16.1), which will help to identify the
∆H+ + ∆PaCO2
specific disorder.
If both PaCO2 and pH change in a direction opposite from
● (where: >0.8, acute; 0.3–​0.8, acute on chronic; <0.3, chronic)
each other, the primary abnormality is respiratory. ◆ If the primary disturbance is metabolic, also calculate the expected
If both PaCO2 and [HCO3−] change in the same direction
●
PaCO2.
(either increasing or decreasing), the primary disorder is
metabolic.
pH

Table 16.6  ABG interpretation: biochemical changes in acid–​base

disturbances Low Normal High
−
Disturbance Acute/​chronic pH PaCO2 HCO3 Base excess
Acidaemia No abnormal Alkalaemia
Respiratory Acute ↓ ↑ ↔ ↔ or mixed acid–
acidosis Chronic ↔ ↑ ↑ ↑ base disorder

Respiratory Acute ↑ ↓ ↔ ↔ High Low Low High

alkalosis Chronic ↔ ↓ ↓ ↓ PCO2 HCO3 PCO2 HCO3

Metabolic Acute ↓ ↔ ↓ ↓
acidosis Chronic ↔ ↓ ↓ ↓ Respiratory Metabolic Respiratory Metabolic
acidosis acidosis alkalosis alkalosis
Metabolic Acute ↑ ↔ ↑ ↑
alkalosis Chronic ↔ ↑ ↑ ↑ Figure 16.1  Algorithm for initial acid–​base interpretation.
 Water a n d volum e   di sorde r s 171

Table 16.7  Normal ABG values to alterations in intake, utilization (including uptake, usage, and
release), or excretion [2]‌.
Parameter Value/​units
pH 7.35–​7.45
[H+] 35–​45 mEq/​L Water and volume disorders
PaCO2 35–​45 mmHg
Water is the most abundant substance in the body, and disorders
PaO2 70–​100 mmHg
of water homeostasis are common. It has several chemical prop-
SaO2 93–​98% erties that are essential for supporting life. It is the major solvent
HCO3− 22–​26 mEq/​L into which other molecules are dissolved in solution, and it has
Base excess –​2.0 to +2.0 mEq/​L a high molar concentration and a small dissociation constant
AG 8–​16 mEq/​L (Kw) [13]. Under normal conditions, the concentration of water
within the human body is extremely high (55.5 mol/​L at normal
body temperature) [13] and it has the potential to dissociate to
● Respiratory compensation for metabolic disorders can be yield H+ ions. The importance of this is that water can provide
marked. This can be investigated using the Winter’s formula the body with an almost endless supply of H+ ions, but with a
to calculate the expected PaCO2: very small dissociation constant (Kw = 4.3), very little is actually
dissociated [13].
PaCO2 = (1.5 × HCO3 −  ) + 8 ± 2 Water constitutes about 60% of the total body weight of the
average human. It occupies two main body compartments, with
● If the actual PaCO2 is the same as the expected PaCO2, then two-​thirds in the intracellular fluid (ICF) and one-​third in the
there is adequate respiratory compensation. ECF, the interstitial fluid, and plasma compartments. Total body
If the actual PaCO2 is less than the expected PaCO2, then
● water (TBW) is dependent upon age and sex, as its value is in-
there is concomitant respiratory alkalosis. versely proportional to total body fat. Water is regulated between
If the actual PaCO2 is more than the expected PaCO2, then
● the two main compartments by the permeability of cellular mem-
there is concomitant respiratory acidosis. branes. Most cellular membranes are relatively permeable to
In general, respiratory compensation results in a 1.2 mmHg
● water; however, they are less permeable to other ions and mol-
change in PaCO2 for every 1.0 mEq/​L change in plasma ecules such as proteins. This causes an osmotic gradient between
[HCO3−], down to a minimum of 10–​15 mmHg and a max- cells and compartments, allowing movement of water across the
imum PaCO2 of 60 mmHg. membranes, down a concentration gradient, until equilibrium is
◆ If the primary disturbance is metabolic acidosis, calculate the AG. achieved. This is the main mechanism by which cells maintain
If it is >11 mEq/​L, then the metabolic acidosis is due to one of
● their fluid volume [13].
the disorders noted in E Table 16.4. If it is normal, then any Movement of fluid across capillary membranes (i.e. between
metabolic acidosis is likely to be GI or renal in origin. the vascular and interstitial spaces) is governed by the Starling
equation [14]. This relates hydrostatic and oncotic forces (Starling
◆ If the AG is normal and the cause is unknown, then calculate the
forces) to the rate of diffusion, as follows:
urine AG (UAG).
This will help to differentiate renal tubulopathies from other
Rate of diffusion ( Jv ) = (K f × ∆P ) − ( σ × ∆ π)
●

causes of non-​elevated AG acidosis.
If UAG is positive: renal tubular acidosis or early acute renal
●
(where Kf is the filtration coefficient, i.e. water permeability; ΔP
failure is the likely diagnosis. is the difference between the capillary and interstitial hydrostatic
If UAG is negative:  most likely a GI cause of metabolic
●
pressure; Δπ is the difference between the capillary and intersti-
acidosis. tial oncotic pressure; and σ is the correction factor or reflection
coefficient).
It is important to conceptualize this equation, as critical care
Introduction to fluid and patients may have significant fluid shifts from one compartment
to another, due to alterations in either hydrostatic (congestive car-
electrolyte disorders diac failure) or oncotic (hypoalbuminaemia) pressure gradients,
Under normal conditions, the fluid and electrolyte contents combined with the loss of capillary membrane integrity, leading
within the cells of the body are maintained at a constant level, des- to the formation of oedema.
pite a constant flux in intake and cellular requirements. This equi- Water balance is regulated by intake and loss (urine, faeces, in-
librium is maintained by control over intake, fluid, solute, and sensible loss). Plasma volume is approximately 4.5–​5 L in a 70-​kg
electrolyte shifts across these cells, and the capacity of the kidney male, with a normal 24-​hour intake of 2–​2.5 L (see E Table 16.8).
to adjust excretion to match the intake and needs of the body. Fluid turnover by the kidney can vary markedly, from 0.5 L
Disorders of water or electrolyte balance therefore can occur due (the minimum to excrete the solute load) to over 20 L per day,
172 CHAPTER 16   B l o od gas analysis: acid–base, flu i d, a n d el ectroly te di s order s

Table 16.8  Daily water balance in healthy adults Table 16.9  Causes of ECF volume depletion

Daily water intake Volume (mL) Gastrointestinal causes

Fluids 1000–​1500 Vomiting (or NG tube suctioning)
Semi-​solid and solid food 700 Diarrhoea
Oxidation 300
Intestinal obstruction (fluid sequestered, rather than excreted)
Total 2000–​2500
Peritonitis
Daily water output Volume (mL)
Pancreatitis
Urine 1000–​1500
Renal causes
Skin 500
Salt and water loss
Lungs 400
Diuretics
Stools 100
Osmotic diuresis
Total 2000–​2500
Acute tubular necrosis (recovery phase of acute renal failure)
Salt-​losing nephropathy
to maintain a tight control over the ECF volume and electrolyte Adrenal insufficiency (e.g. hypoaldosteronism, adrenocortical insufficiency)
concentrations (and indirectly the interstitial and ICF volume) Renal tubular acidosis
[14]. This homeostasis includes the cardiovascular and renal
Water loss
systems. In response to a reduced ECF volume, there will be a
rapid alteration in heart rate, peripheral vascular resistance, Nephrogenic diabetes insipidus
and venoconstriction mediated by catecholamine release, while CNS causes
the slower renal alterations include the activation of the renin–​ Cerebral salt-​wasting syndrome
angiotensin–​ aldosterone pathway and increased aldosterone Cranial diabetes insipidus
secretion, leading to salt and water retention and restoration of
Other causes
the ECF volume [13]. Critically ill adult water requirements start
at 30–​35 mL/​kg/​day or 1–​2 mL/​kg/​hour. These will need to be Bleeding (all sources)
uptitrated in sepsis (capillary leak and relative hypovolaemia), Sepsis
septic shock, and burns. They may also need to be restricted in Shock (septic, neurogenic)
states of volume excess. Burns
Disorders of water balance are those of either volume depletion
Fever
(dehydration) or volume excess (fluid overload).
Source data from Andreoli TE, Abul-​Ezz SR. Fluid and electrolyte disorders. In Cecil
Essentials of Medicine. 8th edition, Saunders: 2010.
Volume depletion
With mild volume depletion, the compensatory haemodynamic
effects include tachycardia, an increase in SVR, and an increase in urine can be inappropriately dilute and have a high salt con-
venoconstriction of the venous capacitance vessels. Arterial blood tent (e.g. nephrogenic diabetes insipidus). High urinary Na+
pressure will be maintained. These compensatory responses (>20 mEq/​L) can also be found with diuretic use and adrenal
to maintain cardiac output continue until the ECF volume is insufficiency [15].
normalized through renal mechanisms [13]. In minor ECF deple- Volume depletion can also be characterized as being isotonic,
tion, there may be minimal clinical findings, apart from a raised hypertonic, or hypotonic. The most common is isotonic and is
heart rate. Moderate to severe ECF volume depletion will result characterized by the loss of both water and Na+ from the ECF
in significant tachycardia and vasoconstriction, poor skin turgor, in equal amounts (e.g. through poor intake, vomiting, or diar-
and increased capillary refill time, with a reduced urine volume. rhoea). As a result, there is no osmotic shift from the intracellular
Severe ECF volume depletion will result in hypotension, mental to extracellular space [15]. Hypertonic dehydration occurs when
obtundation, and oligo-​anuria. These findings may be masked water loss exceeds Na+ loss. This is characterized by an osmotic
by the administration of cardiovascular medications, including shift of water from the ICF to the ECF. This can occur due to os-
β-​blockers and diuretics. The common causes of volume deple- motic diuresis (e.g. hyperglycaemia in diabetes mellitus) and the
tion are shown in E Table 16.9. use of diuretic drugs. It is also the form of volume loss that oc-
During extrarenal volume depletion, the renal system curs in diabetes insipidus. Hypotonic volume loss results in an os-
works to conserve Na+ and water, with a resultant reduc- motic shift of water from the ECF to the ICF and can occur when
tion in urine output, an increase in urinary osmolality (>450 volume depletion is treated with hypotonic solutions. It can also
mOsmol/​kg), and a reduction in urinary Na+ (<15 mEq/​L). occur with diarrhoea (15% of cases) and salt-​wasting syndromes
However, when the cause is an intrinsic renal pathology, the [15]. It is particularly dangerous as water leaves the ECF into the
 El ectroly tes a n d el ectroly te   di sorde r s 173

ICF to equalize the osmotic gradient, causing oedema of tissues

which can include cerebral tissue. Electrolytes and electrolyte disorders
Treatment includes slow correction of the volume deficit and
Maintenance of electrolyte concentrations within narrow limits
monitoring of electrolyte concentration. The choice of fluid to use
is vital to maintain bodily functions. Electrolytes maintain the
for volume expansion is contentious; however, hypotonic solu-
resting membrane potential of cells and the generation of action
tions should be avoided, as these will worsen the imbalance in
potentials and are vital in cotransport mechanisms throughout
Na+ homeostasis and do not stay long in the extracellular space,
the body [13]. Therefore, imbalances, even in single electrolyte
worsening oedema. Hypertonic solutions are reserved for the
concentrations, can have significant multiorgan effects, ranging
treatment of cerebral oedema and should be managed by phys-
from alterations in muscular contraction to arrhythmia [18].
icians with experience in their use.
Fluid osmolality is also carefully maintained between body com-
partments within a narrow range (285–​295 mOsmol/​kg). This is
Volume excess calculated using the formula:
This occurs when salt and water intake (via any route) exceeds
the capacity for excretion by the renal system. Na+ and water re- Osmolality = (2 ×[Na + ]) + [glucose] + [urea]
tention ensues that may be either primary in origin (e.g. renal
and endocrine diseases) or secondary (e.g. heart failure and Increases in plasma osmolality will result in water flux between
pregnancy). The overall effect is that capillary hydrostatic pres- the ICF and ECF and the release of ADH, leading to increased
sure is increased, leading to a net efflux of fluid from the ECF water reabsorption in the collecting ducts and restoration of the
to the interstitial space. Tissue oedema may then ensue. In car- osmolality to within its normal range. Large swings in osmolality
diac failure, poor cardiac output leads to the activation of the lead to excessive fluid movements between the body compart-
renin–​angiotensin–​aldosterone system (RAAS), leading to in- ments that can be harmful.
creased Na+ and water retention and an effective increase in ECF
volume [16]. Sodium disorders
Volume excess can be characterized as being isotonic, hyper- These are usually caused by a free water excess (hypernatraemia)
tonic, or hypotonic. or loss (hyponatraemia). Changes in [Na+] are more likely to
Hypotonic volume excess is the result of an excess of water cause changes in serum osmolality than any other electrolyte
(without concomitant Na+ excess). Most commonly, this is disturbance and therefore have the potential to cause significant
through polydipsia and water intoxication with other causes, fluid shifts.
including increased antidiuretic hormone (ADH) activity and
liver failure. Iatrogenic causes include excessive administration Hyponatraemia
of low-​salt or salt-​free solutions and the use of salt-​poor solu- Hyponatraemia is one of the most common electrolyte abnormal-
tions in prostate and bladder surgery (transurethral resection ities seen and is defined as serum [Na+] <135 mEq/​L. Its aetiology
syndrome). With elevation in ECF volume, capillary hydrostatic is often multi-​factorial, and diagnosis involves taking a thorough
pressure is increased and water diffuses from the ECF into the history to identify the possible cause and any associated symp-
ICF space to balance the osmotic difference, increasing the risk toms and to clarify its duration. Assessment also involves thor-
of cerebral oedema [16]. An excess of water and Na+ in equal ough clinical examination to assess the patient’s overall volume
measures will result in isotonic volume excess, without any status. Treatment is based on the underlying cause and is deter-
transport of fluid between the two compartments [17]. Causes mined by the degree of chronicity and any associated symptoms.
include excessive administration of isotonic solutions (par- Hyponatraemia is considered acute if it has developed in under a
ticularly in patients with anuric renal failure), cardiac failure, 48-​hour period, while it is classified as chronic if present for 48 or
and other renal diseases. Symptoms might include cerebral ir- more hours [19]. Severe hyponatraemia is characterized by [Na+]
ritation, confusion, hypertension, oedema, effusions, and pul- of <120 mEq/​L and is associated with a higher risk of neurological
monary oedema. Hypertonic volume excess results when there sequelae such as low GCS, confusion, and seizures [16].
is an excess of Na+ over water. This results in an increase in Na+ is a major extracellular cation and a major determinant of
serum osmolality and an increase in the ECF volume. To re- serum osmolality. An acute fall in [Na+] results in an associated
store the osmotic equilibrium, water diffuses from the ICF to fall in plasma osmolality levels, with movement of water down
the ECF, further increasing the ECF volume [18]. Causes in- the osmotic gradient, increasing the risk of cerebral oedema [19].
clude the iatrogenic administration of hypertonic solutions, In chronic hyponatraemia, serum [Na+] is often over 120 mEq/​L.
steroid use, Cushing’s syndrome, and states associated with The brain has often had time to adapt to chronic hyperosmolality,
hyperaldosteronism (Conn’s syndrome/​ mineralocorticoid ex- leading to fewer changes in brain cell volume. Paradoxically,
cess). Symptoms are similar to isotonic volume excess, with agi- this adaptation increases the risk of cerebral pontine myelinosis
tation, reduced consciousness, and vomiting. (CPM) if over-​rapid correction of [Na+] occurs [19].
Treatment of volume excess is usually with restriction of fluid Hyponatraemia can be classified according to its volume asso-
intake, salt restriction, and diuretics. ciation; it can be hypervolaemic, euvolaemic, or hypovolaemic.
174 CHAPTER 16   B l o od gas analysis: acid–base, flu i d, a n d el ectroly te di s order s

Hyponatraemia

Hypovolaemia Euvolaemia Hypervolaemia

Renal losses Extrarenal losses Glucocorticoid deficiency Nephrotic Acute and

Diuretic excess, Vomiting, diarrhoea, Hypothyroidism syndrome, chronic renal
mineralocorticoid burns, pancreatitis, ↑ ADH levels cirrhosis, cardiac failure
deficiency, ketonuria, muscle tremors, Psychogenic polydipsia failure
renal tubular acidosis, repletion by Na+- Body cavity irrigation with
metabolic alkalosis, depleting solutions Na+-free solutions
osmotic diuresis Use of non-electrolyte Urinary Na+ Urinary Na+
solutions (prostate surgery) <10 mEq/L >20 mEq/L

Urinary Na+ Urinary Na+ Urinary Na+

>20 mEq/L <10 mEq/L >20 mEq/L Water restriction

Isotonic
Normonatraemia
saline

Figure 16.2  Hyponatraemia: causes, diagnosis, and management.

Management of mild to moderate hyponatraemia Management of severe hyponatraemia

E Figure 16.2 demonstrates the different causes of hyponatraemia Severe symptomatic Na+ depletion (e.g. with neurological
and the basic tenets of acute management. Treatment primarily sequelae) is a medical emergency. These patients should be
depends on the underlying cause, and any overt exacerbating fac- moved to an area capable of providing closer monitoring such as
tors, such as drug precipitants, should be discontinued. level 2 care. Acute management involves the use of hypertonic
Hypovolaemic patients should be treated with 0.9% saline. In saline to gradually correct the hyponatraemia, with the goal of en-
the critically ill, the aim is to increase serum [Na+] by a maximum suring that [Na+] does not rise by >6 mmol/​L in the first 6 hours
of 0.5 mEq/​L/​hour. In these patients, the Na+ deficit should be or 10 mmol/​L in the first 24 hours. Advice from an endocrinolo-
calculated as follows: gist should be sought. Patients who have hyponatraemia for >48
hours are at risk of neurological sequelae if the correction of [Na+]
Na +deficit = [0.6 × ideal body weight × 140 − measured Na + ] occurs too rapidly, due to the development of osmotic demyelin-
ation (CPM) [20].
Hypervolaemic hyponatraemia management should focus on Current UK national guidance is to start with 150 mL of 3% sa-
treating the underlying cause to improve hyponatraemia. In these line IV over 15 minutes [20]. If there is no clinical improvement,
circumstances, water restriction may be all that is required or the dose should be repeated after 20 minutes. Serum [Na+] should
loop diuretics can be used that will produce diuresis that exceeds then be checked at 6, 12, 24, and 48 hours to ensure that over-​
the increased 24-​hour urine Na+ losses they produce and so can correction (serum [Na+] rise of 10 mmol/​L or more in 24 hours or
be used safely. less) has not occurred. If [Na+] rises excessively, then IV dextrose
If a patient is euvolaemic, it is important to confirm that the or desmopressin (e.g. DDAVP) may be required [20]. Serum [Na+]
patient has hypotonic hyponatraemia [18]. Plasma and urine does not need to be normalized with hypertonic saline; an increase
osmolality should be checked and if plasma osmolality is >275 of 4–​6 mmol/​L often leads to major clinical improvements.
mOsm/​ kg, the causes of hypertonic hyponatraemia, such as Treatment of syndrome of inappropriate antidiuretic
hyperglycaemia or mannitol infusions, should be considered. hormone secretion
If the urinary osmolality is <100 mOsm/​kg, primary polydipsia SIADH is characterized by the presence of hypotonic
should also be considered [20]. hyponatraemia in the context of inadequately diluted urine (given
If plasma osmolality is <275 mOsm/​kg and the urinary osmo- the hypo-​osmolality in plasma) [21]. The most common cause of
lality is >100 mOsm/​ kg, urinary [Na+] should be measured. hyponatraemia is non-​osmotic release of arginine vasopressin
SIADH is the likely diagnosis if urinary [Na+] is <20 mmol/​L. If (AVP) [21]. The mainstay of SIADH treatment is fluid restric-
urinary [Na+] is >20 mmol/​L, then the volume status of the pa- tion; however, the degree of restriction varies, depending on the
tient needs to be reconsidered, as this usually reflects intravas- patient’s ability to excrete electrolyte-​free water. This can be ascer-
cular volume depletion [20]. tained using the Furst formula.
 El ectroly tes a n d el ectroly te   di sorde r s 175

The Furst formula ingestion. Hypernatraemia can also be classified as hypervolaemic,

The rationale for the use of this formula is that urine is made of euvolaemic, or hypovolaemic, depending on the volume status
two components—​the free water component and the isotonic of the patient (see E Figure 16.4). Symptoms and signs vary,
aspect [22]. Limiting the intake of water to a level that exceeds depending on the rapidity of development and the severity of the
that of the amount of free water loss will have a direct impact disturbance. In hypovolaemic patients, features of dehydration
on overall plasma tonicity, causing a rise in serum [Na+] [23]. By will also be apparent. In severe hypernatraemia, CNS involve-
determining the amount of free water loss in an individual patient ment can lead to symptoms such as agitation, restlessness, de-
by using this formula, a response to fluid restriction can be creased reflexes, seizures, and coma [20].
The equation: Treatment is focused on diagnosing and managing the under-
lying disorder, and on fluid replacement therapy to treat accom-
Urine sodium concentration (mmol/L)) + panying dehydration. In hypovolaemic hypernatraemia, there is a
urine potassium concentration (mmol/L) Na+ deficit in addition to the water deficit and treatment includes
U/P electrolyte ratio =
ncentration ( mmol/L )
Serum sodium con an isotonic 0.9% saline infusion until the patient is euvolaemic.
In other patients, 0.45% saline can be used. In non-​ severe
A ratio of >1 is suggestive that fluid restriction is unlikely to be hypernatraemia, free water may be used also as replacement [21].
of any benefit due to a lack of free water loss. In those with a ratio The same principles guiding the management of hyponatraemia
of <0.5, fluid restriction is suggestive of response to fluid restric- should be used for the treatment of hypernatraemia, specifically
tion and a restriction of 1 L is recommended [22]. the rate of decrease of serum [Na+]. In patients with central dia-
A state of nephrogenic diabetes insipidus can be induced by drugs betes insipidus, synthetic arginine vasopressin (DDAVP) may be
such as demeclocycline—​a tetracycline derivative that is occasionally used, in conjunction with a specialist endocrinology opinion. In
used to treat SIADH. Its onset of action is unpredictable and it is also nephrogenic diabetes insipidus, salt restriction, in combination
associated with nephrotoxicity. More recently, the use of drugs spe- with a thiazide diuretic, may be successful [21].
cifically targeting vasopressin receptor antagonists, called ‘vaptans’,
have been found to be effective in the management of SIADH. They Potassium disorders
are classified as aquaretics and have a role in specifically inhibiting
K+ is the major cation in the intracellular fluid (ICF). Ninety-​
the reabsorption of water from the renal tubules [21]. Tolvaptan
eight per cent of its total body store is within this compartment,
is one such drug, licensed for the management of euvolaemic
with a normal range of 140–​150 mEq/​L, and amounts to approxi-
hyponatraemia, and binds competitively to V2 receptors, resulting in
mately 3500 mEq. The ECF contains a much smaller amount,
solute-​free aquaresis [21]. Advice on their initiation and ongoing use
with a serum [K+] of 3.5–​5.0 mEq/​L. Approximately 65–​75% of
should be gained from an endocrinologist. A summary of the man-
total body K+ is stored in muscle. The ratio of intracellular-​to-​
agement options discussed above are represented in E Figure 16.3.
extracellular [K+] determines the resting membrane potential
Management of hyponatraemia in renal failure of the cell membrane, controlling the excitability of nerve and
The critically ill cardiac patient may occasionally present with muscle cells, as well as the contractility of skeletal, cardiac, and
an AKI and severe hyponatraemia (e.g. from excessive use of smooth muscle [25]. The main method of maintaining plasma
diuretics). In this scenario, haemodialysis or haemofiltration [K+] within normal limits is by rapid redistribution from the
on the ICU may be required to control fluid, electrolyte, and ECF to the ICF, under neuroendocrine control (e.g. insulin and
acid–​base balance. However, during continuous veno-​ venous catecholamines) [25]. Acid–​base disorders are of profound im-
haemofiltration (CVVH), serum electrolytes tend to equilibrate portance in K+ homeostasis. Acidaemias cause a net movement
with their concentrations in the replacement fluid, the rate of of K+ out of cells and into the ECF (potentially to life-​threatening
which is under the influence of the concentration gradient be- levels), while the converse is true of alkalaemias.
tween the plasma and the replacement fluid [24]. In patients with
severe hyponatraemia, rapid over-​correction may lead to cerebral Hypokalaemia
oedema or central pontine myelinolysis. To prevent these electro- This is defined as serum [K+] of <3.5 mEq/​L. It is usually caused
lyte shifts, the usual replacement fluid [Na+] (usually 140 mmol/​ by excessive loss, decreased intake, or a side effect of medications
L) needs to be adjusted to allow for more gentle shifts [24]. (e.g. diuretics). Common causes are shown in E Table 16.10.
For severe hyponatraemia ([Na+] <125  mmol/​L), the [Na+] Signs and symptoms of hypokalaemia include:
of the replacement fluid needs to be reduced by the addition of
◆ Polyuria.
sterile water [24]. As the patient’s plasma [Na+] rises, the amount
◆ Polydipsia.
of sterile water can be reduced until equilibrium is reached. This
◆ Anorexia, nausea, and vomiting.
requires regular checking of plasma [Na+], most usually by ABG.
◆ Muscle weakness and fatigue.
Hypernatraemia ◆ Paraesthesiae.
This is defined as serum [Na+] of >145 mEq/​L. It is usually caused ◆ Sensitivity to digoxin.
by excess water loss but can also be caused by excessive Na+ ◆ Confusion and depression.
176 CHAPTER 16   B l o od gas analysis: acid–base, flu i d, a n d el ectroly te di s order s

Acute symptomatic Screening blood panel

hyponatraemia HYPONATRAEMIA Na <130 mmol
Glucose, lipids
CNS disturbance Cortisol
Confusion Thyroid function
Headache Liver function
Consider the context
Drowsiness Plasma osmolality
e.g. known cancer, polydipsia
Coma/altered GCS
Seizures Stop any offending medications Urine osmolality
Encephalopathic e.g. thiazide diuretics, SSRI’s Urine Na + K

Assess patient’s hydration status

Move to a Level 2
monitored
environment
EUVOLAEMIA HYPOVOLAEMIA HYPERVOLAEMIA
Reduced skin Oedema
turgor Raised JVP
Administration of
Dry membranes LVF
hypertonic 3% saline
Confirm Tachycardia Ascites
150 mL IV over 15 min hypotonic Low BP or
hyponatraemia postural
Repeat after 20 min if hypotension Treat the
no clinical i.e. Plasma Osm underlying cause
improvement <275 mOsm/kg e.g. Cardiac failure
Urine Osm Treat with 0.9% Renal failure
Recheck serum Na at >100 mOsm/kg saline Liver cirrhosis
6,12, 24 and 48 h for
over correction
(no more than Check urine Na Urine Na <20 reconsider hypo/hypervolaemia
10 mmol/L in 24 h

Urine Na >20 Investigate underlying cause—consider CT

Likely SIADH chest/abdomen/pelvis/head

Calculate electrolyte free <0.5: commence 1.0 L fluid restriction Assess

water clearance using Furst response after
formula 0.5–1.0: commence 0.5 L fluid restriction 24–48 h
Re-evaluate
Urine Na + K
Serum Na >1.0: fluid restriction not advised

Consult with Specialist If poor

e.g. Consultant Endocrinologist response

Consider tolvaptan 15 mg od or demeclocycline 150–300 mg Aim for target Na

Monitor Na (6 hourly check) 130 mmol/L

Figure 16.3  Algorithm for management of inpatients with hyponatraemia. CNS, central nervous system; CT, computerized tomography; GCS, Glasgow Coma
Scale; IV, intravenous; JVP, jugular venous pressure; K, potassium; LVF, left ventricular failure; Na, sodium.
Reproduced from Grant P, Ayuk J, Bouloux PM, et al. The diagnosis and management of inpatient hyponatraemia and SIADH. Eur J Clin Invest 2015;45(8):888-​894. Doi:10.1111/​
eci.12465 with permission from John Wiley and Sons.

Characteristic ECG changes include: exceed 0.3 mEq/​kg/​hour, as, if exceeded, there is a risk of signifi-
◆ Mild:  flat or inverted T-​waves, ST-​segment depression, and cant arrhythmia and cardiac arrest.
prolonged QT interval. Hyperkalaemia
◆ Severe: prominent U-​waves, VT, or VF. This is defined as serum [K+] of >5.0 mEq/​L and is usually caused
Treatment is based on replacement of the deficit. Severe hypo- by excessive intake, decreased elimination, or redistribution from
kalaemia (<2.0 mEq/​L) or a K+ deficit in patients at risk of ar- the ICF to the ECF. Tissue trauma can result in a rapid release
rhythmias will require IV correction, with ECG monitoring and of large quantities of K+, leading to potentially life-​threatening
potentially central venous access [25]. Correction should not hyperkalaemia. As ECF [K+] increases, cellular membranes
 El ectroly tes a n d el ectroly te   di sorde r s 177

Hypernatraemia

Hypovolaemia Euvolaemia Hypervolaemia

Renal losses Extrarenal losses Renal losses Extrarenal losses Administration of hypertonic saline
Osmotic diuresis, Excessive sweating, Diabetes insipidus Respiratory and dermal or bicarbonate, hypertonic feeds,
excess–mannitol, diarrhoea Poor intake Insensible losses primary hyperaldosteronism,
glucose, urea Cushing’s syndrome

Urinary Na+ Urinary Na+ Urinary Na+ Urinary Na+ Urinary Na+
>20 mEq/L >10 mEq/L variable variable >20 mEq/L

Diuretics and water

Hypotonic Water replacement
saline replacement

Normonatraemia

Figure 16.4  Hypernatraemia: causes, diagnosis, and management.

depolarize and the ability for Na+ to be transported across the ◆ Muscle weakness.
membrane to re-​establish the resting membrane potential is ◆ Paralysis.
reduced. Therefore, action potentials cease to be created. This Characteristic ECG changes include:
leads to conduction defects, arrhythmias and characteristic ECG
changes, and weakness in skeletal muscles. [K+] of 7.0–​8.0 mEq/​L ◆ Mild: peaked T-​waves and premature ventricular contractions
predispose patients to VF in 5% of cases, and [K+] of 10 mEq/​L (PVCs).
in 90% of cases [25]. The most common causes are shown in ◆ Severe:  widening of QRS, depressed ST segments, prolonged
E Table 16.11. Signs and symptoms of hyperkalaemia include: PR interval, sinus arrest, and ventricular arrhythmias (tachy-
cardia, fibrillation, or cardiac arrest).
◆ Nausea and vomiting.
◆ Intestinal cramps. Treatment depends on the level of hyperkalaemia—​ either
◆ Paraesthesiae. emergency therapy or correction of the underlying disorder with

Table 16.10  Common causes of hypokalaemia Table 16.11  Causes of hyperkalaemia

Increased intake
Reduced intake
Excessive oral intake
Reduced dietary intake
Iatrogenic—​excessive infusion
Increased loss
Impaired renal excretion
Vomiting
Renal failure (GFR <15 mL/​min)
GI tract losses, e.g. chronic laxative use, intestinal obstruction, villous
adenoma of the colon Hypoaldosteronism (Addison’s, ACE-​Is)
Acute tubular necrosis phase of acute renal failure Renal tubulopathies (including amyloid)
Diuretic therapy K+-​sparing diuretics
Primary hyperaldosteronism (mineralocorticoid excess) Redistribution from ICF to ECF
Steroid use Acidosis
Redistribution to ICF Reduced insulin secretion (e.g. DKA)
Alkalosis Tissue trauma (crush injuries)
β-​agonist therapy Burns
Insulin therapy β-​blocker therapy
2+
Mg deficiency Seizures
178 CHAPTER 16   B l o od gas analysis: acid–base, flu i d, a n d el ectroly te di s order s

restriction of dietary sources of K+ [13]. Emergency therapies in- the latter [26]. Mg2+ deficiency can contribute to cardiac dys-
clude administration of: rhythmias, due to the hypokalaemia it produces. Symptoms
◆ IV insulin (causing a shift of K+ from the ECF into the ICF), and disorders caused by deranged Ca2+ and Mg2+ balance are
usually in a dose of 5 U in 50 mL of 20% dextrose. shown in E Table 16.12.
◆ β-​agonist therapy (either IV or nebulized salbutamol, causing Treatment of hypocalcaemia
the same shift of K+ into the ICF).
Treatment should always include the diagnosis and manage-
◆ Calcium resonium or a sulfonate rectally (to bind excess K+—​ ment of the underlying disorder. Acute symptomatic treatment
each gram of sodium polystyrene sulfonate eliminates 1 mEq
of tetany requires an IV infusion containing Ca2+ ions (either cal-
of K+).
cium gluconate, gluconate, or chloride). The usual dose is 100–​
◆ 10 mL of 10% calcium gluconate (to avoid arrhythmias—​should 200 mg of elemental Ca2+ over 10 minutes in 50–​100 mL of 5%
be used in patients with established ECG changes).
dextrose, followed by an infusion containing 1–​2 mg/​kg/​hour
over 6–​12 hours [26]. Chronic hypocalcaemia may be treated
Disorders of calcium and magnesium balance with oral dietary supplementation. Depending on the underlying
Ca2+ and Mg2+ are cations with serum concentrations lower cause, vitamin D supplementation may also be required (particu-
than their total body stores, as the majority is stored in bone. larly in children).
Only 0.1% of Ca2+ and 1% of Mg2+ are present in ECF [26].
In plasma, Ca2+ exists in three main forms:  bound to plasma Treatment of hypercalcaemia
proteins (40%), bound to anions such as phosphate and lac- Treatment of symptomatic hypercalcaemia consists of rehydra-
tate (12%), or in the free ionized form (48%). Ca2+ balance is tion (large volume of 0.9% saline), with the use of loop diuretics
achieved primarily through parathyroid hormone action on (which leads to Ca2+ ion excretion). For more chronic conditions,
bone, absorption from the intestinal tract, and excretion by the drugs that prevent Ca2+ mobilization from bone are used (e.g.
kidney. As ionized Ca2+ is the active form, total serum [Ca2+] bisphosphonates and calcitonin) [26]. Dialysis can also be used
needs to be adjusted for serum albumin [24]. There is an inter- for patients with renal or heart failure with acute hypercalcaemia.
dependence between [Mg2+] and both [Ca2+] and [K+], such Plicamycin, an antineoplastic antibiotic, can be used as a final
that a reduction in the former leads to a reduction in both of therapy [27].

Table 16.12  Symptoms and disorders due to calcium and magnesium imbalance

Hypercalcaemia Hypocalcaemia Hypomagnesaemia

Symptoms Neuropsychiatric: Seizures Tetany
Depression
◆ Tetany
Psychosis
◆

Neuromuscular: Neuromuscular: Neuromuscular:

Muscle weakness
◆ Paraesthesiae
◆ Choreiform movements
◆
Loss of muscle tone
◆ Muscle cramps
◆ Nystagmus
◆
Ataxia
◆ Hyperactive reflexes
◆
Carpopedal spasms
◆

GI/​renal:
Constipation
◆
Abdominal cramps
◆
Polyuria
◆

Cardiovascular: Cardiovascular: Cardiovascular:

Arrhythmias
◆ Arrhythmias
◆ Arrhythmias
◆
Hypertension
◆ Hypotension
◆
Shortening of QT
◆ Prolongation of QT
◆

Disorders Acute pancreatitis Rickets Hypokalaemia

Vascular calcification Cataracts Hypocalcaemia
Chondrocalcinosis Diabetes mellitus
Nephrolithiasis
Interstitial nephritis
Source data from Hoorn EJ, Zietse R. Disorders of calcium and magnesium balance: a physiology-​based approach. Pediatr Nephrol Springer Berlin
Heidelberg; 2013;28(8):1195–​6.
 Fu rth e r re a di n g 179

Treatment of hypomagnesaemia
Symptomatic moderate to severe deficiency can be treated with Personal perspective
IV administration for several days to replace depleted stores
ABG analysis is one of the most frequently ordered laboratory
and plasma levels. Common treatment doses are 2 g magne-
tests in the clinical setting as part of POCT. Almost all patients
sium sulfate (where 1 g  =  8.3  mmol/​L of Mg2+) in IV boluses,
requiring ICCU admission need at least one ABG test under-
infused over 10–​20 minutes, until the desired plasma concen-
taking for evaluation of gas exchange and the acid–​base status.
tration is achieved. Mg2+ is often used to treat arrhythmias (for
The ABG report provides useful information regarding gas
its membrane-​stabilizing action) and in the treatment of pre-​
exchange and acid–​base disorders commonly seen in patients
eclampsia and eclampsia (for its hypotensive and membrane-​
with cardiac diseases, to guide therapy and adequate manage-
stabilizing actions) [26].
ment. Thus, an ABG analyser seems to be mandatory in the
ICCU for the prompt evaluation and management of poten-
tially life-​threatening, but also reversible, conditions, including
Conclusion respiratory failure, and metabolic and respiratory acidosis.
The interpretation of ABG sampling, together with that of fluid Education regarding the use of an ABG analyser is easy and the
and electrolyte disturbances, is pivotal to the ongoing assess- investment is cost-​effective. ABG interpretation includes simple
ment of the critically ill patient. Although the compensatory and easy-​to-​learn steps which enable cardiologists to manage
systems of the body are complex, some basic principles apply simple, as well as mixed, acid–​base disorders. The ability also to
that can be used to guide any intervention. The key, however, diagnose water and electrolyte disorders requires the combin-
is to understand the underlying reason for the abnormality and ation of clinical skills and the availability of an ABG analyser for
treat the underlying cause, rather than the abnormal numbers the measurement of serum [K+], [Na+], [Ca2+], and osmolality.
per se. Future developments in POCT, which allows the ana- Most therapeutic strategies for water and electrolyte disorders
lysis of regional acid–​base and metabolic disturbances, are likely require easily applied measures, including water restriction or
to significantly enhance the management of such critically ill the administration and substitution or removal of electrolytes.
patients. Only in extreme cases, the application of invasive techniques,
including haemodialysis, is required as a definite measure.

Further reading
Acid–​base physiology. Available from:  M http://​www.anaesthesiamcq. Kellum JS. Determinants of blood pH in health and disease. Crit Care
com/​AcidBaseBook/​. 2000;4:6–​14.
Ackrill P, France MW. Common electrolyte problems. Clin Med (Lond) Kumar S, Berl T. Sodium. Lancet 1998;352:220–​8.
2002;2:205–​8. MedicalEducator. Arterial blood gas demonstration. Available from: M http://​
Bushinsky DA, Monk RD. Calcium. Lancet 1998;352:306–​11. www.youtube.com/​watch?v=0Rr6vpFMKPE.
Fluid physiology: an on-​line text. Available from: M
M http://​www.anaesthesiamcq. Moore K, Thompson C, Trainer P. Disorders of water balance. Clin Med
com/​FluidBook/​index.php. 2003;3:28–​33.
Gilfix BM, Bique M, Magder S. A physical chemical approach to the analysis Narins RG, Emmett M. Simple and mixed acid–​base disorders: a practical
of acid-​base balance in the clinical setting. J Crit Care 1993;8: 187–​97. approach. Medicine (Baltimore) 1980;59:161–​87.
Gluck SL. Acid–​base. Lancet 1998;352:474–​9. Narins RG, Gardner LB. Simple acid–​base disturbances. Med Clin North
Grogono AW. Acid–​base balance tutorial. Available from: M http://​www. Am 1981;65:321–​46.
acid-​base.com/​. Swaminathan R. Magnesium metabolism and its disorders. Clin Biochem
Halperin ML, Kamel KS. Potassium. Lancet 1998;352:135–​40. Rev 2003;24:47–​66.
Harber RJ. A practical approach to acid–​base disorders. West J Med The Virtual Anaesthesia Textbook. Acid–​base physiology. Available from: M
1991;155:146–​51. http://​www.virtual-​anesthesia-​textbook.com/​vat/​acidbase.html# acidbase.
Kellum JA. Determinants of plasma acid–​base balance. Crit Care Clin Weisinger JR, Bellorín-​ Font E. Magnesium and phosphorus. Lancet
2005;21:329–​46. 1998;352:391–​6.
180 CHAPTER 16   B l o od gas analysis: acid–base, flu i d, a n d el ectroly te di s order s

References
1. Powers A. Acid–​base balance. In:  Curley MAQ, Moloney-​Harmon 15. Andreoli TE, Abul-​ Ezz SR. Fluid and electrolyte disorders.
PA (editors). Critical Care Nursing of Infants and Children, second In:  Andreoli T, Benjamin IJ, Griggs RC, Wing EJ (editors). Cecil
edition. WB Saunders: Philadelphia, PA; 2001. pp. 309–​21. Essentials of Medicine, eighth edition. Saunders:  Philadelphia, PA;
2. Khurana I. Essentials of Medical Physiology. Elsevier India Pvt 2010. pp. 305–​21.
Limited; 2008. 16. Lien YH, Shapiro JI. Hyponatremia: clinical diagnosis and manage-
3. Hamm LL, Nakhoul N, Hering-​Smith KS. Acid–​base homeostasis. ment. Am J Med 2007;120:653–​8.
Clin J Am Soc Nephrol 2015;10:2232–​42. 17. Shapiro BA, Peruzzi FT, Kozelowski-​Templin R. Clinical Application
4. Thomas C, Lumb AB. Physiology of haemoglobin. Contin Educ of Blood Gases, fifth edition. St Louis: Mosby: St Louis, MO; 1994.
Anaesth Crit Care Pain 2012;12:251. 18. Carroll RG. Integrated Physiology. Elsevier Health Sciences:
5. Lahiri S, Forster II RE. CO2/​H+ sensing:  peripheral and central Philadelphia, PA; 2006.
chemoreception. Int Biochem Cell Biol 2003;35:1413–​35. 19. Reddy P, Mooradian AD. Diagnosis and management of hyponatraemia
6. Hinwood B. A Textbook of Science for the Health Professions, second in hospitalised patients. Int J Clin Pract 2009;63:1494–​508.
edition. Nelson Thornes: Sydney; 1997. 20. Spasovski G, Vanholder R, Allolio B, et al. Clinical practice guide-
7. Madias NE, Adrogué HJ. Cross-​talk between two organs:  how the line on diagnosis and treatment of hyponatraemia. Nephrol Dial
kidney responds to disruption of acid–​base balance by the lung. Transplant 2014;29 (suppl 2):i1–​39.
Nephron Physiol 2003;93:61–​6. 21. Yasir M, Mechanic OJ. Syndrome of Inappropriate Antidiuretic Hormone
8. Sirker AA, Rhodes A, Grounds RM, Bennett ED. Acid–​base physiology: Secretion (SIADH). StatPearls Publishing: Treasure Island, FL; 2018.
the traditional and the modern approaches. Anaesthesia 2002;57:348–​56. 22. Furst H, Hallows KR, Post J, et  al. The urine/​plasma electro-
9. Fencl V, Jabor A, Kazda A, Figge J. Diagnosis of metabolic acid–​base lyte ratio: a predictive guide to water restriction. Am J Med Sci
disturbances in critically ill patients. Am J Respir Crit Care Med 2000;319:240–​4.
2000;162:2246–​51. 23. Cuesta M, Ortolá A, Garrahy A, Calle Pascual AL, Runkle I,
10. Figge J, Jabor A, Kazda A, Fencl V. Anion gap and hypoalbuminemia. Thompson CJ. Predictors of failure to respond to fluid restriction in
Crit Care Med 1998;26:1807–​10. SIAD in clinical practice; time to re-​evaluate clinical guidelines. QJM
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Clin J Am Soc Nephrol 2015;10:2232–​42. 25. Wiseman AC, Linas S. Disorders of potassium and acid-​base balance.
13. Pocock G, Richards CD, Richards DA. Human Physiology. Oxford Am J Kidney Dis 2005;45:941–​9.
University Press: Oxford; 2013. 26. Hoorn EJ, Zietse R. Disorders of calcium and magnesium balance: a
14. BC Open Textbook Project. Capillary exchange. In:  Anatomy and physiology-​based approach. Pediatr Nephrol 2013;28:1195–​206.
Physiology. Available from: M M https://​opentextbc.ca/​anatomyandphysio 27. Esbrit P, Hurtado J. Treatment of malignant hypercalcaemia. Expert
logy/​chapter/​20-​3-​capillary-​exchange/.​ Opin Pharmacother 2002;3:521–​7.
 CHAPTER 17

Interpretation and clinical

use of chest radiographs
Alexander Parkhomenko, Olga S Gurjeva,
and Tetyana Yalynska

Contents
Summary  181 Summary
Introduction: chest radiography in the This chapter covers the most common conditions for which chest radiographs are
intensive cardiac care unit  181
useful.
Quality of images and conundrums of
It includes a brief summary of a systematic, multistep approach of evaluating
interpretation  182
Image label  182 the quality of radiographs and describing step by step the images (chest wall, pul-
Image quality (EPIS)  182 monary parenchyma and vasculature, costophrenic sinuses, cardiac size and shape,
Projection and depth of inspiration  183 great vessels, extrathoracic soft tissues, and position of tubes, lines, and devices).
Interpretation and reporting  183
Recent advances in CXR interpretation  184 This chapter reviews the main problems in obtaining chest X-​rays and their inter-
Water retention-​related problems on
pretation in intensive care unit settings and describes specific related features of
chest X-​ray  184 radiographs taken in the supine anteroposterior position.
Pleural effusion  184 This chapter provides intensivists, cardiologists, cardiology fellows, and med-
Pericardial effusion  187 ical students with basic information on radiographic features of water retention-​,
Air-​related problems on chest X-​ray  188 air collection-​, and lung-​related problems. It also focuses on the applicability
Subcutaneous emphysema  188
Pneumothorax  188 of the chest X-​ray for monitoring of line and device placements (e.g. central
Pneumomediastinum  190 venous catheters, tube malposition) and on the diagnostics of procedure-​related
Pneumopericardium  190 abnormalities.
Lung-​related problems on chest X-​ray  191
We have updated our chapter focusing on: (1) the novel approaches to chest
Pneumonia  191
Pulmonary embolism  191 X-​ray interpretation; (2)  air-​related problems, with more details on the diag-
Pulmonary oedema  191 nostic features and quantification of pneumothorax; (3)  alternative imaging
Acute respiratory distress syndrome  193
Aspiration  193
modalities, with use of ultrasound; and (4)  updated images in some medical
Atelectasis  193 conditions.
Lines, tubes, and temporary pacemakers
on chest X-​ray  194
Endotracheal tubes  194
Chest tubes  194
Nasogastric tubes  195
Central venous catheters  195
Pulmonary capillary wedge pressure
catheters and central venous pressure
Introduction: chest radiography in the intensive
monitors  195 cardiac care unit
Intra-​aortic balloon pumps  196
Pacemaker leads  196 CXR is an easy-​to-​perform diagnostic tool which remains informative and helpful, al-
Monitoring of post-​resuscitation and though nowadays daily routine CXR practice in the ICU is being eliminated, due
post-​procedure complications  197
to clear indications for selective CXRs and wider use of clinically integrated US.
Conclusion  198
There is a growing body of evidence on clinical relevance of simplified US proto-
Personal perspective  198
cols use in ICCU settings, although drawbacks, e.g. accuracy of interpretation ac-
Acknowledgements  198 cessibility of US devices, may vary among institutions [1–​5]. There is evidence that
Further reading  198 the CXR can reveal important abnormalities and can sometimes enable clinicians to
References  198 make the diagnosis of unexpected conditions that may prompt changes to treatment
plans [2]‌. Placement of CVCs, pacemaker leads, IABPs, ETTs, feeding and chest tubes
182 CHAPTER 17   In terpretat ion and clinica l u se of chest r a di o g r a phs

and drains, and circulatory support devices is of critical import- (a)

ance in patient management, and correct placement needs to
be assessed radiographically, looking for signs of misplacement,
along with other typical CXR features. Portable chest radiography
is a reliable screening technology and, with implementation of
new technologies (e.g. use of enhancement software for detection
of pneumothorax), allows health care professionals with varied
clinical experience to correctly interpret CXRs in a timely manner
[6]. In difficult-​to-​diagnose cases, chest radiography is one of the
initial steps in diagnostics. It may suggest further examination
protocols such as US, CT, or MRI.
In patients with acute or severely decompensated CVD, both ac-
quiring and interpreting radiographic images are often challenging
due to time constraints and the need for rapid clinical decision-​
making, as well as difficulty of obtaining an optimal posteroanterior
(PA) projection and a lack of inspiratory effort due to the severity
of patients’ clinical conditions. Hence, using a systematic approach
in CXR assessment, while keeping it relatively simple, remains key
to making a successful diagnosis and enabling correct device place-
ments and treatment progress monitoring.
Figure 17.1A  Shift of the heart to the right in a patient after heart surgery
with non-​properly sutured pericardium, resulting in severe displacement of
the heart. (a) Mediastinum shifted to the right; (b) right lung with reduced
Quality of images and conundrums volume; (c) right-​sided segmentary atelectasis; (d) ETT; (e) NG tube; (f) CVC;
(g) pacemaker leads; (h) kinked chest tube.
of interpretation
There are various proposed approaches to CXR evaluation, and Image quality (EPIS)
the choice for each specific method often relies on the physician’s
preference in terms of convenience and time [7, 8]. In the ICCU, ◆ E (for exposure):  film exposure with adequate penetration is
it is important to review and interpret images promptly and sys- characterized by barely visible lower thoracic intervertebral disc
tematically and not to omit details, including:  label and quality spaces through the cardiac shadow. An overexposed film would
assessment; viewing of visible structures—​lung fields, trachea
and bronchi, pleura, costophrenic angles, cardiac silhouette and
mediastinum, hemidiaphragms, hilar regions, hidden areas (b)
(apices, posterior sulcus); areas below the hemidiaphragms; soft
tissues and bones; and presence of any additional devices. It is
also important to check if any previous images are available to
compare the patient’s clinical/​treatment progress. A  suggested
systematic approach to evaluating CXRs comprises the following
steps: (1) checking the image label; (2) assessing the image quality;
and (3) proceeding to interpretation.

Image label
When interpreting a CXR, it is useful to have a checklist that in-
cludes the following:
◆ Patient’s name.
◆ Date of the CXR.
◆ Anteroposterior (AP) versus PA projection.
◆ Side label.
The image label is important not only for identification of the
patient, but also for assessing for unexpected findings which may
question the sidedness of the acquired image on review—​‘right’ Figure 17.1B  CXR appearance after chest revision and pericardial sac
or ‘left’ should be marked as ‘R’ or ‘L’, respectively. For lateral pro- closure. Heart position is normal. Segmental atelectasis of the right lung
jections, the acquisition size should be also noted (see E Figure persist.
17.1A, B).
 Qua l i t y of i m ag es a n d c onu n drum s of i n terpretat i on 183

appear diffusely lucent, with lung fields appearing too dark Table 17.1  Simplified systematic image review reporting (A, B, C, D, E)
and poor visibility of the vasculature. An underexposed image
Description step Data described
would be too white or in light greyscale, obscuring structures
behind the heart. Label Name, age, weight, date, projection (AP, PA, lateral)

Nowadays, digital technology allows for the brightness of films Image quality Exposure, position, inspiration effort
and colour scheme to be altered, which may help to adjust image Interpretation
properties and improve the quality of interpretation. A—​Airway Trachea position (central, displaced)
◆ P (for posture):  it is useful to compare the position of the B—​Breathing Lung appearance, vasculature, masses, and lesions
medial ends of the clavicles and the symmetry of structures C—​‘Circulation’ or Heart borders (enlarged, opacified), aorta (enlarged,
such as the scapular edges. ‘Cardiac contour’ calcified, etc.), pulmonary artery, mediastinum
◆ I (for inspiration): an image taken with an ideal inspiratory effort appearance, hila
would show six ribs anteriorly (AP and PA projections) or ten D—​‘Diaphragm’, Diaphragm position (elevation, herniation), gastric
ribs posteriorly (on lateral projection). The diaphragm should lie ‘Details’, or bubble, costophrenic angle, gas under diaphragm,
between the fifth and seventh ribs, and the right hemidiaphragm ‘Delicates’ skeleton
is usually 3–​4 cm higher than the left. The relationship between E—​‘Extras’ Tubes, catheters, pacemaker leads, devices, valves, other
the structures should be described—​the position of the media- Conclusion Based on radiological findings and clinical data
stinum (central if normal) and trachea (central and slightly to
the right inferiorly due to the oesophagus).
◆ S (for structures): the presence of all chest structures (pulmonary
main problems and, on the other, is still systematic and includes
apices, both costophrenic angles) should be noted.
the main parameters (e.g. cardiothoracic index, etc.). One should
evaluate the lung parenchyma, trachea and bronchi, cardiac size
Projection and depth of inspiration
and shape, chest wall and bones, extrathoracic soft tissues, and
It should be noted that in most ICCU patients, obtaining optimal the presence of additional structures and their placement. The
PA radiographs, while keeping a uniform distance to the cassette ‘ABCDEFGHI’ approach is one of the frequently used CXR in-
(183 cm in the upright position; 102 cm in the supine position), is terpretation protocols where the letters can have variable mean-
not possible. Due to severity of the illness, CXRs are usually taken ings:  A, airways; B, bones; C, cardiac shadow or circulation; D,
in a supine AP, semi-​recumbent, or decubitus projection. diaphragm; E, effusion, empty space (and also ‘extras’); F, fields
In AP projection, the heart structures appear more magnified (lungs); G, gastric bubble; H, hilum; and I, inspiration. A simpli-
and somewhat less sharp due to a shorter distance to the cas- fied approach may be also suggested using the ‘ABCDE’ system: A,
sette, compared to PA CXRs. For example, in the same patient, airways; B, breathing; C, circulation; D, diaphragm and details;
the mediastinum would appear about 10–​15% wider on a supine and E, extras. This mnemonic has been described elsewhere and
AP CXR. different versions are available in the literature and Internet re-
It is also important to remember that, in the supine position, sources [9]‌(see E Table 17.1).
the physiology of the lung changes, due to intra-​and extravas- The importance of accuracy of bedside CXRs and the need
cular fluid redistribution, which should be considered when for a radiology specialist to interpret bedside CXRs in the ICCU
interpreting a suboptimal supine AP CXR; for example, the initial has been discussed, revealing good diagnostic capabilities from
signs of ‘cephalization’ when upper lobe vessels increase in dia- cross-​talk among senior intensivists and specialists, if care is
meter may be pseudopositive in diagnosing pulmonary oedema. provided by less experienced residents [7, 8, 10]. Spiritoso et al.
In the supine patient, some conditions are difficult to diagnose. [10] demonstrated that 44% of chest radiographs were reviewed
One example of such conditions is pneumothorax which can be by radiologists, 33% by ICU clinicians, 25% jointly by both, and
easily missed on supine AP projection, as air redistributes and 14% by other specialists. In this study, the majority of physicians
usually rises medially and anteriorly. Hence, apical lucency in a preferred joint radiology reporting in addition to a clinician’s
supine patient would indicate a large amount of air in the chest. review, as interpretation of CXRs by clinicians only may result
The appearance of the CXR also depends on the inspiratory in low therapeutic impact and misinterpretation of radiological
effort taken by the patient. Excessive inspiration can complicate signs and features. This may occur due to different specialist back-
the diagnosis of pulmonary congestion, oedema, and small lower grounds among clinicians. Moreover, survey data collected from
lobe lung atelectasis. In contrast, a CXR taken of a patient with 80 ICUs revealed that about half of CXR reports were recorded
poor inspiratory effort may reveal false basal clouding or opacities in patients’ notes and reports per se were described as ‘could be
and mediastinal widening; these signs completely resolve if the delayed from 1–​2 to several days, very variable or not usually re-
CXR is repeated with deeper inspiration. ported’. Therefore, physicians’ understanding of the main radio-
graphic features and cross-​talk among specialists remain crucial
Interpretation and reporting and implementation of standardized, systematic, and easy-​to-​fill
When inspecting a CXR, it is useful to apply a simplified, easy-​ reports may impact on the quality of CXR reporting and decrease
to-​remember approach which, on the one hand, focuses on the decision-​making time [11].
184 CHAPTER 17   In terpretat ion and clinica l u se of chest r a di o g r a phs

(a)
Recent advances in CXR
interpretation
Recent advances in software development and image processing
have allowed for more accurate interpretation of chest radio-
graphs by physicians with variable levels of expertise. According
to a Canadian group, implementation of enhancement software
improved pneumothorax detection by less experienced phys-
icians with high reliability (AUC 0.88–​0.971) and did not impact
on the accuracy of reviewing by experienced readers [6]‌, thus
enabling appropriate decision-​ making on initial CXR review.
Furthermore, currently, major efforts are focusing on improving
and unifying protocols for CXR reviewing and creating a reliable
and efficient automated diagnostic tool, by prioritizing the inter-
pretation of radiographs containing information on potentially
threatening conditions such as large or moderate pneumothorax,
severe pneumonia, etc. [12,  13]. For this purpose, deep convo-
lutional neural networks were created and deep-​learning models Figure 17.2A  Right-​sided pleural effusion (diffuse hazy opacification,
were implemented, showing excellent performance of artificial obscured right hemidiaphragm, mild mediastinal shift to the left). AP film,
intelligence (AI) (with high sensitivity and specificity of approxi- patient in supine position.
mately 80–​95%) in automatically triaging radiographs and iden-
tifying those showing serious medical problems, with no human pneumonia (see E Figures 17.4 and 17.5). Atelectasis may have
input, thus flagging up images that would require immediate at- an inhomogenous density, whereas interlobar effusions are usually
tention from the responsible physician [12–​14]. Hence, AI can be homogenous and do not cause obliteration of the minor fissures;
expected to gradually change clinical practice by helping phys- they should be better seen on lateral CXR.
icians through efficient and reliable initial imaging reviews and Sometimes elevated hemidiaphragms (see E Figure 17.6) may
improved workflow and timely recommendations. mimic pleural effusions. In such situations, use of US is useful and
may easily differentiate between the absence of diaphragm move-
ment and fluid accumulation in the pleural cavity.
Water retention-​related problems Smaller effusions are easier to diagnose using US examination,
which is more sensitive than CXRs in the detection of small to
on chest  X-​ray
Pleural effusion
(b)
Fluid collections are not uncommon findings on CXRs in ICCU
patients. Pleural effusions may result from thoracic surgery, fluid
overload, decompensation of congestive heart failure, infection,
PE, neoplasms, and other causes [15]. The content of the pleural
cavity may be a transudate, an exudate, blood, and, less frequently,
pus or chyme. On the chest radiograph, obtained in an upright
position, pleural fluid is seen to accumulate usually in the basal
spaces and appears as blunting of the costophrenic angle (see
E Figure 17.2A, B). Lower lobe vessels may also not be clearly vis-
ible if an effusion is present. These findings are common after car-
diac surgery and usually resolve completely. With larger effusions,
a homogenous density would be present; the diaphragmatic con-
tour would not be clearly seen, and the costophrenic angle would
be obliterated (see E Figure 17.3A, B). Larger effusions require
fluid evacuation (see E Figure  17.3). In the majority of ICCU
patients, it would be difficult to obtain a CXR while standing;
therefore, physicians would face challenges in identifying water
retention-​ related abnormalities. Water would redistribute and Figure 17.2B  Residual right-​sided effusion after drainage (blunting of left
accumulate posteriorly to the lung in basal spaces. Loculated costophrenic angle, homogenous density, vessels not clearly seen). AP film,
effusions may be difficult to differentiate from atelectasis and sitting position.
 Water reten ti on - rel ated prob l em s on  c h e st   X-r ay 185

(a)
e
d
c
e

Figure 17.4  Pleural effusion (haemothorax) confined to lower lobe of left

Figure 17.3A  Complications after heart surgery. (a) Massive haemothorax lung (dense shadow) in a patient after transcatheter mitral valve replacement.
(diffuse, dense left-​sided opacification); (b) signs of pulmonary congestion AP film, patient in sitting position.
(mild opacification, increased vasculature in right lower lobe); (c) CVC in SVC;
(d) ETT; (e) ECG leads. AP film, patient in sitting position.
Pleural effusions should be differentiated from other condi-
tions associated with similar radiological findings. E Figure
moderate amounts of fluid in pleural cavities. Assessment for better 17.5A illustrates the presence of an elevated right hemidiaphragm
access site for pleural drainage in moderate to large effusions may which was found in a patient admitted for chest pain and short-
also be done under US guidance [16]. (See also E Chapter 45.) ness of breath (due to severe aortic stenosis and concomitant is-
Loculated effusions may not always be visible on US examin- chaemic heart disease and mild pericardial effusion which was
ation and are easier to discern using CXR (see E Figure 17.5A) seen as smothering of the heart contours).
and they are not always drained correctly (see E Figure 17.5B).
(a)
(b)

f
e

b
c
b
c
d
h
a
g

Figure 17.3B  Complications after heart surgery. (a) Incomplete resolution

of massive haemothorax after drain placement (dense left-​sided opacification
and blunting of costophrenic angle); (b) signs of pulmonary congestion
bilaterally; (c) multiple small plate atelectases of left lung; (d) subcutaneous Figure 17.5A  (a) Loculated pleural effusion (haemothorax) and (b) small
air due to improper drainage sealing (lucent streaks of air) on the left side; discoid right lung atelectasis in a patient after aortic and mitral valve
(e) CVC in SVC; (f) ETT; (g) chest tube; (h) stented mitral bioprosthesis. AP replacement; (c) ETT; (d) NGT; (e) CVC; (f) sternal sutures; and (g) aortic and
film, sitting position. mitral prostheses shadows. AP film, patient is in supine position.
186 CHAPTER 17   In terpretat ion and clinica l u se of chest r a di o g r a phs

(b) (b)

Figure 17.6B  Dense opacification with horizontal level on the right

(elevated right hemidiaphragm). AP film, supine position.

Figure 17.5B  (a) Incomplete resolution of loculated pleural effusion Sometimes, complex situations may occur and pleural effusions
(haematoma) after chest tube placement; (b) overadvanced chest tube; secondary to intrathoracic bleeding may coincide with other le-
(c) iatrogenic pneumothorax; (d) aortic and mitral prostheses shadows; sions. E Figure 17.7A and B illustrates a massive haemothorax
(e) sternal sutures. AP film, patient in supine position.
in a patient with bleeding from a perforated subclavian artery.
The images confirm extra-​and intrapleural haematomas, compli-
In some cases, relaxation of the hemidiaphragms can mimic cated by right lung atelectasis, fluid retention in the mediastinum
pleural effusion and US may be more informative as a diagnostic (A, prior to chest draining) with further incomplete resolution
tool (see E Figure 17.6A). E Figure 17.6B shows a dense opa- of the haematoma, left-​sided pleural effusion, and subcutaneous
city on the right side which can be misinterpreted as pleural ef- emphysema (B, after drain placement).
fusion. The changes almost completely resolved after plication of
the right hemidiaphragm (see E Figure 17.6C).
(c)

(a)

Figure 17.6A  Elevated right hemidiaphragm and change in cardiac Figure 17.6C  Normal appearance of right hemidiaphragm after plication.
silhouette with smoothing of heart contours. Small segmental atelectasis on the left. AP film, supine position.
 Water reten ti on - rel ated prob l em s on  c h e st   X-r ay 187

(a) (a)

Figure 17.8A  Mass adjacent to the right atrium and widening of the heart
shadow. Blunting of the left costophrenic angle suggestive of mild pleural
Figure 17.7A  Complications of CVC placement (before chest drain
effusion in a patient with pericarditis hospitalized for shortness of breath and
placement). (a) Massive right-​sided effusion (haemothorax) with absence
pitting oedema in the lower extremities.
of pulmonary vasculature; (b) lung atelectasis; (c) ‘mass’ in the subclavian
region—​haematoma secondary to bleeding from perforated subclavian artery;
(d) shifted, smoothened, and widened mediastinal border; (e) tip of ETT
shifted to the left (due to incorrect patient position and mediastinal shift); Pericardial effusions are difficult to diagnose on the CXR,
(f) NG tube; (g) calcification of the ascending aorta; (h) caged-​ball prosthesis. and small effusions of <200–​ 300 mL may be easily missed.
Echocardiography and CT scanning stand as better imaging mo-
Pericardial effusion dalities to diagnose pericardial effusions and determine whether
Fluid may accumulate in the pericardium due to post-​operative restriction is present [17, 18]. With large effusions (400–​500 mL),
bleeding, infection, or obstruction of drainage by a tumour, or in the heart shape changes and effusions usually appear like a heart
patients with renal failure (see E Figure 17.8A–C). enlargement, without specific radiographic features. Sometimes
the heart appears ‘globular-​shaped’, with a disproportionately in-
creased transverse diameter, or may reflect on X-​ray as a ‘water
(b)
bottle’ shape (see E Figure 17.9).

(b)

Figure 17.7B  Complications of CVC placement (after chest drain

placement). (a) Massive the subclavian region (incomplete resolution of
drained haematoma originating from perforated subclavian artery); (b) tip of
chest tube; (c) mildly shifted, smoothened, and widened mediastinal border; Figure 17.8B  CXR after tumour removal. (a) Changes in cardiac silhouette
(d) calcification of the ascending aorta; (e) blunting of the left costophrenic and widened superior vena cava; (b) signs of residual right-​sided pleural
angle (pleural effusion); (f) lineal lucency upward to the chest tube effusion—​blunting of right costophrenic angle; (c) chest tube in right pleural
(subcutaneous emphysema). cavity; (d) CVC; (e) sternal sutures. AP film, supine position.
188 CHAPTER 17   In terpretat ion and clinica l u se of chest r a di o g r a phs

(c)

Figure 17.8C  CT scans. (a) Tumour localized in upper-​mid anterior mediastinum, adjacent to the right atrium; (b) pericardial effusion; (c) bilateral pleural
effusions; (d) atelectasis of lateral and anterior segments of right lower lobe.

from the pleural cavities (pneumothorax) or mediastinum

Air-​related problems on chest X-​ray (pneumomediastinum) (see E Figures 17.10B, C and 17.11). In
these cases, lucent bubbles or gas streaks along the sheaths are
Extra-​alveolar air collection is quite a frequent finding on chest
seen. In the case of a pneumomediastinum, air may extend to the
films in ICCU patients and could result from surgery, percu-
neck (see E Figure 17.10A, C). If an isolated subcutaneous em-
taneous interventions, mechanical ventilation, and placement
physema in the neck is present, examination for upper airway in-
of lines, drains, and devices. Intrathoracic air collections (e.g.
jury should be performed and a lateral CXR taken.
pneumothorax, pneumomediastinum, pneumopericardium) and
subcutaneous emphysema can be visualized on CXRs (see also
E Figures 17.3B, 17.5B, 17.7B and Figure 17.10A, B, C).
Pneumothorax
Air collection within the pleural cavity may occur either spontan-
Subcutaneous emphysema eously or can result from lung injury and may lead to precipitous
deterioration of the patient’s condition. It is also not a rare finding
Subcutaneous emphysema may follow catheterization of the sub-
clavian vein or placement of mediastinal and pleural drains and
may resolve completely without serious clinical impact. Large (a)
subcutaneous emphysema can make the detection of other ab- c
normalities (e.g. pneumothorax) difficult (see E Figure 17.10A). a
In some cases, air may dissect through muscle bundles extending

a
b
c
b

c c

Figure 17.10A  (a) Subcutaneous emphysema. (b) Large bilateral

tension pneumothorax—​bilateral consolidated lung shadows, prominent
white lung border lines, apical air accumulation bilaterally without
lung parenchyma markings, lucent contour above the right diaphragm.
(c) Pneumomediastinum—​linear streaks of air seen along the sheaths and
dissecting up to the root of the neck, lucency along the great vessels—​air
Figure 17.9  Pericardial effusion (cardiomegaly, change in cardiac silhouette around the medial border of the superior vena cava, pulmonary artery, and
with smoothing of heart contours) in a patient with right-​sided pneumonic aortic arch. (d) Pneumopericardium: broad band of gas around which wraps
opacification and left-​sided blunting of the costophrenic angle due to mild the LV and right atrium, extending to the main pulmonary artery and visible
pleural effusion. above the diaphragm.
 A i r - rel ated prob l em s on  c h e st   X-r ay 189

(b)

Figure 17.10B  Serial CT scans confirming the presence of subcutaneous emphysema, pneumomediastinum, pneumothorax, and pneumopericardium in a
patient with extensive right-​sided pneumonic infiltration.

after cardiothoracic surgery or ventilation support. Air leaks into subpulmonically, between the diaphragmatic surface and the lung,
the pleural space alter normal negative intrapleural pressure, and and may be seen as basal lucency in supine patients. The deep
even a ‘slight’ increase from  –​5 to  –​2.5  cmH2O results in lung sulcus sign, suggestive of anterolateral air collections, appears as
compression and 33% decrease in vital capacity [19]. increased lucency of the costophrenic sulcus. It is important to
Air leak persisting for >2  days may be defined as persistent obtain and review CXRs, assessing the lateral costophrenic angles
pneumothorax and can occur after procedures, e.g. improper to rule out pneumothorax.
chest tube and drain placement (see E Figure 17.5B), incom- The diagnosis of tension pneumothorax is usually made clin-
plete seal, malposition, kinking or obstruction, catheterization of ically. Sometimes lung atelectasis or collapse would not be seen
the subclavian vein, pleural puncture, etc. on CXR, due to reduced lung compliance resulting from COPD,
The diagnosis of pneumothorax and appearance of air on CXRs lung fibrosis, ARDS, etc. A shift of the mediastinum, heart border,
largely depend on the patient’s position. In the upright patient, and cava veins may or may not be present if the patient is on
air most frequently collects in an apicolateral location and ap- mechanic ventilation with PEEP regimens. Depression of the
pears on chest films as a thin, white pleural line, along with loss hemidiaphragm should also be kept in mind when a tension
of normal lung markings peripheral to it (see E Figure 17.5B). pneumothorax is suspected. In difficult-​ to-​
resolve cases, CT
In most ICCU patients, radiographs would be taken in a supine
position, and therefore, visualization could be hampered and air
would be visible anteromedially and better seen on a lateral CXR
as increased lucency. In supine patients, it is necessary to look for
other signs such as medial air collection. Air sometimes collects

(c)

Figure 17.11  (a) Subcutaneous emphysema; (b) pneumomediastinum;

(c) lucent linear streaks of air seen along the sheaths and dissecting up to
the root of the neck; (d) apical air accumulation on the left side; (e) calcified
Figure 17.10C  Pneumomediastinum (linear lucent streaks around the descending aorta; (f) occluder in proper position, after endovascular PDA
superior vena cava, extending upwards). closure; (g) suture on fractured rib.
190 CHAPTER 17   In terpretat ion and clinica l u se of chest r a di o g r a phs

scanning certainly would be a more accurate imaging modality be a consequence of manipulations or recent surgery (e.g. upper
and would elucidate subtle signs as visceral pleura discontinuity airway, oesophagus injury, chest tube malposition, kinks, or im-
due to the presence of bronchopleural fistula causing long-​ proper sealing; see E Figure 17.10A, C) or air extension to the
persisting pneumothorax. In the case of post-​operative diaphrag- chest cavity from a pneumoperitoneum.
matic perforation, air can be seen over and under the diaphragm, There are several typical radiographic findings, including lu-
above the liver shadow. Small air collections would resolve cent gas bubbles or streaks outlining mediastinal structures,
without special treatment, whereas leaks via an oesophago-​pleural which sometimes are better seen on lateral view than on AP pro-
fistula would prompt a timely diagnosis and immediate closure. jection, especially if located anteriorly to the heart [24].
Pneumothorax ex vacuo is another distinct entity resulting Typically, gas collects between the visceral pleura of the lung
from increased negative intrapleural pressure. This condition and the parietal pleura of the mediastinum and forms a pleural
may occur after rapid evacuation of a large amount of pleural line above the heart, on the left, outlining the aortic arch and the
fluid in cases when the lung is unable to completely expand and main pulmonary artery on AP CXR; it may be seen more clearly
fill the pleural space. Pneumothorax ex vacuo may also be seen on CT scan (see E Figure 17.10A, C). The ring-​around-​the-​
secondary to lobar atelectasis from acute bronchial obstruction. artery sign occurs when gas wraps around the extrapericardial
This gas accumulation in the pleural space usually resolves spon- portion of the right pulmonary artery. Gas may collect around
taneously once bronchial obstruction is relieved [20]. the superior vena cava (see E Figure 17.10C), azygos vein, and
Large pneumothorax appears as a lucency in the apical re- brachiocephalic veins (V-​sign—​gas outlining the brachiocephalic
gions in a supine patient, indicating significant air collection (see veins superiorly). Gas separating the pericardium from the dia-
E Figure 17.10A–C). Quantification of pneumothorax is needed phragm forms the continuous left hemidiaphragm sign, which
for clinical decision-​making. Air quantity may be roughly quan- often helps to differentiate between a pneumomediastinum
tified as ‘large’ and filling up to 50% of chest space if the distance and a pneumopericardium [25]. The superior margin of the
from the visceral pleura to the chest wall exceeds 2 cm, and vice left hemidiaphragm is normally not seen, as it is obscured
versa—​pneumothorax can be discerned as ‘small’ if this distance by its contact with the heart structures. The continuous left
is <2 cm [21]. Additionally, volumetric assessment of pneumo- hemidiaphragm sign is seen as a line separating the diaphragm
thorax on a frontal CXR in a supine patient can be estimated from the heart. The Naclerio’s V-​sign is another V-​sign that is
by measuring the distances from the collapsed lung to the chest detected when an oesophageal rupture is present, although it is
wall using the formula: % pneumothorax = 8.73 + 10.03 × AID not always specific. This sign is described when a lucent band
(where AID denotes the average intrapleural distance, calculated of gas outlines the lateral margin of the descending aorta and
as (a + b + c)/​3 where ‘A’ is the distance from the lung apex to is seen between the medial left hemidiaphragm and the parietal
the cupola, ‘B’ is the distance from the upper mid portion of the pleura. Sometimes gas separates the parietal and visceral pleurae
collapsed lung, and ‘C’ is the distance from the lower mid por- from the apical chest wall, simulating a pneumothorax. If air ex-
tion of the collapsed lung) [22]. This formula was simplified by tends further, it may result in a pneumothorax, although both a
authors to: (% pneumothorax = 9 + 10 × AID), which still had a pneumomediastinum and a pneumothorax may be present sim-
good correlation with CT data [22]. Large volumes of air collec- ultaneously (see E Figure 17.10A). The presence of air collec-
tion (>25% of the corresponding chest cavity) require chest tube tions may be confirmed by CT scanning (see E Figure 17.10B).
placement.
It should be noted that the diagnosis of pneumothorax needs Pneumopericardium
accurate interpretation of radiographs. More accurate quanti- Pneumopericardium is a less common condition than pneumo­
fication can be obtained using CT. Pneumothoraces can also mediastinum. It is found in post-​operative patients and rarely as
be diagnosed using US with sufficient certainty, when sono- an extension of a pneumothorax. Gas collected in the pericardium
graphic signs (e.g. motionless pleural line as ‘stratosphere’) are often forms a broad band, which wraps around the LV and right
seen [23]. atrium and, if large, creates the halo sign (see E Figure 17.10A).
Sometimes excessive diagnostics of misinterpretation could As gas is confined to the pericardial sac, it does not extend along
occur, e.g. skinfolds or scapular margins may have a similar ap- the trachea and bronchi into the neck. It should be noted that gas
pearance and occasionally could be described as a pneumothorax. around the main and right pulmonary arteries, ascending aorta
(to the level of the brachiocephalic artery), and superior vena
Pneumomediastinum cava (below the azygos vein) must be inside the pericardium (see
Pneumomediastinum occurs when an alveolar rupture is pre- E Figure 17.10A, C), whereas gas visible around the aortic arch,
sent. Alveolar rupture may develop in patients with acidosis superior vena cava (above the azygos vein), and distal pulmonary
(Kussmaul respiration), after vomiting, in airway obstruction and artery must be outside the pericardium.
aspiration, in patients on PEEP respiratory support, and under Another distinguishing feature of the location of gas collection
some other conditions (e.g. ARDS, emphysema, infection). It re- is that with change in position (upright to supine or decubitus
sults in interstitial emphysema, with gas dissecting medially to position), the gas does not shift if located in the mediastinum but
the mediastinum. Gas collection in the mediastinum can also easily redistributes within the pericardium.
 Lu n g - rel ated prob l em s on  c h e st   X-r ay 191

Lung-​related problems on chest X-​ray

Pneumonia
Community-​acquired, as well as nosocomial (3 days after admis-
sion), pneumonia complicates the course of cardiac disease in the
ICCU and is associated with high mortality [26]. Predisposing
factors to pneumonia are usually congestive heart failure,
immunocompromise, mechanical ventilation, and others. On
the CXR, sometimes it is difficult to distinguish between a pneu-
monic consolidation and a small atelectasis, PE-​associated lung
infarction shadowing, early stage of ARDS, and loculated pleural
effusions. Consolidation can appear localized or patchy and may
be uni-​or bilateral or multifocal (see E Figures 17.12 and 17.13).
Signs of air bronchograms may be apparent. Pneumonia could
be accompanied by pleural effusions (including empyema), lung
atelectasis, and coexisting congestion or oedema, which makes
differential diagnosis difficult (see E Figure 17.14). CXR in chan- Figure 17.13  Pneumonia (diffuse opacity over left lung projection) and
ging positions (upright, decubitus) may help to differentiate be- mild left-​sided pleural effusion (blunting of cardiodiaphragmatic sinus);
tween congestion, fluid collections, and pneumonic opacification. CVC; pacemaker lead in RV; mitral valve prosthesis (biological, transcatheter);
With lung consolidation and alveolar filling with fluid, the air-​ kinked chest tube.
filled bronchi are clearly seen as ‘air bronchograms’.
described as the ‘knuckle’ (Palla’s sign) or ‘sausage’ (see E Figure
Pulmonary embolism 17.14) [27]. It should be noted that there is no association be-
Although the majority of patients with PE have abnormalities on tween enlargement of the pulmonary artery and RV hypokinesis.
CXR, those abnormal findings are quite non-​specific and chest Beyond the occlusion, oligaemia of pulmonary vessels could be
films aim more towards assessing for underlying and concomi- present (Westermark’s sign) [27,  28]. Pulmonary infarction oc-
tant disorders, rather than for confirmation of PE diagnosis. curs only with massive embolism and could be misdiagnosed
Radiographic signs believed to be suggestive of PE include ele- for pneumonia. A Hamptom’s hump is a late radiographic feature
vation of the hemidiaphragm, lung discoid atelectases, signs of which is considered to be associated with pulmonary infarction
pulmonary infarction (triangular-​ shaped shadow or consoli- and described as a rounded pleural-​based opacity, without air
dation), and enlargement of the pulmonary artery, which is bronchogram, which may later convert into a thick-​walled cavity.
Although those features described may suggest PE, to a cer-
tain extent, they have a very low sensitivity and specificity and are
poor predictors of PE. Moreover, it should be noted that 12–​14%
of patients with a confirmed diagnosis of PE had an admission
CXR interpreted as normal [29]. (See also E Chapter 63.)

Pulmonary oedema
There are several scenarios for the development of pulmonary
oedema [30]. Increased hydrostatic pressure is observed in the
majority of patients, implying cardiac oedema [30]. About one-​
third of patients would have non-​cardiac pulmonary oedema
secondary to increased permeability of the pulmonary capillary
endothelium resulting from various causes such as infection and
aspiration of acidic gastric contents. Decreased oncotic pressure is
a rare cause in the ICCU patient.
The CXR is an easily accessible assessment method for pul-
monary oedema. Radiographic features characteristic of pul-
monary oedema include long (5–​10 cm) septal lines, called Kerley
A lines, which occur with fluid collection in deep septae. Kerley
Figure 17.12  Pneumonia (opacity in right lower lobe) and mild right-​sided A lines run from the lung hilum laterally to the periphery. Kerley
pleural effusion (blunting of cardiodiaphragmatic sinus); overadvanced ETT; B lines are shorter lines (approximately 2 cm long) that appear on
correctly placed CVC. the periphery and run to the pleura. Alternatively, US methods of
192 CHAPTER 17   In terpretat ion and clinica l u se of chest r a di o g r a phs

(a)

Figure 17.15  Pulmonary oedema (‘bat wing’ opacities, Kerley A lines

(b) running to the periphery).

pulmonary blood flow (upper lobe blood diversion) are common,

although in patients with ACS, these signs may not be present.
In some cases, the features of pulmonary oedema on CXR
are not ‘classical’ and may pose a challenge for interpretation.
Unilateral and lobar pulmonary oedema may develop. Pulmonary
oedema confined to the lower lobes or one lobe may develop
in patients with pre-​existing COPD. Miliary oedema is usually
observed during the transition of interstitial oedema into al-
veolar oedema, with further generalized bilateral ‘clouding’ (see
E Figure 17.16). Among the methods distinguishing the origins
of lung consolidation, gravitational shift may help to rule in pul-
monary oedema. Serial CXRs should be taken before and after
keeping the patient for 2–​3 hours in the decubitus position. In

Figure 17.14  (A) CXR showing massive PE (enlargement of right pulmonary

artery—​Palla’s sign, oligaemia of pulmonary vessels, pulmonary consolidation
beyond enlarged pulmonary artery). (B) CT scan confirming massive PE in
same patient.

quantification of B lines could also be a good additional tool to

confirm extravascular water in ICCU patients [31].
The presence of bilateral opacities seen laterally to the hila implies
that interstitial oedema has progressed to alveolar oedema. This
syndrome is described as ‘bat wing’ opacity (see E Figure 17.15).
An air bronchogram is a radiographic sign which is detected when
lung consolidation due to alveolar fluid collection is present in pa-
tients with oedema or pneumonia [32]. With increased density of
the surrounding lung tissue, air-​filled bronchi would have more dis-
tinct inner contours. Increased opacification towards the bases and
air bronchograms in the right upper lobe may be present in patients
Figure 17.16.  Generalized bilateral ‘clouding’ in patient with pulmonary
with congestive heart failure. In patients with pulmonary oedema of oedema. (a) Tip of IABP; (b) correctly placed CVC; (c) ETT. AP film, patient in
cardiac origin, pleural effusion, cardiomegaly, and redistribution of supine position.
 Lu n g - rel ated prob l em s on  c h e st   X-r ay 193

most patients with pulmonary oedema, there would be an ap- Acidic gastric contents cause not only irritation of the upper
parent shift in opacity. airway and bronchospasm, but also the release of inflammatory
Transformation of opacification into homogenous densities factors and increased membrane permeability. Patients rapidly
(see E Figure 17.16) implies worsening of oedema and is diffi- progress from dyspnoea and pneumonitis (Mendelson syndrome)
cult to differentiate from ARDS. (See also E Chapter 45.) to chemical pulmonary oedema. Further aspiration pneumonia,
secondary to infection, may develop. On CXR, bilateral symmet-
Acute respiratory distress syndrome rical opacities can be seen in most patients. However, in some
ARDS is associated with poor patient survival and results from cases, a post-​aspiration chest film would show unilateral opacities
pulmonary infection, sepsis, aspiration, or other causes leading (see E Figure 17.18) [37]. These opacities may be asymmetrical
to alveolar capillary endothelial damage and the development of and localized around the hila. Signs of pulmonary consolidation
interstitial and further alveolar pulmonary oedema [33]. Although may either resolve completely or persist and progress to other
a variety of radiographic ARDS criteria have been described, the complications such as abscesses.
CXR remains an important tool for the diagnosis of ARDS, along
with confirmation of severe acute-​onset hypoxaemia (PaO2/​FiO2 Atelectasis
≤300) and absence of PH (PCWP ≥18 mmHg). The diagnosis of Total or partial lung collapse may develop due to airway obstruc-
ARDS is more clinical (and could also be confirmed with other tion (tumour, mucus, compression of the left lower lobe bronchus
additional tools such as pulse oximetry and US [34]), but quite by the heart in the supine position), poor ventilation (misplace-
distinct if bilateral infiltrates, consistent with pulmonary oedema ment of ETT during mechanical ventilation, failure to breathe
(see E Figure 17.17), or dense alveolar consolidation are present deeply after surgery, general anaesthesia), pneumothorax, and
in all lung quadrants [35]. A ‘reduction in longitudinal lung diam- pneumonia (see E Figures 17.5B, 17.8C, and 17.10). Atelectases
eter’ has also been described in the literature. Sometimes infiltrates may appear as plate-​like, small, linear opacification or slight in-
limited to the lower lobes attributable to ARDS may be mistaken filtration or as parietal, lobar, or uni-​or bilateral atelectases (see
for atelectases. Increased interstitial markings, indistinct vessels, E Figures 17.5B, 17.7B, 17.10A, and 17.19). Small atelectases
and blurring of hilar structures are all problematic for interpret- may occur quite frequently post-​operatively, due to incomplete
ation as interstitial and alveolar pulmonary oedema and may be mucus suction (see E Figure 17.19), and may not always be ap-
stages of ARDS. In addition, patients with ARDS may have pre-​ parent on CXR [38]. Also, sudden mucus plugging of a larger
existing congestive heart failure, in which case basal opacifications bronchus may cause hypoxia and should be differentiated from
and upper lobe blood diversion, which are usually not character- PE. Lung consolidations which occur with small or moderate
istic of ARDS, could still coexist [36]. (See also E Chapter 64.) atelectasis may be mistaken for pneumonia; they may either be
caused by pneumonia or coexist with it. Lung collapses, in most
Aspiration cases, follow certain radiographic patterns which are helpful in
In ICCU patients, especially those who are unconscious, aspiration reaching a diagnosis. Radiographic features of atelectasis include
of gastric contents may occur and cause serious consequences. crowded vessels in a collapsed lobe or segment, displacement of

Figure 17.17  ARDS (bilateral airspace opacities and increased interstitial Figure 17.18  Aspiration pneumonia (right lower lobe consolidation, right-​
markings in a patient with acute respiratory failure). sided pulmonary oedema).
194 CHAPTER 17   In terpretat ion and clinica l u se of chest r a di o g r a phs

Figure 17.19  Small discoid subsegmental middle lobe atelectasis, left-​sided Figure 17.20  Correctly placed ETT and CVC.
pleural effusion (obscures left cardiodiaphragmatic sinus, dense shadow with
horizontal level).
is not uncommon and has been reported in about 10% of patients
(see E Figure 17.20) [42]. Existing data show that, even when
the hilum and/​or trachea, with upper lobe collapse and heart dis-
breath movements are present on both sides and respiration is
placement, and an elevated hemidiaphragm on the side of atelec-
heard on auscultation bilaterally, the ETT may still have been
tasis with lower lobe collapse (see E Figure 17.19) [39].
placed in the proximal right bronchus [43]. Therefore, radio-
Minor subsegmental atelectasis in basal lobes does not impair
graphic monitoring is desirable. The tip of the ETT, if placed
ventilation and appears as linear streaks on CXR (see E Figure
correctly, should be detected at 2–​7 cm above the carina on a suf-
17.19). Displacement of interlobar fissures also may be visible on
ficiently exposed CXR. The safe distance from the carina should
the chest film. If the collapse is extensive, compensatory hyper-
not be shorter than 2 cm, in order to allow for movement of the
inflation of the remaining lung may be seen.
ETT tip 2 cm distally with head flexion and 2 cm proximally with
In clinical practice, the extent of atelectasis could be described
head extension. If the position of the carina is not obvious, the
using a quantification system based on simple scoring. Different
level of other anatomic landmarks, such as T4–​T5, should be
approaches have been proposed such as a traditional radiological
noted. The level of T4–​T5 corresponds to the carina, and there-
5-​point atelectasis score (RAS):  0, clear lung fields; 1, plate-​like
fore, insertion of the ETT with its tip advanced to this level would
atelectasis or slight infiltration; 2, partial atelectasis; 3, lobar atel-
be correct (see E Figure 17.20). Another approach, described by
ectasis; and 4, bilateral atelectasis [40].
Lee, recommends the following:  (1) to identify the aortic arch;
A newer modified scoring approach (m-​RAS) was validated
(2) to draw a line through the middle of the aortic arch at 45° to
by authors in terms of the need for O2 supplementation for SpO2
the midline; and (3)  to identify the point of intersection of the
<94% (SpO2 %/​FiO2 ratio of <445) predictive value [41]. This
midline and the diagonal line which, in most cases, would accur-
system assesses each lobe (including the lingula) and gives a total
ately correspond to the carina. In addition, other data show that
of up to 19 points (0–​18): 0, normal; 1, plate or minor infiltrate;
in the majority of patients, the placement of an ETT may be aided
2, moderate atelectasis; and 3, total lobe atelectasis. A score of 5
by the length marks on the tube [44]. In 97.6% of patients, the
or more can predict, with 93–​100% specificity, an SpO2%/​FiO2
position of the ETT would be correct if adjusted at the corner of
ratio of <445 on the day after atelectasis is diagnosed, but with
the mouth to 21 cm for women and 23 cm for men.
low sensitivity.
Chest tubes
Effective drainage of the pleural cavities should be ensured by
Lines, tubes, and temporary checking the position of the thoracostomy tube. The position
pacemakers on chest X-​ray of the tube is visible at the site of interruption of the radio-​
opaque line which should lie within the thoracic cavity. The
Endotracheal tubes presence of subcutaneous air, incompletely drained fluid in
Adequate airway maintenance depends on appropriate posi- pleural cavities, tube kinking, overadvancement, etc. should
tioning of the ETT which can migrate with head movement or be checked (see E Figures 17.5B, 17.7B, 17.21, and 17.22).
may have been incorrectly placed initially. Misplacement of ETTs (See also E Chapter 26.)
 Lin es , tu b es , a n d tem p or a ry pacem a k er s on  c h e st   X-r ay 195

Figure 17.21  Partial resolution of right-​sided pneumothorax (see E Figure Figure 17.23  Coiled CVC in a patient with a small left upper lobe atelectasis
17.10A) after chest tube placement. Signs of subcutaneous emphysema, and decompensated chronic heart failure.
pneumomediastinum, and pneumopericardium are present.

verifying NG tube localization with high sensitivity, achieved by

Nasogastric tubes adding a water–​air mixture and by auscultation [46].
Generally, a chest film is seldom needed to ensure the correct
position of an NG tube; abdominal auscultation is used to check Central venous catheters
the placement of NG tubes. If there is uncertainty about the Misplacement of CVCs occurs quite frequently. The position of
proper advancement of an NG tube, it is necessary to order an the tip of the central line should be visible between the right
abdominal X-​ray, rather than a CXR, as the tip of the NG tube atrium and the proximal valves of the subclavian or jugular
normally should lie in the upper small bowel (duodenum) (see veins (see E Figure 17.12). The CXR is a simple diagnostic tool
E Figure 17.12) (the distal tip of the NG tube is not visible on to detect misplacement or catheter coiling [47] (see E Figure
the CXR) [45]. According to a recent study, neck and subxiphoid 17.23). To check the placement of CVCs, US scanning and/​or
US scanning seems to be comparable to direct radiography for a CXR should be used [48]. Complications associated with in-
correct line placement are pneumothorax, haematomas, venous
injury, and thrombosis (with difficult venous punctures), as
well as arrhythmias and right atrial or RV perforation (from the
distal tip being advanced too far) (see E Figure 17.5B). CVC
fracture may also occur, and the CXR may help to locate parts of
the catheter (see E Figure 17.24).

Pulmonary capillary wedge pressure catheters

and central venous pressure monitors
PCWP catheters are usually introduced via the right jugular vein,
placed into the distal pulmonary artery (or interlobar pulmonary
artery), and wedged with balloon inflation. Less frequently, the
subclavian or right femoral vein is used as access site. After PCWP
measurement is taken, the balloon should be deflated and the
catheter pulled back to the main pulmonary artery. Malposition
of the Swan–​Ganz catheter or failure to fully deflate the balloon
may lead to serious consequences such as balloon rupture, lung
infarction, pneumothorax due to catheter coining or pulmonary
artery rupture, pulmonary artery thrombosis, valve trauma, and
Figure 17.22  Partial resolution of left-​sided haemothorax (see E Figure
arrhythmias. Therefore, caution is required during manipulations
17.4) after chest tube placement (see also E Figure 17.5B—​imaging right-​
of PACs [49].
sided haemothorax and overadvanced chest tube).
196 CHAPTER 17   In terpretat ion and clinica l u se of chest r a di o g r a phs

Figure 17.24  Fractured CVC (AP projection). Distal portion of fractured

CVC seen in right pulmonary artery. Figure 17.25  Correctly placed temporary pacemaker leads in the RV and
right atrium in a patient with pulmonary oedema.

Intra-​aortic balloon pumps
the left, anterior projections. Both the right atrium and RV are
The device is usually inserted via the femoral artery, and, under
paced if the catheter is placed in the coronary sinus. To check the
fluoroscopic guidance, the tip of the IABP should be visible,
catheter position, a lateral CXR is helpful. For ventricular pacing,
2 cm below the carina and 1 cm below the left subclavian artery.
ideal catheter placement is on the diaphragmatic surface of the
Additionally, the distance from the sternal angle, formed by the
RV between the midpoint and apex (see E Figure 17.12).
junction of the manubrium and the sternal body (angle of Louis),
Catheter position in the RV outflow tract (RVOT) is not stable,
to the umbilicus and the insertion site (the common femoral artery)
and leads could be easily displaced. AP and lateral chest films re-
may be used to approximate the distance over which the balloon
veal the tip of the catheter, located within cardiac trabeculae and
should be advanced. These anatomical landmarks are helpful when
3–​
4  mm beneath the epicardial fat (see E Figure 17.26).
direct fluoroscopic control is not available. The balloon can be visu-
Dislodgement of pacemaker leads could be seen radiologically and
alized in the region of the aortic isthmus or the left main bronchus.
Although an IABP is usually placed under fluoroscopic con-
trol, a chest film should be obtained after pump insertion. Daily
CXRs are recommended to monitor the proper positioning of the
balloon catheter. A balloon inflated during diastole can be easily
visualized, and during systole, a deflated fusiform balloon is seen.
The CXR may provide important information where the IABP tip
is seen (see E Figure 17.16). The position may be considered ‘ac-
ceptable’ if the tip is seen below the aortic arch at the T2–​T5 ver-
tebrae, malpositioned if the tip is >50 mm below the aortic arch
at T5–​T6, and severely malpositioned if the tip is at T7 or below,
10 cm below the aortic arch [50].

Pacemaker leads
Although temporary pacers are inserted under ECG and fluoro-
scopic guidance, a chest radiograph should be obtained to check
the leads position when the pacemaker is in place (see E Figure
17.24). Preferred sites for pacemaker insertion are the internal
jugular and subclavian veins. Sometimes a femoral approach
is used. Right atrial pacing is easiest to achieve, but the pos-
ition of the catheter there is not stable. Advancing the catheter Figure 17.26  Pacemaker leads placed correctly in the RV in post-​MI patient,
with LV aneurysm, after urgent CABG, with pulmonary congestion and small
to the atrial appendage anteriorly above the tricuspid valve an- discoid atelectases located in the right middle lobe and left upper lobe (lateral
nulus under fluoroscopic control increases stability. In this case, projection is suggested). Both cardiodiaphragmatic sinuses are blunted,
the catheter would appear L-​shaped in the right, and J-​shaped in suggesting pleural effusions. Chest drainage tube placed in right pleural cavity.
 Monitoring of   p o st- resu s ci tati on a n d p o st- pro cedu re c o mpl i c at i on s 197

is referred to as macrodislodgement. Microdislodgement as the (b)

cause of device failure or ‘non-​capture’ is not a case for single-​shot
CXR diagnostics and could be easily missed radiographically. On the
CXR, the appearance of pacemaker wires should be assessed for con-
tinuity and the presence of buckling and sharp angulations. Some
degree of buckling is acceptable, but excessive buckling is associated
with a risk of right heart perforation. If the tip of the pacemaker lead
is advanced further and becomes apparent beyond the epicardial fat
stripe, this is suggestive of RV perforation.

Monitoring of post-​resuscitation and

post-​procedure complications
In rare cases, patient resuscitation may be associated with unin-
tended trauma such as rib and sternal fractures, pneumothorax,
subcutaneous emphysema, and misplacement of lines, tubes, and
devices, which may be apparent on CXR.
Figure 17.27B  Residual right-​sided haemothorax and subcutaneous
Malposition of lines, tubes, and devices is not an infrequent emphysema in a patient after pleural drainage.
finding on CXRs taken in the ICCU. Placement of the ETT in the
right main bronchus may result in left lobe atelectasis, and an ETT rupture, haemothorax, and pneumothorax (see E Figures 17.5B,
positioned in the right intermedial bronchus would lead to right 17.7A, B, and 17.27). These complications may be diagnosed
upper lobe collapse. In patients on ventilation, overadvancement using radiographic assessment (see E Lines, tubes, and tem-
of the ETT may cause oesophageal rupture with mediastinal gas porary pacemakers on chest X-​ray, p.194).
accumulation. An incorrect ETT position may be associated with Although recently new advances in remote CXR interpretation
tracheal perforation, mediastinal or cervical emphysema, infec- have been introduced (e.g. such as hands-​free Google Glass) [51],
tion, vocal cord paralysis, and aspiration. To diagnose these com- classic-​style image reviewing using desktop or mobile devices
plications, a lateral CXR should be taken and the space between by physicians remains more accurate and preferable. Sometimes
the trachea and the vertebral column should be assessed for ab- devices and their position are not accurately visible on CXR but
normalities suggestive of air or fluid (haematoma, pus) collec- could be quite accurately visualized using different modalities of
tions posterior to the trachea. image viewing. In many cases, adjustment of the intensity/​con-
Placement of central venous lines, pressure monitors, PCWP trast mode may help to improve visualization of implanted de-
catheters, IABPs, and pleural drains may sometimes lead to ser- vices (see E Figures 17.11 and 17.28).
ious complications such as haematomas, thrombosis, vessel

(a)

Figure 17.27A  Post-​drainage placement for right-​sided haemothorax and Figure 17.28  (a) Occluder in proper position after endovascular patent
subcutaneous emphysema in a patient with pneumonia, pleural effusion, and ductus arteriosus closure; (b) calcified descending aorta; (c) suture on
severe aortic arch calcification. fractured rib.
198 CHAPTER 17   In terpretat ion and clinica l u se of chest r a di o g r a phs

Conclusion ideal PA position. Despite this, AP images and those taken

Although the quality of CXRs is not always ideal, it is still time-​ in the decubitus or supine position are essential for moni-
saving and essential for clinical decision-​making. Therefore, max- toring the proper positioning of chest tubes, central lines,
imum effort should be made to ensure optimal patient positioning IABP balloons, pacemaker leads, etc. CXRs should be taken
and appropriate inspiration. In some cases, other methods (ultra- after device placement and in cases when malposition is
sound, CT, MRI) may give additional information but still would likely to occur. The portable CXR is an easy-​to-​use and
not completely replace the CXR. In ICCU settings, this simple and informative diagnostic tool and quite often, in critically
cheap imaging technology is helpful for the differential diagnosis ill patients with underlying cardiopulmonary problems,
of key clinical conditions, some of which may not be suspected may reveal unsuspected clinical conditions. Besides an ini-
on patient examination. Timely performance of CXRs also allows tial CXR, radiographs should be taken daily in patients on
monitoring of the correct placement of lines, tubes, and other mechanical ventilation and those with IABP-​assisted circu-
devices, and it may rule out procedure-​related complications. In lation. Otherwise there is no need for daily routine CXRs
addition, recent studies have shown evidence for the safety of this in ICCU patients. In addition, in many cases, portable US
procedure in terms of scattering radiation exposure of medical may substantially reduce the use of CXR and still give re-
personnel who are not prompted to leave the ICCU during the liable information on certain medical conditions (e.g.
time when CXRs are being taken [52, 53]. Hence, an initial CXR pleural fluid accumulation, relaxed diaphragm, pulmonary
should be suggested for all ICCU patients, whereas the decision oedema, PE, pneumothorax).
to take further CXRs should be based on the patient’s condition
and the need for monitoring device and central line placements.

Acknowledgements
Personal perspective
Figure 17.24 (fractured CVC) in this chapter is courtesy of
Our clinical experience suggests that in ICCU patients, it Professor Marco Tubaro, MD, FESC, Intensive Cardiac Care
is rarely possible to obtain good-​quality CXR images in the Unit, Cardiovascular Department, San Filippo Neri Hospital,
Rome, Italy.

Further reading
1. Corne J, Kumaran M. Chest X-​ray Made Easy, fourth edition. Elsevier: 3. Dobranowski J, Dobranowski AJ, Levinson AJ. Discover Radiology:
Oxford; 2015. Chest X-​ Ray Interpretation:  Knowledge Through Discovery. J2D
2. Delrue L, Gosselin R, Ilsen B, Van Landeghem A, de Mey J, Duyck P. Publishing; 2014.
Difficulties in the interpretation of chest radiography. In: Coche EE, 4. Walker CM, Chung JH. Müller’s Imaging of the Chest: Expert Radiology
Ghaye B, Mey J, Duyck P (editors). Comparative Interpretation of CT Series, second edition. Elsevier: Philadelphia, PA; 2018.
and Standard Radiography of the Chest. Berlin Heidelberg: Springer-​
Verlag; 2011. pp. 27–​52.

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 CHAPTER 18.1

Echocardiography and
thoracic ultrasound
Frank A Flachskampf, Pavlos Myrianthefs, and
Ruxandra Beyer

Contents
Summary  201 Summary
Introduction  201 For the emergency management of cardiovascular disorders, echocardiography
Technical and equipment and thoracic ultrasound are indispensable imaging techniques at the bedside. In
considerations  202
the intensive care environment, crucial questions, such as left and right ventricular
Training  203 function, valvular heart disease, volume status, aortic disease, cardiac infection,
Echocardiography in specific scenarios  203 pleural effusion, pulmonary oedema, pneumothorax, and many others, can be
Acute coronary syndromes  203
Shock and hypotension  205 sufficiently and reliably answered by using these techniques; in fact, it is almost
Heart failure  206 impossible to manage patients with acute severe haemodynamic impairment rea-
Assessment of systolic left ventricular sonably well without prompt and repeated access to echocardiography. This is con-
function  206
Assessment of diastolic left ventricular firmed by the prominent place that echocardiography has in the guideline-​based
function  207 diagnosis and treatment of all major cardiovascular emergencies, from acute heart
Other aspects of heart failure  208
Echocardiography of left ventricular assist
failure to acute coronary syndrome to pulmonary embolism, etc. Moreover, it is
devices  208 the ideal tool to follow up the patient, since repeat examinations pose no risk to
Left and right ventricular function in the patient and demand relatively little logistics and resources. To benefit from the
LVAD circulation  208
Aortic valve and LVAD cannulae  208 wealth of information that echocardiography and thoracic ultrasound can provide,
Assessment of cardiac output and volume modern equipment (including a transoesophageal probe) and systematic training
status  209
of echocardiographers must be ensured. The availability of prompt and experi-
Endocarditis, acute valvular regurgitation,
and prosthetic valve dysfunction  210 enced echocardiography and thoracic ultrasound services at all times is funda-
Infective endocarditis  210 mental for sound contemporary cardiovascular intensive care.
Acute mitral or aortic regurgitation  210
Prosthetic valve thrombosis  211
Pericardial disease and trauma  211
Traumatic cardiac and aortic injury  212
Pulmonary embolism  213
Aortic emergencies  213 Introduction
Systemic embolism  216
Personal perspective  216 The intensive care environment poses specific and rigorous demands on the availability,
Further reading  216 speed, versatility, and accuracy of cardiac imaging. Echocardiography is by far the tech-
References  217 nique which best matches these demands in the vast majority of cases and thus is clearly—​
Additional online material  217
as in cardiology in general—​the ‘first-​line’ imaging technique in intensive care. Prompt
availability of echocardiography is indispensable to any ICU and, of course, central to
cardiac care units. In this chapter, a basic knowledge of echocardiographic techniques
and examination procedures is assumed; strengths, weaknesses, pitfalls, and particular-
ities of echocardiography in specific situations are discussed. New techniques are briefly
presented, but the main emphasis rests on the most appropriate use of standard arma-
mentarium, corresponding to the typical needs of intensive care management. The text
has been arranged according to clinical scenarios.
202 CHAPTER 18.1   E c ho cardio graph y and t hor aci c u ltr as ou n d

under a variety of names (FEEL, FATE, FoCUS, POCUS, etc.) and

Technical and equipment are mostly directed to non-​cardiologists, with the goal of enabling
considerations fast and critically important US diagnostics in emergency situ-
ations such as cardiac tamponade or RV failure. As may be ex-
While echocardiography has always been a relatively small, port- pected, the main problem is training. The critical issues of training,
able, and deployable technique at the bedside, in contrast to other competence, certification, and others are discussed in [3]‌.
imaging modalities, technical progress in recent years has led The selection of an US machine for an ICU should consider the
to further reductions in size, even of state-​of-​the-​art machines, following fundamental issues:
making them well usable in an intensive care setting [1]‌. Besides,
◆ 2D image quality remains the cornerstone of echocardiographic
the industry has produced miniaturized echocardiography ma-
diagnosis.
chines which have begun to be differentiated into two main lines.
◆ Reasonably good colour Doppler and, often neglected, continuous-​
The first line of products comprises laptop-​type devices which es-
wave Doppler are very important, e.g. to assess aortic stenosis (AS)
sentially have all the capabilities of larger machines, including full
or pulmonary systolic pressure via the TR profile.
digital storage and transoesophageal imaging. These devices typic-
TOE is an essential option [4]‌.
◆
ally still need a power supply or an additional battery package and,
although eminently mobile, a table or a similar support platform. ◆ Newer techniques are of limited importance; tissue Doppler is
The other line of products is further miniaturized to allow effort- useful to assess LV diastolic pressures and RV free wall function,
but more sophisticated techniques rarely are necessary to deal
less portability (‘ultrasound stethoscope’, ‘hand-​held ultrasound’,
with emergencies. Global LV (and RV) strain is increasingly part
‘point-​of-​care ultrasound’), with a minimal weight of <1 kg; they
of the full standard examination and therefore desirable to have.
can be carried in a coat pocket or around the physician’s neck (see
E Figure 18.1.1). These devices have limited options, e.g. they ◆ Digital storage, including long-​ term storage, is mandatory,
do not provide spectral Doppler and have limited storage cap- ideally via a digital network. Technically, even wireless op-
abilities and they cannot be used for transoesophageal imaging tions today are already available, although still rare. It is very
[1, 2]. However, they provide reasonable two-​dimensional (2D) important to be able to promptly recall previous examinations
quality that is sufficient to identify major pathology, e.g. impaired to monitor changes, e.g. in wall motion, and given the life-​and-​
LV function, manifest valvular disease, or pericardial effusion. death character of daily decisions in the intensive care envir-
Their role is to offer an extension of the physical examination, not onment, full documentation is vital to protect patients and
to replace a full echocardiographic examination. Their scope of physicians.
application, the necessary training, and their relation to standard In the intensive care setting, the maintenance of echocardio-
echocardiography are discussed in depth in a position state- graphy equipment is a constant headache, often because no clear
ment from the European Association of Cardiovascular Imaging responsibilities exist. This relates to equipment maintenance,
(EACVI) [2]. cleaning, proper disinfection of transoesophageal probes, house-
Another important development in the field is the recent cre- keeping of reports and other documentation, management of
ation of limited, focused US diagnosis protocols, which are not digital storage, including protection against loss of data, regular
necessarily confined to cardiac diagnostics. Such protocols exist software updates, providing sufficient space, and other issues.

Figure 18.1.1  Modern mobile, miniaturized echocardiographic devices from different manufacturers. Weights are indicated.
 Echo ca rdi o g r a phy i n speci fi c sc e na ri o s 203

Table 18.1.1  Training requirements in echocardiography of the European Association of Echocardiography to achieve basic and advanced
levels of competence

Echocardiography Minimum number of examinations Level of Minimum number of examinations performed

technique performed to become competent competence per year to maintain competence
TTE 350 (basic) III Reasonable exposure
750 (advanced) III 100
TOE 75 (advanced) III 50
Stress echocardiography 100 (advanced) III 100
Level III: the ability to perform the procedure independently (unsupervised).
Reproduced from Popescu BA, Andrade MJ, Badano LP, et al. European Association of Echocardiography recommendations for training, competence, and quality improvement in
echocardiography. Eur J Echocardiogr 2009;10(8):893–​905. doi:10.1093/​ejechocard/​jep151 with permission from Oxford University Press.

earliest possible point in time [6, 7]. The echocardiographic hall-

Training mark of ACS is wall motion abnormality as a marker of ongoing
or recent myocardial ischaemia (see E Figure 18.1.2). Wall mo-
Minimal training requirements are provided in Additional on-
tion abnormalities result from impaired systolic wall thickening
line material. The ICU is often the first place where a cardiology
and reduced systolic endocardial inward motion. They range in
or internal medicine fellow in training operates an echocardio-
degrees, from hypokinesia (reduced thickening and inward mo-
graphy machine, usually under informal supervision of a more
tion) through akinesia to dyskinesia (systolic outward movement
experienced colleague. Because of the frequent direct impact of
and thinning) and aneurysm (systolic and diastolic outward bul-
the echocardiographic diagnosis on management, this is a par-
ging and thinning), and in extent by the number of wall segments
ticularly impressive and enlightening situation to learn echocar-
affected, which most conveniently are described by the standard
diography. However, this must be accompanied or followed by
16-​or 17-​segment schemes. The wall motion score is a semi-​
systematic training, in particular because time pressures in the
quantitative way to express this; each segment receives a score
intensive care setting often lead to incomplete and hurried exam-
from 1 (normokinetic) to 4 (dyskinetic), and the sum of all scores
inations. Also, crucial competencies, such as eyeballing LV pump
divided by the number of segments, called the ‘wall motion score
function or assessing valvular regurgitation, are not acquired suf-
index’, is a dimensionless semi-​quantitative parameter of wall mo-
ficiently without systematic training and comparison to other
tion impairment, 1 being for a normal ventricle and increasing in
techniques. In a study of the diagnostic accuracy of ‘point-​of-​care’
value with increasing wall motion abnormalities. The pattern of
echocardio-graphy with portable devices, the diagnosis of im-
affected segments may indicate which coronary artery is affected.
paired LV function were in agreement in only 75% of cases among
The degree and extent of wall motion abnormalities depend on
fellows with limited training and fully trained echocardiographers.
the severity of ischaemia, which, in turn, depends mainly on the
Therefore, the training recommendations of the EACVI [5]‌(see
location of the occlusive thrombus and the duration of ischaemia.
E Table 18.1.1) or national societies should be followed and it
However, it is frequently not possible to decide whether a wall
should be ensured that definitive reports are reviewed beforehand
motion abnormality is new or old, although myocardial thin-
by a trained echocardiographer. For a fully trained cardiologist
ning or increased echogenicity implying fibrosis are signs of an
subspecializing in intensive cardiac care, the curriculum of the
older scar. Also, whether a new wall motion abnormality is re-
ECS-​ACVC requests the ability to fully and independently per-
versible by an acute intervention (myocardial hibernation) is not
form TTE and TOE (level III competence, including performance
of at least 350 transthoracic and 50 transoesophageal studies).
Digital data storage and written reporting of echocardiographic
findings are of critical importance in the intensive care setting, not
only for patient management, but also for medicolegal reasons.
Understandably, there is a tendency to neglect these tasks in the
context of life-​threatening scenarios, which nevertheless should
be counteracted. (See also E Chapter 2.)

Echocardiography in specific
scenarios
Acute coronary syndromes Figure 18.1.2  Wall motion abnormality in the anteroseptum (LAD
territory). Left, systole; right, diastole. The wall segment between the white
Echocardiography is extremely valuable in ACS, and therefore, arrows does not thicken or move, in contrast to the basal septum. This is a
an echocardiographic examination should be performed at the sign of ischaemia or scar.
204 CHAPTER 18.1   E c ho cardio graph y and t hor aci c u ltr as ou n d

immediately possible to decide, although some newer techniques, sought, especially in two-​chamber views, to minimize apical
like left heart contrast echocardiography or deformation imaging, foreshortening, which is usually present, to some degree, in
may be helpful. Although echocardiography is quite good at four-​chamber views. Left heart contrast application can help in
detecting acute myocardial ischaemia, wall motion abnormalities delineating thrombi. Fresh LV thrombi are potential sources of
may be missed, depending on the image quality, or if they are systemic embolism and require anticoagulation.
small; and therefore, echocardiography is not 100% sensitive for ◆ Aneurysm formation:  aneurysms are large wall motion abnor-
ACS. However, good-​quality echocardiography without any wall malities due to myocardial scar, with an outward bulging shape
motion abnormalities makes acute myocardial ischaemia highly that does not change during the cardiac cycle. They most fre-
unlikely. On the other hand, the extent and severity of a detected, quently occur at the LV apex and are prone to thrombus forma-
and presumably new, wall motion abnormality is important for tion (see Figure 18.1.12).
global LV function and also predicts the prognosis and likelihood ◆ MR:  acute ischaemic MR may develop due to several mech-
of post-​infarction remodelling. anisms. Most frequently, LV global dilatation and remodel-
A second crucial piece of information is global LV pump func- ling lead to functional regurgitation (see E Figure 18.1.4). In
tion, usually expressed as EF, with well-​known prognostic and rarer cases, the subvalvular apparatus of the mitral valve may
management implications (see E Figure 18.1.3). EF can be eye- be directly damaged by ischaemia, most dramatically in papil-
balled by experienced (!) observers and can be measured by 2D lary (head) muscle rupture, with sudden onset of torrential re-
and 3D methods with sufficient image quality. A useful surrogate gurgitation (see E Endocarditis, acute valvular regurgitation,
parameter for EF in patients who are difficult to image is the ex- and prosthetic valve dysfunction, p. 210). Chordal rupture
cursion of the mitral annulus (mitral annular plane systolic ex- may also occur, leading to less dramatic presentations. In any
cursion, or MAPSE) or the regional longitudinal strain. Besides case, new ischaemic MR is a recognized negative prognostic
this information, echocardiography is able to provide evidence sign and typically leads to pulmonary congestion or oedema.
for increased filling pressures; for more detail, see E Assessment MR is detected easily by colour Doppler, and the underlying
of diastolic left ventricular function, p. 207. mechanism should always be sought. In papillary muscle rup-
Finally, complications of an AMI can be quickly detected in the ture, hypermobile mitral leaflets flapping back and forth from
acute phase of an ACS: the LV to the LA, with an attached solid structure representing
◆ Thrombus formation:  this is quite frequent in patients with the ruptured distal papillary structure, are seen, together with
large wall motion abnormalities, especially anterior aneurysms signs of severe MR.
(see E Figure 18.1.4). Thrombi are often accompanied by ◆ RV infarction: this complication of inferior infarcts manifests as
spontaneous echocardiographic contrast or ‘smoke’, a marker of an enlarged, hypokinetic RV, with new onset of TR. Recognition
thrombogenic flow conditions caused by red blood cell aggre- is important, because fluid restriction in this scenario is
gation. To detect apical thrombi, they should be systematically deleterious.

(a) (b)

Figure 18.1.3  Calculation of EF by monoplane modified Simpson’s rule (summation of discs) in a patient with mildly impaired LV pump function. Apical four-​
chamber view. (A) End-​systolic frame, yielding a volume of 104 ml. (B) End-​diastolic frame, yielding a volume of 202 ml. The EF is (202 –​104)/​202 = 51%. Note
that the papillary muscle is included in the volume.
 Echo ca rdi o g r a phy i n  speci fi c sc e na ri o s 205

LV

LA

Figure 18.1.4  Ischaemic cardiomyopathy. All heart chambers are dilated, particularly the LV and LA. Note typical configuration of the closed mitral valve on
the left, with closure line of leaflets (arrow) pulled into the LV by eccentric tug of the papillary muscles. Right, colour Doppler of functional, or ‘ischaemic’, mitral
regurgitation (arrow).

◆ Ischaemic VSD (see E Figure 18.1.5): rupture of the ventricular a ‘neck’ which is narrower than the maximal diameter of the
septum occurs in the muscular part of the interventricular body of the pseudoaneurysm (see Figure 18.1.13). There
septum, and the murmur is often taken for MR. Colour Doppler may be paradoxical systolic inflow into the pseudoaneurysm
shows the jet in the RV and the rupture site can often be seen dir- and diastolic outflow. Distinction between a true aneurysm
ectly on 2D images, but sometimes the course of the rupture line and a pseudoaneurysm is important, because the latter is, in
is tortuous and not directly visualizable. Subcostal images are principle, an urgent indication for surgery; the situation is
very useful to detect VSDs, since the echocardiographic beam not always clear, and additional imaging modalities may be
is almost coaxial to the shunt jet. VSDs are easily overlooked if necessary.
the colour Doppler sector is not positioned in the appropriate
region, which is the apical and mid RV. In the subacute phase and before release from hospital, it
is important to provide a baseline study of wall motion and
◆ Ventricular free wall rupture (FWR) and pseudoaneurysm
ventricular function for later follow-​up. Regional and global
formation: complete rupture of the LV myocardium leads ei-
function may still undergo changes in this phase, both in the
ther to a rapidly lethal tamponade, detectable as pericardial
direction of improvement if there is still myocardial stunning or
fluid and (usually) asystole, or, if the rupture is contained
of deterioration due to LV post-​infarction remodelling. Other
by the parietal pericardium, to pseudoaneurysm formation.
concerns are the presence of inducible ischaemia from coronary
Typical signs of a pseudoaneurysm are an abrupt decrease
territories other than the culprit one and the question of myo-
of myocardial thickness, an abrupt outward course (as if
cardial viability in areas of wall motion abnormality; these ques-
around a sharp corner) of the endocardial contour, and often
tions can also be addressed by (stress) echocardiography. (See
also E Chapters 38 and 41.)
(a) (b)
Shock and hypotension
LV Severe hypotension, shock, and cardiac arrest all call for imme-
diate echocardiographic support. When performing such emer-
RV gency echocardiography, it is useful to have a list of the most
important echocardiographic features in mind to search for (see
LA E Table 18.1.2). The imaging conditions are almost always sub-
optimal, with many individuals surrounding the patient, fre-
quently in cramped conditions of an invasive laboratory, with
simultaneous procedures such as establishing IV access or frank
resuscitation going on in parallel. Obviously, portable echocardio-
Figure 18.1.5  Post-​infarction ischaemic VSD. (A) Apical four-​chamber view. graphic machines are beneficial in these circumstances. Contrary
The discontinuity in the muscular ventricular septum is visible (arrow). (B) There to the typical protocol of echocardiography that begins with para-
is a colour Doppler jet towards the RV, indicating left-​to-​right shunting. Note
that this jet is easily missed if the septum is not investigated by colour Doppler.
sternal imaging, often only apical or subcostal windows are usable
206 CHAPTER 18.1   E c ho cardio graph y and t hor aci c u ltr as ou n d

Table 18.1.2  Typical echocardiographic features of shock and hypotension of different aetiologies

Aetiology Key echocardiographic signs Remarks

LV pump failure Enlarged hypokinetic, spheroid LV, functional MR
PE Enlarged RV apex reaching cardiac apex, hypokinetic RV, TR,
elevated pulmonary pressure (degree varies with pre-​existing
PH, RV function, and extent of embolism)
Pericardial tamponade Pericardial fluid compressing the RV and/​or right atrium; Look for signs of aortic dissection, MI, trauma, or other thoracic
exaggerated respiratory variation in LV and RV inflow disease, e.g. tumours
Acute left-​sided valvular Structural damage of aortic or mitral valve, e.g. papillary Look for signs of inferior MI in papillary muscle rupture and for
regurgitation muscle rupture; Doppler signs of severe AR or MR; signs of aortic dissection in AR
hyperkinetic LV, often of normal size
Acute right heart failure Enlarged hypokinetic RV; may occur with PE, chronic PH, or
as RV infarction complicating MI
Aortic dissection or Aortic enlargement, aortic valvular regurgitation, dissection The typical site of aortic rupture, e.g. after deceleration trauma,
rupture flap in the aorta, pericardial tamponade is the proximal descending aorta, which is visualizable by TOE
Sepsis Endocarditic vegetation on valve or pacemaker electrode, In sepsis due to non-​cardiac causes, the discrepancy between
abscess, or destruction of valves systemic hypotension in the presence of an often hyperkinetic
heart is typical
Prosthetic valve ‘Frozen’ occluder position in mitral prostheses, often with Always use TOE; compare to earlier transprosthetic gradients, if
obstruction clear thrombus; in the aortic position, difficult to see, even by possible
TOE. Massive transvalvular gradient elevation by Doppler
Prosthetic valve Abnormal mobility (‘rocking’) of prosthesis, (colour)
regurgitation or Doppler signs of severe regurgitation, premature mitral
dehiscence valve closure in AR
AS Severe AS, typically with severely depressed LV Continuity equation must be used to evaluate stenosis severity;
gradients may be deceptively low

and should be quickly sought. In the ventilated patient, TOE, if [8, 9]. Global LV function is typically categorized into systolic or
quickly available, is very helpful. In the patient in cardiac arrest pump function (which assesses the ability of the LV to create an
undergoing resuscitation, or shortly thereafter, it is typical to see adequate stroke volume) and diastolic function (which relates to
diffusely hypokinetic, dilated ventricles. This per se does not es- the ability of the LV to fill adequately at low diastolic pressures).
tablish a cause for the cardiac arrest. However, the presence of a The evaluation of global LV systolic function consists of:
pericardial effusion or a disproportionately large RV points to tam- ◆ EF, calculated from end-​diastolic and end-​systolic LV volumes
ponade (see E Chapter 25) or PE (see E Chapter 63) as the most (see E Figure 18.1.3). It may be visually estimated from sev-
likely causes of arrest, and these two conditions can be detected or eral cross-​sections or preferentially measured by tracing the
excluded by echocardiography within seconds, even in very un- LV in end-​diastole and end-​systole in the four-​chamber view
favourable circumstances, and may lead to lifesaving treatment. (monoplane EF) or additionally in the two-​chamber view (bi-
Most aetiologies of an acute drop in blood pressure are dis- plane EF), enabling the calculation of LV volumes and EF by
cussed in more detail in the pertinent sections of this chapter. the modified Simpson’s rule method. If 3D echocardiography is
Volume depletion, which is a frequent cause of hypotension, does available, volumes can be calculated from the full ‘volume data
not have specific echocardiographic signs; typically, the RV is rela- set’ without any geometric assumptions.
tively small (underfilled) and the inferior caval vein collapses with ◆ End-​ systolic [LV end-​ systolic diameter (LVESD)] and end-​
inspiration. The value of echocardiography in this scenario lies diastolic [LV end-​diastolic diameter (LVEDD)] LV short-​axis
mainly in the exclusion of cardiac pathology. See E Assessment diameters (by M-​ mode or 2D echocardiography measured
of cardiac output and volume status section, p. 209 for more de- from a parasternal long-​axis view) and the shortening fraction
tail. (See also E Chapter 47.) [(LVEDD –​LVESD)/​LVEDD] are the oldest quantitative para-
meters of global LV function. However, they only take into
Heart failure account wall motion at the base of the LV.
(See also E Chapter 45.) ◆ The systolic excursion (normally >12  mm) of the AV plane of
the LV, i.e. the apical displacement of the mitral annulus during
Assessment of systolic left ventricular function systole, can serve as a measure of global systolic function.
(See Table 18.1.6.) ◆ On tissue Doppler recordings from the mitral annular region of the
Echocardiography provides crucial information on the mechan- septal and lateral wall in the apical four-​chamber view, peak systolic
isms, severity, and therapeutic options in congestive heart failure longitudinal velocities are normally >5 cm/​s (see E Figure 18.1.6).
 Echo ca rdi o g r a phy i n  speci fi c sc e na ri o s 207

(a) in a longitudinal (apico-​basal) direction. It is a dimensionless

percentage, relating the difference in length from end-​diastole
to end-​systole to baseline length; a peak systolic longitudinal
strain of 20% in a segment means that the myocardium shortens
in the longitudinal direction during systole by 20%. The most
common strain-​related parameter is GLS, which reflects the
strain of the whole LV imaged in the three apical standard
views (see Figures 18.1.14 and 18.1.15). The normal value
of GLS, which varies somewhat by machine and software, is
approximately 20%. GLS has consistently shown higher prog-
nostic power than EF, and in patients with heart failure with
preserved EF, a decrease in GLS reflects diastolic dysfunction.
It is also more sensitive to small decreases in systolic function
than EF. Thus, it is particularly valuable in the detection of early
(b)
subclinical myocardial damage, e.g. under cardiotoxic therapy
such as cancer chemotherapy with anthracyclines. All major
manufacturers of echocardiographic equipment now offer the
option to calculate longitudinal (and other) strain, although
numerical values vary to a minor degree, dependent on hard-
ware and software. Importantly, although GLS measurement
does not require top-​quality images, it will decrease with bad
image quality, making it impossible to be sure whether such
a decrease is due to myocardial disease or only due to ‘bad
pictures’.
(See E Table 18.1.6 for normal values.)

Assessment of diastolic left ventricular function

In practice, assessment of LV diastolic function means detection
of elevated diastolic LV pressures, although the two are funda-
mentally not the same [11]. Patients with heart failure symptoms
(c)
can have preserved or reduced EF. Heart failure patients with pre-
served EF, having, for example, hypertensive heart disease, hyper-
trophic cardiomyopathy, or cardiac amyloidosis, typically have
diastolic dysfunction, and heart failure with preserved EF often
is called diastolic heart failure. On the other hand, in heart failure
patients with reduced EF, often diastolic dysfunction is also pre-
sent and plays an independent prognostic role. While echocar-
diography cannot directly measure LV diastolic pressures, it can
provide data that make diastolic pressure elevation likely or un-
likely. The following signs and parameters should be systematic-
ally used to evaluate diastolic LV filling pressures:
◆ Impaired systolic function (EF) very often is accompanied by
elevated filling pressures.
Figure 18.1.6  (A) Transmitral restrictive filling pattern with high and short ◆ The presence of LV hypertrophy, independent of the cause, in-
E wave and small A wave; the peak E wave is more than double as high as dicates impaired relaxation and reduced chamber compliance,
the peak A wave. The E wave deceleration (time interval between arrows) is which requires higher-​than-​normal filling pressures. This is the
103 ms. (B) In the same patient, basal myocardial velocities by tissue Doppler. case in hypertensive heart disease, AS, hypertrophic cardio-
Reduced early diastolic peak velocity e’ (5 cm/s, arrow) and also low peak
systolic velocities (4 cm/s). E/e’ in this patient was 29, indicating massively
myopathy, amyloidosis, and others.
elevated LV filling pressures. (C) LA volume calculation from the four- ◆ The size of the LA, measured as LA volume from the apical four-​
chamber view by summation of discs (different patient from panels A and B). chamber view or in both apical four-​chamber and long-​axis
The LA is mildly enlarged at 36 mL/m2. views (see E Figure 18.1.6). Normal size (≤34 mL/​m2) excludes
chronic substantial elevation of LV filling pressures. However,
◆ Peak systolic LV global longitudinal strain (GLS) is increasingly the LA may also enlarge in other conditions, e.g. AF.
recognized as a useful adjunct to, or even a replacement of, EF The ratio E/​e’ (where E is the peak transmitral early diastolic
◆
[10]. Strain describes local myocardial length change, typically flow velocity, divided by e’, the peak early diastolic mitral annular
208 CHAPTER 18.1   E c ho cardio graph y and t hor aci c u ltr as ou n d

tissue velocities averaged from the septal and lateral mitral an- Echocardiography also plays a critical role in identifying can-
nular region) (see E Figure 18.1.6). A ratio of >14 suggests sub- didates for therapies and procedures which may improve heart
stantially elevated filling pressures. failure or its prognosis, e.g. implantable defibrillators or CRT.
◆ Increased RV systolic pressure with a peak systolic TR velocity
of >2.8 m/​s corroborates diastolic dysfunction, if other reasons Echocardiography of left ventricular assist devices
for elevated pulmonary pressures can be excluded, e.g. substan- Although there are several forms of mechanical circulatory sup-
tial MR or PH of other aetiologies (e.g. lung disease). port, fully implanted non-​pulsatile LVADs are the most common
If at least two out of the three principal criteria for diastolic and are used increasingly not only acutely in heart failure, but also
dysfunction (E/​e’ ratio, LA size, and RV systolic pressure) are as long-​term ‘destination’ therapy. Echocardiographic assessment
elevated, this argues strongly for the presence of diastolic dys- of LVADs is crucial, but difficult [12, 13]:
function. If only one or two apply, other parameters should be as- 1. The assessment of a severely failing LV and RV, operating under
sessed (pulmonary venous flow, mitral E wave deceleration time, unphysiologic conditions (permanently closed aortic valve, de-
and others [11]) (see Figure 18.1.16). creased LV afterload, and increased RV preloads), and
◆ A restrictive transmitral flow pattern (peak E >2 × peak A wave 2. Evaluating the functionality of the implanted device with its in-
velocity and E wave deceleration time <150 ms) indicates se- flow and outflow cannulae at a given (and changeable) machine
verely impaired prognosis (see E Figure 18.1.6), regardless of setting. The task is complicated by the fact that LVADs are im-
EF. A pseudorestrictive pattern may be observed in young, per- planted in failing hearts, and therefore, most parameters of size
fectly healthy individuals due to very vigorous relaxation. and function of the LV and RV are already pathological at base-
◆ A transmitral flow pattern with E < peak A velocities is very fre- line and typically will only recover partially, if at all. Therefore,
quent, with prolonged isovolumic relaxation (>100 ms). This is the diagnostic problem is detection of small increments of im-
normal in patients aged >60 years. The pattern excludes substan- provement of deterioration, e.g. is this clearly an impaired RV
tially elevated filling pressures, since these would increase the performing better or worse than before?
peak E wave velocity. 3. Image quality tends to be suboptimal due to post-​operative
Other aspects of heart failure status. Cooperation and discussion of findings with other dis-
ciplines involved in the management of patients with assist
Further important information in patients with heart failure
devices, such as cardiac surgeons and cardiothoracic anaesthe-
gleaned from echocardiography includes:
tists, are therefore of utmost importance.
◆ The presence and degree of MR.
Left and right ventricular function in LVAD circulation
◆ Signs of coronary artery disease (CAD) (e.g. regional wall motion
The goal of an LVAD is partial functional substitution (‘un-
abnormalities), cardiomyopathy (especially the dilated form),
loading’) of the LV. When LVAD pump speed (rounds per
myocarditis, or constrictive pericarditis causing heart failure.
minute) is increased, the LV is unloaded and systolic LV con-
◆ Signs of RV dysfunction:  isolated RV dysfunction most fre-
traction is enhanced, while reduction of the LVAD contribution
quently is due to chronic PH or acute pulmonary pressure
increases the afterload and reduces systolic LV contraction. The
elevation following PE (see E Chapter 63). Hallmarks are an
RV also is profoundly affected by LVAD-​induced load changes.
enlarged and globally hypokinetic RV, with TR and elevated
LVAD contribution to cardiac output increases the venous re-
peak tricuspid velocity, which enables an estimate of peak sys-
turn and RV size, which may lead to more TR and a septal shift
tolic RV, and thus pulmonary, pressure. Importantly, in severe
to the left side with left-​sided ‘underfilling’. The septal shift can
right heart failure after PE, the RV may not be able to generate
be well appreciated by echocardiography (see z Video 18.1.1).
high pressures, leading to deceptively low peak transtricuspid
Although the LVAD-​induced fall in left-​sided afterload should
regurgitant velocities and RV pressure estimates. The ventricular
also decrease the right-​sided afterload, RV function is often de-
septum is shifted to the left side, giving the cross-​section of the
pressed after LVAD implantation and is often the most critical
LV a ‘D’ shape, instead of a circular appearance (‘D sign’). RV
issue in LVAD patients, requiring fine-​tuning of volume and
size and function are usually eyeballed, due to unreliability of
pump seed.
M-​mode or 2D measurements. A useful practical measure of RV
function is the systolic excursion of the tricuspid annulus, with Aortic valve and LVAD cannulae
values <16  mm indicating impairment of RV function. Other In LVAD circulation, since the aortic outflow cannula bypasses
useful measures of RV function are the peak systolic tissue vel- the aortic valve, the aortic valve often stays entirely closed or only
ocity of the basal RV free wall, which normally is >10 cm/​s, and opens intermittently and partially (see z Video 18.1.1). The pres-
RV peak systolic longitudinal strain (normally >20% for all six ence and duration of systolic aortic valve opening, for a given
segments of the RV in the apical four-​chamber view or >23% level of LVAD contribution, can be interpreted as a parameter of
for the three RV free wall segments). RV end-​diastolic free wall residual systolic LV function, and increasing systolic aortic valve
thickness of >5 mm indicates chronic PH. Rarely, advanced car- opening reflects improvement in LV function. Native aortic re-
diomyopathy, e.g. RV arrhythmogenic cardiomyopathy, may be gurgitation (AR) is a contraindication to LVAD implantation.
the cause of right heart failure. Over time, however, AR often develops even in LVAD patients
 Echo ca rdi o g r a phy i n  speci fi c sc e na ri o s 209

with initially entirely competent aortic valves; this needs to be

carefully echocardiographically monitored and may have to be
treated surgically.
The inflow cannula can usually be seen echocardiographically
at the LV apex (see z Video 18.1.2). The orientation of the can-
nula, ideally coaxial with the long axis of the LV, the presence of
thrombi, and high inflow velocities (>2 m/​s) suggesting stenosis/​
thrombosis should be examined. If the cannula is malaligned, it
may ‘suck in’ the ventricular septum, leading to decreased inflow.
The outflow cannula conveys blood into the ascending aorta.
It is often difficult or impossible to visualize well, although flow
signals can usually be registered by Doppler. As for the inflow
cannula, high-​flow velocities raise the suspicion of an obstruc-
tion by thrombus or kinking. Outflow is pulsatile (see Figure
18.1.17), and pulsatility can be measured by several indices, the
simplest of which is the ratio of maximal to minimal flow vel-
ocity during a cardiac cycle. Flow pulsatility reflects the interplay
between the pulsatile action of the LV and the continous flow of
the LVAD.
Finally, attention should be paid to the possibility of right-​
to-​left shunts which may become haemodynamically important
under the non-​physiologic conditions of LVAD-​supported circu-
lation, e.g. across an open foramen ovale or a small atrial septal
defect.

Assessment of cardiac output and volume status

Knowledge of cardiac output and intravascular volume status is
crucial in intensive care. These parameters can be estimated, to
a degree, from echocardiography. Cardiac output is most easily
calculated by measuring the LV outflow tract (LVOT) diameter
(D) and the velocity time integral (VTI) of LVOT flow by pulsed-​
wave Doppler, taking care to align the Doppler beam as well as
possible with the long axis of the outflow tract (see Figure
18.1.18) (see E Chapter 63). Provided there is no AR, the sys-
temic stroke volume (SV) is approximated as (assuming a circular
outflow tract cross-​section):

SV =π × D2 × VTI/4

A similar calculation can be made at the pulmonary valve level

to calculate the pulmonary SV. The product of the SV and the Figure 18.1.7  Respiratory variability of the diameter of the inferior vena
heart rate is the cardiac output. The calculation is far from precise cava, modified subcostal view. (A) Expiration. (B) Inspiration. (C) Dilated
but will give a reasonable estimate of the cardiac output. inferior vena cava (IVC; 24 mm) due to right heart failure.
The estimation of the intravascular volume status, specifically
of central venous pressure (CVP) and pulmonary capillary pres-
right atrial pressures of above 10  mmHg, and no diameter
sure, relies on indirect signs and is more complex.
change at all with severely elevated mean right atrial pressures
◆ CVP may be estimated by assessing the respiratory variation of ≥20  mmHg. Furthermore, the systolic portion of hepatic
of the diameter of the inferior vena cava from a subcostal venous flow, which usually shows a systolic and diastolic for-
echocardiographic window (see E Figure 18.1.7) (see also ward wave towards the right atrium, decreases with increasing
E Chapter 63). Exact measurements are rather difficult, since right atrial pressures. This is accentuated if there is substantial
the inferior vena cava itself moves in and out of the cross-​ TR, which will lead to backward systolic flow in the hepatic
section during respiration, but total obliteration of the vena veins. The hepatic veins can be easily sampled by pulsed-​wave
cava during inspiration (‘sniff ’) is usually associated with Doppler in held respiration from the subcostal window. PEEP
mean right atrial pressures of 5  mmHg or less. A  <50% in- elevates right atrial pressures and makes it difficult to use
spiratory decrease in caval diameter is associated with mean them to assess volume status.
210 CHAPTER 18.1   E c ho cardio graph y and t hor aci c u ltr as ou n d

attached to valvular structures and valvular destruction, leading to

regurgitation; in fact, echocardiographic evidence of IE is a major
diagnostic criterion. Mitral and aortic valves are affected with similar
frequency. Tricuspid endocarditis occurs mainly in drug addicts
and patients with long-​standing disease necessitating the insertion
of indwelling central catheters and ports. Vegetations may also be at-
tached to cardiac foreign bodies, such as pacemaker electrodes, and,
in rare cases, directly to the endocardium, e.g in the proximity of a
VSD. Abscess formation in the perivalvular tissue may be observed,
especially in aortic valve endocarditis (see Figure 18.1.20) and
prosthetic valves. Further sequelae of endocarditis are fistulae,
perforations, or the formation of a mitral pseudoaneurysm. Valve
endocarditis may induce regurgitation of all degrees by perforation
or rupture of valvular structures. Transoesophageal examination,
because of its higher spatial resolution and better image quality, is
Figure 18.1.8  Large left pleural effusion (arrow) and collapsed left lung (LL).
Transducer placed in the left posterior axillary line.
superior to TTE and should always be used if there is a substantial
suspicion of IE (e.g. positive blood cultures) and no definite diagnosis
can be established by TTE. In the presence of prosthetic valves, the
◆ PAP:  systolic pulmonary pressure is assumed to be equal to use of TOE is mandatory [11], since IE is frequent, difficult to detect,
peak RV pressure, which can be estimated using the TR Doppler and more prone to complications, especially ring abscesses, in the
signal (see E Pulmonary embolism, p. 213). In the absence of presence of prosthetic valves. In fact, the latest guidelines recommend
a usable TR signal, the acceleration time (time from the onset TOE in all cases of endocarditis [14]. (See also E Chapter 57 and
of pulmonary ejection to peak velocity) of the transpulmonary Figure 18.1.21.)
pulsed-​wave Doppler flow profile may be used as a very rough
estimate of pulmonary pressure; acceleration times >100 ms Acute mitral or aortic regurgitation
make substantial PH unlikely.
Acute severe MR occurs in several scenarios. Due to systolic re-
◆ Assessment of elevated LV filling pressures, and thus ele-
gurgitation into the LA, there is acute volume overload, and con-
vated pulmonary capillary pressures (this is detailed in E
sequently pressure overload, of the LA, leading to increases in
Assessment of diastolic left ventricular function, p. 207).
Elevated pulmonary capillary pressures due to LV dysfunction pulmonary capillary pressures and pulmonary oedema. Forward
usually are associated with E/​e’ ratios of >15 [8]‌. Furthermore, SV is low, causing hypotension and ultimately CS. Key echocar-
high pulmonary capillary pressures and high LV filling pres- diographic findings are [14]:
sures will generate a tall, short transmitral E wave; a transmitral ◆ A clear structural abnormality of the mitral valve, with exces-
E/​A wave ratio of <1 makes high filling pressures unlikely and sive mobility of a part of the valvular apparatus, such as a flail
may be normal for age or caused by hypovolaemia or slowed leaflet, or papillary muscle or chordal rupture (see Figures
LV relaxation. 18.1.23 and 18.1.24).
◆ Pleural effusions are easily diagnosed and semi-​quantitated by ◆ A  large, consistently imaged proximal acceleration zone
applying the echocardiographic transducer to the intercostal (>1  cm2 at aliasing velocities of ≥50  cm/​s) on the ventricular
spaces over the lungs, preferentially with the patient sitting (see side of the mitral valve; the regurgitant jet in the LA is often
E Figure 18.1.8). hard to interpret due to tachycardia, low systemic pressure, and
A chapter on TTE is available in the online data supplement. other factors.
Systolic pulmonary venous flow reversal.
◆

◆ In extreme cases, the typically symmetrical, bell-​ shaped

Endocarditis, acute valvular continuous-​wave Doppler profile of MR becomes triangular due
to dramatic late systolic pressure increase in the LA.
regurgitation, and prosthetic ◆ The LV is often hyperkinetic due to massive volume over-
valve dysfunction load. The LA may be of normal size due to the acuteness of
regurgitation.
(See E Chapter 57.)
Acute severe AR causes sudden LV volume overload and in-
Infective endocarditis creased diastolic pressures, leading ultimately to pulmonary
IE may necessitate intensive care for several reasons: sepsis, acute oedema, and, with reduced forward SV, also leads to CS. Key
valvular regurgitation, and central or peripheral systemic em- echocardiographic findings are:
bolism. The echocardiographic hallmark of IE are new mobile ◆ A  clear structural abnormality such as endocarditic destruc-
mass lesions (vegetations) (see E Figures 18.1.19 and 18.1.22) tion, rupture of a leaflet, or an aortic dissection membrane
 Peri ca rdia l di sease a n d   t r aum a 211

prolapsing into the outflow tract and precluding diastolic leaflet(s). Symptoms and clinical findings depend on how rap-
closure of the valve. idly the prosthetic obstruction develops and on the severity of the
◆ Doppler and colour Doppler signs of severe AR, including obstruction [15]. The incidence of prosthetic valve thrombosis
marked holodiastolic backward flow in the descending aorta is twice as high in the mitral as in the aortic position, and even
and, if present, a large proximal acceleration zone (>1  cm2 at higher in the tricuspid position, independently of the prosthesis
aliasing velocities of ≥50 cm/​s) on the aortic side of the valve. type. Echocardiographic signs are increased transprosthetic
◆ Premature closure of the mitral valve on mitral M-​mode re- Doppler gradients and, especially in mitral prostheses, absent
cording or the transmitral Doppler profile. motion of one or both occluders. TOE is mandatory and some-
Prosthetic mitral or aortic valves may develop sudden se- times can distinguish obstruction by thrombus or by pannus.
vere regurgitation due to ring dehiscence (e.g. in the course Fluoroscopy is very helpful and indispensable in aortic prosthetic
of IE, endocarditic destruction, or degenerative rupture of thrombosis (see Figure 18.1.26). (See also E Chapter 57.)
bioprosthetic leaflets) or thrombotic fixation or embolization of
a mechanical occluder (see Figure 18.1.25) (e.g. after strut
fracture of a tilting disc prosthesis). (See also E Chapter 57 and Pericardial disease and trauma
Table 18.1.7.)
The two main pericardial pathologies important for cardiac in-
tensive care are pericardial effusion, including tamponade, and
Prosthetic valve thrombosis constrictive pericarditis. Pericardial effusions occur in many cir-
Prosthetic valve thrombosis occurs almost exclusively in mech- cumstances, including infectious, immunological, and malignant
anical valves, leading to predominant stenosis, with or without diseases, as well as in perforation or rupture of coronary vessels or
regurgitation, depending on the dynamics of the prosthetic cardiac chambers and traumatic damage.

(a) (b)

(c) (d)

Figure 18.1.9  Circular pericardial effusion with onset of haemodynamic compromise (tamponade). (A) Apical four-​chamber view in diastole, with normal
convex contour of the right atrial free wall, and (B) systole, with compression of the right atrium (arrows). (C) Parasternal short-​axis view in diastole, with
compression of the RV (dotted arrows) and no compression of the right atrium (continuous arrow), and (D) systole, with compression of the right atrium and
no compression of the pressurized RV.
212 CHAPTER 18.1   E c ho cardio graph y and t hor aci c u ltr as ou n d

Cardiac tamponade is a life-​threatening complication of pericar- catheter introduced in the pericardial space may be confirmed by
dial effusion and can occur even with small, but acutely developing, injecting an agitated infusion solution, which will create a bright
effusions, e.g. after coronary artery perforation or rupture due to contrast echo in the pericardial space.
PCI (see also E Chapter 25). Due to limited intrapericardial space In constrictive pericarditis, a thickened (>5  mm) or calcified
and low compliance of the pericardium, compression of cardiac pericardium may be apparent but often is not. The ventricles are of
chambers ensues, typically the right atrium (in late diastole and normal size, whereas the atria are enlarged. Global LV and RV sys-
early systole) and RV (in early diastole) due to their relatively low tolic functions are normal, but paradoxical septal motion is present.
inside pressures. This ‘collapse’, along with the effusion, can be seen In clear-​cut cases, there is an inspiratory decrease in transmitral
directly on 2D echocardiography, especially in the four-​chamber flow and an increase in transtricuspid flow, with opposite changes
and subcostal views (see E Figures 18.1.9 and 18.1.10). The dur- in expiration. Sometimes, however, this sign is blunted by massive
ation of collapse during the cardiac cycle parallels the severity of diuretic therapy. The transmitral flow in a typical case is character-
haemodynamic compromise. While temporary inward displace- ized by tall, short E waves, with short deceleration time (‘restrictive
ment of the right atrial wall during the cardiac cycle is an early and transmitral pattern’). (See also E Chapters 25 and 56.)
sensitive sign of the haemodynamic significance of the pericardial
effusion, its specificity for tamponade is low; on the other hand, Traumatic cardiac and aortic injury
RV collapse has lower sensitivity, but higher specificity for haemo- A detailed discussion on traumatic cardiac and aortic injury is
dynamic compromise. In rare cases of localized pericardial effusions provided in E Chapter 60. A focus on echocardiography is pro-
(e.g. post-​operatively), the LA or LV may be primarily compressed; vided in the online data supplement.
these localized effusions may be difficult to detect and may necessi- Virtually all cardiac structures may be damaged by blunt trauma
tate TOE, especially in the post-​operative patient. Compression of [16]. The ventricles may develop intramyocardial haematoma,
the heart chambers leads to an exaggeration of the respiratory vari- myocardial necrosis, or frank rupture, leading to usually a lethal
ation of inflow and outflow patterns of the ventricles; mitral inflow tamponade, if a free wall is affected, or else to a VSD. The RV free
and aortic SV decrease with inspiration, whereas tricuspid inflow wall is most often affected due to its anterior localization in the
increases. A >25% decrease in peak transmitral E wave velocity with chest. The atria may also rupture. Coronary vessels may be lacer-
inspiration is considered a sign of haemodynamic compromise. ated, leading to haematopericardium and tamponade. Valvular
A ‘paradoxical’ septal shift to the left in early diastole, created by structures may also be damaged, including leaflets and the support
the increase in transtricuspid flow, is also observed. In expiration, apparatus, most prominently the papillary muscles or chordae.
these changes are reversed. Furthermore, the inferior vena cava Tears of the pericardium, with or without other cardiac injury,
is usually distended and does not collapse with inspiration (see may lead to herniation of other organs into the pericardial sac (e.g.
Table 18.1.8). intestinal herniation through an also ruptured diaphragm) or dis-
To prepare for pericardial puncture, the subcostal view is useful placement of cardiac structures outside the pericardial sac.
to determine the location, angle, and depth of the puncture. If The thoracic aorta is affected, especially by deceleration trauma
the subcostal approach is not feasible, echocardiography helps to (e.g. traffic accidents or falls) (see also E Chapter  59). Traffic
select alternative sites for puncture, i.e. sites where the distance accidents typically cause aortic damage at the aortic isthmus,
between the skin and pericardial fluid is minimal, e.g. the apex. the junction of the aortic arch, and the descending aorta. Falls
After puncture, the location of the tip of the needle or of the may lead to aortic damage at the level of the innominate artery.
Damage to the aorta ranges from intramural haematoma to com-
plete transection of the vessel.
Echocardiography, and especially TOE, is very helpful after
blunt chest trauma. In a study, more than half of 117 patients
with blunt chest trauma showed clearly pathological findings on
TOE, ranging from RV wall motion abnormalities to pericar-
dial effusions; the ECG was often normal in these patients [16]
(see E Table 18.1.3). Penetrating trauma of the heart or large

Table 18.1.3  Echocardiographic signs of cardiovascular trauma

Pericardial effusion
◆
Wall motion abnormalities
◆
Rupture of valve leaflets or papillary muscles, with signs of acute
◆
regurgitation (especially in aortic or mitral valve damage)
LV or RV FWR
◆
IMH of the aorta
◆
Aortic dissection
◆
Figure 18.1.10  Large, circular pericardial effusion (arrows). Parasternal Aortic rupture/​periaortic haematoma
◆
long-​axis  view.
 Aorti c em e rg e n c i e s 213

vessels is typically rapidly deadly, precluding echocardiographic echocardiography therefore is not in the definitive exclusion of a
examination. (small) PE, but in the assessment of whether a haemodynamic-
ally significant embolism has taken place and whether RV com-
promise warrants thrombolytic therapy.
Pulmonary embolism Echocardiographic differentiation of chronic and acute pul-
monary pressure elevation is difficult. RV hypertrophy, with an
A dilated and hypokinetic RV is a typical echocardiographic end-​diastolic free wall thickness of >5  mm, supports chronic
finding in severe PE. Additionally, there is a variable increase PH but does not exclude an additional acute pressure increase.
in RV systolic pressure, as estimated by measuring the peak Several signs that have been described as relatively specific (but
tricuspid regurgitant velocity (see E Figure 18.1.11). This is not sensitive) for acute PE are:
done by measuring the peak tricuspid regurgitant velocity using
◆ McConnell’s sign: a hypokinetic RV free wall, together with a
continuous-​wave Doppler, calculating the peak pressure differ-
hyperkinetic or normokinetic RV apex.
ence between the RV and the right atrium from the Bernoulli
◆ The transpulmonary pulsed-​ wave Doppler flow profile that
equation (Δp = 4 × v2) and adding an estimate of the mean right
may show shortened acceleration time (<100 ms) and notching,
atrial pressure, e.g. 10  mmHg (for more detail on right atrial
which is believed to result from reflected pressure waves created
pressure estimation, see E Heart failure, p. 206). Note, however,
by a central pulmonary thrombus.
that in the acutely failing RV associated with fulminant PE, this
◆ The ‘60/​60’ sign: a pulmonary systolic pressure <60 mmHg due
pressure may be deceptively normal or only minimally elevated.
to TR and a pulmonary acceleration time <60 ms. It should be
Very high peak pulmonary pressures (e.g. >80  mmHg) cannot
clear, however, that these signs are far from being ideally pre-
be generated by a previously normally loaded RV and do not
dictive for an acute PE. (See also E Chapter 63.)
occur in response to an acute embolism, unless there is previous
PH. A  shift of the ventricular septum to the left, flattening the
cross-​section of the LV into a ‘D’ shape, instead of the normal
circular shape, in short-​axis views and paradoxical septal mo- Aortic emergencies
tion are important signs of acute RV pressure overload. TR is The ascending aorta can be seen over its first few centimetres from
invariably present, and the inferior vena cava may be distended the left and right parasternal echocardiographic windows, and the
and lack inspiratory collapse. Thrombi may sometimes be seen aortic arch is seen from the suprasternal window, which, however, is
directly in the pulmonary artery imaged in the parasternal or often obstructed in elderly or emphysematous individuals. A much
subcostal view. If TOE is performed, the right pulmonary ar- better evaluation of the thoracic aorta is afforded by TOE where
tery can also be evaluated quite well and thrombotic material almost the entire course is visible, except for a ‘blind spot’ created
may be seen there. Acute pressure increase in the right atrium by tracheal and left bronchial interposition at the distal ascending
leads to a shift in position of the atrial septum to the left side aorta and proximal arch. Dilatation and aneurysms, atheromatous
and may create continuous right-​to-​left shunt through a patent disease, plaque-​adherent thrombi, aortic dissection or intramural
foramen ovale. In the presence of severe PE, paradoxical em- haematoma, and traumatic damage (see E Traumatic cardiac and
bolism of thrombotic material through a patent foramen ovale is aortic injury, p. 212) can be diagnosed by TOE. The following are
a recognized and devastating complication. On the other hand, important pathological features of the aorta [17, 18] (see E Table
small PEs are not detectable on echocardiography. The role of 18.1.4):
◆ Enlarged aortic diameters: these are important, since the risk
of rupture and also of dissection depends on aortic diameters.
Diameters of >55 mm, in general, are an indication for surgery,

Table 18.1.4  Classification of aortic dissection

◆ Stanford A: dissection involves the ascending aorta and may also involve
the aortic arch and descending aorta
RV
Stanford B: dissection involves only the descending aorta
◆
A more recent classification of acute aortic syndromes [17] distinguishes as
follows:
47 mmHg Class I: classic dissection of all types
◆
Class II: IMH
◆
Class III: subtle circumscript dissection representing a localized tear
◆
without a clear-​cut haematoma
Class IV: plaque ulceration (mostly in the descending aorta and often in
◆
Figure 18.1.11  PE. (A) Dilated, hypokinetic RV which reaches the apex
the abdominal aorta)
and appears larger than the LV. Note the shift of the basal septum to the left
Class V: traumatic or iatrogenic (mostly catheter-​induced, retrograde)
◆
(arrow). (B) Continuous-​wave Doppler of tricuspid regurgitation showing
dissection
elevated peak RV pressure (peak tricuspid regurgitant velocity 47 mmHg).
214 CHAPTER 18.1   E c ho cardio graph y and t hor aci c u ltr as ou n d

Figure 18.1.19  Infective endocarditis of the aortic valve, with vegetation attached to the right coronary cusp. Transoesophageal long-axis view at 120°. Note
vegetation (arrow) changing position during the cardiac cycle. The vegetation is echo-dense, suggesting chronic or healed endocarditis. (A) Diastole. (B) Systole.

Figure 18.1.22  Unusual presentation of mitral valve endocarditis. Modified apical four-chamber view. A ball-like mass, unusual for a vegetation, is attached to
the atrial aspect of the anterior mitral leaflet (arrow). The surgical specimen confirmed a vegetation caused by Staphylococcus aureus.
 Aorti c em e rg e n c i e s 215

Figure 18.1.27  Thrombi in a non-aneurysmatic descending aorta. After a few weeks of anticoagulation, the thrombi dissolved, and only atherosclerosis of the
aortic wall was seen. (A) Transoesophageal short-axis view. (B) Transoesophageal long-axis view.

even in asymptomatic patients, and in patients with Marfan’s (see E Table 18.1.5). It is characterized by a thickened aortic
syndrome or bicuspid aortic valve, lower values have been re- wall (>7 mm) with echolucent areas, a smooth intimal surface,
commended for replacement. and sometimes a displacement of superficial calcifications to-
◆ Atheromatosis is mainly observed in the descending aorta and wards the lumen. Differentiation from severe atherosclerotic
the arch. Sometimes, mobile thrombi may be noted which may wall thickening or the thrombosed false lumen of a classic dis-
embolize (see E Figure 18.1.27). section can be difficult.
◆ Aortic dissection is diagnosed by identifying the pathognomonic Dissection and intramural haematoma are life-​threatening dis-
dissection membrane, a thin and undulating membrane (‘in- eases which require emergency surgery if they affect the ascending
timal flap’) separating the true and false lumen. Reverberations aorta [19]. The questions that an echocardiographic examin-
of the posterior wall of the ascending aorta (see E Figure ation should quickly and decisively address are summarized in
18.1.28) or the posterior wall of the right pulmonary artery may Additional online material. Importantly, non-​classical forms
create aortic intraluminal linear, horizontal lines and need to be
of the acute aortic syndrome, such as an intramural haematoma
differentiated from true flaps, which are usually very well delin-
or a penetrating ulcer, are often difficult to detect by echocardio-
eated and crisp. Entry and re-​entry sites may be identified by 2D
graphy. CT or nuclear MR should be used liberally in any cases of
echocardiography and colour flow Doppler. The false lumen typ-
doubt. (See also E Chapter 59.)
ically is larger, has slower flow (often spontaneous contrast or
even thrombosis is present), and is convex towards the higher-​
pressurized, but smaller, true lumen (see Figure 18.1.29).
The site of the intimal rupture and the extent of the dissection
are crucial for the identification of the type of dissection and Table 18.1.5  Critical information to obtain by echocardiography
its management. Type A  dissection typically is accompanied in acute aortic dissection or intramural haematoma
by some amount of AR and pericardial haemorrhage, which
1. Is there a dissection (i.e. the presence of a dissection membrane)? Does it
abruptly may progress to a lethal tamponade. These two signs are involve the ascending aorta? Where is the entry tear?
easily recognized on TTE and should raise the ‘red flag’ of a pos- 2 . Is there pericardial effusion?
sible aortic dissection in the context of chest pain or other clin- 3 . Is there AR, and what is the mechanism (aortic dilatation, rupture of
ical presentations such as sudden hypotension or shock. When valvular apparatus, prolapse of dissection membrane through the aortic
a patient with a suspected aortic dissection is examined by TOE, valve into the LV)? This is important to guide surgery as to whether
aortic valve replacement is necessary.
blood pressure must be controlled tightly, since death due to pro-
4 . Does the dissection involve the coronary ostia, in particular the right
gressive rupture during TOE has been reported. ostium?
◆ Intramural haematoma of the aorta is a variant or precursor of 5 . Is there IMH (may coexist with, or precede, classic aortic dissection), and
dissection, which often coexists with areas of classic dissection does it involve the ascending aorta?
216 CHAPTER 18.1   E c ho cardio graph y and t hor aci c u ltr as ou n d

Figure 18.1.28  Dissection of the ascending aorta. (A) Transoesophageal short-axis view. Note the mobile flap (arrow). AV, aortic valve. (B) Transoesophageal
long-axis view at 120°. Note the circular flap (arrows). FL, false lumen; TL, true lumen.

◆ Atrial septal defect or patent foramen ovale as the gate for para-
Systemic embolism doxical embolism.
◆ Aortic atheromatosis with superimposed thrombi (TOE).
Echocardiography is the method of choice if a cardiovascular
source of embolism is suspected [20]. TOE has a higher yield than
TTE in identifying such sources and should be used if results may
lead to a change in management. TOE is particularly valuable in Personal perspective
assessing LA thrombi, endocarditic vegetations, tumours, and Every intensive care patient with a CVD needs echocardio-
aortic atheromas. The presence of the following potential sources graphy [3], and the sooner the better. Especially in the car-
of embolism should be systematically sought: diac intensive care environment, there is simply no other
◆ Atrial thrombi, in particular thrombi of the LA appendage, imaging method even remotely as valuable as echocardi-
which frequently occur in AF (see E Chapter  53) and, in ography. The challenge today, and in the future, is to en-
some instances (e.g. AS), also in sinus rhythm. However, sure adequate training and to use the method, which is so
in AF, which is by far the most frequent cardiac source of conveniently available at the bedside, to the full extent of
embolism, a negative TOE does not exclude that an LA or its diagnostic possibilities. This requires proper and dedi-
appendage thrombus was present before the embolism; there- cated training, which is not acquired ‘on the fly’. There is
fore, independent of TOE findings, anticoagulation usually is no doubt that further echocardiographic refinements in
indicated. haemodynamic assessment, diagnosis of myocardial is-
◆ IE (see E Endocarditis, acute valvular regurgitation, and pros- chaemia and viability, myocardial perfusion, coronary
thetic valve dysfunction, p. 210). flow reserve, and others will arrive and further improve
◆ LV thrombi from regions with severe wall motion abnormal- our diagnostic capabilities. The limiting factor, however,
ities, e.g. apical aneurysm. TOE has no advantage in detecting LV is often the ‘human factor’ that needs sufficient experience
thrombi, but left heart contrast echocardiography may be helpful. and expertise to harness the abundant imaging data for
◆ Tumours, e.g. myxoma or fibroelastoma, best diagnosed or ex- better patient care and outcomes.
cluded by TOE.

Further reading
Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/​EACTS Guidelines for the Hiratzka LF, Bakris GL, Beckman JA, et  al. 2010 ACCF/​AHA/​AATS/​
management of valvular heart disease. Eur Heart J 2017;38:2739–​91. ACR/​ASA/​SCA/​SCAI/​SIR/​STS/​SVM Guidelines for the diagnosis and
Flachskampf F (section editor). Section 10:  Cardiac ultrasound. In: management of patients with thoracic aortic disease. J Am Coll Cardiol
Camm JA, Lüscher TF, Maurer G, Serruys PW (editors). The ESC 2010;55:e27–​129.
Textbook of Cardiovascular Medicine, third edition. Oxford University Neskovic AN, Flachskampf FA, Picard MH (editors). Emergency
Press: Oxford; 2018. Echocardiography, second edition. CRC Press: Boca Raton, FL; 2017.
 RE F E RE N C E S 217

References
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cardiography:  current status and future perspectives. Circulation J Cardiovasc Imaging 2016;17:1321–​60.
2017;136:2178–​88. 12. Ammar KA, Umland MM, Kramer C, et al. The ABCs of left ven-
2. Cardim N, Dalen H, Voigt JU, et  al. The use of handheld ultra- tricular assist device echocardiography: a systematic approach. Eur
sound devices:  a position statement of the European Association Heart J Cardiovasc Imaging 2012;13:885–​99.
of Cardiovascular Imaging (2018 update). Eur Heart J Cardiovasc 13. Stainback RF, Estep JD, Agler DA, et  al.; American Society of
Imaging 2019;20:245–​52. Echocardiography. Echocardiography in the Management of Patients
3. Neskovic AN, Hagendorff A, Lancellotti P, et  al.; Association with Left Ventricular Assist Devices:  Recommendations from the
of Cardiovascular Imaging. Emergency echocardiography:  the American Society of Echocardiography. J Am Soc Echocardiogr
European Association of Cardiovascular Imaging recommendations. 2015;28:853–​909.
Eur Heart J Cardiovasc Imaging 2013;14:1–​11. 14. Habib G, Lancelotti P, Antunes M J, et  al. 2015 ESC Guidelines
4. Flachskampf FA, Badano L, Daniel WG, et al.; European Association for the management of infective endocarditis. Eur Heart J
of Echocardiography; Echo Committee of the European Association 2015;36:3075–​128.
of Cardiothoracic Anaesthesiologists, Roelandt JR, Piérard L. 15. Zoghbi WA, Chambers JB, Dumesnil JG, et al. Recommendations for
Recommendations for transoesophageal echocardiography:  update evaluation of prosthetic valves with echocardiography and doppler
2010. Eur J Echocardiogr 2010;11:557–​76. ultrasound. J Am Soc Echocardiogr 2009;22:975–​1014.
5. Popescu BA, Stefanidis A, Nihoyannopoulos P, et al. Updated stand- 16. Garcia−Fernandez MA, Lopez−Perez JM, Perez−Castellano N, et al.
ards and processes for accreditation of echocardiographic labora- Role of transesophageal echocardiography in the assessment of pa-
tories from The European Association of Cardiovascular Imaging. tients with blunt chest trauma:  correlation of echocardiographic
Eur Heart J Cardiovasc Imaging 2014;15:717–​22. findings with the electrocardiogram and creatine kinase monoclonal
6. Roffi M, Patrono C, Collet JP, et al.; Task Force for the Management of antibody measurements. Am Heart J 1998;135:476–​81.
Acute Coronary Syndromes in Patients Presenting without Persistent 17. Evangelista A, Flachskampf FA, Erbel R, et al.; European Association
ST-​Segment Elevation of the European Society of Cardiology (ESC). of Echocardiography; Document Reviewers:  Pepi M, Breithardt
2015 ESC Guidelines for the management of acute coronary syn- OA, Plonska-​ Gosciniak E.  Echocardiography in aortic diseases.
dromes in patients presenting without persistent ST-​segment eleva- Recommendations of the European Association of Echocardiography.
tion. Eur Heart J 2016;37:267–​331. Eur J Echocardiogr 2010;11:645–​58. Erratum in: Eur J Echocardiogr
7. Steg PG, James SK, Atar D, et  al. ESC Guidelines for the manage- 2011;12:642.
ment of acute myocardial infarction in patients presenting with ST-​ 18. Erbel R, Aboyans V, Boileau C, et al.; ESC Committee for Practice
segment elevation. Eur Heart J 2012;33:2569–​619. Guidelines. 2014 ESC guidelines on the diagnosis and treatment of
8. Ponikowski P, Voors AA, Anker SD, et  al.; Task Force Members. aortic diseases: Document covering acute and chronic aortic diseases
2016 ESC Guidelines for the diagnosis and treatment of acute and of the thoracic and abdominal aorta of the adult. The Task Force for
chronic heart failure: The Task Force for the diagnosis and treat- the Diagnosis and Treatment of Aortic Diseases of the European
ment of acute and chronic heart failure of the European Society of Society of Cardiology (ESC). Eur Heart J 2014;35:2873–​926. Erratum
Cardiology (ESC). Developed with the special contribution of the in: Eur Heart J 2015;36:2779.
Heart Failure Association (HFA) of the ESC. Eur Heart J 2016;37: 19. Erbel R, Alfonso F, Boileau C, et al. Diagnosis and management of aortic
2129–​200. dissection. Recommendations of the Task Force on Aortic Dissection,
9. Lang RM, Badano LP, Mor-​Avi V, et al. Recommendations for cardiac European Society of Cardiology. Eur Heart J 2001;22:1642–​81.
chamber quantification by echocardiography in adults:  an update 20. Pepi M, Evangelista A, Nihoyannopoulos P, et  al.; European
from the American Society of Echocardiography and the European Association of Echocardiography. Recommendations for echo-
Association of Cardiovascular Imaging. Eur Heart J Cardiovasc cardiography use in the diagnosis and management of cardiac
Imaging 2015;16:233–​7. sources of embolism: European Association of Echocardiography
10. Mor-​Avi V, Lang RM, Badano LP, et al. Current and evolving echo- (EAE) (a registered branch of the ESC). Eur J Echocardiogr
cardiographic techniques for the quantitative evaluation of cardiac 2010;11:461–​76.
mechanics: ASE/​EAE consensus statement on methodology and in-
dications endorsed by the Japanese Society of Echocardiography. Eur
J Echocardiogr 2011;12:167–​220.
ADDITIONAL ONLINE MATERIAL
11. Nagueh SF, Smiseth OA, Appleton CP, et al. Recommendations for
the evaluation of left ventricular diastolic function by echocardio- For additional multimedia materials, please visit the online
graphy: an update from the American Society of Echocardiography version of the book (M
M oxfordmedicine.com/ESCIACC3e).
 CHAPTER 18.2

Echocardiography and
thoracic ultrasound
Frank A Flachskampf, Pavlos Myrianthefs,
and Ruxandra Beyer

Contents
Summary  218
Introduction  218 Summary
Principles, equipment, and patient
positioning  218 Thoracic ultrasound is a rapidly evolving method in assessing diseases of the chest
Principles  218 and particularly in emergency conditions for the evaluation of dyspnoeic and hyp-
Equipment  219 oxic patients. An increased number of B-​lines are an unspecific sign for an in-
Patient positioning  219
Lung signs, points, lines, and patterns  219 creased quantity of fluid in the lungs, resembling interstitial syndromes such as
cardiogenic pulmonary oedema. The presence of a B-​line pattern allows the dif-
Clinical applications of TUS in everyday
practice  220 ferentiation between a cardiogenic and a respiratory origin of acute respiratory
Chest wall and parietal pleura  220 failure. Also, ultrasound can be used for the diagnosis and monitoring of pul-
Pneumothorax  220 monary consolidation, for the diagnosis and quantification of pleural fluid, and for
Pulmonary interstitial syndrome  221
Pneumonia  221 the diagnosis of pneumothorax using the ‘lung point’. Finally, thoracic ultrasound
Pulmonary embolism  221 can be used for guided pleural fluid aspiration, closed intercostal tube drainage,
The diaphragm  222
and central vessel catheterization.
Ultrasound-​guided procedures  222
Conclusion  222
References  222
Additional online material  223

Introduction
Thoracic ultrasound (TUS) is an elegant diagnostic technique used in modern clinical
practice that requires adequate training, experience, and skills to be useful. TUS is a fast,
mobile, cheap, radiation-​free, painless, repeatable, and non-​invasive examination. TUS
is applied at the bedside by a single clinician, with minimal monitoring, as part of point-​
of-​care testing (POCT). Also, TUS reduces the risk of iatrogenic complications and in-
creases the diagnostic yield and patient and clinician satisfaction, augmenting physical
examination with accurate and fast answers and facilitating decision-​making in critical
conditions  [1–​4].

Principles, equipment, and patient positioning

Principles
The energy of a US probe is translated into a picture on the screen, based on the piezo-
electric effect, which converts electrical energy into mechanical energy. Also, the distance
of a structure from the US transducer on the screen is determined by the time required
for the mechanical energy to return as its echo. Finally, the greyscale representation on
the screen is determined by the intensity of the returning echo signal [5, 6].
 Lu n g si g n s , p oi n ts , l i n es , a n d   pat t e rn s 219

US waves have poor penetration through air and thus it is vital

to recognize that, unlike other structures in the body, a normal
healthy lung is not visualized on the screen and instead the lung
tissue is seen as artefacts when pathology develops [7]‌.
Thus, the basic physical principle of lung US is that the less air
there is in the lungs, the easier the detection of lung abnormal-
ities. The only visible structure is the pleura. As the air content de-
creases (e.g. from pulmonary oedema to lung consolidation), the
acoustic window on the lung opens and the lung may be directly
visualized as solid parenchyma like the liver [8, 9].

Equipment
Figure 18.2.1  The rib pattern with its prominent acoustic shadow
Any basic 2D-​mode black-​and-​white scanner unit is appropriate represents a well-​defined landmark. Chest wall muscles appear as multiple
for clinical use (B-​and M-​mode). A linear transducer (high fre- layers of echogenicity. The outer two layers (external and internal) of
quency of 6–​12 MHz) is suitable for visualizing surface structures intercostal muscles are usually visible in a rib space (between the rib
(e.g. pleura–​lung interface to evaluate for pneumothorax or B-​ shadows), deep to which can be seen the pleural space and lung. The
visceral pleura (Pv) is marked sonographically by the sharp, bright linear
lines), and a phased array probe (1–​5 MHz) or a curvilinear probe interface of the lung surface and together form the so-​called ‘pleural line’,
(2–​5 MHz) for deeper penetration for obese patients through ex- a roughly horizontal echogenic line 0.5 cm below the upper and lower ribs.
cess soft tissues [10]. The parietal pleura (Pp) is a less distinct, weakly echogenic line, the location
of which is inferred by its relationship to the ribs and the visceral pleura. The
Patient positioning pleural space (Ps) is a thin (usually <1 mm) hypoechoic line just superficial
to the visceral pleura–​air-​filled lung interface, located within 1 cm of depth
A systematic approach is recommended to ensure high diag- from the rib interface.
nostic accuracy and repeatable images. The patient is scanned
in the supine, sitting, and lateral decubitus positions [11, 12].
Patients are scanned using an intercostal approach from the (see EFigure 18.2.3), the seashore sign (see E Figure 18.2.4),
second to the fourth (left) or fifth (right) intercostal space of the ‘B’-​lines (see E Figure 18.2.5), the lung point (see E Figure
anterior and lateral chest using the parasternal, mid-​clavicular, 18.2.6), the lung pulse, air bronchogram (see E Figure 18.2.7),
anterior axillary, and mid-​axillary lines as anatomical land- pleural fluid (see E Figure 18.2.8), ‘E’-​line artefacts, and sub-
marks (Volpicelli zones) [13,  14]. The transducer is moved cutaneous emphysema (see E Figure 18.2.9 and z Video
longitudinally and transversely to visualize the lung surface 18.2.2) [9, 16–​21].
through the intercostal spaces avoiding the ribs. An abdom- The most informative lung US sign for the cardiologist is the
inal window can be used for the sonographic imaging of caudal sum of B-​lines denoting the extent of extravascular lung water
parts of the lungs, passing through the liver, diaphragm, spleen, (EVLW) [15]. In each scan, the number of B-​lines may range from
and diaphragm. A water-​soluble gel is used on the skin and dis- zero to ten. A total severity score is calculated: 0 (≤5 B-​lines, no
infection measures are applied to the transducer and hands of sign), 1 (6–​15 B-​lines, mild degree), 2 (16–​30 B-​lines, moderate
the operator. degree), and 3 (>30 B-​lines, severe degree), indicating the amount
of EVLW [11].

Lung signs, points, lines, and patterns

Various US signs and lines can be recognized related to the normal
lung and pleura (see E Figure 18.2.1). Localization of the pleura
constitutes a basic anatomic landmark in the examination of the
lung, described as an intense hyperechoic line that is created by
the surface of the visceral pleura against that of the air-​filled lung
moving synchronously with respiration [15].
The thoracic wall is recognized by the characteristic posterior
shadowing of the ribs. The intercostal muscles extend between
the ribs, creating a useful intercostal monographic window.
Due to the varying thickness of the subcutaneous tissues, the
ribs constitute the most suitable anatomical landmark for rec-
Figure 18.2.2  Lung sliding. Power colour Doppler imaging. The visceral
ognition of the pleura, which can be found 0.5–​1  cm deep and parietal layers of the pleura sliding over each other is illustrated as a
below the hyperechoic surface of the ribs. Signs, points, lines, hyperechoic line moving forward and backward during respiration. The
and patterns are shown in Table 18.2.1 and include ‘lung power colour Doppler signal along the pleural line reveals a breath-​dependent
sliding’ (see E Figure 18.2.2 and z Video 18.2.1), ‘A’-​lines movement of the lung.
220 CHAPTER 18.2   E c ho cardio graph y and t hor aci c u ltr as ou n d

Figure 18.2.5  ‘B’-​lines or ‘comet tail artefacts’ (CTAs) lines or ‘lung rocket’.

Figure 18.2.3  Horizontal artefacts—​the ‘A’-​lines. Single and multiple Lines vertical to the pleural line originating from the visceral pleura erase ‘A’-​
horizontal hyperechoic repetition artefacts parallel to the pleural line. These lines on their passage. (A) In normal lung, CTAs are seen. (B) In the case of
result from intense reflection between the surfaces of contact of soft tissues pneumothorax, CTAs are not seen and reverberation artefacts generated by
and air-​filled lung. pleural air form parallel, horizontal echoic lines.

(volume size, depth, and free, septated, or loculated fluid), and

Clinical applications of TUS in management of pleural effusion and pleural thickness [23].
everyday practice Pneumothorax
For the cardiologist, TUS is helpful to diagnose interstitial The diagnostic hallmark of pneumothorax is the ‘lung point’, with
syndrome (B-​ lines, pulmonary oedema), alveolar syndrome a specificity of 100% and a sensitivity of about 65%. It corresponds
(consolidation—​pneumonia, atelectasis), and pleural syndrome to the point where visceral and parietal pleura regain contact with
(pneumothorax and pleural effusion). Clinical applications of each other. M-​mode US performed at the lung point shows a clear
lung US in the ICU are shown in Table 18.2.2. change from one pattern (seashore sign) to another (stratosphere
sign), indicating air in the pleural space [19, 24].
Chest wall and parietal pleura A simple algorithm from international recommendations on
TUS is used to characterize palpable chest wall lesions, to fur- point-​of-​care lung US has been proposed for the exclusion of
ther explore and examine in detail pleural or parietal abnor- pneumothorax. Pneumothorax is present if a ‘lung point’ is pre-
malities seen on CT, and to evaluate patients with localized sent and there is no lung pulse sign [25]. However, absent lung
thoracic lesions or chest trauma [22]. Chest wall pathologies sliding does not always mean pneumothorax. Pneumothorax is
include soft tissue and bony lesions (see Table 18.2.2). TUS excluded if there is lung sliding, lung pulse, or even a single B-​
is the cornerstone for the detection, diagnosis, characterization line, with a negative predictive value of 100% [16, 26, 27].

Figure 18.2.4  Seashore or beach sign. Time motion mode (M-​mode). Figure 18.2.6  Lung point. Seashore or beach sign. Time motion mode
A dynamic monographic sign of normal lung seen in M-​mode, having (M-​mode). (A) In the case of pneumothorax and absent lung sliding,
two parts—​the superficial part is composed of multiple horizontal lines only horizontal lines are visualized—​the ‘stratosphere or barcode sign’—​in
corresponding to motionless, soft subcutaneous tissues ending to the pleural contrast to (B) showing the ‘seashore sign’ which is seen in normal lung. The
line; the other part corresponds with the motion of normal lung giving a point at which there is a clear change from one pattern (seashore sign) to
sandy, granulous pattern that looks like sand on the beach. another (stratosphere or barcode sign) is pathognomonic of pneumothorax.
 Cl i n i ca l a ppl i cati on s of TU S i n every day   pr ac t i c e 221

Figure 18.2.7  Air bronchogram. Hyperechoic punctiform or linear

elements inside a tissue-​like pattern of pulmonary consolidation. Dynamic Figure 18.2.9  Subcutaneous emphysema. ‘E’-​line artefacts. Reverberation
air bronchograms are characterized by the presence of air inside the bronchi echoes caused by subdermal gas collections create a ‘snow flurry’ image. These
in dynamic movement within the tissue. Static air bronchograms are an reverberation artefacts, also referred to as ‘E’-​line artefacts (arrowheads) are
indication of atelectasis and are characterized by the motionless entrapment vertical laser-​like lines that reach the edge of the screen, usually not allowing
of air inside the atelectatic region of the lung. visualization of underlying structures, but in contrast to comet tail artefacts,
they do not arise from the pleural line (pl), but from the chest wall. Similar
artefacts can be generated by parietal shotgun pellets that, along with parietal
emphysema, are two situations where pneumothorax may be present.
Pulmonary interstitial syndrome
Pulmonary interstitial syndrome (PIS) encompasses a variety of
cardiogenic cause of dyspnoea. In ARF of respiratory origin, in con-
diseases affecting the lung interstitium and is characterized by dif-
trast to cardiogenic causes, a non-​interstitial pattern is found [30–​34].
ferent degrees of partial deaeration of the pulmonary parenchyma
B-​lines are related to radiographic Kerley B-​lines and lung water
(increase in interstitial fluid) and therefore can be seen in the pres-
score on CXR [30], to EVLW accumulation and pulmonary con-
ence of hydrostatic and inflammatory pulmonary oedema, but also
gestion [30, 35], and to the severity of diastolic dysfunction [36].
in pulmonary fibrosis. Diseases include heart failure, end-​stage
The number of B-​lines increases with worsening NYHA functional
renal disease, ARDS, interstitial lung disease, and pre-​eclampsia.
class [35] and they allow monitoring of pulmonary congestion by
The hallmark of PIS is the presence of B-​lines, and for differential
assessing for their clearance [36–​38]. The clinical usefulness of B-​
diagnosis, the clinical history and clinical picture are mandatory,
lines has been demonstrated not only for diagnosis and the differ-
but also certain lung US characteristics and focused cardiac US can
ential diagnosis of dyspnoea and respiratory failure, but also for
significantly improve B-​line specificity and diagnostic accuracy
monitoring, evaluation of response to therapy, and prognosis [39].
(pattern of distribution over the thorax, response to therapy, and
association with other lung US signs such as pleural line alterations,
small and large consolidations, and pleural effusion).
Pneumonia
In ARDS, alterations of the pleura (subpleural consolidations), The characteristic sonographic signs of pneumonia include
‘spared areas’ (defined as areas of normal sonographic lung appear- hypo­ echoic liver-​or tissue-​like subpleural consolidation and a
ance surrounded by areas of multiple B-​lines), and large consolida- marked dynamic bronchoaerogram with blurred and serrated bor-
tions of various sizes are found [28, 29]. Also, PIS and B-​lines are ders, often accompanied by comet tail artefacts and parapneumonic
not found in COPD and asthma exacerbation, in contrast to the effusion (50%). Pneumonia is a characteristic alveolar syndrome
(lung consolidation, even with complete air loss) [40, 41].
Consolidation is also found in infarction due to PE and contu-
sion in trauma and in obstructive or compressive atelectasis [28].
Reaeration of the consolidated area from an alveolar pattern to an
interstitial pattern and finally normal aeration are used for moni-
toring [28, 30].

Pulmonary embolism
In patients with suspected PE, a multiorgan approach including lung,
cardiac, and venous US and considering the possibility of alterna-
tive cardiac and pulmonary diagnoses to PE may be considered safe
to rule PE in or out [42]. The presence of peripheral pulmonary in-
farcts plus a dilated RV plus DVT is highly specific and allows the
diagnosis to be conclusive, especially in the absence of an alternative
pulmonary or cardiac diagnosis. Absence of pulmonary infarcts, a
normal RV, compressible deep veins, plus an alternative pulmonary
Figure 18.2.8  Pleural and perisplenic fluids. diagnosis allows the exclusion of PE with the highest sensitivity (NPV
222 CHAPTER 18.2   E c ho cardio graph y and t hor aci c u ltr as ou n d

100%) [42]. This approach is a valid alternative to multidetector CT iatrogenic complications, including pneumothorax or other vis-
scanning when the latter is unavailable or contraindicated. ceral puncture [45–​48]. TUS is useful to find optimal site, volume of
Lung US may have a role in risk stratification, as it is a valid fluid, septations/​loculated fluid, and pneumothorax after puncture/​
technique that is highly specific for diagnosing typical peripheral fluid aspiration [45, 49, 50]. US is ideal and strongly recommended
lung infarctions and highly sensitive for ruling out alternative for identifying the optimal site for safe and effective intercostal fluid
pulmonary diagnoses to PE [42]. drainage [50, 51]. Appropriate steps for thoracocentesis and tube
Also, integrating lung and venous US with the Wells score and D-​ thoracostomy should be applied for safety reasons [44].
dimer results in a patient with suspected PE improves the assessment Advanced interventions are those that are performed by TUS
of clinical risk. Negative venous US excluding DVT, a Wells score of practitioners with a specific interest in pleural disease and/​or
≤4, and a negative D-​dimer measurement rule out PE, allowing the interventional pulmonology and for whom these procedures
avoidance of unnecessary multidetector CT scanning [42]. would be considered part of their everyday practice, including
lymph node sampling, closed pleural biopsy, lung aspiration and
The diaphragm biopsy (pleural, lung), and medical thoracoscopy [44].
Diaphragmatic US identifies diaphragm dysfunction (measures
movement and thickening; minimal thickness in the resting dia-
phragm is 12–​15 mm), monitors muscle activity (e.g. paralysis) Conclusion
over time, and assesses the diaphragm structure (e.g. atrophy). Focused TUS in intensive and acute cardiology aims to answer
Assessment of the diaphragm may be of value in patients with whether pulmonary oedema, lung parenchymal pathology (PE,
critical illness polyneuropathy, lung hyperinflation (COPD/​ pneumonia, atelectasis, lung contusion), pleural effusion, or
asthma), ascites, drug-​induced muscle dysfunction (e.g. gluco- pneumothorax is present or not. The origin of pulmonary oedema,
corticoids), and neurological and muscle diseases [43]. dyspnoea, or respiratory failure should then be addressed. A com-
bination of focused TUS with focused cardiac US may help to dif-
ferentiate the main causes of acute dyspnoea and life-​threatening
Ultrasound-​guided procedures conditions in critically ill hypoxic patients with respiratory failure.
TUS limitations are essentially patient-​and operator-​
There are many advantages to using TUS as a guide for invasive dependent. Obese patients are frequently difficult to examine
procedures, including reduced risk of iatrogenic complications, because of the thickness of their rib cage and soft tissues. The
increased diagnostic yield, patient and clinician satisfaction, cost presence of subcutaneous emphysema or large thoracic dressings
savings, and avoidance of ionizing radiation. is a significant limitation. The main limitation of B-​lines is the
Procedural TUS should be practised in a safe and evidence-​based lack of specificity for cardiogenic pulmonary oedema. We should
manner [44]. These interventions are considered basic such as bear in mind that all imaging data should be evaluated within the
thoracocentesis (pleural aspiration) and tube thoracostomy (chest clinical context and integrated with the patient’s history, clinical
drain insertion or indwelling pleural catheter insertion) for pleural presentation, and other laboratory data.
fluid only, which are performed by the vast majority of physicians.
TUS substantially reduces the risk of either a failed ‘dry tap’ or

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 CHAPTER 19

Computerized tomography:
coronary angiography and
cardiac imaging
Jeff M Smit, Mohammed El Mahdiui, Michiel
A de Graaf, Arthur JHA Scholte, Lucia Kroft,
and Jeroen J Bax

Contents
Summary  224 Summary
Introduction  225 Patients presenting with chronic and acute chest pain constitute a common and
Coronary computerized tomography important diagnostic challenge. There is increased interest in using computerized
angiography: patient preparation,
tomography for non-​invasive visualization of coronary artery disease in patients
acquisition, and post-​processing  225
Patient preparation  225 presenting with acute chest pain to the emergency department, particularly the
Acquisition  225 subset of patients who are suspected of having an acute coronary syndrome, but
Post-​processing  227 without typical electrocardiographic changes and with normal troponin levels at
Interpretation of coronary artery disease
presentation. As a result of rapid developments in coronary computerized tomo-
on coronary computerized tomography
angiography  227 graphy angiography technology, high diagnostic accuracies for excluding coronary
Coronary artery calcium score  227 artery disease can be obtained. It has been shown that these patients can be dis-
Coronary computerized tomography charged safely. The accuracy for detecting a significant coronary artery stenosis is
angiography  227
Extracardiac findings  227 also high, but the presence of coronary artery atherosclerosis or stenosis does not
Patients with non-​acute chest pain  228 imply necessarily that the cause of the chest pain is related to coronary artery dis-
Coronary artery calcium score  228 ease. Moreover, non-​invasive detection of coronary artery disease by computerized
Coronary computerized tomography tomography has been shown to be related with an increased use of subsequent in-
angiography  228
Patients with suspected acute coronary vasive coronary angiography and revascularization, and further studies are needed
syndrome  230 to define which patients benefit from invasive evaluation following coronary com-
Coronary artery calcium score  230 puterized tomography angiography. Conversely, implementation of coronary com-
Coronary computerized tomography puterized tomography angiography can significantly reduce the length of hospital
angiography  230
Computerized tomography angiography of stay, with significant cost reduction.
the aorta and pulmonary arteries  234 Additionally, computerized tomography is an excellent modality in patients
Thoracic aortic aneurysm  235 whose symptoms suggest other causes of acute chest pain such as aortic an-
Pulmonary embolism  235 eurysm, aortic dissection, or pulmonary embolism. Furthermore, acquisition of
Triple rule-​out computerized
tomography  235 the coronary arteries, thoracic aorta, and pulmonary arteries in a single compu-
Technical developments  236 terized tomography examination is feasible, allowing ‘triple rule-​out’ (exclusion
Coronary artery plaque quantification  236
Developments in computerized tomography
scanners  237
Novel applications of cardiac computerized
tomography  237 Evaluation of myocardial infarction  238 Conclusion  241
Assessment of coronary artery plaque Fractional flow reserve  239
Personal perspective  241
composition  237 Transluminal attenuation gradient  240
Evaluation of myocardial perfusion  238 Evaluation of myocardial function  240 References  241
 C orona ry c o m pu teri z ed to mo g r a phy a n g i o g r a ph y 225

approach for patients with acute CP leads to many unnecessary

of aortic dissection, pulmonary embolism, and coronary hospital admissions and is both time-​consuming and expen-
artery disease). Finally, other applications, such as evalu- sive, and thus resource-​intensive. Therefore, non-​invasive and
ation of coronary artery plaque composition, myocardial rapid examination to establish or exclude CAD as the underlying
function and perfusion, and non-​invasive assessment of cause of symptoms could substantially improve the clinical care
fractional flow reserve from coronary computerized tom- of patients admitted to the ICCU, reducing hospital admissions
ography angiography, are currently being developed and and costs. This chapter focuses on the evolving role of CCTA,
may also become valuable in the setting of chronic and including coronary artery calcium (CAC) scoring, in the diag-
acute chest pain in the future. nosis of patients presenting with acute CP. An overview of a wide
range of other CT applications is also provided, including triple
rule-​out, evaluation of plaque composition, and myocardial func-
tion and perfusion.

Introduction Coronary computerized tomography

The present chapter is an update of the chapter from the previous
edition [1]‌. Those parts on which new literature is available have
angiography: patient preparation,
been updated, whereas other parts have been left unchanged. acquisition, and post-​processing
Since the introduction of CT in the early 1970s, the technique has CT is an imaging modality which has an X-​ray source (tube) and
evolved into an essential imaging tool in general medicine. With detectors on opposite sides of a gantry that continuously rotates
this technique, non-​ invasive, high-​
resolution cross-​ sectional around the patient. During CT scanning, the patient is moved
imaging of internal structures, such as the brain, thorax, and ab- through the gantry. Subsequently, the X-​ray source emits photons
domen, became possible, thereby gradually replacing the more collimated into a fan beam which are, after partial absorption and
invasive radiographic techniques [2]. Moreover, CTA has evolved dispersion, reabsorbed by the detectors. Computer systems pro-
into a very accurate tool for visualization of the aorta and pul- cess these data into three-​dimensional (3D) volumetric informa-
monary arteries. However, high-​quality imaging of the coronary tion, which can be transferred to CT workstations and evaluated
arteries remained challenging, because of their small vessel size, using multiple post-​processing techniques.
movement, and tortuous anatomy requiring high temporal, spa-
tial, and contrast resolution. In the late 1990s, the first four-​slice Patient preparation
spiral CT scanner was developed, with sufficient resolution to
Proper patient preparation is important for obtaining diagnostic
allow visualization of the coronary arteries, establishing the po-
image quality. Therefore, before referring a patient for CCTA, a
tential of multi-​slice CT for detecting significant coronary artery
short patient history should be obtained. Overall, a history of
stenosis, in comparison to invasive coronary angiography (ICA)
severe allergic reaction to contrast agents, impaired renal func-
[3–​5]. Since then, multi-​slice CCTA has developed into a prom-
tion (GFR <30 mL/​min), presence of AF, and pregnancy are con-
ising non-​invasive alternative to ICA. With each successive gen-
sidered as contraindications. The patient should refrain from food
eration of scanners, from the four-​slice scanner to the present
and liquids, preferably 3 hours before the examination, to prevent
64-​, 256-​, and 320-​slice scanners, temporal and spatial resolution
nausea as a reaction to the contrast agent. Moreover, a low and
improved markedly, due to faster gantry rotation times, thinner
stable heart rate, in the range of approximately 50–​60 bpm, is pre-
detectors, and volumetric coverage. These new developments
ferred during image acquisition. To achieve a low and stable heart
currently allow motion-​free visualization of the entire coronary
rate, a β-​blocker is frequently administered prior to the examin-
artery tree with high diagnostic accuracy for detecting coronary
ation, unless contraindicated. Preferably, sublingual nitrates (0.4
artery stenosis [6, 7]. Thanks to these rapid developments, interest
mg) are administered to the patient. The resulting vasodilatation
has been raised in using CT for the evaluation of patients pre-
facilitates the assessment of small coronary arteries [10]. Last, to
senting with acute CP. In the ICCU, acute CP is the most common
ensure rapid delivery of the contrast agent bolus for CCTA, an IV
clinical presentation of CAD.
catheter should be present for delivery of the contrast agent, pref-
The diagnosis of ACS is straightforward in high-​risk patients
erably in the right antecubital vein (18–​20G).
with typical CP, typical ECG changes, and elevation of serum
cardiac markers (enzymes), whereas it is difficult in patients pre-
senting with atypical CP, non-​diagnostic or normal ECGs, and Acquisition
normal markers on presentation. Indeed, up to 8% of patients The scan range of current 64-​slice scanners is not large enough to
with ACS are misdiagnosed and inappropriately discharged cover the entire heart in one rotation, and therefore, several heart
home [8]‌. Conversely, only a minority of ‘low-​risk’ patients (i.e. cycles are needed to image the entire heart. To compensate for
those with initially normal ECGs and cardiac enzymes) actually cardiac motion and synchronize the start of systole, ECG gating
suffer from myocardial ischaemia [9]. Hence, the conventional is needed to obtain phase-​ compatible images. Currently, the
226 CHAPTER 19   C omp u terized tomo graph y: c orona ry a n g i o g r a phy a n d ca rdiac i m ag i n g

majority of cardiac CTs are acquired using prospective triggering, For CAC scoring, a low-​dose, ECG-​triggered, non-​contrast-​
in which the start of scanning is triggered by the preceding R-​ enhanced scan is performed before the contrast-​enhanced CT
wave. Most often, the scan is triggered in the relatively motion-​free examination and reconstructed to 3-​mm slices. Additionally,
phase of mid diastole (70–​80% of the R–​R interval) to minimize this scan can be used to determine the proper location and scan
motion artefacts. Depending on the scanner type, imaging can range for coronary CT imaging. For a regular CTA, a rapid in-
be performed in the helical (‘spiral’) mode, with continuous table fusion of 60–​100 mL of contrast material, with a flow rate of 5
movement and modulated acquisition, or in the step-​and-​shoot mL/​s, is used, followed by a saline flush. Typical scan parameters
mode, with multiple volumetric acquisitions reconstructed into a are a pitch of 0.375, rotation time of 333–​500 ms, tube voltage
single data set. A wide-​volume detector allows full cardiac acqui- of 100 or 120 kV, and tube current of 300–​500 mA, depending
sition in a single gantry rotation, e.g. a 256-​or 320-​detector row on the body mass index (BMI). However, with novel iterative
scanner that allows a maximum of 16-​cm scan range in a single reconstruction algorithms, lower radiation exposure can be
rotation [11, 12]. Novel dual-​source CT scanners, equipped with achieved by lowering the tube voltage and current, with pre-
two X-​ray tubes and two detectors at a 90° angle, provide a high served image quality. When using a bolus-​triggered start of the
temporal resolution of 80–​100 ms. This is achieved by the fact that CT scan, the start is automatically initiated if the preset con-
with only 90° rotation of the gantry, 180° of the full rotation is trast enhancement threshold level in the descending aorta is
covered by combining data of the two detectors. As a result, these reached. Alternatively, a test bolus injection can be used to de-
scanners are able to produce images of high quality in patients termine the contrast transit time. Subsequently, data acquisition
with high heart rates. Besides, with these 64-​slice dual-​source CT is performed at half-​inspiratory breath hold of approximately
scanners, using a high-​pitch spiral technique, the entire heart can 10 seconds.
be depicted in one cardiac cycle with an ultra-​low radiation dose
(<1 mSv) [13].

Figure 19.1  Typical example of axial contrast-​enhanced images (0.5-​mm slice thickness), which can be used to evaluate cardiac structures—​such as the left
ventricle (LV), left atrium (LA), right ventricle (RV), and aorta (Ao)) and coronary arteries—​by scrolling through the slices in a craniocaudal direction. Four
images have been selected to demonstrate the anatomy of the heart. (A) Axial image showing the left main (LM) coronary artery at the level of the ostium
which arises from the left coronary cusp and bifurcates first into the left anterior descending coronary artery (LAD). (B) Slightly more distal axial image showing
the left circumflex coronary artery (LCx) and the first diagonal branch (D1) which has originated from the LAD. (C) Axial image demonstrating the origin of the
right coronary artery (RCA) from the right coronary cusp and the mid segments of the LCx, LAD, and D1. (D) Axial image at mid-​ventricular level which shows
the mid segment of the right coronary artery (RCA) and the distal segments of the LAD and LCx (the latter is seen in the left atrioventricular groove).
Interpretation of coronary artery disease on coronary computerized tomography angiography 227

Post-​processing Coronary artery calcium score

After data acquisition, images are reconstructed and sent to a For quantification of coronary calcifications, the Agatston
dedicated workstation for post-​processing. Commonly, CCTA method (a method that multiplies the calcified area by a density
data sets are reconstructed with continuous images, using thin factor, based on the highest Hounsfield values within this area)
increments (typically 0.5-​to 0.6-​mm slice thickness). For post-​ is routinely used [14]. Total CAC scores are generally stratified
processing, various types of algorithms are available. into normal (zero Ca2+), mild (1–​100), moderate (101–​400), and
◆ The thin axial slices, as depicted in E Figure 19.1, are con- severe (>400) [15]. Several population-​based studies have dem-
sidered the source information of CT imaging. Accordingly, onstrated that the CAC score increases with higher age, thereby
the cardiac structures and coronary arteries can be easily reflecting the natural progression of atherosclerosis. In addition,
evaluated by scrolling through the images in an axial direction. men tend to have higher CAC scores than women of similar
age. Therefore, the CAC score should be ranked in percentiles,
◆ Curved multiplanar reconstructions (MPRs) allow visualiza-
according to the distribution within age and gender [16,  17].
tion of the entire coronary artery in a single image, which is
Although newer quantification methods have been introduced—​
useful for depicting the entire coronary lumen and evaluating
calcified volume (mm3) and mass (mg) measurements, these met-
the degree of stenosis.
rics are not commonly used in clinical practice [18]. With novel
◆ Maximum intensity projections (MIPs) can be reconstructed,
algorithms, quantification of CAC on contrast-​enhanced scans is
which represent a series of contiguous CT slices stacked into a
feasible [19]. However, these techniques are not currently used in
single image (‘slab’). Moreover, MIPs are very suitable for the as-
sessment of longer lengths of vessel segments and may facilitate clinical practice.
in evaluating the degree of stenosis.
◆ 3D volume rendering provides a 3D image of the heart and
Coronary computerized tomography
vessels. An excellent overview of the coronary anatomy is pro- angiography
vided, although 3D volume rendering is not used generally for With regard to CCTA, the quality of the scan should be men-
assessing stenosis severity. E Figure 19.2 provides an example tioned, as this influences the diagnostic certainty of the study.
of a 3D volume-​rendered image. Findings are commonly reported similarly to the reporting of
ICA. Typically, each coronary segment of the AHA 17-​segment
model [20] is described as normal, mild (<30% wall irregular-
ities), non-​ significant (30–​50% stenosis), significant (>50%
Interpretation of coronary artery stenosis), severe stenosis (>70%), and occlusion. In addition to
disease on coronary computerized stenosis severity, the plaque composition of each lesion should be
tomography angiography described as non-​calcified, calcified, or mixed (i.e. a combination
of calcified and non-​calcified plaques). The presence and patency
A systematic approach is important when evaluating a CCTA. of stents and bypasses are reported, if evaluable. Segments that are
If CAC scoring has been performed, the Agatston score is re- uninterpretable, due to severe calcifications, motion, or breathing
ported on a patient and vessel basis. Thereafter, the CCTA is artefacts, should be mentioned as such in the report.
interpreted to assess for coronary atherosclerosis and stenosis
severity. In addition to the analysis of the coronary arteries, Extracardiac findings
the entire scan range should be examined to detect potential
Beyond evaluating the coronary arteries, other cardiac and/​
extracardiac findings.
or extracardiac findings may be identified during CCTA.

Figure 19.2  Surface-​rendered volumetric 3D images of the coronary arteries and side branches, providing a 3D overview of the coronary artery tree and
their position relative to the underlying cardiac structures, including the left ventricle (LV) and right ventricle (RV). (A) Anterior view of the left circulation
demonstrating the left anterior descending coronary artery (LAD) with the first diagonal branch (D1). In addition, the left circumflex coronary artery (LCx) can
be identified. The left atrium (LA), aorta (Ao), and right ventricular outflow tract (RVOT) can be also appreciated in this view. (B) Cranial view demonstrating
a volume-​rendered image of the right coronary artery (RCA) and left main coronary artery (LM) and their main branches originating from the right and left
coronary cusp, respectively. (C) Posterior view of the RCA and the posterior descending coronary artery (PDA).
228 CHAPTER 19   C omp u terized tomo graph y: c orona ry a n g i o g r a phy a n d ca rdiac i m ag i n g

Interestingly, extracardiac findings provide an explanation for score [33]. Moreover, Mitchell et al. investigated the prognostic
CP complaints in 4–​8% of patients or may be incidental find- value of CAC scoring in 23  637 consecutive subjects without
ings not related to chest complaints [21, 22]. Clinically important known atherosclerotic CVD who were followed over a median
findings that require immediate therapy, intervention, additional period of 11.4  years [35]. It was found that the addition of the
diagnosis, or follow-​up are reported in approximately 13% of car- CAC score to cardiovascular risk factors significantly improved
diac CT examinations [23,  24]. These include suspected malig- risk stratification for MI, stroke, and all-​cause mortality.
nancy, which may necessitate immediate therapeutic actions, or
the presence of acute PE or pneumonia [21, 25–​27]. Incidental Coronary computerized tomography
lung cancers are found in 0.24% of patients [23]. For coronary angiography
artery assessment, a zoomed-​in, small field of view, focused on With the current generation of CT scanners, with improved tem-
the heart, is reconstructed to obtain maximal spatial resolution poral and spatial resolution, good diagnostic accuracy for the
for evaluation. However, this focused view reveals only 36% of detection of obstructive CAD has been reported, for both the
the total chest volume, whereas 70% of the total chest volume has proximal and distal parts of the coronary arteries. In comparison
been exposed to radiation [27]. Substantially more significant with ICA, high sensitivity (85–​99%) and high specificity (83–​
extracardiac pathology is found on maximum full-​field recon- 90%) have been reported for the detection of obstructive sten-
structions than on small-​field reconstructions [23]. Therefore, the oses [6, 7]. More importantly, as demonstrated by the high NPV,
maximum full-​field reconstructions should be reviewed for op- CCTA is an excellent tool to exclude significant CAD. This im-
timal identification of extracardiac pathology [21, 23, 25, 27, 28]. plies that in the presence of normal coronary arteries on CCTA,
no further testing is required and patients can be reassured. The
PPV, however, is lower (64–​93%) and the severity of atheroscler-
Patients with non-​acute chest pain otic lesions is frequently overestimated on CCTA.
Recently, new low-​radiation dose algorithms have been intro-
Coronary artery calcium score duced, which resulted in a significant reduction in radiation. This
It has been widely verified that the presence of CAC only occurs was confirmed by the international dose survey PROTECTION
in the presence of coronary artery atherosclerosis [29]. Both elec- VI (Prospective Multicenter Registry on RadiaTion Dose
tron beam CT (EBCT) and multi-​slice CT have been used over Estimates of Cardiac CT AngIOgraphy IN Daily Practice in 2017),
the past years for non-​invasive evaluation of CACs, both dem- for which 4502 patients undergoing cardiac CTA in 2017 were
onstrating high sensitivities for the detection of CAD, indicating enrolled from 32 different countries [36]. To study the effect of
that a large proportion of patients with CAD are accurately de- recent advances in CT technology on the reduction in radiation
tected by CAC scoring [17, 30]. The relation between the presence dose in a real-​world setting, the results of this survey were com-
of obstructive CAD and the presence and extent of CAC has been pared to a similar dose survey performed in 2007. Importantly,
extensively studied [31]. The CAC score has a high sensitivity and the authors reported that the radiation dose was reduced by 78%
NPV for the presence of obstructive CAD, but its specificity is (P <0.001) without an increase in non-​diagnostic CCTAs (1.7% in
limited [31,  32]. The high NPV indicates that patients without 2007 versus 1.9% in 2017; P = 0.55).
CAC virtually never have obstructive CAD. In contrast, the lower A meta-​analysis of these studies confirmed the diagnostic ac-
specificity indicates that patients without obstructive CAD still curacy [37]; pooled data from 15 studies (with varying novel CT
often present with CAC. For instance, Haberl et al. [31] evaluated scanners), including 960 patients, reported a sensitivity of 100%,
1764 patients who underwent both EBCT (CAC score) and ICA. with a specificity of 89%. The NPV was 99%, with a PPV of 93%,
The absence of CAC was associated with an extremely low prob- indicating an overestimation of stenosis severity in 7% of patients.
ability of disease (<1%) and thus being highly accurate to exclude Moreover, the diagnostic performance of CCTA is influenced by
obstructive CAD. However, specificity was only 23% in men and the pretest likelihood of obstructive CAD. Indeed, as shown in
40% in women. Therefore, the technique may be more suited to E Table 19.1, the benefit from CT is highest in patients with a
providing an estimate of total plaque burden, rather than stenosis low to intermediate pretest likelihood for CAD due to the high
severity. accuracy to exclude obstructive CAD [38].
Furthermore, numerous investigations have shown that the ex- In line with these observations, Henneman et al. demonstrated
tent of CAC provides prognostic information. CAC scoring has that CCTA was able to exclude coronary artery atherosclerosis
therefore been proposed as a tool for cardiac risk stratification. in 58% of patients with a low pretest likelihood of CAD, with
Several large trials have reported that elevated CAC scores have no need for further routine visits to the outpatient clinic [39].
predictive value for cardiovascular events, both independently and Conversely, CCTA demonstrated atherosclerosis and/​or stenosis
incrementally to cardiovascular risk factors [33, 34]. Budoff et al. in 83% of patients with a high pretest likelihood of CAD. These
assessed the prognostic value of CAC scoring in 25 253 asymp- patients may thus benefit more from non-​invasive testing for is-
tomatic individuals over a mean follow-​up period of 6.8  years. chaemia and/​or direct ICA with FFR assessment, to determine
The survival of individuals without CAC was excellent (99.6%), optimal therapy (medical management or revascularization).
with a gradual reduction in survival rates with increasing CAC Indeed, the 2013 ESC guidelines for stable CAD indicate that
 Pati en ts w i th n on - acu te c h e st   pa i n 229

Table 19.1  Diagnostic accuracy of 64-​slice CCTA for the detection 6

of significant stenosis (≥50%), categorized according to pretest 5
probability

Mortality (%)
4
Pretest N Sens (%) Spec(%) PPV (%) NPV (%) 3
probability
2
Low 66 100 93 78 100
1
Intermediate 83 100 84 80 100 0
No CAD Non-obstructive Non-high-risk High-risk CAD
High 105  98 74 93  89
CAD CAD
N, number; NPV, negative predictive value; PPV, positive predictive value; Sens,
sensitivity; Spec, specificity. Figure 19.3  Bar graph illustrating the prognostic value of CCTA for the
Source data from Meijboom WB, Mollet NR, Van Mieghem CA et al. 64-​Slice CT prediction of all-​cause mortality. Non-​obstructive coronary artery disease
coronary angiography in patients with non-​ST elevation acute coronary syndrome. (CAD) was defined as <50% stenosis, non-​high-​risk CAD was defined as ≥50%
Heart 2007 November; 93 (11): 1386–​92. stenosis, and high-​risk CAD included left main stenosis (≥50%) or three-​vessel
disease (≥70%) or two-​vessel disease (≥70%) including the proximal left
anterior descending artery.
Source data from Chow BJ, Small G, Yam Y et al. Incremental prognostic value of
CCTA is particularly useful in patients with low to intermediate cardiac computed tomography in coronary artery disease using CONFIRM: COroNary
pretest likelihood of CAD (Class IIa) [40]. computed tomography angiography evaluation for clinical outcomes: an InteRnational
Multicenter registry. Circ Cardiovasc Imaging 2011 September; 4 (5): 463–​72.
Although the aforementioned studies confirm the ability
of CCTA to detect obstructive coronary stenoses on ICA, it is
known that a visual assessment of coronary stenosis severity on A meta-​analysis by Bamberg et al. focused on the prognostic
ICA is inaccurate to determine its functional consequences [41]. value of CCTA and included nine studies with 3760 patients, with
Therefore, several meta-​analyses have been performed which an average follow-​up varying from 14 to 78 months [46].
used invasive FFR as the reference standard to define function- The overall event rate was 6.8%, but it should be noted that
ally significant CAD. In a meta-​analysis by Knuuti et al., the diag- two-​thirds of the events were coronary revascularizations. (Early)
nostic performance of CCTA was investigated in 2756 patients revascularization is not an ideal endpoint, since the findings on
from nine studies that used ICA as reference standard and 1140 CCTA may have triggered the revascularization. Patients with a
patients from seven studies using invasive FFR [42]. The authors normal CCTA had an event rate of 0.4%. Patients with obstructive
showed a high pooled sensitivity (97%) and specificity (78%) for CAD had a sixfold increased risk for death, infarction, or ACS.
CCTA to detect anatomically significant CAD (as defined by cor- Importantly, a significant stenosis on CCTA remained predictive
onary narrowing of >50%). However, the pooled specificity of of events after correction for the CAC score and cardiovascular
CCTA to detect functionally significant CAD (as defined by an risk factors.
invasive FFR of ≤0.80) was relatively modest (53%). Moreover Besides stenosis severity, the plaque composition, extent, and
in a recent meta-​analysis by Danad et al., 1167 patients from ten location may provide important prognostic value for the pre-
studies were included to assess the diagnostic performance of diction of events. The authors included a total of 2134 patients
CCTA versus an invasive FFR reference standard [43]. Although with suspected CAD, with a mean follow-​up of 3.6 years. It was
CCTA showed an excellent pooled sensitivity (90%) to diagnose concluded that the new comprehensive risk score provides incre-
functionally significant CAD, the pooled specificity was relatively mental prognostic value over stenosis severity for the prediction
low (39%). Similar results were reported in a meta-​analysis by of MI or death. Moreover, the comprehensive risk score correctly
Gonzalez et al. in which 1535 patients from 18 studies were in- reclassified a significant proportion of patients, compared to sten-
cluded [44]. On a patient-​based analysis, the pooled sensitivity osis severity (net reclassification improvement 12.4%; P <0.001).
and specificity of CCTA to detect functionally significant CAD The prognostic value of a CCTA-​based strategy was com-
(as defined by an invasive FFR of ≤0.75 or ≤0.80) were 92% and pared to routine functional testing in the PROMISE (Prospective
43%, respectively. Multicenter Imaging Study for Evaluation of Chest Pain) trial
In addition to the diagnostic value, CCTA provides prognostic [48]. For this study, 10  003 patients with suspected CAD were
information. Chow et al. reported in the CONFIRM (Coronary randomized to either CCTA or routine functional testing (exer-
CT Angiography Evaluation for Clinical Outcomes) registry (with cise ECG, nuclear imaging, or stress echocardiography). Patients
14 064 patients in 12 different centres) that a normal CCTA was were followed-​up for the occurrence of death, MI, unstable angina
associated with an annual mortality rate of 0.65% over a mean (UA), or major complications for a median period of 25 months.
follow-​up of 22.5 months (see Figure E 19.3) [45]. Conversely, Interestingly, there was no significant difference in the occurrence
patients with obstructive CAD had an annual mortality rate of of the primary endpoint between the two strategies (3.3% for the
2.9%, which increased to almost 5% in patients with three-​vessel, CCTA-​based strategy versus 3.0% for routine functional testing).
left main, and/​or proximal LAD disease. It is important to realize It was concluded that in patients with stable angina, a strategy of
that the annual mortality in the CONFIRM registry was only initial CCTA did not improve clinical outcomes over a median
1.1%, indicating a relatively low-​risk population. follow-​up of 2 years, when compared to routine functional testing.
230 CHAPTER 19   C omp u terized tomo graph y: c orona ry a n g i o g r a phy a n d ca rdiac i m ag i n g

However, in the CCTA arm, more patients were referred for ICA, cardiac event rate was <1%, whereas the event rate increased in
as compared to patients who underwent functional testing (12% parallel with an increasing CAC score. The various prognostic
versus 8%, respectively). studies using the CAC score in patients with acute CP and/​or sus-
More recently, the effect of a CCTA-​based strategy on 5-​year pected ACS are summarized in E Table 19.2. The results of six
clinical outcomes was reported in the SCOT-​HEART (Scottish studies, with a total of 3035 patients, were included in a pooled
Computed Tomography of the Heart) trial [49]. In this trial, pa- analysis [54]. In total, 62% of patients with acute CP or suspected
tients with stable chest pain were randomly assigned to either ACS presented with a CAC score of 0 (indicating relatively low-​
CCTA plus standard care (2073 patients) versus standard care risk populations). However, there was a large variation in the in-
alone (2073 patients). The authors noted that the 5-​year rate of the cidence of a CAC score of 0 between studies, ranging from 36%
primary endpoint (defined as death from CAD or non-​fatal MI) to 76%. The pooled analysis demonstrated an NPV of 99% for
was significantly lower in the CCTA group versus the standard the occurrence of future events. In contrast, the PPV was only
care group (2.3% versus 3.9%; P = 0.004). Although, in the first 14%. The long-​term prognostic value of the CAC score in patients
few months, a higher rate of ICA and coronary revascularization with suspected ACS has also been evaluated. Forouzandeh and
was observed in the CCTA group versus the standard care group, colleagues acquired long-​term follow-​up data (median 3.3 years)
no significant difference was found at 5  years’ follow-​up in the in 760 patients presenting with acute CP who underwent 16-​slice
rate of ICA (23.7% versus 24.2%) and coronary revascularization CT [55]. Events occurred in 45 (6%) patients; the long-​term event
(13.5% versus 12.9%). Importantly, preventive therapies (statin rate was 0.4% in patients without CAC and increased to 11% in
use) were more frequently initiated (and adhered to) in the CCTA patients with a CAC score of >400. Although a CAC score of 0 has
group versus the standard care group (19.4% versus 14.7%), which been associated with an excellent prognosis, it has simultaneously
could partially explain the reduction in cardiovascular events in been observed that patients with ACS or acute infarction can pre-
the CCTA group. sent without CAC in the culprit vessel [56]. Thus, particularly
in the acute setting, the absence of CAC may not always imply
the absence of atherosclerotic plaque. This was demonstrated by
Chang et  al. showing that obstructive atherosclerosis was pre-
Patients with suspected acute sent in 17 of 795 (2%) patients with a suspected ACS and a CAC
coronary syndrome score of 0 [57]. In addition, 12% of patients with a CAC score of
0 had non-​obstructive CAD. Accordingly, Biegel et al. performed
Coronary artery calcium score CCTA in 785 consecutive patients with acute CP [58]. Of the 255
The prognostic value of the CAC score has been widely estab- patients with a CAC score of 0, significant CAD was observed on
lished in patients with stable angina, but some studies evaluated ICA in 2.7% of patients. E Figure 19.4 provides an example of a
the use of CAC score in patients with acute CP. Earlier studies with patient with an obstructive, non-​calcified plaque, despite a CAC
EBCT reported a high NPV of the CAC score, demonstrating that score of 0.
patients with a CAC score of 0 had an excellent prognosis [50–​
52]. Georgiou et al. reported in 192 patients with acute CP that
Coronary computerized tomography
the absence of CAC had a very low risk for future cardiac events angiography
(<1%), whereas the presence of CAC was a strong predictor of Previous studies have demonstrated that CCTA has a high sensi-
events [50]. More recently, Nabi and co-​workers reported on the tivity and specificity for the detection of CAD, compared to ICA, in
use of the CAC score in 1031 patients with acute CP using 16-​ patients with stable CAD. More importantly, due to the high NPV,
slice CT [53]. In 625 (61%) patients with a CAC score of 0, the CCTA can reliably exclude significant CAD, which is of potential

Table 19.2  Diagnostic accuracy of a CAC score of 0 for the prediction of ACS or events

Author N N (%), CAC = 0 Follow-​up Sens (%) Spec (%) PPV (%) NPV (%)
Chang et al. [57] 1047 795 (76) Prospective, 30 days 67 77 4 99
Georgiou et al. [50] 192 76 (40) Prospective, 50 ± 10 months 97 64 48 97
Hoffman et al. [60] 368 197 (54) Prospective, 6 months 97 58 18 99
Laudon et al. [51] 263 133 (51) Prospective, 6 months 97 57 23 99
McLaughlin et al. [52] 134 48 (36) Prospective, 30 days 88 37 8 98
Nabi et al. [53] 1031 625 (61) Prospective, 6 months 94 62 7 99
Pooled 3035 1874 (62) –​ 93 65 14 99
CAC, coronary artery calcium; N, number; NPV, negative predictive value; PPV, positive predictive value; Sens, sensitivity; Spec, specificity.
Source data from Tota-​Maharaj R, McEvoy JW, Blaha MJ, Silverman MG, Nasir K, Blumenthal RS. Utility of coronary artery calcium scoring in the evaluation of patients with chest
pain. Crit Pathw Cardiol 2012 September; 11 (3): 99–​106.
 Pati en ts w i th su spected acu te c orona ry   sy n dro m e 231

Figure 19.4  Example of a patient presenting with suspected ACS, in whom coronary artery calcium (CAC) scoring and contrast-​enhanced CCTA were
performed to exclude CAD. Although the CAC score was 0 (A), an obstructive, non-​calcified plaque with a superimposed thrombus in the right coronary artery
(RCA) was detected on CCTA (B, C). The volume-​rendered 3D reconstruction (B) and curved MPR (C) show an occlusion in the mid segment of the RCA
(white arrows). (D) This finding was confirmed on invasive coronary angiography (white arrow). Ao, aorta; LAD, left anterior descending coronary artery; LCx, left
circumflex coronary artery; RCA, right coronary artery.
Reproduced from Henneman MM, Schuijf JD, Pundziute G, et al. Noninvasive evaluation with multislice computed tomography in suspected acute coronary syndrome: plaque
morphology on multislice computed tomography versus coronary calcium score. J Am Coll Cardiol 2008;52(3):216–​222. doi:10.1016/​j.jacc.2008.04.012 with permission from Elsevier.

value in patients presenting with suspected ACS in the emergency

room, but without specific ECG abnormalities and serum troponin
levels in the normal range on admission. Limited studies are avail-
able that assess the diagnostic value of CCTA for the detection of
significant CAD, compared to ICA, in patients presenting with sus-
pected ACS. Meijboom et al. evaluated 104 patients with NSTE-​ACS
using 64-​slice CTA, compared with ICA [38]. In total, 88 patients
(85%) presented with significant CAD on ICA. Reported sensitivity
and specificity of CCTA for detecting or excluding significant cor-
onary artery stenosis were 100% and 75%, respectively. E Figure
19.5 shows an example of a patient presenting with suspected ACS
with a significant stenosis in the RCA. More importantly, several
investigations have addressed the predictive value of CCTA for the
detection of ACS in patients with acute CP. E Table 19.3 demon-
strates the diagnostic accuracy of CCTA for the detection of ACS.
In most of these studies, ACS is defined as either AMI or unstable
angina pectoris, according to the ACC/​AHA criteria [59], prefer-
ably with evidence of myocardial ischaemia on functional testing
[60]. In the ROMICAT I  study, 368 patients presenting with CP
and possible ACS (but with normal initial troponin levels and non-​
ischaemic ECG) underwent 64-​slice CTA [60]. Of these 368 pa-
tients, 8% eventually developed an ACS, according to the definition Figure 19.5  Example of non-​invasive coronary angiography with CT
in a patient presenting with suspected ACS. (A) A 3D volume-​rendered
described previously. On 64-​slice CT, 183 did not have any cor- reconstruction showing a large dominant right coronary artery (RCA) with
onary atherosclerosis (no CAD), whereas 117 had non-​obstructive signs of luminal narrowing (white arrow). (B) A curved MPR of the RCA
coronary artery stenoses. Of these 300 patients, only seven (2%) demonstrating the presence of significant luminal narrowing in the mid
were diagnosed with ACS, yielding an NPV of 98%. Conversely, segment (white arrow). (C) Another curved MPR in a different view revealing
68 patients had obstructive CAD on CTA and 24 developed an the presence of significant stenosis (white arrows). Cross-​sectional CT images
(inlays) show the presence of calcified plaque proximal to the stenosis (a),
ACS; accordingly, the PPV was 35%. Similarly, Gallagher et  al. exclusively non-​calcified plaque within the stenosis (b), and no coronary plaque
evaluated 85 patients with suspected ACS using 64-​slice CTA; 73 distal from the stenosis (c). (D) Conventional coronary angiography confirming
patients had non-​obstructive or no CAD on the CT scan, and one the presence of significant luminal narrowing of the RCA (white arrow).
Table 19.3  Diagnostic accuracy of CTA for the detection of ACS

Author N Pretest probability % ACS % patients Definition Sens (%) Spec (%) PPV (%) NPV (%)
negative CTA of ACS
TP/​(TP + FN) TN/​(TN + FP) TP/​(TP + FP) TN/​(TN + FN)
White et al. [81] 69 Low to high 17 82 Clinical 83 (10/​12) 96 (55/​57) 83 (10/​12) 96 (55/​57)
Gallagher et al. [131] 85 Low 8 86 Clinical 86 (6/​7) 92 (72/​78) 50 (6/​12) 99 (72/​73)
Hoffman et al. [132] 40 All 13 65 Clinical 100 (5/​5) 74 (26/​35) 38 (5/​14) 100 (26/​26)
Hoffman et al. [133] 103 Low 14 71 Clinical 100 (14/​14) 82 (73/​89) 47 (14/​30) 100 (73/​73)
Olivetti et al. [134] 31 Low to intermediate 58 52 ICA 83 (15/​18) 100 (13/​13) 100 (15/​15) 81 (13/​16)
Sato et al. [135] 31 Low 71 29 Clinical 95 (21/​22) 89 (8/​9) 95 (21/​22) 89 (8/​9)
Goldstein et al. [63] 99 Low 8 89 Clinical 100 (8/​8) 97 (88/​91) 73 (8/​11) 100 (88/​88)
Meijboom et al. [38] 33 Low + 85 12 ICA 100 (28/​28) 75 (4/​5) 96 (28/​29) 100 (4/​4)
Rubinshtein et al. [136] 58 Intermediate 34 60 Clinical 100 (20/​20) 92 (35/​38) 87 (20/​23) 100 (35/​35)
Hoffman et al. [60] 368 Low 8 82 Clinical 77 (24/​31) 84 (293/​337) 35 (24/​68) 98 (293/​300)
*
Meta-​analysis 917 –​ 16 72 –​ 92 (151/​165) 89 (667/​752) 64 (151/​236) 98 (667/​681)
+
Only a portion of patients with low risk were included in this meta-​analysis.
*
Meta-​analysis adapted from Vanhoenacker et al. [137].
ACS, acute coronary syndrome; FN, false negative; FP, false positive; ICA, invasive coronary angiography; NPV, negative predictive value; PPV, positive predictive value; Sens, sensitivity; Spec, specificity; TN, true negative; TP, true positive.
Source data from Vanhoenacker PK, Decramer I, Bladt O, Sarno G, Bevernage C, Wijns W. Detection of non-​ST-​elevation myocardial infarction and unstable angina in the acute setting: meta-​analysis of diagnostic performance of multi-​
detector computed tomographic angiography. BMC Cardiovasc Disord 2007 December 19;7:39.
 Pati en ts w i th su spected acu te c orona ry   sy n dro m e 233

of these developed an ACS, resulting in an NPV of 99%. On the 10 P = 0.030

other hand, six of the 12 patients with obstructive CAD on the CT
scan developed an ACS, yielding a PPV of 50%. A meta-​analysis 8
combining the results of ten studies with a total of 917 patients
confirmed an NPV of 98%, with a lower PPV of 64%. The high 6 P = 0.004

Incidence
NPV enabled ruling out future development of ACS. In contrast,
significant CAD on CCTA has a lower predictive value for the de- 4
velopment of ACS. These observations indicate that the absence of
significant CAD on CCTA can rule out the development of ACS, 2
but the presence of significant CAD does not indicate that these
patients will always develop an ACS. 0
Invasive coronary angiography Revascularization
In addition, CCTA has been used for the prediction of short-​
and long-​term outcome of patients presenting to the emergency Standard care
CCTA-based strategy
room with suspected ACS. In the ROMICAT I  study, none of
the 300 patients with a ‘negative CCTA’ (defined as no coronary Figure 19.6  Difference in referral rate for invasive coronary angiography and
atherosclerosis or non-​obstructive CAD) experienced a subse- subsequent revascularization between patients randomized to either a CCTA-​
quent cardiovascular event during a 6-​month follow-​up period based strategy or standard care.
[60]. Based on these initial observations, subsequent studies have Reproduced from Hulten E, Pickett C, Bittencourt MS, et al. Outcomes after coronary
computed tomography angiography in the emergency department: a systematic review
focused on the potential implementation of CCTA in the man- and meta-​analysis of randomized, controlled trials. J Am Coll Cardiol 2013;61(8):880–​892.
agement of patients presenting to the emergency room with sus- doi:10.1016/​j.jacc.2012.11.061 with permission from Elsevier.
pected ACS (but with normal troponin levels and non-​ischaemic
ECG). For example, Litt et al. performed an RCT in 1370 patients
with suspected ACS [61]. Patients were randomized to either is associated with an increased use of ICA and subsequent
CTA or standard care. Of the 908 patients referred for CTA, 640 revascularization.
(70%) had a negative CTA (no atherosclerosis or non-​significant At the same time, the CCTA-​based strategy resulted in a sig-
CAD). These patients were discharged, and none of these patients nificant reduction in the length of stay (ED or hospital stay) by
died or presented with MI within the next 30 days. 3.4–​11.6 hours, compared to patients receiving standard care [61,
At present, four large RCTs have been conducted to assess the 63–​65]. For example, 50% of the patients randomized to CCTA
value of a CTA-​based strategy, compared to standard care. The in the ROMICAT II study could be safely discharged within 8.6
results of these four trials have been pooled in a meta-​analysis by hours, compared to 26.7 hours for patients receiving standard
Hulten et al. [62]. This meta-​analysis included the results of 1869 care (see E Figure 19.7) [64]. Moreover, a CCTA-​based strategy
patients undergoing CCTA and 1397 patients receiving standard positively affected ED costs; in three of the four trials, a significant
care. Of the 1869 patients undergoing CCTA, only 4.2% had a reduction in costs was observed in the group of patients random-
significant coronary artery stenosis (≥70% luminal narrowing) ized to CTA, ranging from $286 to $1321.
on CTA. None of the patients died during the trials. In total, 142 The number of post-​discharge hospitalizations for ACS is ex-
(7.6%) of the patients in the CCTA group underwent ICA, of tremely low in these four trials (ranging from 0% to 3.1%), which
which 76 (4.1%) were revascularized. Patients referred to CCTA further supports the safety of CCTA-​guided discharge of patients.
more often underwent ICA than patients receiving standard care. Therefore, the 2014 AHA/​ACC guidelines on NSTEMI recom-
As depicted in E Figure 19.6, the ICA referral rate was 6.3% in mend performing non-​invasive angiography with CCTA in pa-
patients receiving standard care, compared to 8.4% in patients tients with possible ACS but normal ECG and troponin levels,
randomized to CTA (P = 0.003). The absolute increase in ICA for to exclude significant CAD (Class  IIa, LoE A) [66]. Similar re-
a CCTA-​based strategy was 21 per 1000 patients [62]. Of interest, commendations are included in the 2015 ESC guidelines, which
the majority of these downstream referrals for ICA were during state that CCTA should be considered as an alternative to ICA to
the index hospitalization. Similar to the increase in ICA in the exclude ACS in low intermediate-​risk patients with inconclusive
CCTA group, a significant increase in revascularization was ob- ECG and/​or troponin levels (Class IIa, LoE A) [67].
served in this group (both PCI and CABG). The revascularization Further evidence for the safety of CCTA to exclude CAD in pa-
rate was 2.6% in patients receiving standard care, compared to tients with suspected ACS was provided by Hollander et al. who
4.6% in patients randomized to CCTA (P = 0.004). The absolute published the 1-​year outcomes of the ACRIN (American College
increase in revascularization for a CCTA-​based strategy was 20 of Radiology Imaging Network-​Pennsylvania) trial [61,  68]. In
per 1000 patients. this trial, patients presenting with acute CP were randomized to
The information from these four RCTs underscores the value CCTA or standard care, with follow-​up of 1 year. There were no
of CCTA in the emergency room for patients presenting with significant differences between the two groups regarding MACEs,
acute CP and suspected ACS in the emergency room, namely in new ED visits, hospital admissions, or subsequent ischaemia
the exclusion of CAD. At the same time, however, this approach testing. Only one of 640 patients with a negative (i.e. normal CTA
234 CHAPTER 19   C omp u terized tomo graph y: c orona ry a n g i o g r a phy a n d ca rdiac i m ag i n g

100
90

Proportion of patients discharged (%)

80
70 CCTA
60
8.6 hour 26.7 hour
50
40
30
50
Standard evaluation in ED
10
0
0 6 12 18 24 30 36 42 48
No. of patients in Length of stay (hour)
ED or hospital
CCTA 501 404 191 174 159 95 70 66 57
Standard evaluation 499 484 403 387 331 135 77 72 63

Figure 19.7  Difference in length of hospital stay between patients referred to CTA or standard care. The horizontal line indicates the median length of stay in
both study groups, which was significantly different.
Reproduced from Hoffmann U, Truong QA, Schoenfeld DA, et al. Coronary CT angiography versus standard evaluation in acute chest pain. N Engl J Med 2012;367(4):299–​308.
doi:10.1056/​NEJMoa1201161 with permission from Massachusetts Medical Society.

or non-​obstructive CAD) CCTA experienced an adverse cardiac bolus timing for optimization of contrast delivery in the vessel,
event during follow-​up (0.16%). fast high-​resolution acquisition, and administration of approxi-
mately 60–​120 mL of contrast material (dependent on patient
size, contrast agent used, and scanner type) injected at rapid in-
fusion rates (4–​5 mL/​s).
Computerized tomography Because of the availability, excellent image quality with good
angiography of the aorta and spatial resolution, high sensitivity, and fast imaging speed,
multi-​slice CT has become the first-​choice imaging tool for the
pulmonary arteries evaluation of acute aortic syndrome [69] and traumatic aortic
Non-​cardiac causes of acute CP concerning vascular structures pathology [70]. Multi-​slice CT is also widely used in the evalu-
in the thorax, such as in acute aortic syndrome and PE, can be ation of non-​acute pathology such as aneurysm or aortic coarc-
easily visualized by CT. CTA of vascular beds other than the tation, and inflammatory and infective aortic disease, and after
heart is less complex if non-​ECG gating techniques are used. aortic surgery [71].
ECG gating may be used to improve image quality. In addition, Acute aortic syndrome encompasses a variety of life-​threatening
contrast enhancement in the blood pool is required to visualize conditions that require emergency diagnosis and management,
the vascular structures, and thus IV contrast is still needed. including aortic dissection (see E Figure 19.8), intramural
Several common principles should be applied to all imaging haematoma (IMH), penetrating aortic ulcer (PAU), and symp-
protocols to provide optimal diagnostic image quality such as tomatic aortic aneurysm.

Figure 19.8  (A) Thoracic CTA showing a type A aortic dissection. (B) The RCA is contrast-​enhanced and has its origin from the true lumen (arrow). The RCA
has a double appearance due to motion artefacts in this non-​ECG-​gated scan. (C) The left main coronary artery stem (arrow) is also contrast-​enhanced and has
its origin from the true lumen. The carotid and subclavian arteries, as well as the visceral arteries, all have their origins from the true lumen. (B, C) Note the almost
complete disruption between the true and false lumen of the descending aorta (arrowheads). F, false lumen; T, true lumen.
 C ompu t erized tomo graph y a n g i o g r a phy of the aorta a n d pu l mona ry   a rt e ri e s 235

If a patient presents with suspected acute aortic syndrome, the

CT protocol should include a non-​contrast-​enhanced scan from
the proximal part of the arch vessels to the diaphragm, followed
by CTA from the proximal part of the arch vessels to the femoral
arteries. The non-​contrast scan is to evaluate the possible pres-
ence of an IMH as an aortic wall thrombus [71]. An IMH of the
ascending aorta is clinically regarded as high risk for complica-
tion (evolving into dissection) and death, and surgery is usually
indicated [72].
A PAU is usually located in the mid-​descending thoracic aorta
where it presents as a mushroom-​like contrast outpouching be-
yond the expected contours of the aortic lumen. The PAU rep- Figure 19.9  (A) Patient with acute PE and high embolus load. Massive
emboli in the left and right pulmonary arteries can be observed (arrows).
resents an atherosclerotic ulceration that penetrates the internal (B) Note severe dilatation of the right ventricle (RV), with an interventricular
elastic lamina, allowing haematoma formation within the aortic septum shift to the left and compression of the left ventricle (LV) due to high
media, and may develop into an IMH, an aortic dissection, or a embolus load. Normally, the RV diameter does not exceed that of the LV.
vessel rupture [73].
intermediate, or high risk. If a patient has a score of 4 or more,
Thoracic aortic aneurysm further testing is required. In routine clinical practice, multi-​slice
Aneurysm is defined as a permanent localized dilatation of an ar- CT pulmonary angiography (CTPA) has become the first-​choice
tery, having at least 50% increase in diameter, compared with the imaging method for evaluating the pulmonary arteries when PE
normal diameter [72]. In general, an ascending aortic diameter is suspected [76] (see E Figure 19.9). A normal CTPA can safely
≥4 cm (in an individual <60 years old) is considered an aneurysm. exclude PE without the need for additional tests [77]. On CT, PEs
The size of the thoracic aorta increases with age and depends on are shown as filling defects in the contrast-​enhanced central or
sex and body size. The normal ascending aorta diameter is ap- segmental pulmonary arteries. In patients with PE, clot burden
proximately 27 mm in 20-​year olds and 36 mm in 80-​year olds is related to RV dysfunction where the measure of a right-​to-​left
[72]. Thoracic aortic aneurysms can be true or false aneurysms. ventricular diameter ratio exceeding 1.0 indicates a risk for short-​
In a true aneurysm, all three layers of the vessel wall are involved term death [78].
(intima, media, and adventitia), and it is characterized by a fu-
siform shape. In a false aneurysm (or pseudoaneurysm), the in- Triple rule-​out computerized tomography
tima is disrupted and the blood is contained by the adventitia. The concept of the ‘triple rule-​out’ protocol is to simultaneously
Atherosclerosis is the most frequent cause of thoracic aneurysms exclude all three potentially life-​threatening causes of acute CP
(70%). Several genetic syndromes, vasculitis, and inflammatory (ACS or infarction, acute aortic dissection or syndrome, and PE) in
diseases are also associated with aortic aneurysm and dissection. a single CT examination. A triple rule-​out scan protocol includes
Asymptomatic patients with an ascending aorta or sinus diam- coverage of the entire thorax cavity, including the aortic arch.
eter >5.5 cm and a growth rate of >0.5 cm per year in aortic an- State-​of-​the-​art 64-​slice scanners, with wide anatomical coverage,
eurysms of <5.5 cm, those with genetically mediated syndromes, are able to scan the entire thorax, including the pulmonary ar-
and a thoracic aorta aneurysm exceeding 4.0–​5.0 cm are candi- teries, thoracic aorta, and coronary arteries, in a single breath-​
dates for elective surgical repair. Symptomatic patients suggestive hold of approximately 15–​20 s. An important technical challenge
of expansion of a thoracic aneurysm should be evaluated for of a triple rule-​out scan protocol is to ensure that high contrast
prompt surgical intervention [72]. enhancement is present simultaneously in both the pulmonary
CTA is the most robust tool for evaluating aortic aneurysms, and systemic circulation to evaluate the pulmonary arteries and
and some key features should be evaluated when using CTs such aorta, including the coronary arteries. Injection protocols should
as maximal aortic diameter, presence of thrombus, shape and ex- be adapted to scanner type and acquisition settings.
tent of the aneurysm, involvement of aortic branches, relation- The triple rule-​out approach may improve the triage of patients
ship to adjacent structures, and presence of aortic calcifications. presenting to the ED with acute CP and provide a faster algorithm
In 23% of cases, a thoracic aneurysm coexists with an abdominal to make a diagnosis. However, it is crucial that patients should be
aortic aneurysm, and thus evaluation of the entire aorta is indi- carefully selected to ensure the appropriate use of a triple rule-​
cated. Most importantly, CT shows excellent accuracy for charac- out CT protocol. If the triple rule-​out protocol involves retro-
terizing important features of aneurysms [74]. spective gating of the entire thorax, radiation dose is high, even
more so than the radiation dose observed in dedicated CCTA
Pulmonary embolism [79, 80]. Prospective gating techniques strongly reduce the radi-
The well-​known Wells’ clinical decision rule is used to risk-​ ation dose but may not be applied effectively in patients with high
stratify patients suspected of PE [75]. This is a scoring method, or irregular heart rates. Therefore, patients with symptoms highly
based on various clinical risk factors, and stratifies patients as low, suggestive for ACS, acute PE, or acute aortic dissection should
236 CHAPTER 19   C omp u terized tomo graph y: c orona ry a n g i o g r a phy a n d ca rdiac i m ag i n g

be referred for a work-​up specifically designed for this purpose of hospitalized patients and total health costs [85]. Indeed, more
(such as ICA if a patient has a high risk for ACS). As discussed RCTs are needed to determine how the triple rule-​out protocol is
previously, the presence of a significant stenosis on CCTA does best applied to improve clinical decision-​making and justified use.
not automatically confirm the presence of ACS. In the remaining
patients with an uncertain cause of CP, a triple rule-​out protocol
can be considered.
Initial studies suggest that a triple rule-​out CTA protocol for Technical developments
the evaluation of patients with acute CP is feasible and that quan-
titative parameters of image quality may be comparable to the Coronary artery plaque quantification
conventional, dedicated coronary and pulmonary CTA protocol Currently, the assessment of stenosis severity on CCTA is per-
[81, 82]. A study evaluating the diagnostic value of triple rule-​out formed visually. This requires, however, significant experience
with 64-​slice CT in 55 patients admitted to the ED demonstrated and is characterized by limited reproducibility [86]. Novel soft-
that this technique facilitated the differential diagnosis of CP ware tools have become available to (automatically) quantify
[82]. Furthermore, the triple rule-​out protocol could potentially the stenosis severity on CTA, the so-​ called quantitative CTA
identify a subset of patients with acute CP who can be discharged (QCT) [87, 88]. These algorithms usually consist of various steps.
safely from the ED without AEs during a 30-​day follow-​up [83]. First, the coronary tree is extracted from the CTA data set and
A study in 100 patients with acute CP and an intermediate car- a multiplanar reformation is created of each coronary artery or
diac risk profile used either CCTA or a triple rule-​out protocol side branch. Thereafter, the lumen and vessel wall are delineated
in cases of elevated D-​dimer levels. Based on a negative CCTA on these MPR images. Based on these segmented contours, the
or triple rule-​out findings, 60 of 100 patients were discharged on severity of coronary artery stenosis can be quantified, but also the
the same day, without major cardiac events at 90-​day follow-​up. amount of coronary atherosclerosis (the plaque burden) can be
Also, those patients with significant coronary artery stenosis were derived (see E Figure 19.10). Previous investigations using QCT
identified [84]. The use of this protocol in patients with an inter- have demonstrated a good agreement between stenosis severity. as
mediate cardiac risk profile was calculated to reduce the number assessed with QCT, compared to ICA and intravascular ultrasound

Figure 19.10  Example of quantitative CTA (QCT) analysis of a 48-​year-​old male patient referred for evaluation of stable CP. Panel (A) demonstrates a stretched
MPR of the LAD with a calcified lesion. QCT was used to detect both lumen (yellow) and vessel wall (orange) contours. Longitudinal lumen and vessel wall
contours are shown in panel (A), whereas transversal lumen and vessel wall contours at the level of the minimal lumen area (MLA) are shown in panel (B). Panel
(C) shows the quantification of coronary plaque constitution. Calcium is labelled in white, fibrotic tissue labelled in dark green, fibrofatty tissue in light green,
and necrotic core in red. Quantification of the calcified lesion was performed using proximal (green) and distal (red) reference markers, as well as lumen (yellow)
and vessel wall (orange) reference lines, as illustrated in panel (D). In this graph, the x-​axis represents the distance from the coronary ostium in millimetres. The
y-​axis represents the area of either the lumen (lower part of graph) or the vessel wall (upper part of graph) in mm2. The part between the two graphs shows the
plaque constitution. Stenosis severity was quantified as 35%.
 Nove l a ppl i cati on s of ca rdiac c o m pu teri z ed  to mo g r a ph y 237

(IVUS) [87, 88]. It was also shown that stenosis severity derived dual-​source CT scanners with 2 × 128 detector rows have been
from QCT was related to the presence of ischaemia on SPECT introduced, and these systems demonstrate a high temporal reso-
perfusion imaging [89]. Besides these geometrical parameters, lution of 75 ms (approximately half of the temporal resolution of
it is also feasible to automatically assess and quantify coronary the fastest 64-​slice scanners), making it possible to freeze cardiac
plaque composition with QCT using predefined intensity cut-​off motion and obtain diagnostic quality images of the coronary ar-
values in Hounsfield units (HU). In a head-​to-​head comparison teries, regardless of the heart rate or rhythm. Initial studies with
between QCT and IVUS with virtual histology, a good agreement dual-​source coronary CT in patients presenting with CP have
was shown for the assessment of different plaque types (calcified, reported high NPVs approaching 100%, enabling to reliably ex-
mixed, or non-​calcified) [90]. clude coronary artery stenoses also in patients with higher heart
Recently, Chang et al. investigated the incremental predictive rates [94]. Recently, high-​ pitch, ECG-​ triggered (‘flash spiral’)
value of these QCT parameters for the development of subse- dual-​source CT scanners have shown promising results [13]. The
quent ACS [91]. For this purpose, 234 patients who experienced novelty of this technique lies in the very high pitch which results
ACS after CCTA were matched with 234 patients without ACS, in fast image acquisition, without cardiac motion artefacts, and
based on risk factors and CAD severity. Importantly, the authors a very low radiation exposure (<1 mSv) [13]. Currently, only
found no significant association between calcified and fibrous limited data in selected patients are available with these newer
plaque and the occurrence of ACS (P = 0.092 and P = 0.94, re- scanners, and larger studies are needed to determine the value of
spectively). However, fibro-​fatty and necrotic core plaques, which these novel equipment in routine clinical practice. In addition to
are both part of the non-​calcified portion of the coronary plaque, novel protocols aiming to reduce radiation exposure, novel strat-
were both significantly associated with ACS beyond stenosis se- egies to reduce iodine contrast burden are being developed. For
verity (P = 0.048 and P = 0.009, respectively). Accordingly, QCT example, Benz et al. performed CCTA in 89 patients with reduced
provides important prognostic information for the identification contrast use [35 mL, interquartile range (IQR) 30–​40 mL] without
of vulnerable (non-​calcified) coronary plaques that may poten- affecting image quality or diagnostic accuracy [95]. Compared to
tially cause a future ACS. the standard volume of 60–​100 mL for CCTA, this approach al-
Since ACS is frequently associated with rupture of vulnerable lows a significant reduction in contrast use, which is important
coronary plaques, stabilization of these plaques with medication for patients with impaired renal function.
may lead to a significant reduction in the ACS incidence. In this
regard, serial evaluation by CCTA has been particularly useful to
study the effect of medication on atherosclerosis progression/​re-
gression, as well as plaque composition and stabilization [92]. The Novel applications of cardiac
effect of statin therapy on coronary atherosclerotic plaques was computerized tomography
investigated in the multinational PARADIGM (Progression of
AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Assessment of coronary artery
Angiography Imaging) study in patients who underwent serial plaque composition
CCTA [93]. In total, 1079 coronary artery lesions from 474 non-​ Since CCTA allows for the visualization of the coronary vessel
statin users and 2496 coronary lesions from 781 statin users were wall, coronary atherosclerosis on CCTA can be further character-
analysed using QCT. Although the progression of total and non-​ ized (beyond stenosis severity), enabling the assessment of plaque
calcified plaques was significantly reduced in statin users, com- composition. The plaques can be divided into non-​calcified, calci-
pared to non-​statin users (respectively, 1.76 mm3 versus 2.04 mm3, fied, and mixed plaques. Interestingly, coronary plaque compos-
P = 0.002 and 0.49 mm3 versus 1.06 mm3, P <0.001), statin users ition has been linked to clinical presentation; patients presenting
showed a more rapid progression of calcified plaque (1.27 mm3 with an ACS were shown to have more non-​calcified and/​or
versus 0.98  mm3; P <0.001). These results strongly suggest that mixed plaques in the coronary arteries, whereas patients with
statin therapy, besides influencing overall plaque progression, has stable CAD presented with more calcified plaques [96]. In add-
an important effect on the composition of coronary plaques. As ition, it has been suggested that plaque composition may provide
such, statins may potentially exert a ‘healing’ effect on coronary prognostic information [97].
plaques by increasing coronary calcification, which could repre- Specifically, non-​calcified plaques with low attenuation values
sent a mechanism of coronary plaque stabilization. and positive remodelling have been associated with the subsequent
development of ACS and are therefore considered as high-​risk
Developments in computerized plaque characteristics [98]. This was demonstrated by Motoyama
tomography scanners et al. evaluating the presence of high-​risk plaques in 3158 patients
The technology of CT scanners is evolving rapidly. With the intro- who previously underwent CCTA [99]. After a mean follow-​up
duction of 256-​and 320-​slice scanners, complete volume coverage period of 3.9 years, 16.3% of patients with high-​risk plaques devel-
of the heart becomes possible in a single heartbeat [11, 12]. This oped ACS, as compared to only 1.4% of the patients without high-​
may potentially reduce motion artefacts, particularly in patients risk plaques. Moreover, the presence of high-​risk plaque was an
with irregular heart rates or rhythm abnormalities. Moreover, independent predictor for the development of ACS, irrespective
238 CHAPTER 19   C omp u terized tomo graph y: c orona ry a n g i o g r a phy a n d ca rdiac i m ag i n g

of stenosis severity (P <0.001). Gaemperli et al. evaluated 220 pa- to CCTA alone, for the detection of myocardial ischaemia
tients with known or suspected CAD, using 64-​slice CCTA, and [105,  111]. George et  al. demonstrated in 53 patients with an
demonstrated worse outcome in patients with mixed or non-​ intermediate to high pretest likelihood of CAD that the diagnostic
calcified plaques [100]. This was further confirmed by Hou et al. accuracy of CTP to predict reversible ischaemia on SPECT was
in 4425 patients with suspected CAD, over a follow-​up period of higher than that of CCTA [105]. In the multicentre CORE 320
nearly 3 years. The authors demonstrated that patients with non-​ (Coronary Artery Evaluation Using 320-​Row Multidetector CT
calcified plaque were at five times higher risk for the combination Angiography) study, 381 patients who had been clinically referred
of death, infarction, or revascularization, compared to patients for ICA were included [112]. All patients underwent CCTA plus
with calcified plaques, and the risk of patients with mixed plaques CTP and SPECT MPI prior to ICA. Haemodynamically signifi-
was nearly ten times higher [101]. Interestingly, it was shown that, cant CAD (defined as >50% of luminal stenosis on ICA and an ac-
in 163 patients with CP and suspected CAD, mixed plaques were companying perfusion defect on SPECT MPI) was present in 38%
also correlated with the presence of ischaemia on SPECT perfu- of patients. For the combination of >50% of stenosis on CTA and
sion imaging [102]. The relationship between plaque compos- a myocardial perfusion defect on CTP, the sensitivity, specificity,
ition and myocardial ischaemia was further evaluated in a study and PPV and NPV were 80%, 74%, 65%, and 86%, respectively.
by Driessen et al. [103]. In total, 208 patients with suspected CAD The diagnostic accuracy (defined by the AUC) of CTA alone was
were prospectively included to undergo CCTA, positron emission 0.84 and increased to 0.87 for CTA in combination with CTP. It
tomography (PET), and invasive FFR. QCT was performed in all was concluded that the combination of CTA and CTP more ac-
coronary vessels to assess the impact of plaque composition and curately identifies patients with flow-​limiting CAD. Moreover, the
morphology on downstream myocardial perfusion. The authors incremental diagnostic value of CTP was recently evaluated by
showed that positive remodelling, but also non-​calcified plaques, Pontone et al. in intermediate-​to high-​risk symptomatic patients
were independently associated with myocardial ischaemia, as as- suspected of CAD, using invasive FFR as the reference standard
sessed using PET (P = 0.004 and P <0.001, respectively) and in- [113]. It was shown that the combination of CCTA with CTP,
vasive FFR (P = 0.007 and P = 0.010, respectively), independent compared to CCTA alone, significantly improved specificity and
of lesion severity. These results may indicate that positively re- diagnostic accuracy for the detection of functionally significant
modelled plaques containing a large necrotic core are associated CAD (from 54% to 83% and 76% to 91%, respectively). A meta-​
with an inability of the vessel to dilate and could therefore lead to analysis, combining the results of five studies, including 264 pa-
myocardial ischaemia [104]. tients who underwent both CTP and invasive FFR, demonstrated
good agreement between both techniques [114]. For individual
Evaluation of myocardial perfusion patients, the pooled sensitivity of CTP to detect a significant sten-
Recent developments in CT scanner technology have enabled osis on invasive FFR assessment was 83%, with a specificity of
the evaluation of LV myocardial contrast attenuation, enabling 76% and PPV and NPV of 61% and 91%, respectively.
CT myocardial perfusion imaging (MPI) (of the LV). This func- Dynamic CTP protocols use a different approach that facili-
tional information is of particular importance to determine the tates (semi-​) quantitative assessment of myocardial perfusion.
haemodynamic significance of intermediate coronary artery sten- Data acquisition is performed continuously during injection and
oses (around 50% of luminal narrowing). Standard CT perfusion passage of iodinated contrast through the coronary arteries and
(CTP) protocols include a rest study for the evaluation of the cor- the myocardium. Therefore, the distribution of contrast can be
onary arteries and the resting myocardial perfusion, followed by assessed during the entire influx. Using automatic algorithms,
an adenosine-​induced stress study to determine the stress per- myocardial blood flow can be quantified. Currently, there are little
fusion [105]. Similar to perfusion imaging with SPECT or MRI, data on the diagnostic accuracy of this technique. Small studies
reversible or fixed perfusion defects can be detected, indicating comparing dynamic CTP with ICA show different results, with
ischaemia or scar tissue, respectively [106–​109]. A  major ad- sensitivity ranging from 78% to 100% and specificity from 82%
vantage of CTP is the combination of coronary artery anatomy to 100%. Although this technique has potential value, further
(CTA) and function (CTP) in one examination. studies are necessary [115].
Currently, most experience has been gained in static perfu-
sion, whereby data are acquired at a single specific time point of Evaluation of myocardial infarction
the cardiac cycle after iodinated contrast injection. Blankstein Over recent years, MRI has been successfully employed to image
et al. demonstrated with 64-​slice CT that an adenosine stress CT the presence of infarcted myocardium with delayed contrast en-
protocol can identify stress-​induced myocardial perfusion defects hancement imaging. However, several studies have demonstrated
with a diagnostic accuracy comparable to that of SPECT [110]. that the presence of infarction can be also identified on CT
Additionally, the average radiation required in this protocol was [105]. Because of the pharmacokinetics of the contrast material,
similar to the radiation dose of SPECT perfusion imaging. It is a difference between the accumulation of contrast in infarcted
anticipated that, with improved dose reduction protocols, the and normal myocardium can be visualized. Accordingly, early
radiation dose will be reduced significantly. Recent studies have hypoenhancement can be observed on the CT images during
indicated an improved diagnostic accuracy for CTP, compared the first pass of contrast medium in the area of the infarcted
 Nove l a ppl i cati on s of ca rdiac c o m pu teri z ed  to mo g r a ph y 239

myocardium. In addition, delayed hyperenhancement of the revealed an overall diagnostic accuracy of 83%, compared to
infarcted tissue can be detected similarly by MRI. Good cor- invasive FFR assessment. The pooled NPVs and PPVs were 89%
relations between infarct imaging with CT and other imaging and 69%, respectively. Of particular interest, addition of FFRct
modalities, such as MRI and SPECT imaging, have been dem- to CCTA increased the specificity from 35% to 70%, without
onstrated [106–​ 108]. Moreover, a good correlation between loss of sensitivity (89% for FFRct combined with CCTA versus
enhancement patterns (both early hypoenhancement and late 90% for CCTA alone) [119]. These results were confirmed in
hyperenhancement) and recovery of myocardial function at 3-​ the NXT-​study (Analysis of Coronary Blood Flow Using CT
month follow-​up post-​infarction was reported, suggesting that Angiography: Next Steps), using an improved algorithm [120].
CT may be useful to predict functional recovery after infarction This study with a similar design included 254 patients, of
[109]. However, it is important to realize that, in general, delayed whom 32% had positive FFR. The study confirmed the diag-
enhancement imaging with CT requires additional imaging and nostic accuracy and demonstrated that FFRct correctly reclas-
thus involves additional radiation exposure. Also, a larger amount sified 68% of patients with a false-​positive CCTA. It should
of contrast agent is required for delayed enhancement imaging, be noted, however, that 13% of CTA scans were deemed non-​
compared to imaging the coronary arteries alone. evaluable. More recently, the diagnostic value of FFRct and
CTP, in addition to CCTA, was evaluated, using invasive FFR
Fractional flow reserve as the reference standard [121]. For this purpose, 147 patients
It has been shown in the FAME (FFR vs Angiography for were prospectively included to undergo CCTA, FFRct, CTP,
Multivessel evaluation) trial that revascularization guided by the and invasive FFR. It was shown that use of FFRct and CTP,
invasive assessment of the FFR is superior in terms of outcome in addition to CCTA, increased specificity (from 54% to 85%
over revascularization driven by angiographic stenosis severity and 87%, respectively) and diagnostic accuracy (from 73% to
for up to 2 years after the procedure [116, 117]. This observation 87% and 92%, respectively) to detect functionally significant
highlights that functional (ischaemia) assessment may be pre- CAD. Although both FFRct and CTP provided incremental
ferred over anatomical assessment (stenosis severity) to guide the diagnostic value for the assessment of the functional rele-
need for revascularization. Invasive assessment of the FFR, how- vance of CAD, no significant difference was found between
ever, may not be the first choice in patients with stable CP, and the two techniques. At the end of 2014, based on these valid-
a non-​invasive approach may be preferred. With the application ation studies, the Food and Drug Administration (FDA) has
of computational fluid dynamics and complex mathematical cal- granted the marketing of FFRct as a non-​invasive approach to
culations, novel software tools allow for the non-​invasive assess- evaluate myocardial blood flow. Further evidence for the clin-
ment of FFR from CCTA data sets (FFRct), without additional ical use of FFRct is provided by the PLATFORM (Prospective
imaging, modification of CT acquisition protocols, or adminis- LongitudinAl Trial of FFRCT: Outcome and Resource IMpacts)
tration of medication [118]. An example of this approach (com- trial. In this trial, 584 patients with stable CP who were sched-
pared to ICA and invasive FFR) is shown in E Figure 19.11. uled for either non-​invasive ischaemia detection or ICA were
The clinical diagnostic value of FFRct was summarized by a randomized to a standard care protocol or an FFRct-​guided
meta-​analysis including 765 patients from five studies, which protocol. Further downstream management was based on

Figure 19.11  Case example of FFRct with corresponding invasive coronary angiogram. Multiplanar reformat of a CCTA demonstrating several intermediate
calcified and mixed plaques of the proximal and mid portion of the left anterior descending coronary artery (LAD) and a computed fractional flow reserve
(FFRct) value of 0.82, indicating absence of ischaemia. Invasive coronary angiography demonstrates an intermediate stenosis of the proximal portion of the LAD
and a measured FFR value of 0.85, confirming the absence of ischaemia.
240 CHAPTER 19   C omp u terized tomo graph y: c orona ry a n g i o g r a phy a n d ca rdiac i m ag i n g

clinical decision-​making. The primary endpoint was the rate of Transluminal attenuation gradient
ICA with no obstructive CAD. Most importantly, in the FFRct
Another method to improve the assessment of the haemo-
cohort, fewer patients underwent ICA (only 76 of the initial
dynamic significance of a coronary stenosis with CTA could be
193)  and the percentage of patients without obstructive CAD
calculation of the transluminal attenuation gradient (TAG) [125].
was significantly lower, compared to standard care (12% versus
For this purpose, an MPR is generated of each coronary artery.
73%; P <0.001) [122]. The use of FFRct in real-​world practice
Along the centre line of this MPR, the luminal intensity is meas-
and its impact on clinical decision-​making, subsequent inva-
ured at 1-​mm increments. The TAG is then defined as the slope
sive procedures, and outcome was recently investigated in the
of the regression line of the decrease in luminal intensity from the
multinational ADVANCE (Assessing Diagnostic Value of Non-​
proximal to the distal part of the coronary artery (see E Figure
invasive FFRCT in Coronary Care) Registry [123]. In total,
19.12). A steep decrease in intensity (i.e. a more negative TAG)
5083 patients with confirmed atherosclerosis on CCTA were
was associated with the presence of an obstructive lesion in that
prospectively enrolled at 38 centres. FFRct changed the treat-
coronary artery [125]. Recently, Wong et  al. have reported the
ment recommendation in 67% of patients, when compared to
incremental value of TAG measurements on 320-​row CTA over
the initial treatment plan based on CCTA. Moreover, patients
CTA alone for the prediction of invasive FFR significant lesions
with a negative FFRct (FFRct >0.80) underwent significantly
[126]. However, to date, the exact clinical value of TAG is un-
less revascularizations and were less likely to experience car-
known and requires further trials and investigations.
diovascular death or MI, compared to patients with a positive
FFRct (FFRct ≤0.80) after 1-​year follow-​up [124]. These results
indicate that clinical decision-​making based on FFRct could be Evaluation of myocardial function
considered safe and effective to reduce the rate of unnecessary Besides the assessment of the coronary arteries, cardiac CT
diagnostic procedures and to improve risk stratification. imaging also enables the assessment of LV volumes and function.

(a) (b)

500
Luminal attenuation (HU)

400

300

200
Y = –1.195* X + 506
100 TAG = –11.95 (HU/10 mm)

0
0 40 80 120 160
QCA: MLD = 1.30 mm, DS = 52.7% Length from ostium (mm)

(c)

522 HU 503 HU 642 HU 301 HU 344 HU 316 HU

6.6 mm2 7.9 mm2 4.1 mm2 2.9 mm2 3.2 mm2 2.8 mm2
2.9 mm 3.2 mm 2.3 mm 1.9 mm 2.1 mm 1.7 mm

Figure 19.12  Patient example of TAG calculation. (A) CCTA demonstrating calcified lesions in the proximal LAD coronary artery and moderate
stenosis in the mid LAD traject, confirmed by invasive coronary angiography. (B) Luminal attenuation plot. Black dots represent 5-​mm intervals at which
intraluminal attenuation (in Hounsfield units, HU) and luminal area (in mm2) were measured. TAG is shown by the yellow line and was –​11.95 (HU/​10 mm).
(C) Representative axial cross-​sectional views of CCTA. MLD, minimal lumen diameter; QCA, quantitative coronary angiography.
Reproduced from Choi JH, Min JK, Labounty TM, et al. Intracoronary transluminal attenuation gradient in coronary CT angiography for determining coronary artery stenosis
[published correction appears in JACC Cardiovasc Imaging 2012 Jan;5(1):129]. JACC Cardiovasc Imaging 2011;4(11):1149–​1157. doi:10.1016/​j.jcmg.2011.09.006 with permission
from Elsevier.
 REFERENCES 241

If data have been collected during the whole cardiac cycle, im- Four RCTs have been performed, comparing a CT-​based ap-
ages can be retrospectively reconstructed in several phases to de- proach in the emergency room versus a standard of care approach.
rive the LVEF from the LV volumes. Indeed, numerous studies These trials confirmed the value of CCTA to exclude CAD, with
have shown that global LV function assessed by CT correlates good outcome after discharge and a reduction in hospital stay and
well with echocardiography and MRI, although CT appeared to costs. At the same time, an increase in ICA and revascularization
minimally overestimate the end-​systolic volume and may thus rate was observed in patients with CAD on CCTA; this warrants
slightly underestimate the LVEF [127–​129]. In addition, regional further studies to determine the precise relation between the CCTA
wall motion abnormalities can be reliably evaluated, compared to findings and referral for ICA. In current guidelines for the manage-
MRI [120]. However, as images should be acquired throughout ment of patients with acute CP suspected for ACS, CCTA can be
the cardiac cycle, LV function protocols are associated with in- used to exclude CAD in patients with low intermediate risk without
creased radiation exposure, and CT may not be the first-​choice ECG changes or rise in troponin levels. Finally, other applications,
technique but could be considered as an alternative for patients such as evaluation of coronary artery plaque composition, myocar-
who are not suitable to undergo MRI [130]. dial function and perfusion, and non-​invasive assessment of FFRct,
are currently being developed and may also become valuable in the
setting of chronic and acute CP in the future.
Conclusion
Patients may present with acute CP to the emergency room, sus- Personal perspective
pected for an ACS, but without the diagnostic ECG and troponin
criteria. This poses an important dilemma in clinical cardi- CTA provides prognostic information in patients with stable
ology. On one hand, this population constitutes a large number angina. In patients presenting with possible ACS, the out-
of patients with a low prevalence of ACS; on the other hand, a come after normal CTA is excellent, which allows safe dis-
substantial number of patients appear to develop an ACS once charge and a shorter length of stay and may reduce costs. CTA
discharged. CCTA is a feasible technique for a non-​invasive, fast, showing significant stenosis is associated with worse outcome
and accurate exclusion of obstructive CAD in patients presenting but does not translate directly to individual outcome, and the
with acute CP. Moreover, a normal CCTA allows safe discharge, optimal management (medical/​interventional) is unclear.
with good short-​to mid-​term prognosis. This has led to increased Attempts are made to integrate stenosis severity with
interest in using CT for the non-​invasive assessment of CAD in haemodynamic information. Myocardial perfusion can be
the ED, and in addition, the technique can evaluate the presence/​ measured, but also the FFR can be determined. This allows
absence of other causes of acute CP such as aortic aneurysm, a more comprehensive assessment and may facilitate pa-
aortic dissection, or PE. tient management.

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 CHAPTER 20

Cardiac magnetic
resonance in the intensive
and cardiac care unit
Juerg Schwitter and Jens Bremerich

Contents
Summary  246 Summary
Introduction  246 Current applications of cardiac magnetic resonance offer a wide spectrum of in-
Acute coronary syndromes: acute dications in the setting of acute cardiac care. In particular, cardiac magnetic res-
myocardial infarction  247
onance is helpful for the differential diagnosis of chest pain by the detection of
Viability imaging by cardiac magnetic
resonance: quantification of necrotic ischaemia, myocardial stunning, myocarditis, and pericarditis. Also, Takotsubo
tissue  247 cardiomyopathy and acute aortic diseases can be evaluated by cardiac magnetic
Microvascular obstruction  248
Oedema and haemorrhage  249
resonance and are important differential diagnoses in patients with acute chest
Assessment of complications of acute pain. In patients with restricted windows for echocardiography, according to
myocardial infarction  249 guidelines, cardiac magnetic resonance is the method of choice to evaluate compli-
Acute coronary syndromes: differential cations of an acute myocardial infarction.
diagnoses in acute chest pain  250
Myocarditis and perimyocarditis  250
In an acute myocardial infarction, cardiac magnetic resonance allows for a
Takotsubo cardiomyopathy  251 unique characterization of myocardial damage by quantifying necrosis, micro-
Evaluation of patients after out-​of-​hospital vascular obstruction, oedema (i.e. area at risk), and haemorrhage. These features
cardiac arrest  252
will help us to understand better the pathophysiological events during infarction
Aortic dissection A/​B, aortic ulcer, and
intramural haematoma  253 and will also allow us to assess new treatment strategies in acute myocardial infarc-
Aortic dissection  253 tion. To which extent the information on tissue damage will guide patient manage-
Intramural haematoma  256 ment is not yet clear, and further research is ongoing to address this issue. Recent
Penetrating aortic ulcer  256
studies also demonstrated the possibility to reduce costs in the management of
Pulmonary embolism and pulmonary
diseases  257 acute coronary syndromes when cardiac magnetic resonance is integrated into the
Performance and cost-​effectiveness of routine work-​up.
cardiac magnetic resonance in the In the near future, applications of cardiac magnetic resonance will continue to
emergency room  257 expand in acute cardiac care units, as manufacturers are now strongly focusing
Limitations and contraindications of on this aspect of user-​friendliness. Finally, in the next decade or so, magnetic res-
cardiac magnetic resonance  258 onance imaging using other nuclei, such as fluorine and carbon, might become a
Other limitations of cardiac magnetic
resonance  258 reality in clinics, which would allow for metabolic and targeted molecular imaging
Personal perspective  258 with excellent sensitivity and specificity.
Further reading  259
References  259

Introduction
In recent years, cardiac magnetic resonance (CMR) imaging emerged as a very
powerful tool in the evaluation of a variety of cardiac diseases [1–​3]. CMR is now
accepted as a useful imaging technique in the work-​up of patients with heart failure,
 Acu t e c orona ry sy n dro m es :  acu te m yo ca rdia l   i n fa rc t i on 247

[4–​6] in particular after an MI [6–​8], of patients with known or

Box 20.1  CMR applications in the setting of acute cardiac care
suspected CAD [9–​16], in cardiomyopathies [17,  18], in sus-
pected myocarditis [19–​21], and also in congenital heart dis- Myocardial function (without CM)
ease (CHD) [22]. However, CMR utilization is less frequent in
Cine acquisitions: SSFP pulse sequence
◆
the setting of the cardiac care unit. One major reason for this
Tagging acquisitions (apply grid pattern onto tissue)
◆
situation is most likely the still limited availability of CMR and
the transportability of the acutely unwell patient. Nevertheless, Tissue characterization
for a broad spectrum of acute CVDs, CMR can yield crucial, or ◆ Without CM:
at least additional, information relevant to the management of Oedema:  quantitative T2-​mapping techniques (preferable
●

critically ill patients. over T2-​weighted imaging)

Haemorrhage: T2-​weighted imaging—​dark core surrounded
●

by bright oedema tissue
Acute coronary syndromes: acute With CM:
◆

myocardial infarction ● Necrosis:  LGE—​ bright area (increased CM distribution

volume due to loss of cell membrane integrity)
Acute coronary artery occlusions with consequent STEMI rep- Microvascular obstruction: LGE—​dark core surrounded by
●

resent a generally accepted indication for primary PCI in order bright necrotic tissue
to revascularize the culprit lesion. As the ischaemic time is a Ischaemia:  perfusion CMR—​low signal (delayed wash-​in
●

strong predictor of salvaged myocardium, there is no indication during first pass) in viable tissue (with vasodilator stress)
for these patients to undergo pre-​interventional, non-​invasive
Scar: LGE—​bright area (increased CM distribution volume
●
imaging. However, in patients with unspecific ECG changes and in extracellular space of fibrosis)
little or no troponin elevation, non-​invasive imaging may add
relevant information for risk assessment, and consequently for
further patient work-​up and treatment decisions. Accordingly,
the 2018 ESC guidelines on the definition of myocardial infarc- with NSTE-​ACS for the detection of ≥70% coronary stenoses
tion also underline the advantages of using imaging, in particular [25]. In E Figure 20.1, CMR findings of an acute LAD occlusion
CMR, to establish the diagnosis of myocardial infarction [7]‌. In are shown in a patient with a history of LAD stenting. (See also
a patient population with ≥30 minutes of CP, compatible with E Chapters 38 and 41.)
an AMI, but with an inconclusive ECG, Kwong and co-​workers
[23] studied the effect of non-​invasive CMR examinations on
Viability imaging by cardiac magnetic
patient management and outcome. In this setting where per- resonance: quantification of necrotic tissue
sistent or transient repetitive episodes of myocardial ischaemia In acute plaque rupture, thrombogenic material of the plaque
occur, the investigators assessed global and regional LV function core may cause thrombosis and acute occlusion of the epicardial
parameters, viability, and resting perfusion by CMR. This CMR coronary vessel. Alternatively, this material may also embolize
protocol detected an underlying ACS with a sensitivity and spe- into the vessel periphery to cause microinfarctions. Viability
cificity of 84% and 85%, respectively. Multivariate logistic regres- imaging by CMR is sensitive enough to detect necrosis below 1 g
sion analysis showed CMR as the strongest predictor of ACS and of mass [26] (see E Box 20.1). Accordingly, this CMR tech-
it added diagnostic value over clinical parameters such as ECG nique was able to detect microinfarctions after PCIs in patients.
or troponin measurements. These results identified stunning as a Viability imaging by CMR is performed after injection of a con-
particularly important and sensitive finding to detect ACS as the ventional MR contrast medium (CM), i.e. gadolinium chelates,
cause of CP. In this situation, functional imaging is advantageous, which are excluded from the intracellular space by intact cell
as it is able to detect stunning as a consequence of ischaemia before membranes. In the case of acute damage of cell membranes, as
any necrosis, and thus enzyme leak, may occur (see E Box 20.1). during prolonged ischaemia and ischaemia/​reperfusion, the CM
Perfusion CMR during adenosine-​induced hyperaemia was also also distributes into the intracellular space, which increases the
shown to be highly predictive of future cardiac events in pa- CM content per volume of tissue [27–​29]. This increase in CM
tients presenting with acute CP in the emergency room [24]. concentration is visualized as a bright area in the myocardium.
In patients with >30 minutes of CP, negative troponins, and a This approach is called the ‘late gadolinium enhancement’ tech-
non-​diagnostic resting ECG, a CMR examination negative for nique (LGE) and detects myocyte necrosis due to a loss of cell
ischaemia had 100% sensitivity and 93% specificity to predict membrane integrity [28]. The images are acquired during a
a future diagnosis of CAD in these patients. CAD was defined short breath-​hold whereby the imaging parameters are selected
as >50% of diameter stenosis on coronary angiography, an ab- to set the signal of a viable intact myocardium to zero [3]‌. This
normal stress test, MI, or death occurring in the first year after approach results in a superb contrast-​to-​noise ratio between vi-
the CMR examination. A high sensitivity and specificity of 96% able and necrotic tissue [27]. This unique feature, together with
and 83%, respectively, was also reported by Plein et al. in patients an excellent spatial resolution of the technique, results in an
248 CHAPTER 20   C ardiac magnetic resonanc e i n  the i n ten si ve a n d ca rdiac ca re u n i t

Figure 20.1  In this 16-​year-​old patient, stenting of the proximal LAD was performed because of a severe stenosis (located close to a coronary artery
aneurysm) following Kawasaki disease. Approximately 3 months after a successful stent implantation, the patient reported some minor exertional
dyspnoea over a few days, and a CMR study was initiated to test for ischaemia, i.e. stent patency. The cine short-​a xis acquisitions demonstrate akinesia
of the anteroseptal wall, and a moderate pericardial effusion is also present (A). In this situation, perfusion CMR was immediately performed, following a
3-​minute infusion of adenosine. The perfusion CMR study shows severe ischaemia in the anteroseptal wall which also extends towards the inferior wall
in the more apical segments; thus, approximately three-​quarters of the LV myocardium are ischaemic (B; yellow arrowheads). Of note, the patient was
still completely free of symptoms and lying flat on the MR examination table. As severe ongoing ischaemia was present, viability imaging by LGE-​CMR
was performed a few minutes later, which demonstrated a small necrosis in the subendocardium of the anterior wall at the mid-​ventricular level (D; red
arrow). This finding would predict an almost complete recovery of function after successful revascularization. X-​ray coronary angiography confirmed a
proximal LAD occlusion at the stent site, but unfortunately recanalization was not possible (C). The patient underwent CABG a few hours later. In (E),
an almost complete functional recovery of the anterior and septal walls is documented by cine CMR 3 months after CABG. A viability LGE-​CMR study
shows a few minor areas of scarring (F; red areas). To monitor the patency of the left internal mammary artery (LIMA) graft, a perfusion study using
adenosine was performed, demonstrating no ischaemia, i.e. good function of the graft (G). Small hypoperfused areas (G; red areas) correspond to the
small areas of scar in (F).

unbeatable sensitivity and reproducibility to detect and quan- Microvascular obstruction

tify myocardial necrosis non-​invasively [5, 30–​32]. The amount
When performing viability imaging by CMR in acute and subacute
of necrosis, as measured by LGE-​CMR, has been shown to be
MI, another phenomenon, in addition to necrosis formation, was
a strong predictor of the future recovery of segmental function
observed, the so-​called microvascular obstruction (MVO). The
in patients after an AMI [33, 34]. E Figure 20.2 shows an ex-
LGE technique probes cell membrane integrity by measuring
ample of a patient with a large AMI, imaged by CMR at day
CM concentrations, i.e. distribution volumes of the CM in the
5, demonstrating akinesia of the anterior wall and necrosis
steady-​state condition that occurs typically 10–​15 minutes after
with microvascular obstruction, as well as oedema with central
CM injection. In severe myocardial damage, however, an equilib-
haemorrhage.
rium distribution of the CM may not yet be achieved at this time
As the LGE technique is able to quantify necrosis mass with
point. This is encountered when the microvasculature of the core
high precision and reproducibility, this technique was used in a
region of the infarct is disrupted and/​or plugged with blood cells,
large multicentre European trial to assess the efficacy of a new
preventing the CM to reach the infarct core. Under these circum-
fibrin-​derived compound to reduce ischaemia–​ reperfusion
stances, the core of the infarct region accumulates less CM and it
injury in patients with STEMI [35]. This fibrin derivative re-
appears as a dark core region called the MVO zone (see E Box
duced leucocyte penetration into reperfused ischaemic tissue
20.1 and Figure 20.2). A  large body of evidence demonstrates
in animals, and the clinical proof of concept trial was positive
that the occurrence of such an MVO zone goes along with a par-
by showing a reduced necrosis mass in the treatment arm [35].
ticularly poor prognosis [39]. In a large multicentre registry ex-
CMR necrosis and function assessment is also increasingly util-
ploring the prognostic impact of MVO on outcome, MVO was the
ized to assess the effect of stem cell strategies in AMI patients
strongest predictor of all-​cause mortality and hospitalization for
[36, 37]. LGE-​CMR was also applied to compare treatments of
decompensated heart failure in 810 patients revascularized after
AMI by pre-​hospital combination fibrinolysis (FL) (reteplase
STEMI and followed up for a median of 5.5 years [40]. MVO re-
and abciximab) versus pre-​hospital combination FL with facili-
mained the strongest predictor after correction for clinical, haemo-
tated PCI. Facilitated PCI resulted in a significantly reduced in-
dynamic, and angiographic parameters. MVO mass of >2.6%
farct size in this study [38].
of LV mass was associated with hazard ratios of approximately
 Acu t e c orona ry sy n dro m es :  acu te m yo ca rdia l   i n fa rc t i on 249

Low contractility in these areas causes stagnant blood to appear

as high-​signal areas near the endocardial surface, making its dis-
crimination sometimes difficult versus the high-​signal oedema
territory. To circumvent this particular problem, newer bright
blood T2-​weighted sequences can be used for this purpose. In
70 patients with STEMI and PCI treatment, this area-​at-​risk as-
sessment by CMR demonstrated a salvage of up to 90% when
interventions were performed within 90 minutes of coronary
occlusion [44]. Recently, T2-​mapping techniques have been de-
veloped to assess myocardial oedema, based on direct T2 meas-
urements, offering the advantage of a more quantitative approach
[45]. By comparing the extent of oedema and necrosis in AMI
and of fibrosis during infarct healing, Manka and co-​workers
demonstrated a correlation between the myocardial oedema ex-
tent and the degree of LV dyssynchrony in the acute phase, and
a correlation with tissue fibrosis 4 months later, suggesting that
the indication for cardiac resynchronization treatment (CRT)
should consider the extent of oedema as a factor contributing to
dyssynchrony, particularly in the acute state of an MI [46].
In the era of PCI for AMI, intramyocardial haemorrhage can de-
velop as a complication of reperfusion. This intramyocardial haem-
Figure 20.2  In this patient, with recanalization of a proximal LAD occlusion orrhage can be readily visualized on T2-​weighted images as dark
by PCI, the CMR study at day 5 demonstrates an akinetic anteroseptal wall in
regions in the high-​signal oedema territory (see E Figure 20.2) or
the short-​axis cine acquisitions (A, end-​diastolic phase; B, end-​systolic phase).
In (C), a T2-​weighted acquisition in the same short-​axis orientation is shown. as areas with decreased T2 on T2-​mapping images. Haemorrhage
The bright area (arrows) delineates myocardial oedema, which corresponds was visualized in up to 25% of PCI-​treated AMI and was shown to
to the area at risk, supplied by the LAD. In the central regions, a dark core predict adverse remodelling 4 months after AMI [47].
is identified, which corresponds to haemorrhage in this patient. In (D), the
LGE-​CMR technique demonstrates necrotic tissue in the anteroseptal wall Assessment of complications of acute
(same short-​axis orientation as in A–​C). In this patient, the area at risk (C) and
necrosis extension are similar, indicating that myocardial salvage by PCI in this myocardial infarction
patient was minimal. In the LGE-​CMR acquisition, a dark central core in the Necrosis of the interventricular septum, a rare complication
necrosis territory is visualized, which corresponds to tissue with MVO.
of AMI, and consequent VSD can be easily visualized by cine
imaging using steady-​state free precession (SSFP) sequences. To
2.0 and 5.0 for all-​cause death and decompensated heart failure, undergo CMR for this indication might be relevant for patients
respectively [40]. In STEMI patients treated by PCI in the acute with an inappropriate acoustic window. An example for an apical
stage, manual thrombectomy was associated with the occurrence VSD detected by CMR is given in E Figure 20.3. In addition,
and extent of MVO on CMR, especially in patients with a high CMR offers also a highly accurate technique—​the phase-​contrast
thrombus burden [41]. pulse sequence—​to quantify fluxes in the aorta and pulmonary
artery, so as to quantify shunting in this condition. Phase-​contrast
Oedema and haemorrhage CMR yields velocity information in each pixel covering the cross-​
Recently, an attractive CMR application evolved to assess the sectional area of a vessel. This approach therefore is not limited
myocardium at risk in the setting of reperfusion AMI. T2-​ by assumptions on the flow profile in the vessel and yields highly
weighted magnetic resonance (MR) pulse sequences are sensitive reproducible and accurate measurements of flow. This phase-​
to water content and thus are able to visualize tissue oedema (see contrast or velocity CMR technique can also be used to visualize
E Box 20.1 and Figure 20.2). Accordingly, T2-​weighted CMR was pseudo-​aneurysms that might form in the setting of an AMI.
shown in animal models of AMI to delineate tissue oedema, thus Necrosis of the papillary muscles is easily detected by LGE-​CMR,
allowing for accurate quantification of the area at risk [42]. While and in the case of rupture, quantification of MR is also possible by
viability imaging by LGE-​CMR yields excellent signal from ne- phase-​contrast CMR [48]. However, it should be mentioned that
crosis, being 5–​10 times higher than in the normal myocardium, echocardiography is certainly the method of choice in the emer-
T2-​weighted imaging yields signals in oedema being only about gency situation of an acute papillary muscle rupture. MR-​based
twice as high as in the normal myocardium [43]. Therefore, oe- T2-​mapping techniques are ideal to identify myocardial oedema,
dema imaging based on T2-​weighted CMR pulse sequences is as they provide quantitative results, in comparison to T2-​weighted
challenging, and expertise is needed for correct interpretation. MR techniques. T2-​mapping techniques are used to get insight
Oedema regions are often located in a stunned myocardium. into the pathomechanisms of ischaemia–​reperfusion [49] and are
250 CHAPTER 20   C ardiac magnetic resonanc e i n  the i n ten si ve a n d ca rdiac ca re u n i t

Figure 20.3  At day 2 post-​acute STEMI treated by successful stenting of a mid-​LAD occlusion, a 64-​year-​old female patient undergoes a CMR examination
for the assessment of myocardial viability. The examination shows severe hypoakinesia of the anterior and septal walls of the LV (cine acquisitions in A and B).
In addition, the cine images in long-​axis (A, B) and short-​axis orientation (C) show a small ventricular septal defect (VSD; red arrows). LGE and T2-​weighted
images show extensive necrosis, with substantial microvascular obstruction (purple arrows in D and F), oedema (green arrows in E), and apical rupture. CMR
also confirms necrosis and oedema extending into the apex and the RV (D and E, respectively, red arrow). LGE in short axis visualizes the VSD at the apex of
the ventricle (red arrow in G). The defect was successfully corrected by surgery the day after the CMR examination. Dotted lines in A, B, D, and E represent the
location of the short-​axis acquisitions in C, F, and G.

helpful for the detection of infarct complications such as LV rup-

ture or pseudo-​rupture. An example of a covered LV rupture is Acute coronary syndromes:
shown in E Figure 20.4. differential diagnoses in acute
Intracavitary thrombus formation, a frequent complication of
AMI, is easily detected by LGE-​CMR, which visualizes thrombi
chest pain
as dark, non-​enhancing masses adherent to necrotic, bright tissue Myocarditis and perimyocarditis
(see E Figures 20.5 and 20.6). The sensitivity of LGE-​CMR to
CP, along with ST-​segment alterations in the resting ECG and
identify thrombi is excellent and was shown to be superior to
elevated troponins, is highly suspicious for an ACS. However,
TTE [50]. Similarly, in a comparative study of 361 patients with
a fraction of these patients do not exhibit relevant coronary
surgical or pathological confirmation of intracardiac thrombus,
stenoses on X-​ray coronary angiography. Patients with these
LGE-​CMR, TTE, and TOE had excellent specificities of 99%,
characteristics should certainly undergo invasive coronary
96%, and 96%, respectively, to detect thrombi, while CMR was
angiography as the first-​line examination in order to treat imme-
also excellent with a sensitivity of 88% (versus 23% and 40% for
diately in the case of a coronary artery occlusion. Nevertheless,
TTE and TOE, respectively) [51]. In severely sick patients, free-​
in cases without significant coronary stenosis and/​or occlusions,
breathing MR pulse sequences are increasingly used, as they do
CMR can add relevant additional information. In the 2017 ESC
not require patient collaboration. In particular, 3D self-​navigation
guidelines, CMR is recommended to establish the diagnosis
strategies to correct for respiratory motion of the heart are highly
in patients with MI with non-​ obstructive coronary arteries
reliable [52] and allow for the detection of pathological anatomy
(MINOCA), i.e. to demonstrate, for example, the presence of
and infarct complications at high spatial isotropic resolution.
myocarditis, pericarditis, Takotsubo cardiomyopathy, small MI
Also thrombus detection is feasible with this technique, as shown
(after autolysis of intracoronary thrombi), and this work-​up is
in E Figure 20.6. (See also E Chapter 40.)
 Acu te c oronary sy n dro m es : di fferen tia l diag n o ses i n  acu te c h e st   pa i n 251

acute from chronic myocarditis [60]. However, combinations

of these different imaging approaches (i.e. oedema imaging and
LGE imaging) did not perform better than LGE imaging alone
(yielding overlapping 95% CIs of the various imaging sequences
for sensitivity, specificity, and accuracy) [60]. Most often, the
inferolateral wall is affected in myocarditis, but any other region
of the LV or RV may be involved (see E Figure 20.8). The de-
piction of inflammatory foci may guide endomyocardial biopsy
(EMB), e.g. in patients with an unstable course of myocarditis
[61]. In a recent study, Biesbroek et  al. [62] assessed the added
value of CMR when applying the ESC position statement cri-
teria (ESC-​PSC) to diagnose acute myocarditis in 303 patients
presenting with suspected acute myocarditis, of whom 82% had
elevated troponins, 32% ST-​elevation, and 12% OHCA, and 20%
presented with severe arrhythmias (VF, sustained VT, third-​
degree AV block, or asystole). In this population with suspected
acute myocarditis, when applying the ESC-​PSC (using clinical
criteria, ECG, troponins, invasive X-​ray coronary angiography,
Figure 20.4  In a 57-​year-​old patient with respiratory-​dependent chest pain
and elevated troponins, echocardiography shows an LVEF of 24%, global and cardiac imaging such as echocardiography and CMR), the
hypokinesia, akinesia of the lateral wall, and a posterolateral pericardial added value of CMR was highly evident. In the ESC-​PSC negative
effusion. The ECG shows low voltage in the peripheral leads at a heart rate group (before using CMR), adding CMR excluded acute myocar-
of 116 bpm, diffuse alterations of repolarization, flat T-​waves, ST-​segment ditis in all patients but also found AMI in 33% and Takotsubo
depression in V1–​V3, and ST-​segment elevation in V6 of <1 mm. Acute
cardiomyopathy in 7% of patients. In the ESC-​PSC positive group
perimyocarditis is suspected. To confirm the diagnosis, a CMR is performed
which detects a high signal area in the lateral wall in cine SSFP images (red (before using CMR), adding CMR confirmed acute myocarditis
arrow in A). In addition, the pericardial space in the region of the lateral in 33% of patients but reclassified 18% into the ESC-​PSC nega-
LV wall is enlarged. LGE images show a transmural necrosis with a central tive group (by diagnosing AMI in 16%, as well as arrhythmogenic
extensive microvascular obstruction of the lateral LV wall (yellow arrows in right ventricular cardiomyopathy and hypertrophic cardiomyop-
B). The pericardium of the lateral wall also enhances in the LGE images. The
T2 map in (C) demonstrates an area of high T2, identifying the bright area in
athy in 2%). This study thus illustrates the high diagnostic yield of
(A) as blood pool that penetrates just beneath the subepicardium of the CMR in these patients with suspected acute myocarditis.
LV lateral wall. The pericardial space (white asterisks in C) is of low T2 value, In pericarditis, tamponade can be assessed by CMR; how-
consistent with a haematoma. Thus, the CMR study shows a contained LV ever, echocardiography is clearly the method of choice for these
rupture of the lateral LV wall with a haematoma in the pericardial space and emergency situations. In acute pericarditis or perimyocarditis,
excludes the diagnosis of perimyocarditis in this patient. The patient was
successfully operated within 24 hours confirming the diagnosis. In (D), for
CMR yields detailed information on the thickened pericardium,
comparison, CMR of a patient with acute myocarditis is shown, with a T2 map and after CM administration, an enhancing pericardium is in-
demonstrating very high T2 values in the pericardium, typical for an effusion, dicative of an active form of the disease which is responsive to
and T2 values between 60 and 65 ms in the subepicardium of the lateral wall anti-​inflammatory treatment [63]. AHF may also complicate
(black arrows) confirming an acute myocarditis (normal T2 values 45–​50 ms). cardiotoxicity in the setting of anti-​cancer treatment. In situ-
ations with an unclear diagnosis, CMR may help to identify the
also recommended in the 2018 ESC guidelines on myocardial aetiology of decompensation in these patients as it can differen-
revascularization [53]. An example of a MINOCA work-​up is tiate, for example, a reduction in LVEF due to acute or chronic
given in E Figure 20.7. infarction versus chronic damage with increased interstitial fi-
Recently, several reports described fulminant myocarditis in- brosis of the myocardium (using pre-​/​post-​contrast T1-​mapping)
duced by check-​point inhibitor chemotherapy and CMR was used [64] versus myocardial oedema (using T2-​mapping techniques)
to detect this potentially lethal complication using LGE imaging [65], and due to its 3D application, it can detect metastases com-
and oedema detection by T2-​weighted imaging [54, 55]. With the promising valvular function or causing pericardial effusion [66].
increasing use of check-​point inhibitors, an increase in severe For both myocarditis and pericarditis, CMR is an ideal tool to
cases of myocarditis has been observed since 2017, with a mor- monitor disease activity over time and to assess the effect of treat-
tality rate as high as 46% [56]. ment [3]‌. (See also E Chapter 56.)
One major differential diagnosis in this setting is myocarditis.
CMR, particularly its LGE application, is ideal for detecting in- Takotsubo cardiomyopathy
flammatory foci, visualized as high-​signal tissue, typically located With improved access to invasive X-​ray coronary angiography,
in the subepicardial layers of the LV myocardium [17, 19, 20, Takotsubo cardiomyopathy is now more often observed. While
57, 58]. T2-​weighted images, and particularly the recently emer- its aetiology and pathophysiology are not yet fully elucidated,
ging T2-​mapping techniques [59], may be useful to distinguish the typical findings are major ECG changes, going along with
252 CHAPTER 20   C ardiac magnetic resonanc e i n  the i n ten si ve a n d ca rdiac ca re u n i t

Figure 20.5  In this 70-​year-​old patient with a subacute anteroseptal infarction, an apical mural thrombus is detected by CMR. The cine CMR acquisition (A) is
suspicious for the presence of an apical thrombus, whereas the LGE-​CMR technique clearly demonstrates the thin thrombus in the apex as a dark mass (B and
C, arrowheads) adjacent to the bright infarcted tissue of the apex. Six months after oral anticoagulation, the thrombus has disappeared (E, F), and an adverse
remodelling of the LV cavity has occurred due to the large infarction (D).

severe regional hypo-​or akinesia of the LV walls, most often manyfold and the resuscitation procedure may result in add-
involving the LV apex, and non-​stenosed coronary arteries. In itional cardiac injury. Known underlying causes of arrhythmic
this situation, CMR can demonstrate preserved viability in the cardiac arrest are:  (1) electrical instability during STEMI, i.e.
hypo-​akinetic regions, which predicts a full recovery of func- acute ischaemia, or myocarditis; (2)  chronic post-​infarction
tion and a good outcome (see E Figure 20.9). Thus, this infor- scar or scar in cardiomyopathy as a substrate for re-​entry VTs;
mation is useful for patient management and differentiates this and (3) genetically determined ion channel diseases, drug tox-
disease from others, such as myocarditis or AMI, with a mixed icity, or electrolyte imbalances (primarily electrical diseases).
prognosis [17, 67]. Also, the indication for ICD implantation is based on the pres-
ence of irreversible myocardial damage, e.g. scar tissue, whereas
Evaluation of patients after out-​of-​hospital patients who suffered VT/​VF due to a reversible cause should
cardiac arrest not receive an ICD [68,  69]. Accordingly, ECG, echocardio-
This patient population is particularly challenging regarding graphy, and coronary angiography may not be straightforward
diagnosis and treatment, as the aetiologies for OHCA are in detecting the underlying cause of OHCA. With increasing

Figure 20.6  In a patient, 1 day after acute STEMI, a self-​navigation technique is used to allow for free-​breathing high-​resolution 3D CMR, demonstrating
the cardiac anatomy in any desirable plane. The addition of an inversion pulse yields necrosis imaging at 1.15-​mm isotropic resolution. Red arrows in (A) and
(B) show microvascular obstruction in the septum and LV apex. Image reconstruction along the dotted yellow line in (A) and (B) yields plane (C) which
visualizes an 8-​mm thrombus in the LV apex [red arrow in (C)]. No necrosis is detected in the LV lateral wall (‘black’ tissue).
 Aort ic dissecti on A /B, aorti c u l cer, a n d i n tr a m u r a l  ha e m ato m a 253

(a) (b) (e) (f) (g)

(c) (d) (m) (n)

(h) (i) (k) (k)

Figure 20.7  An 88-​year-​old patient was admitted to hospital with chest pain. The ECG demonstrated subtle ST-​segment elevation in aVL and V5 and V6, and
troponins were slightly elevated. Coronary angiography revealed a stenosis of the RCA, which was identified as the culprit lesion (A) and successfully stented
(C). No stenoses were found in the LAD and left circumflex (B, D). Troponins, however, continued to rise during the next 4 days. CMR was performed to
exclude an inflammatory process or other reasons for the troponin rise. On the CMR study, an old inferior MI scar was found with akinesia (E, F), thinned wall
(E, F), transmural LGE (G, N; arrows), and no oedema on T2-​mapping (M, arrows). However, the mid-​ventricular and apical anterior LV wall was hypo-​akinetic
(H, I; arrows), with extensive oedema on T2-​mapping (K, arrows), transmural LGE, with microvascular obstruction (K, arrows). CMR examination identified the
LAD as the culprit coronary artery and excluded acute ischaemic tissue damage in the RCA territory (M, N; arrows). The most likely explanation is autolysis of
an intracoronary thrombus. This case represents a patient with a MINOCA for which the 2017 guidelines recommend the use of CMR for a comprehensive
work-​up  [53].

availability of CMR in these acute situations, knowledge in this

patient group has increased [70, 71]. In the most recent study Aortic dissection A/​B, aortic ulcer,
by Zorzi et al. [72], convincing data in a relatively large cohort and intramural haematoma
of OHCA patients were reported. In 139 consecutive patients,
CMR was performed within 1 week of OHCA in order to as- Aortic dissection, IMH, and penetrating ulcer are acute aortic
sess LV and RV function, as well as tissue characteristics, i.e. disorders that can present similarly, with severe CP radiating to
myocardial oedema, necrosis, and scar. Approximately half of the back. Moreover, there is also an overlap in pathophysiology
patients were not investigated by CMR due to severe neuro- among these entities, which is also reflected by corresponding
logical deficits and/​or mechanical ventilation. In the remaining imaging findings [73]. (See also E Chapter 59.)
patients, CMR confirmed the diagnosis of obstructive CAD in
all patients (41%) by the typical LGE pattern and the presence of Aortic dissection
myocardial oedema. In patients without obstructive CAD, CMR Dissection is the most common among these disorders, with an
modified the diagnosis in 42% and identified an arrhythmic incidence of up to 0.8%, and also carries the highest mortality
substrate in 73% (diagnoses were dilated, hypertrophic, and [74]. Aortic dissection is a typical complication in Marfan’s dis-
Takotsubo cardiomyopathy; myocarditis; non-​ ischaemic iso- ease, and thus regular controls to monitor vessel diameters are
lated myocardial scar; and ischaemic scar without obstructed recommended to be performed, ideally by MRI, as it does not
CAD). Importantly, patients with myocardial oedema, i.e. 23% use ionizing radiation and thus allows for repetitive studies (see
of the patients after OHCA, showed no arrhythmic events over E Figure 20.10). In the case of a dissection, an intimal tear of
3  years (versus 23% in the non-​oedema group). Finally, in an abnormal vessel wall enables blood to enter the wall, with
OHCA patients, CMR demonstrated no tissue abnormalities subsequent propagation in the media, both proximally and dis-
suggestive of post-​resuscitation myocardial contusion. tally, displacing the intima inward. The Stanford classification
254 CHAPTER 20   C ardiac magnetic resonanc e i n  the i n ten si ve a n d ca rdiac ca re u n i t

Figure 20.8  In this 43-​year-​old woman with dyspnoea progressing to New York Heart Association (NYHA) class IV, a CMR study demonstrates a massive
enhancement by the LGE-​CMR technique, predominantly involving the RV in the horizontal long axis (A) and short axis (B). Only a small region of the basal RV
free wall is not affected. Also large portions of the interventricular septum and anterior wall of the LV are involved (B, vertical long axis). EFs of the RV and LV
were 18% and 19%, respectively. The next day, the patient developed an AV block. Histology confirmed giant cell myocarditis. The patient could be stabilized
with immunosuppressive therapy and remained in NYHA III since 3 years.

distinguishes type A  (which involves the ascending aorta or systemic hypertension, cystic media necrosis, bicuspid aortic
aortic arch, with or without the involvement of the descending valve, coarctation, pregnancy, trauma, and arteritis. A  clinically
aorta) from type B (with the involvement of the descending suspected aortic dissection requires urgent imaging with CT or
aorta only). Type A dissection is a surgical emergency, whereas MRI to confirm or exclude the diagnosis [74]. Both CT and MRI
type B is generally treated conservatively. Major risk factors are enable imaging of the entire aorta and its major branches, with

Figure 20.9  Serial LGE-​CMR studies in Takotsubo cardiomyopathy. Images acquired at baseline (A–​C) demonstrate vigorous basal systolic function with
apical hypokinesia (A, B) in the absence of LGE (C). A repeat study 3 months later shows complete normalization of the ventricular function (D, E), with no LGE
detectable (F).
Reproduced from Schwitter J, Arai AE. Assessment of cardiac ischaemia and viability: role of cardiovascular magnetic resonance. Eur Heart J. 2011;32(7):799-​809. doi:10.1093/​eurheartj/​
ehq481 with permission from Oxford University Press.
 Aort ic dissecti on A /B, aorti c u l cer, a n d i n tr a m u r a l  ha e m ato m a 255

(a)

(a) (b)

(b) (c)

(c) (d)

Ao
(e)

(f)

Figure 20.10  Marfan’s syndrome with typical features on MRI such as (g) (h)
pectus excavatus (arrow) on axial SSFP images (A), pear-​shaped aneurysm
of the sinus portion of the ascending aorta (arrowheads) on parasagittal Figure 20.11  A 54-​year-​old patient with non-​acute chest pain and
maximum intensity projection of contrast-​enhanced 3D fast, low-​angle-​shot detection of a type A aortic dissection. In a dark blood (HASTE, A)
images (B), and scalloping (double arrow) and enlargement of the dural sac acquisition, the dissection flap is visualized in the ascending and
(*) on sagittal T2-​weighted turbo-​spin-​echo images of the lumbar spine (C). descending aorta. For more detailed information, cine MRI loops are
acquired covering the ascending and descending aorta (B–​G). Note the
small true lumen in the ascending aorta bulging into the false lumen
excellent reproducibility [75]. MRI does not require ionizing ra-
during systole (C) and collapsing in diastole (D). (E–​G) Examples of
diation and can be acquired without contrast material in cases additional axial cine loops (out of a series of axial contiguous acquisitions
of renal failure. ECG-​gated SSFP images show blood with high covering the thoracic and abdominal aorta) to assess the extent of the
signal intensity and allow clear delineation of the intimal flap with dissection. In B, the dissection membrane location in the non-​coronary
low signal intensity (see E Figure 20.11). Moreover, the cardiac sinus is seen (red arrowhead) and the right coronary artery (red arrow)
is not involved in the dissection. For an overview, 3D MR angiography
function and aortic valve are readily assessed with MRI. Typical
was also acquired (H). The brachiocephalic trunk is perfused via the false
complications, such as pericardial tamponade and occlusion of lumen, while the left common carotid artery and the left subclavian artery
major side branches, are readily identified. Contrast-​enhanced are perfused via the true lumen. Mild aortic regurgitation was present, but
MR angiography may be helpful to visualize the whole aorta and no pericardial effusion.
256 CHAPTER 20   C ardiac magnetic resonanc e i n  the i n ten si ve a n d ca rdiac ca re u n i t

to semi-​quantitatively assess organ perfusion. The convexity of because of intraluminal pressure and wall stress, with a risk of
the intimal flap is usually towards the false lumen that surrounds aneurysm formation and rupture.
the true lumen. The false lumen usually has a larger diameter and
a slower flow. Thus, spin-​echo images show higher signal inten- Intramural haematoma
sity from blood in the false, as compared to the true, lumen (see IMH is defined as bleeding in the medial layer of the aorta,
E Figure 20.12). The false lumen tends to enlarge over time with no blood flow within the media. The most frequent source
of IMH is in the media itself, representing spontaneous haem-
orrhage from the vasa vasorum. Other potential causes include
trauma or a penetrating aortic ulcer bleeding into the aortic wall
[74]. IMH is considered as an early stage or variant of dissection,
and systemic hypertension is the leading risk factor. IMH is clas-
sified as Stanford A and B, similar to aortic dissection. On non-​
enhanced CT, IMH can be appreciated as a thickened aortic wall,
with high attenuation extending longitudinally. In contrast to dis-
section, the lumen is rarely compromised. MRI shows the same
but can provide additional information, because it may allow de-
termination of the age of a haematoma, based on the signal char-
acteristics of haemoglobin degradation products. On T1-​weighted
images, a haematoma appears with intermediate signal intensity
in the acute stage because of the presence of oxyhaemoglobin,
and with high signal intensity in the subacute stage caused by the
presence of methaemoglobin.

Penetrating aortic ulcer
Penetrating aortic ulcers occur when atherosclerotic plaques dis-
rupt the intima, with subsequent haemorrhage into the media
(see E Figure 20.13). Thus, a penetrating ulcer may progress
to an IMH, a dissection, or a rupture of the aorta through the
adventitia. A potential complication is embolization of thrombi
from within the ulcer. Penetrating aortic ulcers most frequently
occur in elderly hypertensive patients and most frequently in the
mid-​descending thoracic aorta [74]. CT and MRI show a local-
ized ulcer penetrating through the aortic intima into the aortic
wall and adjacent IMH. An important disadvantage of MRI, com-
pared to CT, is its inability to reveal intimal calcification and its
dislodgement which is a frequent finding in aortic ulcers.

Figure 20.12  Aneurysm and dissection of the descending aorta

(arrowheads) at the level of the diaphragm on T1-​weighted turbo-​spin-​
echo images (A) and fast, low-​angle-​shot gradient-​recalled echo images (B).
Thrombus (T) has an intermediate signal in (A) and (B); a perfused lumen
with high flow (L1) is identified as signal void in (A) and high signal in (B). Figure 20.13  Penetrating ulcer with IMH of the ascending aorta (Ao) on
Slowly perfused lumen (L2) provides low signal in (A), but high signal in (B). contrast-​enhanced 3D MR angiography (A) and axial T1-​weighted turbo-​spin-​
These images illustrate the potential pitfall of low-​signal areas on T1-​weighted echo with fat suppression prepulse (B). Angiography shows outpouching of
turbo-​spin-​echo images, which might be misinterpreted as thrombus. the lumen (A, arrows), whereas tomography also shows IMH (B, *).
Performance and cost-effectiveness of cardiac magnetic resonance in the emergency room 257

Both MRI and CT are robust tools for the evaluation of aortic 100
dissection, IMH, and penetrating ulcer. Advantages of CT are its
80
availability, particularly in emergencies, its short imaging time,

Sensitivity (%)
and its sensitivity for calcification. Advantages of MRI are the ab- 60
sence of ionizing radiation and the possibility to image without
contrast material when renal function is impaired. 40

20

Pulmonary embolism and 0

0 20 40 60 80 100
pulmonary diseases 1-Specificity (%)
CMR CCT SPECT
PE is problematic to diagnose in critically ill patients who are
commonly immobile and may have a decreased ability to com- Figure 20.14  Similar diagnostic performances of various non-​invasive
municate. Moreover, diagnostic testing in such patients may be imaging modalities to detect ACS in patients with acute CP are shown.
Triangles, squares, and circles represent CMR [23, 81–​83], cardiac CT (CCT)
hampered by mechanical ventilation or impaired renal func-
[84–​89], and SPECT [90–​97], respectively.
tion, precluding IV contrast-​enhanced imaging such as CT [76]. Reproduced from Schwitter J, Arai AE. Assessment of cardiac ischaemia and viability:
Today, MRI is not established in the routine work-​up of critically role of cardiovascular magnetic resonance. Eur Heart J 2011;32:799–809. doi: 10.1093/
ill patients with suspected PE but holds vast potential [77]. Kluge eurheartj/ehq481 with permission from Oxford University Press.

et al. compared a three-​component MR protocol with: (1) SSFP;

CP patients is given in E Figure 20.14, demonstrating similar
(2)  contrast-​enhanced perfusion imaging; and (3)  MR angio-
performances for CMR [23, 81–​83], cardiac CT [84–​89], and
graphy with parallel imaging, with multidetector CT as standard
SPECT [90–​96]. In a single centre trial, NSTEMI patients were
of reference. Sensitivities/​specificities for the three components
randomized to three arms: routine clinical care, CMR first, or
were 85%/​98%, 77%/​100%, and 100%/​91%, respectively. Most
CT angiography first. CMR reduced invasive CXA during hos-
interestingly, the sensitivity of MR angiography for subsegmental
pitalization down to 87% (P <0001 vs routine) and outcomes
clot was only 55%, compared to 93% with perfusion MR [78].
showed a trend towards fewer events by the CMR. Overall, CMR
Perfusion MR is sensitive but not specific, while angiography
was performed in 67% of all patients and yielded a new diag-
is specific but not as sensitive. Thus, the combination of angio-
nosis in 33% [97]. After adequate management of AMI, the new
graphy with perfusion imaging appears to be attractive for the
ESC guidelines on STEMI recommend, as a class I indication,
detection of central and peripheral emboli. This comprehensive
to systematically search for residual ischaemia and viability as-
assessment of pulmonary angiography and perfusion may be
sessment by imaging methods, such as CMR, in patients with
combined with venography of the lower limbs [79]. These data
multivessel disease or those in whom vessels other than the
show that MRI may play an important role in the imaging of sus-
infarct-​related artery are considered for revascularization [98]
pected PE in the future. (See also E Chapter 63.)
(see also E Chapter 38). This work-​up for residual ischaemia
in post-​AMI patients before discharge can involve radiation ex-
posure. Therefore, Eisenberg and colleagues studied in approxi-
Performance and cost-​effectiveness mately 82  000 patients after AMI the relationship of radiation
of cardiac magnetic resonance in the exposure (associated with invasive coronary angiography/​PCI
and non-​invasive SPECT and CT imaging) with the incidence of
emergency room cancer. In comparison to the subgroup of AMI patients without
In acute CP patients with suspected ACS, the ESC guidelines on any X-​ray exposure, a significant increase in cancer incidence
ACS [8]‌recommend the use echocardiography as the first-​line was observed over the first year after AMI of approximately one
method, followed by CMR if further information is needed, in additional cancer per 1000 examinations with an exposure of 10
particular, to detect necrosis, ischaemia, or inflammation, which mSv [99]. This incidence is in line with large epidemiological
is in line with the new ESC guidelines on acute and chronic heart studies [100] and the position of the National Research Council
failure [6] (see also E Chapter 10). Similarly, the AHA guide- of the US [101].
lines stress the value of tissue characterization in terms of high-​ In the patient population referred with acute CP for work-​up in
resolution necrosis and ischaemia detection by CMR in this an emergency room, the costs for their management are of interest
patient population [80]. As a class I indication before discharge, (see also E Chapter  10). Therefore, Miller and co-​workers ex-
these guidelines [80] recommend a non-​invasive imaging mo- plored the utility and costs of CMR to detect or exclude ischaemia
dality for patients with resting ST-​segment depression (≥0.10 in this population [102]. In their study, patients were either ran-
mV), LV hypertrophy, bundle branch block, intraventricular domized to hospital admission with routine work-​up or to be
conduction defect, pre-​excitation, or digoxin, even when the evaluated in an observation unit by CMR. As a result, 79% of pa-
patient is able to exercise. An overview of the diagnostic per- tients could be dismissed safely and a cost reduction of approxi-
formance of non-​invasive imaging tests to detect ACS in acute mately 35% was achieved [102]. These preliminary data indicate
258 CHAPTER 20   C ardiac magnetic resonanc e i n  the i n ten si ve a n d ca rdiac ca re u n i t

the potential for significant cost reductions when CMR-​based al-

gorithms are implemented. Personal perspective
Currently, considerable efforts are focusing on increasing
the user-​friendliness of MR machines. The next gener-
Limitations and contraindications ation of CMR machines will be able to run many appli-
of cardiac magnetic resonance cations automatically. This will make the utilization of
Probably the most important limitation of CMR today is the still CMR much easier, faster, and even more reproducible.
restricted availability of the technique and patient mobility/​trans- Recommendations on CMR training at the European
portability in the acute setting. As cardiologists and radiologists level are now available [107], and CMR quality criteria
are expected to obtain more experience with the technique, its are defined and applied within the EuroCMR registry
utilization, and thus availability, will most likely improve in the [108], which currently runs a prospective substudy on
near future. the evaluation of ACS by CMR. The device industry is
Absolute contraindications to undergo CMR are electronic de- very active in developing new pacemakers and ICDs, with
vices, such as cochlear implants, some insulin pumps, and others the long-​term goal to offer MR compatibility for the en-
[3,  103], while the latest generation of pacemakers [104] and tire spectrum of devices. The latest generation of an MR-​
ICDs [105] are often designed to undergo CMR examinations conditional pacemaker passed all safety endpoints in a
safely. Under certain circumstances, recent publications suggest large multicentre trial [104] and yielded diagnostic quality
to use CMR, even in patients with non-​MRI-​conditional pace- of cardiac studies in >95% of all cases [109]. Similarly, the
makers, when a potentially life-​threatening condition, such as first MR-​conditional ICD was proven safe for whole-​body
malignant ventricular arrhythmia, is present [106]. Furthermore, MRI [105] and yielded diagnostic quality of cardiac images
some older cerebral clips post-​neurosurgery, as well as ferromag- in a multicentre setting in 74% of LV and 84% of RV fast-​
netic bodies in the eye, are contraindicated for CMR. Other for- gradient-​echo acquisitions [110].
eign ferromagnetic bodies to consider include shrapnel. Most In experimental models, a fascinating new field of CMR is
other surgical metallic implants are CMR-​compatible. In par- currently being explored. This is based on the imaging of nu-
ticular, valvular heart prostheses are MR-​compatible (the old ball-​ clei other than protons. Fluorine is amenable to MR imaging
type Edwards prosthesis is a rare exception). Also, coronary and due to its favourable magnetic properties similar to those of
other vascular stents can be scanned by CMR without risk. For protons. However, fluorine offers the advantage of being vir-
each implant, detailed information on MR compatibility can be tually absent in the human body. Thus, any fluorine-​labelled
obtained from specific literature, from the Internet (e.g. M http://​ CM will yield theoretically an excellent contrast-​to-​noise
www.mrisafety.com/​), or typically from the website of the device ratio, as no background signal from body tissues is altering
manufacturer. the signal behaviour of these CMs. Fluorine-​labelled CMs
are available, which are selectively taken up by macrophages.
Other limitations of cardiac magnetic After IV injection of these CMs, active macrophages can
resonance be detected with high sensitivity and specificity, even be-
fore any macroscopic lesions occur. This approach allowed
From an imaging point of view, small and irregularly moving
visualization of macrophage activity during infarct healing,
structures, such as valvular vegetations, are difficult to detect by
during orthotopic heart transplantation rejection, and in
CMR, and echocardiography is certainly the method of choice in
autoimmune myocarditis [111–​113]. In a recent study by
patients with suspected endocarditis. Frequent extrasystoles (>20/​
Boenner and co-​workers, this macrophage imaging tech-
minute or AF) limit the accuracy of volume and function meas-
nique was applied in a porcine infarct model and successfully
urements by CMR, whereas viability and inflammation imaging
transferred to a clinical 3T MR system [114]. Fluorine-​
is not compromised by arrhythmias if the acquisition window is
labelled CMs can also target specific epitopes. This applica-
set to occur in mid to late systole.
tion was shown to detect sub-​millimetric thrombi with very
For cardiac applications of MR, conventional CMs (i.e. gado-
high sensitivity and specificity in a murine model [115], and
linium chelates) are used. These CMs are very safe, with minimal
thus epitope-​specific 19F-​MRI could be used in a wide spec-
risk of allergic reactions. About a decade ago, another complica-
trum of acute cardiac diseases.
tion of CM administration was observed. Insufficient elimination
Another nucleus of interest is 13C-​carbon. Compounds
of CMs in patients with severe renal failure can induce systemic
containing 13C can undergo a process of hyperpolarization.
nephrogenic fibrosis (SNF) [3]‌. This complication has so far been
This technique yields CMs that produce signals up to
linked to linear CMs only, whereas the next generation of macro-
10 000 times higher than in conventional proton imaging.
cyclic gadolinium chelates appears to be free from this compli-
This enormous signal is typically available for 2–​3 min-
cation; as few as <10 cases of ‘non-​confounded’ SNF have been
utes and allows for, for example, a real-​time assessment of
reported worldwide for each of the macrocyclic CMs. The inci-
Krebs cycle metabolism in normal and ischaemic hearts
dence of SNF with linear CMs is low-​ranging, from 1 out of 1–​
[116]. With this 13C hyperpolarization CMR technique,
1.5 million injections.
 RE F E RE N C E S 259

13
severe metabolic alterations in the myocardium were iden- C-​CMR technique allows for rapid repetitions of meas-
tified in an animal model several hours after an ischaemic urements and a first application in humans to measure lac-
episode [117]. Potentially, this technique could directly tate and bicarbonate production after IV pyruvate injection
demonstrate the cause for CP, based on the detection of was recently reported [119].
metabolic changes, rather than on functional (stunning, Recently, a highly accelerated CMR acquisition strategy
ischaemia) or anatomical alterations (coronary artery sten- emerged—​ the so-​called ‘compressed sensing’ technique.
osis/​occlusion). Hyperpolarization of 13C-​fumarate allowed This technique acquires cine images 5–​10 times faster than
imaging of necrosis in vivo by CMR and depletion of myo- currently available routine cine CMR techniques. This com-
cardial ATP concentration (measured by 31P-​spectroscopy) pressed sensing approach was successfully validated in pa-
of >50% triggering cell membrane damage and fumarase tients [120] and may be of particular value for examinations
leakage [118]. Interestingly, this hyperpolarization of very sick patients with limited breath-​hold capabilities.

Further reading
Assomull R, Lyne J, Keenan N, et al. The role of cardiovascular magnetic in patients with acute chest pain: a randomized study for comparison
resonance in patients presenting with chest pain, raised troponin, and with inpatient care. JACC Cardiovascular Imaging 2011;4:862–​70.
unobstructed coronary arteries. Eur Heart J 2007;28:1241–​9. Schwitter J. MRI and MRA of the thoracic aorta. Appl Radiol 2006;Suppl
Eisenberg MJ, Afilalo J, Lawler PR, Abrahamowicz M, Richard H, Pilote May:6–​13.
L. Cancer risk related to low-​dose ionizing radiation from cardiac Schwitter J. Myocardial perfusion imaging by cardiac magnetic resonance.
imaging in patients after acute myocardial infarction. Can Med Ass J J Nucl Cardiol 2006;13:841–​54.
2011;183:430–​6. Schwitter J. CMR Update, third edition. 2020. Available from: M M http://​
Giang T, Nanz D, Coulden R, et al. Detection of coronary artery disease www.herz-​mri.ch.
by magnetic resonance myocardial perfusion imaging with various Schwitter J, Nanz D, Kneifel S, et al. Assessment of myocardial perfusion
contrast medium doses: First European Multicenter Experience. Eur in coronary artery disease by magnetic resonance: a comparison with
Heart J 2004;25:1657–​65. positron emission tomography and coronary angiography. Circulation
Greenwood JP, Maredia N, Younger JF, et  al. Cardiovascular magnetic 2001;103:2230–​5.
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designed for the MRI environment. Circ Cardiovasc Imaging necrosis. JACC Cardiovasc Imaging 2018;11:1594–​606.
2016;9:e004025. 119. Cunningham CH, Lau JYC, Chen AP, et  al. Hyperpolarized 13C
111. Flogel U, Ding Z, Hardung H, et al. In vivo monitoring of inflam- metabolic MRI of the human heart:  initial experience. Circ Res
mation after cardiac and cerebral ischemia by fluorine magnetic 2016;119:1177–​82.
resonance imaging. Circulation 2008;118:140–​8. 120. Vincenti G, Monney P, Chaptinel J, et  al. Compressed sensing
112. Schwitter J. Extending the frontiers of cardiac magnetic resonance. single-​breath-​hold CMR for fast quantification of LV function, vol-
Circulation 2008;118:109–​12. umes, and mass. JACC Cardiovasc Imaging 2014;7:882–​92.
 SECTION IV

Procedures in the
intensive cardiovascular
care unit

21 Non-​invasive ventilation  267

Josep Masip, Kenneth Planas, and Arantxa Mas
22 Mechanical ventilation  284
Luigi Camporota and Francesco Vasques
23 Temporary pacing  306
Bulent Gorenek
24 Ultrasound-​guided vascular access in intensive/​acute cardiac care  314
Richard Paul
25 Pericardiocentesis 323
Caterina C De Carlini and Stefano Maggiolini
26 Chest tubes  331
Giulio Maurizi, Camilla Vanni, and Erino Angelo Rendina
27 Renal support therapy  338
Claudio Ronco, Stefano Romagnoli, and Zaccaria Ricci
28 Percutaneous (short-​term) mechanical circulatory support  351
Holger Thiele and Pascal Vranckx
29 Nutrition support in acute cardiac care  360
Michael P Casaer and Greet Van den Berghe
30 Physiotherapy in critically ill patients  373
Rik Gosselink and Jean Roeseler
 CHAPTER 21

Non-​invasive ventilation
Josep Masip, Kenneth Planas,
and Arantxa Mas

Contents Summary
Summary  267 Over the last 25  years, the use of non-​invasive ventilation has grown substan-
Introduction  267 tially. Non-​invasive ventilation refers to the delivery of positive pressure to the
Principles of non-​invasive ventilation  268 lungs without endotracheal intubation and plays a significant role in the treat-
Modes of non-​invasive ventilation  268 ment of patients with acute respiratory failure and in the domiciliary manage-
Continuous positive airway pressure  268
Non-​invasive pressure support ventilation ment of some chronic respiratory and sleep disorders. In the intensive and acute
(bi-​level non-​invasive ventilation)  268 care setting, the primary aim of non-​invasive ventilation is to avoid intubation,
High-​flow nasal cannula (Optiflow®, and it is mainly used in patients with chronic obstructive pulmonary disease ex-
Salter®, Comfort Flo®, Vapotherm®,
Aquinox™)  268
acerbations, acute cardiogenic pulmonary oedema, immunocompromise, or in
Other modalities  269 the context of weaning, situations in which a reduction in mortality has been
Interfaces  270 demonstrated. The principal techniques are continuous positive airway pressure,
Nasal interface  270 bi-​level pressure support ventilation, and more recently high-​flow nasal cannula.
Face masks  271
Helmet  271
Whereas non-​invasive pressure support ventilation requires a ventilator, the other
Other  271 two techniques are simpler and can be easily used in non-​equipped areas by less
Ventilators  271 experienced teams, including the pre-​hospital setting. The success of non-​invasive
Complements: humidifiers and aerosols  271 ventilation is related to adequate timing, proper selection of patients and inter-
Indications for non-​invasive ventilation in
faces, and close monitoring, as well as the achievement of a good adaptation to
acute care patients  271
Chronic obstructive pulmonary disease patients’ demand.
exacerbation  272
Asthma exacerbation  272
Acute cardiogenic pulmonary oedema  272
Weaning and post-​extubation  273
Other indications  273
Adequate patient selection for non-​invasive
treatment  273
Introduction
How to apply non-​invasive ventilation  274 NIV started in the 1930s when continuous negative extrathoracic pressure was ap-
Preparing the scenario  274 plied (iron lung, chest shell, rocking bed, pneumobelt) in the treatment of epidemic
Applying the technique  274
poliomyelitis [1]‌. In the late 1950s, mechanical ventilation through endotracheal in-
Continuous positive airway pressure  274
High-​flow nasal cannula  275 tubation led to a dramatic decrease in the use of NIV. However, after the introduction
Non-​invasive pressure support ventilation  275 of pressure support ventilation in the late 1980s, NIV began to be used again in pa-
Ventilator settings in NIPSV  275 tients with ARF as an alternative to endotracheal intubation in critical care settings
Monitoring non-​invasive ventilation  275
[2, 3], as well as in chronic domiciliary ventilation and sleep disorders. Currently, the
Assessing asynchrony  275
Use of sedation  276 rate of NIV in European ICUs is 12–​25% [4, 5], and >50% of all patients with respira-
When to stop non-​invasive ventilation  277 tory failure without intubation at ICU admission will end up with NIV. This rate in-
Where to apply non-​invasive ventilation  277 creases to over 90% in patients with COPD or acute cardiogenic pulmonary oedema
Staffing, costs, and resources  277 (ACPO). NIV is now a first-​line therapy in the ED [6], regular hospital wards [7],
Conclusion  277 and palliative [8] or paediatric [9] care units, and even for patients out of hospital
Personal perspective  277 [10, 11].
Further reading  278
References  278
268 CHAPTER 21  N on - i nvasive  vent il ation

Continuous positive airway pressure

Principles of non-​invasive ventilation Although it was introduced earlier, it is not essentially a ‘true’ ven-
NIV refers to the delivery of ventilatory support or positive pressure tilation mode, because it does not provide any inspiratory support
into the lungs without an ETT [12,  13]. There are several advan- [18]. CPAP can be generated with a simple O2 source through a
tages over ‘invasive’ mechanical ventilation. NIV techniques leave hermetical mask with a PEEP valve or a Boussignac mask, which
the upper airway intact and may avoid the complications and draw- holds a quantity of air in the lungs on expiration (see E Figure
backs that might occur during the procedure of endotracheal intub- 21.1). The continuous positive intrathoracic pressure recruits col-
ation (i.e. upper airway trauma, laryngeal swelling, cardiovascular lapsed alveolar units and increases the functional residual cap-
complications in difficult cases), during mechanical ventilation (i.e. acity (FRC) and lung compliance, improving oxygenation and the
oversedation, infections, weaning failure, tracheal granuloma), and work of breathing. However, control of the FiO2 can be difficult,
at the time of extubation (i.e. reintubation, vocal cord dysfunction). unless a mixer or a ventilator is used. CPAP is currently applied to
The most relevant difference with intubated patients is the reduced hypoxaemic patients, particularly those with atelectasis or ACPO.
incidence of infections, especially ventilator-​acquired pneumonia
[14,  15], due to preservation of the natural upper airway defence
Non-​invasive pressure support ventilation
(bi-​level non-​invasive ventilation)
mechanisms. By avoiding intubation and its inherent consequences,
the length of stay, costs, and mortality in the ICU may be reduced Unlike CPAP, this modality requires a ventilator and constitutes the
[16]. Furthermore, patients do not need sedation, allowing for oral essence of NIV. It is usually programmed with two levels of pres-
nourishment and communication. sure: expiratory positive airway pressure (EPAP) (similar to CPAP
Besides all these benefits, there are some disadvantages. NIV or PEEP) and inspiratory positive airway pressure (IPAP) (see
does not allow the same ventilation performance as invasive ven- E Figure 21.1). When the patient starts the inspiratory effort,
tilation and often requires increasing nursing attention, especially the ventilator delivers inspiratory assistance (pressure support)
in cases of respiratory impairment due to device uncoupling. In using a decelerated flow, which keeps the prefixed IPAP constant.
addition, NIV may have some complications [17] (see E Box When the inspiratory flow descends below a preset percentage
21.1), which are usually mild and related to the mask. Major com- of its maximum value (usually 25–​30%) or the patient ends the
plications are very uncommon. inspiratory drive, the ventilator assistance is discontinued and
the pressure drops down to the predetermined EPAP (see E
Modes of non-​invasive ventilation Figure 21.2).
There are three major modes of NIV: continuous positive airway High-​flow nasal cannula (Optiflow®, Salter®,
pressure (CPAP), non-​ invasive pressure support ventilation Comfort Flo®, Vapotherm®, Aquinox™)
(NIPSV), and high-​flow nasal cannula (HFNC). The system delivers a humidified O2–​gas mixture that may meet
or exceed a patient’s spontaneous inspiratory demand, which may
be up to 35 L in adult patients with ARF (see E Figure 21.3). It is
Box 21.1 NIV complications generally used in subacute or moderate ARF. The main difference
between HFNC and NIV is that HFNC maintains a fixed flow and
Related to interface generates variable pressures, while NIV provides a variable flow
Discomfort
◆
to generate a fixed pressure. Three action mechanisms of HFNC
Facial erythema
◆ have been postulated:  (1) a washout effect in the nasopharyn-
Claustrophobia
◆ geal dead space, simulating the benefits of tracheal gas insuffla-
Skin ulcers
◆ tion; (2) a reduction of upper airway resistance, which constitutes
Nasal (oronasal mask, pillows)
● nearly 50% of the total airway resistance; and (3) a low level of
Forehead (total face mask)
● positive intrathoracic pressure (low CPAP). However, the latter
Axillae (helmet)
●
depends on the absence of significant leak around the nares and
mouth and seems less likely to be the predominant factor [19].
Related to airflow HFNC has been generally used in patients with subacute or not
Nasal congestion
◆
very severe respiratory failure from different aetiologies. In AHF,
Sinusitis
◆ it has been used in cases that required prolonged NIV [20]. In
Oral and nasal dryness
◆ a randomized trial comparing this technique to conventional O2
Ocular irritation
◆ therapy or bi-​level pressure support ventilation in patients with
Gastric insufflation
◆ hypoxaemic ARF, HFNC showed a similar intubation rate, but
Major complications lower 90-day mortality rate [21]. Two meta-​analyses comparing
HFNC to NIPSV and conventional O2 therapy in adult ARF
Aspiration pneumonia
◆
[22, 23] concluded that HFNC was superior to conventional O2
Hypotension
◆
therapy to reduce the rate of intubation, with no differences with
Pneumothorax
◆
NIPSV. In some studies, HFNC was better tolerated than NIPSV
 Pri n ci pl es of n on - i n vasi ve ve n t i l at i on 269

Spontaneous CPAP BiPAP

Pressure (cmH2O)
20
IPAP 22 cmH2O
PS 12 cmH2O
10 EPAP 10 cmH2O

PEEP 10 cmH2O

0
Time

Figure 21.1  Pressure–​time curves. Spontaneous breathing, CPAP (10 cmH2O), and bi-​level pressure support (IPAP 22 cmH2O, EPAP 10 cmH2O) with pressure
support (PS) 12 cmH2O.

[24], which anticipates an extension of its use in hypoxaemic acute delivered. The EAdi is the expression of the patient’s inspiratory
settings and patients needing prolonged respiratory support. demand generated in the brainstem and occurs earlier than any
flow or pressure variation used to trigger the ventilator during
Other modalities NIPSV [29]. Ventilator support begins when the neural drive
to the diaphragm begins to increase, and pressure is cycled off
◆ Proportional assist ventilation (PAV): the inspiratory support is when the respiratory centre ends the EAdi [30]. A catheter with
regulated by analysing the elasticity and resistance of the lung, an array of eight electrode pairs (or nine single electrodes) on its
delivering assisted ventilation proportional to the patient’s distal end is placed in the oesophagus, so that the centre of the
effort. Although this modality has demonstrated a better electrode pairs is ideally positioned at the diaphragm level [29].
patient–​ventilator synchrony [25], this advantage has not been NAVA improves patient–​ventilation synchrony and has been
translated into clinical outcomes [26–​28]. shown to be superior to NIPSV by decreasing ineffective efforts
◆ Neurally adjusted ventilatory assist (NAVA): the device uses a and premature and delayed cycling [30]. However, the impact
neural signal (the electrical activity of the diaphragm, or EAdi, on relevant outcomes remains unclear. NAVA also has important
independent of airway pressure and flow signals) to trigger and limitations: (1) the system needs the insertion of an oesophageal
cycle off the ventilator, as well as to adapt the amount of pressure catheter; (2) changes in patient position can deteriorate the EAdi
signal; (3) the neural drive may be affected in some diseases or
with sedation; and (4) high NAVA gains may cause an irregular
Inspiration Expiration respiratory pattern.
Fmax

20%
Flow (F)
Fmax

30% 25%
Fmax Fmax

Pressure

Volume

Time

Figure 21.2  Flow–​time, pressure–​time, and volume–​time curves in pressure Figure 21.3  High-​flow nasal cannula administered through a ventilator to
support ventilation modalities, with the inspiration cycle set at 20% of the generate high flows and regulate FiO2.
maximal flow achieved at the onset of inspiration. Note the differences in Reproduced from Masip J, Peacock WF, Price S, et al. Indications and practical approach
volume (dashed line curves) when TI is limited to different percentages (30%, to non-​invasive ventilation in acute heart failure. Eur Heart J. 2018;39(1):17–​25.
25%) of maximal flow. doi:10.1093/​eurheartj/​ehx580 with permission from Oxford University Press.
270 CHAPTER 21  N on - i nvasive  vent il ation

◆ Adaptive pressure control (APC): consists of an adaptive targeting exchange and reducing the duration of ventilation and length of
scheme to adjust the inspiratory pressure to deliver at least a stay in the ICU [35, 36].
minimum target tidal volume [31]. The ventilator provides ◆ Volume control ventilation: this is mainly reserved for obtunded
progressively higher or lower pressure support, according to patients with preset respiratory rhythm (RR) and tidal volume.
the patient’s inspiratory effort and tidal volume. Depending ◆ Negative pressure ventilation (NPV): there are few groups still
on the ventilator, this modality has different names, with little using this modality.
differences in their algorithms:  AutoFlow (Dräger Evita XL),
VC+ (Puritan Bennett 840), APV (Hamilton Galileo), PRVC Interfaces
(Siemens, Servo-​ i), and AVAPS (Average Volume Assured
Whatever NIV technique used, an interface is needed to connect
Pressure Support) (Respironics BiPAP Synchrony) [31,  32]. In
the acute setting, it has been used in adults with COPD and se- the patient to a ventilator or air/​O2 source (see E Figure 21.4).
vere hypercapnic encephalopathy (GCS <10), showing better That interface is the component that most defines NIV, and it is cru-
clinical and gasometrical improvement than NIPSV [32]. cial for the success of the treatment. In order to avoid leaks, a tight
◆ Adaptative servoventilation (ASV): this modality, used in com- seal between the patient’s face and the device is essential, but it is
plex sleep disturbances, compensates central apnoeas and upper often difficult to obtain. There are different types of interfaces [37].
airway obstructions by auto-​cycling and regulation of IPAP and
auto-​adjustment of the end-​EPAP. In spite of these hypothetical
Nasal interface
advantages, it has recently been shown to increase mortality in This has been proven useful in chronic patients or those with
patients with congestive heart failure with low EF and central sleep apnoea disorders. Although nasal masks can be better tol-
apnoeas [33] and it has recently been successfully used in acute erated [37], they are less useful in critical situations, generating
pulmonary oedema [34]. more resistance [38, 39] and massive leakage through the mouth,
◆ Intrapulmonary percussive ventilation (IPV): this has been shown often requiring mask change [40]. Conversely, they permit
to be useful in secretion mobilization. It has been tested in paedi- speech, feeding, coughing, and secretion expectoration, reducing
atrics, cystic fibrosis, and COPD exacerbations, improving gas the risk of vomiting [41]. A  variant is the nasal pillow inserted

INTERFACES

(a) (b) (c) (d)

(e) (f) (g) (h)

Figure 21.4  Interfaces for NIV. (A) Helmet. (B) Boussignac mask. (C) Mouthpiece. (D) Nasal mask. (E) Nasal pillows. (F) Oronasal mask. (G) and (H) Full face
(total face) masks.
 Indications for  n on - i n vasi ve ven ti l ati on i n  acu te ca re   pat i e n ts 271

into the nostrils, which are commonly used in paediatrics. In neo- specifically for NIV, transport ventilators, and ICU ventilators.
natal units, heated and humidified HFNC delivering O2 is widely Classical ICU ventilators and transport ventilators were primarily
used to support breathing, as an alternative to nasal CPAP and for configured to be used with endotracheal intubation and provided
weaning off CPAP [42]. different levels of monitoring and security alarm systems, but
they often failed during NIPSV when leaks were present. Modern
Face masks ICU ventilators and some transport ventilators have solved this
This is the most used interface in clinical practice, in over 70% drawback by incorporating NIV algorithms.
of all patients requiring NIV [43]. Disadvantages include lack of Non-​invasive ventilators are more economical, have a higher
protection from vomiting, nasal skin injuries, nasal congestion, mobility, and do not need an airflow source. A wide range of port-
mouth dryness, eye irritation, speaking difficulty, and possible able ventilators is currently on the market from the most simple
claustrophobia [40]. (only pressure is modifiable) to the latest-​generation high-​tech
There are three different types of face masks: ventilators (monitoring, alarm setting, leakage compensation,
◆ Oronasal mask: covers the mouth and nose. It increases minute different triggers, cycling, and flow ramp control, etc.) [56]. These
volume ventilation and reduces PaCO2 more effectively than non-​invasive ventilators usually allow better synchrony than ICU
nasal masks [38]. It was the most frequently used interface in and transport ones, even those that have NIV algorithms [56].
Europe [43], being indicated specifically in mouth-​breathing The most important attribute of the equipment is leakage com-
patients with dyspnoea. Different sizes and models are neces- pensation through an increase of airflow (up to 120–​180 L/​min),
sary for correct adaptation to the patient. which maintains the tidal volume, thus producing better patient–​
◆ Total/​full face mask: covers the mouth, nose, and eyes. In gen- ventilator synchrony and higher efficacy of the system. Since
eral, little cooperation is required to achieve correct adaptation, pressure cycling can increase auto-​PEEP, a trigger is usually ac-
with easy fitting and application and provoking less skin injuries, tivated with airflow [57]. Auto-​PEEP is defined by air trapped at
compared to full face masks [44, 45]. They may be more com- end-​expiration due to inadequate time for expiration (too short),
fortable than oronasal masks in longer treatments [46] and have bronchoconstriction, or mucus plugging. In this case, flow and
been associated with better outcomes in do-​not-​intubate pa- pressure curves do not arrive to zero.
tients [47], although its superiority has not been demonstrated
in other scenarios [46, 48]. Complements: humidifiers and aerosols
◆ Boussignac mask: used for CPAP only. O2 flows through small-​ NIV is often applied without humidifying devices. However, dry
diameter channels in cylinder walls and is injected at high speed gas provokes dryness of the mouth, nose, and respiratory tract,
into the cylinder through angled side channels. The resulting resulting in nasal congestion and an increase of airway resist-
turbulence, together with air friction, creates pressure on the ance. Consensus statements and guidelines contain conflicting
patient’s side cylinder opening producing a barrier effect and, recommendations concerning humidification and interactions
acting as a virtual PEEP valve. This is a very simple technique with the ventilator system [58]. Heat humidification was recom-
that may be used in areas with little equipment [49].
mended, because it seemed to facilitate NIV [59, 60] by reducing
Helmet nasal resistance, helping expectoration, and improving adherence
and comfort [61], especially in patients with secretions. Heat and
The helmet covers the whole head and part of the neck, without
moisture exchangers were not indicated when using NIV, since
contact with the patient’s face. It is very useful when anticipating
they might increase circuit dead space (increased PaCO2) and
prolonged NIV treatment. It can be attached to the patient’s ax-
work of breathing [62, 63]. However, in a recent randomized trial,
illae, to the abdomen, or even to the bed. It allows more patient
there were no differences in the intubation rate between both sys-
autonomy (speaking and eating), but its noise may occasionally
tems [64]. When using HFNC, it is mandatory to use humidifi-
be uncomfortable [50]. It is not recommended with traditional
cation. On the other hand, nebulizers can be used safely without
ventilators, as a fresh gas flow, high enough to minimize re-
interrupting NIV therapy. The association of O2 and helium has
breathing, is necessary [51]. It is more useful for CPAP, because
been tested, with no clear advantages [65]. It is important to use
the increased dead space may generate asynchrony when NIPSV
skin protectors to avoid face mask skin injuries.
is applied [52, 53].

Other
Mouthpieces placed between the lips and held in place by lip seals Indications for non-​invasive
are less effective due to higher leak and asynchrony rates and
greater patient discomfort [54, 55]. Laryngeal masks with volume
ventilation in acute care patients
control may be useful for patients in coma. NIV can be used in a wide range of disorders that may lead to
ARF. There are different levels of evidence to support its use in
Ventilators most of these disorders. This is a key point for the appropriate
All ventilators have particular settings for CPAP. Indeed, there are selection of patients who may benefit from this therapy (see
three types of ventilators for NIPSV: portable ventilators designed E Box 21.2) [37].
272 CHAPTER 21  N on - i nvasive  vent il ation

decrease pulmonary congestion and increase cardiac output

Box 21.2  Acute pulmonary diseases that may benefit from NIV
[93–​94]. Since 1985, numerous studies have proved the su-
NIV recommended periority of CPAP over standard O2 therapy in patients with
COPD exacerbation
◆ ACPO, improving gas exchange and symptoms [95–​97] and
ACPO
◆
reducing the endotracheal intubation rate [92, 98–​102]. The
technique has also been experienced in the pre-​hospital set-
Weaning from mechanical ventilation
◆
ting [11, 103, 104]. In most of the studies, CPAP is generally
ARF in immunocompromised patients
◆
set at 10 cmH2O.
NIV suggested On the other hand, the first randomized trial with NIPSV was
Pneumonia
◆ published in 2000 [105]. Although a contemporary study carried
Early ARDS
◆ out in Israel with very low-​level pressure support showed worse
Post-​operative respiratory failure
◆ outcomes with NIPSV [106], several trials [102, 105, 107] showed
Do-​not-​intubate patients
◆ a reduction in the intubation rate, compared to standard therapy,
ACPO, acute cardiogenic pulmonary oedema; ARDS, acute respiratory dis- especially in hypercapnic patients [108].
tress syndrome; COPD, chronic obstructive pulmonary disease. Several meta-​analyses were concordant in demonstrating that
CPAP and NIPSV reduced nearly to half the risk of endotracheal
intubation when compared with standard therapy [109–​113]. In
Chronic obstructive pulmonary addition, both techniques reduced mortality by nearly 40%, al-
disease exacerbation though only CPAP reached statistical significance. No superiority
of one technique over the other was shown in clinical trials de-
Many randomized trials have compared the efficacy of NIPSV
signed to compare both techniques (and sometimes PAV) [114–​
with conventional O2 therapy in patients with exacerbation of
122] or in meta-​analyses [109–​113], although NIPSV tended to
COPD, showing NIPSV significantly better in improving gas
show a faster improvement in some respiratory parameters.
exchange and symptoms [64–​ 70]. Several meta-​analyses and
However, the results of the 3CPO study [123], the largest clin-
systematic reviews confirmed the superiority of NIPSV over
ical trial on NIV carried out to date and designed to assess mor-
conventional O2 therapy by reducing the intubation rate, ICU or
tality, contradicted the results of the previous meta-​analyses.
hospital length of stay, and mortality [71–​76]. Therefore, NIPSV
Although NIV patients showed faster improvement in acidosis
should be considered the first-​line treatment for decompensated
and respiratory distress, short-​term mortality was not different
COPD patients [77–​79] in the ED, ICU, and even on general
when comparing both techniques to conventional therapy. The
wards, although the latter is suggested in less severe cases (pH
fact that patients were not hypoxaemic at study entry (average
>7.30) [69,  79]. Recent guidelines [80] recommended a trial of
PaO2 was 100 mmHg in all groups) and showed a very low in-
bi-​level NIV, even in COPD patients considered to require endo-
tubation rate (<3%) suggested that they were less severe than
tracheal intubation (unless in cases of immediately deterioration),
those included in the meta-​analyses [124]. In addition, the de-
but not in COPD exacerbation without acidosis.
sign of the trial not restricting the use of rescue NIV would
probably have induced bias against NIV, because there was a
Asthma exacerbation
significantly higher crossover rate to NIV due to respiratory
Although some studies [81–​85] suggested that NIPSV may be distress. However, recent meta-​analyses, including the 3CPO
effective in improving airflow, correcting gas exchange abnor- trial, continued to reflect a significant reduction in mortality
malities, avoiding intubation, and reducing the need for hospital- rate with CPAP [125, 126] (RR 0.75 [0.61–​0.92]) [113], showing
ization, the evidence is low and it is not generally recommended maximal benefit in patients with AMI or myocardial ischaemia
[80, 86, 87]. [113]. This finding reinforces the role of NIV in AMI [100, 127],
which has also been described recently to be successful during
Acute cardiogenic pulmonary oedema primary angioplasty [128]. However, prognosis in this setting
ACPO and COPD exacerbations are the most frequent indica- does depend on the severity of myocardial injury, rather than
tions for NIV in acute care settings [4, 5, 88, 89]. Either CPAP or the degree of respiratory failure [127, 129], and a strong impact
NIPSV is used in ACPO. on mortality may not be expected with the use of NIV. Further
The utilization of CPAP in patients with cardiac failure has research will be necessary to define which patients are most
a physiological basis. In addition to previously mentioned likely to benefit from NIV in terms of mortality [130]. Probably
effects on oxygenation, positive intrathoracic pressure re- those with a high risk for intubation, defined by severe acidosis,
duces venous return and LV transmural pressure (systolic hypercapnia, being non-​hypertensive, or having ACS, would be
wall stress) [90–​93]. In patients with normal cardiac func- the target population [131]. Recent ESC consensus papers have
tion, this may produce a mild decrease in blood pressure and recommended the use of NIV in patients with AHF who show
cardiac output. Conversely, in patients with decompensated increased work of breathing with tachypnoea and O2 saturation
heart failure with hypervolaemia and elevated preload, it may <90% [132], defined criteria for the diagnosis of ACPO and the
 Adequate pati en t sel ecti on for n on - i n vasi ve  t re atm e n t 273

role of different modalities of NIV in several AHF scenarios Other indications

[133, 134].
The latest update of the ESC guidelines for the diagnosis and ◆ Community-​acquired pneumonia (CAP): several randomized
treatment of acute and chronic heart failure, published in 2016, trials comparing the efficacy of NIV over conventional O2
considered NIV to be a class  IIa recommendation [135]. NICE therapy in patients with CAP found a significant clinical im-
guidelines recommended NIV in patients with ACPO showing provement [153], a reduction in endotracheal intubation rate
severe dyspnoea and acidaemia [136]. [154,  155], shorter ICU stay [154,  155], and lower mortality
In conclusion, NIV is indicated as the first-​line therapy in [155] with the use of NIV, mainly in patients with COPD [154].
ACPO, since it improves ARF more rapidly and may reduce the It may be concluded that NIPSV may be used in patients with
intubation rate and mortality when compared with standard ARF due to severe CAP, mainly if they have COPD. On the
therapy. CPAP may certainly be the technique of choice for its other hand, the use of NIV may reduce the risk of nosocomial
low cost and simplicity, being easily implemented in the pre-​ pneumonia [15].
hospital setting. NIPSV may be equally effective but should be ◆ Covid-19: Although there is some concern about aerosolization

performed by experienced personnel and may be specially indi- and infection spread, HFNC, NIV (mainly helmet), and awake
cated in the most severe patients (hypercapnia or respiratory fa- proning have been widely used as a second step treatment of
tigue). Although a recent randomized trial comparing HFNC to ARF or in the extubation process of Covid patients, but fol-
conventional O2 therapy in ACPO demonstrated its feasibility in lowing strict safety rules [156].
this setting [137], further research is necessary to establish the ◆ ALI/​ARDS: clinical studies and meta-​analyses have shown nega-
real indications of this technique. tive results with the use of NIV in ALI/​ARDS [157,  158]. The
delay in endotracheal intubation may be associated with major
Weaning and post-​extubation complications. In a prospective survey, in patients with very
early ALI/​ARDS (no MOF or haemodynamic instability) who
NIV has been proven to be useful in patients with persistent
were treated with NIV, nearly 50% avoided intubation [159].
weaning failure [138], showing shorter time with mechanical
A recent meta-​analysis showed similar results [160]. Therefore,
ventilation, shorter length of stay, lower incidence of com-
NIV can be used with caution in a selected subgroup of patients
plications (ventilator-​acquired pneumonia or septic shock),
with early [161] ALI/​ARDS without high O2 requirements, MOF,
and better survival, mainly in COPD patients [139–​146]. On or haemodynamic instability. Recent guidelines could not rec-
the other hand, because of the high rate of complications ob- ommend the use of NIPSV in ‘de novo’ ARF (mainly comprising
served in patients who need reintubation (around 15% of cases) pneumonia and ARDS) [80].
[147], NIPSV has been used to prevent ARF after extubation. ◆ Immunocompromised patients: the use of NIV in ARF of dif-
Some studies [140,  141] demonstrated that the use of NIV ferent aetiologies in immunocompromised patients [162], after
was more effective than standard therapy in preventing post-​ solid organ transplant [163], and in those with haematological
extubation ARF and reintubation in high-​risk patients, but malignancy [164] is well supported in terms of intubation and
not in unselected patients [148], with a reduction in mortality mortality reduction.
in hypercapnic patients and chronic respiratory disorders ◆ Post-​operative respiratory failure: NIV may be useful in the treat-
[141, 142]. ment or prophylaxis of ARF of some post-​operative states such
Another issue is the effect of NIV to treat established ARF as lung surgery [165, 166], thoracoabdominal aortic aneurysm
after extubation where no trial has reported benefits [149, 150]. [167], and obesity. CPAP and HFNC may be considered in this
A  multicentre study found an even slightly higher mortality in setting [168, 169]. Recent guidelines have recommended the use
the group of patients on NIPSV, which was attributed to delayed of NIV in patients with post-​operative ARF [80].
reintubation (12 hours versus 2.5 hours). Although this trial in- ◆ Do-​not-​intubate patients: the use of NIV in patients with ARF,
cluded only 8–​12% of COPD patients and could be biased by a but with a do-​not-​intubate status, has been well described and
high crossover rate, the authors concluded that NIPSV was not shown to have positive effects [170] such as reducing dyspnoea
effective in averting the need for reintubation in unselected pa- and decreasing the dose of morphine in palliative use in patients
tients [150]. More recently, in the post-​extubation period, HFNC with end-​stage cancer [171]. Recovery possibilities mainly de-
has been shown to be superior to conventional O2 therapy in pend on the characteristics of the patient [172] and the aetiology
low-​risk patients and equivalent to NIPSV in those at high risk of of the ARF (best results in COPD and heart failure) [173].
reintubations [151, 152].
In conclusion, it seems reasonable to use NIPSV as an al-
ternative to traditional weaning and in the prevention of post-​ Adequate patient selection for
extubation ARF in patients at risk, especially those with COPD
or hypercapnia, but should not be used generally in the treatment
non-​invasive treatment
of post-​extubation ARF, since a reintubation delay may be haz- Before starting NIV, it is crucial to identify if the patient is a good
ardous. HFNC may be a somewhat less effective alternative in this candidate [174, 175]. This should be done considering the cause
setting. and severity of ARF, which should be moderate to severe. There is
274 CHAPTER 21  N on - i nvasive  vent il ation

Table 21.1  Contraindications of NIV
Patient Team
Absolute Cardiac or respiratory arrest
Anatomical abnormality (unable to fit the interface) Appropriate
Inability to keep patent airway Severity patient Concomitant therapy
Adaptation selection Experience
Sustained severe hypotension Mental status Team attitude
Relative Mild hypotension
Agitated or uncooperative patient SUCCESS
Excessive secretions
Ventilator
Multiple organ failure Synchrony
tuning

a therapeutic window when NIV should be used, avoiding those

Incorrect adjustment
patients with mild ARF who would easily respond to conventional Inadequate interface
O2 therapy or conversely those who present with very severe ARF Excessive leakage
needing intubation [60]. It is necessary to check contraindications
Device
for the technique (see E Table 21.1) and consider predictors of
failure (see E Table 21.2) that warrant closer monitoring, paying
Figure 21.5  The success puzzle for NIPSV.
attention to possible complications (see E Box 21.1). Intubation
may be preferred if the likelihood of NIV failure is very high.
Subjects who have a pH <7.25, an APACHE II score >29, and a GCS mental status); (2)  the physician (concomitant therapy, experi-
score <11 have failure rates ranging from 64% to 82% [59, 60, 176]. ence, team attitude); and (3) the device (incorrect adjustment, in-
Patients with excessive secretions or without improvement after 60 adequate interface, excessive leakage).
minutes of NIV may be at high risk of failure [177–​180]. Clinical
signs that are only equivocal on presentation become more defini-
tively predictive of failure if they persist after 2 hours of NIV [176]. How to apply non-​invasive ventilation
In our experience, there are three levels that may influence NIV
success (see E Figure 21.5): (1) the patient (severity, adaptation, Preparing the scenario
Clear explanations and instructions should be given to the pa-
Table 21.2  Predictors of failure of NIV therapy in ARF tients about the technique. Select the mask of appropriate size
and shape to improve patient comfort, minimizing the risk of ul-
Before starting Clinician inexperience cers [181]. Prepare the straps, skin protections, and connections,
Inadequate equipment and set the ventilator in order to minimize the time wasted on
High risk of failure ARDS changing the mode. Hold the mask manually at the beginning,
even having the patient do it by themself. Spend the initial time
Altered mental status
stimulating the respiration and teaching the patient the clues for
Shock
synchronization.
High severity scores
Copious secretions Applying the technique
Extremely high respiratory rate Continuous positive airway pressure
Severe hypoxaemia despite high FiO2 The technique is very simple and does not require special training.
After initiation Inappropriate ventilator settings However, it is important to use appropriate masks, adjusted with
Wrong interface head straps, and to monitor, when possible, the resultant FiO2. The
initial CPAP may be 5 cmH2O. If the patient is correctly adapted,
Excessive air leakage
the CPAP may be increased to 10 cmH2O, the most common level
Breathing asynchrony with ventilator of pressure applied in the majority of trials.
Bad subjective tolerance Outside sleep disorders and treatment of atelectasis, CPAP is
Neurological or underlying disease impairment mainly restricted to patients with ACPO. Improvement in these
After 60 minutes No reduction in respiratory rate cases is mostly due to changes in the haemodynamic state and
oxygenation, rather than the ventilatory effect of the technique.
No improvement in pH
In the majority of cases, there is a progressive improvement in
No improvement in oxygenation
physiologic parameters and blood gases in minutes, and CPAP
No reduction in CO2 may be stopped when a negative balance has been obtained and
Signs of fatigue the patient has no dyspnoea. CPAP does not improve outcomes
 How to  a pply n on - i n vasi ve v e n t i l at i on 275

in patients with hypoxaemic ARF of different aetiologies. When

Box 21.3  Monitoring NIV in ARF
response to CPAP is poor, a trial with NIPSV may be attempted
in patients who show ventilatory impairment, reflected in CO2, Vital signs (respiratory rate, blood pressure, heart rate)
◆

although there is no evidence to support this recommendation. Dyspnoea/​accessory muscle use/​abdominal paradoxical
◆

breathing
High-​flow nasal cannula
Consciousness level
◆
In critically ill patients, HFNC is often started with a FiO2 of Mask comfort
◆
100% and the maximum tolerated flow. Later, the FiO2 and flow Collaboration
◆
rate can be decreased according to SpO2 [42] and the patient’s
demand. In less severe cases, it is usually started with lower flow Ventilator parameters
and FiO2. Tidal volume (>4 mL/​kg: 6–​7 mL/​kg) and minute ventilation
◆

Air leakage volume (<0.4 L/​sec)

◆

Non-​invasive pressure support ventilation Pressure support and PEEP setting

◆

This modality requires more experience. The selection or pre- Asynchrony (ineffective efforts, auto-​triggering, double trig-
◆

ferred use of specific interfaces, the main modalities, and the type gering, short/​long cycle)
of ventilators have been presented previously. Trigger/​slope (ramp)/​TI/​expiration setting
◆

Auto-​PEEP
◆

Ventilator settings in NIPSV Alarms (maximal peak pressure, minimal minute ventilation)
◆

It is recommendable to start with low levels of pressure (IPAP Gas exchange

8–​10 cmH2O/​EPAP 3–​4 cmH2O), increasing pressure support Continuous pulse oximetry (SpO2)
◆
progressively, according to patient adaptation, ensuring expired ABG sample (baseline and after 60 minutes of NIV for: PaO2/​
◆
tidal volumes of >4–​6 mL/​kg (can be lower in COPD patients). FiO2, pH, PaCO2, bicarbonate)
If there is no control display of the expired volume, pressure Venous blood gas sample (good for pH, may be an alternative
◆
support must be increased while tolerated. Normally, with a to ABG sample)
pressure support of 12–​18 cmH2O above PEEP, a tidal volume
FiO2, fraction of inspired oxygen; NIV, non-​invasive ventilation; PaCO2, ar-
of 400–​500 mL is reached. Elevated pressures may cause ex- terial partial carbon dioxide pressure; PaO2, arterial partial oxygen pressure;
cessive air leakage, asynchrony (especially when the patient is PEEP, positive end-​expiratory pressure; TI, inspiratory time.
tachypnoeic), and discomfort. On the other hand, a PEEP of
>4 cmH2O is necessary to avoid rebreathing when using port-
able ventilators, which may not include an expiratory valve Figure 21.6). Although several mechanisms may be respon-
or a double inspiratory–​expiratory circuit [56, 176]. The FiO2 sible for asynchrony, air leakage is involved in many of them.
should be titrated to achieve an SpO2 of >95%. Visualization In general, a leak of <0.4 L/​s is well tolerated (<30 L/​min) [186].
of flow and pressure waveforms on display is essential. In a Higher levels of leakage may interfere with the patient’s efforts.
study, physicians obtained better results analysing the flow In these cases, it is recommended to manually adjust the inter-
and pressure waveforms than just controlling the numerical face, reduce pressure support, and help the patient gain confi-
variables [182]. dence with the technique.
◆ Trigger asynchrony: (A)  ineffective triggering (ineffective ef-
Monitoring non-​invasive ventilation forts): incidence 13% [184]. Combination of inspiratory effort
To ensure the success of NIV, close monitoring is necessary (see and an abrupt airway pressure drop (0.5  cmH2O), simultan-
E Box 21.3), especially the patient’s O2 saturation (to adjust the eous with an inspiratory flow increase (if effort during in-
FiO2), PaCO2 (to assess efficacy), and synchrony. Overall reassess- spiration) or a small expiratory flow and pressure decrease
ments are usually performed at 60 and 90–​120 minutes. (if effort during expiration), not followed by an assisted cycle.
(B)  Double triggering (15%): Two cycles separated by a very
Assessing asynchrony short expiratory time that could be defined as less than half
Pressure support ventilation unavoidably induces a certain de- of the mean inspiratory time (TI) and an inspiratory effort.
gree of synchrony. In intubated patients, significant asynchrony (C) Auto-​triggering (13%): A cycle delivered by the ventilator
has been found in 25% of patients, especially at the begin- without a patient’s prior inspiratory effort and airway pressure
ning of, or after prolonged, ventilation [183]. In patients with decrease. In general, flow triggering reduces inspiratory effort,
NIPSV, it may be nearly 50% [184, 185]. An asynchrony index compared with pressure triggering.
(AI) of >10% [AI (%)  =  number of events/​(ineffective breaths ◆ Flow asynchrony: in this asynchrony, rising time and flow cycle
+ ventilator cycles) ×  100] is considered as severe, leading to are not in accordance with the patient’s demand. A shorter rise
an increase in work of breathing and patient discomfort [184]. time and higher flow cycle should be considered in patients with
Asynchrony is usually manifested under different forms that tachypnoea, while a slower rise time may be more comfortable in
need specific approaches [182, 184, 185] (see E Box 21.4 and patients with a low respiratory drive.
276 CHAPTER 21  N on - i nvasive  vent il ation

◆ Cycle asynchrony: (D)  short cycle (premature cycling) (12%).

Box 21.4  General approach for optimized ventilation, based
on signs of asynchrony (patient–​ventilator mismatch) A cycle with a mechanical TI less than the patient’s TI. Many
ventilators have cycling off, set at 25–​30% of the peak in-
Auto-​triggering spiratory flow. In COPD patients, it is often set at 50% [182].
(Supported cycles not triggered by patient’s effort) (E)  Prolonged cycle (delayed cycling) (23%). A  cycle with a
Action: reduction of air leaks and/​or reduction of inspiratory mechanical TI greater than twice the patient’s TI. If RR is con-
trigger sensitivity stant, a prolonged TI shortens the expiratory time (TE) and
may produce auto-​PEEP. Auto-​PEEP makes triggering more
Ineffective efforts
difficult. (F) Auto-​PEEP. The flow curve does not reach zero at
(Patient’s effort fails to trigger a supported cycle) the end of expiration.
Action: titration of pressure support, inspiratory and expiratory
(Based on [182, 184, 185].)
triggers, and PEEPext
Late cycling off Use of sedation
(Pressure increase at end of inspiratory cycle or flow and pres- Mild agitation and poor tolerance of the interface or the ven-
sure prolonged plateau) tilator can provoke malfunction of, or patient refusal to, NIV.
Action: reduction of air leaks, titration of expiratory trigger or Although sedation can play a role in avoiding intolerance, it is
maximal TI and/​or reduction of pressure support also potentially dangerous because of the risk of oversedation
Early cycling off [187]. In a large survey involving American and European phys-
(Convex pattern of expiratory flow waveform, concavity of pres- icians, use of sedation in patients on NIV was infrequent and
sure waveform, and shorter cycle) mainly determined by clinical experience [187]. Use of seda-
tives can improve tolerance and eventually avoid NIV failure.
Action: titration of expiratory trigger
Morphine, remifentanil, dexmedetomidine, propofol, and
Signs of potentially not balanced PEEPi midazolam-​based regimens have been used, with no serious
(Expiratory flow that does not reach zero prior to inspiration or complications, in experienced units [185, 188, 189]. It is better
ineffective efforts) to use intermittent doses, rather than continuous infusion [190].
Action: titration of PEEPext The new α2 adrenoreceptor agonist dexmedetomidine showed
As a general rule, changes in pressure support may be in steps of better results than midazolam in patients with ACPO intolerant
2 cmH2O, and changes in expiratory triggers in steps of 5–​10%. to NIV [188].
PEEPext, external (set at the ventilator) positive expiratory pressure; PEEPi, Sedation should only be considered when other manoeuvres
intrinsic positive expiratory pressure. (reducing leakage, pressure support, etc.) have failed.
(See also E Figure 21.6.)
Based on [182, 184, 185].

Ineffective efforts Double triggering Auto-triggering

(a) (b) (c)
FLOW

FLOW

FLOW
Paw

Paw

Paw
EMGdi

EMGdi

EMGdi

Premature cycling Late cycling and ineffective triggering Auto-PEEP

(d) (e) (f)
FLOW

FLOW

FLOW
Paw

Paw

Paw
EMGdi

EMGdi

EMGdi

Figure 21.6  Asynchrony during NIPSV.

 Per s ona l  pe r spe c t i v e 277

When to stop non-​invasive Staffing, costs, and resources

ventilation Optimal staffing and location for NIV therapy are needed. After
NIV is usually stopped when satisfactory recovery has been connecting a patient to NIV, close attention from the therapeutic
achieved or conversely there are signs of NIV failure. The iden- team is required. Several trials reported that patients on NIV may
tification of NIV failure has been presented previously (see E need more attention than intubated patients [195]. In our ICU
Adequate patient selection for non-​invasive treatment, p.  273). and regarding workloads, NIV patients are considered as critical.
Although there is some concern about the risk of delayed intub- When comparing costs, NIV seems to have a better cost–​benefit
ation [150], NIV is sustained while patients improve or at least relationship than invasive ventilation [196]. Maximal attention is
maintain functional respiratory status. The approach would required within the first hours of starting NIV and especially in
be different, depending on the cause and duration of NIV. In the first 20 minutes [182].
mid-​or long-​term use, a weaning period is often carried out by
decreasing PEEP and ventilatory settings progressively. The ap-
plication of protocol-​directed weaning has shown clear advan- Conclusion
tages in this context [191]. This approach does not seem to be
NIV plays an important role in the management of ARF in acute
necessary in short-​term use. Typically, the interface will be re-
care areas (ICU, ICCU, ED) and on general wards. It is indicated
moved, as requested by the patient, to provide facial hygiene or
in patients with acute exacerbations of COPD and ACPO where
to administer oral medications. If the patient deteriorates when
it must be considered as a first-​line treatment. NIV may be also
NIV is interrupted, therapy is resumed, but otherwise NIV may
indicated in difficult weaning, in ARF in immunocomprom-
be discontinued [176].
ised patients, and in the prevention of post-​extubation failure.
However, even in the best scenario and when applying NIPSV
Depending on an adequate selection of patients, it can be used in
appropriately, a substantial number of patients will fail and need
the post-​operative period and in cases of pneumonia and asthma
intubation. A prospective observational study reported a nearly
or as a palliative treatment. Caregivers must develop skills in
40% failure rate in a mixed population of patients with ARF
the technique, paying special attention to face mask fitting and
[4,  176]. In patients with signs of NIV failure, endotracheal in-
patient–​ventilator synchrony. Many other potential applications
tubation is performed. Although some criteria for intubation may
are undergoing further investigation, and additional studies are
have been proposed [182] (see E Box 21.5), in everyday practice,
necessary to confirm all the benefits of NIV, extending its indica-
clinicians typically decide to institute ventilation based on their
tions in the future.
assessment of a patient’s signs and symptoms [91].

Personal perspective
Where to apply non-​invasive
Although in developed countries NIV has shown sus-
ventilation tained growth for nearly three decades, it seems to have
NIV developed in critical care areas and rapidly spread to ED, stabilized in recent years. There are several reasons to ex-
specialist areas, and finally to the ward [4, 5, 88, 192]. The main plain this situation. First, familiarity with the technique has
concern is that NIV needs device monitoring, expertise, and a reached extensive areas of the health care system. Second,
higher rate of nursing staff than general wards. However, tele- the number of trials analysing NIV has decreased, since
metry and some advanced alarm systems may facilitate its appli- they usually repeat previous data, resulting in a lower ac-
cation. An attractive alternative is control of peripheral NIV by ceptance rate in relevant medical journals. Third, no sig-
medical emergency teams [193] that may be included in the or- nificant technological discoveries have been presented in
ganizational area of ‘rapid response’ or ‘immediate vital support’ the last few years. Finally, the real weight of NIV therapy
teams [194]. has become more evident, since it cannot be considered as
a substitute for mechanical ventilation through intubation
for all patients. In spite of this, there are still many patients
Box 21.5  Criteria for endotracheal intubation who would benefit from NIV, but in current practice, they
Cardiac and respiratory arrest
◆ are not treated with the technique. However, new improve-
Progressive worsening of pH and CO2 despite NIV
◆
ments in devices, whether they are ventilators, interfaces,
or complementary material, are expected to improve pa-
Need to protect the airway
◆
tient comfort and adaptation and will extend the technique
Persistent haemodynamic instability
◆
to different scenarios, including pre-​hospital, home and
Agitation and inability to tolerate the mask
◆
particularly developing countries.
Based on [182].
278 CHAPTER 21  N on - i nvasive  vent il ation

Further reading
Bersten AD, Holt AW, Vedig AE, Skowronski GA, Baggoley CJ. Treat­ Hess DR. Patient-​ventilator interaction during noninvasive ventilation.
ment of severe cardiogenic pulmonary edema with continuous positive Respir Care 2011;56:153–​65.
airway pressure delivered by face mask. N Engl J Med 1991;325:1825–​30. Keenan S, Sinuff T, Burns K, et al. Clinical practice guidelines for the use of
Brochard L, Mancebo J, Wysocki M, et al. Noninvasive ventilation for acute noninvasive positive-​ pressure ventilation and noninvasive continuous
exacerbations of pulmonary disease. N Engl J Med 1995;333:817–​22. positive airway pressure in the acute care setting. CMAJ 2011;183:E195–​214.
Carteaux G, Lyazidi A, Cordoba-​Izquierdo A, et  al. Patient-​ventilator Masip J, Betbesé AJ, Páez J, et  al. Non-​ invasive pressure support
asynchrony during noninvasive ventilation: a bench and clinical study. ventilation versus conventional oxygen therapy in acute cardiogenic
Chest 2012;142:367–​76. pulmonary oedema: a randomized trial. Lancet 2000;356:2126–​32.
Di Marco F, Centanni S, Bellone A, et  al. Optimization of ventilator Nishimura M. High-​ flow nasal cannula oxygen therapy in adults:
setting by flow and pressure waveforms analysis during noninvasive physiological benefits, indication, clinical benefits, and adverse effects.
ventilation for acute exacerbations of COPD:  a multicentric Respir Care 2016;61:529–​541.
randomized controlled trial. Crit Care 2011;15:R283. Rochwerg B, Brochard L, Elliott MW, et  al. Official ERS/​ATS clinical
Gray A, Goodacre S, Newby DE, Masson M, Sampson F, Nicholl J; 3CPO practice guidelines:  noninvasive ventilation for acute respiratory
Trialists. Noninvasive ventilation in acute cardiogenic pulmonary failure. Eur Respir J 2017;50:1602426.
edema. N Engl J Med 2008;359:142–​51. Weng CL, Zhao YT, Liu QH, et  al. Meta-​analysis:  noninvasive
Hess D. Noninvasive ventilation for acute respiratory failure. Respir Care ventilation in acute cardiogenic pulmonary edema. Ann Intern Med
2013;58:950–​72. 2010;152:590–​600.

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 RE F E RE N C E S 283

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 CHAPTER 22

Mechanical ventilation
Luigi Camporota and Francesco Vasques

Summary
Acute respiratory failure is the most common cause of admission to critical care.
Contents
Many patients presenting to the intensive care unit have pre-​existing heart disease
Summary  284
and 13.1% will be diagnosed with chronic New York Heart Association class IV heart
Pathophysiology of respiratory failure  285
failure. In addition, global left ventricular hypokinesia frequently occurs in adults
Definition  285
Classification  285 with septic shock and around 20% of patients with acute respiratory distress syn-
Pathophysiology  285 drome have acute pulmonary hypertension and right heart failure. The presence of
Hypoxaemic respiratory failure  285 heart failure adds significant challenges in the management of mechanically ven-
Hypercapnic respiratory failure  286 tilated patients and increases their morbidity and mortality. Furthermore, positive
Interpretation of arterial gases  287
pressure ventilation can exert profound cardiovascular effects through heart–​lung
Indices of oxygenation and ventilation  287
P(A–​a)O2 difference  287
interactions. It is thus essential for the cardiologist to have an appreciation of the
P(a/​A)O2 ratio or respiratory index  287
PaO2/​FiO2 ratio  287
Oxygenation index (OI)  287
Dead space ventilation (wasted PC-​SIMV (pressure-​controlled Classification of asynchronies  299
ventilation)  287 synchronized intermittent mandatory Trigger delay and ineffective inspiratory
Interpretation of central venous blood ventilation)  293 trigger  299
PC-​BIPAP (pressure-​controlled biphasic Modification of the waveforms  299
gases  287
positive airway pressure)  293 Causes  299
SvO2/​ScvO2  287 PC-​APRV (pressure-​controlled airway
How to correct IIE  300
Interaction of arterial oxygenation and mixed pressure release ventilation)  293
venous oxygenation  288 Auto-​triggering  300
Assisted and spontaneous modes  294
Venous–​arterial PCO2 gradient  288 CPAP/​PS (continuous positive Causes  300
Veno-​arterial carbon dioxide difference/​ airway pressure/​pressure support Modification of waveforms  300
arterial–​venous oxygen difference ventilation)  294 Double triggering  300
ratio  288 ASV (adaptive support ventilation)  295 Causes  300
Respiratory mechanics  288 PAV (proportional assist ventilation)  295 Reverse triggering  300
Assessment of lung mechanics in NAVA (neurally adjusted ventilatory Phase or cycle asynchrony  300
mechanically ventilated patients  288 assist)  295 Expiratory time asynchronies  300
Chest wall mechanics and ATC (automatic tube compensation)  295 Premature (short) cycling  300
transpulmonary pressure  289 General approach to ventilation Waveform identification of premature
cycling  301
Mechanical ventilation  290 management  295
Causes  301
Classification of mechanical ventilation  291 Respiratory support  295 Delayed cycling  301
Ventilation modes  291 Ventilator-​induced lung injury  296 Waveform identification of delayed
Phase variables  291 Mechanism of VILI  296 cycling in pressure support  301
Volume-​controlled modes  292 Diagnosis  297 Causes  301
VC-​CMV (volume control–​continuous Prevention  297 Weaning  301
mandatory ventilation)  292 PEEP and VILI  297
VC-​AC (volume-​controlled Invasive mechanical ventilation: ‘lung-​ Types of weaning  301
assist-​control)  292 protective ventilation’  297 Readiness testing: clinical assessment  301
VC-​SIMV (volume-​controlled PEEP setting  297 Readiness testing: weaning predictors  301
synchronized intermittent Prone position  298 Weaning tests: spontaneous awakening trials
mandatory ventilation)  292 and spontaneous breathing trials  302
Effect of positive ventilation on
Pressure-​controlled modes  293 Spontaneous awakening trials—​daily
cardiovascular function  298
PC-​CMV (pressure-​controlled interruption of sedatives  302
continuous mandatory Bedside detection of patient–​ventilation Spontaneous breathing trials  302
ventilation)  293 asynchrony  299 Conclusion  303
PC-​AC (pressure-​controlled Mechanisms of patient–​ventilation
assist-​control)  293 References  303
asynchrony  299
 Pathophysi ol o g y of respi r atory   fa i lure 285

alveolar ventilation and blood flow to each alveolar unit. In

assessment and management of patients with respiratory normal lungs, V/​Q is around 1 but ranges from 0.6 to 3.0, with
failure, particularly if the patients are mechanically ventilated. regional variations. In view of the different dissociation curves of
Mechanical ventilation is used to assist or replace spontan- O2 and CO2, the earliest sign of V/​Q mismatching is hypoxaemia,
eous respiration. Gas flow can be generated by negative pres- rather than hypercapnia. When alveolar units are poorly venti-
sure techniques, but it is positive pressure ventilation that is lated (V)  in relation to their perfusion (Q)—​low V/​Q units—​a
the most efficacious and most commonly used in intensive proportion of the pulmonary blood flow (mixed blood) ‘shunts’
care. There are numerous pulmonary and extrapulmonary or bypasses the ventilated alveoli and returns to the LA deoxygen-
indications for mechanical ventilation, and it is the under- ated or poorly oxygenated. At low shunt fractions (<30%), PaO2
lying pathology that will determine the duration of ventila- will increase with higher FiO2, whereas when the shunt fraction is
tion required. Ventilation modes can be broadly classified >30% (note that in severe ARDS, the shunt fraction can be >50%),
as volume-​or pressure-​controlled, but modern ventilators an increase in FiO2 will have little effect on PaO2, as the excess of
combine the characteristics of both in order to complement O2 coming from capillary blood of ventilated units will be unable
the diverse requirements of individual patients. To avoid to offset the effect of the shunted blood.
confusion, it is important to appreciate that there is no inter- The second mechanism is ‘true’ shunt where mixed venous blood
national consensus on the classification of ventilation modes. bypasses ventilated alveoli, resulting in blending of mixed venous
Ventilator manufacturers can use terms that are similar to blood with arterial blood, a condition named ‘venous admixture’.
those used by others that describe very different modes or The shunt fraction [ratio of shunted blood (Qs) to total pulmonary
have completely different names for similar modes. This blood flow (Qt)] can be calculated after administering an FiO2 of
chapter provides an introduction to the mechanisms of re- 1 for 15 minutes using Equation 6 in E Table 22.1. The value de-
spiratory failure, the principles of physiological assessment, rived by the venous admixture represents the calculated quantity
and the modes and strategies of invasive mechanical venti- of mixed blood that would be required to reduce the saturation of
lation. Whenever possible, the chapter discusses the heart–​ the pulmonary end-​capillary blood to the observed value [1, 3].
lung interactions of relevance to the cardiologist. The shunt may be either intracardiac (e.g. a right-​to-​left shunt due
to a patent foramen ovale) or more commonly intrapulmonary
(e.g. pneumonia). It is difficult in practice to distinguish between
a true shunt and V/​Q mismatch. However, when inspired O2 is
100%, alveolar O2 tension becomes uniform and V/​Q mismatch
has a negligible effect on the alveolar–​arterial O2 gradient, and
Pathophysiology of respiratory failure therefore, it is possible to distinguish between the two processes.
Definition The V/​Q effect is approximately equal to the difference between
the venous admixture at the lower FiO2 and that at FiO2 of 1.
Respiratory failure is a condition in which the respiratory system
It is important to note that the effect of shunt on PaO2 is cru-
is unable to maintain adequate gas exchange to satisfy meta-
cially dependent on the mixed venous saturation (SvO2)—​the
bolic demands (i.e. oxygenation and/​ or elimination of CO2).
lower it is, the lower is PaO2 for the same degree of intrapulmonary
Respiratory failure is conventionally defined by a PaO2 of <8.0
shunt. Hence, an understanding of the balance between O2 de-
kPa (60 mmHg), a PaCO2 of >6.0 kPa (45 mmHg), or both [1, 2].
livery and the metabolic demands is key to appreciating respira-
tory failure. The total amount of O2 delivered to the tissues (DO2)
Classification is the product of cardiac output (CO) and the arterial O2 content
Respiratory failure is traditionally classified as either type 1, with (CaO2), which, in turn, is dependent on arterial O2 saturation
oxygenation failure (resulting in hypoxaemia with normocapnia (SaO2), haemoglobin (Hb), and a minimal contribution from
or hypocapnia) or type 2, with ventilatory failure (character- O2 dissolved in plasma (see E Table 22.1, Equation 1). The Fick
ized by alveolar hypoventilation and subsequent predominant equation for VO2 helps to interpret the mixed venous oxygen sat-
hypercapnia). Both types can be acute or chronic. Although uration (SvO2):
their features often coexist, this distinction is sustained by patho-
physiological difference and has implications for the choice of re- SvO2 = SaO2 − ( VO2 / CO)
spiratory support [1, 3].
This means that, for a given arterial saturation, an increase
of the ratio VO2/​CO (increase in VO2 or a decrease in cardiac
Pathophysiology output) will result in a decrease of SvO2.
Hypoxaemic respiratory failure Normally the tissues extract around 20–​30% of the delivered
Hypoxaemic (type 1) respiratory failure derives from the effects of O2 to satisfy their metabolic requirements—​this is known as the
one or more of the following five pathophysiological mechanisms. oxygen extraction ratio (O2ER) (see E Table 22.1, Equation 2).
The first and most common mechanism is ventilation/​perfu- The remaining O2 returns to the right heart via the large veins, and
sion (V/​Q) mismatching. This variable describes the ratio between it can be measured using a catheter placed in the superior vena
286 CHAPTER 22  Me c ha nical ventil at ion

Table 22.1 Equations

Equation 1 DO2 DO2 = CO × CaO2

DO2 = CO × [(SaO2 × Hb × 1.39) + (PaO2 × 0.023*)]
Equation 2 O2ER O2ER = SaO2 –​ SvO2/​SaO2
Equation 3 PaCO2 PaCO2 = VCO2K/​Va; PaCO2 = VCO2 K/​VE –​  VD
PaCO2 = VCO2/​VE × (1 –​ VD/​VT)
Equation 4 VO2 VO2 = CO × (CaO2 –​  CvO2)
CvO2 = CaO2 –​  VO2/​CO
CvO2/​CaO2 = 1 –​ VO2/​(CaO2 × CO) = 1 –​VO2/​DO2
Equation 5 SvO2 SvO2/​SaO2 = 1 –​ VO2/​DO2
SvO2 = SaO2 –​ (VO2/​CO)
Equation 6 Qs/​Qt Qs/​Qt = (CcO2 –​ CaO2)/​(CcO2 –​ CvO2) × 100
If the dissolved oxygen is ignored, the equation can be simplified as: Qs/​Qt = (1 –​SaO2)/​(1 –​ SvO2)
Equation 7 P(A–​a)O2 gradient PAO2 = PIO2 –​ (PaCO2/​R)
PIO2 = FiO2 × (barometric pressure –​water vapour pressure)
At steady state, at sea level, at 37°:
PAO2 (kPa) = [0.21 × (101.3 –​6.2)] –​(PaCO2/​0.8)
Or more generally:
PAO2 (kPa) = FiO2 × 0.95 –​PaCO2 × 1.25
Equation 8 P(v–​a)CO2/​C(a–​v)O2 ratio P(v–​a)CO2/​C(a–​v)O2 ratio =
P(v–​a)CO2 = PvCO2 –​  PaCO2
C(a–​v) O2 = CaO2 –​  CvO2
CaO2 = (1.39 × SaO2 × Hb) + (0.023 × PaO2)
CvO2 = (1.39 × SaO2 × Hb) + (0.023 × PvO2)
* When PaO2 is in kPa or 0.003 if PaO2 is expressed in mmHg.
DO2, oxygen delivery; VCO2, carbon dioxide production (normally around 200 mL/​min); VO2, oxygen consumption; CO, cardiac output; CvO2, venous oxygen content; CaO2, arterial
oxygen content; Hb, haemoglobin; Qs/​Qt, shunt fraction (shunted cardiac output/​total cardiac output); VE, minute ventilation; VD, dead space ventilation; VT, tidal volume; CcO2,
pulmonary capillary oxygen content in normally ventilated and perfused alveoli; PaCO2, partial pressure of arterial carbon dioxide; ScvO2, oxygen saturation in central venous blood;
SvO2, oxygen saturation in mixed (pulmonary artery) blood; O2ER, oxygen extraction ratio.
K, constant required because VCO2 is expressed at standard temperature and pressure, dry (STPD), denoting a volume of dry gas at 0°C and a pressure of 760 mmHg, whereas Va is
expressed at body temperature and pressure, saturated (BTPS), denoting a volume of gas saturated with water vapour at 37°C and ambient barometric pressure. K = 0.863.

cava (SVC) (central venous O2 saturation, ScvO2) or in the pul- the pulmonary capillary blood volume. When the cardiac output
monary artery using a PAC (mixed venous O2 saturation, SvO2). In is high, the time available for equilibration between the alveolar
low cardiac output states, tissues will adapt to lower O2 delivery by and capillary gases is too short and it increases the difference be-
increasing O2 extraction. Increased O2ER will result in a reduction tween alveolar and arterial PO2 (see further text).
of ScvO2 and SvO2. Therefore, these parameters can be seen as an The fourth mechanism is alveolar hypoventilation where a reduc-
indicator of the balance between O2 delivery and tissue O2 con- tion in alveolar ventilation decreases the V/​Q ratio and causes hyp-
sumption and adequacy of cardiac output [4–​6]. The relationship oxaemia through a low alveolar PO2. In the absence of underlying
between O2ER and SvO2 is apparent from the following equation: pulmonary disease, hypoxaemia accompanying hypoventilation
is easily corrected by increasing the FiO2 [1, 3] and is character-
O2ER = SaO2 − SvO2 /SaO2
ized by normal alveolar–​arterial O2 difference (P(A–​a)O2). The latter
Global and regional SvO2 are used as surrogates for O2ER. SvO2 characteristic distinguishes hypoxaemia caused by hypoventila-
values between 70% and 80% represent an optimal balance be- tion from that caused by V/​Q mismatch or diffusion limitation.
tween global O2 supply and demand. Given that the lower the The fifth mechanism is caused by low inspiratory O2 partial pres-
SvO2, the greater the effect of shunt or low V/​Q ratio on PaO2, sure (i.e. high altitude).
increasing SvO2 with fluids, blood transfusion, and inotropic sup-
port (e.g. dobutamine) to optimize cardiac output can have a fa- Hypercapnic respiratory failure
vourable effect on arterial oxygenation and also survival [7–​8]. In normal conditions, PaCO2 is maintained within limits (4.8–​
The third mechanism is diffusion impairment. However, this 5.9 kPa) as alveolar ventilation (Va) remains proportional to CO2
rarely occurs in clinical practice as a sole cause of respiratory production (VCO2), despite wide variations in minute venti-
failure. Conditions that cause a reduction in gas diffusion are re- lation. The relationship between PaCO2 and Va is described in
lated to increased thickness of the alveolar capillary membrane E Table 22.1, Equation 3. At constant CO2 production, PaCO2
(interstitial lung disease), decreased capillary transit time (e.g. will depend upon the proportion of dead space (‘wasted ventila-
heavy exercise or hyperkinetic states with significant tachycardia tion’ alveolar units that are ventilated, but not perfused, and there-
and high cardiac output such as severe sepsis), and a reduction in fore not contributing to gas exchange) and alveolar ventilation,
 I n terpretati on of CEN TR A L VEN OU S B L O OD G ASE S 287

which, in turn, depends upon the tidal volume (VT) and respira- shunt fraction of >20%. It is important to remember that PaO2/​
tory frequency (f). If a patient’s ventilatory capacity is impaired, FiO2 varies within an individual patient and with ventilator set-
an increase in CO2 production leads to an increase in PaCO2. tings, PEEP, and FiO2 [13–​16]. Furthermore, the relationship be-
Hypoxaemic (type 1) respiratory failure is frequently associated tween the PaO2/​FiO2 ratio and FiO2 is not linear and depends on
in the initial phases with an increase in the total (Ve) and alveolar multiple factors, including the cardiac output, the intrapulmonary
(Va) ventilation, and therefore with decreased PaCO2. However, shunt fraction, and the arterial-​to-​venous difference in O2 con-
as the condition persists or progresses, fatigue of the respiratory tent. Recent evidence suggests that patients with the same PaO2/​
muscles or CNS impairment can lead to a decrease in Va and an FiO2 ratio have greater mortality if higher FiO2 is required, indi-
increase in PaCO2. cating a more severe pulmonary impairment. If a patient is ven-
There are three major conditions leading to hypercapnia [1, 3]: tilated on 100% O2, logarithmically transforming the PaO2/​FiO2
1. Central depression with a reduction of the respiratory drive ratio allows estimation of the shunt [17].
(e.g. drugs, CNS diseases). Oxygenation index (OI)
2. Reduced respiratory muscle strength (e.g. neuromuscular dis- This index takes into account the mean airway pressure and is
eases, malnutrition, drugs, skeletal deformities, respiratory calculated as: OI = (FiO2 × mean airway pressure × 100)/​PaO2.
muscle dysfunction or fatigue). This index expresses ‘the pressure cost’ to maintain a certain
3. Ventilation–​perfusion mismatch (high V/​Q), with increased PaO2/​FiO2 ratio. The OI allows comparison of patients with the
‘wasted ventilation’ [9–​11]. same PaO2/​FiO2 ratio, but with different ventilator pressures. The
higher the OI, the higher the ‘price’ for oxygenation and the more
severe the lung condition.
Interpretation of arterial gases Dead space ventilation (wasted ventilation)
The assessment of respiratory failure includes careful consid- Wasted ventilation is the portion of minute ventilation that does
eration of the degree of gas exchange disturbance, the under- not participate in gas exchange. Its calculation is based on the dif-
lying cause of the respiratory failure, and patient comorbidities. ference between end-​tidal CO2 (PECO2)—​taken from exhaled
Interpretation of both arterial and venous gases is necessary for gas using capnography—​and PaCO2, using the Bohr equation:
the evaluation of cardiorespiratory interactions. Vd/​Vt = (PaCO2 –​ PECO2)/​PaCO2. In normal conditions, Vd/​Vt
is around 0.3. Increased dead space ventilation has been associ-
Indices of oxygenation and ventilation ated with greater mortality in patients with ARDS [2, 18, 19].
Besides PaO2 (arterial O2 tension) and SaO2 or SpO2 (O2 satur-
ation of haemoglobin), a series of indices are used in clinical
practice to assess and monitor gas exchange in ventilated and Interpretation of central venous
non-​ventilated patients. blood gases
P(A–​a)O2 difference In addition to ABGs, the assessment of simultaneous venous
The alveolar to arterial (A–​a) O2 difference is calculated by sub- gases taken from the superior vena cava (central venous blood) or
tracting PaO2 from alveolar PAO2 calculated using the alveolar gas from the pulmonary artery (mixed venous blood) allows indirect
equation (see E Table 22.1, Equation 7). The normal A–​a differ- assessment of haemodynamics, and therefore of cardiorespiratory
ence varies with age and FiO2 and can be estimated from the fol- interactions. The most important variables are: the central venous
lowing, assuming the patient is breathing room air: P(A–​a)O2 = 2.5 oxygen saturation (ScvO2), the venous–​ arterial O2 difference
+ 0.21 × age in years (divided by 7.5 for kPa) [12]. However, with (∆avO2), the venous–​arterial PCO2 difference (∆PCO2), and the
increasing FiO2, PAO2 increases disproportionately, compared to lactate concentration. ScvO2 values <65–​70%, ∆avO2 >4–​5 mL/​dL,
PaO2, causing the A–​a difference to increase and the measure- ∆PCO2 >0.8 kPa, and blood lactate levels >2 mmol/​L suggest a
ments becoming much less reliable and clinically useful. discrepancy between O2 delivery and demand [5, 20, 21].

P(a/​A)O2 ratio or respiratory index SvO2/​ScvO2

This is calculated by dividing the P(A–​a)O2 gradient by PaO2. Unlike SvO2 values between 70% and 80% represent an optimal balance
the P(A–​a)O2 gradient, this index is relatively unaffected by FiO2. between global O2 supply and demand. A value <50% corresponds
A normal P(a/​A)O2 ratio varies from 0.74–​0.77 when FiO2 is 0.21 to to the theoretical critical PvO2 of 3.5 kPa. SvO2 >80% is gener-
0.80–​0.82 when FiO2 is 1. ally seen in hyperdynamic shock and can reflect the high cardiac
output and low O2 extraction by tissues in response to sepsis. Since
PaO2/​FiO2 ratio SvO2 reflects the flow-​weighted average O2 content of venous ef-
The PaO2/​FiO2 ratio is widely used and easy to calculate and is fluents from various tissues, hypoxia may still be present in a
a good estimate of the shunt fraction. A normal PaO2/​FiO2 ratio tissue receiving only a small proportion of the cardiac output, des-
is >53 kPa. A PaO2/​FiO2 of <40 indicates ARDS and relates to a pite relatively normal mixed venous O2 saturation. Despite this
288 CHAPTER 22  Me c ha nical ventil at ion

limitation, SvO2, and especially changes in this value, will still re- generate a negative intrapleural pressure. Inspiration occurs
flect the adequacy of O2 delivery in common clinical conditions. mainly through diaphragmatic contraction and augments the
A low SvO2 should always prompt suspicion of inadequate negative intrapleural pressure. This decrease in TPP (alveolar
tissue perfusion, as lower values of SvO2 are in relation to an in- minus pleural) draws air in. The volume of gas that remains in the
crease in VO2 and a decrease in cardiac output, haemoglobin, and lungs at the end of normal expiration and holds the lungs open
SaO2 (see E Table 22.1, Equations 4 and 5). It is important to is the FRC and represents a point of equilibrium between the
remember that a high or normal SvO2 does not always signify ad- opposing recoil of the lungs and the thoracic cage. Lung volumes
equate oxygenation in all organs, but it can reflect an impaired vary with age, gender, and height; in an adult, the tidal volume is
O2ER or abnormal vasoregulation. In these circumstances, lactate approximately 7 mL/​kg (500 mL) and the FRC is 2500 mL.
levels will be elevated to reflect the cellular O2 debt of anaerobic The ease with which the lungs inflate in response to a change
metabolism. As a practical guide, an increased risk of tissue hyp- in TPP is the lung compliance. The more distended alveoli at the
oxia or inadequate perfusion should be considered in the acutely lung apex and the more collapsed alveoli at the base have lower
ill patient when SvO2 is <60–​65%. compliance, compared to those in the mid zones. Surfactant has
As for the other O2 transport-​related variables, changes in SvO2 a crucial role in maximizing lung compliance by reducing the
in response to therapy are more important than single values. The surface tension within the alveoli. Pressure in the alveoli is re-
changes can be monitored continuously using fibreoptic PACs or lated to tension and the radius: PA = 2T/​r. In the absence of sur-
by repeated gas analysis. factant, alveoli with the smallest radius would have the greatest
pressure and therefore would tend to collapse and empty into
Interaction of arterial oxygenation and mixed larger alveoli.
venous oxygenation Total respiratory compliance combines lung and chest wall
As discussed earlier, when the venous admixture (Qs/​Qt) in- compliance. Any alveolar or interstitial infiltrate, such as pul-
creases, changes in the venous O2 content (CvO2) will have a clin- monary oedema or fibrosis, will decrease lung compliance,
ically relevant interaction with the arterial O2 content (CaO2). whereas chest wall compliance is decreased by conditions such as
Hence, an increase in O2 consumption (or a decrease in O2 de- chest oedema and obesity. At FRC in normal conditions, respira-
livery) will decrease CvO2, worsening arterial hypoxaemia (see tory compliance is optimal; the lung sits on the steepest part of
E Table 22.1, Equation 6). the pressure–​volume (P/​V) curve; subsequently, a small change
This expression indicates that arterial oxygenation (SaO2) is in pressure results in the largest change in volume.
directly related to cardiac output and haemoglobin, and inversely Note that, during spontaneous respiration, the basal alveoli sit
related to O2 consumption. When Qs/​Qt is small, this interaction on a more favourable part of the P/​V curve and therefore are more
has no clinical relevance. In contrast, in the presence of large Qs/​ compliant than the apical alveoli. Greater expansion of these al-
Qt, this interaction is clinically highly relevant [22]. veoli gives preferential ventilation to the lung bases, matching the
greater basal blood flow. In situations where the FRC is reduced
Venous–​arterial PCO2 gradient (supine position, mechanical ventilation), the lungs shift down
The difference between venous and arterial PCO2 is measured as the P/​V curve and compliance and the distribution of ventilation
the difference between contemporaneous measurements of cen- changes will be greater at the apices, thereby increasing the V/​Q
tral venous or mixed PCO2 and the arterial PCO2. It reflects the mismatch and contributing to the basal collapse seen commonly
adequacy of venous blood flow to remove tissue CO2 and there- in ventilated patients.
fore is an expression of the cardiac output. The venous-​to-​arterial Gas flow into the lungs is proportional to pressure change, but
PCO2 gradient is increased in low cardiac output states. The inversely related to airways resistance. In larger airways (gener-
normal value is approximately 6 mmHg (0.8 kPa) [5, 20, 21]. ations 1–​5), flow is predominantly turbulent and accounts for
higher resistance, whereas resistance in more distal airways is
Veno-​arterial carbon dioxide difference/​ lower due to laminar flow. High-​velocity flow increases turbu-
lence, and therefore airways resistance. During deep inspiration,
arterial–​venous oxygen difference ratio
flow rates as high as 60  L/​min can be reached. The energy re-
The ratio between the veno-​arterial CO2 tension gradient (P(v–​ quired to overcome airways resistance and elastance (reciprocal
a)CO2) and the arteriovenous O2 content gradient (C(v–​a)O2) is sug- of compliance) amounts to the work of breathing.
gested to reflect the occurrence of anaerobic metabolism and to be
correlated with lactate [5, 20, 21] (see E Table 22.1, Equation 7).
Assessment of lung mechanics in mechanically
ventilated patients
Assessment of lung mechanics is best performed using volume
Respiratory mechanics control ventilation with constant flow and a brief inspiratory
The thoracic cage, formed by ribs and intercostal muscles, along pause (see further text).
with the diaphragm, represents the chest wall (and the abdomen). From E Figure 22.1, it is possible to see an initial pressure
The thoracic cage has a tendency to spring outwards, whereas increase due to resistance (1–​2), followed by a further increase
the lungs, being elastic, tend to collapse; these opposing forces in pressure to peak pressure due to an elastic component (2–​3).
 Respi r atory   m e c ha n i c s 289

60 conditions of increased expiratory resistance causing gas trapping

through airflow limitation (e.g. COPD and asthma). PEEPtot can

Flow (Ipm)
0
be measured in a relaxed and passive patient through an end-​
expiratory hold manoeuvre (closure of inspiratory and expira-
tory valves at end-​expiration) (see E Figure 22.2). During the
–60 manoeuvre, the alveolar pressure and pressure at the mouth will
equilibrate.
600
Volume (mL)

Elastance of the respiratory system is the inverse of compliance

300 Vt (i.e. 1/​Crs).
The shape of this segment during constant flow depends on
0 the rate of change of the elastic characteristics of the respiratory
3 system. This concept can be quantified using the ‘stress index’. The
40
Paw (cmH2O)

stress index is a dimensionless number that describes the shape

2 of the pressure–​time curve in segment 2–​3. In a system with
20
decreasing elastance, segment 2–​3 will have a downward con-
0
1 cavity (stress index <1; see E Figure 22.3A). In a system with
0 1 2 3 4 5 6 increasing elastance, segment 2–​3 will have a upward concavity
Time (s) (stress index >1; see E Figure 22.3C), while if the elastance
Figure 22.1  Pressure, flow, and volume in volume-​controlled ventilation is constant, the segment will be linear (stress index =1; see
during an inspiratory pause. Paw, airway pressure; Vt, tidal volume. E Figure 22.3B).

Chest wall mechanics and transpulmonary pressure

Maximal resistance of the respiratory system can be
What is generally measured with the ventilator is the compliance
calculated as:
(or elastance) of the respiratory system. The elastance of the re-
R rs = Ppeak − Pplat /flow Equation 22.1 spiratory system (Ers) is the sum of the elastance of the chest wall
(Ecw) and that of the lung (EL):
Compliance of the respiratory system is calculated as:
Ers = Ecw + EL Equation 22.3
(
C rs = Vt/ Pplat − PEEPtot ) Equation 22.2
To distinguish between the two elastances is necessary to
PEEPtot is the total PEEP which is the sum of the set PEEP and measure the oesophageal pressure using an air-​filled oesopha-
the intrinsic PEEP (see E Figure 22.2). Intrinsic PEEP can be pre- geal balloon catheter. The changes in oesophageal pressure
sent if the respiratory rate is elevated and there is not enough time during tidal breathing are equivalent to the changes in pleural
for the respiratory system to empty completely, or in pathological pressure.

Figure 22.2  Measurement of autoPEEP during an expiratory hold manoeuvre. Flow and airway pressure during expiratory hold manoeuvre. At flow 0, the
cursor will indicate the amount of pressure at end-​expiration. This will correspond to the PEEPtot. The difference between PEEPtot and the set PEEP will be equal to
the intrinsic PEEP (PEEPi).
290 CHAPTER 22  Me c ha nical ventil at ion

A B C 15

(cmH2O)
10

Paw
1 5
Flow (L/s) 0

(mL) (L . S–1) (cmH2O)

0 –5

Poes
–10

–1 10

Volume Flow
0
–10
500
30 250
Paw (cmH2O)

0
20 1s

Figure 22.4  Transpulmonary pressure: effect of inspiratory effort. With

10 the same positive pressure, a greater spontaneous effort (second breath)
generates a greater transpulmonary pressure.

Figure 22.3  During the inspiratory pause, the inspiratory pressure falls to a

‘plateau pressure’, which corresponds to the alveolar pressure. 22.7), the pleural pressure will increase more—​and the haemo-
dynamic consequences more marked—​in the presence of increased
chest wall elastance. During spontaneous breathing, a negative
pleural pressure increases the venous return (RV inflow) and pre-
Therefore, Ecw can be calculated as:
load, decreases RV afterload, and increases LV afterload (increases
Ecw = Poes end-inspiratory − Poes end-expiratory /VT  Equation 22.4 LV transmural pressure). However, large swings in pleural pressure
and TPP can significantly increase LV wall stress and work and
And elastance of the lung is calculated as: can exacerbate heart failure and promote the formation of lung oe-
EL = Ers + Ecw Equation 22.5 dema. In poorly compliant lungs, changes in intrathoracic pressure
will have more pronounced effects on pleural pressure and haemo-
Measuring the oesophageal pressure has another important
dynamics (i.e. changes in pleural pressure are more pronounced
role—​estimation of TPP. TPP is the difference between airway
with high lung elastance (see E Equation 22.8).
pressure and pleural pressure and represents the true lung
distending force; it is equivalent to lung stress.
The TPP can be estimated using the following equation:
Mechanical ventilation
∆TPP = ∆Pao × ( EL /Ers ) Equation 22.6
Mechanical ventilation is a machine-​driven method of assisting
The adverse effects of mechanical ventilation may be caused or replacing spontaneous breathing to provide adequate gas ex-
either by excessive ΔTPP or by excessive variation in pleural change and control the work of breathing by unloading the
pressure, either positive (mechanical ventilation) or negative (ex- respiratory muscles. In order for gas to flow into the lungs, a pres-
cessive spontaneous breathing). sure difference between the atmosphere (or airway opening) and
Changes in pleural pressure (ΔPpl) can be calculated as: the alveoli is required. In spontaneous respiration, the respiratory
muscles need to generate a negative pleural pressure sufficient to
∆Ppl = ∆Pao × ( Ecw /Ers ) for positive pressure ventilation
 overcome the elastic and resistive forces of the respiratory system.
Equation 22.7 The muscular pressure (Pmus) expands the chest wall and gener-
Or ates alveolar inflation.
This relationship is described by the ‘equation of motion’, which
− ∆Ppl = ∆Pspont × ( Ecw /Ers ) Equation 22.7 states that the total pressure generated by the respiratory muscles
(Pmus) is equal to the pressure required to overcome the elastic
where ΔPspont is the negative airway pressure generated
forces (Pel) and the pressure required to overcome resistive forces
during spontaneous inspiration by the respiratory muscles (see
(Pres):
E Figure 22.4).
During assisted ventilation, these two forces can happen simul- Pmus = Pel + Pres Equation 22.9
taneously; therefore: Looking at all components, Equation 22.9 can be rewritten as:
   ∆Ppl = ∆Pao × ( Ecw /Ers ) − ∆Pspont × ( EL /Ers )  Equation 22.8 Pmus = ( Ers • V ) + ( R rs • F) + P0 Equation 22.10

From a haemodynamic perspective, changes in pleural pressure where Ers is elastance of the respiratory system; V is tidal volume;
influence intrathoracic vascular pressure and venous return, and Rrs is resistance of the respiratory system; F is flow; and P0 is total
therefore cardiac output. During passive inflation (see E Equation PEEP (externally set PEEP + intrinsic PEEP).
 M echa n i ca l  v e n t i l at i on 291

During mechanical ventilation, the ventilator provides a pres- The time ot the entire breath cycle is the sum of Ti and Te, ex-
sure (Pvent) equal to the entire pressure required to move the re- pressed in seconds, and the RR or frequency is the number of
spiratory system (i.e. in controlled mechanical ventilation) or a cycles per minute.
variable proportion of that pressure, therefore assisting the re- To understand the nomenclature of mechanical ventilation,
spiratory muscles (assisted ventilation). it is worth reminding that mechanical breath includes various
Equation 22.10 then becomes Equation 22.11 for controlled characteristics:
ventilation and Equation 22.12 for assisted ventilation: 1. Control. The control is the main variable determined by the set-
ting of the ventilator (mode). Depending on the control, mech-
Pvent = ( Ers • V ) + ( R rs • F) + P0 Equation 22.11 anical breaths can be classified into volume (flow)-​controlled
and pressure-​controlled. Examples of volume-​controlled ven-
   Pvent + Pmus = ( Ers • V ) + ( R rs • F) + P0 Equation 22.12
tilation are volume-​controlled continuous mechanical ventila-
tion (VC-​CMV), volume-​controlled assist-​control ventilation
Classification of mechanical ventilation (VC-​AC), and volume-​controlled synchronized intermittent
Mechanical ventilation is classified, based on the primary mech- mandatory ventilation (VC-​ SIMV). Examples of pressure-​
anism of lung inflation (i.e. to increase the TPP—​airway pressure controlled ventilation are pressure-​ controlled continuous
minus pleural pressure) and the consequent effects on the pleural mechanical ventilation (PC-​CMV), pressure-​controlled
pressure into: assist-​control ventilation (PC-​AC), pressure-​controlled syn-
chronized intermittent mandatory ventilation (PC-​ SIMV),
1. Negative pressure ventilation (NPV)—​where the chest wall is
pressure-​ controlled biphasic positive airway pressure (PC-​
expanded by generating an external negative pleural pressure;
BIPAP), and pressure-​controlled airway pressure release ven-
airflow occurs when the alveolar pressure is more negative than
tilation (PC-​APRV).
the pressure at the mouth.
2. Trigger (the variable that initiates inspiration). A  mechan-
2. Positive pressure ventilation (PPV)—​where both airway pres-
ical breath can be machine-​triggered or patient-​triggered. The
sure and pleural pressure are positive; airflow occurs when the
machine-​triggered breath is controlled by time alone and de-
pressure at the mouth is greater than the alveolar pressure.
pends on set parameters such as Ti, Te—​frequently set as the
Positive mechanical ventilation is the most commonly used I:E ratio and respiratory rate. The patient has no role in starting
mechanical ventilation modality in the ICU. In practice, however, the inspiration.
these two modes happen by default during assisted ventilation
3. Cycling (controls the transition from inspiration to expir-
when the PPV provided by the ventilator occurs concurrently
ation). The control of cycling can be by time (time-​cycled
with spontaneous breathing, resulting in negative pressure in the
breath) or flow (flow-​cycled breath). In time-​cycled breath, in-
pleura. Understanding this concept is important to understand
spiration occurs at the end on Ti; while in flow-​cycled breath,
the mechanisms of ventilator-​induced lung injury (VILI) and
expiration starts when inspiratory flow reaches a certain per-
patient-​self-​induced lung injury (P-​SILI) and some of the haemo-
centage of the peak inspiratory flow (e.g. during pressure sup-
dynamic consequences of excessive effort during spontaneous
port ventilation).
ventilation (see further text).
Based on how the relative proportion between Pmus and Pvent,
Ventilation modes the modes of mechanical ventilations are classified into:
Ventilation modes are classified according to:  (1) the type of 1. Controlled (mandatory). During controlled ventilation, both
breath delivered in terms of cycling (phase variables); and (2) how the respiratory power and respiratory control/​ pattern are
the gas flow is driven (control variables). provided by the artificial ventilator. The ventilator provides
for the entire minute ventilation requirements necessary for
Phase variables oxygenation and CO2 clearance. The patients are usually sed-
The terminology used to describe ventilator breaths revolves ated (and—​if required—​on neuromuscular-​blocking drugs).
around the two phases of the natural respiratory cycle: inspir- The ventilator provides all the work necessary to breathing,
ation and expiration. Like normal respiration, ventilators pro- and the patient’s respiratory drive and work of breathing are
vide active inspiration and passive expiration. The inspiratory abolished. If the ventilator determines both inspiratory and
time (Ti) and expiratory time (Te) represent the duration of expiratory cycling, so that the patient has no control over ven-
inspiration and expiration, respectively, while the transition tilation, the mode is described as mandatory. This is the mode
from one phase to another is known as trigger and cycling. The used intraoperatively, as patients are often paralysed or their
trigger marks the beginning of inspiration, and expiratory cyc- respiratory drive is abolished by deep anaesthesia. Terms that
ling marks the beginning of expiration. These four variables are describe this mode are intermittent positive pressure ventila-
referred to as the phase variables, as they can be manipulated tion (IPPV), continuous mandatory ventilation (CMV), or, if
to suit the patient’s respiratory mechanics and gas exchange the patient is allowed to take other breaths in between, inter-
requirements. mittent mandatory ventilation (IMV).
292 CHAPTER 22  Me c ha nical ventil at ion

2. Assisted-​controlled. During assist-​ controlled ventilation, the and plateau (pressure during an inspiratory pause) pressures
ventilator provides most of the respiratory power and control, depend on the resistance and elastance of the respiratory
but it also allows for the patient’s own respiratory muscles and system. The tidal volume during VC-​CMV can be supplied by
respiratory drive. Unlike in theatre, in most ICU patients, the the ventilator at a constant flow-​square wave (breaths 1 and 2
sedation dose used is the lowest that will keep the patient com- in E Figures 22.6 and 22.7) or at decelerating flow (activating
fortable. It is preferable to allow the patient to make some re- the ‘autoflow’ system in some ventilators) (breaths 3 and 4 in
spiratory effort to minimize respiratory muscle weakness and E Figure 22.6).
facilitate weaning off the ventilator. If the patient’s respiratory VC-​CMV can be described as: volume-​controlled, time-​cycled,
effort determines the inspiratory cycling, then the breath is said and machine (time)-​ triggered, with constant or decelerating
to be triggered and the ventilator is on demand, assist, or sup- inspiratory flow.
port mode. A hybrid mode is a combination of mandatory and VC-​AC (volume-​controlled assist-​control)
triggered ventilation. SIMV is a hybrid mode where mandatory During volume-​controlled ventilation, the set and target variable
breaths are set at a certain frequency. If the patient makes an is the tidal volume (flow × inspiratory time), and the peak and
inspiratory effort, this triggers the ventilator to give a breath, plateau (pressure during an inspiratory pause) pressures depend
instead of the mandatory breath (this breath will have the same on the resistance and elastance of the respiratory system, as in
control characteristics as the mandatory breath in terms of VC-​CMV. However, in VC-​AC, the patient can trigger additional
pressure or volume). This will not happen every time an in- ‘mandatory breaths’—​within a defined time or ‘trigger window’,
spiratory effort is made, but only when that inspiratory effort which have the same morphology as machine-​triggered VC-​AC
falls within a ‘trigger window’. breaths. Therefore, the minute ventilation (tidal volume × RR)
3. Assisted. During assisted ventilation, the respiratory power is can vary, depending on the patient’s frequency.
shared in variable proportion between the artificial ventilator VC-​AC can be described as:  volume-​controlled, time-​cycled,
and the patient’s own respiratory muscles, while the respiratory and machine (time)-​or patient-​triggered, with constant or decel-
control of breathing is mainly determined by the patient’s own erating inspiratory flow and a set (backup) frequency.
respiratory drive. VC-​SIMV (volume-​controlled synchronized intermittent
4. Spontaneous. An intubated patient who is breathing spontan- mandatory ventilation)
eously controls every aspect of the breathing cycle. During VC-​SIMV, the set and target variable is the tidal volume
This nomenclature expresses a progressively increasing work of and the mechanical breaths are synchronized with the patient’s
breathing performed by the patient and less support provided by spontaneous effort. In addition, the patient can trigger add-
the ventilator. The work carried out by the ventilator ranges from itional breaths, as in VC-​AC. However, the patient-​triggered
full control of a passive respiratory system to no inspiratory sup- spontaneous breaths are ‘pressure-​supported’, with a morph-
port with the patient breathing spontaneously, with or without ology similar to that of assisted breaths during CPAP/​PS (see
additional end-​expiratory pressure (PEEP or CPAP) (see E Figure further text).
22.5). The choice will depend on the severity of the respiratory or VC-​SIMV can be described as:  volume-​ controlled, time-​
extra-​respiratory condition and the progression of the disease. cycled, and machine (time)-​or patient-​triggered, with constant
Examples of assisted modes of ventilation are:  continuous or decelerating inspiratory flow and a set (backup) frequency with
airway pressure ventilation/​pressure support ventilation (CPAP/​ pressure-​supported spontaneous breathing.
PS) and continuous airway pressure ventilation/​volume support
ventilation (CPAP/​VS). Continuous airway pressure ventilation
(CPAP) is a completely spontaneous mode of ventilation. Paw (cmH2O)
40

Volume-​controlled modes 20

VC-​CMV (volume controlled continuous mandatory ventilation) 0

2 4 2 2
During volume-​controlled ventilation, the set and target vari- –20
able is the tidal volume (flow × inspiratory time). The peak 80 Flow (L/min) Flow (L/min) Flow (L/min)
40
0
2 4 2 2
Spontaneous –40
100% (CPAP) –80
Assisted Vt (mL) Vt (mL) Vt (mL)
(% of total work)

750
Patient effort

(PS)
500
Assist-control/SIMV 250
0
1 2 2 4 3 6 8 4
–250
Controlled/mandatory
0% (VC/PC)
Figure 22.6  Volume control ventilation with square flow versus decelerating
Figure 22.5  Modes of mechanical ventilation in relation to patient effort. flow patterns.
 M echa n i ca l  v e n t i l at i on 293

Figure 22.7  Volume control ventilation with square flow.

Pressure-​controlled modes PC-​SIMV can be described as:  pressure-​ controlled, time-​

PC-​CMV (pressure-​controlled continuous mandatory ventilation) cycled, and machine (time)-​or patient-​triggered, with decel-
During pressure-​controlled ventilation, the set and target variable erating inspiratory flow and a set (backup) frequency, with
is the inspiratory pressure. The tidal volume depends on the re- pressure-​supported spontaneous breathing.
sistance and elastance of the respiratory system. Inspiratory pres- PC-​BIPAP (pressure-​controlled biphasic positive airway pressure)
sure during PC-​CMV is provided with decelerating flow (breaths During PC-​BIPAP, the set and target variable is the inspiratory
3 and 4; see E Figure 22.6). pressure and the mechanical breaths have inspiratory and ex-
PC-​MV can be described as: pressure-​controlled, time-​cycled, piratory synchronization. In addition, the patient can trigger
and machine (time)-​triggered, with decelerating inspiratory flow. additional breaths. However, the patient-​triggered spontaneous
PC-​AC (pressure-​controlled assist-​control) breaths are ‘pressure-​supported’, with a morphology similar to
During pressure-​controlled ventilation, the set and target vari- that of assisted breaths during CPAP/​PS (see further text).
able is the inspiratory pressure, and the tidal volume depends on PC-​BIPAP can be described as:  pressure-​ controlled, time-​
the resistance and elastance of the respiratory system for a given cycled, and machine (time)-​or patient-​triggered, with decel-
driving pressure (difference between plateau pressure and PEEP). erating inspiratory flow and a set (backup) frequency, with
However, in PC-​AC, the patient can trigger additional ‘manda- inspiratory and expiratory synchronization and pressure-​
tory breaths’—​within a defined time or ‘trigger window’—​which supported spontaneous breathing.
have the same morphology as that of machine-​triggered PC-​AC PC-​APRV (pressure-​controlled airway pressure release ventilation)
breaths. Therefore, the minute ventilation (tidal volume × RR) During PC-​APRV (see E Figure 22.8), the set and target vari-
can vary, depending on the patient’s frequency. able is the inspiratory pressure (Phigh). Breathing occurs, cycling
PC-​AC can be described as: pressure-​controlled, time-​cycled, between Phigh maintained for an inspiratory time (Thigh) and a
and machine (time)-​or patient-​triggered, with decelerating in- lower pressure (Plow) maintained for a time (Tlow). In addition,
spiratory flow and a set (backup) frequency, with possible add- the patient can breathe spontaneously. The patient-​ triggered
itional spontaneous breathing. spontaneous breaths have a morphology similar to that of assisted
PC-​SIMV (pressure-​controlled synchronized intermittent breaths during CPAP (see further text). Typically, there is no add-
mandatory ventilation) itional PS in this mode.
During PC-​SIMV, the set and target variable is inspiratory pres- The main characteristic of this mode of ventilation is that Thigh
sure and the mechanical breaths are synchronized with the is much longer than the other modalities (usually 4–​6 seconds)
patient’s spontaneous effort during a trigger window. In addition, and Tlow is short (usually between 0.3 and 0.8 seconds, but it is
the patient can trigger additional breaths. However, the patient-​ adjusted based on the expiratory flow characteristics, which re-
triggered spontaneous breaths are ‘pressure-​supported’, with the flects the elastance and resistance of the respiratory system).
morphology similar to that of assisted breaths during CPAP/​PS PC-​ APRV can be described as:  pressure-​ controlled, time-​
(see further text). cycled, and machine (time)-​ triggered, with decelerating
294 CHAPTER 22  Me c ha nical ventil at ion

Figure 22.8  Airway pressure release ventilation.

inspiratory flow and a set frequency. Spontaneous breathing is the patient triggers the ventilator from PEEP and the ventilator
possible throughout the respiratory cycle. delivers a set level of pressure assistance (pressure support). The
optimal level of PS will depend on the strength of the respiratory
Assisted and spontaneous modes muscles.
CPAP/​PS (continuous positive airway pressure/​pressure support Expiratory cycling starts when the inspiratory flow reaches a
ventilation) certain percentage of the peak inspiratory flow (e.g. 25%). This
CPAP/​PS (see E Figure 22.9) is the most popular mode for par- decay in the inspiratory flow is the signal that a patient has ter-
tial mechanical ventilation and during weaning. During CPAP/​PS, minated the neural inspiratory time and is ready to cycle into

Figure 22.9  Pressure support ventilation.

 G en er a l a pproach to  ven ti l ati on m a nag e m e n t 295

expiration. The cycling variable can be modified to adjust the resultant additional work of breathing. It then adjusts the circuit
spontaneous inspiratory time, and therefore the inspiratory/​ex- pressure to overcome this additional work.
piratory ratio, to improve synchrony or allow more time for ex- The compensation may be applied during inspiration alone (in-
piration in case of intrinsic PEEP (e.g. COPD). creased circuit pressure) or also during expiration (decreased cir-
ASV (adaptive support ventilation) cuit pressure).
ASV is a proprietary mode of ventilation available on Hamilton
Medical ventilators that deliver a set minute ventilation (e.g. 100
mL/​kg of predicted body weight) using a combination of tidal General approach to ventilation
volume and respiratory rate that minimizes work of breathing. management
ASV uses the Otis et al. and Mead et al. equation developed in
1950 that states for a given level of alveolar ventilation, there is a The most important initial management of patients with respira-
combination of tidal volume and respiratory rate which achieves tory failure is early identification and treatment of the under-
lower work of breathing and minimizes the elastic and resistive lying condition. As the most common risk factor is sepsis—​this
load imposed on the respiratory system. The system is based on a can be pulmonary, e.g. pneumonia (the most common cause), or
closed-​loop system that automatically calculates compliance, re- extrapulmonary, e.g. pancreatitis, intra-​abdominal collections,
sistance, and work of breathing. urinary infections—​careful fluid management and resuscitation,
early appropriate use of antibiotics, and, if required, control of the
PAV (proportional assist ventilation)
source of infection (through surgical and percutaneous drainage)
During PAV, the ventilator provides variable assistance, depending
are essential. In addition, multifaceted supportive management
on the patient’s own effort. This is a spontaneous mode—​there
includes: supplemental O2, PPV, brief utilization of sedatives and
are no mandatory breaths. With PAV, the target is a set level of
neuromuscular blockers, targeted haemodynamic management,
respiratory muscle unloading. The ventilator pressure is in pro-
metabolic support (enteral or parenteral nutrition, with avoidance
portion to the instantaneous patient-​generated flow and volume
of hyperglycaemia), and measures to prevent DVT, GI bleeding,
(which are proportional to the muscular effort). In PAV mode, the
and secondary nosocomial infections. Patients with ARDS often
clinician sets the ‘flow assist’ (FA) and ‘volume assist’ (VA).
require initial aggressive fluid management and resuscitation to
The resulting pressure is:
restore tissue perfusion. The general approach to fluid manage-
ment includes use of balanced crystalloid solutions targeted to
Pao = VA × VT + FA × F Equation 22.13
haemodynamic parameters, minimization of chloride-​rich so-
From the equation of motion, it is possible to understand that lutions (normal saline), and avoidance of artificial starch-​based
VA unloads the elastic work and FA the resistive work, therefore colloid solutions. There is now growing evidence that beyond the
multiplying Pmus by a set gain or assist level. initial resuscitation period, maintaining a restrictive/​conservative
VA and FA can be adjusted if there is an instantaneous cal- fluid replacement strategy, avoiding a positive fluid balance, im-
culation of the resistance or elastance of the respiratory system proves survival without increasing the risk of shock or RRT [23].
(PAV+). The overall effect is that the assistance varies with effort
and work of breathing is controlled. Pressures and tidal volumes
will vary, depending on the clinical conditions.
Respiratory support
Initial management of patients in respiratory failure includes
NAVA (neurally adjusted ventilatory assist)
use of high-​flow O2. The change in SaO2 between room air and
The NAVA algorithm relies on the measurement of electrical ac-
100% FiO2 (non-​rebreathing mask) will allow an approximate
tivity of the diaphragm (EAdi in microvolts) using an NG tube,
estimation of the true shunt, and therefore the severity of dis-
with electrodes placed at the level of the lower oesophagus, using
ease. Failure of SaO2 to increase to >95% will indicate a shunt
oesophageal ECG to guide optimal placement. This neural signal
fraction of >30%. Patients with respiratory failure will often re-
triggers the ventilator (neural trigger) and provides pressure assist-
quire partial or full ventilatory support to achieve correction of
ance in proportion to instantaneous diaphragmatic electrical ac-
hypoxaemia, hypercapnia, and exhaustion. In addition, mechan-
tivity, which reflects the neural drive (gain in cmH2O/​microvolt).
ical ventilation can achieve airway protection, decrease O2 con-
The proportionality can be adjusted by changing the NAVA level.
sumption by reducing respiratory muscle work, and facilitate
The assist is cycled off when the EAdi decreases to a percentage
safe patient transfer and investigations (e.g. CT scan or coronary
of the peak EAdi (40–​70% of the peak EAdi, depending on the
angiography).
amplitude of the signal). The cycling-​off criterion during NAVA
Effective positive pressure mechanical ventilation can be pro-
are non-​adjustable. NAVA has the advantage of restoring neuro-​
vided either invasively (through an ETT) or non-​ invasively
ventilatory coupling and reducing asynchronies.
(through an interface—​most commonly a face mask or helmet),
either as continuous airway pressure alone (i.e. without add-
ATC (automatic tube compensation) itional inspiratory support—​CPAP) or with additional inspira-
ATC uses instantaneous flow, as well as the diameter and length tory pressure support (non-​invasive ‘ventilation’—​NIV) if work
of the ETT, to calculate the pressure drop along the tube and the of breathing is elevated or there is hypercapnia [24–​26].
296 CHAPTER 22  Me c ha nical ventil at ion

The most common indications for acute non-​invasive respiratory Among these, VILI is an ‘umbrella term’ that identifies the ana-
support are: tomical and functional lung damage that may develop as a result
◆ Acidotic hypercapnic ventilatory failure due to COPD of mechanical ventilation, ranging from microscopic lung matrix
exacerbations (NIV). alterations, to a variable degree of lung oedema, to gross stress-​at-​
◆ ACPO (CPAP or NIV). rupture barotrauma (i.e. pneumothorax).
VILI originates from the interaction between the patient
◆ Immunocompromised patients with mild to moderate acute re-
and the ventilator. Risk factors for VILI are summarized in
spiratory failure (NIV).
E Table 22.2.
◆ Mild ARDS (NIV in ICU).
◆ Ventilatory failure in obesity/​obstructive sleep apnoea (OSA) Mechanism of VILI
(CPAP or NIV). When discussing VILI, there is a risk of crossing the bound-
Absolute contraindications to non-​invasive respiratory support aries of philosophy, stating that this acronym may indicate both
are: ventilator-​induced and ventilation-​ induced lung injury. The
latter underlines that even spontaneously breathing patients are
◆ Immediate need for intubation.
at risk of developing damage (a phenomenon often referred to
◆ Severe haemodynamic instability.
as P-​SILI), as the key factor is elevated and inhomogenously dis-
◆ Extensive facial trauma or upper airway obstruction.
tributed transpulmonary stress, rather than the mere ventilator
◆ Life-​threatening hypoxaemia. setting—​regardless of it being generated by the patient or de-
◆ Severe bulbar weakness. livered by a machine.
The delivery of acute NIV is a complex intervention and can Over the last decades, the focus of experimental and clinical re-
improve survival, unless it delays intubation and institution of in- search has moved across different potential mechanisms of VILI,
vasive mechanical ventilation. Therefore, prompt recognition of introducing the concepts of barotrauma (i.e. excessive pressure),
NIV failure is essential for timely intubation. volutrauma (i.e. excessive volume), atelectrauma (i.e. repeated
The criteria for NIV failure are: opening and closing of collapsed lung units), and biotrauma (i.e.
extracellular matrix damage and inflammation) [27–​35]. All are
◆ No improvement in pH at 4–​6 hours (approximately 25% of
true, and more recently, the theory of ergotrauma, i.e. mechan-
cases).
ical energy and power applied by the ventilator, was introduced in
Physiological deterioration.
◆
an effort to unify all the different aspects related to the setting of
◆ pH <7.20 or pH 7.20–​7.25 on two occasions 1 hour apart. mechanical ventilation potentially causing damage.
◆ PaO2 <6.0 kPa despite maximum FiO2 (15 L/​minute). Patient-​related factors play a crucial role too. In particular, in
◆ New onset of contraindications to NIV (e.g. pneumothorax, ARDS patients, the smaller size of the non-​pathological lung (i.e.
haemodynamic instability, vomiting). baby lung concept) primarily determines its mechanical proper-
◆ Intolerance/​agitation or patient’s wish to withdraw. ties (e.g. small FRC, low compliance), setting a new limit to the
It is important to spend some time optimizing NIV upon ini- total lung capacity and influencing the strain and hazard related to
tiation, as often patient intolerance can be due to inappropriate a ventilation set. Another key factor is lung inhomogeneity, which
NIV setting or type/​size of the interface. diverts the distribution of pressure and volume, multiplying the
The PPV (invasive or non-​invasive) provided in an appropriate risk of damage (stress riser) at the interface of areas with different
environment (high dependency environment or ICU) is gener- mechanical properties (e.g. between atelectatic and ventilated
ally able to restore gas exchange, relieve work of breathing, and lung regions) in an unpredictable way [36]. Pulmonary perfusion
improve lung volume by recruiting collapsed or fluid-​filled al- flow and pressure, as well as microvascular permeability, are im-
veoli. In addition, reduction in O2 demand (following reduction portant, yet often underestimated, causes of VILI.
in work of breathing), together with improvement in oxygen-
ation, reduces cardiac stress (see further text), while improve-
Table 22.2  Risk factors for VILI
ment in lung volume and normalization of PCO2 can decrease
pulmonary vascular resistance (PVR) and improve right heart Lung-​related factors Ventilator-​related factors
function. Severity of lung disease Airway pressure, e.g. plateau pressure,
(i.e. baby lung size) driving pressure, PEEP
Ventilator-​induced lung injury Lung inhomogeneity Transpulmonary pressure
Mechanical ventilation is often required in critically ill patients Elevated respiratory drive Tidal volume
with ARF who are no longer able to achieve sufficient gas ex-
Parenchymal recruitability Respiratory rate
change through sustainable spontaneous, unassisted ventilation.
Degree of inflammation Respiratory flow
In many cases, mechanical ventilation is a lifesaving treatment.
However, as most medical interventions, mechanical ventilation Pulmonary perfusion flow Mechanical energy and power
and pressure
is associated with potential complications.
 G en er a l a pproach to  ven ti l ati on m a nag e m e n t 297

Finally, the haemodynamic consequences of mechanical pressure/​volume (i.e. energy) threshold for initiating lung damage
ventilation—​particularly evident at higher absolute pressure (e.g. over time (i.e. power) [40, 41].
high PEEP, high mean airway pressure, or recruitment man-
oeuvres)—​are not included in the concept of VILI but must be Invasive mechanical ventilation: ‘lung-​protective
ventilation’
considered when setting the ventilator.
Despite the clear advantages of using mechanical ventilation in
Diagnosis respiratory failure and ARDS, MV may, in itself, cause additional
Experimentally, VILI may be obtained by applying an aggressive trauma to the lung in the form of excessive volume and pressure
ventilation scheme on previously healthy or preconditioned lungs (volutrauma) and repetitive lung opening or collapse during
(i.e. one-​or two-​hit model). Unfortunately, in the clinical setting, tidal breathing (atelectotrauma). These mechanisms can cause
when mechanical ventilation is given to patients with already a pulmonary inflammatory response (VILI), which can involve
pathological lungs, it is usually impossible to distinguish VILI extrapulmonary organs, leading to MOF.
from ARDS caused by other processes. It follows that the diag- Therefore, the cornerstone of supportive management is the pro-
nosis of VILI in practice is not feasible, as VILI and ARDS—​with vision of ‘lung-​protective’ mechanical ventilatory support. A lung-​
the exception of stress-​at-​rupture—​are mostly clinically, radio- protective ventilation strategy consists of the provision of low tidal
logically, and pathologically undistinguishable. volumes (6 mL/​kg of ideal body weight), keeping inspiratory pres-
sures <28–​30 cmH2O and moderate to high PEEP levels, depending
Prevention on the severity of oxygenation and lung disease. It is important to
Following the results of mainstream experimental and clinical understand that as the proportion of lung collapse increases with
research, preventive measures for VILI—​ sometimes referred disease severity, a tidal volume of 6 mL/​kg of ideal body weight
to as ‘protective ventilation strategies’—​have targeted low tidal can cause lung injury, as the inspired volume will ‘stretch’ a much
volume (≤6 mL/​kg of predicted body weight), lower plateau smaller ventilatable lung. The goals of ventilation are to maintain
pressure (<30  cmH2O), lower driving pressure (<15  cmH2O) PaO2 at 7.3–​10.6 kPa and accepting a rise in PaCO2 (permissive
[37], higher PEEP levels (in the open lung approach, recently hypercapnia) to enable low-​volume ventilation if inspiratory pres-
questioned by experimental and clinical evidence), and reduced sures reach 30 cmH2O. In addition to the uncertainty of ‘safe’ tidal
frequency of injurious strain cycles (i.e. lower respiratory rate) volume, there is no generally accepted way of setting PEEP.
[38–​39].
The propagation of these ‘magic numbers’ through clinical PEEP setting
practice have oriented ICU doctors towards less injurious venti- Different strategies have been trialled; the most common ones are
lation settings, but such practice has a huge limit of considering based on a PEEP scale, depending on the PaO2/​FiO2 [42] (where
the many ventilation settings separately, one from the other, and it the lower the PaO2/​FiO2, the higher the PEEP) (see example in
often ignores (i.e. does not measure) patient-​related factors such E Table 22.3).
as the FRC and ventilatable lung volume. An alternative approach consists of ‘opening the lung’ with
Furthermore, VILI is a complicated phenomenon and there is pressures of 40–​50  cmH2O for 40 seconds and then gradually
hardly any single ventilation variable sufficient to explain or avoid reducing the PEEP level, calculating at each step the static com-
VILI. Conversely, in the unifying concept of ergotrauma (i.e. lung pliance (the ratio between the tidal volume and the difference
injury explained by excessive energy delivered to the lungs over between the plateau pressure and PEEP) [43]. PEEP can be set
time)—​in which all the respiratory variables mentioned above are 2  cmH2O above the level, which corresponds to the best com-
considered together—​prevention of lung injury is achieved by the pliance of the respiratory system [44, 45]. However, this strategy,
reduction of ventilation energy and power by tailored minimiza- when combined with high-​pressure recruitment manoeuvres, has
tion of tidal volume, absolute and driving pressures, flow, and re- been shown to increase mortality in patients with ARDS [ART
spiratory rate [40]. trial]. A more pragmatic initial approach can be to set a PEEP of
5–​10 cmH2O for mild ARDS, 10–​15 cmH2O for moderate ARDS,
PEEP and VILI and >15–​20 cmH2O for severe ARDS [46].
PEEP was long considered mainly for its protective effects in High PEEP stabilizes the alveoli (reducing end-​expiratory col-
maintaining lung recruitment and preventing collapse. However, lapse), improves oxygenation, increases ventilator-​free days, and
although not traditionally considered within the work of decreases the need for rescue therapy, but the overall effect on mor-
breathing—​as it does not determine flow/​tissue movement after tality in unselected ventilated patients is unclear. However, there
the first breath—​PEEP sets the pressure level upon which the seems to be a benefit of using higher PEEP in patients with severe
driving pressure is delivered at each tidal volume. Therefore, to ARDS. The effect of PEEP in more severe ARDS is explained by
increment pressure by a constant amount, greater inflation energy the fact that these patients have a larger proportion of the lung that
is necessary when starting from a higher PEEP, as opposed to a is collapsed and therefore has the potential to regain aeration with
lower PEEP. The presence of PEEP and PEEP-​related volume usu- higher PEEP levels [47, 48] (see Figure E 22.3). However, careful
ally requires a higher absolute pressure (and potentially a greater consideration of haemodynamic changes and deterioration when
driving pressure) to achieve a given tidal volume exceeding the increasing PEEP is mandatory (see further text).
298 CHAPTER 22  Me c ha nical ventil at ion

Table 22.3  PEEP settings

Lower PEEP scale

FiO2 0.3 0.4 0.4 0.5 0.5 0.6 0.7 0.7 0.7 0.8 0.9 0.9 0.9 1.0 1.0 1.0 1.0
PEEP 5 5 8 8 10 10 10 12 14 14 14 16 18 18 20 22 24
Higher PEEP scale
FiO2 0.3 0.3 0.4 0.4 0.5 0.5 0.6 0.6 0.7 0.8 0.8 0.9 1.0 1.0
PEEP 12 14 14 16 16 18 18 20 20 20 22 22 22 24

Prone position ◆ Spontaneous ventilation represents stress to the cardiovascular

system (latent heart failure can be unmasked during weaning of
In addition, in the supine position, gravitational forces—​which in- mechanical ventilation).
crease from the anterior (sternum) to the posterior (spine) regions
(see E Figure 22.3)—​contribute to lung collapse. Therefore, re- ◆ Excessive inspiratory efforts can cause RV and LV dysfunction.
versing the gravitational effects on the lung by ventilating patients These effects can be due to changes in lung volume and
in prone positioning can improve ventilation in the posterior intrathoracic pressure (pleural pressure). Many of the haemo-
regions (where the majority of the lung mass is located) and im- dynamic effects of all forms of ventilation are similar, despite
prove PaO2 in most patients with severe ARDS [49–​59]. Around differences in the mode of ventilation. Both spontaneous ventila-
two-​thirds of patients with ARDS show a 25–​36% improvement in tion and mandatory PPV increase lung volume. Pleural pressure,
PaO2/​FiO2 during the first 3 days of prone positioning. One large however, decreases during spontaneous inspiration and increases
randomized trial and a meta-​analysis have reported mortality during PPV [66–​70]. Thus, the primary reasons for different
benefits from ventilation in the prone position in patients with se- haemodynamic responses seen during spontaneous and positive
vere ARDS (PaO2/​FiO2 <20 kPa) if they remain prone over 12–​17 pressure breathing are related to changes in pleural pressure. This
consecutive hours and receive lung-​protective ventilation with low is particularly important in patients with hypovolaemia and those
tidal volumes. When prone positioning and lung-​protective venti- with greater chest wall elastance (e.g. obesity and increased intra-​
lation are delivered together, mortality is reduced [49–​54]. In the abdominal pressure) in whom an increase in pleural pressure can
most recent RCT, patients ventilated in the prone position had a cause a reduction in venous return (right heart filling, and there-
HR for death of 0.39 at 28 days and 0.44 at 90 days [49–​54]. Prone fore a reduction in preload and cardiac output). In contrast, in
positioning decreases mortality by reversing hypoxaemia and patients with LV dysfunction, an increase in pleural pressure is
preventing ventilator-​associated lung injury. These effects are due transmitted to the pericardium, causing an increase in pericar-
to greater alveolar recruitment with reduction in overdistension dial pressure, which causes a decrease in LV transmural pressure
and consequent homogenous distribution of lung stress and strain and LV dimensions, relieving LV wall stress (which represents
[49–​59]. an important aspect of the ventricular afterload) and therefore
Additional supportive and rescue treatments, including extra- improving LV performance [71].
corporeal support (CO2 removal or full ECMO), may be required The beneficial effects of PPV can be unmasked during
in severe ARDS and are best provided in specialist centres with a weaning from mechanical ventilation or following extubation
high volume of activity [60–​65]. when an abrupt decrease in pleural pressure can cause more
negative intrathoracic pressure swings [72]. This can acutely
increase venous return, increase cardiac filling pressures, and
impair LV ejection and LV afterload, which increases trans-
Effect of positive ventilation on mural pressure (the difference between the positive ventricular
cardiovascular function pressure and the negative pleural pressure) [68–​70]. Ultimately,
this can trigger LV failure and cardiogenic pulmonary oedema
Despite all the benefits on oxygenation, PEEP can exert a pro-
(see E Figure 22.4). In E Figure 22.5, it is possible to see
found haemodynamic effect and it is essential to closely monitor
how an increase in PEEP from zero to 10 causes a reduction in
patients, using echocardiography and changes in arterial blood
pleural swings, indicating a reduction in inspiratory efforts. It
pressure and cardiac output when PEEP is increased.
is important to realise that in the treatment of acute pulmonary
The main cardiovascular consequences can be summarized as
oedema from LV failure, CPAP is only effective if the CPAP
follows:
level is able to minimize pleural pressure swings, and therefore
◆ Mechanical ventilation with spontaneous breathing can in- LV wall stress [73].
crease RV preload and LV afterload. The increase in venous return can be further increased by forced
◆ Mandatory mechanical ventilation decreases RV preload and LV expiratory efforts caused by increased work of breathing or ven-
afterload. tilator dyssynchrony. This can lead to an increase in NT-​proBNP
◆ Lung inflation (lung volumes) increases RV afterload. and a decrease in central venous O2 saturation, the difference
 Bed si de detecti on of pati en t–ven ti l ati on asy n c h ron y 299

between arterial and venous saturation, and the venous–​arterial Table 22.4  Patient–​ventilator asynchrony in relation to different
pCO2 difference, and hyperlactataemia. phases of breathing
To reduce the incidence of ventilator weaning failure, it is im-
Phase of assisted ventilated PVA
portant that cardiac function is optimized and attention is paid to breath
fluid balance (through diuresis) pre-​extubation and management
Initiation of breathing Trigger asynchrony:
of hypertension peri-​extubation [74]. Delayed triggering
◆
Ineffective triggering
◆
Double triggering
◆
Auto triggering
Bedside detection of patient–​
◆
Reverse triggering or ‘entrainment’
◆

ventilation asynchrony Gas delivery Flow asynchrony

End of inspiration Termination asynchrony
◆
During assisted or supported breathing, the total pressure applied
Premature cycling
◆
to the respiratory system to overcome the patient’s inspiratory Delayed cycling
◆
pressure load and generate inspiratory flow is shared between
the patient’s muscular pump and the mechanical ventilator. Any
discrepancy between the volume, timing, and duration of the set of all asynchronous breaths). Ineffective inspiratory trigger can be
mechanical breath and the magnitude of the support required seen during mechanical expiration, as well as during inspiration.
by the patient will fail to relieve the work of breathing and can In volume-​assist ineffective inspiratory efforts (IIE), it can be de-
have important consequences in terms of dyspnoea, sleep quality, tected by observing the pressure waveform, while in pressure sup-
and negative outcome, including duration of mechanical ven- port ventilation (PS), it is best observed in the flow waveform. An
tilation and mortality [75–​ 84]. Patient–​
ventilator asynchrony abrupt increase in flow suggests IIE.
(PVA) is common, but under-​recognized and under-​reported. IIE is generally caused by dynamic hyperinflation with intrinsic
The frequency of PVA is reported to be around 23%, but up to PEEP (PEEPi) generated by low elastic recoil, high tidal volume,
93% of patients have at least one episode of PVA. While sporadic and short expiratory time.
asynchronies may have an uncertain clinical impact, when they In the presence of PEEPi, the respiratory system fails to reach
amount to >10% of the total breaths, PVA can increase the need equilibrium at the end of expiration. The elastic threshold load
for sedation and reduce sleep quality. (PEEPi) is imposed on the respiratory muscles at the begin-
While traditionally PVA has been detected by oesophageal ning of inspiration, requiring additional efforts (pressure) to
and gastric pressure monitoring, the bedside clinician can de- overcome PEEPi.
tect such asynchronies less invasively by observing the flow and The ventilator can trigger inspiration only after PEEPi is over-
pressure waveforms that are routinely displayed on mechan- come. The time spent by the respiratory system to dissipate the
ical ventilators, as well as by inspecting the patient’s breathing elastic threshold load caused by PEEPi causes a delay between the
pattern. initiation of inspiration (muscle contraction) and triggering. If
PEEPi is higher or the patient is weak or too sedated, PEEPi is not
Mechanisms of patient–​ventilation  overcome and the respiratory effort is unable to cause triggering
asynchrony [85, 86].
Three variables determine breath delivery on a mechanical venti- Modification of the waveforms
lator: (1) breath initiation—​the trigger (the signal initiating pres-
◆ IIE:
sure/​flow delivery); (2)  flow delivery—​the control variable (the
Flow: positive deflection of the expiratory flow waveform.
●
algorithm that controls the delivery of flow/​pressure during in-
Pressure (less sensitive): negative deflection during pressur-
●
spiration); and (3) breath termination or the cycling off variable
ization and inspiration.
(the signal terminating the delivery of flow or pressure).
When interpreting ventilator waveforms, it is important to dif- ◆ Trigger delay:
ferentiate between dependent and independent variables, based Flow: positive deflection of the expiratory flow.
●

on the set mode of ventilation. Pressure (less sensitive): time between negative deflection of
●

the flow waveform and beginning of pressurization.

Classification of asynchronies Causes
(See E Table 22.4.) ◆ Low respiratory drive.
Trigger delay and ineffective inspiratory trigger ◆ Low PaCO2.
◆ High tidal volumes.
The triggering time delay is the time from onset of triggering ef-
fort to onset of flow delivery. Ineffective trigger is an inspiratory ◆ Over-​sedation.
effort that does not trigger the ventilator. Ineffective triggering ◆ High level of assistance.
(or wasted effort) is one of the most frequent asynchronies (88% ◆ PEEPi.
300 CHAPTER 22  Me c ha nical ventil at ion

How to correct IIE ◆ Oversensitive trigger settings.

◆ Decreasing PEEPi: lowering the tidal volume or decreasing the ◆ Ventilator unable to pressurize the circuit appropriately.
level of pressure support, particularly in COPD. Reverse triggering
Lengthening the expiratory time.
◆
Reverse triggering, or respiratory entrainment, is a phenomenon
◆ Decreasing resistance of the airways (i.e. bronchodilators). that occurs when a ventilator insufflation elicits a diaphragmatic
◆ Decreasing sedation levels. contraction and a spontaneous breath, with a ratio varying be-
◆ Increasing external PEEP. tween 1:1 and 1:3 [87, 88].
◆ Decreasing the trigger threshold (increasing trigger sensi-
tivity):  the trigger should be as sensitive as possible without Phase or cycle asynchrony
causing auto-​triggering (see E Auto-​triggering, p. 300). A phase/​flow/​cycle asynchrony occurs when the delivery of a
◆ Assessing the respiratory drive. mechanical breath is inappropriate for the patient’s demand. In
◆ Using a larger ETT (generating greater pressure to overcome in- volume-​assist, inadequate flow delivery can cause redaction in the
creased airway resistance from smaller tubes that requires time instantaneous pressure–​time airway curve, giving a ‘concave’ or
and greater effort). ‘sucked-​down’ appearance of the assisted breath (in comparison
◆ Using a ‘flow waveform’ trigger system. with the controlled breath), indicating that the flow provided
by the mechanical breath is lower than that required for muscle
Auto-​triggering unloading.
These are mechanical breaths delivered by the ventilator in the ab- The pressure waveform will then decrease with any increase in
sence of the patient’s triggered inspiratory effort. Auto-​triggering the patient’s inspiratory effort. In PS/​PC ventilation, the above
causes discomfort and can increase PEEPi. considerations apply to the flow waveform. In addition, the re-
spiratory efforts during inspiration determine the duration of
Causes
inspiration, as the inspiration time in PS is dependent on the de-
◆ Any distortion in flow/​pressure in the presence of low respira- cline of inspiratory flow up until the cycling off criterion—​set as a
tory drive and respiratory rate and in the absence of PEEPi. percentage of peak inspiratory flow. In PS, two signs may indicate
Low-​threshold trigger.
◆ flow asynchrony: (1) a ‘square’ or constant inspiratory flow wave-
◆ Circuit leaks. form appearance caused by large, continuous inspiratory effort;
◆ Water in the circuit. and (2) changes in tidal volume for the same driving pressure—​
◆ Vigorous cardiac oscillations. the larger the tidal volume, the better the synchrony.
In contrast, excessive flow or pressure can overwhelm the re-
◆ Hiccups.
spiratory centre and cause episodic breathing or an abrupt termin-
Modification of waveforms ation of inspiration, with early activation of expiratory muscles.
◆ Inspiration not preceded by a pressure drop below PEEP. Expiratory time asynchronies
◆ Variation in peak inspiratory flow in the absence of dynamic
Cycling from inspiration to expiration is determined—​depending
hyperinflation.
on the mode of ventilation—​by time, volume, or flow. In pressure
◆ Breath-​by-​breath variability in tidal volume. support mode, transition from inspiration to expiration (cycling)
◆ Variation in shape of flow waveform (flow–​time). occurs when the inspiratory flow decreases to a set proportion (usu-
ally 25%) of the peak inspiratory flow, so that the inspiratory time
Double triggering
is dependent on the effort. In ideal conditions, cycling coincides
Double triggering is defined as two consecutive inspiratory cycles with the end of neural inspiration. However, these signals rarely
not separated by an expiration, occurring within a time frame of less completely match the patient’s own neural inspiratory time. As a
than half of the mean inspiratory time. If the patient’s respiratory consequence, the mechanical inspiration can be longer (i.e. termin-
drive increases, the duration of inspiratory effort becomes longer ated later—​delayed cycling) or shorter (i.e. terminated earlier—​
than the mechanical inflation time. This will cause the ventilator premature cycling) than the neural inspiratory time [89–​90].
to be triggered more than once within the same neural inspiration.
Premature (short) cycling
Therefore, double triggering is multiple consecutive breath cycles in
which only the first is triggered by the patient. The tidal volume of Premature cycling occurs when there is persistence of an inspira-
the second breath will be smaller than the first in pressure support, tory flow after termination of a mechanical breath. This indicates
while in volume-​assist ventilation, the tidal volume will be similar a shorter mechanical inspiratory time (premature cycling), com-
to the first breath and associated with higher airway pressure. pared to the neural inspiratory time. The patient will continue to
contract the inspiratory muscles during mechanical expiration.
Causes The effort reduces airway pressure and increases flow, resulting in
◆ Patient’s effort is greater than support delivered. a ‘notch’ in the early part of the expiratory flow, with a decrease in
◆ Longer neural inspiratory time, compared to inspiratory time of the peak expiratory flow. In addition, inspiratory muscle activa-
the mechanical breath. tion can trigger inspiration, resulting in double triggering.
 Weaning 301

Waveform identification of premature cycling patient aims to achieve liberation from the ventilator) from ‘titra-
◆ Flow: positive inflection at the end of expiration. tion’, a process aimed at optimizing the level of support in patients
not yet deemed suitable for liberation from mechanical ventila-
◆ Pressure: negative deflection ‘notch’ at the end of expiration. tion (see E Types of weaning, p. 301).
Causes
◆ Low level of PS. Types of weaning
◆ Short time constant (low lung compliance). Patients can be categorized into three groups in relation to the
◆ Setting a short cycling off criterion. time needed to achieve liberation from the ventilator [91]:
◆ Dynamic hyperinflation—​which reduces expiratory flow and 1. Simple weaning (60% patients): patients who can be extubated
therefore causes early termination of inspiration. after the first weaning test (SBT). The main clinical goal is iden-
Delayed cycling tification of readiness to wean through a systematic screening
This occurs when the ventilator breath cycle is longer than the strategy, avoiding delays in extubation.
patient’s inspiratory time. If the mechanical breath persists after 2. Difficult weaning (30–​40% of patients): patients who require up
completion of muscular inspiration, the airway pressure and flow to three SBTs (or as long as 7 days) to be successfully extubated.
waveforms will reflect the summation of two opposing forces—​ The reasons for failed weaning have to be explored and cor-
mechanical inspiration and activation of the expiratory muscles, rected. The pathophysiology of weaning failure needs to be
giving the appearance of the patient fighting the ventilator. This understood for optimal management of the patient.
asynchrony can be difficult to identify. Delayed cycling can ex- 3. Prolonged weaning (6–​15% of patients): this term applies to pa-
acerbate dynamic hyperinflation and, as a consequence, cause tients who exceed the limits of difficult weaning.
triggering asynchronies.
In addition, some patients will need mechanical ventilation for
Waveform identification of delayed cycling in pressure support >21  days and >6 hours per day and are classified as ‘long-​term
◆ A rapid decrease in inspiratory flow. weaning’. These patients—​generally with a tracheostomy—​will
◆ An increase in airway pressure at the end of inspiration (spike) require an individualized and multidisciplinary approach to
due to a combination of abrupt relaxation of the inspiratory weaning.
muscles and active contraction of the expiratory muscles. Regardless of the time required to achieve liberation, the ac-
◆ The increasing pressure can itself cause an inspiratory cepted extubation failure rate is 10–​20%. A reintubation rate of
termination. <5–​10% may indicate a too conservative approach to extubation,
which may lead to delayed liberation in some patients. By con-
Causes
trast, a reintubation rate of >20–​30% may indicate premature
◆ Excessive PS.
extubations. In order to monitor both occurrences, this guideline
◆ Long expiratory time constants. is structured to support an auditing tool to monitor weaning and
In patients with ARDS with low compliance and short expira- extubation practice.
tory time constant, increasing the pressurization rate (ramp or
rising time) has a greater impact on reducing work of breathing, Readiness testing: clinical assessment
compared to adjusting the cycling off criterion. In contrast, in Readiness testing has the double purpose of identifying patients
COPD, increasing the cycling off criterion (earlier cycling) has who are ready to be liberated from mechanical ventilation—​
a significant impact on lung mechanics, reduction of PEEPi, and avoiding extubation delays—​but also of identifying patients who
work of breathing. are unable to be liberated, thereby avoiding the risks of premature
extubation.
Before initiating the ‘liberation process’, the patient must satisfy
the conditions shown in E Box 22.1.
Weaning Patients who fulfil the readiness-​to-​wean criteria, if not al-
Discontinuation of mechanical ventilation is a two-​phase pro- ready receiving PS, can be started on a trial of PS. The level of
cess, consisting of evaluation of readiness to wean (through readi- PS will be titrated to patient comfort to achieve tidal volumes
ness testing) and weaning itself (discontinuation or liberation). of 6–​8 mL/​kg ideal body weight and a respiratory rate of <30
Readiness testing is evaluation of objective criteria to determine breaths/​minute.
whether a patient could be successfully and safely liberated from
the ventilator, while weaning may involve either an immediate Readiness testing: weaning predictors
switch from full ventilatory support to a period of breathing A weaning predictor or index is a criterion that evaluates an aspect
without assistance from the ventilator or a gradual reduction in of the respiratory function, with the objective of identifying pa-
the amount of ventilator support [2]‌. It is useful to distinguish tients who might tolerate the weaning trial (generally known as
‘weaning’ (in which the reduction of assistance given to the spontaneous breathing trial or SBT).
302 CHAPTER 22  Me c ha nical ventil at ion

Box 22.1  Readiness testing clinical assessment Weaning tests: spontaneous awakening trials

and spontaneous breathing trials
Conditions that must be satisfied before commencing the lib-
Spontaneous awakening trials—​daily interruption
eration process
of sedatives
1. Improvement or resolution of the underlying cause of ARF
A time and a safe modality should be established to interrupt or
2. Patient cooperative and pain-​free reduce all sedatives and analgesics used for sedation, excluding
3. Able to sustain spontaneous breathing analgesics needed for active pain. If the patient opens their
4. Able to cough, minimal secretions (defined as the need for eyes to verbal stimuli or tolerates sedative interruption without
suctioning >2 hours) exhibiting failure criteria, it is possible to proceed to SBT. If
5. PEEP ≤8 cmH2O, pressure support ≤8–​10 cmH2O; FiO2 the patient fails an SAT, sedatives should be restarted at half
≤0.4 with SaO2 >90% and PaO2 >8–​9 kPa; PaO2/​FiO2 the previous dose and then titrated to achieve patient comfort
>20–​26.6  kPa [92–​94].
6. Stable haemodynamics; no or minimal vasopressor support
7. No uncorrected metabolic abnormalities Spontaneous breathing trials
8. Fluid balance optimized An SBT refers to a time during which the patient breathes
9. Consider measuring NT-​proBNP for patients with LV dys- through the ETT either without any ventilator support (e.g.
function—​this may guide fluid management through a ventilator in ‘flow-​by’) or with minimal ventilator
10.  Tympanic temperature between 36°C and 38°C support (e.g. low level of pressure support). There is strong evi-
1 1. No relevant electrolyte disorder and haemoglobin level dence to support the recommendation of an SBT as the initial
70–​80  g/​L liberation strategy for patients with ARF [95–​98]. The SBT pro-
vides objective criteria to determine if patients can be success-
fully extubated. The SBT should not include PEEP. A  ‘T-​piece
Weaning indices should be evaluated before the SBT, which test’ (here performed in ‘flow-​by’ mode on the ventilator) ac-
functions as a diagnostic test to determine the probability of suc- curately replicates the work of breathing required from the pa-
cessful extubation. Integrative weaning indices evaluate more than tient after extubation and constitutes a reliable assessment of the
one aspect of respiratory function. Although few of the weaning ability of an intubated patient to maintain sufficient ventilation
indices are predictive per se, the following indices should be rou- once extubated. By contrast, adding PS levels may lead to under-
tinely measured in clinical practice. The weaning index criteria can estimation of the risk of extubation failure in some patients (see
be particularly useful in situations in which the decision to liberate E Box 22.2). PS is commonly believed to be needed to over-
from mechanical ventilation is problematic (see E Table 22.5). come the resistance of the ETT. These beliefs fail to account for
the increased resistance of the inflamed natural upper airways
following extubation, so that the work of breathing through a
Table 22.5  Weaning indices that predict successful ventilator T-​piece is similar to the work of breathing following extubation
discontinuation [99]. In other words, post-​extubation work of breathing is best
Indices Cut-​off value Ref AUC
RSBI = f/​VT <105 breaths/​min/​L [100] 0.89
P0.1 < –​5.0 cmH2O* [101] 0.93
Maximum < –​30 cmH2O (i.e. the more [100] 0.61 Box 22.2  Risk factors associated with high risk
inspiratory pressure negative, the better) of extubation failure
(PImax) > −15 cmH2O**
1. Age >65 years or underlying chronic cardiorespiratory
MIP or NIF
disease
P0.1/​MIP <0.09–​0.14 cmH2O [101, 102] 0.99
2 . COPD*
P0.1 × f/​VT <270 cmH2O/​breaths/​min/​L [103, 104] 0.81 3 . Heart failure/​LV dysfunction*
Or
<450 cmH2O/​breaths/​min/​L 4 . OSA/​obesity*
IWI >25 mL/​cmH2O/​breaths/​min/​L [104] 0.96 5 . Low PImax*
(CRS × SaO2)/​(f/​VT) 6 . PaCO2 >6.5 kPa*
VT, tidal volume; P0.1, airway occlusion pressure; IWI, integrative weaning index; AUC, 7 . Neuromuscular disorders*
area under the curve; RSBI, rapid shallow breathing index. 8 . Positive fluid balance
* A P0.1 value of 3.5 cmH2O corresponds to a respiratory effort of approximately 0.75 J/​
9 . Ventilation >6 days
L. Respiratory effort values lower than 0.75 J/​L are considered predictive of successful
weaning from MV. * These patients may benefit from ‘prophylactic’ NIV immediately post-​
** A low PImax is a valuable parameter because patients who present with extreme extubation if SBT is successful.
inspiratory muscle weakness (MIP > −15 cmH2O) will probably be unable to.
 RE F E RE N C E S 303

approximated by an SBT without assistance or tube compen-

sation. Therefore, a low-​PS SBT may underestimate the risk of Conclusion
extubation failure, especially if the prevalence of extubation
During assisted mechanical ventilation, patient and ventilator inter-
failure is high (e.g. in patients under prolonged mechanical ven-
action needs to be monitored. Asynchronies are prevalent and, if
tilation or having ICU-​acquired polyneuromyopathy), while low
frequent, can affect important patient-​centred outcomes, including
PS (5–​7 cmH2O) may be used in patients at low risk of failure.
mortality. A systematic approach to detection of common abnormal-
ATC can be added if the internal diameter of the ETT is ≤7 mm
ities in flow and pressure waveforms can allow the clinician to diag-
[91]. Similarly, maintaining PEEP during the SBT may increase
nose and correct asynchronies. Holistic management of sedation,
the rate of extubation failures, as PEEP may mask worsening in
sleep, and ventilator settings is required to harmonize interaction
LV function. Eliciting the patient’s subjective impression about
with the ventilator and aid liberation from mechanical ventilation.
the ability to breathe unassisted at the end of the weaning test
Newer modes of ventilation (e.g. PAV+ based on analysis of respira-
has been shown to improve the predictive value of the weaning
tory mechanics, and NAVA based on neural respiratory output) that
test [96]. SBT should not be performed more than once a day to
are designed to detect inspiratory muscle activity may improve syn-
prevent fatigue.
chrony and support the breath in proportion to the patient’s efforts.

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 CHAPTER 23

Temporary pacing
Bulent Gorenek

Summary
Contents Temporary cardiac pacing by electrical stimulation of the heart is indicated as a
Summary  306 short-​term treatment of life-​threatening bradyarrhythmias or tachyarrhythmias. It
Introduction  306
can be used temporarily until the arrhythmias resolve or as a bridge to permanent
pacing.
Indications  306
Acute coronary syndrome patients  307
Symptomatic bradycardias needing temporary pacing may occur in AMI, during
Patients undergoing percutaneous coronary percutaneous coronary intervention, and in patients with sinus node dysfunction.
intervention  307 Temporary pacing can also be useful for terminating or suppressing some types of
Sinus node dysfunction  308 supraventricular and ventricular arrhythmias.
Prevention, diagnosis, and termination of
tachycardias  308 Single-​chamber, dual-​chamber, or biventricular pacing modes can be used.
Methods of temporary pacing  308 In haemodynamically compromised patients, dual-​chamber pacing is preferred.
Transvenous (endocardial) pacing  308 Ideally, this procedure is performed under fluoroscopy, but electrode catheters can
Modes of pacing  308 also be inserted without fluoroscopy, with ECG and/​or pressure monitoring.
Single-​chamber pacing  308
Several methods of temporary pacing are available: transvenous, external, and
Dual-​chamber pacing  308
Parts of transvenous (endocardial) transoesophageal pacing. Transvenous pacing is the most commonly used tech-
pacing  309 nique. Although this method is safe and easy, some complications related to venous
Electrode catheters (leads)  309 access or caused by the inserted electrode catheters or by an electrical dysfunction
The external generator  309
Implantation procedure  309
of the pacing device may occur, either during or after the implantation.
Complications  310
Complications related to venous
access  310
Complications related to electrode
catheters  310
Complications related to the electrical
performance of the pacemaker  310 Introduction
External (transcutaneous) pacing  310
Transoesophageal pacing  311 The contribution of the ICCU to the reduction in mortality from acute cardiovascular
Biventricular pacing  311 events over the past 30 years has been well documented. Many patients with acute CVDs
Conclusion  311 hospitalized in the ICCU are at high risk of developing advanced degrees of conduction
Personal perspective  311 block or cardiac arrest that may necessitate temporary pacing, which is therefore con-
Further reading  312 sidered to be a necessary skill for every cardiologist.
References  312 Temporary pacing was first accomplished transcutaneously by Zoll in 1952 [1]‌and
transvenously by Furman in 1958 [2]. Pacing techniques have since been refined, and
new pacing modalities have been developed. The goal of temporary cardiac pacing in the
ICCU is to restore effective cardiac depolarization and myocardial contraction, resulting
in the delivery of adequate cardiac output.
This chapter reviews the indications and methods of temporary pacing in the ICCU.

Indications
The indications for temporary pacing are less certain than those for permanent pacing.
Indeed, there is no clear consensus on many of the indications for temporary pacing,
 In di c at i on s 307

with most recommendations coming from clinical experience, ra- myocardial damage and a greater chance that the bradycardia
ther than from clinical trials. and conduction abnormalities will resolve. There may, however,
As recommended in the 2013 ESC guidelines on cardiac pacing be a need for temporary pacing. Temporary pacing is necessary
and CRT, the following issues are relevant as guidance for clinical for patients with symptomatic bradycardias but should also be
practice  [3]‌: considered for those at high risk of developing a third-​degree AV
◆ Temporary transvenous pacing shall not be used routinely and block as a consequence of an ACS, particularly AMI.
only as a last resort when chronotropic drugs are insufficient. Patients with a third-​degree AV block and a wide QRS com-
◆ Positive chronotropic drug infusion (e.g. isoproterenol, adren- plex escape rhythm require a temporary pacemaker, even though
aline, etc.) may be preferred for a limited time, unless there is a symptoms are absent. The same is true of new-​onset type 2
contraindication. second-​degree AV block. Temporary pacing is also indicated in
◆ Temporary transvenous pacing should be limited to cases of trifascicular block. However, there is no common consensus for
high-​degree AV block without escape rhythm, life-​threatening the use of temporary pacing in patients with bifascicular block,
bradyarrhythmias, such as those that occur during interven- which carries a 15–​31% risk of progression to a second-​or third-​
tional procedures (e.g. PCI), or rarely in acute settings such as degree AV block in AMI [9, 10]. A first-​degree AV block requires
AMI, drug toxicity, or concomitant systemic infection. no treatment. A  new LBBB usually is associated with extensive
If the indications for permanent pacing are established, every ef-
◆ anterior infarction, with a high likelihood for developing a com-
fort should be made to implant a permanent pacemaker as soon plete AV block and pump failure. Preventive placement of a tem-
as possible. porary pacing electrode may be warranted.
◆ In general, temporary cardiac pacing should not be considered Temporary pacing may also need to be considered if the pa-
for asymptomatic patients who have a stable rhythm (like first-​ tient with AMI experiences episodes of asystole or develops VT
degree AV block or Mobitz 2 or stable escape rhythm). Although or VF in response to bradycardia. Bradycardia-​induced sustained
the mentioned rhythms are stable for most patients, there are ventricular arrhythmias can be prevented by rapid pacing in AMI
exceptions. If there is doubt, having transcutaneous pacing ready patients. One example is torsades de pointes (TdP) that are as-
for use in emergencies may be reasonable for daily practice. sociated with a long QT interval. Atrial or ventricular pacing at
higher rates can prevent the initiation of TdP by shortening the
Acute coronary syndrome patients QT interval and preventing ventricular ectopic beats that might
Bradyarrhythmias are particularly well-​ recognized compli- initiate the tachycardia.
cations of AMI. Bradyarrhythmias, including AV block and While pacing has not been shown to increase long-​term sur-
sinus bradycardia, occur most frequently with an inferior MI. vival, it may still be indicated in symptomatic bradyarrhythmias
Complete AV block occurs in approximately 20% of patients that are associated with AMI. In the current ESC guidelines for
with an acute RV infarction. Infranodal conduction disturb- the management of AMI in patients presenting with ST-​segment
ances with wide-​ complex ventricular escape rhythms occur elevation, temporary pacing is indicated in cases of failure to re-
most frequently in large anterior MI and portend a very poor spond to atropine, sinus bradycardia associated with hypoten-
prognosis. sion, AV block II (Mobitz 2), or AV block III with bradycardia
Sinus bradycardia is common in the first hours, especially in that causes hypotension or heart failure [11].
inferior infarction. It is estimated that approximately 20% of pa-
tients with an AMI develop an AV block [4–​6], which can be in- Patients undergoing percutaneous
duced either by ischaemia or necrosis of the conduction system coronary intervention
or by an autonomic imbalance. Patients with a peri-​infarction New conduction defects occur in approximately 1% of patients
AV block have higher in-​hospital and late mortality than those who undergo PCI [12]. RBBBs are the most common conduction
with preserved AV conduction. The increased mortality is related disturbances in these patients, and this is followed by first-​degree
to the extensive myocardial damage that is required to develop a AV blocks. Although these defects almost always disappear
heart block, rather than to the heart block itself. without treatment before the time of hospital discharge, they oc-
Management of patients with conduction disturbances after an casionally require the elimination of drugs that depress cardiac
MI depends, in part, on the location of the infarct. A high-​degree activity [13].
AV block that is associated with an inferior wall MI is located Conduction disturbances are more common in AMI patients
above the His bundle in 90% of patients [7, 8]. As a result, a third-​ undergoing primary PCI. In a study published a few years ago,
degree AV block often results in only modest and usually transient 6.3% of AMI patients developed a third-​degree AV block. In
bradycardia, with escape rhythm rates above 40 bpm. However, a 86.3% of these cases, the block occurred before or during PCI.
high-​degree AV block that is associated with an anterior MI is And in 94.5% of the patients, resolution of the block occurred in
more often located below the AV node [7]‌, is usually symptom- the catheterization laboratory [14].
atic, and has been associated with a higher mortality rate. Pacing is rarely required during PCI. Among interventional
Reperfusion strategies with thrombolysis and angioplasty cardiologists, there is no consensus regarding the need for tem-
have reduced the need for permanent pacing, since there is less porary pacemaker placement during PCI. When a third-​degree
308 CHAPTER 23  Temp orary  pacing

AV block develops, atropine (though rarely helpful in the set- might be more likely to be accelerated by anti-​tachycardia pacing
ting of inadequate escape and deterioration) should be given. and subsequently deteriorate into VF.
Coughing may help support the circulation and maintain con- There are no known contraindications to the use of temporary
sciousness while a temporary pacing catheter is inserted. pacing as a therapeutic or prophylactic modality. Nevertheless,
Although there is no consensus, prophylactic lead insertion certain relative contraindications may exist in any given patient.
can be performed before intervention in some high-​risk patients Among others, application of asynchronous pacing, in competi-
undergoing PCI for the RCA or circumflex artery. However, it is tion with an intrinsic rhythm, may provoke arrhythmias in elec-
not indicated in total occlusion patients. trically unstable individuals.

Sinus node dysfunction
In sinus node dysfunction, when signs or symptoms of haemo- Methods of temporary pacing
dynamic compromise exist, temporary pacing may be necessary
if IV atropine administration fails to stabilize the patient. Patients For most other patients, a rate of 60–​70 bpm will likely be ad-
with compromised sinus node function may develop sinus nodal equate. If the patient is pacemaker-​dependent, the pacemaker
depression following drug therapy with antiarrhythmic drugs can be turned to the least sensitive value. Methods of temporary
in the ICCU. Therapy with these agents can be carried out with pacing include transvenous (endocardial) pacing, external (trans-
greater safety if a temporary pacemaker is inserted to prevent cutaneous) pacing, and transoesophageal pacing.
drug-​induced bradycardia and circulatory decompensation; per-
manent pacing is frequently required, and its early use in selected
Transvenous (endocardial) pacing
patients can avoid the need for the additional invasive procedure Although transvenous pacing is the most reliable pacing method
of temporary pacing [15]. available, its effective use requires an invasive procedure, as well
In a tachycardia–​bradycardia syndrome, there is often an oscil- as an experienced operator [23, 24].
lation between rapid rates that are due to AF and slow rates that
Modes of pacing
are caused by sinus bradycardia. The slow sinus rates can result
in AF as an escape arrhythmia; maintenance of a faster heart rate A number of pacing modes are available for temporary use; pacing
with pacing may prevent this. can be single-​chamber (atrial or ventricular) or dual-​chamber.
Single-​chamber pacing
Prevention, diagnosis, and termination In single-​chamber temporary pacing, only one electrode catheter
of tachycardias is placed into a chamber of the heart. Most often, it is placed into
Temporary pacemakers can be used for the prevention of pause-​ a ventricle, but on certain other occasions, an atrium is used.
dependent VTs, which may occur in some patients with long QT Ventricular pacing (VVI) is the most commonly used pacing
syndrome, with the use of antiarrhythmic drugs, and also in AMI. mode in the ICCU. The advantages of ventricular pacing in-
In the current ESC guidelines for the management of AMI in pa- clude the requirement for only a single electrode catheter and
tients presenting with ST-​segment elevation, temporary pacing is the ability to protect the patient from dangerous bradycardias. As
indicated in cases of failure to respond to atropine in patients with for the technical aspect of implantation, it is a relatively simple
polymorphic VT [11]. procedure, as just a single lead needs to be implanted. The pro-
Pacing may also be used for the differential diagnosis of cedure time is shorter. Complication rates are lower, as only a
tachycardias. In patients with wide-​complex tachycardia, an atrial single needlestick is needed to get venous access. However, ven-
recording may differentiate between VT and supraventricular tricular pacing cannot maintain AV synchrony and a lack of AV
tachycardia (SVT) with aberrancy. The atrial recording may be synchrony can result in ‘pacemaker syndrome’, which can be de-
either transvenous or transoesophageal. fined as loss of AV synchrony, retrograde ventriculoatrial con-
Anti-​tachycardia or overdrive pacing may be helpful for duction, and absence of a rate response to physiological needs.
acute management of patients with frequent recurrent episodes, Atrial pacing is appropriate for patients with sinus node dysfunc-
particularly when drug therapy is ineffective. Although this tion who have an intact AV nodal function or for termination of
method is not effective in converting AF to sinus rhythm, many some SVTs.
supraventricular re-​entrant tachycardias can be terminated by Dual-​chamber pacing
pacing techniques if the pathway is susceptible to penetration by Temporary dual-​chamber pacing may be useful for patients who
exogenous electrical stimuli, a phenomenon known as ‘entrain- require AV sequential pacing for haemodynamic benefit, for in-
ment’ [16–​18]. Re-​entrant arrhythmias that can be interrupted stance, during AMI, particularly when associated with haemo-
following entrainment include sinus node re-​ entrant tachy- dynamic instability. It can be used to assess the benefit of AV
cardia, AV nodal re-​entrant tachycardia (AVNRT), atrial tachy- synchrony when permanent pacing is contemplated.
cardia (AT), atrial flutter, and AV re-​entrant tachycardia (AVRT) In dual-​chamber pacing, electrode catheters are placed in two
[15, 19–​23]. Re-​entrant monomorphic VT can also be ended by chambers of the heart. One paces the atrium, and the other paces
anti-​tachycardia pacing. However, VT rates that exceed 200 bpm the ventricle. This approach more closely matches the natural
 M ethod s of tem p ora ry   pac i n g 309

pacing of the heart, and this type of pacing can coordinate func- sensing, ventricular pacing on demand), or DDD (dual-​chamber
tion between the atria and the ventricles. sensing and pacing on demand).
This was demonstrated by Murphy and colleagues in 1992; Generators either can be small enough to allow the patient to
temporary ventricular pacing at 80 bpm was found to be no better be ambulant or require to be placed at the bedside. Batteries must
than spontaneous bradycardia, whereas dual-​chamber pacing re- be checked at least daily and the generator sited, so that it cannot
sulted in improved cardiac output and blood pressure and falls in fall and exert traction on the pacing electrode catheter. Spare bat-
the pulmonary wedge pressure and right atrial pressure [25]. This teries should be kept available at all times. It is recommended that
would suggest that the majority of temporary pacing should be new batteries be used with each patient. Low battery condition is
AV synchronous in the presence of normal sinus node activity; usually signalled by a flashing red light during sensing or pacing.
however, despite these findings, the more complex procedure as- When this occurs, the batteries should be replaced without delay.
sociated with temporary transvenous dual-​chamber pacing has Some generators may also offer high-​rate pacing to allow over-
led to the continued routine use of ventricular pacing in the tem- drive pacing of tachyarrhythmias [26].
porary setting [26].
Implantation procedure
Parts of transvenous (endocardial) pacing Implantation can be done at the bedside in the ICCU or in a
A transvenous pacemaker system has two parts:  the electrode specially equipped room that is near the ICCU. The equipment
catheters (leads) and the external generator. needed for implantation includes an introducer sheath, an elec-
trode catheter, and an external generator. An ECG machine and a
Electrode catheters (leads)
cardiac monitor should also be available. Once all the equipment
The tip of a bipolar temporary pacing electrode catheter has a
has been assembled, the patient is prepped in the usual sterile
distal tip electrode and a proximal ring electrode. As cathodal
fashion. A wide area should be cleaned, and the patient should be
pacing has a lower threshold, it is customary to give a negative
generously draped to ensure that all the equipment remains in a
polarity to the tip and a positive polarity to the ring electrode. The
sterile field [30].
proximal connectors of the electrode catheter are connected to an
Venous access may be achieved via the internal jugular, ex-
external pacemaker.
ternal jugular, subclavian, antecubital, or femoral veins. However,
Temporary pacing electrode catheters are classified as flexible,
the best access site for temporary pacing leads is via the left sub-
semi-​floating, or non-​floating catheters. The latter group carries
clavian vein or the right internal jugular vein. On the other hand,
a higher risk of cardiac perforation, and thus they are gener-
the choice of a venous access site may depend on the physician’s
ally used only under fluoroscopic guidance where their stiffness
preference and experience and on the urgency of the clinical
yields the benefit of easier manipulation [27]. In emergency
situation. The subclavian route should be avoided following FL
situations, a semi-​floating catheter, with or without a balloon
or in the presence of antithrombin therapy. If a permanent pace-
tip, is used most commonly [27–​29]. In patients who are experi-
maker is anticipated, the left subclavian site should generally
encing cardiac arrest, inflating the balloon carries no benefit;
be preserved and a different site should be used for temporary
this is because there is no forward flow of blood to guide an
pacing. The right internal jugular and left subclavian veins may
inflated balloon through the venous system into the right side
be accessed quickly in an emergency, and they may afford direct
of the heart [30].
passage of the pacing catheter to the RV apex without requiring
Most manufacturers misguidedly pack their temporary ven-
fluoroscopic imaging [24].
tricular electrodes with a near 90° bend fashioned at the tip, often
If fluoroscopy is available, a semi-​rigid pacing lead can be used.
with a stiff former to keep this shape. This does not aid placement
The lead is advanced until it reaches the right atrium. The pre-
of the electrode. Ideally, there should be a 20–​30° curve at the tip,
ferred location for pacing in the RV is usually the apex. If fluoros-
and it may be necessary to straighten some of the bend out of the
copy is not available, ECG can be used to guide lead placement.
electrode before insertion [31].
In such cases, it is recommended to use a balloon-​tipped catheter.
The external generator When the catheter enters the right atrium, the A wave becomes
The external pacing generator is used to deliver the electrical larger than the V wave. And when the catheter enters the RV, the
current through the pacing catheter. The various available gener- A wave becomes smaller than the V wave.
ators share the same basic features; these allow adjustment of the The chamber must be paced at 10 bpm above the patient’s rate,
pacing output, pacing rate, pacing mode, and sensitivity to the and then the amplitude of the voltage delivered is slowly turned
intrinsic activity. Dual-​chamber generators will allow a greater down until capture is lost. Capture is depolarization and re-
flexibility in pacing mode and will enable the adjustment of AV sultant contraction of the atria or ventricles in response to a pace-
delay and refractory periods [26]. maker stimulus. The threshold is the minimum voltage needed
Several types of external generators are available which permit for capturing the chamber paced. Ideally, the ventricular capture
single-​and dual-​ chamber pacing. The single-​ chamber units threshold should be lower than 1 mA. The output should be set at
function in a VVI or AAI mode if demand pacing is used or in 3–​5 times the capture threshold [24].
a VOO or AOO mode when fixed rate pacing is preferred; the Sensing is the ability of the pacemaker to sense an intrinsic
dual-​chamber modes are DOO (fixed rate), DVI (dual-​chamber electrical signal, which depends upon the amplitude, slew rate,
310 CHAPTER 23  Temp orary  pacing

and frequency of the signal. The sensing threshold should also be consideration of this complication. Definitive correction needs
measured if an intrinsic ventricular activity is present. Following electrode catheter repositioning or replacement. Diaphragmatic
positioning of either or both of the electrode catheters, they must stimulation results from phrenic nerve stimulation. Screening for
be secured to the skin to prevent displacement by movement or this complication by pacing at maximum output is a requisite part
traction [26]. of correct implantation procedure. Malposition is diagnosed by
unacceptable implant pacing, sensing, or defibrillation thresholds.
Complications The presence of an atrial or ventricular septal defect can allow
Transvenous cardiac pacing may be associated with a number of the passage of an electrode catheter to the left heart, which is one
different complications, which occur in over 20% of patients [32]. of the most common causes of malposition. Passage into the left
These complications not only are restricted to the implantation heart is more common with ventricular electrode catheters [33].
per se, but also involve securing the position of the implanted The operator must be alert to the resultant paced ECG QRS com-
lead, the change of capture threshold, malfunction, faulty pro- plex morphology. If a right bundle is involved, a left-​sided ven-
gramming, or battery depletion of the external pacemaker; it tricular lead position should be excluded. Various arrhythmias,
also includes those complications related to the patient who may including VT and VF, may also occur in some patients as an elec-
extract the pacing lead accidentally. Furthermore, longer use of trode catheter-​related complication which requires repositioning
temporary transvenous pacing may restrict the patient to being of the electrode catheter. Rarely, such arrhythmias (when they are
bedridden, with accompanying risks of infection and thrombo- frequent) do not allow the electrode catheter to be placed [33].
embolic events [8]‌.
Complications related to the electrical performance
After lead placement, a chest radiograph should be obtained to of the pacemaker
establish the position of the lead, to evaluate for any evidence of Some complications may be related to the electrical performance
pneumothorax. And in addition, an ECG should be recorded to of the pacemaker electrode catheter and generator (see E Boxes
determine the electrocardiographic appearance of the QRS com- 23.1, 23.2, and 23.3). If pacing suddenly fails, the connections to
plex. The following sections review the complications related to the external generator, generator batteries, and the possibility of
venous access, electrode catheters, and the electrical performance oversensing must be checked. If pacing spikes can be seen, but no
of the device. capture occurs, the output should be increased and consideration
Complications related to venous access should be given to repositioning or replacing the electrode [26].
Venous access-​ related complications include pneumothorax,
haemothorax, and air embolism. The risk of pneumothorax External (transcutaneous) pacing
is related to the experience of the implanter and the number
Transcutaneous (or external) pacing is a temporary means of
and difficulty of subclavian punctures. Pneumothorax is often
pacing a patient’s heart during a medical emergency. It is ac-
small, asymptomatic, and noted incidentally on follow-​up CXR.
complished by delivering pulses of electric current through the
However, tension pneumothorax should always be part of the
patient’s chest, which stimulates the heart to contract. During
differential diagnosis when hypotension or PEA ensues during
transcutaneous pacing, pads are placed on the patient’s chest, ei-
an implantation. Haemothorax results from trauma to the great
ther in the anterior/​lateral position or in the anterior/​posterior
vessels [33]. Special care with regard to catheter insertion and
position. The anterior/​posterior position is preferred, as it min-
manipulation should be taken in order to prevent air embolism,
imizes transthoracic electrical impedance. Chest wall electrodes
especially in patients with coexisting pulmonary disease, in
with a high impedance interface are required for external pacing.
whom coughing may increase the likelihood of venous air em-
Although these can be used during an asystolic cardiac arrest,
bolism. Massive air embolism, which is very rare, is potentially
fatal and should be recognized and treated promptly.
Complications related to electrode catheters Box 23.1  Causes of loss of capture*
Electrode catheter-​ related complications include perforation,
dislodgement, diaphragmatic stimulation, malposition [34], and Perforation
◆

catheter-​induced arrhythmias. Perforation, which is very rare, Electrode catheter dislodgement

◆

can involve the great vessels, the right atrium, or the RV. It usu- Electrode catheter fracture
◆

ally occurs without serious sequelae. However, a most devastating Generator malfunction or battery depletion
◆

manifestation is cardiac tamponade, which requires prompt diag- Generator lead connection problems
◆
nosis and pericardiocentesis. An initial suspicion should be evalu- Poor endocardial contact
◆
ated by fluoroscopy of the heart border, which is an immediately Local myocardial necrosis or inflammation
◆
available diagnostic method. Confirmation of the diagnosis is Hypoxia acidosis
◆
obtained by emergent bedside echocardiography. Electrode cath-
Electrolyte disturbances
◆
eter dislodgement takes place in 2–​5% of implants, usually in the
* Depolarization and resultant contraction of the atria or ventricles in re-
first 24–​48 hours post-​implantation. Intermittent undersensing sponse to a pacemaker stimulus.
or loss of capture on post-​implantation telemetry should prompt
 Per s ona l  pe r spe c t i v e 311

Box 23.2  Causes of undersensing* Transoesophageal pacing

Transoesophageal pacing is useful in selected patients in the
Perforation
◆
ICCU to diagnose and treat arrhythmias. It is feasible because of
Inadequate cardiac signal
◆
the proximity between the oesophagus and the posterior aspect of
Exit block
◆
the atria. In this technique, a transoesophageal pacemaker cath-
Electrode catheter dislodgement
◆
eter can be used for atrial pacing and/​or recording. Depending on
Electrode catheter fracture
◆
the type of catheter used, it can be inserted through the mouth
Generator malfunction or battery depletion
◆ or the nose. This approach is effective to convert SVTs such as
Local myocardial necrosis or inflammation
◆ atrial flutter. It results in immediate restoration of the sinus
* Failure of the pacemaker circuitry to sense intrinsic P or R waves. rhythm in 15–​50% of patients with atrial flutter. Oesophageal
ventricular pacing has also been well described. However, the use
of transoesophageal pacing is not common in daily practice, as
there is little evidence that external pacing is successful in this set- the catheter is uncomfortable to place, pacing is usually unreli-
ting. In addition to synchronized transcutaneous pacing offered able, and pain is common because it requires a high current for
by newer cardiac monitors/​defibrillators, there is also an option capture.
for asynchronous pacing.
Another possible indication is its use as a standby therapy for Biventricular pacing
patients at high risk of developing symptomatic bradycardia. The Temporary biventricular pacing, which is rarely indicated,
available external pacemaker systems are suitable for providing may improve cardiac performance in patients with major
standby pacing in AMI, especially for those not requiring imme- intraventricular conduction block and severe heart failure that is
diate pacing and only at moderate risk of progression to an AV related to LV dysfunction [35]. CRT with biventricular pacing re-
block. These do not entail the difficulty in application and risk of duces heart failure symptoms and improves survival in patients
complications of IV systems. External pacing technology is also with advanced heart failure, reduced LV systolic function, and
well suited to patients receiving thrombolytic therapy, as it re- mechanical dyssynchrony.
duces the need for vascular interventions. A transvenous pacing catheter, placed in a coronary vein via
This method can also be used to terminate some sustained the coronary sinus, may improve heart failure symptoms in these
tachycardias. Single and multiple beat pacing stimulations have patients. It was demonstrated that this mode of pacing may pro-
been described as a useful treatment for these arrhythmias. vide short-​term benefits to selected patients in CS [36]. Moreover,
Despite some advantages, external pacing is not a preferred responses to this therapy may also help to determine the benefit
pacing technique for many physicians. In addition to causing sig- of permanent biventricular pacing. However, clinical experience
nificant discomfort, sedation or a state of unconsciousness is re- on the use of temporary biventricular pacing is limited, and this
quired to use this approach effectively for more than backup or method does not change the mortality rate within the ICCU.
emergency pacing. Reliability limits its use, and it is often difficult
to determine if there is adequate ventricular capture.
The task force members of the 2013 ESC guidelines on car- Conclusion
diac pacing and CRT warn that external pacing provided by
patches and an external defibrillator does not provide reliable ICCU patients have an increased risk of new-​ onset cardiac
ventricular stimulation and therefore should only be used under conduction abnormalities. Temporary pacing is a potentially
strict haemodynamic and ECG monitoring, when no other op- lifesaving intervention, used primarily to correct profound brady-
tion is available. As soon as possible, an alternative action should cardia in these patients. Any patient with acute haemodynamic
be undertaken such as administration of chronotropic drugs or compromise that is caused by bradycardia or episodes of asys-
temporary or permanent pacing [8]‌. tole should be considered for temporary cardiac pacing in the
ICCU. However, because of high complication rates, temporary
transvenous pacing should not be used routinely and only as a last
Box 23.3  Causes of oversensing* resort when chronotropic drugs are insufficient.

Myopotentials
◆

Electromagnetic interference
◆
Personal perspective
Extrasystoles
◆

Electrode catheter dislodgement

◆ Although the techniques of cardiac pacing have been de-
Electrode catheter fracture
◆
veloped since 1958, there are still some problems with tem-
porary pacing. For instance, the complication rates remain
Generator malfunction
◆
high. In the future, we believe that easier, less complicated,
* The sensing of events other than P or R waves by the pacemaker circuitry.
and faster electrode catheter placement methods will be
312 CHAPTER 23  Temp orary  pacing

developed. Non-​invasive pacing methods will become more pacing, and the use of temporary biventricular pacing will
comfortable and more effective. Furthermore, physiological be a routine therapeutic approach in the ICCU in selected
pacing modes will be commonly preferred over ventricular patients with severely reduced LV function.

Further reading
Brignole M, Auricchio A, Baron-​Esquivias G, et al. 2013 ESC Guidelines From the Joint EHRA, ACCA, and EAPCI Task Force. Europace
on cardiac pacing and cardiac resynchronization therapy:  the Task 2014;16:1655–​73.
Force on cardiac pacing and resynchronization therapy of the Hamad MA, van Gelder BM, Bracke FA, van Zundert AA, van Straten
European Society of Cardiology (ESC). Developed in collaboration AH. Acute hemodynamic effects of cardiac resynchronisation therapy
with the European Heart Rhythm Association (EHRA). Eur Heart J in patients with poor left ventricular function during cardiac surgery. J
2013;34:2281–​329. Card Surg 2009;24:585–​90.
Echt DS, Cowan MW, Riley RE, Brisken AF. Feasibility and safety of a novel Harrigan RA, Chan TC, Moonblatt S, Vilke GM, Ufberg JW. Temporary
technology for pacing without leads. Heart Rhythm 2006;3:1202–​6. transvenous pacemaker placement in the emergency department. J
Fitzpatrick A, Sutton R. A guide to temporary pacing. BMJ Emerg Med 2007;32:105–​11.
1992;304:365–​9. Lee KL, Tse HF, Echt DS, Lau CP. Temporary leadless pacing in heart
Gammage MD. Temporary cardiac pacing. Heart 2000;83:715–​20. failure patients with ultrasound-​ mediated stimulation energy and
Ganz LI. Temporary cardiac pacing. Cardiac Electrophysiology Review effects on the acoustic window. Heart Rhythm 2009;6:742–​8.
1999;2:389–​92. Silver MD, N Goldschlager. Temporary transvenous cardiac pacing in the
Gorenek B, Blomström Lundqvist C, Brugada Terradellas J, et al.; European critical care setting. Chest 1988;93;607–​13.
Heart Rhythm Association; Acute Cardiovascular Care Association; Steg PG, James SK, Atar D, et  al. ESC Guidelines for the management
European Association of Percutaneous Cardiovascular Interventions. of acute myocardial infarction in patients presenting with ST-​segment
Cardiac Arrhythmias in Acute Coronary Syndromes: Position Paper elevation. Eur Heart J 2012;33:2569–​619.

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 CHAPTER 24

Ultrasound-​guided vascular
access in intensive/​acute
cardiac care
Richard Paul

Contents
Summary  314 Summary
Introduction  314 Vascular access is an essential requirement for the care of the critically ill cardiac
Reduced central venous cannulation patient, being necessary for drug and fluid delivery and for monitoring of a patient’s
complications with ultrasound  315
haemodynamic response to an instigated therapy. The most common vascular ac-
Arterial access  315 cess procedures conducted in the acute cardiac care unit are central venous and per-
Indications for vascular access  315 ipheral venous access and arterial cannulation. Traditional landmark methods are
Contraindications to vascular access  316 associated with complication rates ranging from 18% to 40%, depending on the site
Equipment and operation  316 of access. The use of ultrasound to guide venous and arterial access has been shown
Probe type  316 to reduce the incidence of complications, such as inadvertent arterial puncture and
Probe orientation  316
Type of images  316
pneumothorax formation (venous) and posterior wall puncture (arterial), to re-
Real-​time versus static imaging  317 duce the time taken and number of attempts to place a catheter, and to reduce the
Vessel identification  317 incidence of complete failure to insert a vascular access device. Since 2002, inter-
Anatomy  317 national consensus groups have published recommendations that two-​dimensional
Doppler  317
Specific information for access via different ultrasound guidance should be the preferred method for elective and emergency
routes  317 internal jugular catheter insertion. This chapter explores the evidence for the use of
Internal jugular  317 ultrasound to guide vascular access across multiple sites of insertion and describes
Subclavian  318
the basic equipment and techniques necessary for successful deployment.
Femoral  319
Arterial cannulation  319
Peripheral venous access  319
Training  320
Personal perspective  320
Further reading  320
References  320
Introduction
Vascular access is vital for the care of the critically ill cardiac patient, with procedures
including central venous, arterial, and peripheral venous cannulation. It is estimated that
approximately 200 000 CVCs are inserted annually in the NHS in the UK [1]‌and >15 mil-
lion devices sited per year in the US [2]. Historically, the preferred method to guide cen-
tral venous cannula insertion was using anatomical landmarks; however, this depends
upon the experience and skill of the operator, patient comorbidities (e.g. coagulopathy,
obesity, previous surgery), the environment (e.g. resuscitation, mechanical ventilation),
and crucially on the mistaken assumption that all patients share the same anatomy.
Consequently, failure rates of 7–​26% have been reported in the literature [3–​5]. In the
1990s, multiple randomized clinical trials demonstrated the superiority of US-​guided
vascular access over landmark techniques [6–​8]. These findings were supported by two
meta-​analyses [9, 10]; however, with limited availability of equipment or formal training
 I n di cati on s for  vas cul a r   ac c e s s 315

and poor recognition of the benefits of using US, adoption Table 24.1  Relative risk reduction with ultrasound guidance
was not immediately widespread [11–​13]. An analysis of cost-​ for internal jugular venous access over use of the landmark technique
effectiveness estimated the economic cost of using US for central
Complication type Relative risk reduction (%)
venous cannulation was <£10 per procedure (<€12) [14], with an
estimation that, for every 1000 patients, 90 complications would Failed placement 86 (CI 67–​94; P <0.001)
be avoided, with a net cost saving of £2000 (€2400). What this Complications 57 (CI 13–​78; P = 0.02)
study failed to factor in was the cost of litigation. Cook (2011) re- Failure on first attempt 41 (CI 12–​61; P = 0.009)
ported data from the NHS Litigation Authority (NHSLA) relating Fewer attempts to successful 1.5 fewer attempts (CI 0.47–​2.53; P = 0.004)
to central venous access between 1995 and 2009 [15]. A total of 26 cannulation
claims were made during this period (2.5% of all assessable anaes- Adapted from Hind et al. (2003).
thetic claims); 19 were closed, of which 13 led to costs. The total
cost of closed claims was £1.68 million, suggesting a higher saving
per procedure. Multiple international consensus committees now with the image displayed on the screen or directing it too deeply
advocate the use of US to guide central venous access. The Agency and puncturing a posteriorly lying artery. Both complications
for Healthcare Quality and Research (AHQR) rated this as one of can be reduced by aligning the probe and screen direction pre-​
its top 11 ways of reducing medical error [16], and NICE published procedurally and using the long-​axis view for cannulation.
evidence-​based recommendations for 2D US guidance to be the While US guidance has now become the gold standard, the
preferred method for elective and emergency insertion in both landmark technique still has its place. For many senior phys-
adults and children [17–​20]. Consequently, there have been wide- icians, their complication rates using this technique are similar to
spread increases in implementation, machine purchasing, and less experienced physicians using US [29]. The landmark method
training in anaesthetic and critical care departments [3, 21, 22]. additionally remains important in circumstances when US equip-
With cheaper, more portable, higher-​resolution equipment and ment or expertise may not be immediately available [17]‌.
more freely available and validated training programmes, many
of the barriers to adoption have been removed. It is no longer a
new or controversial technique, and all involved in acute cardiac Arterial access
care should use US to guide central venous access [23].
Conventional arterial access uses a combination of landmark as-
sessment and palpation of the artery. The main complications
arise from accidental arterial transfixation, subsequent failure to
Reduced central venous cannulation cannulate, and associated haematoma. As with central venous ac-
complications with ultrasound cess, there is still a risk of this complication when using short-​axis
imaging, either in real time or with static US; however, this risk
Compared with the landmark method, real-​time 2D US guidance should be reduced upon switching to long-​axis images where the
for cannulating the internal jugular, subclavian, femoral, and ax- needle tip and shaft can be viewed and posterior wall puncture
illary veins in adults is associated with [9, 10, 24, 25]: avoided.
◆ Lower rates of failed catheter placement.
◆ Lower rates of failure on first attempt.
◆ Fewer total number of attempts at cannulation. Indications for vascular access
◆ Fewer complications.
Arterial catheterization enables beat-​ by-​beat blood pressure
◆ Shorter time to cannulation. measurement, allowing clinicians to use lithium dilution or pulse
Hind et al. (2003), using data from seven RCTs, demonstrated contour analysis to monitor trends in cardiac indices, and blood
that using US to guide internal jugular venous access was superior gas analysis to monitor gas exchange and acid–​base balance.
to the landmark technique in all measured outcome variables Peripherally inserted central catheter (PICC) lines are useful for
[10]. These are shown in E Table 24.1. patients on short-​term chemotherapy or long-​term antibiotic
With the removal of a single outlying study from the meta-​ therapy to prevent multiple peripheral venous cannulations.
analysis, US guidance was also shown to reduce the time to Although central venous access is usually achieved through the
cannulation by an average of 69 seconds [17]‌. Similar data have three previously mentioned routes, other large veins can also be
been reported in RCTs for real-​time, US-​guided catheter inser- used (e.g. axillary, median cubital, basilic, and external jugular
tion using the subclavian and femoral vein sites [26–​28]. US can veins) [24, 25]. Common uses for a CVC on the acute CCU or
also aid central venous access by demonstrating abnormal vas- ICU are shown in E Table 24.2.
cular anatomy and intraluminal thrombosis that may impede The most common indication is haemodynamic monitoring and
venepuncture. The most common complication, after failure, guidance for fluid resuscitation, using central venous (or right atrial)
with US guidance remains inadvertent arterial puncture. This pressure as a marker of volume status. This was first postulated by
tends to occur when the operator aligns the needle incorrectly Weil and Henning in 1979 with the ‘5–​2’ and ‘7–​3’ rules of fluid
316 CHAPTER 24   Ultr asou nd-gu ided vascu l a r ac ces s i n  i n ten si ve/acu te ca rdiac ca re

Table 24.2  Common uses for a CVC on the acute CCU or ICU

Use Examples
Haemodynamic monitoring Fluid balance, right atrial pressure, central or mixed venous oxygen saturation (ScvO2, SvO2)
Cardiac output monitoring Pulmonary artery catheter (PAC)
IV drug delivery Inotropes and vasopressors with very short circulating half-​lives
IV blood product delivery Packed red cells, plasma, platelets, recombinant products
Venous access Blood sampling
Haemodialysis Continuous veno-​venous haemo-​(dia)filtration (CVVHF, CVVHDF)
Parenteral nutrition
Temporary pacemaker lead placement
Right heart function monitoring
CVVHF, continuous veno-​venous haemofiltration; CVVHDF, continuous veno-​venous haemodiafiltration.

challenge [30], but despite its validation by international consensus visuospatial skills required to coordinate the probe and needle
groups [31–​33], there is a body of evidence arguing that filling position to perform the task of real-​time needle insertion using
pressures, such as CVP and pulmonary artery occlusion pressure 2D images.
(PAOP), have little correlation with fluid responsiveness [34–​36].
Probe type
US probes have either a linear or a curvilinear surface, ranging
Contraindications to vascular access from 25 to 50  mm, with smaller footprints useful for confined
areas such as the axillary artery or vein cannulation and in children
There are few absolute contraindications to CVC and arterial or [6]‌. Transducer frequency determines the axial image resolution,
peripheral line insertion, with or without US guidance. An ab- and expert consensus groups have recommended the use of linear
normal anatomy, even significant neck deformity such as that probes of high frequency (7.5–​15 MHz), as they provide greater
seen with rheumatoid disease, poses more difficulty for airway resolution of superficial structures, enabling the visualization of
management than central venous access insertion. CHD, such as adjacent nerves and smaller arterial branches [17–​19]. Lower fre-
coarctation, may dictate which site is chosen for arterial cannula- quencies (5–​7 MHz) may be required for deep target vasculature
tion, depending on the position of the coarctation, but it does not (>8–​10 cm) [40]. The focal length is usually set at a depth of 2 cm
prevent insertion. The only caveat for arterial access is avoidance for adults and 1.5 cm for children [19]. Some probes allow the use
of arterial sites where there is no collateral flow. of a needle guide to direct the needle into the correct plane, with
Respiratory comorbidity, such as acute and chronic respiratory evidence to show that this improves the success of cannulation [41].
failure, can limit the positioning of a patient for successful central
venous access but is not a contraindication. Pneumothorax ex- Probe orientation
cludes attempting a contralateral internal jugular or subclavian ap-
Conventional probe orientation for US and echocardiography
proach but does not exclude ipsilateral re-​insertion (as is routinely
does not apply to US for venous access. Whether the probe in-
conducted in thoracic surgery when one lung is intentionally de-
dicator corresponds to the left or right of the screen will depend
flated) or femoral access. Avoidance of internal jugular cannulation
upon the site of venous access (the target vessel) and the position
in patients with raised ICP is anecdotal, and jugular bulb oxygen-
of the operator relative to that vessel. The operator must orientate
ation measured by retrograde catheterization is a useful marker of
the probe so that the structures beneath the left-​hand side of the
global cerebral oxygenation [37]. High-​risk conditions that cause
probe are viewed on the left-​hand side of the display [18]‌.
concern, but are not absolute contraindications, include disorders
of coagulation, hypovolaemia, multiple previous catheter inser-
Type of images
tions, and patients who are uncooperative or aggressive [18, 38, 39].
Two-​dimensional US demonstrates vascular structures in short-​
axis, long-​axis, or oblique views (see E Figure 24.1). Short-​axis
(SAX) US allows the operator to visualize structures adjacent to
Equipment and operation the target vessel, conferring the advantage that these structures
The modes used include 2D US and Doppler colour flow. The can be avoided by directing the needle away from them during
acute cardiac care clinician must understand how the image is cannulation. The long-​axis (LAX) view demonstrates the path of
created and displayed and how to acquire an image of the vessel the needle from tip to shaft and therefore has the advantage of
to be punctured and its surrounding structures. Furthermore, better visualization of the depth of insertion [42]. This reduces
they need to be familiar with probe orientation and develop the the risk of inadvertent arterial puncture by advancing the needle
 Equ i pm en t a n d   ope r at i on 317

Figure 24.1  Short-​axis (A) and long-​axis (B) views of the right internal jugular vein with guidewire in situ. The path of the wire is easier to visualize in the long-​
axis, compared to the short-​axis, view [5]‌.
Images courtesy of Troianos CA, Hartman GS, Glas KE, et al; Councils on Intraoperative Echocardiography and Vascular Ultrasound of the American Society of Echocardiography.
Guidelines for performing ultrasound guided vascular cannulation: recommendations of the American Society of Echocardiography and the Society of Cardiovascular
Anesthesiologists. J Am Soc Echocardiogr 2011;24(12):1291–318..

through the wall of the target vessel. The oblique view com- Doppler
bines the advantages of both methods, allowing for simultaneous Doppler US can help to distinguish an artery from a vein, in
viewing of the needle shaft and surrounding structures [43]. For particular where 2D imaging is challenging. Here, colour flow
inexperienced operators, the SAX view has been shown to be sim- Doppler can demonstrate pulsatile blood flow in an artery.
pler to use and to produce quicker times to cannulation [44]. Pulsed-​wave Doppler through the lumen of each vessel will dem-
onstrate systolic flow in an artery and biphasic (systolic and dia-
Real-​time versus static imaging stolic components), reduced velocity flow within a vein [18]‌.
US guidance can be categorized as static or dynamic/​real-​time.
The former refers to the method of identifying the target vessel, as- Specific information for access via
sessing its patency, and marking an appropriate insertion site with different routes
US. Cannulation is then continued ‘blind’. With real-​time imaging,
Internal jugular
the operator visualizes the needle as it punctures the vessel wall, al-
lowing for adjustment of the depth of the needle tip and avoidance of The position of the internal jugular vein, in relation to the carotid
adjacent structures. This method requires better hand–​eye coordin- artery, is variable, at times deviating from its anterolateral position
ation but has been shown to be superior to both static guidance and to sit either lateral or medial to the artery. This needs to be taken into
landmark techniques in terms of cannulation success, reducing the account when orienting the probe direction. The vein lies at a depth
number of attempts at cannulation, and speed of cannulation [45]. of 1–​2 cm below the skin, with the depth to the centre of the lumen
averaging 14 mm and a shallow anterior–​posterior (AP) diameter
Vessel identification
Anatomy
Several US characteristics distinguish a vein from an artery.
Morphologically, the central veins are larger and more ovoid in
shape, with thinner vessel walls. They collapse with external pres-
sure and are non-​pulsatile (see E Figure 24.2).
Respiratory variation in the central vein diameter/​ cross-​
sectional area is seen with both spontaneous and mechanical
ventilation. Valsalva manoeuvre or hepatic compression can aug-
ment the diameter of the vessel, aiding vascular identification (see
E Figure 24.3); however, 20° Trendelenburg abolishes their aug-
menting effects [47]. Careful positioning and use of these adjuncts,
or administration of IV fluids to increase preload, may be particu-
larly useful in critically ill patients with hypovolaemia, reduced
transmural pressure, and a tendency for venous collapse on inspir-
ation. Identification of the femoral vein can be facilitated by reverse
Trendelenburg positioning [48] and PPV, and further augmented Figure 24.2  External compression of the internal jugular vein (IJV). Note its
by both Valsalva manoeuvres [49] and inguinal compression [50]. compressibility, compared to that of the common carotid artery (CCA) [46].
Reproduced courtesy of Sloan J (2012), Ultrasound.
318 CHAPTER 24   Ultr asou nd-gu ided vascu l a r ac ces s i n  i n ten si ve/acu te ca rdiac ca re

This overlap is seen more frequently on the left than on the

right side [54] and increases the risk of inadvertent puncture of
the carotid artery. Other considerations for left internal jugular
cannulation include the apex of the left lung sitting higher than
the right and the risk of injuring the thoracic duct [51]. Obesity
and patients with short necks will cause increased difficulty in
cannula insertion on both sides, due to increased difficulty in
visualizing deep vascular structures and accessing sites for vene-
puncture, with an increase in vessel overlap, compared to non-​
obese patients [55].

Subclavian
Serious complications of attempted subclavian venous access in-
clude arterial puncture and pneumothorax. The artery is vulner-
able to injury, as it lies behind, and slightly superior to, the path of
the vein in the plane of the needle during insertion (see E Figure
Figure 24.3  Valsalva manoeuvre increasing the diameter of the internal
jugular vein [49]. IJV, internal jugular vein; CCA, common carotid artery. 24.5). The pleura can also be punctured, as it lies only 5 mm pos-
Produced courtesy of Sloan J 2012), Ultrasound. terior to the vein, beyond the edge of the first rib [56].
Several techniques have been described for the infraclavicular
approach to the subclavian vein. The most common involves
(<1 cm) [51]. Therefore, it is important to set the depth of the US needle insertion at a point 1 cm inferior to the clavicle in the mid-​
machine appropriately. Use a high probe frequency to achieve the clavicular line. The needle tip is directed at the upper border of
best image resolution, and consider using a LAX view to reduce the the suprasternal notch, keeping parallel to the coronal plane (i.e.
possibility of posterior vessel wall or carotid artery puncture. While not going too deep), with venepuncture occurring at the junction
US will aid visualization of the vascular lumen, the right internal between the middle and medial thirds of the clavicle. The bevel
jugular vein remains technically easier to cannulate than the left, of- of the needle is initially directed anteriorly, and upon successful
fering a straighter, more direct path to the superior vena cava and vessel puncture, it is then turned caudally in order to direct the
right atrium and has been shown to be wider, with a larger AP diam- guidewire into the right atrium. The wire is then advanced, leaving
eter [51]. Left internal jugular vein cannulation has been shown to enough outside the skin to allow for ‘railroading’ of the catheter
be more difficult and more time-​consuming and results in a greater over the wire. A small footprint US transducer probe should be
number of complications and failures than using the right side, with used due to space limitations between the clavicle and the second
both the landmark and US techniques [52]. Care should be taken rib [18]‌. The transducer should be oriented to image the vein in
not to rotate the head and neck >40°, as the percentage of overlap the SAX view in the coronal plane, with the positioning marker
between the internal jugular vein and the carotid artery increases pointing towards the contralateral shoulder. Compression of
after this point [55]. This is demonstrated in E Figure 24.4 [52]. the subclavian vein with the US probe is not possible; therefore,

Figure 24.4  Short-​axis views of the internal jugular vein. Image A (left) has been taken with little contralateral head rotation, and image B (right) with
significant head rotation and significant vessel overlap [56].
Reproduced from Feller-Kopman D. Ultrasound-guided internal jugular access: a proposed standardized approach and implications for training and practice. Chest 2007
Jul;132(1):302-9. doi: 10.1378/chest.06-2711 with permission from Elsevier.
 Equ i pm en t a n d   ope r at i on 319

higher risk of catheter-​related infections, preventing their recom-

mendation for routine use [61].
Real-​time US has been shown to improve the first attempt suc-
cess rate and reduce the number of needle passes for femoral vein
cannulation, compared to the landmark technique. However, this
study was in the paediatric population [28], and little evidence
exists in adults to recommend routine US use for femoral cannu-
lation, except for static imagery to determine vessel overlap [61].

Arterial cannulation
Prospective randomized trials have demonstrated the superiority
of US guidance over the landmark technique and the LAX over
the SAX view for radial arterial line insertion [61, 62]. First at-
tempt success was improved, the number of attempts at cannu-
lation reduced, and the LAX view shown to reduce the incidence
of puncture to the posterior wall of the artery. In one study, the
Figure 24.5  Short-​axis view of the left subclavian vessels in the coronal majority of participating anaesthetists were novice US operators,
plane. Note the close proximity of the vein to the subclavian artery [5]‌. proving that the US-​guided technique was easy to learn [61].
Image courtesy of Troianos CA, Hartman GS, Glas KE, et al; Councils on
With both SAX and LAX views, arteries should be pulsatile and
Intraoperative Echocardiography and Vascular Ultrasound of the American Society of
Echocardiography. Guidelines for performing ultrasound guided vascular cannulation: minimally compressible. Colour flow Doppler may also aid the
recommendations of the American Society of Echocardiography and the Society of identification of an artery from a vein with the presence of phasic
Cardiovascular Anesthesiologists. J Am Soc Echocardiogr 2011;24(12):1291–318.
blood flow within the artery (see E Figure 24.6).
US guidance is useful for arterial access in the following
colour flow Doppler imaging should be used to assist with the circumstances  [18]‌:
differentiation of the vein from the artery.
1. Obesity.
Other techniques using more lateral approaches have been ad-
vocated to improve the safety of the procedure [57]. One study 2. Altered anatomy.
using US guidance to cannulate the axillary vein just lateral to the 3. Low cardiac output states.
subclavian vein concluded that the axillary approach was safer 4. Hypovolaemia.
than the conventional mid-​clavicular approach, as the axillary ar-
5. Non-​pulsatile blood flow, e.g. cardiac arrest, cardiopulmonary
tery could be manually compressed if inadvertently punctured, in
bypass (CPB).
contrast to the subclavian artery [24]. However, they failed to find
a difference in complication rates between US and landmark tech- 6. Previous unsuccessful cannulation attempts using the land-
niques, and it has been suggested that US may lead inexperienced mark approach.
operators to use very steep angle approaches that may lead to punc-
ture of the underlying pleura and subsequent pneumothorax [18]‌. Peripheral venous access
The subclavian route is recommended as the optimum site for US may be useful in patients with difficult peripheral venous ac-
access by the Centers for Disease Control and Prevention in the cess where peripheral veins may not be visible or palpable. Groups
United States to reduce catheter-​related infections [58]. However, that may benefit include:
while two RCTs have reported improvements with using US guid-
ance over the landmark technique in terms of success rate, re- ◆ Obese patients.
duced access time, and reduced arterial punctures [26, 27], its ◆ IV drug users.
routine use has not been recommended [17, 59]. ◆ Oedematous patients (including those with pre-​eclampsia who
are oedematous, but significantly hypovolaemic).
Femoral ◆ The critically ill.
The common femoral vein has several advantages that make it an ◆ Patients requiring chemotherapy or long-​term antibiotic therapy.
attractive site for central venous access. It is easy to access and rela-
In these groups, US can be used to locate deeper, non-​palpable
tively free from medical equipment (e.g. monitoring, ventilator
vessels and guide peripheral cannula insertion. A  2005 study
tubing, ETT ties), is easily compressible in case of arterial punc-
comparing the use of US versus standard techniques for cannula-
ture, and avoids some of the risks associated with internal jugular
tion of peripheral veins demonstrated a threefold improvement in
and subclavian venous access (e.g. pneumothorax, haemothorax).
success rate, reduced time to secure access, and improved patient
Therefore, it represents the best site for emergency central venous
satisfaction in the US group [63].
access. However, femoral venous lines are associated with a
PICC line insertion, for long-​term therapy in acute or chronic
higher rate of DVT [60], especially in the hypovolaemic, critic-
care patients, uses a 16–​18G split cannula to feed the catheter
ally ill population. Due to their proximity to the groin, there is a
through, so larger peripheral vessels are desirable for initial
320 CHAPTER 24   Ultr asou nd-gu ided vascu l a r ac ces s i n  i n ten si ve/acu te ca rdiac ca re

Figure 24.6  Short-​axis and long-​axis ultrasound views with colour flow Doppler to assist radial artery cannulation [63].
Images courtesy of Berk D, Gurkan Y, Kus A, et al. Ultrasound-guided radial arterial cannulation: long axis/in-plane versus short axis/out-of-plane approaches? J Clin Monit Comput
2013;27(3):319–24.

venepuncture. Significant improvements in success rate for inser- venous catheters and for use, when feasible for both subclavian
tion have been shown with the use of real-​time US guidance [64]. and femoral approaches.

Training Personal perspective
Standardized approaches to training have shown improvements The use of US to guide vascular access has been shown to
in clinician competence in US-​ guided vascular access [65]. reduce complications associated with landmark techniques
Improvements in clinician training have been advocated by na- and improve the chances of successful cannulation. Its use
tional and international consensus groups, emphasizing specific in critical care has been recommended by national and
education in image acquisition, interpretation, and real-​time use international consensus groups, and its use is now wide-
of US for vessel puncture and cannulation to improve success spread. With improvements in training and greater avail-
rates, and ultimately patient safety [17–​19]. With cheaper, more ability of equipment in critical care units, US guidance
portable US equipment now widespread, US should now be con- should replace landmark techniques for vascular access in
sidered first line for the insertion of internal jugular vein central the majority of critical care patients.

Further reading
American Society of Anesthesiologists Task Force on Central Venous of Cardiovascular Anesthesiologists. J Am Soc Echocardiogr
Access. Practice guidelines for central venous access: a report by the 2011;24:1291–​318.
American Society of Anesthesiologists Task Force on Central Venous Trush A, Hartshorne T. Vascular Ultrasound—​How, Why and When?,
Access. Anesthesiology 2012;116:539–​73. third edition. Churchill Livingstone: London; 2010.
Troianos CA, Hartman GS, Glas KE, et  al. Guidelines for performing Wilson S. Vascular Access: Principles and Practice, fifth edition. Lippincott
ultrasound guided vascular cannulation:  recommendations Williams and Wilkins: London; 2009.
of the American Society of Echocardiography and the Society

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 CHAPTER 25

Pericardiocentesis
Caterina C De Carlini and Stefano Maggiolini

Summary
Contents Pericardiocentesis, the percutaneous drainage of pericardial effusion, is the tech-
nique of choice for the treatment of cardiac tamponade. In addition, it could be
Summary  323
useful for diagnostic purposes in specific situations.
Introduction  323
The pericardial puncture could be associated with serious complications, and as
Cardiac tamponade  323
it can be performed in a wide variety of clinical settings, from an emergency to a
Indications  324
programmed diagnostic procedure, it is mandatory for the clinician to know how
Contraindications  324
to plan and safely perform the procedure.
Imaging guidance  325
This chapter will deal with indications, contraindications, different approaches,
Fluoroscopy-​guided pericardiocentesis  325
Echocardiographically guided complications, and periprocedural management of the pericardiocentesis
pericardiocentesis  325 procedure.
Computerized tomography-​guided
pericardiocentesis  325
Procedure  325
Puncture site selection  326
Complications  327
Myocardial and coronary puncture  327 Introduction
Haemothorax  328
Puncture of abdominal viscera  328 Pericardiocentesis is a lifesaving procedure in cases of cardiac tamponade. It is indicated
Pericardial decompression syndrome  328 also for diagnostic purposes in cases of suspected bacterial or neoplastic effusions.
Pneumothorax  328
Pneumopericardium  328
The first cardiac decompression goes back to 1653, when Riolanus reduced
Management and pitfalls  328 intrapericardial pressure by sternal drilling. Subsequently, in the early nineteenth cen-
Medical management  328 tury, the first surgical drainage procedure was performed in Spain. The first blind percu-
Respiratory management  328 taneous approach was attempted by Schuh in 1840, and finally the subxiphoid approach
Catheter drainage care  328 was described in 1911 by Marfan [1]‌.
Prevention of recurrences  328
Until the introduction of imaging guidance, in the eighties, pericardiocentesis had
Haemorrhagic effusion  329
False echocardiographic findings  329 been a ‘blind’ or ECG-​guided procedure, carrying high rates of morbidity and mortality
Personal perspective  329 (50% and 6%, respectively) [2]‌. In this perspective, surgical drainage was the procedure
References  329 of choice, although associated with high morbidity. In subsequent years, with the intro-
Additional online material  330 duction of imaging modalities (echocardiography, fluoroscopy, and CT) to guide the pro-
cedure, multiple observational studies have reported improved safety and success rates
for percutaneous pericardiocentesis [3].

Cardiac tamponade
Cardiac tamponade is a life-​threatening condition that results from an increase in
pericardial fluid, leading to cardiac compression and haemodynamic instability. The
most common causes of pericardial effusions leading to tamponade are acute pericar-
ditis, neoplasia, and iatrogenic injuries. These causes have changed over time. In fact,
in recent years, pericardial effusions leading to cardiac tamponade as a complication
324 CHAPTER 25  Pe ric a rdio centesis

of percutaneous catheter-​based procedures has been increasing, tuberculous or purulent, or when neoplastic pericarditis is sus-
compared to pericardial effusions due to neoplasia [4]‌. pected (Class 1C)  [6]‌.
The pericardium is a fibroserous, double-​walled sac that sur- Purulent pericarditis is a rare condition that should be man-
rounds the heart and the origin of the great vessels. It normally aged aggressively, as it carries a high mortality rate if untreated.
contains 25–​50 mL of fluid in adults, which serves as a lubricant Purulent pericarditis commonly originates from severe infectious
that allows cardiac chamber motions without attrition [1]‌. Since disease caused by Gram-​positive cocci (pneumonia and em-
the pericardium is relatively inelastic, a rapidly increasing amount pyema), especially in immunocompromised patients [7]‌.
of pericardial fluid may elevate the intrapericardial pressure and Empirical systemic antibiotic therapy should be started
cause cardiac tamponade, whereas if the fluid accumulates slowly, promptly and complete surgical drainage performed, because a
over weeks or months, the pericardium can increase in size up to purulent effusion is often loculated and associated with dense
a maximum capacity of 1–​2 L. The increase in transmural pres- adhesions. An alternative and less invasive method consists of
sure results in the collapse of the right atrium first, and then of the percutaneous drainage associated with intrapericardial infusion
RV. Tamponade is a continuum from an early echocardiographic of streptokinase. Fibrinolytic therapy can enhance the removal
sign of chamber compression, with poor clinical signs, to haemo- of material that would otherwise be too viscous or particulate to
dynamic instability and shock. be removed by tube drainage [8]‌. This treatment should be con-
Clinically, cardiac tamponade is defined as the decompen- sidered before undertaking surgery.
sated phase of cardiac compression. The clinical signs include In cases of chronic (lasting >3  months) large pericardial ef-
Beck’s triad (elevated JVP, hypotension, tachycardia) and pulsus fusions (>20  mm on echocardiography in diastole), optimal
paradoxus. Conventionally, pulsus paradoxus is defined as a fall management is controversial. Some authors suggest that peri-
in systolic arterial pressure of >10 mmHg during normal inspir- cardiocentesis should be performed to avoid unexpected pro-
ation. It should be noted that conditions other than tamponade gression to tamponade [9]‌. However, the actual outcome of this
(e.g. obesity, cardiac failure, pulmonary emphysema, asthma, pul- clinical condition is poorly known.
monary embolism cardiogenic shock (CS), constrictive pericar- A recent large prospective study has demonstrated that the
ditis, and CS) can be associated with pulsus paradoxus. risk of cardiac tamponade is not as high as previously thought
Echocardiography is the most useful diagnostic tool for evalu- (2.2% per year) and the effusion spontaneously decreased in the
ating cardiac tamponade. It can show collapse of the right atrium majority of cases. In this setting, a careful follow-​up with clinical
or the RV and ventricular volume interdependence. and echocardiographic examination every 3–​6 months could be
Right atrial collapse over more than one-​third of the cardiac the best way to approach pericardial effusion, with particular at-
cycle is highly sensitive, but not specific, for cardiac tamponade. tention to the fact that cardiac tamponade may be precipitated if
By contrast, RV diastolic collapse is less sensitive, but more spe- pericarditis occurs [10].
cific. Doppler echocardiography can show an exaggerated re- Pericardiocentesis for diagnostic purposes is not justified in the
spiratory variation in mitral and tricuspid inflow velocity, in majority of cases of mild or moderate small effusions (<20 mm)
accordance with pulsus paradoxus (≥25% mitral and ≥40% tri- for the following reasons: (1) low diagnostic power (the under-
cuspid suggest ventricular interdependence). Finally, inferior lying pathology is often already known or identifiable through
caval plethora reflects elevated central venous pressure [5]‌(see different non-​invasive tests); (2) viral (idiopathic) pericarditis is
Figure 25.3). usually self-​limiting and only requires anti-​inflammatory treat-
ment; and (3)  high procedural risk against a low diagnostic
yield [11].
Indications
Overt cardiac tamponade represents a straightforward indication
for the procedure, according to the ESC guidelines (Class 1C)  [6]‌.
Contraindications
In haemodynamically unstable patients, an emergency pro- There are no absolute contraindications to pericardiocentesis
cedure is mandatory. Otherwise, the procedure can be post- when shock occurs.
poned and the most appropriate approach can be planned. Aortic dissection and post-​infarction rupture of the free wall
Recently, a non-​ validated scoring index has been proposed are contraindications to needle pericardiocentesis due to the po-
by the ESC Working Group on Pericardial and Myocardial tential risk of aggravating the dissection or myocardial rupture
Diseases to guide the timing of drainage in patients with sus- via rapid pericardial decompression and restoration of systemic
pected cardiac tamponade. It combines three clinical features arterial pressure. However, if the patient is very unstable, peri-
at presentation:  suspected aetiology, clinical presentation, and cardiocentesis with controlled drainage of very small amounts of
echocardiographic findings. In the presence of a score of >6, ur- the haemopericardium can act as a temporizing measure in order
gent pericardiocentesis is suggested (see Figure 25.4) [5]‌. to maintain the blood pressure at approximately 90 mmHg as a
In cases of pericardial effusion without haemodynamic com- bridge to surgery [12].
promise, pericardiocentesis may be considered for moderate to Relative contraindications include uncorrected coagulo-pathy,
large effusions that are non-​responsive to medical therapy, when thrombocytopenia (platelet count <50 000/​mm3), and anticoagulant
 Pro c e dure 325

therapy, which may impact on the risk profile of the procedure. In Computerized tomography-​guided
the last few years, an increasing number of complex catheter-​based pericardiocentesis
procedures has led to more acute cardiac tamponades in patients
on anticoagulant/​antiplatelet therapy. These patients are more likely This has shown good safety and feasibility in recent years. A plan-
to present with overt tamponade, and urgent pericardiocentesis is ning CT scan is performed to evaluate the full extension of the
unavoidable, even if anticoagulated. In this perspective, it is clear pericardial effusion and the optimal entrance point. Once the
that nowadays cardiologists should know how to manage problems needle is advanced through the tissue towards the pericardial
related to immediate reverse anticoagulation [13]. space, a single CT scan allows to verify the correct position.
This technique, that carries some disadvantages (time-​
consuming, significant exposure to radiation, no wide avail-
ability), could be very useful indeed in patients with a poor
Imaging guidance US window or those with a loculated or posterior effusion.
In recent years, percutaneous pericardial drainage has become Moreover, CT scanning can measure the density of the pericar-
much safer, thanks to imaging modalities such as fluoroscopy, dial effusion, avoiding a failing procedure in cases of highly vis-
echocardiography, and computed tomography (CT). cous effusions such as purulent effusions and intrapericardial
haematoma [3]‌. Finally, CT scanning could be fundamental
Fluoroscopy-​guided pericardiocentesis in the diagnostic work-​up of severe effusions, allowing the as-
sessment of the entire chest and the detection of associated
This is performed through the subxiphoid access with a needle at
abnormalities [16].
30° angle to the skin directed towards the heart shadow and the
epicardial halo phenomenon (the epicardial halo delineates the
heart shadow under fluoroscopy and seems to be a highly sensi-
tive sign for the detection of pericardial effusion). Procedure
The needle position in the pericardial space is confirmed by in-
For a list of the minimum equipment required, see Box 25.1.
jection of a contrast agent, before the introduction of a guidewire.
Patient ECG monitoring in an appropriate environment, with
It is essential to check the guidewire position from at least a lateral
resuscitation equipment, is required.
view and an anteroposterior view [3]‌.
In non-​ emergency procedures, a central venous catheter
This procedure is well standardized and effective, but it can
(CVC) is essential for monitoring right atrial pressure and
only be performed in heart catheterization laboratories and in-
allowing a rapid infusion of fluids and drugs if indicated.
volves exposure to radiation for both the patient and the phys-
Continuous arterial pressure monitoring is indicated to detect
ician. However, it could be very useful to treat tamponade
the presence of pulsus paradoxus and to rapidly detect and cor-
secondary to cardiac perforation from catheter-​based proced-
rect sudden haemodynamic instability.
ures. In our view, an echocardiographic examination to assess
A basic laboratory panel, including platelet counts and coagu-
the distribution and amount of pericardial effusion should al-
lation profile, should be checked and packed red cell units should
ways precede the fluoroscopy-​ guided procedure, whenever
be readily available.
possible.
Placing the patient in a semi-​reclining position at an angle of
about 30–​45° and slightly rotated leftwards enhances fluid collec-
Echocardiographically guided tion in the inferior–​anterior part of the chest and brings the heart
pericardiocentesis closer to the chest.
This was first described by the Mayo Clinic in 1979 and has revo- A preliminary echocardiographic evaluation is recommended
lutionized the procedure by increasing the safety and feasibility of to assess the distribution of the effusion, select the proper entry
this technique, and it is widely used nowadays. site, and also monitor the procedure.
Echocardiographic examination is essential in planning the It is important to proceed under adequate aseptic conditions,
procedure—​it allows to define the position of the effusion, the even in emergency situations.
ideal entry site, and the needle trajectory. Anaesthetize the puncture site and the needle route via local
There are two different modalities of echocardiographic anaesthetic infiltration.
guidance. First is the echo-​assisted method (as described by In the echo-​ assisted technique, advance a 16–​ 18G Teflon-​
the Mayo Clinic), in which the operator advances the needle sheathed needle attached to a saline-​filled syringe in the direction
towards the pericardial space without continuous ultra- of the fluid-​filled space.
sound (US) visualization, after the optimal needle trajectory When fluid is aspirated, the steel core should be withdrawn,
is memorized [14]. The second approach is an echo-​g uided while only maintaining the sheath in the pericardial space.
method with continuous echocardiographic monitoring. The Advance a guidewire through the sheath, which can then be
use of a needle-​c arrier mounted on the US transducer to removed.
advance the needle into the pericardial space has also been A bloody aspirate may indicate a myocardial puncture or a
proposed [15]. haemorrhagic pericardial effusion. The extracardiac position of
326 CHAPTER 25  Pe ric a rdio centesis

the tip can be confirmed by injecting 5 mL of agitated saline in-

fusion; the bubbles can be visualized by echocardiography in the Puncture site selection
pericardial space.
In the era of pericardiocentesis without imaging guidance, the
Introduce a sheathed dilator (6–​8F) over the guidewire. The di-
subcostal approach was the preferred one. However, as pericar-
lator should be removed and a pigtail catheter directly inserted in
dial effusion is not always equally distributed, a US evaluation of
the sheath.
the ideal entry site for tapping is fundamental to the success of
A different approach utilizes a needle carrier mounted on the
the procedure. The Mayo Clinic has suggested the selection of the
transducer to advance the needle under continuous visualization
proper puncture site purely based on echocardiographic findings
(real-​time echo-​monitored procedure).
by searching the point where the pericardial space is closest to the
Patient preparation is the same as described above (see
probe and the fluid accumulation is maximal, with no intervening
E Figure 25.1A).
vital organs (see Figure 25.5). Furthermore, an observational
The bracket should be mounted on the probe to support the
series has demonstrated a bigger successful rate and a minor
needle-​guide kit and covered with a sterile sheath (see E Figure
complication rate when the entry site was echocardiographically
25.1B).
selected, rather than when the subxiphoid approach was routinely
The bracket supports the needle with different angles, and the op-
used [14, 15].
erator can choose between a closer or a wider angle (see E Figure
Three main approaches can be used:  apical, subcostal, and
25.1C).
parasternal (see E Table 25.1 and Figure 25.2).
Once the placement and direction of the needle are chosen, a
In the case of posterior or extremely loculated effusions, sur-
16–​18G, 9-​cm needle is slowly advanced in aspiration through
gical drainage should be considered, as it allows to better break
the tissue until there is visualization of the tip (see E Figure
up adhesions and loculations and to place a larger drainage tube
25.1D).
(especially important in purulent pericarditis).
When the pericardial effusion is reached and the placement is
Alternatively, posteriorly located effusions can also be reached
echocardiographically confirmed, a j-​tipped wire is introduced
via posterior pericardiocentesis, in the presence of a concomi-
into the pericardial space under continuous visualization and a
tant large left pleural effusion. Pulmonary atelectasis, in fact, al-
pigtail catheter should be inserted according to the Seldinger’s
lows US transmission from a patient’s back to the heart through a
technique (see E Figure 25.1E–​F and z Video 25.1).

Figure 25.1  Echo-​guided pericardiocentesis procedure. Patient position (A); covered probe-​mounted needle (B); choose the proper angle for the needle (C);
continuous visualization of the needle tip (white arrow) (D); J-​tipped wire into the pericardial space (white arrow) (E); drainage (F).
 C o m pl i c at i on s 327

Table 25.1  Characteristics of the different pericardiocentesis approaches

Place of puncture Description Disadvantages Advantages

Apical/​para-​apical The needle insertion site is 1–​2 cm lateral Risk of ventricular puncture due to The thicker LV wall is more likely to
to the apex beat in the fifth, sixth, or seventh proximity to LV self-​seal after puncture
intercostal space. Advance the needle over Risk of pneumothorax due to proximity Because US does not penetrate air,
the superior border of the rib to avoid to left pleural space using echocardiographic guidance
intercostal nerves and vessels ensures to avoid the lung
The path to reach the pericardium
is shorter
Parasternal The needle insertion site is in the fifth left Risk of pneumothorax and puncture of Echocardiographic guidance also
intercostal space, close to the sternal margin. internal thoracic vessels (if the needle is with phase array probe provides
Advance the needle perpendicular to the inserted >1 cm laterally) good visualization of pericardial
skin (at the level of the cardiac notch of structures
the left lung)
Subxiphoid The needle insertion site is between the A steeper angle may enter the peritoneal Lower risk of pneumothorax
xiphisternum and the left costal margin. cavity and a medial direction increases the
Once beneath the cartilage cage, lower risk of right atrial puncture. In some cases,
the needle to a 15–​30° angle, with the the left liver lobe may be transversed
abdominal wall directed towards the left intentionally if an alternative site is not
shoulder available
The path to reach the fluid is longer

liquid interface and allows to advance a needle transpleurally into

the pericardial space [17].
(a)

Complications
After the introduction of imaging-​ guided pericardiocentesis,
a large number of clinical series have documented a low rate of
major and minor complications (0.3–​3.9% and 0.4–​20%, respect-
ively) [15, 18, 19]. Mortality related to the pericardiocentesis pro-
cedure is very low (<1%) (see Table 25.2).
Major complications include death, puncture of cardiac cham-
bers, laceration of coronary arteries or intercostal vessels, punc-
ture of the abdominal viscera or peritoneal cavity, pneumothorax
requiring chest tube placement, pneumopericardium, ventricular
arrhythmias, and pericardial decompression syndrome. Minor
complications are transient vasovagal hypotension, pneumo-
thorax not requiring chest tube placement, and pleuropericardial
(b) fistula.
The choice of different imaging assistance, as well as of the entry
Internal
thoracic site, should focus particularly on the reduction of life-​threatening
artery complications.

Heart
Myocardial and coronary puncture
Lung
This is the most serious complication. It may present with delayed
haemopericardium or intrapericardial thrombus.
The puncture of the cardiac chambers with the needle can be
Liver
solved in most cases with needle retraction and insertion of the
Pericardial
catheter into the pericardium.
notch of left lung If the perforation is carried out by the catheter, this must be
left in place and a new pericardiocentesis procedure must be car-
ried out by placing another catheter in the pericardium before
Figure 25.2  Three main approaches for pericardiocentesis: parasternal, removing the previous one. If controlled drainage resolves the
substernal, and apical (A). Anatomic structures to avoid (B).
328 CHAPTER 25  Pe ric a rdio centesis

tamponade, also with potential autotransfusion of pericardial

blood, surgery can be avoided. This is very probable in the case Management and pitfalls
of puncture of the ventricular chambers. Puncture of the right
atrium is more problematic, because of a thin and poorly con-
Medical management
tractible myocardium and it poses a greater risk of persistent Medical management is only a temporary measure for tamponade
bleeding after needle injury, compared to the ventricles. In the patients while waiting for pericardiocentesis.
case of laceration of an arterial vessel, recourse to cardiac surgery Hypotensive patients (systolic arterial pressure <100  mmHg)
is more probable. can be treated with a low volume (250–​500 mL) of normal saline,
as it has been demonstrated to improve haemodynamic param-
Haemothorax eters. However, infusion of higher volumes can increase wedge
pressure, as well as intrapericardial pressure, and can reduce car-
The parasternal and transthoracic approaches pose a higher risk diac output [23].
of haemothorax by puncturing the intercostal or internal thoracic IV administration of diuretics is contraindicated and can be
arteries. fatal in patients on the edge of their compensatory mechanism
For this reason, it is important to puncture over the superior in tamponade.
border of the rib in the case of the transthoracic approach, Both dopamine and dobutamine improve haemodynamics.
or close to the sternal margin in the case of the parasternal However, their usefulness is generally limited because en-
approach. dogenous adrenergic stimulation is already enhanced under tam-
When haemothorax occurs, thoracoscopy is required if ponade conditions.
bleeding is not self-​limiting.
Respiratory management
Puncture of abdominal viscera Spontaneous versus mechanical ventilation and PaCO2 levels
The stomach, transverse colon, diaphragm, liver, and phrenic significantly influence the evolution of pericardial tamponade.
nerve are at risk of injury in the subxiphoid approach [20]. Pericardial pressure decreases by 3–​6  mmHg when PaCO2 de-
creases to 24  mmHg; conversely, pericardial pressures increase
Pericardial decompression syndrome
by 2–​ 4  mmHg when PaCO2 reaches 57  mmHg. Increased
This is a rare, but potentially life-​threatening, condition. It is char- intrathoracic pressures during mechanical ventilation can de-
acterized by a wide range of clinical scenarios, from pulmonary crease the cardiac output by up to 25% in patients with tam-
oedema to CS with LV, RV, or biventricular failure [21]. It gener- ponade. These patients therefore should not receive PPV,
ally develops after successful percutaneous or surgical pericardial unless it is absolutely necessary to avoid further haemodynamic
drainage, from a few hours to days later. The mechanism of this compromise.
situation is still not well understood, but it could be related to a
preload/​after-​load mismatch, myocardial ischaemia due to cor- Catheter drainage care
onary artery compression by the pericardial fluid, or changes in
Pericardial catheter care is the same as for CVCs.
sympathetic drive.
Catheter occlusion can occur in up to 10% of cases. In order
To date, the only recommendation to prevent this syndrome is
to optimize catheter patency, it could be useful to perform inter-
to remove enough fluid to normalize central venous and systemic
mittent aspiration every 6 hours and use a disposable continuous
blood pressures (not >1 L) and to complete the removal in subse-
flushing system between aspirations [15].
quent few hours [5]‌.
The catheter can be removed once the drainage volume has de-
creased to <25–​30 mL in 24 hours.
Pneumothorax
This is a possible complication of the apical approach, and in Prevention of recurrences
some situations, it requires a chest tube. This complication may Pericardial drainage for 24–​72 hours is sufficient to avoid recur-
be avoided by echocardiographic selection of the optimal entry rence of pericardial tamponade in the majority of cases. The re-
point, with no interposing lung. currence rate after the initial procedure is 27–​55% for patients
who undergo simple pericardiocentesis and 12–​24% for those
Pneumopericardium who have extended drainage. Omission of extended catheter
This is a rare, but potentially serious, complication of pericardio- drainage is an important independent predictor of recurrence
centesis. It can be seen generally as a bubble ‘swirling’ around the [24]. It is important to empty the pericardial sac as completely as
heart on echocardiographic examination. In the majority of cases, possible, leaving the catheter in place for up to 72 hours or more
it is a self-​limited phenomenon; if a haemodynamic derangement if the fluid has a rate of accumulation of >30 mL in 24 hours. With
occurs, repeated pericardiocentesis could be necessary. In this the appropriate antiseptic procedure, bacterial infections are rare
perspective, it is fundamental to avoid air entry during pericar- during extended pericardial drainage and antibiotic prophylaxis
dial drainage [22]. is not indicated [15, 18].
 RE F E RE N C E S 329

Reaccumulation of pericardial fluid is common in patients intrapericardial pressure, which is sufficient to cause echocar-
with malignant pericardial effusions. In these patients, it is not diographic findings of cardiac tamponade. In this situation,
clear if the gold standard of treatment should be percutaneous the appropriate therapeutic approach is drainage of the pleural
pericardiocentesis with extended drainage or surgery. In patients effusion [27].
with end-​stage disease, the least invasive percutaneous drainage is By contrast, in patients with high right-​sided pressures at-
probably preferable. In addition, surgery should be the first choice tributable to PH, PE, or RV volume overload, cardiac tam-
in posterior, loculated, or frequently recurrent effusions [25]. ponade will not demonstrate right atrial or RV collapse.
Prolonged pericardial drainage could also be useful for The reason for this phenomenon is attributable to elevated
intrapericardial treatment, which should be tailored in collabor- intrapericardial pressure that does not equalize the RV or
ation with the oncologist [6]‌. right atrial pressures.

Haemorrhagic effusion
False-​negative results from pericardiocentesis are obtained in Personal perspective
20–​40% of cases of haemorrhagic effusion, even when pericardial
In our experience, to reduce the rate of pericardiocentesis
puncture can be performed without delay [26]. False-​negative re-
complications and enhance the success rate, an accurate US
sults can be caused by rapid formation of clots, which impede as-
evaluation of the ideal entry site for tapping is fundamental,
piration of blood. Therefore, failure to aspirate blood in cases of
whenever it is possible. The optimal and safest entry site is
traumatic chest injuries should not exclude the possible diagnosis
the point where the largest collection of fluid lies in closest
of haemorrhagic effusion, delaying evacuation. In these cases,
proximity to the transducer, with no intervening vital
visualization of the needle within the pericardial space allows to
organs—​this site is more often apical than subcostal. In par-
confirm reaching into the pericardial space, avoiding repeated
ticular, we have reported high safety of echocardiography-​
punctures.
guided pericardiocentesis under continuous visualization,
with no puncture of the heart chamber or vessels, even in
False echocardiographic findings
hospitals with low volumes of procedures, with or without
The most common false-​positive echocardiographic determinant cardiac surgery [15].
of tamponade is right atrial collapse. This sign, as well as RV dia- Another important issue for the reduction in complica-
stolic collapse, can be highlighted in volume-​depleted patients. tions is represented by the operator’s skills. In fact, a min-
In this setting, intrapericardial pressure is at least equal to right imum of five procedures supervised by an expert physician
atrial and RV pressures, which are decreased as a result of low is recommended during cardiology training [5]‌.
preload. Moreover, a large pleural effusion may cause increased

References
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PH. Pericardiocentesis:  a clinical anatomy review. Clin Anat pericardial drainage be performed routinely in patients who have a
2012;25:872–​81. large pericardial effusion without tamponade? Am J Med 1998;105:
2. Krikorian JG, Mancock EW. Pericardiocentesis. Am J Med 106–​10.
1978;65:808–​14. 10. Imazio M, Lazaros G, Valenti A, et  al. Outcomes of idiopathic
3. Maggiolini S, De Carlini C, Imazio M. Evolution of pericardiocen- chronic large pericardial effusion. Heart 2018;105:477–​81.
tesis technique. J Cardiovasc Med 2018;18:267–​73. 11. Maggiolini S, Osculati G, Vitale G. Utility and safety of diagnostic
4. Kumar R, Sinha A, Lin MJ, et  al. Complications of pericardiocen- pericardiocentesis. Eur Heart J 2005;26:1046–​7.
tesis: a clinical synopsis. Int J Crit Illn 2015;5:206–​12. 12. Cruz I, Stuart B, Caldeira D, et al. Controlled pericardiocentesis in
5. Ristić AD, Imazio M, Adler Y, et al. Triage strategy for urgent man- patients with cardiac tamponade complicating aortic dissection: ex-
agement of cardiac tamponade: a position statement of the European perience of a centre without cardiothoracic surgery. Eur Heart J
Society of Cardiology Working Group on Myocardial and Pericardial Acute Cardiovasc Care 2015;4:124.
Diseases. Eur Heart J 2014;35:2279–​84. 13. Inglis R, King AJ, Gleave M, Bradlow W, Adlam D. Pericardiocentesis
6. Adler Y, Charron P, Imazio M, et al. 2015 ESC Guidelines for the diag- in contemporary practice. J Invasive Cardiol 2011;23:234–​9.
nosis and management of pericardial diseases: The Task Force for the 14. Tsang TSM, Freeman WK, Sinak LJ. Seward JB. Echocardiographically-​
Diagnosis and Management of Pericardial Diseases of the European guided pericardiocentesis: evolution and state-​of-​the-​art technique.
Society of Cardiology (ESC). Eur Heart J 2015;36: 2921–​64. Mayo Clin Proc 1998;73:647–​52.
7. Imazio M, Gaita F. Diagnosis and treatment of pericarditis. Heart 15. Maggiolini S, Gentile G, Farina A, et al. Safe, efficacy and complica-
2015;101:1159–​68. tions of pericardiocentesis by real-​time echo-​monitored procedure.
8. Augustin P, Desmard M, Mordant P, et  al. Clinical review: Am J Cardiol 2016;117:1369–​74.
intrapericardial fibrinolysis in management of purulent pericarditis. 16. Maggiolini S, De Carlini C, Ferri L, et al. The role of early contrast-​
Crit Care 2011;15:220. enhanced chest computed tomography in the aetiological diagnosis
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of patients presenting with cardiac tamponade or large pericardial 23. Singh V, Dwiedi SK, Chandra S. Optimal fluid amount for haemo-
effusion. Eur Heart J Cardiovasc Imaging 2016;17:421–​8. dynamic benefit in cardiac tamponade. Acute Cardiovasc Care
17. Catena E, Addamiano C, Bertoli E, Maggiolini S, Farina A, Achilli F. 2014;3:158–​64.
Pericardiocentesis from back under echographic guidance: an approach 24. Rafique AM, Patel N, Biner S, Eshaghian S, Mendoza F, Cercek B.
for posterior pericardial effusions. Circulation 2011;124:e835–​6. Frequency of recurrence of pericardial tamponade in patients with
18. Tsang TS, Enriquez-​Sarano M, Freeman WK, et al. Consecutive 1127 extended versus non extended pericardial catheter drainage. Am J
therapeutic echocardiographically guided pericardiocenteses:  clin- Cardiol 2011;108:1820–​5.
ical profile, practice patterns, and outcomes spanning 21 years. Mayo 25. Tsang T. Echocardiography-​ guided pericardiocentesis for effu-
Clin Proc 2002;77:429–​36. sions in patients with cancer revisited. J Am Coll Cardiol 2015;66:
19. Akyuz S, Zengin A, Arugaslan E, et  al. Echo-​guided pericardio- 1129–​31.
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term for a well-​defined but rather underreported complication of ADDITIONAL ONLINE MATERIAL
pericardial drainage. Ann Thorac Surg 2010;89:1702–​3.
For additional multimedia materials, please visit the online
22. Yuce M, Sari I, Davutoglu V, Ozer O, Usalan C. Bubbles around
version of the book (M
M oxfordmedicine.com/ESCIACC3e).
the heart:  pneumopericardium 10  days after pericardiocentesis.
Echocardiography 2010;27:E115–​16.
 CHAPTER 26

Chest tubes
Giulio Maurizi, Camilla Vanni, and
Erino Angelo Rendina

Contents Summary
Introduction  331 The indication to insert a chest tube is to evacuate pathologic collected fluids and/​
Indications  332 or air from the thoracic cavity, thus restoring the natural negative pressure within
Technique of chest tube insertion  333 the same pleural space and further allowing the lung to re-​expand. A pleural drain
Complications  334 can constitute a vital measure in some critical situations, as in the case of a medias-
Management  335 tinal shift secondary to tension pneumothorax. More often, chest tubes provide an
References  336 elective standard of treatment in a wide range of conditions, and they still represent
part of perioperative management after cardiothoracic surgery. There are no abso-
lute contraindications for chest tubes. Coagulopathies and platelet defects require
specific considerations on a case-​by-​case basis. Chest drains may be inserted by
surgeons, as well as by interventional radiologists, physicians, or trained nurses.
Proper knowledge of the physiology of the pleural space and expertise in every
aspect of the procedure are key to safety and effectiveness.

Introduction
Insertion of a chest tube is a common therapeutic procedure routinely employed to re-
store the natural negative pressure in the pleural space and ensure complete pulmonary
re-​expansion through drainage of a pathologic collection of fluid and/​or air from the
thoracic cavity.
Pleural drainage can constitute a vital measure in some critical situations, as in the case
of mediastinal shift secondary to tension pneumothorax. More often, chest tube place-
ment provides an elective standard of treatment in a wide range of conditions, and it still
represents part of perioperative management after cardiothoracic surgery.
Drainage placement is, in effect, a surgical operation; otherwise it can be performed
possibly by an experienced emergency practitioner, as well as by a trained physician.
Furthermore, image-​guided chest tube insertion represents a routine procedure in inter-
ventional radiology.
Over the years, several chest tube designs have been developed, which differ in size,
material, and method of insertion. Similarly, different pleural drainage units have been
proposed and commercialized.
The method for inserting the tube, as well as management and withdrawal of the drain
unit, should be guided by clinical judgement and amended depending on different cir-
cumstances. Similarly, the selection of the appropriate size and type of chest tube to be
placed varies according to indications.
332 CHAPTER 26  C hest t u bes

Despite the widespread use of chest drains, only limited There are no absolute contraindications for chest tubes.
evidence-​based guidance on their insertion and management Coagulopathies and platelet defects require specific consid-
is currently available. As part of the existing evidence base, the erations on a case-​by-​case basis. In fact, there is no published
British Thoracic Society (BTS) published in 2003 its clinical prac- evidence that a bleeding dyscrasia or platelet deficiencies can af-
tice guidelines for the insertion of chest drains [1]‌. Moreover, the fect haemorrhagic complications after thoracic drain insertion.
BTS Pleural Disease Guideline Group recently reviewed the indi- Nonetheless, in such cases, it may be preferable to correct the de-
cations on management of spontaneous pneumothorax and ma- fect and delay the procedure whenever feasible [1]‌. If drain in-
lignant pleural effusion [2, 3]. sertion cannot be postponed, all possible precautions (including
coagulation factors, blood, and platelet transfusion) must be
made available. Non-​discontinuable systemic anticoagulation and
Indications antiplatelet therapies have to be considered as a relative contra-
indication when planning an elective procedure [5].
The indication to insert a chest tube is to drain pathologic col- Chest tube insertion in a site with evidence of benign or malig-
lected fluids and/​or air from the thoracic cavity, thus restoring nant skin disorders should always be avoided.
the natural negative pressure within the same pleural space and Despite the historic role and widespread use of pleural drains,
further allowing the lung to re-​expand. the optimal tube size to place is still a topic of debate.
Gas and liquid, when profuse, can completely fill the pleural Different models, materials, and sizes of chest drainage devices
space; in contrast, a smaller amount of fluid may collect only are currently available (see E Figure 26.1) According to their
in selected areas, depending on its nature, viscosity, pulmonary calibre, chest tubes can be divided into large-​bore (≥24F) and
compliance, and the presence of pleural adhesions. small-​bore (<24F) tubes. Furthermore, they are usually classified
Air tends to collect in the apical portion of the chest. Fluids on the basis of the insertion method:
tend to accumulate in the lower part of the pleural cavity, which
◆ Trocar catheters (medium or large bore, 20–​36F; both short and
is inferior in the seated or standing position or posterior when
long trocar models are available)—​they always require a sur-
the patient is supine. These postural variables must be considered
gical procedure for placement.
when selecting the site for drain insertion in the event of either
◆ Seldinger catheters (small or medium bore, 8–​16F)—​they do not
free or multiloculated pleural collections. In the latter case, in-
require a blunt dissection for placement; routinely employed in a
sertion should be guided by radiological images (CXR, chest CT
radiologically guided setting.
scan) or US whenever feasible [4]‌.
◆ Pleural puncture sharp needle (small bore, 8F).
Common indications requiring placement of a chest tube are
listed in E Box 26.1. ◆ Soft catheters (all sizes)—​placed at the end of cardiothoracic
surgery as part of prophylactic post-​operative management.
Traditional teaching provides for the insertion of large-​calibre
Box 26.1  Main indications for chest tube insertion
tubes through the use of a blunt dissection technique. Over the
◆ Trauma:
Penetrating chest trauma
●

Haemothorax, regardless of its size

●

Haemopneumothorax, regardless of its size

●

Pneumothorax, regardless of its size

●

Rib fractures (prophylactic, when mechanical ventilation is

●

needed)
Pneumothorax:
◆

In any case when mechanical ventilation is needed

●

Tension pneumothorax
●

Persistent pneumothorax, after needle aspiration

●

Recurrent spontaneous pneumothorax, after needle aspiration

●

Iatrogenic pneumothorax
●

Symptomatic pneumothorax
●

Haemothorax (other than post-​traumatic)

◆

Chylothorax
◆

Empyema
◆

Malignant pleural effusion

◆

Post-​operative (prophylactic, cardiothoracic surgery)

◆

Bronchopleural and oesophagopleural fistula

◆
Figure 26.1  Chest catheters. Left to right: Seldinger ‘pigtail’ catheter, Monod
trocar tube, and Mallinckrodt trocar tube.
 Techn i qu e of chest tu b e   i n se rt i on 333

past few years, increasing evidence on the efficacy of small-​bore of who performs the operation, proper knowledge of the physi-
tubes are leading towards re-​ evaluating current indications. ology of the pleural space and expertise in every aspect of the
Small-​bore catheters have, in fact, been advocated as being an procedure are key to safety and effectiveness.
easier and less invasive alternative to conventional drainage, with All necessary devices and materials needed for chest tube inser-
comparable efficacy in selected conditions such as malignant un- tion must be available before starting (see E Box 26.2).
complicated effusions and low-​flow rate pneumothorax [6]‌. The procedure is usually carried out in the operating theatre.
In fact, the key to selecting the proper catheter and its size is the However, bedside insertion of a thoracic tube in ward areas, ED,
flow rate of air or liquid that can be purged by the tube. This rate or intensive care settings may be necessary for some critical and
is determined by the Fanning equation: contingent situations. In any case, an aseptic technique must be
used to minimize the risk of infection [1]‌. Patient authorization
ν=π2r5ρ/fl through an individual consent form must always be obtained in
where ν is the flow, r is the inner radius of the catheter, ρ is the non-​imminent life-​threatening conditions.
pressure, f is the friction factor, and l is the length [7]‌. The standard technique for chest tube surgical insertion is me-
Hence, the internal diameter and length of the tube are cru- ticulously described in BTS guidelines [1]‌.
cial flow determinants. In addition, the higher the friction of the The patient is positioned supine, with the affected side slightly
fluid, the slower the flow, as in the case of viscous liquids such as elevated and the ipsilateral arm lifted over the head, in order to
pus or blood, which would require the placement of a large-​bore expose the axillary region. In case of limitation of joint mobility,
device  [8]‌. the arm can be restrained anteriorly. If the patient is conscious,
The selection of the chest tube size must also take into account premedication can be administered.
the amount of fluid output and air leaks. For a constant level of suc- Routinely, the insertion site should be selected between the
tion of at least 20 cm of water, airflow will vary from 5 L/​min for a third and fifth intercostal spaces and within the ‘safe triangle’ area,
small-​bore tube (8F) to 28 L/​min for a large-​calibre tube (28F chest which is defined as the region delineated by the anterior border
tube) [8]‌. High flow leaks, such as those of mechanically ventilated of the latissimus dorsi muscle, the lateral border of the pectoralis
patients with a bronchopleural fistula, can easily exceed 20 L/​min. major muscle, and a line superior to the horizontal level of the
It seems coherent therefore to provide an appropriate large-​sized nipple with the apex below the axilla (see E Figure 26.2). To
chest tube in order to avoid persistent or tension pneumothorax. place a chest tube through this access reduces the risk of vascular
Data from the literature are scarce and often contradictory. injuries (internal mammary artery), as well as damage to the
Broadly speaking, the latest BTS guidelines recommend the use of breast gland and muscles. In the case of a small anterior–​apical
small-​bore drains (10–​14F) in most of the common indications, as pneumothorax, the second intercostal space on the mid-​clavicular
they look to be less painful and better tolerated by the patient [9]‌. line can represent an alternative approach (see E Figure 26.2). At
Nevertheless, there are still no available large randomized trials times, a lower insertion site may be required to drain a collection
comparing outcomes after placement of small-​and large-​bore of fluids, particularly when multiloculated; care must be taken
tubes. Successful treatment of uncomplicated pneumothoraces to avoid any injury to the diaphragm and abdominal organs. In
with the use of small-​size tubes has been long known, with re- these difficult situations, a small-​bore chest tube can be placed
ported success rates of up to 87% [10]. Nevertheless, in the event using the Seldinger method and imaging guidance [18].
of a high-​capacity airflow pneumothorax, placement of a larger-​
bore tube is still recommended.
A US-​ guided radiological hybrid insertion technique of Box 26.2  Materials and devices for chest tube insertion
Seldinger catheters has been extensively investigated and showed Premedication (antibiotics, analgesics, hypnotic sedative)
◆
excellent results in the treatment of malignant pleural effusions Sterile gloves, mask, and cap (gown optional)
◆
[11], even allowing outpatient management of cases of malignant
Antiseptic solution (iodine or chlorhexidine alcohol solution)
◆
effusion unresponsive to chemotherapy [12]. Despite previous re-
Sterile drapes and gauzes
◆
commendations of use of large-​bore drains for thick fluids [13, 14],
Syringes (10 and 20 mL) with intramuscular needles
◆
as it was felt that there was a potential increase in tube obstruc-
tion, conservative therapeutic approaches to empyema through Lidocaine 1% or 2%, with or without adrenaline
◆

the combined use of small-​bore guided drainage and thrombo- Scalpel and blade
◆

lytic agent administration have been proposed recently, with Curved Kelly clamp for blunt dissection
◆

good results [15, 16]. In the case of acute haemothorax, however, Needle holder and suture material (cutting needle)
◆

large-​bore tubes (28F minimum) are always recommended [17]. Scissors

◆

Sterile thoracostomy tubes
◆

Connecting tube devices

◆

Technique of chest tube insertion Closed drainage system (pleural drainage unit or Heimlich
◆

valve)
Chest drains may be inserted by a surgeon, as well as by an inter-
Sterile dressing
◆
ventional radiologist, a physician, or a trained nurse. Regardless
334 CHAPTER 26  C hest t u bes

A
B

Figure 26.2  Traditional insertion site. A: second intercostal space on the

mid-​clavicular line (orange). B: fifth intercostal space, lateral. The blue line
delineates the ‘safe triangle’ area.

The insertion procedure has to be preceded by local anaesthesia.

Aspiration of air or fluid into the syringe indicates entry into the
pleural space. Staying as close as possible to the superior aspect of
Figure 26.3  Blunt surgical dissection. Care must be taken to avoid injuries
the lower rib in the space should aim to avoid injuring the inter- to the neurovascular bundle, which runs along the lower border of the
costal vessels and nerve (see E Figure 26.3). Blunt dissection and superior rib.
finger exploration are, in addition, useful in preventing lung par-
enchymal laceration.
Once proper functioning of the drainage system has been
verified, the chest tube is secured in place with a heavy suture
Complications
(non-​absorbable material). A second suture in a horizontal mat- Despite being a long-​standing standard procedure, insertion of
tress or purse-​string stitch placed around the tube at this time can a chest tube is not a risk-​free intervention, even in experienced
be helpful for prospective drain removal. At the end of the pro- hands. Over the years, possible significant complications, as well
cedure, radiologic assessment of the correct position of the tube as mortality, have been described.
is mandatory; it is also useful to determine the amount of residual In general, minor and major post-​drainage complications can
pneumothorax or undrained fluids. be categorized as acute (with early onset, within the first 24–​48
Needle decompression is a salvage procedure. It is always in- hours) and chronic (occurring late, after this time period); overall
dicated in the event of mediastinal shift with respiratory distress reported incidences are 3% and 8%, respectively [1]‌.
and haemodynamic instability [19]. This condition can be sec- Of the acute complications, tube malposition has been reported
ondary to a tension pneumothorax, as well as the presence of as the most frequent occurrence.
a massive haemothorax or a compressive malignant effusion. CXR can fail to detect tube misplacement in over half of the
In such cases, immediate needle decompression rapidly re- cases, particularly when radiography is acquired only in a PA
duces the excess intrapleural pressure, further confirming the view in emergency contexts. In cases of poor drainage or mal-
suspected diagnosis by the exploration puncture. After skin function of the drain unit, CT scan is helpful to reveal the exact
disinfection, a small venous catheter is inserted in the second location of the chest tube. In a paper published in 2005, Lim and
intercostal space on the mid-​clavicular line. The needle must colleagues [20] reported how CT scan has been able to identify 28
be inserted perpendicularly to the skin and as close as possible malpositioned tubes of a total of 76 emergency thoracostomy pro-
to the superior border of the third rib, in order to prevent in- cedures, compared to six cases of malposition obtained blindly by
juries to the intercostal neurovascular bundle. Aspiration of air reviewing PA CXRs from the same group of patients.
or fluid under pressure into the syringe confirms the diagnosis. Wrong tube insertion can potentially lead to disastrous conse-
Disconnection of the syringe allows the gas (or liquid) to leak out quences. Selection of the proper insertion site, depending on the
of the pleural space until its pressure is equal to that of the atmos- specific condition to be treated, can minimize the risk of injuries.
phere. Symptomatic relief and clinical improvement are typically A history of prior surgical interventions that could result in dia-
immediate. Nevertheless, chest tube placement is also necessary phragm elevation, as well as body size and habitus of the patient
after needle decompression. also must be considered [21].
 M a nag e m e n t 335

integrated disposable chest drainage units have been made avail-

Box 26.3  Potential organ injuries secondary to chest
tube insertion able. Whatever the type, the main purpose of these devices is to
allow air and/​or collected fluids to exit from the pleural cavity
Intrathoracic:
◆ during exhalation, but by preventing the backflow of air on in-
Lung
●
halation; this can be accomplished through the interposition of a
Diaphragm (dysfunction, perforation, laceration with ab-
● one-​way valve (water seal valve, Heimlich valve).
dominal organ herniation) The traditional chest drainage system (vacuum system) is a
Heart
● three-​bottle system, which includes a first collection chamber to
Great thoracic vessels
● gather and quantify liquids, a water seal chamber set with a 2-​
Tracheobronchial tree
● cm water resistance, and a suction control chamber. By means of
Oesophagus
● its unidirectional path, the low-​resistance valve restores physio-
Other mediastinal structures (lymphatic vessels, nerves)
●
logic negative pressure in the pleural space, thus ensuring pul-
monary re-​expansion and preserving the natural mechanics of
Sympathetic trunk
●
respiration.
◆ Extrathoracic:
Air and low-​viscosity fluids generally drain out of the pleural
Liver
●
cavity through the chest tube without the need for suction [8]‌. If
Spleen
●
gravity (water seal) drainage is not effective, suction can be ap-
Stomach
●
plied. In the suction control unit, the amount of negative pressure
Bowel
● can be regulated by the height of the water column (wet suction
Kidney and adrenal gland
● control) or a new-​generation self-​compensating regulator (dry
Great abdominal vessels
● suction control). A pressure of –​20 cmH2O is routinely applied.
Higher suction levels (30–​40 cmH2O) can be used in some spe-
cific circumstances such as high-​capacity air leaks, viscous pleural
Common major thoracic complications include placement of liquids, or limited pulmonary compliance; conversely, lower pres-
an intraparenchymal tube with laceration of the lung and bleeding sure may be indicated in children or patients with friable lung
from an intercostal vessel. Laceration of the diaphragm, oesopha- tissue. As regard to treatment of pneumothorax, the American
geal perforation, and other mediastinal injuries (heart and great College of Chest Physicians (ACCP) guidelines suggest that both
vessels, bronchial tree) have also been reported. Moreover, any suction and non-​suction drains are allowed [23].
anatomical structure in the upper abdominal cavity may be at risk Disadvantages of the three-​bottle system include mandatory
of damage during chest tube insertion, notably in patients with inpatient management and restriction with regard to mobiliza-
ascites or cirrhosis. tion. The Heimlich valve is an example of a passive system that
The main potential organ injuries related to pleural tube inser- allows mobilization and even discharge of the patient without dis-
tion are listed in E Box 26.3. comfort. The use of Heimlich flutter valves has been advocated in
Other minor complications after insertion and permanency these patients, especially as they permit ambulatory management
of a chest tube include:  poorly controlled (acute and chronic) with a high success rate [24].
pain and/​or sensitive dysaesthesia; subcutaneous air collection The need for antibiotics after placement of a pleural drain is
or recurrence of a fluid collection due to malposition, obstruc- still controversial. The majority of published evidence show no
tion, or migration/​dislodgement of the tube; leakage through the benefit, broadly speaking, from their prophylactic administra-
thoracostomy site; drainage system disconnection or technical tion. On this topic, a recent meta-​analysis [25] (including over
malfunction; and fragmentation and partial intrathoracic reten- 1200 chest tube procedures from 11 articles) showed a favourable
tion of the tube. effect of antibiotics use on the incidence of empyema and pul-
Colonization and infection of the insertion site are not a rare monary infections, with emphasis on patients with penetrating
occurrence, particularly in the case of indwelling catheters placed injuries (OR 0.28, 95% CI 0.14–​0.57); by contrast, the benefit has
with a palliative intent. By contrast, secondary empyema is a rare not been confirmed in the subgroup of patients with blunt thor-
complication. When antibiotic therapies fail, tube removal and its acic trauma. Guidelines from the BTS recommend antibiotic ad-
replacement are often required [4]‌. ministration in all patients undergoing chest tube insertion after
chest trauma [1]‌.
As long as the chest tube is in place, it has to be regularly
checked. Every time the patient is examined by both medical
Management and nursing staff, some particular issues should be checked—​
Once the pleural space is drained, the tube must be connected to these include correct functioning of the vacuum unit (water seal
a drainage unit. valve, suction chamber), tubing patency, volume and quality of
Since the first closed drainage system was developed by drained fluids, changes in intrapleural pressure, and presence
Gotthard Bulau early in the last century [22], a variety of new and clinical evolution of air leaks. Moreover, dressing status and
336 CHAPTER 26  C hest t u bes

proper anchorage of the tube should be periodically inspected. generally considered adequate, with a documented incidence of
It is standard practice to monitor for correct positioning of the recurrent pleural effusion of <3% [26, 28].
drain, the quality of lung re-​expansion, and the absence of re- Results from a cohort surgical study including 2077 patients
tained pleural collections by radiographic examinations on a who underwent non-​pneumonectomy pulmonary resections by a
regular basis. single surgeon demonstrated how even high-​volume non-​chylous
The decision to remove a chest tube should be dictated by ex- drainage (450 mL/​day or less) does not affect the incidence of re-
perience, taking into account the primary indication for tube current symptomatic effusions; the reported readmission rate
insertion and the later clinical and radiological evolution of the specific to symptomatic recurrence was 0.55% [29].
condition. Premature discontinuation of thoracic drainage may Whether to remove a chest tube on maximal inhalation or on
lead to early-​onset recurrent pneumothorax and relapse of pleural forced exhalation is still debated. At the end of inhalation, the
effusion. In the case of a pneumothorax, the drain should not be lung is maximally expanded, but the intrapleural pressure reaches
withdrawn until certainty of permanent cessation of air leak, as its peak of negativity; by contrast, the pressure gap between the
well as complete expansion of the lung, has been documented intrapleural space and the atmosphere is minimized on prolonged
[4,  8]. No significant difference has been reported between re- exhalation, despite parenchymal deflation. The BTS guidelines
moving the chest tube on suction and after its discontinuation advocate that the chest tube can be removed either when the pa-
following a pneumothorax [26]. tient performs the Valsalva manoeuvre or during expiration [1]‌.
In general, tube clamping prior to its removal is not necessary. Results from a prospective randomized study have shown no sig-
However, when prolonged air leaks occur, the chest tube can be nificant differences in terms of recurrent pneumothorax (7% in
removed after its provocative clamping [27]. The safety of this each group) when comparing both inspiration and expiration
manoeuvre has been attributed to the development of tight ad- methods of tube withdrawal [28].
hesions perhaps secondary to the prolonged permanency of the Disagreement persists on the proper timing of performing a
catheter. This pleural scarring response prevents pulmonary col- radiological assessment to rule out the presence of a recurrent
lapse after tube withdrawal, even if air leakage is persistent, with pneumothorax after chest tube removal. Recently, a small study
resultant self-​limitation. on mechanically ventilated patients showed that performing a
When considering pleural effusion, the appropriate timing for chest radiograph within 1–​3 hours after chest tube removal iden-
chest tube removal is empirically based on personal opinions, tified all recurrent pneumothoraces [30]. However, it is in the
with resultant wide variation among different institutions. The authors’ current opinion that a chest radiograph may not be ne-
minimum daily chest tube fluid output before tube removal is cessary in the absence of symptoms whenever the clinical exam-
not clearly established; a daily liquid output of 200 mL or less is ination is negative.

References
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Committee, British Thoracic Society. BTS guidelines for the insertion utilizing small caliber chest tubes. Chest 1988;94:55–​7.
of a chest drain. Thorax 2003;58 Suppl 2:ii53–​9. 11. Thompson RL, Yau JC, Donnelly RF, et al. Pleurodesis with iodized
2. MacDuff A, Arnold A, Harvey J; BTS Pleural Disease Guideline Group. talc for malignant effusions using pigtail catheters. Ann Pharmacother
Management of spontaneous pneumothorax: British Thoracic Society 1998;32:739–​42.
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3. Roberts ME, Neville E, Berrisford RG, et  al.; BTS Pleural Disease
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Guideline Group. Management of a malignant pleural effusion: British 1994;54:215–​17.
Thoracic Society Pleural Disease Guideline 2010. Thorax 2010;65 Suppl 13. Harriss DR, Graham TR. Management of intercostal drains. Br J
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5. Abouzgheib W, Shweihat YR, Meena N, et  al. Is chest tube inser- 15. Moulton JS, Benkert RE, Weisiger KH, et al. Treatment of compli-
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6. Fysh ET, Smith NA, Lee YC. Optimal chest drain size: the rise of the 16. Maskell NA, Davies CW, Nunn AJ, et al.; First Multicenter Intrapleural
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 CHAPTER 27

Renal support therapy
Claudio Ronco, Stefano Romagnoli,
and Zaccaria Ricci

Contents Summary
Summary  338 Renal dysfunction is known to be frequently a component of multiple organ failure,
Introduction: the need for multiorgan a complex syndrome affecting the most severely ill critical patients. Bidirectional
support in the critically ill patient  338
interaction between the kidneys and other organs has always been suspected;
Historical notes  340 evidence suggests that severe kidney injury is an important protagonist in acute
Modes of renal replacement therapies and illness, even when managed by dialysis. In fact, if it seems that increasing the dose
technical notes  340
of renal replacement therapy does not reduce mortality, it could be inferred that
Diffusion and convection  341
Dose and prescription  342 acute kidney injury influences mortality through means that are not reversed
Continuous versus intermittent versus by conventional renal support, either because the putative culprit toxins are not
hybrid  342 removed by renal replacement therapy or because renal replacement therapy is
Vascular access  343
Anticoagulation  344
started too late to prevent these effects. It is known that the kidneys exert effects on
Circuit setup optimization and no other organs, such as the lung, liver, heart, and brain, in a process called ‘crosstalk’.
anticoagulation  344 This effect means that the kidney is not only a victim, but also a culprit regarding
Unfractionated heparin (UFH)  344 the malfunction of other organs.
Low-​molecular-​weight heparins
(LMWHs)  344 This chapter will detail some traditional aspects of different renal replacement
Prostacyclin  344 therapy modalities and prescription schedules, but it will also describe the most
Citrate  345 recent evidence on the management and support of the kidney during failure of
Indications to start and stop renal other organs.
replacement therapies  345
When to start  345
When to stop  346
The cardiorenal syndromes  346
Non-​pharmacological management of
cardiorenal syndromes  346
Conclusion  348 Introduction: the need for multiorgan support
Personal perspective  348 in the critically ill patient
Further reading  348
References  348 Multiorgan dysfunction is a complex and multifactorial syndrome that affects the most
Additional online material  350 severe cases of critically ill patients with cardiac failure. Mortality ranges from 50% to
90% of patients. Furthermore, due to improvement of pharmacological and mechanical
support options, in the last 10 years, a cohort of heart failure patients with the most severe
diseases have started being admitted to cardiac intensive care units (CICUs). Therapeutic
options when multiple organ failure (MOF) occurs are currently aiming at supporting the
function of single organs (i.e. application of mechanical ventilation, use of vasopressors,
prescription of dialysis, etc.). The delicate and composite homeostatic functions regulated
by the kidneys are rapidly hampered during MOF; after heart and lung failure, renal dys-
function is certainly the most common occurrence of MOF [1]‌. After >30 years of ap-
plication to critically ill patients, the development and utilization of renal replacement
therapy (RRT) have increased to the point that today a multifaceted intervention, dir-
ected at supporting the function of several organs, appears feasible and rational. The con-
cept of multiorgan support therapy (MOST) [2] perfectly fits this description. The idea at
the base of MOST is to treat patients’ blood artificially outside the body, substituting the
 In trodu ct ion: t h e need for  m u lti org a n su pp ort i n  the cri ti ca l ly i l l   pat i e n t 339

heart, lungs, liver, and kidneys with dedicated pumps, circuits, and Critically ill patients are typically affected by a complex
membranes, in order to allow surgical/​medical therapy to become multiorgan disease; regardless of which organ is injured first (e.g.
effective and ‘homeostasis’ (intended with a broad meaning) to kidney, lung, brain, gut, heart), due to complex connections and
restore. The present chapter adopts the terminology recently and interplay, distal organs are eventually and simultaneously involved
specifically developed in an international consensus conference in critical illness, leading to MOF [4–​5]. Over 50% of patients
on RRT in order to establish a common definition for the compo- develop acute kidney injury (AKI) during their intensive care
nents, techniques, and operation of the machines and platforms unit (ICU) stay and >20% of critically ill patients with AKI will
used for acute extracorporeal therapies [3] (see E Table 27.1). undergo RRT within the first week of their ICU stay [6]‌. It is now

Table 27.1  Renal support modalities, with a brief explanation for indications and prescriptions

Intermittent haemodialysis (IHD) A prevalently diffusive treatment in which blood and the dialysate are circulated in countercurrent mode, and generally
a low-​permeability, cellulose-​based membrane is employed. The dialysate must be pyrogen-​free, but not necessarily
sterile, since dialysate–​blood contact does not occur. The QUF rate is equal to the scheduled weight loss. This
treatment can be typically performed 3–​5 hours thrice weekly or daily
QB: 400–​500 mL/​min; QD: 600–​800 mL/​min [18]
Peritoneal dialysis (PD) A diffusive treatment where blood, circulating along the capillaries of the peritoneal membrane, is exposed to the
dialysate. Access is obtained by insertion of a peritoneal catheter, which allows abdominal instillation of the dialysate.
Solute and water movement is achieved by means of variable concentrations and tonicity gradients generated by the
dialysate. This treatment can be performed continuously or intermittently
Slow continuous ultrafiltration A technique where blood is driven through a highly permeable filter via an extracorporeal circuit in veno-​venous mode.
(SCUF) The ultrafiltrate produced during membrane transit is not replaced, and it corresponds to weight loss. It is used only
for fluid control in overloaded patients (i.e. congestive heart failure patients who do not respond to diuretic therapy)
QB: 100–​250 mL/​min; QUF: 5–​15 mL/​min
Continuous veno-​venous A technique where blood is driven through a highly permeable filter via an extracorporeal circuit in veno-​venous mode.
haemofiltration (CVVH) The ultrafiltrate produced during membrane transit is replaced, in part or completely, to achieve blood purification
and volume control. If the replacement fluid is delivered after the filter, the technique is defined as post-​dilution
haemofiltration. If it is delivered before the filter, the technique is defined as pre-​dilution haemofiltration. The
replacement fluid can also be delivered both pre-​and post-​filter. Clearance for all solutes is convective and equals
the QEFF
QB: 100–​250 mL/​min; QEFF: 15–​60 mL/​min (see E Figure 27.2)
Continuous veno-​venous A technique where blood is driven through a low-​permeability dialyser via an extracorporeal circuit in veno-​venous
haemodialysis (CVVHD) mode and a countercurrent flow of dialysate is delivered n the dialysate compartment. The ultrafiltrate produced
during membrane transit corresponds to the patient’s weight loss. Solute clearance is mainly diffusive, and efficiency
is limited to small solutes only
QB: 100–​250 mL/​min; QD: 15–​60 mL/​min (see E Figure 27.2)
Continuous veno-​venous A technique where blood is driven through a highly permeable dialyser via an extracorporeal circuit in veno-​venous
haemodiafiltration (CVVHDF) mode and a countercurrent flow of dialysate is delivered on the dialysate compartment. The ultrafiltrate produced
during membrane transit is in excess of the patient’s desired weight loss. A replacement solution is needed to
maintain fluid balance. Solute clearance is both convective and diffusive
QB: 100–​250 mL/​min; QD: 15–​60 mL/​min; QR: 5–​15 mL/​min; QD: 5–​15 mL/​min; QEFF: 15–​60 mL/​min, including QRPRE +
QRPOST + QD + QUFNET (see E Figure 27.2)
Haemoperfusion (HP) Blood is circulated on a bed of coated charcoal powder to remove solutes by adsorption. The technique is specifically
indicated in cases of poisoning or intoxication with agents that can be effectively removed by charcoal. This treatment
may cause platelet and protein depletion
Plasmapheresis (PP)/​therapeutic A treatment that uses specific plasma filters. The molecular weight cut-​off of the membrane is much higher than that
plasma exchange (TPE) of haemofilters (100 000–​1 000 000 kDa); plasma as a whole is filtered, and blood is reconstituted by infusion of plasma
products such as frozen plasma or albumin. This technique is performed to remove proteins or protein-​bound solutes
High-​flux dialysis (HFD) A treatment that utilizes highly permeable membranes in conjunction with an ultrafiltration control system. Due to
the characteristics of the membrane, ultrafiltration occurs in the proximal part of the filter that is counterbalanced by a
positive pressure applied to the dialysate compartment. This causes, in the distal part of the filter, a phenomenon called
back filtration that consists of convective passage of the dialysate into blood. Diffusion and convection are combined,
but due to the use of a pyrogen-​free dialysate, replacement is avoided
High-​volume haemofiltration A treatment that utilizes highly permeable membranes and haemofiltration with a high-​volume setting. HVHF is
(HVHF) identified as continuous treatment with a convective target dose (prescribed) of >35 mL/​kg/​hour. Continuous
treatments with a dose of >45 mL/​kg/​hour identify very high-​volume haemofiltration (VHVHF) modalities.
Intermittent procedures with brief, very high-​volume treatments at 100–​120 mL/​kg/​hour for 4–​8 hours, followed by
conventional CVVH, are identified as pulse HVHF [19]
QB >200 mL/​min; QEFF >35 mL/​kg/​hour
340 CHAPTER 27   Renal su pp ort  th erap y

clear that AKI in the ICU is a common syndrome and that acute rate of complications due to the need of arterial cannulation. The
kidney dysfunction can be the cause of further organ dysfunc- driving force was no longer determined by the patient’s MAP but
tion (e.g. respiratory failure secondary to fluid accumulation). By resulted from the mechanical action of the roller pumps [10]. The
contrast, the kidneys may be involved as distal organs in cases new continuous veno-​venous therapies required negative pres-
of acute heart failure (AHF) (e.g. congestive kidney injury due sure measurements and an alarm in the arterial line before the
to sudden increase in CVP and/​or renal hypoperfusion in cases pump, as well as positive pressure measurements and an alarm
of cardiogenic shock (CS)). Mortality is clearly associated with in the venous return line; a bubble trap had to be inserted be-
organ dysfunction, reaching up to 50% when RRT is required [7]. fore the blood was reinfused into the patient in order to prevent
Many patients admitted to the ICU require organ support (e.g. an air embolism (this was not necessary in CAVH where the cir-
mechanical ventilation, RRT, intra-aortic balloon pump (IABP)), cuit operated at positive pressure along the entire length of the
and in most of the cases, simultaneous assistance is required. In system). Roller pumps with improved performance were con-
more complex clinical scenarios, extracorporeal support may be ceived and allowed higher blood flows, producing higher filtra-
applied [e.g. veno-​venous (VV) or veno-​arterial (VA) extracor- tion rates, and significantly increased solute clearance. For this
poreal membrane oxygenation (ECMO) or extracorporeal life reason, roller pumps were also applied to the dialysate or fluid
support (ECLS) and RRT or extracorporeal CO2 removal and replacement delivery section of the circuit, and external scales
RRT]. All extracorporeal therapies that imply blood processing had to be frequently utilized to provide sufficiently accurate fluid
and manipulation with specific devices and techniques are now balance during treatment. The benefits induced by the new tech-
defined as extracorporeal organ support (ECOS) [8]. nology were still counterbalanced by the gross inaccuracy of the
systems and the limited integration between the extracorporeal
circuit and the fluid balance devices [11]. The second-​generation
Historical notes machines were more accurate and reliable devices—​precursors
of the current technology for RRT in CICUs. Modern RRT ma-
The first continuous form of dialysis specifically dedicated to chines specifically dedicated to critically ill patients generally re-
critically ill patients was the so-​called continuous arteriovenous quire 4–​5 roller pumps (blood, dialysate, reinfusion, UF/​effluent,
haemofiltration (CAVH), first described by Peter Kramer in 1977 accessory pump), 3–​4 scales, and pressure sensors (inlet, outlet,
[9]‌. At that time, RRT in the intensive care setting was considered filter, and effluent) to monitor the entire circuit conditions. These
a last-​chance therapy for patients with MOF. In CAVH, the blood machines allow a maximal flow rate of up to about 450 mL/​min
flow in the circuit was driven by a spontaneous arteriovenous for the blood pump and to about 8–​10 L/​hour for the dialysate/​re-
pressure gradient (dependent on the MAP of the patient and placement pumps; this also means that the effluent pump should
the intrinsic resistance of the circuit), and spontaneous ultrafil- be able to increase up to 20–​25 L/​hour [11]. The accuracy of roller
tration (UF) occurred, depending on the transmembrane pres- blood pumps has been increased in order to warrant a wide flow
sure (TMP) gradient (determined by the hydrostatic pressure rate range, keeping flow errors below 2%. New algorithms allow,
drop inside the filter and the negative suction provided by the in some models, to automatically update, hour by hour, the UF
ultrafiltrate column from the patient level to the ground). CAVH prescribed/​delivered gap and to correct it in the next hour, in
enabled slow continuous fluid removal, maintaining steady order to reduce any prescription error. An interesting safety fea-
solute concentrations and preventing peaks of toxic substances. ture of third-​generation machines is the possibility of setting a
CAVH, however, had serious limitations: (1) it required both ar- limit of accepted UF errors (within a predetermined time frame),
terial and venous accesses, at risk of high morbidity; (2) solute after which the session is automatically interrupted and the inter-
clearance was limited by low UF rates imposed by the relatively vention of the operator required [12]; this feature seems im-
low blood flow in the circuit and by the low TMP gradient—​ portant in the light of a possible lethal human mistake that might
this meant that the most haemodynamically unstable patients derive from a prolonged and uncontrolled overriding of UF error
achieved the lowest clearances and developed early clotting of alarms.
the circuit; (3) CAVH rarely exceeded 20 mL/​min of clearance,
hardly sufficient to meet the needs of severely catabolic patients
[10]. In order to overcome such technical limitations, new fil- Modes of renal replacement therapies
ters were designed with increased cross-​sectional area and inner
hollow fibre diameter, a reduced unit length, and a lower re-
and technical notes
sistance to blood flow. Another option explored in those days Extracorporeal blood purification achieved by CRRT should aim
was the use of a second port in the filtrate compartment so that to approach that obtained by the native kidney. Blood driven
the countercurrent dialysate flow could be programmed in the through the semi-​permeable membrane is ‘purified’ in terms of
newly conceived continuous arteriovenous haemodiafiltration water and solute removal. CRRT filters are a key feature of blood
(CAVHD) mode [10]. purification in critically ill patients. These filters are composed of
A significant step further was achieved when a peristaltic pump groups of hollow fibres with different total surfaces (from 0.1 to
was added to the extracorporeal circuit, with subsequent hard- over 2 m2) in order to meet the needs of differently sized patients.
ware evolution. This made possible the use of double-​lumen Polyacrylonitrile, polysulfone, and polymethyl-​ methacrylate
catheters; the puncture of a single vein thus decreased the high membranes allow a high UF coefficient (over 20 mL/​ hour/​
 Modes of rena l repl acem en t ther a pi es a n d techni c a l   n ot e s 341

mmHg) and a high diffusive and convective performance. Such in order to prevent excessive haemoconcentration within the
fibres have a generally high porosity (30–​50 A°), and there is no filtering membrane and to avoid the critical point where the
unequivocal evidence of the superiority of one membrane over oncotic pressure is equal to the TMP, and a condition of filtra-
another, provided their even biocompatibility that is determined tion/​pressure equilibrium is reached. Finally, replacing plasma
by the change in blood factors induced by membrane/​blood water with a substitution solution completes the haemofiltration
contact. (HF) process and returns to the patient’s purified blood. The re-
placement fluid can be administered after the filter, via a process
Diffusion and convection called post-​dilution HF (QRPOST). Otherwise, the solution can
A wide range of substances (water, urea, low-​and middle-​weight be infused before the filter, in order to obtain pre-​dilution HF
molecules) can be transported across RRT membranes, from the (QRPRE). While post-​dilution allows a urea clearance equivalent
blood to the effluent side of the hollow fibres, by the mechan- to therapy delivery, pre-​dilution, in spite of theoretical reduced
isms of diffusion (solutes) and convection (water and solutes) (see solute clearances, allows a prolonged circuit lifespan by redu-
E Figure 27.1). cing haemoconcentration. Notably, among the molecules that are
During diffusion, the movement of solutes depends on their re- physically dragged towards the filter pores, albumin and proteins
spective concentration on each side of the membrane; an osmotic must be considered; since they cannot cross the membrane fibres,
shift of solutes from the compartment with the highest concen- a protein layer deposit tends to progressively close fibre pores and
tration to the compartment with the least concentration occurs. to significantly limit solute transport [14]. A peculiar membrane
Other components of the semi-​permeable membrane deeply af- capacity, defined as adsorption, has been shown to have a major
fect diffusion: dialysate flow (QD), thickness and surface, tempera- role in higher-​molecular weight toxins [14]; however, it should
ture, and diffusion coefficient. The dialytic solution flows through be considered that membrane adsorptive capacity is generally
the filter countercurrent to the blood flow in order to maintain the saturated in the first treatment hours and it has only minor ef-
highest solute gradient from the inlet to the outlet port. Diffusion fects on mass separation processes with respect to diffusion and
is the solute transport method that is applied during continuous convection [15].
veno-​venous haemodialysis (CVVHD), although when a net UF Convection is applied during slow continuous UF (SCUF)
flow rate is prescribed (e.g. 100 mL/​hour), convection is eventu- and continuous veno-​venous haemofiltration (CVVH) and in
ally applied (see E Figure 27.2) [13]. CVVHD only for the prescription of QUFNET (see E Figure 27.2).
During convection, the solutes are transported across the The application of both convection and diffusion configures
semi-​permeable membrane, together with water; plasma water is continuous veno-​ venous haemodiafiltration (CVVHDF) (see
ultrafiltered across the membrane in response to the TMP and E Figure 27.2). Typically, the molecular weight of solutes cleared
solutes are carried with it, as long as the porosity of the membrane during convective treatments is higher than during diffusion, due
allows the molecules to be sieved from blood [12, 13]. The process to physical transportation across the membrane occurring during
of UF is governed by the UF flow (QUF), the membrane UF coef- HF that allows larger-​molecular weight solutes to be removed
ficient (KUF), and the TMP gradient generated by the pressures from blood.
on both sides of the hollow fibre. As UF proceeds and plasma The difference between the volume of ultrafiltered plasma water
water and solutes are filtered from blood, the hydrostatic pressure and that of the reinfused substitution solution gives the QUFNET
within the filter is lost and oncotic pressure is gained, because (or patient fluid removal), which is the fluid that is eventually
blood concentrates and the haematocrit increases. The fraction removed from the patient for fluid balance control. QUFNET pre-
of plasma water that is removed from blood during UF is called scription is based on patient needs and can range from >1 L/​hour
the filtration fraction; it should be kept in the range of 20–​25%, (pulmonary oedema in a patient with congestive heart failure and

Diffusion Convection

Figure 27.1  Mechanisms of blood purification. Diffusion: the movement of solutes depends on their respective concentration on each side of the
membrane—​an osmotic shift of solutes from the compartment with the highest concentration to the compartment with the lowest concentration occurs.
Convection: the solutes are transported across the semi-​permeable membrane, together with water; plasma water is ultrafiltered across the membrane, in
response to the transmembrane pressure, and solutes are carried with it, as long as the porosity of the membrane allows the molecules to be sieved from blood.
342 CHAPTER 27   Renal su pp ort  th erap y

SCUF CVVH QUF and/​or QD, depending on the membrane sieving coefficient
QPRE QPOST
in-flow in-flow
R R
(SC) of the cleared molecule. During continuous treatment, it
P out-flow P out-flow is now suggested to deliver at least a urea clearance of 2 L/​hour,
QUF QEFF
with clinical evidence that maybe 20–​35 mL/​kg/​hour might be
QB = 100–250 mL/min QB = 100–250 mL/min the best prescription (i.e. about 2.8 L/​hour in a 70-​kg patient) (see
QUF = 5–15 mL/min QPRE/POST
R = 15–60 mL/min E Table 27.1). A range as wide as 20–​35 mL/​kg/​hour is related
CVVHD CVVHDF to the concept of down-​time (periods of time when the machine
QPRE
R QPOST
R treatment is stopped). Even if down-​time can be limited as much
in-flow in-flow
P
as possible when the CRRT operation is optimized, still it cannot
P out-flow out-flow
QEFF QD (in) QEFF QD (in) be totally eliminated. This is the main reason why even if 25 mL/​
QB = 100–250 mL/min QB = 100–250 mL/min kg/​hour can be considered an acceptable dose, some degree of
QD (in) = 15–60 mL/min QPRE/POST
R = 7–30 mL/min ‘over-​prescription’ can be suggested. New-​generation CRRT de-
QD (in) = 7–30 mL/min vices have recently been designed with the aim of improving
therapy accuracy in dose delivery. These new systems are able to
Figure 27.2  Modalities applied when RRT is administered: slow continuous
increase the dose delivery, if needed, in order to reach the pre-
ultrafiltration (SCUF), continuous veno-​venous haemofiltration (CVVH),
continuous veno-​venous haemodialysis (CVVHD), continuous veno-​ scribed dose over time [17]. Other authors suggest a prescrip-
venous haemodiafiltration (CVVHDF). P, pump; QB, blood flow rate; QUF, tion based on patient requirements, which are based on the urea
ultrafiltration flow rate; QR, replacement (pre, pre-​filter; post, post-​filter); QD, generation rate and the catabolic state of the single patient. It has
dialysate flow rate. been shown, however, that, during continuous therapy, a clear-
ance of <2 L/​hour will almost definitely result as being insufficient
diuretic resistance) to zero (sepsis with catabolic state increased in a critically ill adult patient.
creatinine levels and conserved diuresis). Finally, the therapeutic needs that can be, or need to be, af-
fected by the ‘dose’ of RRT are not only the simple control of
Dose and prescription small solutes, as represented by urea. They also include the con-
Renal replacement can be prescribed and administered according trol of acid–​base, tonicity, K+, Mg2+, Ca2+, phosphate, the intra-
to a specific dose, as any other medical intervention. The RRT vascular volume, the extravascular volume, temperature, and
dose is a measure of the quantity of blood purified by ‘waste avoidance of unwanted side effects associated with the delivery of
products and toxins’ during a certain time frame; this is the clear- solute control [20]. In a patient with pulmonary oedema after an
ance (k). However, the RRT dose is generally synthetized as the ischaemic ventricular septal defect (VSD) requiring emergency
measure of the clearance of a representative marker solute; urea surgery, AKI, ischaemic hepatitis, and the need for inotropic and
and creatinine are generally used as reference solutes in order to intra-​aortic balloon counterpulsation support, the RRT dose is all
measure renal replacement clearance for renal failure. It must be about removing fluid gently and safely so that the extravascular
acknowledged that such marker solutes cannot, and do not, rep- volume falls while the intravascular volume remains optimal.
resent all the solutes that accumulate during AKI, because the E Table 27.2 shows a potential flow chart that could be fol-
kinetics and volume of distribution are different for each mol- lowed each time an RRT prescription is indicated.
ecule. Despite this premise, the comprehension and application of
the dialysis dose appear to increase the efficacy of RRT and finally Continuous versus intermittent versus hybrid
its clinical utility [16]. The concept of the RRT dose is useful also Multiple modalities of renal support may be used in the manage-
for practical purposes; as it happens for antibiotics, vasopressors, ment of the critically ill patient with severe AKI. These include
anti-​inflammatory drugs, and mechanical ventilation, admin- continuous RRT (CRRT), intermittent haemodialysis (IHD), and
istration of an extracorporeal treatment for blood purification ‘hybrid therapies’ that have the characteristics from both intermit-
requires the operators to know exactly how and how much treat- tent and continuous modalities. These therapies, also called pro-
ment should be prescribed and delivered [9]‌. During RRT, k de- longed intermittent renal replacement therapies (PIRRTs) [21],
pends on the circuit blood flow (QB), haemofiltration (QR) and/​or attempt to optimize the advantages and minimize the disadvan-
dialysis (QD) flow, the molecular weights of solutes, and the tages of both modalities: efficient solute removal, slower UF rates
haemodialyser type and size. QB, as a variable in delivering the for haemodynamic stability, less anticoagulant exposure, shorter
RRT dose, is mainly dependent on the vascular access and oper- duration, lower costs, decreased nurse workload, and improved
ational characteristics of utilized machines in the clinical setting. ICU workflow [19]. IHD, CRRT, and PIRRTs mainly differ by the
QR is strictly linked to QB, during convective techniques, by the duration of therapy and consequently the rapidity of net UF and
filtration fraction. The filtration fraction does not limit QD, but, solute clearance. In addition, IHD is a dialytic (diffusive) therapy,
when the QD/​QB ratio exceeds 0.3, it can be estimated that the while PIRRTs are mainly (but not exclusively) performed with
dialysate will not be completely saturated by blood-​diffusing sol- IHD machines and circuits and predominantly clear solutes with a
utes. As a rough estimate, we can consider that, during continuous diffusive mechanism but can be performed with CRRT machines
slow efficiency treatments, the RRT dose is a direct expression of and circuits with prescriptions that include convection and/​or
 Modes of rena l repl acem en t ther a pi es a n d techni c a l   n ot e s 343

Table 27.2  Algorithm for RRT prescription and indications, based on the clinical state

Clinical variable Operational variable Setting

Fluid balance Net ultrafiltration A continuous management of negative balance (100–​300 mL/​hour) is preferred in
haemodynamically unstable patients with fluid overload
Adequacy and dose Clearance/​modality 2000–​3000 mL/​hour K (or 25–​35 mL/​kg/​hour) for CRRT; consider first CVVHDF. If IHD is selected,
an everyday/​4-​hour prescription is recommended
Acid–​base Solution buffer Bicarbonate-​buffered solutions are preferable to lactate-​buffered solutions in cases of lactic acidosis
and/​or hepatic failure
Electrolyte Dialysate/​replacement Consider solutions without K+ in cases of severe hyperkalaemia. Manage accurately MgPO4
Timing Schedule Early and intense RRT is suggested
Protocol Staff/​machine Well-​trained staff should routinely utilize RRT monitors, according to predefined institutional
protocols
CRRT, continuous renal replacement therapy; CVVHDF, continuous veno-​venous haemodiafiltration; IHD, intermittent haemodialysis.

diffusion. Therefore, IHD provides rapid solute clearance and UF and colleagues [24] conducted a landmark prospective random-
in only 3–​5 hours; CRRTs provide more gradual fluid removal and ized multicentre study in 21 ICUs over a 3.5-​year period. The pri-
solute clearance in (optimally) 24 hours [22]; and PIRRTs are char- mary endpoint was 60-​day mortality following randomization of
acterized by treatments lasting 8–​16 hours [21]. 360 patients with acute renal failure to either CVVHDF or IHD
CRRT and PIRRTs are most commonly used in haemodynam- in centres that were familiar with both techniques. The eligibility
ically unstable patients since slow fluid removal and solute clear- criteria changed after 8  months due to the inclusion rate being
ance can be better tolerated [23]. Nevertheless, there is marked too low. No difference in 28-​, 60-​(CVVHDF, 33%; IHD, 32%),
variation in practice and some centres use CRRT (or PIRRT) in and 90-​day mortality between the two groups was found, and
all ICU patients with renal failure, regardless of haemodynamic the authors concluded that all patients with acute renal failure, as
status, whereas others exclusively deliver IHD. When IHD is ap- part of MODS, can be treated with IHD. The study was well con-
plied to haemodynamically unstable patients (on vasopressors), ducted, and, at the moment, it is the best example of a random-
standard prescription may require some modifications such as ized controlled study comparing effectively the two techniques.
prolongation of treatment time to allow for more gradual UF, Other reports have drawn similar conclusions [25, 26]. One of the
use of higher dialysate Na+ concentrations, and reduced dialysate common key points of these recent trials can be, however, that
temperatures [24]. IHD has become safer and more efficacious with contemporary
Many aspects of the behaviour of different modalities should be dialytic techniques. Furthermore, a liberal and extended use of
taken into account when the decision to apply one or the other is CRRT might have become less safe and/​or efficacious than pre-
made. For instance, an acceptable mean blood urea nitrogen level viously considered or expected. Hybrid techniques have come
of 60 mg/​dL, typically obtainable after some days in a 100-​kg pa- during the last years as a feasible compromise solution to this
tient with 2 L/​hour CVVH, has been shown to be very difficult to eternal dispute [27]. PIRRTs can be found in the literature under
reach, even with intensive IHD regimens [22]. In addition, CRRT a variety of names such as slow low-​efficiency extended daily
allows a gentle and well-​tailored fluid balance control over 24 dialysis (SLEDD), prolonged daily intermittent RRT (PDIRRT),
hours, whereas intermittent treatments, especially when 4-​hour extended daily dialysis (EDD), or simply extended dialysis,
schedules are delivered, need to increase the QUF flow rate per depending on the variations in schedule and the type of solute
treatment, with a relative risk of haemodynamic instability. This removal (convective or diffusive).
is particularly important in patients with congestive heart failure
and haemodynamic instability, who require large removal of Vascular access
fluids. If QUF is slow, enough time is allowed for interstitial fluids Circuit clotting or treatment stopping is more often due to vas-
to refill into the bloodstream; the final net result is that, after 24 cular access inadequacy than insufficient anticoagulation. Thus,
hours, several kilograms of free water will have been ultrafiltered an optimal dialysis catheter can save the patient from an in-
by continuous QUF, without any change in the patient’s volaemia, appropriate increase in anticoagulation dose and allow to sig-
whereas application of an intermittent, short (i.e. lasting 4 nificantly increase the actually delivered RRT dose. On the
hours), and aggressive UF prescription will necessarily affect the other side, an inadequately efficient catheter may lead to a sort
patient’s vascular filling, causing a higher hypotension risk due to of ‘domino effect’ that includes: inadequate dose delivery (solute
hypovolaemia. clearance and/​or negative fluid balance), blood loss, platelet loss,
Most recently, the Surviving Sepsis Campaign guidelines for transfusion needs, circuit loss, and ICU staff workload increase.
the management of severe sepsis and septic shock [23] concluded Veno-​venous RRT catheters are inserted in a central vein and
that, based on present scientific evidence, CRRT should be con- are available in different brands, shapes, and sizes. It is gener-
sidered equivalent to IHD for the treatment of AKI. Vinsonneau ally suggested (KDIGO guidelines 2012) to use the right internal
344 CHAPTER 27   Renal su pp ort  th erap y

jugular vein (if available) as first choice, followed by the femoral The KDIGO guidelines [34] suggest that in a patient with AKI
veins. The left internal jugular vein is the third choice and the requiring CRRT, the decision to use anticoagulation or not should
subclavian veins are the last. Subclavian sites should be avoided be based on the assessment of the patient’s potential risks and
because of a predisposition to venous stenosis (up to 40%) [28]. benefits from anticoagulation (not graded). Moreover, they rec-
The general concept is that the distal tip of the catheter must be ommend using anticoagulation when a patient does not have an
inserted in a central venous territory where blood flow is max- increased bleeding risk or impaired coagulation and is not already
imal (e.g. inside the superior vena cava at the junction with the receiving systemic anticoagulation (1B). For those patients, they
right atrium). A recent randomized trial demonstrated that the suggest using regional citrate anticoagulation, rather than hep-
femoral position was as efficient as the jugular site in terms of arin (except in the case of contraindications for citrate) (2B). In
catheter failures and dialysis performance in ICU patients [29]. patients who have contraindications for citrate, they suggest using
A  fundamental rule is that in the femoral location, catheters either unfractionated or low-​molecular-​weight heparin, rather
shorter than 25 cm may predispose to catheter dysfunction [30]. than other anticoagulants (2C).
An additional advice could be that the internal jugular vein ac-
cess should be considered for patients with a body mass index Circuit set-​up optimization and no anticoagulation
(BMI) above 28 kg/​m2 to avoid maceration and bacterial colon- Several technical features of the RRT circuit are likely to affect the
ization at the femoral vascular access site [31]. success of any anticoagulant approach. Vascular access has to be
Some further advices are:  (1) polyurethane catheters have a of adequate size; tubing kinking should be avoided; the blood flow
larger internal diameter for a constant external diameter, com- rate should exceed 100 mL/​min; pump flow fluctuations must be
pared to silicone catheters; (2) polyurethane catheters are more prevented (in modern machines, this event is mainly due to in-
rigid than silicone ones (easier to place, but with higher probability creased circuit resistances, rather than flow rate inaccuracies);
to damage the vessel), but since thermoplastic, they become more and venous bubble trap where air/​blood contact occurs must be
flexible at human body temperature; (3)  silicone catheters are accurately monitored. In this light, another component of the
more biocompatible, therefore less thrombogenic; (4) a catheter circuit set-​up has to be addressed; the plasma filtration fraction
size between 11.5 and 13.5 Fr is sufficient for all RRT modalities should be kept as far as possible below 20% and, when possible
used in the ICU [32]; (5) the cycle-​C or kidney-​shaped catheter or considered correct, pre-​dilutional haemofiltration should be
seems to exhibit the optimal internal form; (6)  the shotgun tip selected. There is evidence that, when the set-​up is perfectly op-
catheter (step tip) favours less recirculation (having some newly timized, anticoagulants are only a relatively minor component
dialysed blood flowing into the same RRT circuit)—​a 2-​to 3-​cm of circuit patency; in fact, whenever the patient’s clinical fea-
distance is recommended for decreasing this risk; (7) recircula- tures present risk factors for bleeding (prolonged clotting times,
tion is also promoted by lumen reversal that can be performed if thrombocytopenia), RRT can be safely performed without util-
necessary but may partially decrease the dialysis dose [33]. ization of any anticoagulant [35].
When an inadequate blood flow or a catheter malfunction
Unfractionated heparin (UFH)
is suspected, the venous and arterial lumens should be flushed
with saline, with the goal of testing resistance to injection and This agent is a commonly available anticoagulant. It is easy to use,
aspiration. and an antidote is available (protamine). Heparin doses can range
from 5 to 10 IU/​kg/​hour. In patients with a very limited circuit
duration, it can also be used in combination with protamine (re-
Anticoagulation
gional heparinization), with a 1:1 ratio (150 IU of UFH per milli-
The need for anticoagulation of the CRRT circuit arises from the gram of protamine) and strict aPTT monitoring. The problem
fact that contact between blood and the tubing of the circuit and with UFH is its relative unpredictable bioavailability, the necessity
the membrane of the filter induces the activation of the coagu- for optimizing antithrombin (AT) levels, and the occurrence of
lation cascade. This extracorporeal activation inevitably results heparin-​induced thrombocytopenia (HIT).
in filter or circuit clotting. It is evident that an anticoagulation
strategy will change, depending on the prescribed RRT schedule, Low-​molecular-​weight heparins (LMWHs)
being a priority feature of continuous treatments where the Some centres have gained experience with this relatively new kind
blood–​artificial surface interaction is maximized. The aims of of anticoagulants. Prospective studies have not yet shown LMWH
anticoagulation are:  (1) maintenance of the extracorporeal cir- to be superior in order to prolong circuit life. These molecules
cuit and dialyser patency; (2)  reduction of off-​treatment time appear to have better bioavailability than UFH and a lower inci-
(down-​time) that might have a clinical impact on the overall dence of HIT, with a 10% increased cost.
RRT clearance; (3) reduction of treatment cost by utilization of as
little material as possible; and (4) achievement of the above aims Prostacyclin
with minimal risk to the patient. This last concept should per- This agent is a potentially useful drug for RRT anticoagulation,
haps be the first to rule in anticoagulation management; under no being the most potent inhibitor of platelet aggregation, with the
circumstances should patient safety be put at risk of bleeding in shortest half-​life. Prostacyclin (PGI2) is infused at a dose of 4–​8
order to prolong circuit life. ng/​kg/​hour, with or without the adjunct of a low dose of UFH.
 Indicati on s to  sta rt a n d stop rena l repl acem en t   t h e r a pi e s 345

Hypotension might be induced by higher doses of PGI2. Some Instead of assessing exclusively for absolute indications for
studies have demonstrated PGI2 efficacy, but its high cost and CRRT, it may be preferable to tightly diagnose the presence of
harmful side effects might limit the use of this agent in patients AKI, according to newer guidelines, and to examine its severity
with a short circuit duration [36]. [40] (see also E Chapter 66). Increasing AKI severity (e.g. from
a mild class to a more severe condition, according to recent AKI
Citrate classification) and/​or non-​kidney organ dysfunction, as well as
It is a form of regional anticoagulation that depends on the ability fluid accumulation and relative oliguria (i.e. urine output >200
of citrate to chelate Ca2+. Chelation of Ca2+ prevents clot formation. mL/​12 hours, but insufficient to prevent fluid accumulation), all
Briefly, when citrate is infused into the circuit, via the pre-​dilution factor into the decision of when to initiate RRT for those with
pump and line, it combines with Ca2+, creating citrate–​Ca2+ com- AKI [41]. Data to support consideration of early RRT in these
plexes. A decrease in Ca2+ level to 0.25–​0.5 mmol/​L (or 1–​2 mg/​dL) patients are unfortunately controversial and mainly provided by
in the post-​filter line indicates appropriate anticoagulation. These observational and prospective randomized studies [42–​45].
complexes are partially removed by filtration or dialysis (up to Three randomized trials have recently explored the question
30–​60%) performed with dedicated Ca2+-​free solutions [37]. Ca2+ of timing for RRT initiation: the Early versus Late Initiation of
deficiency is replaced in the patient via the post-​filter line. The Renal Replacement Therapy in Critically Ill Patients with Acute
remaining amount of citrate–​Ca2+ complexes not removed by Kidney Injury (ELAIN) trial [43], the Artificial Kidney Initiation
QD and/​or QRPOST and infused into the patient (with the more in Kidney Injury (AKIKI) trial [44], and the Initiation of Dialysis
commonly reported citrate protocols, the citrate load is approxi- Early Versus Delayed in the Intensive Care Unit (IDEAL-​ICU)
mately 10–​20 mmol/​hour) is rapidly metabolized in the citric acid trial [45]. Before the publication of the ongoing and much larger
(Krebs) cycle, especially in the liver, muscle, and renal cortex, in an (>2800 patients) STandard versus Accelerated initiation of Renal
O2-​dependent process. Any citrate–​Ca2+ complex is metabolized Replacement Therapy in Acute Kidney Injury (STARRT-​AKI)
into three HCO3–​ ions. During this metabolism, Ca2+ is released, trial, the preliminary results of the available studies should be
contributing to normalizing the coagulation. Hypoxaemia, shock, critically appraised. Huge differences in inclusion criteria, de-
and liver failure are the most commonly indicated contraindi- signs, and methodology make these three RCTs difficult to
cations to citrate use. The ratio of total-​to-​ionized Ca2+ appears compare [46, 47]. Globally, taken collectively, the results of the
to be the best parameter to detect citrate accumulation, with an three trials inform us that the decision to initiate RRT must
optimal cut-​off at 2.5. Knowledge and application of predefined be integrated in a larger clinical context and must account for
protocols to start and manage citrate anticoagulation are strongly other organ dysfunction, comorbidities, and the patient’s general
recommended. trajectory.
The relative drawbacks of this anticoagulation management It is important to recognize that RRT initiation is not without
include the risk of hypocalcaemia, metabolic alkalosis (over- risks of complications such as hypotension (and exacerbation
production of HCO3–​ and alkalosis due to increase in strong ion of kidney injury), bleeding, dialysis catheter-​related compli-
difference when trisodium citrate is used), metabolic acidosis cations, etc. The presence of one or more mitigating factors,
(citrate accumulation), the cumbersome replacement/​dialysate such as rapidly worsening AKI and/​or the overall severity of
fluid preparation, and potential hypomagnesaemia [38]. illness, the presence of congestive heart failure, severe sepsis,
and reduced renal reserve, would push to consider RRT in the
earlier stages of AKI. Primary diagnoses associated with high
catabolic rates (e.g. septic shock, major trauma, burn injury) or
Indications to start and stop renal those likely to place considerable demand on kidney function
replacement therapies (i.e. GI bleeding, rhabdomyolysis) should be identified in the
context of a potential need for early initiation of RRT. Critically
When to start ill patients with ARDS (see also E Chapter  64) receiving
When a patient has ‘absolute’ or traditional indications for RRT, lung-​protective ventilation may intentionally develop respira-
the decision is fairly straightforward. Widely accepted absolute tory acidosis due to permissive hypercapnia [48]. Coexisting
indications generally are [39]: and/​or evolving AKI in these patients will significantly impair
◆ Diuretic-​resistant pulmonary oedema. the capacity for kidney HCO3–​ regeneration to buffer systemic
◆ Hyperkalaemia (refractory to medical therapy). acidaemia. Earlier RRT may prove beneficial in these patients
◆ Metabolic acidosis (refractory to medical therapy). prior to the development of severe acidaemia, worsening
◆ Uraemic complications (pericarditis, encephalopathy, bleeding). ARDS, and/​or volume overload.
On the other hand, ‘early’ RRT initiation has the potential to
◆ Dialysable intoxications (e.g. lithium, toxic alcohols, and expose a large number of patients to this therapy who may have
salicylates). potentially spontaneously recovered kidney function.
It is important, however, to recognize that RRT initiation for In light of this, many patients allocated to the delayed arm for
these indications may be viewed as a ‘rescue therapy’ where delays RRT initiation in the three RCTs did not receive RRT. Therefore,
may have deleterious consequences for the patient. in a not negligible number of patients, a ‘wait and see’ strategy
346 CHAPTER 27   Renal su pp ort  th erap y

may be the best way to avoid the potential complications related As a general recommendation, before weaning from RRT, phys-
to RRT but obtain spontaneous recovery of kidney function. icians should wait for an adequate urine output (without diuretic
One of the most frequent indications for RRT is fluid accumu- therapy) and optimized creatinine values (the additional effect of
lation, an independent predictor of mortality in ICU patients. patient GFR and treatment clearance should lead to normal or
A  positive fluid balance and overt clinical fluid overload, when subnormal creatinine values while on RRT). Once the renal func-
refractory to medical therapy (i.e. diuretics), are also important tion appears close to the baseline or ‘pre-​AKI’ level, it seems rea-
circumstances where RRT initiation may prove beneficial. Other sonable to interrupt the treatment without any specific weaning
than fluid ‘overload’, in which the patient has obvious clinical protocol. It is possible, on the other hand, that patients with signs
signs of excess fluid (e.g. peripheral or pulmonary oedema, weight of only partial renal recovery may benefit from more specific and
gain), usually in association with oliguria, we also recognize the prolonged weaning algorithms. Examples would be a decrease in
concept of fluid ‘accumulation’. In the latter case, these clinical the UF rate or the prescription of intermittent treatments where
signs may not yet be readily apparent and the patient may have a therapy was previously continuous. Future trials are needed to
urine output above the traditional definition of ‘oliguria’; however, design, if possible, such protocols. Furthermore, the evaluation
this urine output is inadequate for keeping up with the patient’s of new renal biomarkers (see also E Chapter 35) as prognostic
daily intake, resulting in an increasingly positive fluid balance. factors is intriguing, in order to explore if they can predict when
In critically ill patients, fluid overload may be under-​recognized patients have recovered sufficient renal function to allow them to
as an important contributor to morbidity and mortality [48]. remain RRT-​free once RRT is stopped.
Longer durations of mechanical ventilation, weaning failure, de-
layed tissue healing, and cardiopulmonary complications have all
been associated with fluid overload [48]. Likewise, a positive fluid The cardiorenal syndromes
balance has been shown to be associated with higher mortality in
critically ill adults and children [49]. RRT initiation should there- A typical example of organ crosstalk is the cardiorenal syndromes
fore be considered an important therapeutic measure for preven- (CRS); the general definition of CRS is ‘a pathophysiologic dis-
tion (and not only for treatment) of refractory fluid overload. order of the heart and kidneys whereby acute or chronic dysfunc-
tion in one organ may induce acute or chronic dysfunction in the
When to stop other organ’. The heart and kidneys are clearly linked in physio-
In the specific setting of ‘weaning from RRT’, no good evidence logical and pathophysiological terms; both organs contribute to-
exists at present and it is unlikely to be produced in the future. gether to the regulation of blood pressure, vascular tone, diuresis,
An interesting report from the BEST (Beginning and Ending natriuresis, and circulating volume homeostasis. Obviously, alter-
Supportive Therapy) Kidney study group described current ation of one of these functions, due to dysfunction of one of these
practice for the discontinuation of CRRT in a multinational organs, leads to considerable and lasting damage to the other,
setting, in order to identify variables associated with successful in a bidirectional vicious circle. Possible mechanisms of these
discontinuation and if the approach to discontinue CRRT may elective affinities include an altered balance between NO and
affect patient outcomes [50]. A total of 313 patients were weaned reactive oxygen species, systemic inflammation and apoptosis,
from CRRT for at least 7  days and classified as the ‘success’ activation of both the sympathetic nervous system and RAAS,
group; 216 patients were classified as the ‘repeat RRT’ group. and paracrine and systemic actions of various substances such as
Multivariate logistic regression analysis for successful discon- endothelin, prostaglandins, vasopressin, and natriuretic peptides
tinuation of CRRT identified urine output (during 24 hours be- [52]. To recognize and describe the complicated interactions be-
fore stopping CRRT:  OR 1.078 per 100 mL/​day increase) and tween these organ systems, a classification of CRS into four sub-
creatinine (OR 0.996 per mmol/​L increase) as significant pre- types has been proposed. (A brief summary on CRS is provided
dictors of successful cessation. The predictive ability of urine in Additional online material.)
output was negatively affected by use of diuretics. As it always
happens with observational studies, it is not possible to establish
Non-​pharmacological management
if the ‘repeat RRT’ population would have achieved a different of cardiorenal syndromes
outcome by waiting for a better creatinine level or urine output Each time the CRS ends up with severe dysfunction of the kid-
before stopping RRT. neys, extracorporeal renal support should be started and pre-
Risk factors for re-​dialysis were also analysed by the National scribed, according to the same indications as for critically ill
Taiwan University Surgical ICU Acute Renal Failure Study Group patients [48]. For the purposes of this chapter, RRT in the con-
[51]. In this study, RRT weaning of 94 post-​operative patients was text of acute decompensated heart failure (ADHF) patients will
considered successful when prolonged for at least 30 days (21%) be described. In order to manage ADHF, the main target is to
and was correlated with Sequential Organ Failure Assessment remove excess Na+ and water. A declining kidney function during
(SOFA) score, age, dialysis duration, and again urine output. CRS I (where acute cardiac failure, e.g. acute CS or ADHF, leads
Interestingly, of the patients who remained ‘RRT-​free’ for 5 days to AKI) is one of the strongest predictors of short-​and long-​
after RRT discontinuation, more than two-​thirds remained RRT-​ term adverse events (AEs), including readmission and mor-
free up to day 30. tality [53] (see also E Chapter  66). In this field, diuretics and
 The ca rdi orena l   sy n dro m e s 347

blood-​based extracorporeal UF are the main decongestive ther- trial (Continuous Ultrafiltration for cOngestive heaRt failure,
apies. Peritoneal-​based UF has been used as well. Recent studies CUORE) showed that extracorporeal UF was associated with
have shown that UF is a very effective method for removing ex- prolonged clinical stabilization and greater freedom from
cessive fluid from selected patient populations with ADHF. rehospitalization for AHF [59]. Given the apparently controver-
With this background (injured kidneys due to primary cardiac sial results of these trials that are probably due to significantly dif-
illness and pharmacologic management), SCUF was described ferent therapeutic algorithms, clinical targets, and the severity of
many years ago in order to artificially remove plasma water and included patients, it seems currently reasonable to reserve UF to
relieve cardiopulmonary symptoms, bypassing the need for in- the most severely ill patients with initial signs of diuretic resist-
tense diuresis [54]. In the case of a reno-​cardiac syndrome (ADHF ance. Furthermore, pharmacologic and extracorporeal removal of
secondary to acute or chronic renal failure), prescription of arti- water should not be seen as alternative approaches, but they could
ficial fluid balance control and volume unloading for pulmonary also be considered synergistic. Finally, institutional expertise with
oedema management to a dialytic session is a common approach extracorporeal devices should always be taken into account, since
applied by nephrologists [55]. On the other hand, SCUF is cur- it might have a significant impact on final outcomes.
rently considered as a last-​chance therapy by the ESC guidelines The large randomized study Aquapheresis versus Intravenous
algorithm for the management of ADHF in patients refractory to Diuretics and Hospitalizations for Heart Failure (AVOID-​HF)
diuretic therapy [56]. was designed to clarify the issue of UF therapy safety and ef-
Nevertheless, several randomized trials have been conducted, fectiveness [60]. Whereas a stepped approach similar to that of
in order to verify if extracorporeal water removal might be benefi- the CARRESS-​HF trial was designed for the diuretic arm, the
cial with respect to diuretic therapy. The UNLOAD (Ultrafiltration AVOID-​HF study also included a stepped UF prescription [61].
Versus Intravenous Diuretics for Patients Hospitalized for Acute Initially planned to enrol >800 patients, the study was abruptly
Decompensated Heart Failure) Study showed that UF allowed interrupted by the sponsor after the first 224 enrolments (es-
to remove a greater amount of plasmatic water than furosemide sentially due to slow recruitment rate and budget issues) [62].
[57]. Interestingly, however, more patients in the UF than in the Although significantly underpowered, the recently published re-
diuretics arm experienced an increase in creatinine levels of 0.3 sults appear, however, very interesting [63].
mg/​dL. Of note, the timing, dose, duration, and clinical target The first heart failure event in 90  days occurred in 25% of
of UF remained to be investigated. By contrast, the Cardiorenal the adjustable ultrafiltration (AUF) patients and 35% of the ad-
Rescue Study in Acute Decompensated Heart Failure (CARRESS-​ justable loop diuretics (ALD) patients, and the time to the first
HF) trial showed that UF did not allow a significant difference event, the study primary endpoint, was longer in the former arm
in weight loss at 96 hours, and again it was associated with a sig- (62  days versus 34  days, although not statistically significant;
nificantly higher increase in creatinine levels [58]. CARRESS-​HF P  =  0.106). Within 30  days after discharge, compared with the
was a prospective RCT, sponsored by the National Heart, Lung, ALD group, patients in the AUF group had, per days at risk: fewer
and Blood Institute and conducted at 22 centres. Patients with patients rehospitalized for heart failure (P = 0.034); fewer days in
ADHF were eligible if there was evidence of persistent congestion, the hospital due to heart failure readmissions (P = 0.029); lower
with an increase in serum creatinine (SCr) levels of 0.3 mg/​dL. rehospitalization rates due to a cardiovascular event (P = 0.037);
Participants were randomly assigned to either UF (Aquadex fewer rehospitalization days due to a cardiovascular event
System 100; CHF Solutions) or stepped pharmacologic therapy (P = 0.018); and fewer patients rehospitalized for a cardiovascular
involving increasing doses of loop diuretics (with or without event (P = 0.042). Interestingly, this trial did not show any signifi-
metolazone), vasodilators, and/​or inotropes, based on a treat- cant differences between creatinine values in the two arms, likely
ment algorithm. The primary endpoint was a bivariate response, due to the UF stepped and gentler approach.
including changes in SCr levels and body weight 96 hours after Regrets remain for the unanswered questions of this ultimate
randomization. The main finding of this study was that UF was important trial and clinicians may appraise that, likely, careful
inferior to diuretic therapy, with respect to the bivariate primary AUF application may be safe in terms of renal function, espe-
endpoint, primarily because of a significant increase in SCr levels cially once technical aspects (i.e. vascular access-​related adverse
in the UF group (an increase of 0.23 ± 0.70 mg/​dL for the UF events) can be optimized. As far as worsening of renal function
group versus a decrease of 0.04 ± 0.53 mg/​dL for the pharma- during decongestion therapies is concerned, then it must be re-
cologic therapy group; P = 0.002). There was no significant dif- marked that both loop diuretics and UF have been associated
ference in weight loss at 96 hours between the two groups (5.7 with increased creatinine levels. Extracorporeal water removal,
± 3.9 versus 5.5 ± 5.1 kg in the UF and pharmacologic therapy however, has not been associated with neurohormonal activa-
groups, respectively; P = 0.58). At 60-​day follow-​up, there were tion and it should not activate tubuloglomerular feedback, as
no significant differences in weight loss, mortality, or rate of hos- diuretics do [64]. Excessive intravascular depletion due to ag-
pitalization for heart failure between the two groups. Also, during gressive UF prescription or severely decreased GFR before UF
the 60-​day follow-​up period, patients in the UF group had signifi- starts might be considered as possible reasons for the described
cantly higher rates of kidney failure, bleeding complications, and increase in creatinine levels [64]. Furthermore, regardless of
catheter-​related complications. Another recent small randomized whether decongestion is achieved by drugs or UF, a recent post
348 CHAPTER 27   Renal su pp ort  th erap y

hoc analysis of patients enrolled in the Diuretic Optimization recent years, RRT has evolved to the point that other organs can
Strategy Evaluation in Acute Decompensated Heart Failure benefit from extracorporeal management of patient blood. Such
(DOSE-​AHF) and CARRESS-​HF trials showed that only patients evolution is continuing due to intense efforts that are currently
free from signs of orthoedema at discharge had lower 60-​day rates ongoing on the mechanical support of critical patients and ADHF
of death, rehospitalization, or unscheduled visits, compared with patients; in the near future, new diagnostic tools, clinical targets,
those having residual orthoedema [65]. and technical solutions will be proposed and validated in order to
The authors hypothesize that, despite congestion relief, ther- definitely affect and improve the outcomes of patients with AKI
apies might be ineffective to definitively treat orthoedema during and MOF.
hospitalization. It might be speculated that tools, such as bio-
markers, bioimpedance, echocardiography, and minimally in-
vasive haemodynamic monitors, should also be implemented in Personal perspective
order to improve patient care.
As final bricks on the critical interpretation of extracorporeal The history of artificial substitution of the failing kidney
UF for AHF management, two meta-​analyses have been lastly started about a century ago. One of the most important
published with diametric opposite conclusions as far as the utility achievements of ‘modern’ RRT in critically ill patients is its
of UF on rehospitalization is concerned, compared to diuretics evolution into ‘renal support therapy’—​optimal fine tuning
[66, 67]. This is only the ultimate confirmation of research equi- and a combination of timing, dose, modality, anticoagulation,
poise in this field and the urgent need for a conclusive study. and interruption have led to an impressive variety of different
receipts that allow not only to ultimately substitute end-​stage
kidney failure, but also to support the kidney and many other
failing organs, namely the heart, in their earliest dysfunctional
Conclusion states. The next steps will be to provide dedicated standard-
Renal support may be represented by a well-​established series of ized recommendations for each kind of clinical condition
extracorporeal modalities for kidney rescue and substitution. In (e.g. mild AKI, septic AKI, paediatric kidney injury, etc.).

Further reading
Acute Dialysis Quality Initiative. Available from: M
M http://​www.adqi.net. Ronco C, Bellomo R, Kellum J. Critical Care Nephrology, second edition.
European Society of Cardiology. Clinical practice guidelines. Available Saunders Elseviers: Philadelphia, PA; 2008.
from: M
M http://​www.escardio.org/​guidelines. Ronco C, Bellomo R, McCullough PA. Cardiorenal Syndromes in Critical
Care. Karger: Basel; 2010.

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ADDITIONAL ONLINE MATERIAL
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 CHAPTER 28

Percutaneous (short-​term)
mechanical circulatory
support
Holger Thiele and Pascal Vranckx
Contents
Summary   351
Introduction  351
General considerations  352 Summary
Design, performance requirements, and
safety issues  352 Percutaneous mechanical circulatory support can be used to resuscitate patients
Peripheral vascular disease  352 as a stabilizing measure for angiography and prompt revascularization, or to buy
Thromboembolism and bleeding  352 time until more definite measures can be taken. In addition, there is experimental
Valvular heart disease  353
evidence that ventricular unloading of the left ventricle can significantly reduce in-
Right-​sided heart failure  353
Percutaneous devices for short-​term farct size. Different systems for mechanical circulatory support are available to the
percutaneous mechanical support  353 medical community. Treatment options for mechanical circulatory support must
Intra-​aortic balloon pumping  353 be tailored to each patient in order to maximize the potential benefits and min-
Advanced mechanical circulatory imize the risk of detrimental effects.
support  354
Intracardiac axial flow pumps: the Impella Intra-​aortic balloon pumping is still the most widely used mechanical circula-
platform/​the HeartMate PHP  354 tory support therapy. The relative ease and speed with which this device can be
The Impella  354 applied have led to its widespread use as a first-​line intervention among critically
HeartMate PHP  355 unstable patients at a time where evidence for the introduction of new devices was
Centrifugal pumps  355
Extracorporeal membrane not as rigorously required as today. Where more haemodynamic support is re-
oxygenation/​extracorporeal cardiac quired, an immediate triage to a more advanced percutaneous (short-​term) mech-
life support  355 anical circulatory support may be warranted.
Percutaneous left atrial to
femoral artery left ventricular Despite their extensive use, the utility of mechanical circulatory support devices
support device (short-​term, in acute heart failure syndromes and cardiogenic shock remains uncertain. This
centrifugal): TandemHeart™  356 chapter concentrates on the application of mechanical circulatory support relevant
The PulseCath iVAC 2L®  356
Right ventricular support  356 to the interventional cardiologist and cardiac intensive care physician.
The Impella RP  356
Centrifugal blood pumps  356
Conclusion  357
References  357

Introduction
CAD has emerged as the dominant aetiologic factor in acute heart failure syndromes
(AHFS) and CS (see also E Chapters  40 and 42). Invasive management of the com-
plex cardiac patient with advanced (decompensated) heart failure, CS, and/​or potential
haemodynamic compromise during and after PCI has become the remit of specialty
myocardial intervention centres. Such centres provide state-​of the art facilities for
PCI, including experienced senior operators and critical care physicians who are avail-
able 24 hours per day, 7 days per week, with immediate access to cardiac surgery and
mechanical circulatory support (MCS) systems. There are two primary indications for
(short-​term)  MCS:
352 CHAPTER 28   Pe rc u taneou s (sh ort-term) m echa n i ca l ci rcu l atory su pp ort

◆ To resuscitate patients:  to ensure end-​organ perfusion in the choosing portable MCS include patient safety, deliverable flow
event of failure of the heart to meet the metabolic demands of rate, durability, device and cannula size, and ease of handling. The
the body (see E Chapters 11 and 42), to buy time until defini- safety of the patient is the pre-​eminent concern, with the main
tive intervention(s), and to reverse the underlying pathology, considerations outlined in the following sections and potential
and hence potentially to improve survival [1–​3]. contraindications listed in E Table 28.1. In addition, several
◆ As a stabilizing measure for angiography and (prompt) other considerations exist, applicable to all types of MCS.
revascularization:  to withstand transient derangements in
organ perfusion and cardiac function and to allow the original Peripheral vascular disease
cardiac function to resume post-​procedure or immediately In patients with established CAD, potential peripheral artery dis-
thereafter (~72 hours) [4]‌. ease should be a concern [7–​9]. The requirement for large-​bore
Moreover, there is experimental evidence that unloading of cannulation of the femoral circulation is an important limitation
the LV can significantly reduce infarct size and influence myo- of most portable MCS therapies. To make percutaneous insertion
cardial remodelling after an MI. Mechanical offloading of the feasible, the diameters of cannulae are generally downsized to a
myocardium during ischaemia and reperfusion has been shown maximum of approximately 10F. However, since the MCS device
to reduce LV pressure work and myocardial O2 consumption. flow is limited by the size of the arterial cannula, in CS, larger
A reduction in the infarct size has been related to the degree of cannula sizes (13–​17F) are required to achieve adequate organ
pressure unloading of the LV [5]‌. perfusion.
Strategies aimed at reducing femoral artery access site compli-
cations, such as use of pre-​insertion abdominal and iliofemoral
angiography and vascular US to guide femoral access (see
General considerations E Chapter 22), have been introduced and implemented in prac-
Design, performance requirements, and tice [10]. In cases of emergency in patients with severe atheroscler-
otic disease, angioplasty [percutaneous transluminal angioplasty
safety issues
(PTA)] of the femoral artery or direct surgical cut-​down may be
The IABP is a historically old support device that has been used in performed. Ultimately, in patients on ECLS systems, a prophy-
the management of patients suffering from the complications of lactic distal perfusion catheter may be placed antegrade into the
acute CVD. The relative ease and speed with which this device can superficial femoral artery [11].
be applied to patients with a rapidly deteriorating haemodynamic
picture have led to its use as a mainstay intervention among crit- Thromboembolism and bleeding
ically unstable patients despite the lack of sufficient evidence.
The occurrence of thromboembolic events depends on a number
The IABP acts on the concept of counter-​pulsation resulting in
of factors, including the type of device, the duration of support, and
pressure unloading of the LV. The main limitations of the IABP
the location and number of cannulation sites [12, 13]. Numerous
include the lack of active cardiac support, the need for accurate
physical factors must also be considered, including mechanical
synchronization with the cardiac cycle, the requirement of a cer-
trauma, blood temperature, and blood flow. Embolization may
tain level of LV function, and the limit of active support provided.
occur during device insertion, function, and removal [14]. The
In comparison to controls in randomized trials, the IABP did
rate of thromboembolic events is relatively low with a heparin
not have additional beneficial haemodynamic or metabolic ef-
anticoagulation regimen. Heparin therapy remains the mainstay
fects with respect to cardiac output, SVR, arterial lactate, and also
doses of catecholamines. Therefore, in many patients with severe
depression of cardiac function and/​or persistent (tachy-​) arrhyth-
Table 28.1  Complications during IABP use (Benchmark Registry)
mias, haemodynamic support and LV unloading derived from
medical therapy, including IABPs, may be insufficient to maintain Severe access site-​related bleeding 1.4%
end-​organ tissue perfusion. In these circumstances, escalation to Vascular injury 0.7%
more advanced percutaneous (or implanted) (see E Chapter 44)
Major limb injury 0.5%
MCS modalities may be warranted.
Amputation 0.1%
The aims of advanced MCS include increasing myocardial O2
supply and improving O2 delivery to dependent organ systems, Bowel, renal, and spinal cord infarcts 0.1%
thereby preventing multiple organ dysfunction and subsequent Infection 0.1%
death. A minimal flow rate of 70 mL/​kg body weight per minute Stroke 0.1%
(representing a cardiac index of at least 2.5 L/​m2) is generally re- Venous thrombosis 0.1%
quired to provide adequate organ perfusion. This flow is the sum
Death 0.05%
of percutaneous MCS output and residual cardiac pump function.
A number of devices exist, the choice of which depends upon Reproduced from Cohen M, Urban P, Christenson JT, et al. Intra-​aortic balloon
counterpulsation in US and non-​US centres: results of the Benchmark Registry. Eur Heart
the underlying pathology, the expertise of the institution, and J. 2003;24(19):1763–​1770. doi:10.1016/​j.ehj.2003.07.002 with permission from Oxford
the required level of support. The main considerations when University Press.
 Percu taneou s devic es for  short- ter m percu ta n eou s m echa n i c a l   supp ort 353

of anticoagulation during MCS and is monitored using ACT and/​

or activated partial prothrombin time (aPTT) and/​or heparin
level. An ACT of 160–​200 seconds is usually recommended [15].
There is no evidence of benefit of additional antiplatelet therapy
in MCS. Regional anticoagulation (within the device) may reduce
systemic anticoagulation and the risk of bleeding, although sys-
temic anticoagulation is the norm.

Valvular heart disease
Abnormalities of the cardiac valves have important consequences
in patients being considered for MCS, depending on the device
selection and site of cannulation. In cases where LV assistance is
initiated with LA to aortic cannulation, the presence of even mild
to moderate aortic valve insufficiency may result in LV ballooning
in the presence of significant LV dysfunction. Conversely, in cases
of severe mitral valve stenosis and impairment in LV filling, LA
Figure 28.1  Correct timing and pitfalls in the timing of inflation and
to aortic cannulation may become the access route of choice (see deflation of the IABP balloon. The balloon is inflated in diastole, concurrently
E Chapter 55). with closure of the aortic valve, and is held in inflation until the onset of the
next ventricular systole. The balloon is then rapidly deflated. Inflation of the
Right-​sided heart failure balloon displaces blood in the aorta (by an amount equal to the volume of
the balloon) towards the coronary tree, thereby increasing (augmenting) the
An adequate right heart function is required to maintain LV pre- coronary perfusion pressure (CPP) and blood flow. The collapse of the balloon
load [16]. Acute RV failure occurs in multiple settings, including creates a reduction in impedance of the LV ejection and decreased afterload,
acute MI, fulminant myocarditis, ADHF, acute PE, decompen- and consequently reduces LV work.
sated PH, following cardiac transplant, and post-​ cardiotomy With permission from Maquet Getinge Group.
shock, and is a major determinant of survival [16]. Anatomic and
physiologic determinants of RV function are distinct from those augmentation of coronary perfusion and decreases myocardial
of LV function. The management of RV failure and CS should be O2 requirements through reduction of the afterload component
tailored accordingly [16]. of cardiac pressure work (see E Figure 28.1). However, in com-
In patients who fail to respond to first-​line interventions and parison to controls, there are no effects on cardiac output and no
develop refractory CS secondary to RV failure, options for escal- effect on cardiac power index, arterial lactate, or doses of catechol-
ation of care are limited. However, in selected patients where it amines [17,  19]. Reduction of LV afterload may theoretically be
is felt that there is prospect for recovery and survival, temporary helpful in patients with acute mitral valve insufficiency or VSD.
MCS devices may provide an attractive rescue option (see further The haemodynamic effects of the IABP are dependent on several
sections) [16]. factors (see E Box 28.1).
IABP therapy consists of inflating and deflating a Durathane
(Maquet, Fairfield, NJ, USA) balloon catheter in synchrony
Percutaneous devices for short-​term with the patient’s cardiac cycle. Different catheter sizes are cur-
percutaneous mechanical support rently available, allowing tailoring of the balloon size to patient
length. The balloon catheter is commonly inserted through a
This section focuses on devices and modalities of blood flow gen- femoral arteriotomy into the thoracic aorta. Accurate timing
eration available. It is important to understand that the device of the intra-​aortic balloon inflation and deflation is crucial.
never operates in a vacuum. Understanding the interaction of the Timing errors typically produce characteristic pressure wave-
patient–​device circuit is the cornerstone of proper monitoring, form changes that can be easily recognized (see E Figure 28.2).
troubleshooting, and assessment of device performance. The pumping chamber, which is activated by helium, is usu-
ally synchronized with the heart by signals from the ECG or
Intra-​aortic balloon pumping
The IABP is currently the most widely used of all portable devices
for short-​term circulatory support. After publication of the IABP-​ Box 28.1  Conditions interfering with the haemodynamic effects
SHOCK II trial in 2012, implantation rates declined [17, 18]. Its of IABP
action is based on the concept of counter-​pulsation, with the as- Position of the balloon in the aorta
◆
sumption that reduction in end-​diastolic pressure improves LV
Heart rate and rhythm
◆
function. Experimental studies suggest that counter-​ pulsation
Size and volume of the balloon
◆
improves LV performance by favourably influencing myocar-
Compliance of the aorta (aortic pressure/​volume relation)
◆
dial O2 balance. It increases myocardial O2 supply by diastolic
354 CHAPTER 28   Pe rc u taneou s (sh ort-term) m echa n i ca l ci rcu l atory su pp ort

Figure 28.2  Proper positioning of the intra-​aortic balloon catheter in the descending aorta: balloon inflation/​deflation. Diagrammatic representation of IABP
inflation and deflation and its effects on blood flow, as timed by the cardiac cycle. (A) During diastole, the IABP is inflated, increasing the diastolic pressure, thus
augmenting the flow not only into the coronary arteries, but also into the great vessels and the renal arteries. (B) During systole, the IABP is deflated, creating a
void where the inflated balloon was thus increasing the forward flow into the aorta and to the periphery.
With permission from Maquet Getinge Group.

the central aortic pressure transducer. Implementation of fibre- (MACCE), a composite of death, AMI, cerebrovascular event,
optic pressure signal transmission to a patient monitor results or further revascularization, at hospital discharge (capped at
in faster signal acquisition and time to therapy. If paced, then 28 days) [24].
pacing spikes can be used to detect cardiac cycle events. An in- The IABP is a typical example of a treatment based on a concept
ternal trigger mode is available for asystolic arrested patients. which subsequently in trials did not prove to change the outcome
Extreme tachycardia and cardiac arrhythmias may affect the ef- of patients.
ficiency of IABP. Pressure trigger is not recommended in pa-
tients with AF. Advanced mechanical circulatory support
Absolute contraindications for the IABP include severe aortic Although each device has its own characteristics, the available
valve insufficiency and (acute) aortic dissection. The pres- advanced short-​term MCS can be classified into two types: axial
ence of an aortic aneurysm, severe iliofemoral vascular disease, flow and centrifugal pumps. A  novel pulsatile circulatory sup-
and a history of aortic surgery are relative contraindications. port system with an extracorporeal membrane pump was re-
Complications associated with the IABP are less common in the cently introduced as a third type. Today, there are no comparative
modern era. The IABP-​SHOCK II trial did not observe a higher studies analysing any potential advantage of one MCS system
rate of potentially device-​related complications in IABP-​treated over another. Moreover, published randomized trials have failed
patients in comparison to the control group. to demonstrate any outcome benefit for advanced MCS over the
The indications and applications for the IABP have come IABP in AHFS and CS [25–​28].
a long way since the early days of counterpulsation. IABP
counterpulsation does not improve outcomes in patients with Intracardiac axial flow pumps: the Impella
MI and CS without mechanical complications, nor does it sig- platform/​the HeartMate PHP
nificantly limit infarct size in those with potentially large anterior The Impella
MIs [17, 19–​21]. Therefore, the ESC guidelines do not recom- The Impella (Abiomed, Danvers, MA, USA) is a catheter-​
mend routine IABP use in patients with MI and CS [22,  23]. mounted intravascular microaxial blood pump driven by an
However, IABP counterpulsation can be used based on expert external electrical motor for short-​term use (Impella 5.5 up to
consensus, without data on outcome, in selected patients with 30 days in Europe). The Impella catheter delivers blood from the
haemodynamic instability/​CS due to mechanical complications inlet area, which sits inside the LV, through the cannula, to the
(i.e. severe mitral insufficiency or VSD) [22]. Of note also, routine outlet opening in the ascending aorta. The device has a pigtail
use of the IABP prior to high-​risk angioplasty did not reduce the catheter at its tip to ensure a stable position in the LV and to pre-
primary endpoint, i.e. major cardiac and cerebrovascular events vent adherence to the myocardium. The axial flow pump systems
 Percu taneou s devic es for  short- ter m percu ta n eou s m echa n i c a l   supp ort 355

produce unloading of the LV and a reduction in LV wall stress Spinning of the rotor creates a centrifugal force that is imparted to
[28]. The Impella Left comes in four versions. the blood, generating a constant, non-​pulsatile flow. Femoral ar-
The Impella 2.5 (12F), Impella 5.0 (21F), Impella 5.5, and Impella terial access is provided by large-​bore arterial (ranging from 16F
CP (14F) catheters can be inserted percutaneously through the up to 19F) and venous cannulae (17–​21F). Bilateral femoral can-
femoral (Impella 5.0 via femoral cut-​down only) or axillary artery nulation using smaller-​sized cannula may be an option in small
and into the LV. The Impella LD is inserted directly through the patients. Limb ischaemia caused by femoral cannulation can be
ascending aorta and into the LV. The Impella 5.0 and Impella LD prevented by distal leg perfusion with a small catheter (5F) placed
catheters have an electronic differential pressure sensor located at in the distal artery.
the proximal end of the 21F cannula that generates the placement Extracorporeal membrane oxygenation/​extracorporeal
signal, which is used by operators and the controller to monitor the cardiac life support
position of the Impella cannula relative to the aortic valve. ECMO incorporates a centrifugal pump and an extracorporeal
As with all axial pumps, its performance depends on the rotary oxygenator. The percutaneous technique for the initiation of
speed (table) and the ‘pressure head’ (aortic pressure minus LV femoro-​femoral CPB support [percutaneous cardiopulmonary
pressure, continuously monitored). Although the rotary speed is bypass support (PCBS)], using the Bard portable PCBS system,
held constant (to the user selection), variation in the pressure head has been described as far back as 1990 [43].
during the cardiac cycle results generally in a pulsatile flow pattern. Blood is aspirated by a centrifugal pump from the right atrium
Whether the additional mechanical support provided by the through a long 17–​21F bypass cannula in the femoral vein and
smaller Impella 2.5 or the Impella CP will be sufficient for patients is returned by means of a heat exchanger membrane oxygenator
with circulatory collapse still needs to be established [29–​35]. to a femoral artery cannula (16–​19F); flow rates of up to 6 L/​min
More promising in this regard is the Impella 5.0/​LD and the may be obtained, providing near-​complete respiratory and cir-
Impella 5.5, the latter capable of delivering a continuous flow of up culatory support, independent of the intrinsic cardiac rhythm or
to 6.0 L/​min [36–​38]. In a sheep infarction model, the Impella 5.0 ventricular function. The pump provides a continuous flow with
was shown to reduce myocardial O2 demand and infarct size [5]‌. the maintenance of a pulsatile arterial pressure, unless the circu-
The Impella 5.0 is implanted most frequently via the subclavian lation is completely supported by the CPB device.
artery, which allows for patient ambulation, although a minority The ECMO can be configured according to the patient’s
of implants are accomplished through the femoral approach [36]. needs:  venous–​ venous ECMO for respiratory support and
Limitations of axial support devices are related to the position venous–​arterial ECMO for respiratory and haemodynamic sup-
across the aortic valve into the LV. The Impella is contraindicated port (in cases of LV, RV, or biventricular failure) [44–​46]. While
for use in patients with mural thrombus in the LV, the presence venous–​arterial ECMO can support both respiration and circu-
of a mechanical aortic valve, aortic valve stenosis/​calcification lation, optimal functioning of the system is preload-​dependent
(equivalent to an orifice area of 0.6 cm2 or less), moderate to se- and may be hampered if hypovolaemia (e.g. severe bleeding)
vere aortic insufficiency (echocardiographic assessment graded as or tamponade is present. Frequent complications include lower
≥2+), or cardiac tamponade. Because of the high rotation speed extremity ischaemia (16.9%), stroke (5.9%), major bleeding
of the Impella, it can also provoke significant haemolysis mostly (40.8%), and significant infection (30.4%) [13, 14,  47]. The in-
related to a suboptimal or an unstable position of the inlet in the crease in afterload with venous–​arterial ECMO may cause LV
LV or close to the aortic valve [39]. distension, especially when severely limited LV ejection or aortic
HeartMate PHP valve insufficiency is present and may further increase LV and
The HeartMate PHP (percutaneous heart pump) also is a catheter-​ LA pressures [47, 48]. Failure to decompress the left heart under
based axial flow pump. The collapsible elastomeric catheter pump these circumstances can result in pulmonary oedema and upper
is inserted through a 14F sheath, deployed across the aortic valve, body hypoxaemia, i.e. myocardial and cerebral ischaemia [48].
expanding to 24F and able to deliver up to 5 L/​min blood flow In these circumstances, non-​surgical venting can be obtained by
at modest operating speeds [40]. This unique design feature atrial septostomy, a 7F pigtail catheter in the LV connected to the
makes this device the lowest-​profile insertion cannula with the venous limb of the ECMO circuit, and insertion of an additional
highest flow. For removal, the system can be collapsed to the ini- MCS device with LV unloading properties (i.e. Impella, IABP)
tial 13F. Clinical experience with the device is limited to high-​risk [49–​54]. Again, the benefits and risks of venting mechanisms
PCI [41]. Clinical development of the HeartMate PHP is actu- have not been studied extensively and are only theoretical.
ally paused due to a small number of clinical events related to The initial experience with ECMO has been hampered by: the
inappropriate pump stoppage during support in both the Shield relatively complex system setup, necessitating a specialized team,
II clinical trial and commercial uses. including perfusionists; the high morbidity rate due to a high rate
of associated complications; the need for extracorporeal circu-
Centrifugal pumps lation and a membrane oxygenator, with subsequent activation
Centrifugal pumps operate in a fashion similar to that of some of cellular elements; and limited support time (usually <6 hours)
CPB pumps [42]. They typically consist of a cone-​shaped rotor due to severe haematological and pulmonary complications.
contained within a plastic or metal housing. Blood flows into the Extended use of up to several weeks has been made possible by
pump at the apex of the cone and exits at the edge of the base. incorporating a coated circuitry and biocompatible oxygenators
356 CHAPTER 28   Pe rc u taneou s (sh ort-term) m echa n i ca l ci rcu l atory su pp ort

designed for prolonged perfusion incorporating a highly plasma-​ remarkable 6-​month mortality rate of 45.3% [58]. Complication
resistant fibre technology. rates are similar to those of other CPB systems [57].
Rapid percutaneous institution of ECMO remains the most po-
tent means of haemodynamic support in patients suffering from The PulseCath iVAC 2L®
CS, cardiac arrest, and complicated coronary angioplasty [2,  3]. The PulseCath iVAC 2L® (PulseCath BV, Amsterdam, The
The clinical impact of newer and less complicated smaller portable Netherlands) is a next-​generation pulsatile support system driven
devices, such as the Cardiohelp System (Maquet Cardiopulmonary by any standard IABP console and generating pulsatile blood flow
AG, Hirrlingen, Germany) (see E Figure 28.3), remains to be of up to 2 L/​min, depending on preload and afterload conditions
assessed in future trials. and heart rate [59]. An extracorporeal membrane pump is con-
nected to a 17F catheter (19F access sheath), which is inserted
Percutaneous left atrial to femoral artery left ventricular support
device (short-​term, centrifugal): TandemHeart™ across the aortic valve retrogradely into the LV.
In contrast to CPB, closed chest left heart bypass keeps the patient’s In the systolic phase of the heart cycle, blood is aspirated from
lungs as its own ventilator. The TandemHeart™ (Tandemlife, the LV through the catheter lumen into the membrane pump.
Pittsburg, PA, USA) incorporates a low-​speed centrifugal con- During the diastolic phase, the pump returns the blood back
tinuous flow pump with a low blood surface contact area, re- through the catheter, subsequently opening the catheter valve
sulting in reduced potential for haemolysis and thromboemboli. and delivering the blood to the ascending aorta through the side
Oxygenated blood from the patient’s LA is supplied to the outflow port. Data are limited to small case series, and the clinical
pump, via a 21F trans-​septal cannula, and then returned to the impact of this device needs further investigation [41].
patient’s systemic circulation via an arterial cannula in the fem- Right ventricular support
oral artery (12–​19F in most patients) to the lower abdominal
Several approaches for RV support have been described.
aorta (see E Figure 28.4). Successful deployment of this device
requires a team of trained operators, including an operator fa- The Impella RP
miliar with the trans-​septal puncture [55]. The system can deliver The Impella RP system (≥4.0 L/​min) is indicated for providing
up to 4.0 L of blood flow per minute, depending on the size of the temporary RV support for up to 14 days in patients who develop
arterial cannula and the filling conditions of the LA, while oper- acute right heart failure.
ating at a relatively low speed (7500 rpm). As with any left-​sided The Impella RP (11F cannula, 22F pump motor) can be inserted
assist device, the preload to the pump, and therefore the flow, is through a standard catheterization procedure via the femoral
dependent on an adequate right heart function. vein, into the right atrium, across the tricuspid and pulmonary
There is mounting evidence that this device may be sufficient valves, and into the pulmonary artery.
to prevent, or even reverse, organ dysfunction in CS patients. Data are limited to small case series, and the clinical impact of
However, in two randomized trials, there was no indication of this device needs further investigation [30, 59, 60].
reduced mortality [56, 57]. A recent single-​centre study on ‘step-​ Centrifugal blood pumps
up’ therapy with the TandemHeart™ in patients with severe re- This strategy employs an extracorporeal centrifugal pump with
fractory CS despite standard therapy, including IABP, showed a the inflow from the right atrial cannula and the outflow to the

Figure 28.3  The Cardiohelp. The Cardiohelp veno-​arterial extracorporeal life support replaces or supports the patient’s circulation and respiration.
With permission from Maquet Getinge Group.
 RE F E RE N C E S 357

Outflow cannula
insertion into the femoral
artery and advanced to
the common iliac artery

To Inflow cannula insertion

controller into the femoral vein and
advanced through the
inferior vena cava
Pump
Final inflow cannula position
in the left atrium via trans-septal puncture

TandemHeart PVAD

Figure 28.4  The TandemHeartTM. The TandemHeartTM percutaneous ventricular assist device (pVAD) is a percutaneous left atrial to femoral artery LV support
device. Oxygenated blood from the patient’s LA is supplied to a small extracorporeal pump by a 21F trans-​septal cannula, with a large end-​hole and 14 side-​
holes, and then returned to the patient by the femoral route. The close-​up shows the centrifugal pump.
With permission from TandemLife.

pulmonary artery. Several different centrifugal flow pumps have

been used with this cannulation strategy. Two cannulae are Conclusion
used—​typically either two femoral venous cannulae or one fem-
The implementation of percutaneous advanced MCS systems
oral and one internal jugular venous cannula—​with one cannula
holds great promise; yet the paucity of evidence supporting the
positioned in the right atrium and another in the pulmonary ar-
use of these devices at this time is notable. The available devices
tery. As an alternative, a novel dual-​lumen coaxial cannula flex-
differ in terms of the insertion procedure, mechanical properties,
ible enough to be positioned with its distal tip in the pulmonary
and mode of action. Whether this heterogeneity translates into
artery from internal jugular insertion can be used with a centri-
a haemodynamic and clinically meaningful difference in effects
fugal flow pump to achieve a percutaneous RV assist device [60].
remains to be investigated. In all cases, the key requirements for
Because of its internal jugular cannulation site, this configuration
success are appropriate patient selection and care in cardiothor-
allows for ambulation during the period of support. Removal is
acic centres of excellence.
typically via a purse-​string suture at bedside.

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 CHAPTER 29

Nutrition support in acute

cardiac care
Michael P Casaer and Greet Van den Berghe

Contents
Summary  360
Summary
Introduction  361 Malnutrition in cardiac and critical illness is associated with a compromised
Background  361 clinical outcome. The aim of nutrition therapy is to prevent these complications
Nutrition and the fight against lean tissue and particularly to attenuate lean tissue wasting and the loss of muscle force and
wasting in the critically ill patient  361
The cardiac muscle and starvation  361
physical function. During the last decade, several well-​powered randomized con-
Nutrition and cardiac disease  363 trolled nutrition trials have been performed. Their results challenge the existing
Recent data on nutrition research in acute nutrition practices in critically ill patients. Enhancing the nutritional intake and
(cardiac) critical illness  363 administration of specialized formulations failed to evoke clinical benefit. Some
Early enteral nutrition for the critically ill
patient  363
interventions even provoked an increased mortality or a delayed recovery. These
Enhanced enteral intake early in critical unexpected new findings might be, in part, caused by an important leap forward
illness  363 in the methodological quality in recent trials. The recently published guidelines of
How to manage persistent enteral nutrition
failure  364 the European Society for Clinical Nutrition and Metabolism (ESPEN) for nutrition
When parenteral nutrition should be initiated in the critically ill integrate this new evidence and no longer promote the admin-
in the critically ill  365
How much and which amino acids  366
istration of high doses of energy or protein in the acute phase of critical illness.
Immunomodulating lipids  366 Moreover, the guidelines caution against early high-​dose glutamine administration
Vitamins, trace elements, and as it increased mortality.
electrolytes  366
Methodological issues in nutrition research Perhaps reversing early catabolism in the critically ill patient by nutrition or
during critical illness  366 anabolic interventions is impossible or even inappropriate. Nutrients effectively
Nutrition and anabolism in critical suppress the catabolic intracellular autophagy pathway. But autophagy is crucial
illness: where are we today?  367 for cellular integrity and function during metabolic stress, and consequently its
A practical approach to nutrition in acute inhibition early in critical illness might be deleterious.
cardiac care  367
First week in the intensive cardiac care
Evidence from large nutrition trials, particularly in acute cardiac illness, is
unit  367 scarce. Nutrition therapy is therefore focused on avoiding iatrogenic harm. Some
Prolonged critical illness  368 enteral nutrition is administered, if possible, and eventually temporary hypocaloric
Personal perspective  368 feeding is tolerated. Early full-​dose enteral feeding provoked bowel ischaemia in
Further reading  368 a recent RCT. The refeeding syndrome and other nutrition-​related complications
References  369 should be prevented. Patients at risk of refeeding syndrome cannot be identified
based on clinical characteristics upon admission, but a reduction in serum phos-
phate levels should prompt temporary restriction of nutritional intake. There is no
indication for early parenteral nutrition, increased protein doses, specific amino
acids, or modified lipids in critical illness.
 Bac kg roun d 361

ICU-​AW is a bilateral symmetrical, flaccid paresis of the limbs,

Introduction associated with respiratory weakness, prolonged mechanical ven-
tilation [21], and ultimately increased mortality [22]. Clinically,
All along the history of mankind, the devastating consequences of
in cooperative patients, the diagnosis of ICU-​AW can be made
prolonged reduced nutrient intake or starvation in healthy men
by assessment of the MRC sum score, based on the ability to con-
have been observed and reported [1]‌. Additionally, a strong as-
tract three major muscle groups in the four limbs [23]. The loss
sociation between malnourishment and a compromised outcome
of skeletal muscle mass, so-​called muscle wasting, appears to play
after trauma, surgery, and other diseases has been established
a central role in ICU-​AW [24]. The ubiquitin proteasome and
[2,  3]. As a consequence, providing food to patients, particu-
autophagy pathways are the main pathways for (muscle) protein
larly when they are severely ill or malnourished upon admission,
breakdown [25]. These catabolic pathways, however, are also cru-
is considered a moral duty and a medical priority. Nevertheless,
cial for cellular integrity, as they guarantee not only the provision
evidence supporting early artificial nutrition in the critically ill
of substrates to cells in starvation, but also the turnover of regu-
subject is scarce and partially based on association, observation,
latory proteins. The autophagy pathway, moreover, eliminates
and extrapolation from physiological data [4]. The results of re-
toxic protein aggregates and malfunctioning organelles [26, 27].
cent high-​quality RCTs challenged existing nutritional strategies;
Nutrition and anabolic hormones suppress autophagy.
in particular, early nutritional interventions, such as enhanced
Attenuating muscle wasting in critical illness through en-
enteral nutrition (EN), early parenteral nutrition (PN), and high
hanced nutrition is a tempting strategy but turns out to be diffi-
doses of glutamine, failed to evoke convincing clinical benefit and
cult in clinical practice [28]. This is not so surprising, considering
even provoked harm [5–​9], as reflected by the recently published
the very different mechanisms behind lipolysis and protein break-
ESPEN guidelines for nutrition in critical illness [10]. Also the
down in healthy fasting, compared to wasting in critical illness
established concept that cardiac surgery patients react very differ-
(see E Figures 29.1A, B). In the critically ill patient, the role of
ently to feeding, compared to other critically ill patients, now has
reduced nutrient intake might be small, compared to the role of
been refuted [11, 12]. While recommendations on diet modifica-
inflammation and immobilization [29]. This is reflected by the
tions in patients with high cardiovascular risk are based on a body
inability of artificial nutrition to suppress gluconeogenesis in
of evidence generated by large, though at times conflicting, RCTs
critically ill patients, in contrast to stable post-​operative patients
[13–​15], studies comparing nutritional strategies in patients after
[30, 31]. Exogenous nutrients are thus superimposed on the im-
cardiac surgery and in ICCUs are scarce [16]. Therefore, this
measurable ongoing flow of endogenous substrates and might
chapter discussing nutrition in the critically ill cardiac patient fo-
increase the metabolic burden [32]. This possibly leads to lipo-
cuses primarily on avoiding harm, particularly during refeeding,
genesis/​steatosis, hyperglycaemia, and depletion of muscular glu-
and on providing the most uncomplicated feeding therapy pos-
tamine stores [29]. In summary, the time point in recovery from
sible, until strong evidence in favour of more specific or invasive
acute critical illness where enhanced nutrition effectively attenu-
nutrition interventions is available.
ates catabolism remains obscure.
The aim of this chapter is to provide an insight into the physio-
logical relationship between nutrition and the heart. Thereafter,
the results of recent nutrition RCTs in ICUs and their conse- The cardiac muscle and starvation
quences for clinical practice will be discussed. Finally, a pragmatic
Lean tissue wasting is not restricted to skeletal muscle. In the
strategy for nutrition in the critically ill cardiac patient will be
landmark Minnesota experiment, Ancel Keys semi-​starved 36
suggested.
young volunteers for several months. A total of 24 weeks of semi-​
starvation resulted in a reduced total volume of the heart and a
reduced cardiac output. Volunteers developed hypotension and
Background bradycardia, but not cardiac failure. The lower body weight, meta-
bolic demands, and afterload during starvation may mask the low
Nutrition and the fight against lean tissue output, until refeeding is initiated [1]‌. Heymsfield reported re-
wasting in the critically ill patient duced myocardial volume in malnourished patients, compared
An increasing proportion of patients surviving the first acute days to matched non-​malnourished patients. Moreover, subsequent
of life-​threatening disease evolves into a state of prolonged critical enhanced nutrition was associated with improved myocardial
illness. The need for long-​term ventilator and other organ support volume and function [33]. Also hunger strikers develop cardiac
and the presence of ICU-​acquired weakness (ICU-​AW) become myofibre atrophy, again suggesting myocardial wasting, despite
clinically more important than the initial reason for ICU admis- ongoing cardiac activity [34]. In a rabbit model of prolonged
sion. ICU-​AW contributes largely to the burden of prolonged critical illness, increasing glucose intake attenuated the activa-
critical illness in the ICU. This burden may persist long after ICU tion of the myocardial catabolic ubiquitin proteasome pathway
discharge [17, 18]. Improving the functional outcome and quality [35]. Nutrient restriction activates autophagy in the murine
of life after critical illness thus became a priority in intensive care cardiomyocyte [36]. The role of cardiac autophagy, however, is
research and clinical practice [19, 20]. controversial and possibly disease-​, dose-​, and time-​dependent.
362 CHAPTER 29   Nu trit ion su pp ort in acu t e ca rdiac ca re

(a)
Gastrointestinal tract

Reduced circulating glucose, amino acid, and lipids

Amino
Pancreas Adrenal acids
glands Glutamine
Insulin Glucagon Cortisol

Adipose tissue Muscle

lipolysis 2 1
FFA protein
Glycerol Breakdown > synthesis
Amino acids

Liver
Gluconeogenesis
VLDL Glycogenolysis

Brain, heart, kidney

Glucose 1 Survival to next meal

Ketone bodies 2

(b)

?? Gastrointestinal tract ??
Sepsis
Trauma ? ? Amino
acids
Pancreas Adrenal
Glutamine
glands

TNFα, IL-1 Insulin Glucagon Cortisol + catecholamines

Adipose tissue Muscle

lipolysis FFA ++ Amino acids protein
Glycerol Breakdown > synthesis

Liver Immobilization
VLDL Gluconeogenesis
Glycogenolysis Amino
acids
Acute Glutamine
phase Brain, heart, kidney,
Lactate
proteins immune system,
Glucose ++ wound healing
? ? Survival
Ketone bodies ? ?

Figure 29.1  (A) Mobilization of endogenous nutrients during fasting. (1) Early phase: muscle protein (pink) serves hepatic gluconeogenesis (blue) or serves as
a regional energy source in, for example, the GI tract. (2) Later phase of fasting: lipolysis in adipose tissue fuels hepatic ketogenesis (black) and, to a small extent,
gluconeogenesis. FFA, free fatty acids; VLDL, very low-​density lipoproteins. (B) Wasting in critical illness: massive mobilization of endogenous nutrients triggered
by inflammation and immobilization, and largely independent of nutritional (in)adequacy. Amino acids (pink), released by muscle breakdown, are a substrate for
hepatic gluconeogenesis, the production of acute phase proteins, gut metabolism, inflammation, and wound healing. FFA (black) are a direct energy source for
muscle. Insulin resistance reduces glucose (blue) uptake in insulin-​dependent tissues. Incomplete oxidation of glucose results in a lactate flux back to the liver
[29, 32]. VLDL, very low-​density lipoproteins; FFA, free fatty acids; TNFα, tumour necrosis factor α; IL-​1, interleukin-​1.
Reproduced from ‘Impact of early parenteral nutrition on metabolism in critically ill patients’ MP Casaer, Acta Biomedica Lovaniensa 591, 2012, Thesis Dissertation with permission
from Leuven University Press.

Autophagy activation might worsen load-​induced hypertrophic RV failure is particularly associated with weight loss, and both
heart failure [36] (though results are conflicting [37]) but ap- combined are strong predictors of mortality and AEs [40]. The
parently preserves myocardial function in abdominal sepsis in possible roles of a low cardiac output, venous and lymphatic con-
murine experiments [38]. gestion, and intestinal hypoxia have been described extensively
Cardiac failure reciprocally influences the nutritional status and [40]. Clinical features include fat malabsorption [41], losses of
induces tissue wasting, often referred to as cardiac cachexia [39]. protein in paracentesis fluids, and a reduced oral nutrient intake,
 Recent data on  nu tri ti on resea rch i n  acu te ( ca rdiac) cri ti c a l   i l l n e s s 363

all leading to tissue wasting. Also, increased lipolysis due to in- trials put together [56]. Data interpretation is complicated by
creased BNP levels, among others, could play a role [40]. Whether the trial quality and the control patients receiving PN during the
EN or PN can reverse cardiac cachexia and improve survival re- first 2  days in the ICU [57]. The European Society of Intensive
mains to be shown [42, 43]. Care Medicine Metabolism–​ Endocrinology–​ Nutrition Section
(ESICM-​MEN Section) generated a weak recommendation in
Nutrition and cardiac disease favour of early initiation of EN. It reduced the risk of new in-
The importance of nutrition and lifestyle in patients with meta- fections in an unselected population of critically ill patients, but
bolic syndrome, CVD, or increased cardiovascular risks is well the quality of the evidence is very poor [58]. The ESICM-​MEN
established. This has been covered in extensive guidelines by Section suggests to initiate (a gradually increasing dose of) EN
the ESC/​European Atherosclerosis Society, among others. The in patients stabilizing after haemodynamic shock and in those on
cornerstones are total energy intake adjusted to activity and ECMO. In the NUTRIREA-​2 trial, published after publication of
body weight, reduced intake of fat (particularly saturated fat), these ESICM recommendations, early full-​dose enteral feeding
consumption of vegetables and fruit, reduced alcohol intake, en- increased the risk of bowel ischaemia in stabilized shock patients
hanced physical activity, and, of course, cessation of all tobacco receiving substantial doses of vasopressors.
product exposure [44, 45]. The evidence in favour of more spe-
cific nutritional interventions in patients with cardiac disease,
Enhanced enteral intake early in critical illness
however, has been challenged by some of the most recent RCTs
[14, 15,  46]. The disappointing results with omega-​3 fatty acids All strategies aiming at feeding patients early up to the nutritional
(OFAs), despite earlier encouraging results, might be explained target are complicated by the difficulty of defining this energy
by an increased quality of medical care and prevention, wide- target in the individual patient. As discussed in the Background
spread statin use over the last decades, a lower baseline of car- section, the endogenous mobilization of nutrients in the critically
diovascular risk in participating countries, or a beneficial effect ill patient is not measurable and not suppressed by artificial nutri-
of the (olive) oil used in control patients [46]. In the VITAL-​RCT tion. It is thus uncertain whether feeding critically ill patients up to
(N  =  25  871) randomizing patients to OFAs and vitamin D in the energy expenditure, as measured by indirect calorimetry (IC),
a two-​by-​two factorial design, OFAs had no effect on the inci- is the optimal strategy. IC estimates the resting energy expenditure
dence of major cardiovascular complications. However, in 13 514 by analysis of the respiratory gas exchange, with some assump-
patients consuming <1.5 servings/​week of fish, the intervention tions concerning the non-​measured parameters [59]. IC measure-
was beneficial (P-​value for interaction 0.045), supporting the hy- ment is not always feasible; high inspiratory O2 concentrations,
pothesis that the effect of preventive nutritional interventions is chest tubes, and other features of severe critical illness preclude
modified by baseline exposure [47]. correct measurements in about one in three ICU patients, even in
experienced hands [60]. The accuracy of different indirect calor-
imeters is, in fact, questioned [61]. IC-​guided feeding increased
the incidence of infections and the duration of ICU dependency
Recent data on nutrition research in the exploratory Tight Calorie Control Study (TICACOS) trial;
in acute (cardiac) critical illness a multicentre TICACOS RCT has been stopped for reasons of
slow recruitment and the preliminary results, presented at the
Early enteral nutrition for the critically International Symposium on Intensive Care and Emergency
ill patient Medicine (ISICEM) 2019, revealed no benefit [62]. The EAT-​ICU
The aim of artificial nutrition in the (commonly anorectic) crit- RCT evaluating early supplemental PN guided by IC, as compared
ically ill patient is to avoid the morbidity and mortality observed to hypocaloric nutrition, revealed no benefit of this sophisticated
with an increased energy deficit [3, 48, 49]. Nevertheless, no well-​ intervention [63, 64]. Therefore, at present, feeding guided by en-
powered trials comparing artificial feeding with no feeding in the ergy targets, which are based on adjusted ideal body weight de-
ICU have been performed. termined by height, age, and gender, might be just as good as, or
EN is the route of first choice. It might have a beneficial effect better than, IC [62] (see E Figure 29.2).
on the intestinal wall integrity, as suggested by pioneering human Very often, severely ill patients do not receive as much nutrition
and animal experiments [50, 51]. Perhaps more importantly, EN as prescribed [65, 66]. Surgical and diagnostic procedures, airway
is cheaper and technically less complicated than PN. Moreover, management, delayed gastric emptying, and diarrhoea all con-
PN is more likely to induce infections, possibly via hypergly- tribute to the EN flow being reduced or interrupted. Small RCTs
caemia or overfeeding [52–​54]. In observational studies, early provided evidence in favour of reaching a caloric target early in
initiation of EN was associated with improved outcome [55]. critical illness [67]. In two cluster RCTs, the implementation of
However, such studies do not allow answering to the question of guidelines aiming at an improved EN management indeed in-
whether patients are easier to feed if they are less ill or conversely creased the nutritional intake [68, 69]. Unfortunately, the bene-
whether they recover faster when they are more adequately fed. ficial clinical effects observed in the first smaller trial were not
RCT-​based evidence for improved survival with early initiation reproduced in the second larger study. The multicentre TARGET
of EN is very limited; <300 patients were included in all relevant RCT evaluated energy-​dense versus standard feeding in 3957
364 CHAPTER 29   Nu trit ion su pp ort in acu t e ca rdiac ca re

Total energy (kcal) Full (n = 492) Early PN (n = 686) Early PN (n = 2312) SPN (n = 153) REE (n = 65)
Trophic (n = 508) Standard (n = 686) Late PN (n = 2328) EN only (n = 152) Calculated (n = 65)
2500
2000
1500
1000
500
0
ICU day 1 2 3 4 5 6 7 1 2 3 4 5 6 7 1 2 3 4 5 6 7 1 2 3 4 5 6 7 1 2 3 4 5 6 7
EDEN trial Early PN trial EPaNIC trial SPN trial TICACOS trial

Medical (ALI) Mixed medical/surgical Mixed medical/surgical Mixed medical/surgical Mixed medical/surgical
(unselected) (on day 4)
Type of patients
Eligible for EN EN relatively contraindicated With nutritional risk (NRS ≥3) Eligible for EN but <60% target
(short term)

Between day 9 and day 28: less

New infections with SPN
Unaffected Unaffected More with Early PN More with REE
in ICU From randomization to day 28:
unaffected

Duration of
mechanical Unaffected Shorter with Early PN Longer with Early PN Unaffected Longer with REE
ventilation

ICU length of stay Unaffected Unaffected Longer with Early PN Unaffected Longer with REE

Unaffected
Unaffected
ICU mortality Unaffected Unaffected Unaffected (trend towards reduced
(60-day mortality: unaffected)
hospital mortality)

Figure 29.2  The outcomes for new infections, the duration of mechanical ventilation, the duration of stay in the ICU, and ICU mortality are depicted, as only
these were available for all five trials. The outcome measures in italics represent the predefined primary endpoint of each trial. The comparison reveals no benefit
of enhanced macronutrient delivery early during critical illness on survival or on intensive care dependency. It may be that the apparent differences among
the studies for other outcomes are related to the differences in the dose of macronutrients or the route of macronutrient delivery. Filled lines represent days
where, according to the study protocols, patients were not allowed to receive PN. Dashed lines represent days where patients were allowed to receive PN. All
cartoons were drafted, based on the data reported in the original publications. The lines represent mean values for total energy intake. For the SPN trial, only the
percentage of target was available. Based on the published results, the average energy intake between days 4 and 8 was 28 kcal/​day in the SPN arm, which, for
the average patient body weight (74.8 kg), resulted in 2094 kcal, corresponding to approximately 100% of target. n, number of patients randomized per arm; ALI,
acute lung injury; EN, enteral nutrition; ICU, intensive care unit; NRS, nutritional risk score; PN, parenteral nutrition.
Reproduced from Casaer MP, Van den Berghe G. Nutrition in the acute phase of critical illness. N Engl J Med 2014;370(13):1227–​1236. doi:10.1056/​NEJMra1304623 with permission
from Massachusetts Medical Society.

critically ill patients. Energy-​dense feeding resulted in an energy have evaluated hypocaloric versus ‘normocaloric’ feeding, some
intake of around 1800 kcal/​day, as compared to 1200 kcal with of which were iso-​nitrogenous and others not, with the clinical
standard feeding. The intervention was maintained for up to 4 outcome mostly unaffected. The permissive underfeeding trial
weeks. Although energy-​dense feeding was less tolerated than by Arabi and co-​investigators was the largest iso-​nitrogenous
standard EN, no other outcome parameters were affected by this nutrient restriction study extending the randomized interven-
prolonged between-​group difference in energy intake [70]. tion to up to 14 days and was neutral [73]. A post hoc analysis
In the EDEN RCT (n  =  1000), trophic feeding, a very small of the PermiT trial evaluated the effect of nutrient restriction in
amount of EN being infused during the first 6 days, in the ICU did subgroups of patients divided according to the NUTRIC Score, a
not compromise outcome, compared to up-​to-​target feeding (see tool intended to identify patients likely to benefit from enhanced
E Figure 29.2) [5]‌. In a smaller RCT, deliberate underfeeding feeding. No interaction between the randomized intervention
even improved hospital survival, compared to feeding up to the and the nutritional risk score was detected [74].
energy target [71]. The recent INTACT trial evaluating prolonged
hypocaloric EN in ALI was unfortunately stopped prematurely, How to manage persistent enteral
due to an impressive survival benefit with nutrient restriction. nutrition failure
As a consequence, the study is extremely underpowered and it Delayed gastric emptying, resulting in high gastric residual vol-
is impossible to know whether the nutrition truly provoked such umes (GRVs), is a common reason for the interruption of EN,
mortality difference [72]. In conclusion, strong evidence in fa- as aspiration pneumonia is feared. It is, however, uncertain
vour of enhanced enteral feeding early in critical illness is, in fact, whether GRVs should be measured and what the threshold for
lacking. Since the first edition of this chapter, several other RCTs feeding interruption or reduction of the infusion speed should
 Recent data on  nu tri ti on resea rch i n  acu te ( ca rdiac) cri ti c a l   i l l n e s s 365

be. Omission of GRV measurement [75] or tolerating a GRV of difference in the total energy intake between the groups was small
up to 500 mL [76] both safely enhanced the EN intake but did not (see E Figure 29.2). Early supplemental PN reduced the number
provide hard clinical benefit. of infections between days 9 and 28, but not the total number of
Erythromycin and metoclopramide improve gastric emptying infections observed after randomization [86]. Not attributing all
and thus allow more adequate provision of EN when GRVs are events occurring after randomization to the allocated treatment
high. Both drugs, however, are contraindicated in patients suf- complicates the correct interpretation of the data, as was shown
fering from a prolonged QT interval [77–​79]. Feeding below the decades ago in the Anturane reinfarction trial [87]. Mortality and
pylorus bypasses delayed gastric emptying. However, when im- ICU and hospital stay were unaffected by the randomized inter-
plemented in unselected critically ill patients, it delays the initi- vention, while the prescription of antimicrobials was reduced
ation of EN and thus reduces early EN intake [80]. In patients with early PN [60]. In conclusion, the SPN trial revealed neither
with persistently high GRVs, however, post-​bulbar feeding might benefit nor harm after 4 days of supplemental PN in the first week
be considered if no signs of GI impairment, particularly impeding of critical illness. The results of the EAT-​ICU trial cited earlier are
non-​occlusive bowel necrosis, are present [81]. Recent ESPEN consistent with these results [63].
guidelines likewise suggest to consider small bowel feeding in The Early PN trial (see E Figure 29.2) focused on a specific
selected patients in order to achieve adequate enteral intake and patient population (n  =  1372) with a relative short-​term (48
preventing aspiration pneumonia, acknowledging that no hard hours) contraindication for EN. Patients in the intervention arm
benefit for clinical outcome has been demonstrated [10]. received PN within an hour of study enrolment. As one-​third of
the control/​standard therapy patients received PN during the first
When parenteral nutrition should be initiated days in the ICU, this interesting and pragmatic trial could not de-
in the critically ill tect, from its design, an eventual benefit of withholding PN early
PN was initially developed as a therapy for patients in whom GI in critical illness. The 60-​day mortality, the primary endpoint,
agenesis, fistulae, or short bowel syndrome precluded the admin- was similar in both arms, but the length of time on mechanical
istration of EN [82]. Until very recently, it was a common therapy ventilation, a tertiary outcome, was shorter in the ‘early PN’ arm.
for critically ill patients with (partial) GI failure. But it remained New infections occurred equally in both arms. The CALORIES
controversial whether, and at what time point, these patients ef- RCT evaluating EN versus PN had a very different design [88].
fectively benefit from PN [83, 84]. Only patients without contraindication to EN were included. As
In the Early Parenteral Nutrition Completing Enteral Nutrition a consequence, both groups received isocaloric feeding (reaching
in Adult Critically Ill Patients (EPaNIC) trial, 4640 patients were 70–​80% of energy target). The randomized intervention had no
randomized to ‘no PN’ during the first week in the ICU, ‘late PN’, major impact on clinical outcome, suggesting that the dose of
or ‘early PN’, meaning the initiation of PN within 48 hours if EN nutrient administration may be more important than the route
was insufficient (see E Figure 29.2) [8]‌. Patients received trace (EN or PN). The results of the NUTRIREA-​2 RCT are also in fa-
elements and vitamins, until adequate EN was established. Tight vour of this hypothesis; early full-​dose enteral nutrition, as com-
glycaemic control was achieved by insulin infusion. EN intake pared to PN, resulted in similar clinical outcome in mechanically
reached only 20% of estimated energy needs by the end of the ventilated patients receiving substantial doses of vasopressors.
first week in the ICU in these severely ill patients. Tolerating a Isocaloric PN did not increase the incidence of new infections,
pronounced energy deficit by withholding PN unexpectedly im- and forced enteral feeding provoked a small, but significant, in-
proved outcome. ‘Late PN’ patients recovered faster from ICU crease in bowel ischaemia.
and hospital dependency, had a shorter duration of the need for Patients with a prolonged contraindication for EN constitute a
organ-​replacing therapy, and developed fewer new infections in subgroup of great concern to most clinicians; in many nutrition
the ICU. This resulted in an important reduction of health care-​ RCTs, their inclusion was considered unethical. Surprisingly, a
related costs, particularly antimicrobial drug costs, with ‘late PN’ large subgroup of EPaNIC patients with a surgical contraindica-
[85]. Critics suggested that ‘early PN’ might have harmed the less tion to EN upon ICU admission experienced an even more pro-
severely ill patients, obscuring its potential benefit in the more nounced benefit with ‘late PN’ than the overall study population,
severely ill. This interesting hypothesis was rejected by a post hoc despite important nutritional deficits [8]‌. This confirmed the re-
analysis of the effect of the randomized intervention in four sub- sults from smaller historical trials comparing PN to no artificial
groups (n >1100) according to the severity of illness upon ICU nutrition [89].
admission. It showed that more severely ill patients are at higher RCTs focusing on early artificial nutrition in critically ill car-
risk of harm by ‘early PN’, and equally in cardiac surgery and diac patients are scarce. In the EPaNIC trial, the large group of
other patients [12]. Finally, patients with a very low BMI or with a patients admitted after cardiac surgery reacted similarly to the
significantly reduced premorbid nutrient intake benefited equally nutritional intervention as the ‘non-​ cardiac surgery’ patients
from withholding ‘early PN’ [8]. [11,  12]. Observational data suggest that EN can be delivered
The SPN trial studied 305 patients without contraindication for safely in cardiac surgery patients, including patients on IABP, but
EN. PN was initiated on the fourth day in the ICU if EN intake is often hypocaloric [90]. A pioneering exploratory study on the
was <60% of the energy target [6]‌. Control patients continued on effect of EN versus PN or no feeding on ventricular function and
EN only until day 8. As EN was quite successful in both arms, the perfusion after CABG is ongoing [91].
366 CHAPTER 29   Nu trit ion su pp ort in acu t e ca rdiac ca re

How much and which amino acids give early parenteral glutamine in critical illness [10]. The poten-
tial value of completing PN in stable critically ill patients with a
The association between protein intake and clinical outcome is
low dose of glutamine remains to be investigated.
conflicting in different observational trials [12, 92, 93]. The risk of
Finally, arginine does not improve outcome in critically ill pa-
confounding by informative censoring and time bias in such ob-
tients and might increase mortality in sepsis [108].
servational analyses is discussed in the E Methodological issues
in nutrition research during critical illness section, p. 366. Only
Immunomodulating lipids
one RCT including 50 patients studied different protein doses and
failed to show a beneficial clinical effect of increased intake, des- The anti-​inflammatory properties of OFAs are well known and
pite positive nitrogen balances [94]. In addition, a large Australian might explain the beneficial effect of a diet rich in fish or walnuts
RCT was completed recently and presented its findings as follows. [46]. Olive oil, containing omega-​9 fatty acids, has no inflamma-
More than 400 critically ill patients received either standard nu- tory effects, while omega-​6 fatty acids are pro-​inflammatory [109].
trition or an additional parenteral amino acid infusion targeted at These particular properties inspired the use of OFAs in improving
a total of 2 g/​kg of daily protein intake. Additional amino acids, oxygenation in ALI, attenuating inflammation in sepsis, and
despite successfully achieving the protein target, did not generate preventing AF after cardiac surgery [110–​112]. Unfortunately, re-
any clinical benefit [95]. Estimated GFR was improved with add- sults are conflicting on all these indications. Again, early prom-
itional amino acids, yet the need for RRT also tended to be higher ising results are not confirmed by more recent RCTs [112–​114].
in this group. Surprisingly, the extra amino acids had no effect on Surprisingly, high OFA levels in red blood cell membranes were
long-​term functional outcome. A smaller RCT focused primarily associated with an increased risk of AF in an observational ana-
on improving muscle force through enhanced protein adminis- lysis of a recent RCT [115].
tration; the intervention turned out to be ineffective [96]. Analysis
of the metabolic fate of the additional infused amino acids in the
Vitamins, trace elements, and electrolytes
EPaNIC trial revealed that they were largely lost in urinary excre- Upon reinitiation of (artificial) nutrition, a depleted status of
tion [97]. Ureagenesis possibly explained the increased need for vitamins, trace elements, and electrolytes during starvation
RRT with early PN. In a post hoc analysis aimed at identifying may become clinically apparent. The dramatic consequences
the culprit for compromised outcome with early PN, we found of hypokalaemia, hypophosphataemia, and acute thiamine de-
that not glucose, but the cumulative amino acid/​protein dose, was ficiency (arrhythmia, muscle weakness, lactic acidosis, and
associated with delayed recovery [98]. This association was con- cardiac failure, respectively) are well known as the ‘refeeding syn-
firmed and revealed to be even stronger in an observational ana- drome’ [116–​119]. In patients who develop hypophosphataemia
lysis of the paediatric EPaNIC trial (PEPaNIC) which concluded upon initiation of artificial nutrition, early hypocaloric feeding,
in 2016. In the EAT-​ICU RCT, not only energy administration as compared to full feeding, appears to save lives. This survival
was guided by IC, but also protein intake was adjusted. Protein difference occurred despite correction of phosphate levels and
intake in the intervention arm was calculated to cover 1.5 g/​kg micronutrient administration in both study arms [120]. A similar
and was reduced if plasma urea went above 20 mmol/​L. This ex- pattern of improved survival with nutrient restriction upon
pert targeted early protein provision had no impact on outcome, refeeding hypophosphataemia was observed in a larger obser-
except an increase in plasma urea and urinary nitrogen excretion vational study [121]. Strikingly, the patients developing early
[63, 99, 100]. Thus, to date, no recommendations on optimal pro- hypophosphataemia in the latter study could not be identified
tein intake in artificial nutrition in the ICCU can be made. based on admission characteristics!
Of note, small RCTs suggest that preoperative oral supplemen- The alleged beneficial effects of high doses of trace elements
tation of, among others, taurine or parenteral amino acid infusion such as antioxidants have not been confirmed in the REDOXS
during coronary artery grafting could improve, respectively, ven- trial [9]‌. Selenium supplementation may, however, be beneficial
tricular function and the duration of ICU dependency [101, 102]. in deficient populations [107, 122].
Glutamine is a non-​essential amino acid generated predomin-
antly in the muscle. It serves as fuel for hepatocytes, enterocytes, Methodological issues in nutrition research
and immune cells (see E Figure 29.1). The mismatch between during critical illness
endogenous production and increased demands could explain The conflicting results generated by recent RCTs are often at-
the association between low glutamine levels and increased mor- tributed to an inadequate patient selection or a ‘substandard’
tality in the ICU [103, 104]. Despite very promising results from nutrition intervention [11, 123]. The importance of an adequate
earlier trials [105, 106], two recent high-​quality RCTs tempered methodology and trial design is less addressed [4, 57, 124]. A re-
the enthusiasm for glutamine in the ICU. The SIGNET trial in- liable assessment of the clinical effect generated by a therapeutic
vestigated a relatively low dose of glutamine administered in PN, intervention requires an adequately powered RCT [125]. Maximal
demonstrating no benefit [107]. In the REDOXS trial, however, reduction of the risk for bias is crucial, particularly in nutrition,
parenteral plus enteral glutamine (0.6–​0.8 g/​kg/​day) induced an as double blinding is not always possible. An accurate descrip-
alarming 6.5% increase in 6-​month mortality in severely ill ICU tion of the population screened and of patients excluded from
patients. The ESPEN guidelines now strongly recommend not to randomization or from analyses reduces the risk of selection bias
 A practi ca l a pproach to  nu tri ti on i n  acu te ca rdiac   c a re 367

and guarantees a true intention-​to-​treat analysis [126]. A  pre-​ induced intramuscular lipogenesis and suppressed autophagy.
specified and publicly posted primary clinical endpoint precludes Interestingly, suppressed autophagy in muscle was a strong pre-
multiple testing and publication bias [127]. dictor for the development of ICU-​AW. Together, these results in-
Analyses of RCTs in the ICU are often complicated by com- dicate that ‘early PN’ might have delayed the recovery of muscle
peting risks and informative censoring. For example, a patient force via a nutrient-​induced inhibition of autophagy.
should not be censored from an ICU survival analysis on the day In conclusion, none of the recent trials provided evidence for
of a live ICU discharge, as discharge in itself indicates a higher improved muscle force or function with early enhanced nutrition
likelihood of survival [4, 93,  128]. Analysis of crude landmark in critical illness; one RCT even revealed the opposite. The stimu-
(90-​day) survival, independent of the ICU and hospital discharge lation of (voluntary) muscle contraction might protect more ef-
status, is a reliable and simple solution to this problem [129]. fectively muscle integrity and function in the ICU [135, 136].
The observational study of the relationship between nutritional
intake and recovery is often distorted by time bias. Nutrition in-
take mostly improves during recovery from critical illness but A practical approach to nutrition
still falls short of reaching the target. Thus, an insufficient average
energy intake is often associated with shorter ICU stays, while a in acute cardiac care
prolonged ICU stay is associated with a higher cumulative energy First week in the intensive cardiac care unit
deficit, and this despite both parameters being a measure of inad-
The premorbid nutritional status and expected disease course vary
equate feeding [3, 130]. Analyses of the relation between the en-
enormously between different critically ill cardiac patients. Patients
ergy administered from ICU admission up to a given day and the
admitted after elective cardiac surgery, that constitute an important
likelihood of ICU discharge thereafter may resolve this issue [12].
proportion of general ICU admissions, are generally well nourished
In summary, rigorous and public statistical analysis plans might
and are often discharged after a few days, if no unforeseeable com-
contribute to the generation of more reliable scientific evidence
plications occur [2, 137]. Chronic cardiac failure patients present
and consequently improve medical practice.
with significant lean tissue wasting and may develop more often
prolonged organ failure [39]. GI fistulae or anastomoses precluding
the use of the GI tract are rare in the ICCU, but the provision of
Nutrition and anabolism in critical EN can be complicated by compromised intestinal perfusion due to
illness: where are we today? vasopressors, cardiac assist devices, or RV failure [16].
Upon admission, assessments, including macronutrient,
Several recent RCTs on early enhanced feeding in the critically
vitamin, and trace element status, signs of malnutrition, and
ill patient included a preplanned investigation of muscle mass or
measurements of height and weight, are mandatory. Drug use and
function in the ICU and/​or physical function thereafter. Overall,
substance abuse should be registered. No reliable prospectively
their results are not encouraging. Up-​to-​target feeding did not
validated tools identifying patients likely to benefit from early nu-
improve functionality and cognition at 6 and 12  months after
trition interventions or those at high nutritional risk are available
randomization in the EDEN trial [20, 131]. In the Early PN trial,
to date. A dynamic nutrition strategy adapted to the patient’s evo-
early PN attenuated muscle and even more fat wasting, as as-
lution in the ICCU thus remains the only option [8, 138].
sessed by global subjective assessment, but this did not translate
Until the patient has a stable circulation, the provision of 1 L
into better physical functioning [7]‌. Moreover, the accuracy of
of dextrose 5% per day, supplemented with potassium and phos-
such anthropometrics in quantifying body composition in critical
phate, guided by blood analyses, appears sufficient [8]‌. Avoiding
illness is debated [132]. No functional evaluation was performed
hypoglycaemia, hyperglycaemia, hypophosphataemia, hypokal-
in the SPN trial. The Early Goal Directed Nutrition Therapy in
aemia, and acute thiamine deficiency is the focus of nutrition
the EAT-​ICU RCT failed to improve long-​term functional out-
therapy in this phase. Patients receiving diuretics are particularly
come, the primary endpoint [63]—​a disappointing result given
likely to be depleted in potassium, phosphate, and thiamine [116–​
the effort invested in providing individualized nutrition, avoiding
118]. If a thiamine deficiency is suspected, initial thiamine doses
both energy and protein overfeeding and underfeeding from the
of 50–​300 mg IV once daily are recommended [119].
first ICU day on.
Once lactate is no longer increasing and the need for vasopres-
EPaNIC ‘late PN’ patients performed six-​minute walking dis-
sors and inotropes has stabilized, some titrated enteral feeding can
tance tests and activities of daily life at hospital discharge, similar
be considered [90]. PN is not indicated during the first week in the
to ‘early PN’ patients, despite a significantly shorter hospital stay
ICU [6–​8]. Monitoring abdominal distension, high GRVs, pain,
[8]‌. Strikingly, withholding PN reduced the incidence of ICU-​AW
or other disturbing signs is important in this start-​up phase in pa-
and enhanced the recovery of muscle force, as quantified by the
tients at risk of non-​occlusive bowel necrosis [81]. The additional
MRC sum score, upon awakening in long-​stay ICU patients [133].
value of intra-​abdominal pressure monitoring in this setting re-
‘Early PN’ did not prevent macroscopic or microscopic muscle
mains to be established. Relying solely on EN often results in very
wasting, as assessed by quantitative CT and by microscopic
low initial total nutrient intake. This needs to be accepted. As EN
myofibre size quantification [133,  134]. Moreover, ‘early PN’
formulations contain very limited amounts of vitamins and trace
368 CHAPTER 29   Nu trit ion su pp ort in acu t e ca rdiac ca re

elements, parenteral administration of vitamins and trace elem- handling errors and infections [140, 141]. Concentrated EN or PN
ents should be considered early [8]‌, particularly in patients on with reduced phosphate content may be convenient for patients on
chronic renal replacement therapy (CRRT) [139]. Slow parenteral intermittent haemodialysis or with congestive heart failure. When
infusion of vitamins and trace elements over several hours appears plasma triglyceride levels exceed 250 or 300 mg/​dL, reducing the
to be an acceptable clinical strategy in those patients not receiving total energy intake or lipid load might be a solution. If lipid-​free PN
PN. It may avoid a prolonged exposure of vitamins to daylight on is chosen, glucose overload (>5 g/​kg/​day [142]) should be avoided.
the one hand and excessive urinary losses due to bolus adminis- Consequently, hypocaloric feeding is often unavoidable. Essential
tration on the other hand. It is probably safer to reduce manganese free fatty acids are administered at least once weekly. Elementary
and copper administration to twice weekly in cholestatic liver dis- EN containing dipeptides, rather than entire proteins, may provide
ease and to reduce vitamin C doses in renal failure. a solution for EN intolerance/​malabsorption and high GI output
Energy intakes higher than 20–​25 kcal/​kg of the adapted ideal losses in short bowel syndrome, e.g. after bowel ischaemia and
body weight (based on height, gender, and age) are probably resection. The scarce data available, however, are not convincing
not desirable. For the management of blood glucose levels, see [143]. No specific nutritional strategies for patients with persistent
E Chapter 67. If repeated hypoglycaemia occurs, increase the GI failure due to cardiogenic intestinal congestion have been val-
baseline caloric intake, rather than administering repeated glu- idated [42, 43].
cose boluses, as they might provoke large blood glucose fluc- In conclusion, critically ill acute cardiac patients benefit from a
tuations. In cases of persistent hyperglycaemia, despite an simple and standardized feeding management. It might, together
adequate continuous insulin infusion, check the total energy with adequate observations, prevent many complications and ac-
intake. celerate recovery. Clearly, RCTs focused on the metabolic man-
Standardized feeding, guided by a (computer-​assisted) feeding agement of this large ICU population, particularly beyond the
protocol, should aim at simplicity and should take into account first week of critical illness, should be encouraged.
the total energy intake, including calories from (lipid-​containing)
propofol drips and drugs diluted in glucose.
If patients are able to feed by mouth, this is the first choice. Personal perspective
If oral intake is insufficient, oral supplements (liquid feedings)
are the next option in order of simplicity. When feeding by NG Nutrition in the critically ill cardiac patient is not funda-
feeding tubes fails, post-​bulbar feeding or gastro-​prokinetics are mentally different from other critical disease states [12].
carefully considered. PN is reserved for patients not achieving the Until today, no reliable instrument has been validated to
target with EN after 1 week in the ICU. identify the patient ‘at increased nutritional risk’. Moreover,
it is unclear if such a patient would benefit from more ag-
Prolonged critical illness gressive feeding or on the contrary a more restrictive nutri-
tional strategy early in ICU [10].
When spontaneous physical activity and exercise become more
Reversing catabolism of a non-​ nutritional cause
predominant and inflammation regresses, the nutritional intake
through enhanced nutrition might be impossible or even
can probably be increased. Administration of energy levels far
inappropriate [28].
below the resting energy expenditure for several weeks or months
Reducing bias in RCTs through adequate research meth-
will inevitably result in the depletion of all bodily protein and fat
odology is a prerequisite for providing reliable evidence to
stores  [1]‌.
guide clinical (nutrition) therapy [57].
There is no strong clinical indication for adapted EN or PN for-
In order to prevent unintended harm, promising physio-
mulations such as glutamine-​containing, high-​amino acid, OFA, or
logical findings and results from observational or pilot
any other preparation in (cardiac) critical care. Commercially avail-
RCTs should be further explored in large RCTs before
able standard mixtures are good enough to do the job in almost
being applied in clinical practice [9, 144].
all patients and reduce the risk of prescribing errors or technical

Further reading
Allingstrup MJ, Kondrup J, Wiis J, et  al. Early goal-​directed nutrition Brisard L, Le GA, Lascarrou JB, et  al. Impact of early enteral versus
versus standard of care in adult intensive care patients:  the single-​ parenteral nutrition on mortality in patients requiring mechanical
centre, randomised, outcome assessor-​ blinded EAT-​ ICU trial. ventilation and catecholamines:  study protocol for a randomized
Intensive Care Med 1;8:2017. controlled trial (NUTRIREA-​2). Trials 2014;15:507.
Arabi YM, Aldawood AS, Haddad SH, et  al. Permissive underfeeding Casaer MP, Van den Berghe G. Nutrition in the acute phase of critical
or standard enteral feeding in critically ill adults. N Engl J Med illness. N Engl J Med 2014;370:1227–​36.
2015;372:2398–​408. Casaer MP, Wilmer A, Hermans G, Wouters PJ, Mesotten D, Van den
Arabi YM, Casaer MP, Chapman M, et al. The intensive care medicine Berghe G. Role of disease and macronutrient dose in the randomized
research agenda in nutrition and metabolism. Intensive Care Med controlled EPaNIC trial: a post hoc analysis. Am J Respir Crit Care Med
2017;43:1239–​56. 2013;187:247–​55.
 RE F E RE N C E S 369

Doig GS, Simpson F, Heighes PT, et  al. Restricted versus continued Hermans G, Casaer MP, Clerckx B, et  al. Impact of tolerating
standard caloric intake during the management of refeeding macronutrient deficit on the development of intensive care unit-​
syndrome in critically ill adults:  a randomised, parallel-​ group, acquired weakness. Lancet Respir Med 2013;1:621–​9.
multicentre, single-​blind controlled trial. Lancet Respir Med 2015; Heyland D, Muscedere J, Wischmeyer PE, et al. A randomized trial of glutamine
3:943–​52. and antioxidants in critically ill patients. N Engl J Med 2013;368:1489–​97.
Ferrie S, Allman-​Farinelli M, Daley M, Smith K. Protein requirements Koretz RL. Do data support nutrition support? Part I:  intravenous
in the critically ill:  a randomized controlled trial using parenteral nutrition. J Am Diet Assoc 2007;107:988–​96.
nutrition. JPEN J Parenter Enteral Nutr 2016;40:795–​805. Vanhorebeek I, Verbruggen S, Casaer M, et al. Effect of early supplemental
Fivez T, Kerklaan D, Mesotten D, et  al. Early versus late parenteral parenteral nutrition in the paediatric ICU: a preplanned observational
nutrition in critically ill children. N Engl J Med 2016;374: study of post-​randomisation treatments in the PEPaNIC Trial. Lancet
1111–​22. Respir Med 2017;5:475–​83.
Gunst J, Vanhorebeek I, Casaer MP, et  al. Impact of early parenteral Watanabe T, Takemura G, Kanamori H, et al. Restriction of food intake
nutrition on metabolism and kidney injury. J Am Soc Nephrol prevents postinfarction heart failure by enhancing autophagy in the
2013;24:995–​1005. surviving cardiomyocytes. Am J Pathol 2014;184:1384–​94.

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 CHAPTER 30

Physiotherapy in critically
ill patients
Rik Gosselink and Jean Roeseler

Contents
Summary  373
Summary
Introduction  373 Physiotherapists are involved in the management of patients with critical illness.
Respiratory conditions  374 Physiotherapy assessment of critically ill patients is less driven by medical diag-
Prevention of post-​operative pulmonary nosis; instead, there is a strong focus on deficiencies at a pathophysiological and
complications (abdominal and thoracic
surgery)  374
functional level.
Retained airway secretions and An accurate and valid assessment of respiratory conditions (retained airway se-
atelectasis  375 cretions, atelectasis, and respiratory muscle weakness), physical deconditioning,
Mechanically ventilated patients  375
Weaning failure  376 and related problems (muscle weakness, joint stiffness, impaired functional exer-
Early mobility and physical activity  376 cise capacity, physical inactivity, and emotional function) allows the identifying of
The uncooperative critically ill patient  378 targets for physiotherapy.
The cooperative critically ill patient  379 Evidence-​based targets for physiotherapy are deconditioning, impaired airway
Personal perspective  380
clearance, atelectasis, (re-​)intubation avoidance, and weaning failure. Early phys-
Acknowledgements  380
ical activity and mobility are key in the prevention, attenuation, or reversion of
Further reading  380 physical deconditioning related to critical illness. A variety of modalities for exer-
References  381 cise training and early mobility are evidence-​based and implemented, depending
on the stage of critical illness, comorbid conditions, and cooperation of the patient.
The physiotherapist should be responsible for implementing mobilization plans
and exercise prescription and make recommendations for their progression, jointly
with medical and nursing staff.

Introduction
Progress in intensive care medicine has dramatically improved the survival of critic-
ally ill patients, especially patients with ARDS [1]‌. This improved survival is, however,
oftentimes associated with general deconditioning, muscle weakness, dyspnoea, depres-
sion and anxiety, and reduced health-​related quality of life after ICU discharge [2,  3].
Deconditioning, and specifically muscle weakness, but not pulmonary function, is sug-
gested to have a key role in impaired functional status after ICU stay [2].
Optimal physiologic functioning depends on an upright position [4]‌, so bed rest and
limited mobility during critical illness result in profound physical deconditioning and
dysfunction of the respiratory, cardiovascular, musculoskeletal, neurological, renal, and
endocrine systems. These effects can be exacerbated by inflammation and pharmaco-
logical agents such as corticosteroids, neuromuscular blockers, and antibiotics. Skeletal
muscle weakness in the ICU (ICU-​AW) is observed in 25% of patients who were venti-
lated for >7 days [5]. The development of neuropathy or myopathy also contributes to
374 CHAPTER 30   Physioth erap y in  critically i l l pati en ts

weaning failure [6]. Finally, muscle weakness has been linked to following paragraphs, physiotherapy treatment will be discussed
increased mortality [7, 8]. in different clinical conditions.
Respiratory dysfunction is one of the most common causes
of critical illness, necessitating ICU admission. Failure of ei-
Prevention of post-​operative pulmonary
ther of the two primary components of the respiratory system
(i.e. the gas exchange membrane and the ventilatory pump) (see
complications (abdominal and thoracic
E Figure 30.1) can result in a need for mechanical ventilation. surgery)
Respiratory dysfunction includes impaired global and/​or regional The majority of patients undergoing major thoracic or abdominal
ventilation and lung compliance, and an increased airway resist- surgery recover without pulmonary complications. Preoperative
ance and work of breathing. Although most patients under mech- physiotherapy, including inspiratory muscle training, in cardiac
anical ventilation are extubated in <3  days, still approximately surgery patients with an increased risk profile for post-​operative
20% require prolonged ventilatory support [9]‌. Chronic venti- pulmonary complications reduced the development of post-​
lator dependence is a major medical problem, but it is also an operative pulmonary complications [13–​15], while others did not
extremely uncomfortable state for a patient, carrying important find this reduction in patients undergoing oesophageal resection
psychosocial implications. [16]. A  recent study showed a 50% reduction in post-​operative
Physiotherapists are involved in the prevention and treatment pulmonary complications in patients who received preopera-
of deconditioning and in the treatment of respiratory conditions tive face-​to-​face instructions on breathing exercises and early
in critically ill patients. Their role varies across units, hospitals, mobilization [17].
and countries [10] and is appreciated by medical directors, as After routine cardiac surgery, optimal post-​operative man-
well as patients. Physiotherapy assessment of critically ill pa- agement includes early mobilization and body positioning
tients is driven by deficiencies at a physiological and functional [18]. Further prophylactic physiotherapy interventions are
level and less by the medical diagnosis [11]. An accurate and not required in uncomplicated patients [19] or during intub-
valid assessment of respiratory conditions, deconditioning, and ation and mechanical ventilation [20]. Early mobilization and
related problems is of paramount importance for physiotherap- upright body positioning after major surgery is of primary
ists. In addition, physiotherapists can contribute to the patient’s importance to increase lung volume and prevent pulmonary
overall well-​being by providing emotional support and enhancing complications [21]. Routine breathing exercises should not
communication. be used following an uncomplicated coronary artery bypass
surgery. Perioperative physiotherapy should be instituted, if
warranted, e.g. in high-​risk patients, rather than administered
Respiratory conditions routinely. However, a meta-​analysis showed no added value of
physiotherapy (including breathing exercises) to the effective-
The aims of physiotherapy in respiratory dysfunction are to im- ness of early mobilization in high-​risk patients after abdominal
prove lung inflation, clear airway secretions, reduce the work of surgery [22].
breathing, and enhance inspiratory muscle function [12]. In the Incentive spirometry (IS) and NIV (CPAP) are frequently
used in the post-​operative setting. IS has not been shown to be
of added benefit (beyond physiotherapy, early mobilization, and
body position) in the routine management of post-​operative pa-
tients [23]. NIV has been used successfully to support patients
Respiratory insufficiency
following thoracotomy [24]. CPAP is effective in the treatment
of atelectasis, since it increases FRC and improves compliance,
minimizing post-​operative airways collapse. NIV has been shown
Lung failure Pump failure
to be superior to CPAP in the treatment of atelectasis in patients
after cardiac surgery [25]. Jaber et  al. reported in a prospective
Hypercapnia
Hypoxaemia
Hypoxaemia
study in patients who had respiratory failure after abdominal
surgery that the use of NIV decreased the rate of intubation to
Reduced regional Altered 67% and reduced mortality, compared to a group of patients who
ventilation respiratory drive were intubated [26]. In patients after solid organ transplantation
Reduced airway with acute respiratory failure and acute hypoxaemia, a significant
clearance/cough Mechanical defect reduction in the rate of endotracheal intubation, fatal complica-
tions, and mortality was observed in the NIV group, compared to
Impaired diffusion Neuromuscular
capacity dysfunction the oxygen group [27]. In 830 hypoxaemic patients after cardiac
surgery, high-​flow O2 therapy, compared to NIV, did not result in
V/Q mismatch a worse rate of treatment failure [28]. The official ERS/​ATS clin-
ical practice guideline recommended NIV only for patients with
Figure 30.1  Model of causes and consequences of respiratory insufficiency. post-​operative acute respiratory failure [29].
 Respi r atory  c on di t i on s 375

Retained airway secretions and atelectasis of physiotherapy has been confirmed in several studies [35, 36].
Chest wall vibration provided no additional benefit.
E Figure 30.2 provides an overview of pathways and treatment
modalities for increasing airway mucus clearance. Interventions
aimed at increasing the inspiratory volume (deep breathing ex- Mechanically ventilated patients
ercises, mobilization, and body positioning) may affect lung ex- In intubated and ventilated patients, manual hyperinflation
pansion, increase regional ventilation, reduce airway resistance, (MHI) or ventilator hyperinflation, PEEP ventilation, postural
and optimize pulmonary compliance. Interventions aimed at drainage, chest wall compression, and airway suctioning may as-
increasing the expiratory flow include forced expirations (huffing sist in secretion clearance. The aims of MHI are to prevent ven-
and coughing). Manually assisted cough, using thoracic or abdom- tilatory monotony and promote ventilation variability, which can
inal compression, may be indicated for patients with expiratory thus reduce the risk of atelectasis, re-​expand collapsed alveoli, im-
muscle weakness or fatigue [30]. Alternatively, in patients with an prove oxygenation and lung compliance, and facilitate the move-
ineffective cough due to impaired inspiratory volume, expiratory ment of airway secretions towards the central airways [37]. MHI
force, or glottis function, the mechanical insufflator–​exsufflator involves a slow, deep inspiration (maximal inspiratory pressure ±
(MI-​E) can be applied. The MI-​E device delivers adjustable posi- 40 cmH2O), with a manual resuscitator bag, an inspiratory hold
tive inspiratory pressures (+30–​60 cmH2O) and negative expira- of 2–​3 seconds [38], followed by a quick release of the bag to en-
tory pressures (–​30–​60 cm H2O) [31] to enhance lung inflation hance the expiratory flow and mimic a forced expiration. MHI
and increase the expiratory flow rate to mobilize bronchial secre- might have important negative side effects. MHI can precipitate
tions. The effectiveness of the MI-​E has been shown specifically marked haemodynamic changes associated with a decreased car-
in patients with neuromuscular disease and its application has diac output which is associated with a decrease in O2 delivery,
become more popular [32]. However, in the ICU population, the which result from large fluctuations in intrathoracic pressure
MI-​E did not improve secretion removal and respiratory mech- [39]. In addition, MHI can also increase the ICP, which could
anics [33] but increased extubation success significantly [34]. have implications for patients with brain injury. This increase in
Treatment of acute lobar atelectasis and airway clearance should ICP may lead to a decrease in CPP. However, this increase is usu-
incorporate body positioning and techniques to increase the in- ally limited, such that the continuous perfusion pressure remains
spiratory volume and enhance forced expiration. The effectiveness stable [40]. A pressure of 40 cmH2O has been recommended as

Retained airway secretions

Increase inspiratory Increase expiratory Oscillation Increase expiratory Airway suctioning

volume flow rate volume

Mobilization Positioning Percussion Positioning

Positioning Coughing/huffing Manual or mechanical CPAP

vibration

Breathing exercises Assisted coughing PEP

HFO/IPV/flutter

Incentive spirometry Exsufflator

Non-invasive
ventilation
insufflator

Manual or ventilator
hyperinflation

Figure 30.2  Pathways and treatment modalities for increasing airway clearance. PEP, positive expiratory pressure; CPAP, continuous positive airway pressure;
HFO, high-​frequency oscillation; IPV, intrapulmonary percussive ventilation.
Reproduced from Gosselink R, Bott J, Johnson M, et al. Physiotherapy for adult patients with critical illness: recommendations of the European Respiratory Society and European
Society of Intensive Care Medicine Task Force on Physiotherapy for Critically Ill Patients. Intensive Care Med 2008;34(7):1188–​1199. doi:10.1007/​s00134-​008-​1026-​7 with permission
from Springer Nature.
376 CHAPTER 30   Physioth erap y in  critically i l l pati en ts

an upper limit. Two studies in ventilated patients reported that

Box 30.1  Criteria for weaning
bronchoscopy offered no additional benefit over physiotherapy
(postural drainage, percussion, MHI, and suctioning) in the man- Maximal inspiratory pressure >20 cmH2O
◆

agement of acute lobar atelectasis [41, 42]. Minute ventilation <15 L/​min

◆
Airway suctioning may have detrimental side effects (bron- Respiratory frequency <25 breaths/​min
◆
chial lesions, hypoxaemia), but reassurance, sedation, and pre-​ Rapid shallow breathing index (f/​VT) <105
◆
oxygenation of the patient may minimize these effects [43]. PaO2/​FiO2 >200
◆
Suctioning can be performed via an in-​line closed suctioning
system or an open system. The in-​line system does not appear
to decrease the incidence of ventilator-​associated pneumonia score’ has been developed, based on the quality of the patient’s
(VAP) [44] nor the duration of mechanical ventilation, length cough during airway suctioning, the absence of ‘excessive’ secre-
of ICU stay, or mortality [45], but it does increase costs. Closed-​ tions, and the frequency of airway suctioning [54]. NIV can fa-
system suctioning is mainly used in patients with ARDS who cilitate weaning [57], reduces ICCU costs [58], and is effective in
have a high level of FiO2 and a high level of PEEP in order to preventing post-​extubation failure in patients at risk [59].
reduce the risk of alveolar derecruitment. This procedure may be Inspiratory muscle training might be beneficial in patients with
less effective than open suctioning for secretion clearance during weaning failure. There is accumulating evidence that weaning
pressure support ventilation [45]. Routine instillation of normal problems are associated with failure of the respiratory muscles
saline before airway suctioning has potential AEs on O2 satur- to resume ventilation [60]. Two meta-​analyses on inspiratory
ation and cardiovascular stability, and variable results in terms of muscle training (see E Figure 30.3) observed improvement
increasing the sputum yield [46]. Chest wall compression prior in inspiratory muscle function and a reduction in the duration
to endotracheal suctioning did not improve airway secretion re- of mechanical ventilation and weaning time in patients with
moval, oxygenation, or ventilation after endotracheal suctioning weaning failure [61, 62]. In addition, biofeedback to display the
in an unselected population of mechanically ventilated patients breathing pattern has been shown to enhance weaning [63]. Voice
[47]. VAP is a common complication in mechanically ventilated and touch may be used to augment weaning success, either by
patients and is associated with higher mortality rates, prolonged stimulation to improve the ventilatory drive or by reducing anx-
hospitalization, and high medical costs [48]. Studies have shown iety [64]. Environmental influences, such as ambulating with a
that the avoidance of intubation with NIV reduces the incidence portable ventilator, have been shown to benefit attitudes and out-
of nosocomial pneumonia [49,  50]. Physiotherapy, including looks in long-​term ventilator-​dependent patients [65].
MHI, positioning plus suctioning, showed no differences in VAP,
compared to suctioning alone [51]. Yet, in contrast, another study
reported a significantly lower incidence of VAP (8% versus 39%)
in the group receiving physiotherapy [52]. However, the duration Early mobility and physical activity
of mechanical ventilation, length of ICU stay, and mortality were The mentioned changes in functional performance and periph-
not significantly different between the groups. A  recent meta-​ eral and respiratory muscle function indicate the need for re-
analysis concluded that multimodality respiratory physiotherapy habilitation following ICU stay but also underscore the need for
reduced mortality in ventilated patients but did not prevent VAP assessment and measures to prevent deconditioning and the loss
or reduce length of stay in the ICU [53].

Weaning failure
Only a small proportion of patients fail to wean from mechan-
ical ventilation, but they require a disproportionate amount of
resources. A therapist-​driven weaning protocol was shown to re-
duce the duration of mechanical ventilation and ICU cost [54].
An SBT can be used to assess the readiness for extubation with
the performance of serial measurements such as tidal volume, re-
spiratory rate, maximal inspiratory airway pressure, and the rapid
shallow breathing index [55]. Early detection of worsening clin-
ical signs, such as distress, airway obstruction, and paradoxical
chest wall motion, ensures that serious problems are prevented
(see E Box 30.1). Airway patency and protection (i.e. an effective
cough mechanism) should be assessed prior to commencement
of weaning. Peak cough flow is a useful parameter to predict suc-
cessful weaning in patients with neuromuscular disease or spinal Figure 30.3  Inspiratory muscle training with tapered flow-​resistive loading
cord injury when extubation is anticipated [56]. An ‘airway care in a patient weaning from mechanical ventilation.
 Ea rly mob i l i t y a n d physi ca l   ac t i v i t y 377

of physical function during ICCU stay. The amount of rehabili- It is important to prevent or attenuate muscle deconditioning
tation performed in ICUs is often inadequate, and as a rule, re- as early as possible in patients with expected prolonged bed rest
habilitation is better organized in weaning centres or respiratory [71]. Scientific and clinical interest and evidence have given sup-
ICUs [66, 67]. The major reason is that the approach in rehabilita- port for a safe and early physical activity and mobilization ap-
tion is less driven by the medical diagnosis; instead, rehabilitation proach towards the critically ill patient by ICU team members
focuses on deficiencies in the broader scope of health problems, [68–​70, 72–​75].
as defined in the International Classification of Functioning, Exercise training is considered a cornerstone component of
Disability, and Health. This leads to the identification of prob- each rehabilitation programme, in addition to psychosocial inter-
lems and the prescription of one or more interventions at a level ventions. An accurate assessment of the cardiorespiratory reserve
of body structure and function, as well as activities and partici- and rigorous screening for other factors that could preclude early
pation. Members of the rehabilitation team in the ICU (doctors, mobilization is of paramount importance.
physiotherapists, nurses, and occupational therapists) should be E Figure 30.4 outlines the steps involved in the safe mobiliza-
able to prioritize and identify the aims and parameters of treat- tion of critically ill patients [76]. In addition to the assessment of
ments, ensuring that these are both therapeutic and safe by appro- the safety and readiness of the patient for exercise and physical
priate monitoring of vital functions [66]. This team approach has activity, specific measures of function (e.g. muscle strength, joint
been shown to be effective [68–​70]. mobility), functional status (functional independence measure,

MOBILIZING CRITICALLY ILL PATIENTS

REVIEW MEDICAL BACKGROUND

• Past medical history or recent symptoms of cardiovascular/respiratory dysfunction
• Medications which may affect response to mobilization
• Previous level of mobility and exercise capacity

IS THERE SUFFICIENT CARDIOVASCULAR RESERVE?

• Resting heart rate <50% age-predicted maximal heart rate
• Blood pressure <20% variability recently
• ECG normal (i.e. no evidence of MI or arrhythmia)
• Other major cardiac conditions excluded

Defer mobilization or Discuss with

discuss with medical NO UNSURE medical staff
staff
YES

IS THERE SUFFICIENT RESPIRATORY RESERVE?

• PaO2/FIO2 >300, SpO2 >90% and <4% recent decrease in SpO2
• Respiratory pattern satisfactory
• Mechanical ventilation able to be maintained during treatment

Defer mobilization or Discuss with

discuss with medical medical staff
NO UNSURE
staff
YES

ARE OTHER FACTORS FAVOURABLE?

• No orthopaedic or neurological contraindications No attachments that contraindicate mobilization
• No recent SSG/flap to lower limbs or trunk Safe environment, appropriate staffing, and expertise
• Medically stable if DVT and/or PE Patient appearance, pain, fatigue, shortness of breath,
emotional and conscious status acceptable, consent

• Body temperature <38°C

• Blood glucose level 3.5–20 mmol/L

Defer mobilization or Discuss with

discuss with medical medical staff
NO UNSURE
staff

YES

SELECT APPROPRIATE MODE AND INTENSITY OF MOBILIZATION, MONITORING EQUIPMENT, AND PROCEED

Figure 30.4  Overview of safety issues before mobilizing critically ill patients.

Reproduced from Stiller K, Philips A. Safety aspects of mobilising acutely ill patients. Physioth Theory Pract 2003;19:239–​57 with permission from Taylor and Francis.
378 CHAPTER 30   Physioth erap y in  critically i l l pati en ts

Berg balance scale, functional ambulation categories), and Gosselink et al. [77] (see E Figure 30.5) has face validity and is
quality of life (e.g. SF-​36, disease-​specific questionnaires) must be an example of such a step-​up approach.
considered.
Physical activity and exercise should be targeted at the ap-
propriate intensity and exercise modality. These will be de- The uncooperative critically ill patient
pendent on the stability and cooperation of the patient. The The importance of body positioning (‘stirring up’ patients) was
risk of moving a critically ill patient is weighed against the risk reported as early as the 1940s [71]. To simulate the normal per-
of immobility and recumbency and, when employed, requires turbations that the human body experiences in health, the patient
stringent monitoring to ensure mobilization is instituted ap- who is critically ill needs to be positioned upright (well sup-
propriately and safely [76]. Acutely ill, uncooperative patients ported) and rotated when recumbent. These perturbations need
will be treated with modalities, such as passive range of motion, to be scheduled frequently to avoid the AEs of prolonged static
muscle stretching, splinting, body positioning, passive cycling positioning on the respiratory, cardiac, and circulatory function.
with a bed cycle, or electrical muscle stimulation (EMS), that Other indications for positioning include management of soft
will not need cooperation of the patient and will not put stress tissue contracture, protection of flaccid limbs and lax joints, nerve
on the cardiorespiratory system. On the other hand, the stable impingement, and skin breakdown. The efficacy of 2-​hourly pa-
cooperative patient, beyond the acute illness phase, but still tient rotation, which is common in clinical practice, has not been
on mechanical ventilation, will be able to be mobilized on the verified scientifically. Bed design features in critical care should
edge of the bed, transfer to a chair, perform resistance muscle include hip and knee breaks, so the patient can approximate up-
training or active cycling with a bed cycle or chair cycle, and right sitting as much as can be tolerated. Heavy-​care patients,
walk with or without assistance. The flow diagram developed by such as those who are sedated, heavy, or overweight, may need

1S5Q: response to five standardized questions for cooperation:

• Open and close your eyes

• Look at me
• Open your mouth and stick out your tongue
• Shake yes and no (nod your head)
• I will count to 5, frown your eyebrows afterwards
2: FAILS when at least one risk factor is present
3: if basic assessment failed, decrease to level 0
4: safety: each activity should be deferred if severe adverse events (CV, resp, and subject intolerance)
occur during the intervention

MRC (Medical Research Council) muscle strength sum scale (0–60)

BBS: Berg Balance Score
SITTING TO STANDING
4 able to stand without using hands and stabilize independently
3 able to stand independently using hands
2 able to stand using hands after several tries
1 needs minimal aid to stand or stabilize
0 needs moderate or maximal assist to stand

STANDING UNSUPPORTED
4 able to stand safely for 2 minutes
3 able to stand for 2 minutes with supervision
2 able to stand for 30 seconds unsupported
1 needs several tries to stand for 30 seconds unsupported
0 unable to stand for 30 seconds unsupported

SITTING WITH BACK UNSUPPORTED BUT FEET SUPPORTED ON FLOOR OR ON A STOOL

4 able to sit safely and securely for 2 minutes
3 able to sit for 2 minutes under supervision
2 able to sit for 30 seconds
1 able to sit for 10 seconds
0 unable to sit without support for 10 seconds

Figure 30.5  ‘Start to move’ protocol, University Hospital Leuven. A step-​up approach of progressive mobilization and physical activity programme.
Reproduced from Gosselink, R., Robbeets, Gosselink R, Robbeets C, Vanhullenbusch T, Vanpee G, Segers J. (2011). ‘Physiotherapy in the Intensive Care Unit.’ Neth J Int Care 15:2 with
permission from Nederlandse Vereniging voor Intensive Care.
 Ea rly mob i l i t y a n d physi ca l   ac t i v i t y 379

chairs with greater support such as stretcher chairs. Lifts may be found beneficial effects of NMES on muscle mass and strength,
needed to change a patient’s position safely. while others [84, 85] could not confirm these results.
Passive stretching or range of motion exercise may have a
particularly important role to counterbalance the ‘silencing’ of The cooperative critically ill patient
muscles in the management of sedated patients who are unable Mobilization and ambulation have been part of the physio-
to move spontaneously. Continuous passive motion (CPM) pre- therapy management of acutely ill patients for several decades.
vents contractures and has been assessed in patients with critical Mobilization refers to physical activity sufficient to elicit acute
illness subjected to prolonged inactivity [78, 79]. Three hours of physiological effects that enhance ventilation, central and per-
CPM three times daily reduced fibre atrophy and loss of muscle ipheral perfusion, circulation, muscle metabolism, and alertness.
strength, compared with passive stretching for 5 minutes twice Strategies—​in order of intensity—​include sitting over the edge of
daily [78, 79]. For patients who cannot be actively mobilized and the bed, standing, stepping in place, transferring in bed and from
have a high risk of soft tissue contracture, such as following severe bed to chair, and walking with or without support. The approach
burns, trauma, and some neurological conditions, splinting may of early mobilization has been studied in RCTs [68, 70,  75].
be indicated. Morris et al. [70] demonstrated that patients receiving early mo-
The application of exercise training in the early phase of ICU bility therapy had a reduced ICU stay and hospital stay, with no
admission is often more complicated due to a lack of cooperation differences in weaning time. No differences were observed in dis-
and the clinical status of the patient. Recent technological devel- charge location or in hospital costs. Schweickert et al. observed
opment has resulted in a bedside cycle ergometer for (active or that early physical and occupational therapy improved functional
passive) leg cycling during bed rest (see E Figure 30.6). The bed- status at hospital discharge, shortened the duration of delirium,
side cycle ergometer can perform prolonged continuous mobiliza- and increased the ventilator-​free days. These findings did not
tion, allowing rigorous control of exercise intensity and duration. result in differences in the length of ICU or hospital stay [68].
Furthermore, the training intensity can be continuously adjusted Overall, early mobilization and rehabilitation in the ICU has no
to the patient’s health status and the physiological responses to impact on short-​and long-​term mortality but may improve mo-
exercise. Early application of daily in-​bed leg cycling in critically bility status, muscle strength, and days alive and out of hospital to
ill patients showed improved functional status, muscle function, 180 days [86].
and exercise performance at hospital discharge, compared to pa- The team approach (doctor, nurse, physiotherapist, and occupa-
tients receiving standard physiotherapy without leg cycling [73]. tional therapist) is an important and strong point in establishing
In patients unable to perform voluntary muscle contractions, an early ambulation programme. The costs of this approach out-
EMS has been used to prevent disuse muscle atrophy. Results of weigh the benefits. The early intervention approach is, although
studies on neuromuscular electrical stimulation (NMES) in crit- not easy, specifically in patients still in need of supportive de-
ically ill patients are, however, conflicting. Several studies [80–​83] vices (mechanical ventilation, cardiac assists) or unable to stand
without support of personnel or standing aids, a worthwhile ex-
perience for the patient [70, 72]. This difference in mentality of
the team was elegantly demonstrated in the study by Thomsen
et al. [66]. Transferring a patient from acute intensive care to the
respiratory ICU substantially increased the number of patients
ambulating (by threefold), compared with pre-​ transfer rates.
Improvements in ambulation with transfer to the respiratory ICU
were allocated to differences in the team approach towards ambu-
lating the patients [66].
Standing and walking frames (see E Figure 30.7) enable the
patient to mobilize safely with attachments for bags, lines, and
leads that cannot be disconnected. The frame needs to be able to
accommodate either a portable O2 tank or a portable mechanical
ventilator and seat, or a suitable trolley so equipment can be used.
Walking and standing aids and tilt tables enhance physiological
responses and promote early mobilization of critically ill patients.
Transfer belts facilitate heavy lifts and protect both the patient
and the nurse and physiotherapist. In ventilated patients, the ven-
tilator settings may require adjustment to the patient’s needs (i.e.
increased minute ventilation).
Aerobic training and muscle strengthening, in addition to
Figure 30.6  Device for active and passive cycling in a bedridden patient in routine mobilization, improved the walking distance more than
intensive care. mobilization alone in ventilated patients with chronic critical
380 CHAPTER 30   Physioth erap y in  critically i l l pati en ts

capacity, ranging from passive cycling, via assisted cycling, to cyc-

ling against increasing resistance.

Personal perspective
Physiotherapy practice needs to be further utilized in this
highly technological, highly invasive, and costly health care
setting. Evidence exists to support the use of physiotherapy
in ICCU patients, and given this knowledge base, clinical
RCTs with untreated controls would be unethical. The use of
multicentre studies may allow ethical comparisons between
differing physiotherapy strategies in different units, but dif-
ferences in patient characteristics between ICCUs may con-
found the results. In addition to the traditional outcome
measures of the direct effects of physiotherapy interventions
on outcomes, such as oxygenation, lung mechanics, the
rate of respiratory complications, weaning success, muscle
strength, and joint mobility, quality of life outcomes and
functional outcomes at all levels of care should be included.
Critical care, as a whole, has lagged behind, compared
with less acute settings, with respect to inclusion of the
evaluation of these outcomes. Reducing the length of ICCU
Figure 30.7  Walking frame to assist a ventilator-​dependent patient.
and hospital stays are outcomes highly consistent with the
goals of physiotherapy, i.e. to exploit the non-​invasive inter-
illness [67]. An RCT showed that a 6-​week upper and lower limb ventions of care and minimize invasive care as much as
training programme improved limb muscle strength, ventilator-​ possible. This outcome should be associated with reduced
free time, and functional outcomes in patients requiring long-​ health care costs, undoubtedly an important outcome.
term mechanical ventilation, compared to a control group [87]. Physiotherapy might also improve functional outcome after
These results are in line with a retrospective analysis of patients an ICCU stay that should, in turn, reduce health care costs.
on long-​term mechanical ventilation who participated in whole-​ Future studies of the efficacy of physiotherapy need to
body training and respiratory muscle training [88]. In patients include the duration of ICU stay as an essential outcome,
recently weaned from mechanical ventilation [89], the addition recognizing that this measure will be influenced by the care
of upper limb exercise enhanced the effects of general mobiliza- provided by other team members. Further study is required
tion on exercise endurance performance and dyspnoea. Multiple to determine which components of physiotherapy are most
repetitions of low-​resistance resistive muscle training can aug- effective in resolving atelectasis and whether optimal lung
ment muscle mass, force generation, and oxidative enzymes. Sets recruitment, positioning, and mobilization are effective in
of repetitions within the patient’s tolerance can be scheduled both prevention and treatment of atelectasis. Last, but not
daily, commensurate with their goals. Resistive muscle training least, further evaluation of physiotherapy interventions,
can include the use of pulleys, elastic bands, and weight belts. such as inspiratory muscle training and early mobilization
Patients with cardiovascular dysfunction may benefit from re- or exercise training, in the treatment of difficult-​to-​wean
sistance training, although a high resistance of large muscle critically ill patients is needed.
masses may have detrimental cardiovascular effects in elderly
subjects with CVD [90].
The chair cycle and bed cycle mentioned earlier allow patients
ACKNOWLEDGEMENTS
to perform an individualized exercise training programme. The This work is partially funded by FWO grant GOA4516N and KU
intensity of cycling can be adjusted to the individual patient’s Leuven grant C22/​15/​035.

Further reading
Burtin C, Clerckx B, Robbeets C, et  al. Early exercise in critically ill Gosselink R, Bott J, Johnson M, et  al. Physiotherapy for adult patients
patients enhances short-​ term functional recovery. Crit Care Med with critical illness:  recommendations of the European Respiratory
2009;37:2499–​505. Society and European Society of Intensive Care Medicine Task
De Jonghe B, Sharshar T, Lefaucheur JP, et al. Paresis acquired in the intensive Force on Physiotherapy for Critically Ill Patients. Intensive Care Med
care unit: a prospective multicenter study. JAMA 2002;288:2859–​67. 2008;34:1188–​99.
 RE F E RE N C E S 381

Herridge MS, Cheung AM, Tansey CM, et  al. One-​year outcomes in Ntoumenopoulos G, Presneill JJ, McElholum M, Cade JF. Chest
survivors of the acute respiratory distress syndrome. N Engl J Med physiotherapy for the prevention of ventilator-​associated pneumonia.
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 SECTION V

The laboratory
in intensive and acute
cardiovascular care

31 The use of biomarkers for acute cardiovascular disease  387

Allan S Jaffe
32 Biomarkers in acute coronary syndromes  400
Jasper Boeddinghaus, Thomas Nestelberger, Raphael Twerenbold, and Christian Mueller
33 Biomarkers in acute heart failure  409
Rajiv Choudhary, Nicholas Wettersten, Kevin Shah, and Alan Maisel
34 Biomarkers of coagulation and thrombosis  425
Anne-​Mette Hvas, Erik L Grove, and Steen Dalby Kristensen
35 Biomarkers of renal and hepatic failure  434
Mario Plebani, Monica Maria Mion, and Martina Zaninotto
 CHAPTER 31

The use of biomarkers

for acute cardiovascular
disease
Allan S Jaffe

Contents
Summary  387 Summary
Introduction  387 Understanding the proper use of biomarkers requires clinicians to appreciate some
Principles guiding the use of biomarkers in critical pre-​analytic and analytic issues, as well as how to use the markers prop-
acute cardiac care  389
erly. The benefits of such an approach will not only facilitate the care of patients
Pre-​analytic factors  389
Analytic factors  389 today, but also prepare clinicians to understand and embrace the new generation
Normal value issues  391 of markers that is coming and that will continue to make this area transformational
Issues of interpretation  392
Cardiac troponin  392
for cardiology. Two fundamental concepts underlie the clinical use of biomarkers.
Natriuretic peptides  392 First, biomarkers should always be used in conjunction with all other clinical in-
C-​reactive protein  392 formation. Second, in order to maximize their diagnostic and prognostic use, bio-
Contemporary issues with the use of acute markers should be interpreted as quantitative variables. For example, a cardiac
cardiovascular biomarkers  393
Sensitivity and detection of new disease
troponin level which is 50 times the upper limit of normal has a much higher posi-
entities  393 tive predictive value for the presence of an acute myocardial infarction, compared
Issues of organ versus clinical specificity  393 to a level just above the upper limit of normal.
Difficulties with legacies from the past  393
The future  394
Personal perspective  394
Acknowledgements  394
Further reading  394
References  395 Introduction
Additional online material  399
Cardiac biomarkers are used extensively to evaluate patients with acute CVD. They fa-
cilitate the diagnosis of cardiac injury, and thus AMI, as well as haemodynamic cardiac
stress, and thus heart failure. They are instrumental in risk stratification in these acutely
ill patients.
Over the years, the use of these markers has evolved. The first approach evolved when
it was noted that CRP levels rose in patients with AMI [1]‌. Subsequently, the work of
Carmen et  al. in the 1950s described increases in aspartate transaminase [also called
serum glutamic-​oxaloacetic transaminase (SGOT)] [2] and LDH levels [3] in patients
with AMI. At that time, these biomarkers were not considered to be important diagnos-
tically because of their lack of specificity. This changed somewhat with the development
of assays for total creatine kinase (CK) [4]. The use of these markers promulgated by the
work of Sobel et al. enabled the estimation of infarct size [5], which provided potent prog-
nostic information [6]. Subsequently, creatine kinase myoband (CK-​MB) assays [7,  8]
further facilitated the use of cardiac biomarkers. Troponin assays initially were developed
in the 1990s [9, 10] to deal with the problems of specificity seen with CK-​MB, which are
frequent in patients with skeletal muscle disease [11]. In addition, troponin assays are
388 CHAPTER 31   The u se of  biomarkers f or acu te ca rdi ovas cu l a r di sease

substantially more sensitive, leading to many of the issues that the convertases that process proBNP unable to function [25].
still complicate their use today [12]. Increases in the sensitivity of It appears that this problem is less severe in AHF and worse in
cTn assays have continued, while not diminishing their specificity chronic heart failure, perhaps explaining the differences in kin-
for the heart [13]. To qualify as ‘high sensitivity’, assays should etics of BNP in these two situations [26, 27] (see E Figure 31.3).
measure values in over 50% of normal healthy subjects [14] (see In the case of CRP, de Beer et al. [28] and Liuzzo et al. [29] were
E Figure 31.1). However, these novel assays identify many new the first to demonstrate its use to risk-​stratify patients with ACS,
reasons for cTn elevations and thus reduce the specificity of any expanding the data that inflammation was important in acute
given elevation for ischaemic heart disease [15]. CAD [30], using an assay that had been developed for use in in-
In the case of heart failure, it was the appreciation of the endo- fection [30]. CRP is a product of the IL1-​β inflammasome and an
crine nature of the heart itself [16] and, with it, the description of acute phase reactant [1]‌. Therefore, the confounding high levels
atrial natriuretic peptide (ANP) by de Bold et al. [17] that stimu- of CRP are found as a response to necrosis, which may explain
lated the field. The discovery of brain natriuretic peptide (now B-​ some of the prognostic information [31] (see E Figure 31.4).
type natriuretic peptide or BNP) accelerated the use of natriuretic Biomarkers are integral to our diagnostic armamentarium.
peptides as diagnostic markers. However, it did not become ex- Troponin is the marker of choice for the evaluation of patients
tensively used, until a point-​of-​care assay for BNP was developed with possible cardiac injury [32]. Its specificity is high, with rare
[18], which allowed for the Breathing Not Properly trial [19]. exceptions [33], and assays have been improved to reduce the fre-
The trial evaluated the ability of ED physicians to diagnose heart quency of analytic false positives [13]. CK-​MB no longer has a role
failure and compared their diagnostic abilities to that of BNP. The in the evaluation of cardiac patients [34]. BNP has also emerged as
data (see E Figure 31.2) suggested that BNP was modestly su- a valuable marker [12]. Using it in patients with an intermediate
perior to clinical judgement and that the combination added to probability of disease optimizes its cost-​effectiveness [35]. Data
the diagnostic accuracy (from 74% to 81.5%). Over time, cardi- with NT-​proBNP have perhaps really come closer to the mark of
ologists too began to use BNP to assist in the diagnosis of heart clinical utility by using multiple cut-​offs which have recently been
failure. This was facilitated when the prognostic value of the reaffirmed [36]. This is also true for BNP where there is a sub-
marker was documented [20, 21]. Subsequently, a large number stantial grey zone for values between 100 and 500 pg/​mL [37].
of BNP assays, based on different antibodies, and an assay for The use of CRP has also progressed with explanations for the
the NT-​profragment of BNP (NT-​proBNP) were developed. NT-​ late prognostic significance. In PROVE-​IT, continuing increases
proBNP, a 76-​amino acid peptide, is produced when the proBNP in CRP, as well as inadequate treatment of LDL cholesterol, were
is cleaved [22]. We now know that the high values of natriuretic associated with adverse events. CRP was related to comorbid-
peptides reflect a dysfunction in the system and that much of the ities that are associated with increased inflammation such as dia-
circulating protein is uncleaved proBNP or degradation products betes, obesity, smoking, and a lack of exercise [38]. It is now clear
of BNP or NT-​proBNP which the assays detect [23, 24]. Some of from the CANTOS trial how important inflammation is in the
this dysfunction is due to failure of deglycosylation which renders pathobiology of coronary heart disease (CHD) [39].

Singulex hsTnl 100

sensitivity

ARCHITECT hsTnl 96
assays
High-

Siemens hsTnl 86
Beckman Access hsTnl 80
Roche hsTnT 25
Beckman Tnl 35
Siemens Tnl Ultra (Centaur) 6
Contemporary

Siemens Tnl (Immulite) 5

AxSYM TnI 3
assays

ARCHITECT TnI 2
OCD TnI 2
Siemens TnI (Dimension) 2
Roche TnI 1
Siemens TnI (Vista) 1
IL cTnI 28
Point-of-

Abbott I STAT 6
assays
care

Siemens Stratus 2
Alere 1
BioMerleux 1
0 20 40 60 80 100
Detected (%)

Figure 31.1  Percentage of normal subjects detected by various cTn assays presently in use. To qualify as a high-​sensitivity assay, at least 50% of normal subjects
should be detected.
Reproduced from Apple FS, Ler R, Murakami MM. Determination of 19 cardiac troponin I and T assay 99th percentile values from a common presumably healthy population. Clin
Chem 2012;58(11):1574–​1581. doi:10.1373/​clinchem.2012.192716 with Oxford University Press.
 Principles g u i di n g the u se of b i o m a rk er s i n  acu te ca rdiac   c a re 389

ED probability of CHF reported

Principles guiding the use of
Clinical judgement 74.0%
biomarkers in acute cardiac care
BNP 81.2% Understanding the principles relating to how biomarkers are col-
lected and analysed is critical for clinicians. If they are not under-
Combined 81.5%
stood, clinicians will have difficulty in interpreting the results.
Information relevant to the use of BNP, troponin, and CRP is in-
cluded as examples.
70 72 74 76 78 80 82
Diagnostic accuracy (%)
Pre-​analytic factors
Figure 31.2  Accuracy for the diagnosis of heart failure in the ED, based on
clinical judgement, BNP, and their combined use. n = 1538; P >0.0001 from How samples are obtained is critical to the measurement of every
clinical judgement to combined. analyte. When samples are drawn through indwelling lines or if
Reproduced from McCullough PA, Nowak RM, McCord J, et al. B-​type natriuretic contaminating fluids are not removed or adhere to the tubing,
peptide and principles guiding the use of biomarkers in acute cardiac care clinical
judgment in emergency diagnosis of heart failure: analysis from Breathing Not Properly
they can cause alterations in values. For example, in patients re-
(BNP) Multinational Study. Circulation 2002;106(4):416–​422 with permission from ceiving catecholamines, this effect lowers creatinine levels [40].
Wolters Kluwer. This is worse with venous lines and has the potential to delay care
[41]. Major pre-​analytic issues in acute cardiology predominantly
involve troponin and BNP; CRP seems to be reasonably stable.
Troponin is affected and differentially measured in hep-
arin versus non-​heparinized samples [42,  43]. The troponin T
assay was reconfigured to avoid this issue [44]. Values of high-​
Normal Acute HF Chronic HF sensitivity cardiac troponin T (hs-​cTnT) are lowered when haem-
↑ PreproBNP ↑ PreproBNP olysis is present [45]. Troponin I  assays have similar problems
[42, 43]. In addition, there can be differences between serum and
PreproBNP ↑ ProBNP ↑ ProBNP
plasma, independent of heparin [46] (see Figure 31.12). This
Glycosylation Glycosylation may not be very important with insensitive assays, but for highly
Heart sensitive assays, especially where there is a need to evaluate chan-
Circulation Gly proBNP ↑ Non-Gly proBNP ↑ Gly proBNP Non-Gly proBNP ging patterns [47], the differences could be key.
↑ Furin ↑ Furin ↑ Furin
Corin Corin Corin BNP is a fastidious molecule. Some have argued that it requires
BNP (BNP) (BNP) specific protease inhibitors to preserve activity [48], but most
BNP active state BNP deficient state
samples collected on ethylenediaminetetraacetic acid (EDTA)
and ice provide adequate results, if measured expeditiously [49].
Figure 31.3  Schema of proBNP processing in the progression of heart Even samples on ice for prolonged periods degrade [50]. This
failure. BNP, brain natriuretic peptide; HF, heart failure. is one advantage of NT-​proBNP, which is extremely stable [51].
These issues are even more important with long-​term storage.
BNP values diminish, even if stored at –​70°C [51].
100%
90%

80%
Analytic factors
There are a variety of analytic issues to consider. The first is sen-
60%
60% sitivity. This is not a problem for CRP or BNP assays, but it is for
Frequency

45% troponin assays [52]. This issue cannot be evaluated by looking

40%
30% at values for the assays, since there is no standardization. The
20% 18% standard reference material that is used in cTn assays, made by
the National Institute of Standards and Technology (NIST), does
0%
0% not adequately harmonize troponin assays [53].
Angina Revasc D/MI
What are needed are direct clinical comparisons to compare
CRP 3 mg/L CRP >3 mg/L the sensitivity of one assay to another. Recently, the metric of how
Figure 31.4  Relationship of CRP elevations at the time of admission with many apparently putatively normal healthy individuals are meas-
unstable angina and subsequent events. CRP, C-​reactive protein; D/​MI, death ured by a given assay has been proposed as a surrogate [52]. All of
or myocardial infarction. these comparisons depend on using the appropriate cut-​off value
Source data from Liuzzo G, Biasucci LM, Gallimore JR, et al. The prognostic value of C-​
which is often something that is not done [54–​56], which exag-
reactive protein and serum amyloid A protein in severe unstable angina. N Engl J Med
1994;331(7):417–​424. doi:10.1056/​NEJM199408183310701. gerates the differences seen in clinical studies [54]. In addition,
390 CHAPTER 31   The u se of  biomarkers f or acu te ca rdi ovas cu l a r di sease

many articles touting the use of other markers have used insensi- 1
tive assays or high cut-​off values as comparators, which can make 2
3
the data for a given marker appear better than it is [54].

Participant number
4
This issue of cut-​off values for troponin has been confusing to 5
clinicians. The initial assays for troponin were approved as what 6
7
is known as the ROC cut-​off where troponin was equivalent to 8
CK-​MB in diagnostic performance [56]. Subsequently, the ESC 9
and the ACC [57] suggested that troponin should be used like 10
11
any other analyte, i.e. based on the distribution of normal values. 12
It requires at least 300 subjects to determine a ‘normal’ reference
0.0 1.0 2.0 3.0 4.0 5.0 6.0
range [58]. Since the biomarker values are skewed, the values cTnI (ng/L)
usually need to be normalized by logarithmic transformation to
Figure 31.6  Short-​term biological and analytical variation with the high-​
determine a cut-​off value. The Biochemistry group of the Global sensitivity Singulex assay.
Task Force of the ACC/​ESC Task Force [59] suggested using three Reproduced from Wu AH, Smith A. Biological variation of the natriuretic peptides and
SDs from the mean, so that there would be only 1% of putative their role in monitoring patients with heart failure. Eur J Heart Fail 2004;6(3):355–​358.
doi:10.1016/​j.ejheart.2003.12.011 with permission from John Wiley and Sons.
false positives, might be best. With contemporary cTn assays (not
high-​sensitivity), the 99% value is still substantially higher than
values seen in normals [13]. The accuracy of the ‘normal’ refer- modest imprecision (up to 20%) made little difference to the diag-
ence range depends on how well the individuals used for this pur- nosis or prognosis [62, 63].
pose are screened. Recent data suggest that imaging is necessary However, precision does affect the evaluation of a changing
to be sure hs-​cTn normal values are correct [60, 61]. pattern. In general, the difference between values analytically
The issues of sensitivity are often confused with the issues of is three SDs of the variation around those values [32]. Thus, a
precision, i.e. how accurately one measures a given analyte. Some greater imprecision leads to larger differences in deltas. With
groups have advocated a low degree of imprecision near the cut-​ very high-​sensitivity assays, where one can begin to measure bio-
off value for troponin [32,  59], and if not achieved, some have logical variability (BV), one can add BV to the assays. This makes
even advocated raising the cut-​off value [56]. This has never been the values slightly higher. BV (see E Figure 31.6) for hs-​cTn
endorsed by guideline groups [32, 57, 59]. Some have suggested was first measured by Wu et al. [64]. It cannot be measured for
that imprecision is why minor elevations in troponin are ‘false contemporary assays, but only hs-​cTn assays which measure
positives’. This is not correct. If the assay is properly validated, normal values in the vast majority of patients [65]. Delta change
imprecision will make the upper limit of the normal range higher, values, be they relative or absolute, that are less than the conjoint
protecting against false positives [62]. This has been tested for biological and analytical variation, will invariably compromise
both troponin and BNP (see E Figure 31.5). In both instances, specificity, in an attempt to maximize sensitivity (see E Figure
31.7) [15]. This is a major problem with some of the recently
suggested proposals for ruling out and ruling in AMI [66]. With
1
troponin, some suggest that a 20% change [67] with some as-
0.9 says and a 30% change with others [68] are significant. In fact,
0.8

0.7
100 100
0.6
Probability

0.5 80 80
Sensitivity

Specificity

0.4 60 60
0.3 40 40
CV @ TnI = 0.07 Total prob >99% limit
0.2 10% 0.014
25% 0.020 20 20
0.1
0 0
0 0 50 100 150 200 250
0 0.02 0.04 0.06 0.08 0.1 0.12 0.14 0.16
Relative change in hs-TnI concentration
True TnI concentration
Sensitivity Specificity
Figure 31.5  Probability of one of three values being above the 99th
percentile value predicated on imprecision. The frequency of this Figure 31.7  Sensitivity and specificity for the percentage changes in patients
phenomenon is clinically insignificant. with AMI. Note the tensions between the two. Ruling out and ruling in may
Reproduced from Apple FS, Parvin CA, Buechler KF, et al. Validation of the 99th require different criteria.
percentile cutoff independent of assay imprecision (CV) for cardiac troponin Reproduced from Korley FK, Jaffe AS. Preparing the United States for high-​sensitivity
monitoring for ruling out myocardial infarction. Clin Chem 2005;51:2198–​2200 with cardiac troponin assays. J Am Coll Cardiol 2013;61(17):1753–​1758. doi:10.1016/​
permission from Oxford University Press. j.jacc.2012.09.069 with permission from Elsevier.
 Principles g u i di n g the u se of b i o m a rk er s i n  acu te ca rdiac   c a re 391

135 but there are very little data to substantiate it. There are robust
130
data about BV, and it is, at a minimum, 25%, which supports the
Concentrations relative to idea that much larger RCVs are necessary to be sure a change has
125 *
baseline (%) occurred [70, 71].
* Recently, Miller et  al. showed that either increases or de-
120
creases of 80% or greater were necessary to show associations
115 * * with differences in outcome with BNP [72]. This may be why
110 some trials using natriuretic peptides for titrating therapy have
105 not been positive, as they have not induced sufficient increments
in change [73].
100
08.00 10.00 12.00 14.00 16.00 18.00 For troponin, there are differences between men and women
Clock time with all hs-​cTn assays [32] and there are some data indicating that
BNP NT-proBNP it improves the detection of women with AMI [74]. The most re-
cent Universal Definition of AMI endorses the use of sex-​specific
Figure 31.8  Daily variations in natriuretic peptides.
Reproduced from Wu AH, Smith A, Wieczorek S, et al. Biological variation for N-​
thresholds [32]. There are no data suggesting that there are differ-
terminal pro-​and B-​type natriuretic peptides and implications for therapeutic ences between racial or ethnic groups, but the majority worldwide
monitoring of patients with congestive heart failure. Am J Cardiol 2003;92(5):628–​631. have embraced values generated in the US and Europe, perhaps
doi:10.1016/​s0002-​9149(03)00741-​0 with permission from Elsevier.
incorrectly.

absolute changes appear to be better [32]. These decisions are Normal value issues
assay-​dependent. In addition, some degrees of change, such as a Normal values should be established across different ethnic
difference between 3 ng/​L and 5 ng/​L at 1 hour with the Roche groups and by gender and age. The 99th percentile will increase
assay, will not be reliably determined, given the precision pro- with comorbidities and likely for that reason with age [75–​79]. For
files of some of the present proposed approaches [69]. contemporary troponin assays, correction for age and sex is not
Defining significant changes in natriuretic peptides is even necessary, but that will change at least for sex with high-​sensitivity
more complicated. Both BNP and NT-​proBNP have large BV, assays [65, 76]. Since age-​related changes are related to comorbid-
both short-​term (see E Figure 31.8) and long-​term (see E ities, the use of different cut-​off values would disadvantage indi-
Figure 31.9) [70]. The reference change value (RCV) is between viduals who lack comorbidities and is not recommended [32].
80% and 100%, so only very large differences can be relied on For BNP, differences with age and sex are clear [80, 81]. Recent
[70]. Some have argued that, in critically ill patients, smaller in- data suggest differences are related to testosterone which sup-
crements may still be important and have argued for 20% or 30% presses values [82,  83]. Normal values rise with age [80,  84].
changes. This claim has been included in consensus documents, Women have higher values than men [81,  82]. Black patients
have lower values [85]. Trial data suggest that separate values
do not need to be established [83, 86] to diagnose heart failure.
120 113 Most reports ignore these distinctions to generate simple para-
98 digms [19, 84]. Some authors suggest that using age-​and gender-​
Week-to-week RCV (%)

100
87 determined differences and correcting for BMI [85] would lead to
82 greater accuracy. Substantially lower values are observed in obese
80
69 68 individuals [86,  87]. BNP binds to the BNP clearance receptor
60 64
57 and it was thought that perhaps fat provided more clearance re-
54 ceptors. It now appears that the majority of what is measured by
40 both NT-​proBNP assays and BNP assays is actually proBNP [88]
which binds to the clearance receptor.
20
1 2 3 Subtle comorbidities, such as AF, even if not present at the time
Number of patient samples the patient presents, are associated with increased values [89]
BNP NT-proBNP BNP >350 ng/L and renal dysfunction also increases values. This phenomenon is
more marked for NT-​proBNP than for BNP, for unclear reasons.
Figure 31.9  Long-​term (week-​to-​week) variation in natriuretic peptides, The renal clearance of both peptides is not different across a wide
including in putatively normal subjects and those with elevated values with
RCVs. The RCVs for BNP (yellow), NT-​proBNP (red), and BNP >350 ng/​L
range of renal function [90] (see Figure 31.10). Nonetheless,
(green) are shown separately, as derived from single, duplicate, and triplicate higher cut-​off values to diagnose heart failure are needed for those
sampling, with each sample analysed singly, for estimating the homeostatic with renal failure [91, 92]. For these reasons, the use of multiple
set points of the two serial results. cut-​off values, as opposed to a solitary value, seems prudent, as
Reproduced from Wu AH, Smith A, Wieczorek S, et al. Biological variation for N-​
proposed for NT-​proBNP (see E Table 31.1) [93].
terminal pro-​and B-​type natriuretic peptides and implications for therapeutic
monitoring of patients with congestive heart failure. Am J Cardiol 2003;92(5):628–​631. This consideration is important for CRP as well. There are dif-
doi:10.1016/​s0002-​9149(03)00741-​0 with permission from Elsevier. ferences in values, based on gender and ethnicity [94, 95]. Black
392 CHAPTER 31   The u se of  biomarkers f or acu te ca rdi ovas cu l a r di sease

Table 31.1  Optimal cut-​off values for NT-​proBNP from the Icon group

Age strata Optimal cut-​off point (pg/​mL) Sensitivity (%) Specificity (%) PPV (%) NPV (%) Accuracy (%)
All <50 years
(n = 183) 450 97 93 76 99 95
All 50–​75 years
(n = 554) 900 90 82 82 88 85
All >75 years
(n = 519) 1800 85 73 92 55 83
Overall 90 84 88 66 86
Reproduced from Pascual-​Figal DA, Domingo M, Casas T, et al. Usefulness of clinical and NT-​proBNP monitoring for prognostic guidance in destabilized heart failure outpatients. Eur
Heart J 2008;29(8):1011–​1018. doi:10.1093/​eurheartj/​ehn023 with permission from Oxford University Press.

individuals, especially black women, have higher values [95]. It high values that do not change, until the interfering substance has
is also clear that oestrogens raise CRP, as do inflammatory dis- gone. Thus, samples do not dilute linearly. Many interfering sub-
eases [94]. Thus, if patients are ill at the time of sampling, a second stances are due to antibody problems and can be unmasked with
sample must be taken when the patient has returned to health. If the use of additional blocking antibodies.
the individual is on oestrogens, one should expect higher values.
Similarly, obesity and diabetes are associated with higher values, Natriuretic peptides
likely because they are associated with inflammation (see Natriuretic peptides are also elevated in patients who are critic-
Figure 31.11). ally ill and those with volume increases, renal failure, Cushing’s
disease, and/​or hyperaldosteronism [22]. Thus, one needs to in-
Issues of interpretation terpret increases with close attention to the clinical context. One
of the major differences between BNP and NT-​proNBP is in pa-
Cardiac troponin tients with renal failure. The aetiology for this is not understood,
There is a long list of reasons for cardiac injury, and one of the but increases in NT-​proBNP become very high in many patients
advances troponin has provided is an appreciation of these add- with renal failure, with values that can be as high as 35 000 ng/​mL.
itional diseases that damage the heart [12]. The best way to dif- These high values should not be a problem; the same principles
ferentiate acute elevations from chronic ones is by looking for a in defining the change criteria apply—​the numbers are simply
rising pattern of values. Even changing values have a broad dif- higher. It is not clear to this author whether or not natriuretic
ferential diagnosis and could be due to inflammatory cytokines peptides can be used diagnostically in complicated, critically ill
that damage the myocardium in patients who are septic or due to patients if the renal function is below 30 mL/​min, because the
direct trauma, cardiac infections, such as myocarditis, or CAD. values are so high [103]. Recently, a new agent that inhibits the
One exception to this rule is worth noting. If one is looking for degradation pathways of many vasoactive peptides has been
small changes in values over short periods of time, one can miss linked to an angiotensin receptor blocker (ARB) and has shown
significant changing patterns if one is not astute to the fact that major improvements in heart failure events [104, 105]. The ini-
the downslope (and thus falling patterns) manifests a much tial data suggest that BNP values may increase, while NT-​proBNP
slower time course than increases on the upslope. In one study, values decrease [105]. How this should influence how we inter-
up to 26% of all MIs presented in this manner [96]. pret natriuretic peptide values has become more complex and
Chronic elevations tend not to rise acutely [47]. The best under- controversial. Some thoughtful considerations were provided in
stood paradigm for these chronic elevations are renal failure patients a recent editorial [26].
where elevations, especially of cTnT, are importantly prognostic
and likely to be cardiac injury associated with renal dysfunction C-​reactive protein
[97]. Even when baseline elevations are present, a changing pattern Similar issues exist with CRP, having to do with concomitant
of values occurs during acute events [32]. Many patients with stable illnesses and other inflammatory processes that confound values.
angina [98–​100] and many with heart failure have chronic troponin In this instance, there are few options, because the CRP level needs
elevations, all of which are prognostically important [101]. They to be taken early after presentation, before the acute response to
can also have intermittent acute elevations [101]. For troponin, one necrosis occurs [31]. Thus, correction for concomitant disease
can determine the RCV, as indicated earlier. may not be possible. If the value is elevated in the absence of these
This should be defined by laboratories and reported as part of confounders and it is early after the onset of symptoms, it is likely
the results section of interpretation. If very high values of troponin that increases will persist and have long-​term prognostic signifi-
are present, without a changing pattern, one should always con- cance [29]. From this perspective, the PROVE-​IT data [38], sug-
sider an interfering substance [102]. Interfering substances cause gesting a CRP value at 4–​6 weeks post-​event, make good sense.
 C ont emp orary issu es w i th the u se of acu te ca rdi ovas cu l a r  b i o m a rk e r s 393

of myocarditis, a relatively underdiagnosed, and probably unappre-

Contemporary issues with the use ciated, disease. Indeed, CMR has unmasked a substantial number
of acute cardiovascular biomarkers of cases of myocarditis previously not diagnosed [110, 114]. It
had been previously reported that myocarditis could mimic AMI
Here, we will consider generic issues concerning the contem- [115], but the frequency at which it occurred was unclear. As the
porary use of biomarkers. troponin assay sensitivity improves still further [13], it is likely that
we will find still more new examples of abnormal pathophysiology
Sensitivity and detection of new disease entities manifesting as cardiac injury. It is likely that the findings will be
This issue has been common with cTn [13] and has posed a clinical prognostically important.
challenge. All tests can have false positives, related to analytic issues Some of this type of thinking may be facilitated by the des-
[102]. Alternatively, it appears that additional disease entities cause ignation of what has been termed ‘type 2 MI’ [32]. This is a cir-
most of these elevations. Malignancies are known to increase cTn cumstance where underlying coronary disease may be present
values [106] and we now can monitor doxorubicin drug toxicity but is stable until, in response to haemodynamic stress, increases
with troponins [107]. Furthermore, reducing elevations with ACE-​ in myocardial O2 consumption cause cardiac injury, marked by
Is prevents reductions in ventricular performance. It is likely that the release of troponin. Alternatively, it may be that toxic cyto-
additional drug-​related and toxic aetiologies for cardiac damage kines are predominantly responsible [13]. Irrespective of the
will become clearer as we improve the sensitivities of our assays aetiology, the complication of having cardiac injury associated
[108]. It is known, for example, that carbon monoxide poisoning with critical illness is associated with an adverse prognosis, both
causes troponin elevations acutely and that elevations are associ- short-​and long-​term [116]. One of the dilemmas is that the ap-
ated with an adverse prognosis [109]. Thus, rather than ignoring propriate therapeutic responses are not clear. Physicians need to
or impugning these elevations, clinicians need to explore the ex- think through the pathophysiology of the specific clinical entity
tent to which they open new pathophysiological opportunities. involved to craft a therapeutic response. For example, in patients
This was done by Assomull et al. [110] who investigated 60 patients with sepsis, perhaps using the lowest possible dose of catechol-
with elevated troponins and ECG changes that appeared acute and amines for haemodynamic support might help. There are other
who were thought to have AMI clinically. All of these individuals possibilities as well. However, the purpose of this chapter is not
had ‘normal’ coronary angiograms but underwent CMR imaging. to try to define the entire range of pathophysiological circum-
Diagnoses were elucidated in 65% of patients (see E Table 31.2). stances clinicians should consider, but rather to articulate con-
Some (11%) of these patients had a CMR signal suggestive of AMI cepts for the use of biomarkers. If one does that, it is very likely
and, in this circumstance, it is probably diagnostic. There are now to improve the diagnostic yield from the use of these markers.
several series showing exactly this, especially in women [111–​113]. Similar issues are likely to evolve with natriuretic peptides.
This could occur because of the timing of the angiography, due to
the presence of microvascular disease or endothelial dysfunction, Issues of organ versus clinical specificity
and perhaps yet unappreciated pathophysiological determinants. We would all like all of our markers to be totally specific, but this
Nonetheless, AMI with angiographically normal coronary arteries is not the case and is not likely ever to become so. Troponin comes
is not new [113] and myocardial infarction with non-​obstructed the closest, but tissue specificity does not imply clinical specificity
coronary arteries (MINOCA) is a real entity. In addition, 50% of for the aetiology of elevations [12]. Thus, one needs to appreciate
the patients in Assomull et al.’s study had a CMR pattern suggestive that troponin elevations, as well as those for natriuretic peptides
and CRP, are likely to be observed commonly and that these bio-
markers will unmask new, previously unknown, problems.
Table 31.2  CMR findings in 60 patients who presented with chest Elevations of natriuretic peptides in the absence of heart failure
pain, elevated troponin values, and normal or near-​normal coronary
arteries by angiography likely represent an alternative pathophysiology such as anaemia
or volume overload. Similarly, CRP elevations are often found in
CMR findings Number % obese patients, and perhaps that is a risk factor for CAD.
Myocarditis 30 50
Acute 19 31.7
Difficulties with legacies from the past
Non-​acute 11 18.3 Many clinicians learned about the use of CK-​MB and therefore
have had difficulty giving up its use, despite the fact that there is
MI 7 11.6
no circumstance in which it provides additional information over
Takotsubo cardiomyopathy 1 1.7 and above troponin [34]. It may actually prevent clinicians from
Dilated cardiomyopathy 1 1.7 learning how to use cTn properly [34].
Normal CMR findings 21 35.0 Some clinicians do not like using BNP, because they consider it
Reproduced from Assomull RG, Lyne JC, Keenan N, et al. The role of cardiovascular
as a substitute for clinical judgement. It should be synergistic with
magnetic resonance in patients presenting with chest pain, raised troponin, and clinical judgement. For example, when patients have concurrent
unobstructed coronary arteries. Eur Heart J 2007;28(10):1242–​1249. doi:10.1093/​ COPD and heart failure, it is difficult to determine which of the
eurheartj/​ehm113 with permission from Oxford University Press.
394 CHAPTER 31   The u se of  biomarkers f or acu te ca rdi ovas cu l a r di sease

aetiologies might be responsible for the increasing shortness of patients with chest discomfort will be developed [66]. They also
breath. The use of BNP is remarkably efficacious in that circum- will have pros and cons [69].
stance. However, one can only use the data if one understands the With natriuretic peptides, it is clear that the circulating form of
analytic and pre-​analytic distinctions discussed. Similar caveats BNP is proBNP [88]. Thus, heart failure itself is a failure of the syn-
exist for CRP. The prognostic significance of CRP in the acute set- thesis and release of natriuretic peptides. This opens opportunities
ting is fairly robust [117]. Using CRP to identify those patients not only for therapeutic manipulations, but also for new markers
who may receive a closer follow-​up and who then could/​should such as corin, the protease responsible for cleaving proBNP into
be evaluated, using the PROVE-​IT [38]-​suggested paradigm (see its active form [123]. In addition, multiple new analytes, such as
E Introduction, p. 387), makes sense. However, one cannot do mid-​range ANP, and an assay for proBNP are being developed
that unless one learns the issues related to the measurement of [124,  125]. In addition, although natriuretic peptides predict
CRP. Advocates often believe that it is essential to provide phys- mortality better than recurrent events such as AMI, there may be
icians with a simple paradigm, because they believe that clinicians markers that are still better such as ST2 [126] and growth differ-
will have difficulty if they have to learn too much about a marker. entiation factor-​15 (GDF-​15) [127]. This paradigm may change
That is an insult to clinicians. with the use of neprilysin inhibitor agents [104,  105]. However,
the basic principles governing the use of natriuretic peptide values
should not be markedly changed by this advance [125].
The future New markers to assess inflammation are also present in large
numbers. Finding a marker that would improve the specificity of
Troponin assays have become more sensitive. This increase will CRP would be an advance, especially given recent evidence that
make an understanding of the analytical issues more essential treating inflammation reduces cardiac events, independent of
for clinicians. For example, the minor differences between values any effects on LDL cholesterol [39, 128]. On the other hand, CRP
seen with plasma and serum may become important [13]. There amplifies the inflammatory signals from multiple inputs [129]
will also be differences in sex-​specific thresholds [15,  32]. It is and that may be why it has been so useful.
now clear that there will be large numbers of elevations in many Ultimately, combinations of markers will be employed, but this has
patients with CVD. For example, over 50% of patients with pace- not yet become a priority [130]. Thus, for now, the need is for clin-
makers will have such elevations, and after pacemaker implant- icians to understand only one marker at a time, but to do that well.
ation, an additional 30% or more will manifest elevations, some
with a ‘rising’ pattern [75]. Whether the current treatment para-
digms used in patients with ACS with elevations of contemporary Personal perspective
troponin assays—​aggressive anticoagulation, antiplatelet agents,
and an early invasive strategy—​are still appropriate with the new, There has been a lack of adequate education in this area,
more sensitive assays is unclear [118]. Additional markers in this which leaves clinicians at the whim of lectures and special
area are unlikely to be necessary for AMI diagnosis. It is already guideline documents that may sometimes represent bias,
clear that, when the 99th percentile cut-​off value is used, the rather than facts. Clinicians should know some basic infor-
so-​called ‘rapidly rising markers’ do not add to early diagnosis mation about assays and how to think about them.
[119,  120] with contemporary or high-​sensitivity assays [121].
There are still some questions about additional markers for ruling
out AMI. There is a recently reported trial evaluating copeptin for
that use, in combination with a sensitive cTn assay [120], that sug-
gests some benefit (CHOPIN), but data with hs-​cTn assays are less Acknowledgements
robust [121]. Time will tell. A marker that could help to identify Dr Jaffe is, or has been, a consultant to most of the major
those with ACS who are in need of urgent revascularization would diagnostic companies who produce assays for cardiovascular
be valuable [122]. Easy and novel protocols for the evaluation of biomarkers.

Further reading
Apple FS. A new season for cardiac troponin assays: it’s time to keep a Apple FS, Ranka L, Murakami MM. Determination of 19 cardiac troponin
scorecard. Clin Chem 2009;55:1303–​6. I  and T assay 99th percentile values from a common presumably
Apple FS, Parvin CA, Buechler KF, et  al. Validation of the 99th healthy population. Clin Chem 2012;58:1574–​81.
percentile cutoff independent of assay imprecision (CV) for cardiac Bhatia S, Anstine C, Jaffe AS, et  al. Cardiac magnetic resonance in
troponin monitoring for ruling out myocardial infarction. Clin Chem patients with elevated troponin and normal coronary angiography.
2005;51:2198–​200. Heart 2019;105:1231–​6.
 RE F E RE N C E S 395

Collinson PO, Heung YM, Gaze D, et al. Influence of population selection B-​type natriuretic peptide testing in acute cardiac care? Eur Heart J
on the 99th percentile reference value for cardiac troponin assays. Clin Acute Cardiovasc Care 2017;6:321–​8.
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ADDITIONAL ONLINE MATERIAL
124. Moertl D, Berger R, Struck J, et al. Comparison of midregional
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M oxfordmedicine.com/ESCIACC3e).
 CHAPTER 32

Biomarkers in acute
coronary syndromes
Jasper Boeddinghaus, Thomas Nestelberger,
Raphael Twerenbold, and Christian Mueller

Contents
Summary  400 Summary
Introduction: the role of biomarkers in Biomarkers, particularly high-​sensitivity cardiac troponin T/​I (hs-​cTnT/​I), play a
acute coronary syndromes  400
major role in the early diagnosis and risk stratification of patients presenting with
High-​sensitivity cardiac troponin  401
symptoms suggestive of an acute coronary syndrome such as acute chest pain. As
Central laboratory versus point-​of-​care  403
heart-​specific markers of cardiomyocyte injury, hs-​cTnT/​I complement clinical as-
Other biomarkers  403 sessment and the 12-​lead electrocardiogram in the diagnosis of myocardial infarction,
Rapid ‘rule-​in’ and ‘rule-​out’ risk stratification for life-​threatening arrhythmias and death, and triage towards early
algorithms  404
revascularization. hs-​cTnT/​I allow the reliable measurement of cTnT/​I concentra-
Caveats of using rapid algorithms  404
tions around the 99th percentile and in the normal range and increase the diagnostic
Confounders of cardiac troponin
concentration  405
accuracy for myocardial infarction at presentation. Absolute short-​term changes in
hs-​cTnT/​I within 1 or 2 hours further increase the diagnostic accuracy for myocardial
Practical guidance on how to implement
the ESC 0/​1-​hour algorithm  405 infarction. The European Society of Cardiology (ESC) hs-​cTnT/​I 0/​1-​hour algorithms
Avoiding misunderstandings: time to are assay-​specific, early-​triage algorithms optimized for the early rule-​out and/​or rule-​
decision = time of blood draw + in of myocardial infarction. These algorithms triage patients towards rule-​out (about
turnaround time  405 60%), observe (about 25%), and rule-​in (about 15%). Triage towards rule-​out pro-
Personal perspective  406 vides a very high sensitivity (99%) and negative predictive value (>99%) for the safe
References  407 rule-​out of myocardial infarction, while triage towards rule-​in provides a high specifi-
city (about 96%) and positive predictive value (about 75%) for myocardial infarction.
Other biomarkers quantifying cardiomyocyte injury, e.g. CK-​MB, creatine kinase,
lactate dehydrogenase, myosin-​binding protein C, or other pathophysiological pro-
cesses involved in acute coronary syndromes, e.g. copeptin, B-​type natriuretic peptide
(BNP), N-​terminal pro-​B-​type natriuretic peptide (NT-​proBNP), provide no or only
very little incremental diagnostic value for myocardial infarction on top of the ESC
hs-​cTnT/​I 0/​1-​hour algorithms. However, the latter provide incremental prognostic
value for death and heart failure. Therefore, the use of BNP or NT-​proBNP as quanti-
tative markers of haemodynamic stress and heart failure should be considered.

Introduction: the role of biomarkers in acute

coronary syndromes
The most important advance in biomarker testing in recent years was the clinical imple-
mentation of hs-​cTn assays. In contrast to conventional, less sensitive cTn assays, hs-​cTn
assays have much higher analytical sensitivity and precision. This allows detecting smaller
 Hi g h- sen si ti vi t y ca rdiac   t rop on i n 401

amounts of myocardial necrosis and diagnosing an NSTEMI (c-​MyC) concentrations, have been validated and some of them
earlier and more accurately [1–​4], thereby at large overcoming are clinically applied [5–​14].
the sensitivity deficit of conventional cTn assays at presentation. Other biomarkers involved in different pathways, such as in-
As a consequence, the ESC guidelines [3]‌recommend the flammation, activation of coagulation, myocyte necrosis, vascular
implementation of hs-​cTn assays and their use in combination damage, and haemodynamic stress, have been described. While they
with a diagnostic strategy—​a 0/​1-​hour algorithm with a second are less helpful for diagnosis, they may improve risk stratification
sample already after 1 hour, and a 0/​2-​hour algorithm with a and the selection of optimal treatment strategies. However, as cTn
second sample after 2 hours. If the diagnosis is still uncertain represents the standard of care in the diagnosis of NSTE-​ACS, E
or clinical suspicion for the presence of ACS is high, cTn testing Chapter 33 mainly focuses on the clinical use of hs-​cTn assays.
at later time points is recommended. Furthermore, cTn con-
centrations should always be used in conjunction with the clin-
ical presentation and history, as well as with the 12-​lead ECG. High-​sensitivity cardiac troponin
Alternatives to these algorithms, e.g. a 2-​hour accelerated diag-
nostic protocol with use of cTn concentrations, an instant rule-​ Biomarkers complement clinical assessment and the 12-​ lead
out strategy using a single hs-​cTn concentration with a cut-​off ECG in the diagnosis, risk stratification, and treatment of pa-
at the assay-​specific detection limit, a combination of low cTn tients with suspected NSTE-​ACS. Measurement of a biomarker of
or hs-​cTn concentrations together with low copeptin concen- cardiomyocyte injury, preferably hs-​cTn, is mandatory in all pa-
trations, or a strategy using cardiac myosin-​binding protein C tients with suspected NSTE-​ACS [3, 14–​19] (see E Figure 32.1).

Low Likelihood of myocardial infarction (MI) High

I. Clinical setting
Symptoms
and vital signs
CPR/shock

II. Electro-
cardiogram
(ECG)
Normal ECG ST depression ST depression ST elevation
(mild) (pronounced)

III. Troponin
– –/+ + ++ +++
level at 0h

If any of
Iv. Troponin
the above,
change
– –/+ + ++ consider
within 1h
direct
(or 2, 3h)
rule-in

Triage decision Rule-out MI Observe Rule-in MI

Differential Unstable Other

Non-cardiac NSTEMI STEMI
diagnosis angina cardiac

Figure 32.1  The initial assessment is based on the integration of low likelihood and/​or high likelihood features derived from the clinical setting (i.e. symptoms
and vital signs), 12-​lead ECG, and cardiac troponin level determined at presentation to the ED and serially thereafter. ‘Other cardiac’ includes, among others,
myocarditis, Takotsubo cardiomyopathy, and congestive heart failure. ‘Non-​cardiac’ refers to thoracic diseases such as pneumonia and pneumothorax. Cardiac
troponin and its changes in concentration during serial sampling should be interpreted as a quantitative marker—​the higher the 0-​hour level or the absolute
change during serial sampling, the higher the likelihood for the presence of myocardial infarction. In patients presenting with cardiac arrest or haemodynamic
instability of presumed cardiovascular origin, echocardiography should be performed/​interpreted by trained physicians immediately following a 12-​lead
ECG. If the initial evaluation suggests aortic dissection or pulmonary embolism, D-​dimers and multi-​detector computerized tomography angiography are
recommended according to dedicated algorithms [3, 20, 21, 73, 74]. CPR, cardiopulmonary resuscitation; ECG, electrocardiography; NSTEMI, non-​ST-​segment-​
elevation myocardial infarction; STEMI, ST-​segment-​elevation myocardial infarction.
Reproduced from Roffi M, Patrono C, Collet J-​P, Mueller C, Valgimigli M, Andreotti F, et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients
presenting without persistent ST-​segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-​Segment Elevation of.
Eur Heart J 2016 Jan 14;37(3):267–​315 with permission from Oxford University Press.
402 CHAPTER 32   B io m a rkers in acu t e c orona ry  sy n dro m es

cTn is a more sensitive and specific marker of cardiomyocyte in- to be released immediately following myocyte injury and, as-
jury than CK, its MB isoenzyme (CK-​MB), and myoglobin [3, 14–​ suming normal renal function, this would be cleared promptly.
21]. Troponin is a component of the contractile apparatus within This is contrary to structurally bound cTn, which degrades over a
skeletal and cardiac myocytes. Along with Ca2+ ions, troponin pro- period of hours to several days, causing a more stable and gradual
teins regulate and facilitate the interaction between actin and my- troponin release. The plasma half-​life of cTn seems to be around
osin filaments, as part of the sliding filament mechanism of muscle 2 hours. Although the precise mechanism by which troponin
contraction. cTn is a complex comprising three subunits: is eliminated from the body remains unclear, it is hypothesized
◆ Troponin T attaches the troponin complex to the actin filament. that troponin is cleared, at least in part, by the renal reticulo-​
◆ Troponin C acts as the Ca2+ binding site. endothelial system [25].
If the clinical presentation is compatible with myocardial is-
◆ Troponin I  inhibits the interaction with myosin heads in the chaemia, then a dynamic elevation of cTn above the 99th per-
absence of sufficient Ca2+ ions. centile of healthy individuals indicates MI. In patients with
Troponin C is synthesized in skeletal and cardiac muscle. MI, levels of cTn rise rapidly (i.e. usually within 1 hour if using
Troponin T and I  isoforms are highly specific and sensitive to hs-​cTn assays) after symptom onset and remain elevated for a
cardiac myocytes and therefore are known as cTn. The detection variable period of time (usually several days) [3, 14–​21]. Advances
of cTnT or cTnI in the bloodstream is therefore a highly specific in technology have led to a refinement in cTn assays and have im-
marker for cardiomyocyte injury [22]. According to estimates proved the ability to detect and quantify cardiomyocyte injury
from in vitro models, 92–​95% of cTn is attached to actin thin fila- [3, 14–​21, 26–​31]. Data from large multicentre studies have con-
ments in the cardiac sarcomere and the remaining 5–​8% is free sistently shown that hs-​cTn assays increase diagnostic accuracy
in the myocyte cytoplasm [23]. Free, unbound cTn is thought to for MI at the time of presentation, as compared with conven-
constitute the ‘early releasable troponin pool’ (ERTP) [24]. The tional assays (see E Figure 32.2), especially in patients pre-
concept of the ERTP helps when considering the various mech- senting early after CP onset, and allow for a more rapid ‘rule-​in’
anisms of troponin release into the bloodstream. ERTP is thought and ‘rule-​out’ of MI [3, 14–​21, 26–​31] (see E Box 32.1).

Conventional assay High-sensitivity assay

micrograms/L × 1000 ng/L

0.100 100

Pathologic Most POCT Pathologic

0.030–0.040 CV of 10% 50
Likely pathologic
0.010 Limit of detection
Undetectable

??? 99th percentile 10–20* 99th percentile

Likely normal
Normal
1–5* Limit of detection

Figure 32.2  High-​sensitivity cardiac troponin (hs-​cTn) assays (right) are reported in ng/​L and provide identical information, as compared to conventional
assays (left, reported in micrograms/​L), if the concentration is substantially elevated, e.g. above 100 ng/​L. In contrast, only hs-​cTn allows a precise differentiation
between ‘normal’ and mildly elevated. Therefore, hs-​cTn detects a relevant proportion of patients with previously undetectable cardiac troponin concentrations
with the conventional assay who have hs-​cTn concentrations above the 99th percentile possibly related to acute myocardial infarction. * The limit of detection
varies among the different hs-​cTn assays—​between 1 ng/​L and 5 ng/​L. Similarly, the 99th percentile varies among the different hs-​cTn assays—​between 10 ng/​L
and 20 ng/​L for most of them [14–​17, 20, 21, 26–​28, 74].
 Other  b i o m a rk e r s 403

Box 32.1  Clinical implications of high-​sensitivity cardiac Box 32.2  Conditions other than type 1 acute myocardial
troponin assays infarction associated with cardiomyocyte injury (= cardiac
troponin elevation)
Compared with standard cTn assays, high-​sensitivity assays:
Have higher NPV for AMI.
◆ Tachyarrhythmias
◆

Reduce the ‘troponin-​blind’ interval, leading to earlier detec-

◆ Heart failure
◆

tion of AMI. Hypertensive emergencies

◆

Result in approximately 4% absolute and 20% relative in-

◆ Critical illness (e.g. shock, sepsis, burns)
◆

crease in the detection of type 1 MI and a corresponding de- Myocarditis*

◆
crease in the diagnosis of UA. Takotsubo cardiomyopathy
◆
Are associated with a 2-​fold increase in the detection of
◆
Structural heart disease (e.g. aortic stenosis)
◆
type 2 MI. Aortic dissection
◆
Levels of hs-​cTn should be interpreted as quantitative markers Pulmonary embolism, pulmonary hypertension
◆
of cardiomyocyte damage (i.e. the higher the level, the greater the
Renal dysfunction and associated cardiac disease
◆
likelihood of MI):
Acute neurological event (e.g. stroke or subarachnoid
◆
Elevations beyond 5-​fold the upper reference limit have high
◆
haemorrhage)
(>90%) PPV for acute type 1 MI.
Cardiac contusion or cardiac procedures (CABG, PCI, abla-
◆
Elevations up to 3-​fold the upper reference limit have only
◆
tion, pacing, cardioversion, or endomyocardial biopsy)
limited (50–​60%) PPV for AMI and may be associated with a
broad spectrum of conditions. Hypo-​and hyperthyroidism
◆

It is common to detect circulating levels of cTn in healthy

◆
Infiltrative diseases (e.g. amyloidosis, haemochromatosis, sar-
◆

individuals. coidosis, scleroderma)

Rising and/​or falling cTn levels differentiate acute (as in MI) Myocardial drug toxicity or poisoning (e.g. doxorubicin,
◆

from chronic cardiomyocyte damage (the more pronounced the 5-​fluorouracil, herceptin, snake venoms)
change, the higher the likelihood of AMI). Extreme endurance efforts
◆

AMI, acute myocardial infarction; cTn, cardiac troponin; MI, myocardial in- Rhabdomyolysis and associated cardiac disease
◆

farction; NPV, negative predictive value; PPV, positive predictive value; UA, CABG, coronary artery bypass surgery; PCI, percutaneous coronary
unstable angina. intervention.
Italics: most frequent conditions.
*
Includes myocardial extension of endocarditis or pericarditis.

Central laboratory versus

important contributor to cTn elevation in this setting [30, 34].
point-​of-​care Other life-​threatening conditions presenting with CP, such as
The vast majority of cTn assays run on automated platforms in the aortic dissection and PE, may also result in elevated cTn con-
central laboratory are sensitive (i.e. allow for detection of cTn in centrations and should be considered as differential diagnoses
~20–​50% of healthy individuals) or high-​sensitive (detection in (see E Box 32.2).
~50–​95% of healthy individuals) assays. hs-​cTn assays are recom-
mended over less sensitive ones, as they provide higher diagnostic
accuracy at identical low cost [3, 14–​21, 26–​31]. The majority of Other biomarkers
currently used point-​of-​care assays cannot be considered sensitive
or high-​sensitivity assays [32]. Therefore, the obvious advantage Among the multitude of additional biomarkers evaluated for the
of POCTs, namely a shorter turnaround time, is counterbalanced diagnosis of NSTE-​ACS, only CK-​MB, c-​MyC, and copeptin [5,
by lower sensitivity, lower diagnostic accuracy, and lower NPV. 9, 35–​44] seem to have clinical relevance when used in combin-
Overall, automated assays have been more thoroughly evalu- ation with cTnT/​I. CK-​MB shows a more rapid decline after MI, as
ated, as compared with POCTs, and seem to be preferable at this compared with cTn, and may provide added value for the timing
point in time [3, 14–​21, 26–​31). As these techniques continue of myocardial injury and the detection of early reinfarction [3]‌.
to improve and performance characteristics are both assay-​and c-​MyC is more abundant than cTn and may therefore provide
hospital-​dependent, it is important to re-​evaluate this preference clinical value as an alternative to, or in combination with, cTn [6].
once extensively validated high-​sensitivity point-​of-​care assays Assessment of copeptin, the C-​terminal part of the vasopressin
become clinically available [33]. prohormone, may quantify the endogenous stress level in mul-
In most patients with renal dysfunction, elevations in cTn tiple medical conditions, including MI. As the level of endogenous
should not be primarily attributed to impaired clearance and stress appears to be invariably high at the onset of MI, the added
considered harmless, as cardiac conditions such as chronic value of copeptin to conventional (less sensitive) cTn assays is
coronary or hypertensive heart disease seem to be the most substantial [5, 37,  38]. Therefore, routine use of copeptin as an
404 CHAPTER 32   B io m a rkers in acu t e c orona ry  sy n dro m es

additional biomarker for early rule-​out of MI is recommended were developed in large derivation cohorts and then validated in
in the increasingly uncommon setting that hs-​cTn assays are not large independent validation cohorts. As an alternative, the ESC
available. However, copeptin does not seem to have enough added 0/​3-​hour algorithm is recommended [3,  56]. However, three re-
value for institutions using one of the well-​validated hs-​cTn-​based cent large diagnostic studies suggested that the ESC 0/​3-​hour algo-
rapid protocols in the early diagnosis of MI [9, 35, 36, 39–​44]. rithm seems to balance efficacy and safety less well than more rapid
Other widely available laboratory variables, such as eGFR, glucose, protocols using lower rule-​out concentrations, including the ESC
and BNP, provide important incremental prognostic information 0/​1-​hour algorithm [57–​59].
and therefore help in risk stratification [45, 46]. The ESC 0/​1-​hour and 0/​2-​hour algorithms rely on two con-
cepts. First, hs-​cTn is a continuous variable and the probability
of MI increases with increasing hs-​cTn values [29, 30, 51–​53,
Rapid ‘rule-​in’ and ‘rule-​out’ 60, 61]. Second, early absolute changes of the levels within 1 or
2 hours can be used as surrogates for absolute changes over 3 or
algorithms 6 hours and provide incremental diagnostic value to the cTn as-
Due to the higher sensitivity and diagnostic accuracy for the detec- sessment at presentation [8, 29, 30, 51–​53, 55, 60, 61]. The cut-​off
tion of AMI at presentation, the time interval to the second cTn as- concentrations in the ESC 0/​1-​hour and 0/​2-​hour algorithms are
sessment can be shortened with the use of hs-​cTn assays. This seems assay-​specific (see E Table 32.1) [8, 29, 30, 51–​53, 55, 60, 61].
to reduce substantially the delay to diagnosis, translating into shorter The NPV for MI in patients assigned ‘rule-​out’ exceeded 99% in
stays in the ED and lower costs [15, 47–​50]. It is recommended several large validation cohorts [8, 29, 30, 51–​53, 55,  62]. Used
to use the ESC 0/​1-​hour algorithm or the 0/​2-​hour algorithm (see in conjunction with clinical and ECG findings, the ESC 0/​1-​hour
E Figure 32.3). These have been derived and well validated in and 0/​2-​hour algorithms will allow the identification of appro-
large multicentre diagnostic studies using central adjudication of priate candidates for early discharge and outpatient management.
the final diagnosis for all currently available hs-​cTn assays [29, 30, The PPV for MI in those patients meeting the ‘rule-​in’ criteria
51–​55]. Optimal thresholds for rule-​out were selected to allow for a was about 75% [3, 51, 63, 64]. Most of the ‘rule-​in’ patients with
minimal sensitivity and NPV of 99%. Optimal thresholds for rule-​ diagnoses other than MI did have conditions that usually still re-
in were selected to allow for a minimal PPV of 70%. The algorithms quire inpatient coronary angiography for an accurate diagnosis,
including Takotsubo syndrome and myocarditis.
Those algorithms should always be integrated with a detailed
clinical assessment and a 12-​lead ECG, and repeat blood sam-
Suspected NSTEMI
pling is mandatory in cases of ongoing or recurrent CP.
Patients who do not qualify for ‘rule-​out’ or ‘rule-​in’ repre-
0h Very low* or Low High sent a heterogenous group that usually require a third measure-
cTn: and Other or ment of cTn at 3 hours and echocardiography as the next steps
1h no 1h∆ 1h∆
*if CPO>3h [65]. Coronary angiography should be considered in patients for
whom there is a high degree of clinical suspicion of NSTE-​ACS
Rule-out Observe Rule-in (e.g. relevant increase in cTn from presentation to 3 hours), while
3h cTN + echo in patients with low to intermediate likelihood for this condition,
non-​ invasive imaging using stress testing (stress echocardio-
Disposition: Discharge Ward CCU graphy), PET, myocardial perfusion scanning (MPS), or CMR
or CT coronary angiography should be considered [47, 65]. No
Imaging: optional: Angiography Angiography
further diagnostic testing in the ED is indicated when alterna-
Stress testing or stress testing and echo
or CCTA or CCTA tive conditions, such as rapid ventricular rate response to AF or
or angiography or none hypertensive emergency, have been identified.
or none

Figure 32.3  ESC 0/​1-​hour rule-​out and rule-​in algorithm using hs-​cTn assays
in haemodynamically stable patients presenting with suspected NSTEMI to
the ED. ‘0h’ and ‘1h’ refer to the time from the first blood test. NSTEMI can be
Caveats of using rapid algorithms
ruled out already at presentation if the hs-​cTn concentration is very low and When using any algorithm, three main caveats apply:  (1) al-
if chest pain onset was >3 hours ago. NSTEMI can also be ruled out by the
gorithms should only be used in conjunction with all available
combination of low baseline levels and the lack of a relevant increase within 1
hour. Patients have a high likelihood for NSTEMI if the hs-​cTn concentration clinical information, including detailed assessment of CP char-
at presentation is at least moderately elevated or the hs-​cTn concentrations acteristics and ECG; (2)  in patients presenting very early (e.g.
show a clear rise within the first hour [3, 14–​17, 20, 21, 26–​28, 74]. The same within 1 hour from CP onset), an additional cTn level should
concept applies to the 0/​2-​hour algorithm. Cut-​off levels are assay-​specific. be obtained at 3 hours, due to the time dependency of troponin
Cut-​off levels for other hs-​cTn assays are in development. * Only applicable if
release; (3)  as late increases in cTn have been described in
chest pain onset is >3 hours.
 Avoi di n g m i su n der sta n di n g s 405

Table 32.1  Optimal cut-​off levels

0/​1-​hour algorithm Very low Low No 1 hour ∆ High 1 hour ∆

hs-​cTnT (Elecsys) <5 <12 <3 ≥52 ≥5
hs-​cTnI (Architect) <4 <5 <2 ≥64 ≥6
hs-​cTnI (Centaur) <3 <6 <3 ≥120 ≥12
hs-​cTnI (Access) <4 <5 <4 ≥50 ≥15
hs-​cTnI (Clarity) <1 <2 <1 ≥30 ≥6
hs-​cTnI (Vitros) <1 <2 <1 ≥40 ≥4
0/​2-​hour algorithm Very low Low No 2 hour ∆ High 2 hour ∆
hs-​cTnT (Elecsys) <5 <14 <4 ≥52 ≥10
hs-​cTnI (Architect) <4 <6 <2 ≥64 ≥15
hs-​cTnI (Centaur) <3 <8 <7 ≥120 ≥20
hs-​cTnI (Access) <4 <5 <5 ≥50 ≥15
hs-​cTnI (Clarity) <1 tbd tbd ≥30 tbd
hs-​cTnI (Vitros) <1 tbd tbd ≥40 tbd
Optimal cut-​off levels in ng/​L for use in the ESC 0/​1-​hour and 0/​2-​hour algorithms are assay-​specific and listed for all high-​sensitivity cardiac troponin (hs-​cTn) assays with validated
algorithms available. The algorithms for additional assays are in development.
hs-​cTnT on Elecsys (Roche), hs-​cTnI on Architect (Abbott), hs-​cTnI on Centaur (Siemens), hs-​cTnI on Access (Beckman Coulter), hs-​cTnI on Clarity (Singulex), hs-​cTnI on Vitros (Ortho
Clinical Diagnostics).
tbd, to be determined within the next months (manuscripts either in review or in preparation).

~1% of patients, serial cTn testing should be pursued if clin- 0 and 1 hour in all patients, irrespective of other clinical de-
ical suspicion remains high or whenever the patient develops tails and pending results. This induces in retrospect formally
recurrent CP. unnecessary cTn measurements in perhaps 10–​15% of patients
with very low 0-​hour concentrations and CP onset >3 hours,
but substantially facilitates the process and thereby further in-
Confounders of cardiac troponin creases patient safety. Documentation of the time of the 0-​hour
blood draw allows exact determination of the time window (±
concentration 10 minutes) of the 1-​hour blood draw. If, for whatever reason,
In patients presenting with suspected NSTE-​ACS, beyond the the 1-​hour (± 10 minutes) blood draw is not feasible, then
presence or absence of MI, four clinical variables affect hs-​cTn blood should be drawn at 2 hours and the ESC 0/​2-​hour algo-
concentrations: age, renal dysfunction (both, to a large extent, as rithm applied.
a surrogate for pre-​existing cardiac disease), time from CP onset,
and sex [15, 29, 30, 51, 52, 66–​74]. The effect of age (~300%),
renal dysfunction (~300%), and CP onset (>300%) is substantial,
and modest for sex (~40%). Until information technology tools Avoiding misunderstandings: time
are available that allow incorporating the effect of all four vari- to decision = time of blood draw +
ables, the use of uniform cut-​off concentrations should remain
the standard of care in the early diagnosis of MI.
turnaround time
The use of the ESC 0/​1-​hour algorithm is irrespective of the local
turnaround time. The 0 hour and 1 hour times refer to the time
Practical guidance on how to implement point at which blood is taken (see E Figure 32.4).
The clinical and economic benefit of the ESC 0/​1-​hour algo-
the ESC 0/​1-​hour algorithm rithm versus, for example, the ESC 0/​3-​hour algorithm or other
In order to maximize safety and feasibility of the process, algorithms with the second blood draw later than 1 hour there-
the nursing team should obtain blood samples for hs-​cTn at fore is independent of the local turnaround time [48].
406 CHAPTER 32   B io m a rkers in acu t e c orona ry  sy n dro m es

Population Patients with suspected myocardial infarction

or
Vitals Stable patients Shock or CPR
12-lead ECG No ST-segment elevations ST-segment elevations direct
Rule-in
0h Blood sampling
0h

Turnaround
time ≈ 1h
Rule-out Clinical assessment

0h hs-cTn very low and RESULT

1h 0h-hs-cTn high
CPO >3h
0h 1h

Turnaround
Hospitalization

time ≈ 1h
Rule-out MI
Consider differential diagnosis
Time line

Possible outpatient RESULT

0h hs-cTn low and Monitored unit
2h Relevant 1h-change
management no 1h-change and
1h

All other

3h Early coronary
3h
angiography
Echo

Turnaround
time ≈ 1h
Observe

Disposition according to RESULT

4h differential diagnosis No 3h-change Relevant 3h-change
3h

Risk of Low Intermediate High

risk risk risk
MI at index visit <0.3% ≈10% >65%
30-day MACE <0.5% 15–20% >70%

Figure 32.4  Timing of blood draws and clinical decisions when using the ESC 0/​1-​hour algorithm. ‘0h’ and ‘1h’ refer to the time point at which blood is taken.
The turnaround time is the time period from blood draw in the ED to reporting back the results to the clinician. It is about 1 hour in a well-​run hospital using
an automated platform in the central laboratory and includes transport of the blood tube to the laboratory, scanning of the probe, centrifugation, and putting
plasma on the automated platform, then followed by the test run by the machine, and the test result is reported online to the hospital IT/​electronic patient
record. This turnaround time is identical if using a hs-​cTn assay versus a conventional assay, as long as both are run on an automated platform. Adding the local
turnaround time to the time of blood draw determines the earliest time point for clinical decision-​making based on hs-​cTn concentrations. For example, for the
‘0h’ time point, the time to decision is at 1 hour if the local turnaround time is 1 hour. For blood sampled at 1 hour, the results are reported back at 2 hours (1
hour + 1 hour) if the local turnaround time is 1 hour.

Personal perspective
Currently used hs-​cTn assays are highly valuable for rule-​in and absolute changes over time have now been extensively val-
and rule-​out of MI, even though many factors other than idated in large diagnostic studies, endorsed by current guide-
acute myocardial ischaemia may cause cardiomyocyte injury, lines and being adopted in clinical practice in many countries
and therefore mild hs-​cTn elevations. Dynamic changes of worldwide. One current research priority is the development
hs-​cTn during serial sampling help to distinguish acute from and clinical validation of hs-​cTn point-​of-​care assays, which
chronic causes of CP and mild troponin elevations. Early could help transform clinical practice in the out-​of-​hospital
triage algorithms using hs-​cTn concentrations at presentation and primary care settings.
 RE F E RE N C E S 407

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 CHAPTER 33

Biomarkers in acute
heart failure
Rajiv Choudhary, Nicholas Wettersten,
Kevin Shah, and Alan Maisel

Contents
Summary  409 Summary
Introduction  409 Acute heart failure continues to be a worldwide medical problem, associated with
The ideal biomarker  410 frequent readmissions, high mortality, and a profound economic impact on na-
Natriuretic peptides  410 tional health care systems. Biomarkers have shifted the way in which acute heart
Natriuretic peptide biochemistry  410 failure is managed by the cardiologist. The search for the ideal biomarker to aid
Natriuretic peptide pathophysiology and
function  411 in the diagnosis, prognosis, and treatment of acute heart failure is ongoing. The
Clinical utility of natriuretic peptide in acute natriuretic peptides have proven extremely useful in determining whether acute
heart failure  411
Natriuretic peptide utility in the emergent
dyspnoea has a cardiac aetiology. In addition, recent trials have demonstrated the
setting  412 use of natriuretic peptides in inpatient and outpatient prognosis, and possibly
Natriuretic peptide utility in the inpatient a role in guiding medical therapy, specifically in outpatients with chronic heart
setting  413
Natriuretic peptide utility in the outpatient failure. Other emerging acute heart failure biomarkers include high-​sensitivity
setting  414 troponin, soluble suppression of tumorigenesis-​2 (sST2), galectin-​3, mid-​regional
Interpreting natriuretic peptide levels  415
pro-​adrenomedullin, bio-​adrenomedullin, mid-​regional proatrial natriuretic pep-
New biomarkers for routine assessment in
acute heart failure  416 tide, and procalcitonin.
High-​sensitivity troponins  416
ST2  417
Galectin-​3  417
Concomitant conditions seen in the acute
heart failure patient  418
Procalcitonin  418
Emerging biomarkers  418
Introduction
Copeptin  418 AHF remains a common clinical presentation, with heightened morbidity and mortality
Mid-​regional markers  419
and increasing difficulty in management because of repeated failure of new therapies in
Conclusion  419
patients with increasing medical complexity [1]‌. Biomarkers are essential tools, which
Personal perspective  420
help the clinician to quantify the underlying pathophysiological mechanisms and tailor
Further reading  420
AHF therapy accordingly. With continuously increasing biomarker research, the role of
References  421
biomarkers in managing AHF patients has become evident. With most AHF patients pre-
senting through the ED, early diagnosis and initiation of treatment are key in achieving
positive outcomes. A rapid bedside diagnosis allows the clinician to grade the severity
of AHF and helps to ‘tailor’ therapy effectively. Moreover, in circumstances of equivocal
history and physical and imaging findings, biomarker testing can help clinicians by pro-
viding a more accurate diagnostic view, thus preventing misdiagnosis and aiding an early
initiation of treatment, especially in the acute setting.
In this chapter, we discuss in detail the use of natriuretic peptides, beyond doubt, the
most important biomarkers in AHF with Class 1 recommendations in both European
and American guidelines, but we also address the diagnostic and prognostic utility of
other emerging biomarkers that are increasingly finding clinical use and others that
410 CHAPTER 33   B io m a rkers in acu t e h eart  fa i lu re

might provide added value for the management of patients with

AHF [2, 3].
Broadly
applicable
High Accurate
The ideal biomarker sensitivity

A biomarker must meet several criteria to be considered an

ideal AHF biomarker [4]‌. The ideal AHF biomarker, depending
on the purpose of testing, must be highly sensitive and/​or spe- Diagnostic
Ideal Prognostic
biomarker
cific. For instance, while screening for asymptomatic LV dys-
function, a high specificity for ‘ruling in’ the disease is required
[4, 5], whereas in diagnosing symptomatic life-​threatening con-
ditions, such as AMI, the biomarker must be highly sensitive to High
Precise
allow ‘ruling out’ the disease effectively [4, 5]. Additionally, bio- Guide
specificity
marker testing must be accurate and reproducible. In order to therapy
achieve this, a biomarker must carry a low coefficient of variation
(CV) (<10%), allowing the detection and reflection of even mi-
nute changes in the disease state of the patient [5, 6]. Moreover, Figure 33.1  Qualities of an ideal biomarker. An ideal biomarker should have
all the qualities displayed; however, very few biomarkers in clinical practice
the technical measurement of the biomarker using assays must
meet all criteria.
be easy to perform and be able to be carried out at the bedside,
allowing faster access to the clinical status of the patient. The
ideal biomarker must reflect ongoing pathophysiological changes prognostication of AHF. Natriuretic peptide testing in the ED al-
in the AHF patient, giving a sense of severity of the disease and lows the clinician to accurately diagnose AHF, especially when
helping clinicians chart the disease progression. Moreover, bio- conventional tests, such as physical examinations and radio-
marker levels must respond to ongoing treatment, allowing the graphic imaging, have been inconclusive.
clinician to gauge the effectiveness of the therapy and to titrate
the treatment, as needed, to achieve positive outcomes. Ideally, a Natriuretic peptide biochemistry
biomarker or panel of biomarkers would affect clinical manage- Natriuretic peptides belong to a family of structurally similar
ment. For example, investigators have demonstrated the potential peptides, consisting of atrial natriuretic peptide (ANP), B-​
of a panel of biomarkers to predict poor diuretic response [7]. type natriuretic peptide (BNP), and C-​and D-​type natriuretic
Specifically, incorporation of the biomarkers soluble ST2 (sST2) peptides [9]‌. Of these, BNP has widespread clinical applica-
and NGAL along with other clinical indicators are associated with tions, due to its in vitro stability, compared to other peptides.
poor diuretic response in an AHF population. An additional role The BNP gene is activated as a direct result of several stimuli
for an optimal biomarker would be to provide information which such as cardiomyocyte stretch, injury, and/​or death and hyp-
affects clinical management. Finally, the ideal biomarker must be oxia [9, 10]. This gene encodes the 134-​amino acid pre-​proBNP
cost-​effective and applicable across all diverse populations [5, 6] precursor molecule. Glycosylation of the pre-​proBNP molecule
(see E Figure 33.1). yields a 26-​amino acid signal sequence and the 108-​amino acid
Thus, an ideal AHF biomarker must be multifaceted, aiding proBNP molecule [10, 11]. The protein-​cleaving enzymes corin
clinicians not only with the diagnosis and prognosis of the dis- and furin cleave this proBNP peptide to produce the biologic-
eased state, but also with predicting heart failure recurrence and ally active 32-​amino acid BNP peptide and the inactive 76-​
helping clinicians tailor AHF therapy by monitoring biomarker amino acid amino terminal (NT)-​proBNP fragment [10,  12]
levels. Over time, the criteria which the ideal AHF biomarker (see E Figure 33.2).
must fulfil have certainly evolved. Although natriuretic peptides, Once in the circulation, BNP exerts its physiological effects by
as AHF markers, get close, no single biomarker meets all criteria, binding guanylyl cyclase receptors, referred to as natriuretic pep-
and researchers have therefore suggested a multimarker approach tide receptors A and B, and initiating a signalling cascade medi-
to maximize AHF treatment and management. ated via cyclic guanosine monophosphate (cGMP). Plasma BNP
has a half-​life of about 20 minutes, whereas that of plasma NT-​
proBNP is about 70 minutes [9, 10, 12]. BNP is cleared from the
Natriuretic peptides circulation by binding natriuretic peptide receptor C and, to some
extent, via degradation by neutral endopeptidases. BNP is renally
Natriuretic peptides are circulatory peptide hormones, which excreted, and in patients with renal function impairment, BNP
are synthesized and released from the myocardial cells, in direct levels can be elevated due to decreased excretion. NT-​proBNP,
response to ventricular changes in volume and pressure [8]‌. on the other hand, is mainly excreted via the kidneys (55–​65%)
Natriuretic peptides have gained widespread recognition and and the rest via the liver, musculoskeletal tissue, and head and
are considered benchmark biomarkers in the diagnosis and neck [13].
 Natriu ret i c   pe p t i de s 411

PRECIPITATING FACTORS
• Medication and dietary non-compliance
• Ischaemic heart disease LVD
• Dysrhythmias
• Valvular disorder LVEDP
• Coexisting condition
LVEDV

BNP/NT-proBNP Cardiac output

Mid-regional markers PCWP
ST2

Lung
Procalcitonin

ORGAN
INVOLVEMENT COMPENSATORY PATHWAY ACTIVATION
RAAS activation: ↑Na/H2O retention

Neurohormonal: vasoconstriction; ↑AVP Copeptin

Kidney
NGAL Sympathetic system activation
IN PATIENT WITH
Pro-inflammatory cytokine release EXISTING HF
Compensatory pathways
+
Heart precipitating factor
hs-troponins Preload
Afterload
Sudden increased fluid
SVR Cardiac remodelling retention
Venous congestion
• Fibrosis
HR Galectin-3
• Hypertrophy

ADHF

Figure 33.2  Illustrative representation of the pathophysiology of acute heart failure, along with biomarker-​specific sites of involvement. ADHF, acute
decompensated heart failure; AVP, arginine vasopressin (antidiuretic hormone); HF, heart failure; H2O, water; HR, heart rate; hs-​troponins, high-​sensitivity
troponins; LVD, left ventricular dysfunction; LVEDP, left ventricular end-​diastolic pressure; LVEDV, left ventricular end-​diastolic volume; Na, sodium; NGAL,
neutrophil gelatinase-​associated lipocalin; PCWP, pulmonary capillary wedge pressure; RAAS, renin–​angiotensin–​aldosterone system; SVR, systemic vascular
resistance.
Reproduced from McGrath MF, de Bold AJ. Determinants of natriuretic peptide gene expression. Peptides 2005;26(6):933–​943. doi:10.1016/​j.peptides.2004.12.022 with permission
from Elsevier.

Natriuretic peptide pathophysiology [16, 17]. The physiological functions of BNP counteract adverse
and function pathophysiologic neurohormonal activation in heart failure.
Once in the circulation, BNP induces vasodilatation and pro-
Natriuretic peptides are hormones synthesized in the heart that motes natriuresis and kaliuresis; furthermore, it inhibits the
regulate the water–​electrolyte balance in the body. ANP and BNP actions of the sympathetic nervous system and, more import-
are released in response to atrial and ventricular wall stretch. antly, it inhibits RAAS. Interestingly, BNP has anti-​fibrotic and
Therefore, elevated levels of natriuretic peptides are a result of anti-​inflammatory effects on the heart, thus exerting an overall
the body’s response to a volume-​overloaded state. The compensa- cardioprotective effect [16, 17].
tory mechanisms, which are activated in response to a decreased
plasma volume, include RAAS, the sympathetic system, the in-
flammatory pathway, and the neurohormonal system [14, 15] (see
Clinical utility of natriuretic peptide in
E Figure 33.3). Collectively, they work to maintain the plasma acute heart failure
volume by affecting Na+ and water homeostasis. In healthy in- As a quantitative marker of heart failure, natriuretic peptide levels
dividuals, BNP is synthesized in the atria and ventricles, but in are best interpreted as a continuous variable. The higher the value,
specific conditions, such as heart failure, associated with volume the greater the likelihood that the dyspnoea is due to heart failure.
expansion and pressure overload, BNP gene synthesis occurs The clinical implications of natriuretic peptide use in AHF re-
mainly in the ventricles [16]. Studies have shown that this syn- volve around their ability to differentiate cardiac dyspnoea from
thesis occurs in ‘bursts’, due to the presence of a destabilized nu- non-​cardiac dyspnoea. BNP levels have been shown to correlate
cleic acid sequence in the BNP gene identified as ‘TATTTAT’ with NYHA functional classes and are inversely related to the
412 CHAPTER 33   B io m a rkers in acu t e h eart  fa i lu re

POLY A+
Add. site
5’ TATAAA ATG EXON 1 INTRON 1 EXON 2 INTRON 2 EXON 3 TGA AATAAA 3’

Transcription

pre-mRNA

pre-mRNA processing

mRNA methylguanine AAAA

Translation
–25 1 99 126 –26 1 77 108 –23 1 82 103
pre-proANF pre-proBNP pre-proCNP
S–S S–S S–S
Processing by signal peptidase
1 99 126 1 77 108 1 82103
proANF proBNP proCNP
S–S S–S S–S
Intracellular proteolytic processing
1 98 1 76 1 81
ANF BNP CNP

Figure 33.3  Schematic representation of the natriuretic peptide gene structure and biosynthesis in humans. ANF, atrial natriuretic factor/​atrial natriuretic
peptide; BNP, B-​type natriuretic peptide; CNP, C-​type natriuretic peptide.
Reproduced from McGrath MF, de Bold AJ. Determinants of natriuretic peptide gene expression. Peptides 2005;26(6):933–​943. doi:10.1016/​j.peptides.2004.12.022 with permission
from Elsevier.

calculated LVEF [18]. Moreover, BNP levels directly correlate ED with acute dyspnoea, adding BNP levels to clinical judgement
with measured PCWPs, thus providing an estimation of LV filling improved the diagnostic accuracy to 81%. A BNP level of <100
pressures [19]. Similarly, NT-​proBNP levels provide equivalent pg/​mL was able to rule out heart failure, yielding a 90% sensi-
diagnostic and prognostic utility in the management of heart tivity, 76% specificity, and 90% NPV, whereas a BNP value of
failure patients. With a longer half-​life, when compared to BNP, >500 pg/​mL was able to rule in heart failure, yielding a PPV of
NT-​proBNP survives longer in the plasma and provides similar 87%. Adding BNP levels to clinical decision-​making reduced the
information regarding heart failure severity and disease progres- physician’s indecision rate from 43% to 11%. Finally, a BNP level
sion [16]. Although natriuretic peptide levels are unable to dis- of 100 pg/​mL was found to be the strongest independent pre-
tinguish systolic from diastolic heart failure, elevated BNP and dictor of heart failure (83%), proving to be more accurate than the
NT-​proBNP levels reflect a wide array of cardiac pathophysiology National Health and Nutrition Examination Survey (NHANES)
such as diastolic function, RV size and function, VHD, filling (67%) and Framingham criteria (73%).
pressures, heart rhythm, and coronary ischaemia [20]. Thus, their Studies have demonstrated a comparative efficacy of BNP and
use has gained widespread acceptance as standard of care for the NT-​proBNP levels in discerning heart failure in the acute set-
management of heart failure patients. ting. The Pro-​BNP Investigation of Dyspnea in the Emergency
Natriuretic peptide levels are part of the ESC and ACCF/​AHA Department (PRIDE) study [26] established age-​ stratified
heart failure management guideline algorithm, for diagnosing NT-​proBNP levels for ruling in and ruling out heart failure.
and excluding HF [2, 3,  21]. Natriuretic peptide levels aid in NT-​proBNP levels of <300 pg/​mL achieved an NPV of 99%.
the diagnosis, prognosis, and risk stratification of AHF patients. Furthermore, NT-​proBNP levels were the strongest independent
Measuring natriuretic peptide levels also help the clinician judge predictor for diagnosing AHF. Studies initially evaluating natri-
response to therapy and may allow titration of AHF therapy to uretic peptides were performed in the early 2000s and since
better improve treatment outcome [22,  23]. A  meta-​analysis of then there have been significant changes in heart failure patient
37 unique study cohorts described the rule-​out thresholds re- demographics and therapies. Whether the diagnostic accuracy of
commended in the 2012 ESC guidelines for HF; plasma BNP, natriuretic peptides still holds in the modern era was addressed
NT-​proBNP, and MR-​proANP have excellent ability to exclude in the ICON: Re-​evaluation of Acute Diagnostic Cut-​Offs in the
AHF [24]. Emergency Department (ICON-​RELOADED) study [27]. This
study evaluated NT-​proBNP in over 1400 patients enrolled from
Natriuretic peptide utility in the 2015 to 2016 and confirmed that NT-​proBNP retained its diag-
emergent setting nostic accuracy for AHF. These findings confirm that natriuretic
The Breathing Not Properly study [25] was one of the largest peptides remain a key tool for diagnosis and management of AHF
multicentre trials demonstrating the clinical value of using BNP and will continue to be in the future.
levels in discriminating heart failure patients with acute dys- E Table 33.1 provides an overview of NT-​proBNP cut-​points
pnoea presenting to the ED. In >1500 patients presenting to the for diagnosing and ruling out heart failure.
 Natriu ret i c   pe p t i de s 413

Table 33.1  Natriuretic peptide grey zone values patients presenting to the ED improved diagnostic accuracy when
added to clinical judgement. Moreover, it positively impacted
BNP NT-​proBNP
direct medical costs of ED visits, rehospitalization over 60 days,
100–​400 pg/​mL <50 years: 300–​450 pg/​mL and the duration of ED visits. Rapid BNP testing has been shown
50–​75 years: 300–​900 pg/​mL to reduce the length of stay and thus lower costs of treatment. In a
>75 years: 900–​1800 pg/​mL clinical study of participants randomly assigned to standard care
versus care utilizing BNP levels, it was found that, in the BNP
arm, the total cost of treatment was $5410, compared to $7264 in
the standard care arm [32]. That said, serial natriuretic peptide
BNP serves as an excellent surrogate for LV function, par- testing is usually discouraged, since only marked deviations from
ticularly the end-​diastolic wall stress. In 160 patients with heart the baseline natriuretic peptide levels (>60% for BNP, and >50%
failure, there was a significant correlation between BNP levels and for NT-​proBNP) have been shown to be associated with clinical
LV end-​diastolic stress and LV end-​diastolic pressure (r  =  0.88 improvement in AHF patients.
and 0.29, respectively) [28]. In an attempt to assess the diagnostic While serial testing of natriuretic peptides during hospital-
utility of BNP levels and LVEF, as determined by 2D echocardio- ization currently lacks data of benefit, numerous studies have
graphy, BNP levels achieved an AUC of 0.89 versus 0.78 for LVEF evaluated the usefulness of measuring natriuretic peptide levels
in diagnosing heart failure. Most importantly, a combined know- at discharge. Various different cut-​offs have been assessed for
ledge of BNP levels, along with EF, the clinical history, and radio- predicting outcomes of mortality and readmission, including
graphic imaging, correctly classified 97.3% of the patients with achieving an absolute BNP (often <200 to 300 pg/​mL) or NT-​
heart failure [29]. proBNP (<3000 pg/​mL) level or a percent reduction in natri-
Despite the reported superiority of natriuretic peptides in uretic peptide levels (frequently a 30% decline) from admission.
diagnosing heart failure, natriuretic peptides do not distinguish A  meta-​analysis found, regardless of the criteria used, moni-
HFrEF from heart failure with preserved (HFpEF) or mid-​range toring for a reduction in natriuretic peptide levels at discharge
ejection fraction (HFmrEF). Thus, natriuretic peptide testing re- was prognostic for post-​hospitalization mortality and there was
mains an adjunct to conventional testing and must not be used as a signal for predicting readmission risk [33]. Some argue meas-
a standalone measure or replace current tools, such as echocar- uring discharge levels is as important as assessing at admission,
diography or radiographic imaging, in diagnosing heart failure. given its prognostic utility, and assessment of natriuretic peptides
is endorsed by guidelines [2]‌. However, a recent large multicentre
Natriuretic peptide utility in the study of over 400 patients somewhat brings this practice into
inpatient setting question [34].
A review of heart failure databases and registries estimates in-​ In this study, patients with AHF were enrolled at admission,
hospital mortality of AHF to be around 4–​7%. The most common but not randomized until achieving clinical stability and felt
causes of acute decompensation, leading to admission, include ready for discharge at which time NT-​proBNP was assessed [34].
ACS, arrhythmias such as AF, valvular disorders, impaired renal Patients who had not achieved a >30% reduction in NT-​proBNP
function, and non-​compliance to diet and/​or medications [3]‌. from admission were randomized to a step-​wise care plan until
In a sub-​analysis of the large-​scale prospective Euro-​Heart NT-​proBNP declined by >30%, if possible, (natriuretic peptide-​
Failure Survey II, characterization of AHF patients and iden- guided therapy) or usual care. The authors found this approach
tification of clinical risk predictors revealed that patients with did not lead to a reduction in mortality or heart failure readmis-
lower mortality at 1 year were more likely to have new-​onset or sion at 180 days. Despite these neutral findings, there are some
de novo heart failure, compared to ADHF. Moreover, the use of important takeaways from this study that may explain the find-
ACE-​Is or ARBs, β-​blockers, and lipid-​lowering agents was more ings. First, by the time of randomization, 64% of patients had al-
common among the survivors. Several factors were associated ready achieved a >30% reduction in NT-​proBNP, leaving only 131
with a worse prognosis such as a history of previous MI, elevated patients to randomize to adjustment of therapy versus usual care,
blood urea nitrogen (BUN) and creatinine levels, anaemia, and which significantly limits the cohort size that might be able to dis-
low serum Na+ concentrations. LV systolic dysfunction was found criminate differences in outcomes with targeting a >30% reduc-
to be a strong independent predictor of short-​term and long-​term tion in NT-​proBNP. Subsequently, only 52% of patients (35/​68)
mortality [30]. randomized to NT-​proBNP-​guided therapy with a <30% reduc-
Inpatient monitoring of BNP levels not only allows the clin- tion in NTproBNP at time of discharge attained a >30% reduc-
ician to judge response to therapy, but also provides prognostic tion. These points show the study to be underpowered. However,
information and may lead to adjustment in therapy. Elevated the authors did note that patients who had already achieved a
BNP levels may reflect failure of ongoing treatment, warranting >30% reduction in NT-​proBNP had the best prognosis, while
the need for more aggressive therapy. The Improved Management those who had a <30% reduction but subsequently achieved
of Patients With Congestive Heart Failure (IMPROVE-​ CHF) >30% reduction had an intermediate prognosis and those con-
trial [31] revealed that NT-​proBNP testing in acutely dyspnoeic tinuing to have a <30% reduction had the worst prognosis for
414 CHAPTER 33   B io m a rkers in acu t e h eart  fa i lu re

death or readmission. These latter findings reinforce the prog- event rates and cardiovascular mortality. The Systolic Heart
nostic significance of assessing a discharge BNP/​NT-​proBNP but Failure Treatment Supported by BNP (STARS-​BNP) trial [41]
also suggest that if there is <30% reduction, attempting to obtain randomized participants to receive either standard treatment or
>30% reduction can improve outcomes. treatment titrated to achieve a BNP level of <100 pg/​mL. Results
Renal function frequently fluctuates during hospitalizations for reported a 50% reduction in deaths due to heart failure in the
ADHF, which could impact natriuretic peptide levels since they BNP-​guided arm. The multicentre Trial of Intensified vs Standard
are renally cleared [35]. However, in a retrospective analysis of Medical Therapy in Elderly Patients With Congestive Heart
908 patients hospitalized with ADHF, investigators evaluating the Failure (TIME-​ CHF) trial [42] randomized 499 participants,
effect of renal function on the prognostic accuracy of NT-​proBNP with a mean age of 76  years, to NT-​proBNP-​guided therapy in
found no interaction between eGFR and NT-​proBNP levels in order to achieve NT-​proBNP levels of <400 pg/​mL in participants
predicting mortality risk at 1 year. They also reported that a single <75 years of age and NT-​proBNP levels of <800 pg/​mL in partici-
cut-​off value of NT-​proBNP at 5180 ng/​mL was an independent pants aged 75 years or older, and to symptom-​guided therapy. The
predictor of 1-​year mortality, irrespective of the residual renal results reported an improvement in heart failure admissions and
function. Moreover, in patients with acute worsening of renal overall mortality in the NT-​proBNP arm only in the <75 years of
function, defined as an increase in serum creatinine of >0.3 mg/​dL, age group and in those with one (or fewer) comorbidity. Similarly,
only patients with persistently elevated NT-​proBNP levels, in results from the NT-​ proBNP-​ Assisted Treatment To Lessen
addition to worsening renal function, were at increased risk of Serial Cardiac Readmissions and Death (BATTLESCARRED)
mortality. The study suggests that, in patients hospitalized with multicentre trial [43] revealed a reduction in 3-​year mortality
ADHF and declining renal function, rising NT-​proBNP levels in participants aged 75 years or younger. A meta-​analysis of 12
occur not only due to decreased renal clearance, but also due to trials published in 2014 demonstrated the use of NT-​proBNP-​
progressing disease severity [36]. guided therapy reduced all-​cause mortality and heart failure-​
Discharging patients with AHF is often difficult, due to the related hospitalization, but not all-​cause hospitalization, whereas
complex nature of heart failure aetiology and a poor correlation BNP-​guided therapy did not significantly reduce either mortality
between clinical symptoms and signs and ongoing pathophysio- or morbidity [44]. In another meta-​analysis by Troughton et al.
logical processes. Moreover, over-​aggressive treatment may harm natriuretic peptide-​guided therapy reduced all-​cause mortality in
the kidneys and exacerbate renal dysfunction, associated with an patients <75 years of age with chronic heart failure and impaired
increased risk of morbidity and mortality [31, 37]. Thus, trying LV systolic function [45]. Although the underlying mechanisms
to tailor therapy to achieve euvolaemia without injury to end-​ by which natriuretic peptide-​guided therapy exerts its beneficial
organs such as the kidney is difficult. Patients with AHF can be effect remain unclear, authors have alluded to optimization of
categorized by their haemodynamic profile based on examination dosing as a possible role in improving outcomes, rather than just
findings of tissue perfusion, providing an estimate of the cardiac aggressive therapy.
output, and congestion referring to the level of fluid overload. While these earlier studies showed a benefit of natriuretic
On the basis of this categorization, heart failure patients can be peptide-​guided therapy for reducing morbidity and mortality, the
classified as ‘warm’ or ‘cold’ depending on the level of perfusion, most recent trial in this area challenges these findings. The Guiding
and as ‘dry’ or ‘wet’ depending on their level of fluid congestion. Evidence Based Therapy Using Biomarker Intensified Treatment
In inpatient management of heart failure patients, heart failure in Heart Failure (GUIDE-​IT) study [46] hoped to definitively an-
therapy must be aimed at achieving a dry or euvolaemic state with swer the question of natriuretic peptide-​guided therapy by enrol-
adequate perfusion [32, 38]. This can be achieved by determining ling the largest cohort of patients. There were 894 patients enrolled
the patient’s ‘dry BNP’ level, which refers to the true BNP level in (original goal 1100), with half randomized to biomarker-​guided
the absence of fluid overload, also known as euvolaemic BNP. The therapy, with a goal of achieving an NT-​proBNP level of <1000
BNP level in the presence of fluid congestion or fluid overload is pg/​mL, and half to usual care. The trial was stopped prematurely
referred to as ‘wet BNP’. Thus, adequate diuresis is crucial in the at a median of 15 months for futility, as no difference was found
acute decompensated state with fluid overload [32, 33, 38, 39]. between the two arms for the composite outcome of heart failure
hospitalization or mortality. While overall the findings were neu-
Natriuretic peptide utility in the tral, a closer look at the details offers possible explanations for
outpatient setting these findings. Patients in the natriuretic peptide-​guided arm did
Natriuretic peptide use to guide outpatient heart failure therapy have slightly more clinic visits, but neither group reached target
remains a controversial topic with equivocal results. More than a doses of medical therapy. Both groups achieved similar doses of
decade ago, Troughton et al. [40] demonstrated a positive benefit β-​blockers, ACE-​Is/​ARBs, and mineralocorticoid receptor antag-
by titrating heart failure therapy to achieve NT-​proBNP levels of onists. The inability to achieve target doses may have been a result
<1700 pg/​mL in patients with newly decompensated heart failure, of a sicker patient cohort, as this study was carried out in heart
established after a 9-​month follow-​up period. Since then, several failure specialty clinics. Additionally, almost the same propor-
large multicentre trials have attempted to assess the effects of tion of patients (nearly 50%) in both arms achieved NT-​proBNP
natriuretic peptide-​guided heart failure therapy on future adverse levels of <1000 pg/​mL. Thus, both arms largely followed the same
 Natriu ret i c   pe p t i de s 415

clinical course without differences in medical therapy or changes *Therapy choices

Perform history, physical examination
in NT-​proBNP levels, as if measurement of NT-​proBNP levels did include ACE-I, ARB
Adjust medications to achieve MRA, BB, CRT, and
not change clinicians’ management. guideline-directed goals loop diuretics
By its original trial design, GUIDE-​IT is a neutral study; how-
ever, the natriuretic peptide-​guided arm did not really achieve its 2–4
aim. If one examines the implications of actually achieving an NT-​ Measure BNP or NT-proBNP week Therapy adjustment*
follow-
proBNP level of <1000 pg/​mL versus being unable to attain this up
level, the value of natriuretic peptide-​guided therapy is revealed.
In an echocardiographic substudy of GUIDE-​IT that examined Review lifestyle and
NP elevated? Yes medication programme for
outcomes in those achieving an NT-​proBNP level of <1000 pg/​mL, opportunities to improve care
regardless of treatment arm, achieving an NT-​proBNP level of
<1000 pg/​mL resulted in significant reverse remodelling reflected No
Limit of tolerance reached
by a higher EF and a larger reduction in LV volume, as well as a
lower rate of the composite outcome of heart failure hospitaliza- Standard follow-up No therapy adjustment
tion or mortality, compared to those who did not achieve an NT-​
proBNP level of <1000 pg/​mL [47]. There are important caveats Figure 33.4  Conceptual approach for natriuretic peptide-​guided heart
to recognize between these groups. Patients who achieved an NT-​ failure care.
proBNP level of <1000 pg/​mL more often had non-​ischaemic car- Reproduced from Troughton R, Michael Felker G, Januzzi JL Jr. Natriuretic peptide-​
guided heart failure management. Eur Heart J 2014;35(1):16–​24. doi:10.1093/​eurheartj/​
diomyopathies and fewer comorbidities, with lower rates of AF eht463 with permission from Oxford University Press.
and chronic kidney disease (CKD), and, though not statistically
significant, started with a numerically lower median NT-​proBNP
treatment is associated with poor outcomes; thus, treatment
level, suggesting a less sick population overall. Despite these dif-
should be initiated as soon as a diagnosis is made. Finally, mark-
ferences, these findings demonstrate the prognostic value of
edly elevated BNP levels have been shown to significantly increase
natriuretic peptides and their potential for guiding management.
the risk of mortality; thus, such patients might benefit from in-
If clinicians practice natriuretic peptide-​guided management, all
tensive care monitoring, especially in the presence of other organ
attempts should be made to reach an NT-​proBNP level of <1000
dysfunction.
pg/​mL or a BNP level of <250 pg/​mL to improve prognosis; how-
Another important caveat to monitoring and interpreting BNP
ever, if a patient is unable to achieve this after 12–​18 months, this
and NT-​proBNP levels is recognizing biological variability. In pa-
is prognostic for worse outcomes and may need consideration to
tients admitted with AHF, fluctuation in natriuretic peptide levels
alternative or advanced therapies.
are often seen, and studies have shown that a change in BNP levels
Thus, prior to GUIDE-​ IT, the weight of evidence would
of >40% and a change in NT-​proBNP levels of >25% indicate
suggest natriuretic peptide-​ guided pharmacologic therapy
changing physiological state [48].
significantly reduces mortality and heart failure-​related hospi-
Although the natriuretic peptide cut-​off values used to diag-
talization in patients with chronic heart failure. While GUIDE-​
nose and exclude heart failure have been established, natriuretic
IT questions this conclusion with its overall neutral findings, a
peptide values referred to as grey zone values (see E Table 33.1)
re-​evaluation of the study outcomes shows the utility of natri-
often arise in heart failure patients [49]. Several underlying con-
uretic peptides for prognosis and management in the outpatient
ditions, such as obesity, renal dysfunction, pulmonary disease,
setting. A  patient with symptoms suggestive of heart failure
ACS, diastolic dysfunction, sepsis, and valvular disorders, can
should have natriuretic peptide levels assessed for diagnosis
alter natriuretic peptide levels [49, 50]. Thus, care should be taken
and the value can also inform on prognosis. Subsequently, with
while interpreting natriuretic peptide levels in heart failure pa-
initiation of therapy, titrating medical therapy to achieve low
tients in the presence of concomitant conditions. Confusion has
natriuretic peptide levels can improve outcomes; however, an
arisen in interpreting natriuretic peptides with the development
inability to achieve low levels informs on prognosis and sug-
of the novel angiotensin receptor neprilysin inhibitor sacubitril-​
gests alternative therapies, such as advanced therapies, should
valsartan (LCZ-​696). Neprilysin is an endopeptidase which breaks
be considered. With this in mind, the heart failure treatment
down vasodilatory hormones that have beneficial properties in
and management paradigm has significantly evolved over the
heart failure; thus, inhibition increases the levels of these bene-
past decade. E Figure 33.4 demonstrates a conceptual frame-
ficial hormones. In the landmark PARADIGM-​HF study, LCZ-​
work to manage care in heart failure patients.
696 was shown to significantly reduce morbidity and mortality
in chronic heart failure [51]. The authors found that treatment
Interpreting natriuretic peptide levels with LCZ-​696 led to a decrease in NT-​proBNP levels while BNP
Certain factors must be considered while interpreting natriuretic levels increased [52]. The authors speculated these discordant re-
peptide levels in the acute setting. First, a thorough clinical exam- sults in natriuretic peptide levels were because sacubitril inhibited
ination and rapid BNP testing to establish the diagnosis and ini- the degradation of BNP while NT-​proBNP was not a substrate
tiate therapy must be considered. Second, a delay in initiating for neprilysin; thus, it was suggested NT-​proBNP may be the
416 CHAPTER 33   B io m a rkers in acu t e h eart  fa i lu re

preferred biomarker in the setting of LCZ-​696. However, BNP is stress, inflammation, neurohormonal activation, and exogenous
actually a poor substrate for degradation by neprilysin and high cardiotoxic agents [60]. The prognostic utility of troponin in
levels of BNP actually inhibit neprilysin [53]. The findings of AHF has been known for over a decade, with a landmark paper
PARADIGM-​HF are actually likely far more complex. A  recent by Peacock et al. showing a positive troponin with conventional
study has shown that depending on the assay used, NT-​proBNP assays had 2.5 higher odds for inpatient mortality [61]. hsTn has
and BNP levels change variably after initiation of LCZ-​696 [54]. furthered the utility of troponin in prognosis and possibly with
This is because assays measure different epitopes of proBNP, BNP, guiding management.
and NT-​proBNP which may be variably expressed with LCZ-​696 Analysis of hsTn in large clinical trials of AHF has demon-
[55, 56]. Additionally, recent studies have shown that both BNP strated its importance. One of the most promising uses of hsTn is
and NT-​proBNP retain their prognostic utility in the setting of identifying low-​risk AHF patients. In the Serelaxin, Recombinant
neprilysin inhibition [57]. Thus, appreciation of the caveats to Human Relaxin-​2, for Treatment of Acute Heart Failure (RELAX-​
natriuretic peptide interpretation, especially in the setting of AHF) trial, over 1000 AHF patients had hsTnT measured at base-
neprilysin inhibition, though this is still an area of active research, line [62]. Those with a low hsTnT value had a very low risk of
is paramount when using these biomarkers and in the manage- cardiovascular mortality and heart failure readmission at 180 days
ment of heart failure patients. (four events in 107 patients) [62]. Additionally, a multimarker
E Box 33.1 provides an overview of conditions associated analysis of 43 biomarkers assessed close to discharge in 1653
with increasing or decreasing natriuretic peptide levels. patients from the Placebo-​controlled Randomized Study of the
Selective A1 Adenosine Receptor Antagonist Rolofylline for
Patients Hospitalized with Acute Decompensated Heart Failure
New biomarkers for routine and Volume Overload to Assess Treatment Effect on Congestion
and Renal Function (PROTECT) trial showed hsTnI (using an
assessment in acute heart failure investigational assay) was the strongest predictor of low risk for
High-​sensitivity troponins death and heart failure readmission [63]. Thus, hsTn appears
useful for identifying low-​risk patients, though further studies are
The troponin assay has undergone significant enhancement over
needed to confirm these findings.
time to now reaching a state of high-​sensitivity troponin (hsTn)
While hsTn may identify low-​risk AHF patients, it also can
defined as an assay able to detect troponin in at least 50%, ideally
identify an increased risk for adverse outcomes. Early studies in
95%, of healthy subjects [58]. Troponin is routinely checked
small populations showed hsTn significantly improved prediction
in patients presenting with AHF to screen for an ACS; how-
of mortality over conventional troponin assays [64, 65]. In recent
ever, troponin is often elevated from non-​ACS causes [59,  60].
large clinical trials, hsTn continues to show strong prognostic
Pathophysiologic processes other than plaque rupture causing
utility. An analysis of over 1000 patients from RELAX-​AHF
an elevated troponin level in AHF include demand ischaemia
showed hsTnT assessed at admission was associated with 180-​day
from subendocardial ischaemia, increased wall stress, oxidative
mortality [66]. Additionally, serial assessments during hospital-
ization showed heightened mortality if hsTnT increased during
subsequent hospital days, with a doubling of risk for a ≥20% in-
Box 33.1  Factors affecting natriuretic peptide levels in patients crease in hsTnT from admission to hospital day 2 [66]. Multiple
with heart failure other studies have looked at the utility of serial assessment of
hsTn during hospitalization for AHF.
Factors decreasing natriuretic peptide levels One of the earliest studies to examine serial measurements by
Obesity
◆ Xue et al. showed increasing hsTnI levels during hospitalization
Flash pulmonary oedema
◆ and an elevated level above 23.25 ng/​mL at discharge was a pre-
Pericardial tamponade
◆ dictor for increased risk of death and heart failure readmission at
90 days [67]. An analysis from RELAX-​AHF looked at the change
Factors increasing natriuretic peptide levels
of hsTnT levels from admission to peak value and found higher
Age
◆
peak values and change to peak were associated with worse out-
Right heart failure
◆
comes, especially in terms of mortality at 180 days [68]. An ana-
Renal failure
◆ lysis using the Acute Study of Clinical Effectiveness of Nesiritide
Valvular disorders
◆ in Decompensated Heart Failure (ASCEND-​HF) study showed
Liver disease
◆ serial assessments at baseline and hospital day 2 or 3 improved
Sepsis
◆ prediction of in-​hospital death or worsening heart failure, while
SAH
◆ evaluation at day 30 from initial AHF presentation was strongly
Trauma
◆ associated with 180-​day mortality [69]. Thus, the literature at this
Stroke
◆ time suggests hsTn can serve a role beyond screening for ACS in
Anaemia
◆
AHF. hsTn levels at presentation can identify low-​and high-​risk
 New bioma rk er s for  rou ti n e as ses sm en t i n  acu te hea rt   fa i lure 417

populations, while serial assessments during hospitalization failure readmission [79]. A  more recent and interesting evalu-
can risk-​stratify for heart failure readmission and mortality risk ation of serial sST2 testing in AHF came from the Translational
during the hospitalization and after, and even an assessment fol- Initiative on Unique and novel strategies for Management of
lowing hospitalization can add prognostic information. Evidence Patients with Heart failure (TRIUMPH) study [82]. Almost 500
is mounting for a multimarker approach to evaluation of AHF. patients with AHF had serial samples of sST2 drawn during
AHF hospitalization and in follow-​up after discharge over 1 year.
ST2 The authors found two general trends for sST2 during this time
ST2 is a marker of myocardial remodelling and, at a molecular frame—​a ‘J’-​relationship where levels were high at presentation
level, plays a distinct role in promoting myocardial fibrosis [70]. for AHF and declined with therapy and remained low; and a ‘U’-​
Identified as a member of the IL-​1 receptor family, ST2 has relationship where levels were high at presentation, then declined
two isoforms. The soluble isoform, denoted as sST2, and the during hospitalization, only to rise again during follow-​up [82].
membrane-​bound receptor form, denoted as ST2L, both of which Patients with a U-​relationship were at a much higher risk of death
are expressed in cardiac myocytes. ST2L binds its functional and heart failure hospitalization than those with a J-​relationship,
ligand IL-​33, and this ST2L/​IL-​33 interaction exerts a protective and the rise in sST2 levels with the U-​relationship occurred much
effect by preventing ventricular remodelling in response to mech- earlier than the actual event [82]. The results for sST2 were in-
anical stress by inhibiting fibrosis, hypertrophy, and apoptosis dependent of NT-​proBNP measurements. These findings suggest
[71, 72]. sST2 competes with IL-​33 and prevents binding of IL-​33 serial sampling of sST2 both during and after AHF hospitaliza-
to ST2L, serving as a ‘decoy receptor’. This blocks the protective tion is useful for determining subsequent risk.
effects and promotes myocardial fibrosis [71, 73]. sST2 is a clin-
ically measurable biomarker and detection of increasing levels is Galectin-​3
thought to reflect more maladaptive processes in the heart. Galectin-​3 is a protein secreted by activated macrophages, re-
The evidence for sST2 has significantly increased over the years, sulting in the proliferation of cardiac fibroblasts and collagen
becoming one of the more promising biomarkers for heart failure, deposition, which ultimately causes cardiac fibrosis [83,  84]. In
including AHF. Unlike natriuretic peptides, sST2 is not affected by patients with HF, galectin-​3 levels can be elevated, denoting its
renal function, age, obesity, or AF [74]. In AHF, multiple studies link to cardiac remodelling. Its utility in AHF patients is similar
have now shown a strong prognostic utility for mortality with to that of sST2 for predicting short-​and long-​term prognosis
sST2. One of the earliest studies using an investigational assay [83, 84].
evaluated sST2 in 593 patients from the PRIDE study presenting One of the earliest studies evaluating galectin-​3 in AHF was
with acute dyspnoea to the ED [75]. sST2 levels were significantly from the PRIDE study. In the 599 patients presenting to the ED
higher in those with AHF, though natriuretic peptides were more with acute dyspnoea, measured plasma levels of galectin-​3, along
potent predictors of heart failure, and sST2 was strongly prog- with NT-​proBNP and apelin, revealed that galectin-​3 levels were
nostic for mortality at 1  year [75]. Subsequent studies with the markedly elevated in participants with heart failure, compared
current clinical assay have also shown sST2 measured at admis- to those without [85]. Galectin-​3 was the strongest independent
sion for AHF is strongly associated with heart failure severity and predictor of 60-​day mortality, yielding an AUC of 0.74 and an OR
subsequent mortality [76–​78]. A meta-​analysis of ten studies has of 10.3 (P <0.01) [85]. Furthermore, in combination with NT-​
shown admission sST2 is strongly prognostic for all-​cause and proBNP, elevated galectin-​3 levels were a better predictor of mor-
cardiovascular mortality [79]. tality [85]. Further studies have highlighted that galectin-​3 may be
As with other biomarkers, serial sampling and discharge values a more potent prognostic biomarker for HFpEF than HFrEF. An
have also been examined with sST2 and found to be significantly analysis of 592 patients hospitalized with AHF found galectin-​3
prognostic for mortality. An early single-​centre study showed was prognostic for mortality and heart failure hospitalization
that AHF patients who had an sST2 level decrease of <15.5% on at 18  months; however, when examined by heart failure type
serial sampling during hospitalization had more than fourfold in- (HFpEF versus HFrEF), it was more prognostic in the HFpEF
creased risk of death at 90 days, compared to those with a decline population [69]. Similarly, other studies have shown galectin-​3 is
of >15.5%, independent of BNP [73]. Other studies using different more prognostic in HFpEF than in HFrEF [78, 86–​88]. However,
criteria for a decline in sST2 levels have similarly shown that serial there are studies that question the prognostic utility of galectin-​3
sST2 sampling can further risk-​stratify patients’ disease trajectory in HFpEF [89].
during hospitalization [80, 81]. Overall, these studies show that A unique quality of galectin-​3 may be the ability to identify
patients without declining sST2 levels have a higher mortality low-​risk patients. Discharge values of 29 biomarkers were meas-
than those patients whose sST2 level declines during AHF hos- ured in almost 900 patients with AHF and galectin-​3 was found
pitalization; however, whether an absolute cut-​off or percentage to be the strongest predictor for a low risk of death or heart failure
change criteria is better and the timing of serial measurement of hospitalization at 180 days [90]. Serial sampling has also shown
sST2 levels are still to be determined. The meta-​analysis previ- potential utility. An analysis from the TRIUMPH study showed
ously discussed found discharge sST2 levels were strongly prog- repeated measurements of galectin-​3 improved prognostic utility
nostic for all-​cause mortality, cardiovascular mortality, and heart for all-​cause mortality and heart failure hospitalization, compared
418 CHAPTER 33   B io m a rkers in acu t e h eart  fa i lu re

to an isolated measurement [91]. Thus, serial measurements and retrospectively evaluated outcomes of patients with AHF and had
discharge levels of galectin-​3 could have prognostic implications PCT measured at admission showed that following a PCT-​guided
for mortality and heart failure hospitalization. algorithm reduced adverse outcomes and shortened the duration
of antibiotics, compared to standard of care [100]. This study fur-
ther adds weight to a potential for PCT-​guided therapy in AHF.
Concomitant conditions seen in the In a retrospective multicentre analysis of 4698 patients with
varying severity of HF, PCT levels were found to be significantly
acute heart failure patient higher in patients with bacterial infections complicated by HF,
Procalcitonin compared to those with simple bacterial infections [93]. The
study suggested that heart failure may interfere with PCT expres-
Patients with AHF can frequently have a concomitant infection,
sion. Results revealed that, in non-​infected patients, PCT levels
such as pneumonia, which could be viral or bacterial in aetiology.
were significantly elevated in patients with increasing severity of
Discriminating pneumonia in the setting of AHF can be diffi-
heart failure. The study suggested consideration and implemen-
cult, as both can have similar presenting symptoms, vital signs,
tation of higher PCT cut-​off values in NYHA class  II–​IV heart
and CXR findings, and treatment with antibiotics is not without
failure patients [93]. Other studies have shown that patients with
risks. Since most patients with AHF present to the ED with a
decompensated heart failure, without clear signs of infection,
chief complaint of dyspnoea, it remains crucial to identify and
who have elevated PCT levels have poorer in-​hospital and post-​
treat the non-​cardiac causes of dyspnoea, if any. This is even more
discharge outcomes [101].
relevant in heart failure patients >75 years of age, as mortality is
Although further trials assessing the utility of PCT levels in in-
higher in this age group in the presence of concomitant infection
fected AHF patients are needed, natriuretic peptide use, in con-
[92,  93]. Misdiagnosis and inappropriate treatment can further
junction with PCT, has been shown to improve the diagnostic
exacerbate the problem and worsen the underlying heart failure.
accuracy of an underlying bacterial pulmonary infection [99].
Several mechanisms have been posited to explain a worsening of
Moreover, this study also demonstrated that a BNP level of >400
heart failure in the presence of bacterial infection, some of which
ng/​mL, along with a PCT level of >0.21 ng/​mL, was able to ac-
include impaired cardiac contractility, due to an increased bac-
curately identify all patients with AHF and an underlying bac-
terial uptake by cardiomyocytes, and activation of the inflamma-
terial pneumonia [99]. Thus, the potential for using PCT testing
tory cascade, leading to worsening of haemodynamic pressures
to detect underlying bacterial pneumonia and subsequently guide
[94, 95].
antibiotic therapy in AHF patients warrants further study.
The role of procalcitonin (PCT) in patients with AHF lies in
its ability to discern an underlying bacterial pulmonary infection,
especially in the absence of radiographic signs and negative blood
testing [96]. PCT is a 12.8-​kDa peptide with a 116-​amino acid Emerging biomarkers
structure and is encoded by the CALC 1 gene located on the short
arm of chromosome 11 [97]. In the presence of a bacterial in- Copeptin
fection, PCT messenger ribonucleic acid (mRNA) upregulation The role of arginine vasopressin (AVP), also known as the anti-
is induced by the bacterial endotoxin, resulting in its release from diuretic hormone (ADH), in heart failure patients is well es-
the neuroendocrine cells of the lungs, intestines, and peripheral tablished. A  decrease in plasma volume and increased serum
mononuclear cells. Moreover, certain pro-​inflammatory cyto- osmolality trigger the release of ADH from the posterior pituitary
kines, such as TNF-​α, IL-​1β, and IL-​6, mediate PCT release. In gland, causing fluid retention [102, 103]. In the most severe cases
non-​infective states, PCT is further metabolized to the biologic- of heart failure, hyponatraemia is often observed as a direct result
ally active calcitonin in the neuroendocrine C cells of the thyroid of this mechanism. The AVP precursor molecule is synthesized in
[97, 98]. the hypothalamus and stored in the posterior pituitary gland. Due
Maisel et  al. demonstrated that using PCT can improve the to its in vitro instability and rapid clearance, AVP is difficult to
diagnostic accuracy in detecting bacterial pneumonia in AHF pa- measure. Copeptin is the more stable and measurable portion of
tients [99]. Moreover, PCT levels improved the AUC from 0.79 the AVP molecule. Copeptin is the C-​terminal portion of the AVP
to 0.86 when added to radiographic imaging. In patients with precursor molecule and is released in equimolar amounts, along
pneumonia, PCT levels ranged from 0.07 to 0.58 ng/​mL, com- with AVP. Copeptin has a 39-​amino acid structure and functions
pared to 0.05–​0.12 ng/​mL in patients without pneumonia. PCT similarly to AVP [104].
was found to be superior to white cell counts in predicting pneu- The role of copeptin in AHF is prognostic in nature. In a
monia. Finally, a survival curve analysis revealed that patients in subanalysis of the multicentre Biomarkers in Acute Heart Failure
the lowest quintile (PCT <0.05 ng/​mL) had a 92% 90-​day survival (BACH) trial, patients with elevated copeptin levels were found
rate, compared to patients in the fifth quintile (PCT >0.21 ng/​ to have the highest risk of mortality and readmissions at 90 days
mL) achieving an 80.5% 90-​day survival rate. The study alluded to [105]. Patients at the highest quartile of copeptin levels were at
the possibility of using PCT levels to guide antibiotic use in AHF an increased risk of 90-​day mortality (HR 3.85) [105]. On multi-
patients with bacterial pneumonia. Indeed, another study that variate analysis, copeptin, along with NT-​proBNP and Na+ levels,
 C on c lusi on 419

achieved a net reclassification improvement of 32.7% for the 90-​ with worsened inpatient and long-​term mortality, independent of
day mortality endpoint [105]. Cox regression analysis revealed natriuretic peptides.
that patients with elevated copeptin levels and hyponatraemia In the aforementioned study, MR-​proADM proved superior
were at highest risk of heart failure-​related readmissions, heart to BNP and NT-​proBNP in predicting 90-​day mortality in pa-
failure-​related ED visits, and death. As mentioned before, in tients with AHF [105]. MR-​proADM outperformed troponin in a
patients with severe heart failure, excess AVP levels result in multivariate analysis. Additionally, MR-​proADM has been shown
hyponatraemia. Moreover, excessive diuretic use can also con- to improve the diagnosis of AHF in elderly patients (>70  years
tribute to worsening hyponatraemia. The study alluded to the role old) when combined with natriuretic peptides [107]. Moreover,
of using AVP antagonists to treat hypervolaemic hyponatraemia MR-​proADM, together with copeptin, in predicting 14-​day mor-
in such patients with heart failure. tality yielded the best AUC of 0.81. Similar results were obtained
RCTs testing the role of using AVP antagonists guided by in a study by Potocki et al. which demonstrated the superior per-
copeptin are needed to better judge their effectiveness in AHF formance of MR-​proADM to natriuretic peptides in predicting
patients. Nevertheless, copeptin serves as an excellent prognostic 30-​day mortality [115].
marker for predicting short-​term mortality in AHF patients. While MR-​proADM has demonstrated significant promise and
utility, it does not reflect the amount of the biologically active
Mid-​regional markers ADM and physiology at the time of assessment. MR-​proADM
is released in a one-​to-​one fashion with the inactive ADM pre-
Peptides are often immeasurable, due to several factors such as
cursor; however, only a small fraction of the inactive ADM pre-
in vitro instability and short half-​life due to rapid plasma clear-
cursor undergoes further processing to biologically active ADM
ance. Mid-​regional markers refer to the stable and easily measur-
[116]. Now there is an assay that specifically measures the bio-
able mid-​regional fragments of these peptides. The development
logically active form of ADM, or bioactive adrenomedullin (bio-​
of newer immunoassays makes it easier to measure these mid-​
ADM). bio-​ADM gives a real-​time evaluation of the physiologic
regional epitopes of circulating hormonal peptides [106]. ANP,
state, as it has a half-​life of 22 minutes [117]. In one of the first
as mentioned before, performs an array of physiological func-
studies evaluating bio-​ADM, 246 patients with suspected AHF
tions when released into the bloodstream, in direct response to
were evaluated upon presentation to the ED. Patients with higher
atrial and ventricular volume and pressure [107, 108]. But their
concentrations of bio-​ADM had a significantly higher rate of the
instability, coupled with a high plasma clearance, made it difficult
30-​day primary composite outcome:  death, cardiac arrest, re-
to measure ANP. MR-​proANP, which refers to the more stable
spiratory failure, emergent dialysis, ACS, length of stay > 5 days,
mid-​regional fragment of ANP, can now be measured using novel
return ED visit in 30 days, and readmission within 30 days [118].
immunoassays directed to the mid segment [106].
Findings were similar in the 124 patients with confirmed AHF.
A subanalysis of the BACH trial revealed that a cut-​point of
In a multivariate model with other biomarkers, bio-​ADM re-
130 pmol/​L for MR-​proANP was non-​inferior to BNP at a 100
mained significant, with an adjusted OR of 2.68 (P <0.001) [118].
pg/​mL cut-​point in diagnosing AHF; furthermore, MR-​proANP
This initial study was followed by a much larger study evaluating
significantly added to the diagnostic performance of BNP and
bio-​ADM in almost 4000 patients with AHF.  bio-​ADM correl-
NT-​proBNP [109]. Importantly, MR-​proANP was shown to pro-
ated with more severe HF, more severe congestion, and the need
vide additive diagnostic information where natriuretic peptides
for higher diuretic doses [119]. Additionally, bio-​ADM was as-
were inconclusive [109]. In another study, MR-​proANP levels as-
sociated with all-​cause mortality and the composite of all-​cause
sessed in 187 patients with NYHA functional class III–​IV heart
mortality and HF hospitalization [119]. While bio-​ADM did as-
failure found that patients with increased MR-​proANP levels
sociate with worse outcomes, its strength was in correlating with
were at increased risk of cardiovascular mortality (HR 7.6) [110].
congestion, and the authors suggested bio-​ADM may be a useful
Other studies have confirmed similar diagnostic power between
biomarker for management of congestion in AHF.
MR-​proANP, BNP, and NT-​proBNP for AHF [111].
The diagnostic and prognostic value of mid-​regional markers
Another mid-​regional marker is MR-​ proADM.
and bio-​ADM is apparent. With more clinical trials exploring the
Adrenomedullin (ADM), first isolated from phaeochromocytoma
role of these markers in AHF, their utility in diagnosis and risk
extract, is a vasodilatory peptide with a 52-​amino acid structure
stratification of AHF patients seems highly promising.
[112]. ADM is synthesized in cardiomyocytes and fibroblasts
and released into the circulation, in direct response to increased
wall stretch. Other factors stimulating ADM release are thought Conclusion
to be neurohormonal activation, along with angiotensin II and
endothelin-​1 (ET-​1) [112, 113]. But a rapid plasma clearance and The role of biomarkers in the management and understanding
a short half-​life (22 minutes) make it unfavourable for clinical of AHF continues to evolve. The AHA published a Scientific
use, whereas the mid-​regional fragment MR-​proADM is a more Statement in 2017 specifically addressing the role of biomarkers
stable peptide [112, 113]. Recently, ET-​1 was studied for its prog- in heart failure [120]. This statement addresses the use of bio-
nostic value in the AHF population from the ASCEND-​HF trial markers in screening, diagnosis, management, and prognostic
[114]. ET-​1, a potent vasoconstrictor, was found to be associated assessment of patients with heart failure. With respect to AHF,
420 CHAPTER 33   B io m a rkers in acu t e h eart  fa i lu re

Table 33.2  Strength of evidence for individual markers in diagnosis, prognosis, and guided treatment

Diagnostic capability Prognostic capability Biomarker-​guided treatment

Natriuretic peptides +++ +++ +++
Procalcitonin +++ ++ ++
High-​sensitivity troponins ++ +++ ++
Galectin-​3 –​ ++ +
Copeptin –​ +++ +
MR-​proADM –​ +++ +
ST2 + ++ +

the use of biomarkers, including natriuretic peptides, troponin, elevated levels of troponin, high-​sensitivity assays, detecting even
copeptin, MR-​proADM, bio-​ADM, and sST2, is mentioned to minute changes in troponins, allow a clinician to gauge ongoing
help better understand the pathophysiology and improve man- cellular damage. Newer markers, such as galectin-​3, belong to
agement of this condition. a class of myocyte remodelling markers, and elevated levels sug-
BNP and NT-​proBNP are benchmark biomarkers of cardiac gest ongoing fibrotic change, which requires treatment aimed at
stress and are part of the AHF management guideline algorithm. preventing further worsening of myocardial remodelling. Copeptin
But certain coexisting conditions, such as pulmonary/​systemic in- levels are indicative of salt/​water homeostatic change, necessitating
fection, valvular dysfunction, renal failure, and obesity, can affect the use of AVP antagonists to block the effects of ADH and treat
biomarker levels. In the presence of ‘grey zone’ biomarker levels, hyponatraemia, the electrolyte imbalance most frequently encoun-
clinicians must look for these comorbid conditions before making tered in severe AHF patients. Newer markers, such as mid-​regional
a definitive diagnosis of heart failure. AHF treatment should peptides, are neurohormonal markers. Although current data dem-
be aimed at lowering the ‘wet BNP’ level, in order to achieve the onstrate promising diagnostic and prognostic capabilities of these
patient’s ‘dry BNP’ level before discharge. bio-​ADM may also be- markers in AHF, further research is needed to better define their
come a useful biomarker for determining euvolaemia in AHF. In role in the AHF patient. Finally, sST2 is a marker for myocyte stress,
patients with AHF and superimposed bacterial pneumonia, the use and elevated levels have been shown to favour a poor prognosis.
of PCT allows the clinician to identify underlying bacterial pneu- E Table 33.2 provides an overview of the strength of evidence
monia when other testing has proved inconclusive. Prognostic for biomarkers discussed in this section.
markers, such as mid-​regional peptides, offer additive information The future for AHF biomarkers revolves around a ‘multimarker’
on short-​and long-​term mortality of the AHF patient. strategy. Moreover, their role in guiding AHF therapy remains
Troponins are established markers of myocyte death/​ injury. controversial but has shown promise. Further randomized clin-
Although there are several conditions which result in non-​specific ical trials are needed to better explore this possibility.

Personal perspective
Biomarkers have definitely entered the mainstream in approach, utilizing a ‘multimarker strategy’, to better
treating and managing patients with heart failure presenting evaluate the heart failure patient. Moreover, emerging
through the ED. Their applications in triaging heart failure biomarkers have provided a more comprehensive under-
patients, facilitating early diagnosis, and titrating treatment standing of the complex underlying pathophysiology.
have been successfully demonstrated. Although there exist Finally, the treatment paradigm might see a shift towards a
certain caveats to their use in the emergent and inpatient more biomarker-​guided therapy.
settings, the future will certainly see a more integrated

Further reading
De Luca L, Fonarow GC, Adams KF, et  al. Acute heart failure acute decompensated national registry (ADHERE). Am Heart J
syndromes: clinical scenarios and pathophysiologic targets for therapy. 2007;153:1021–​8.
Heart Fail Rev 2007;12:97–​104. Januzzi JL, Camargo CA, Anwaruddin S, et al. The N-​terminal pro-​BNP
Fonarow GC, Heywood JT, Heidenreich PA, Lopatin M, Yancy CW. investigation of dyspnea in the emergency department (PRIDE) study.
Temporal trends in clinical characteristics, treatments, and outcomes Am J Cardiol 2005;95:948–​54.
for heart failure hospitalizations, 2002 to 2004:  findings from
 RE F E RE N C E S 421

Maisel A, Mueller C, Nowak R, et al. Mid-​region pro-​hormone markers Maisel AS, Nakao K, Ponikowski P, et  al. Japanese-​Western Consensus
for diagnosis and prognosis in acute dyspnea:  results from the Meeting on biomarkers. Int Heart J 2011;52:253–​65.
BACH (Biomarkers in Acute Heart Failure) trial. J Am Coll Cardiol Maisel A, Neath SX, Landsberg J, et  al. Use of procalcitonin for the
2010;55:2062–​76. diagnosis of pneumonia in patients presenting with a chief complaint
Maisel AS, Krishnaswamy P, Nowak RM, et al. Breathing Not Properly of dyspnea:  results from the BACH (Biomarkers in Acute Heart
multinational study investigators. Rapid measurement of B-​ type Failure) trial. Eur J Heart Fail 2012;14:278–​86.
natriuretic peptide in the emergency diagnosis of heart failure. N Engl McMurray JJV, Adamopoulos S, Anker SD, et al. ESC Guidelines for the
J Med 2002;347:161–​7. diagnosis and treatment of acute and chronic heart failure 2012. Eur
Maisel AS, Mueller C, Fitzgerald R, et  al. Prognostic utility of plasma Heart J 2012;33:1787–​847.
neutrophil gelatinase-​associated lipocalin in patients with acute heart Thygesen K, Mair J, Mueller C, et  al. Recommendations for the
failure: the NGAL EvaLuation Along with B-​type NaTriuretic Peptide use of natriuretic peptides in acute cardiac care. Eur Heart J
in acutely decompensated heart failure (GALLANT) trial. Eur J Heart 2012;33:2001–​6.
Fail 2011;13:846–​51.

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 CHAPTER 34

Biomarkers of coagulation
and thrombosis
Anne-​Mette Hvas, Erik L Grove, and
Steen Dalby Kristensen

Contents
Summary  425
Summary
Introduction  425 Coagulation is evaluated by conventional coagulation analyses, increasingly often
Haemostatic disorders in acute cardiac supplemented by point-​of-​care tests (POCTs). A number of point-​of-​care tests for
care and cardiac surgery: point-​of-​ evaluation of platelet function and the efficacy of antiplatelet therapy have been in-
care tests for diagnosis and targeted
treatment  426 vestigated, and laboratory tests to determine the presence of direct oral anticoagu-
The concept of coagulation  426 lants have been introduced. Thrombophilia contributes to the risk of thrombosis,
Acute cardiac care and cardiac surgery  426 and a battery of complex assays is required to identify thrombophilias.
Strengths and limitations of standard
coagulation analyses  426
Disseminated intravascular coagulation is characterized by microthrombosis
Thromboelastometry/​thromboelastography—​ and clinical bleeding. A scoring system for overt disseminated intravascular co-
a dynamic whole blood coagulation agulation provides a five-​step diagnostic algorithm. The cornerstone of managing
profile  426
Evaluation of the response to antiplatelet disseminated intravascular coagulation is treatment of the underlying triggering
therapy  426 condition.
Limitations of point-​of-​care coagulation Heparin-​induced thrombocytopenia is an adverse immunological effect of treat-
tests  428
Laboratory determination of direct oral ment with heparins. Besides thrombocytopenia, the major clinical consequence of
anticoagulants  428 heparin-​induced thrombocytopenia is an increased risk of thrombosis. The diag-
Thrombophilia  428 nosis is based on clinical symptoms and detection of platelet-​activating heparin-​
Disseminated intravascular induced thrombocytopenia antibodies. When heparin-​induced thrombocytopenia
coagulation  429
is strongly suspected, it is recommended to stop heparin treatment, investigate for
Diagnosis and laboratory tests  429
Heparin-​induced thrombocytopenia  430 heparin-​induced thrombocytopenia antibodies, and initiate non-​heparin anti-
Diagnosis and laboratory tests  430 coagulant treatment.
Conclusion  430
Personal perspective  431
Further reading  432
References  432
Introduction
Haemostatic dysfunction ranges from compromised clot formation in patients with
bleeding to increased clot formation in patients with thrombotic disorders. Laboratory
tests are used to detect haemostatic abnormalities and guide proper intervention. In the
present chapter, strengths and limitations of standard coagulation analyses are presented,
as well as POCTs used for guidance in acute cardiac care and cardiac surgery. Tests for
determination of direct oral anticoagulants (DOACs) are shortly presented. In addition,
the diagnosis of thrombophilia and the acute medical complications DIC and HIT are
summarized. (See also E Chapter 68.)
426 CHAPTER 34   B io m a rkers of   c oagu l at ion a n d  thro m b o si s

patients [7]‌. Evaluation of the coagulation status is performed by

Haemostatic disorders in acute routine coagulation analyses, now often supplemented by POCTs,
cardiac care and cardiac surgery: with the goal of assessing haemostatic function [8]. (See also
E Chapter 39.)
point-​of-​care tests for diagnosis and
targeted treatment Strengths and limitations of standard
coagulation analyses
The concept of coagulation
There is no single global test available to adequately evaluate
The concept of the coagulation cascade as a series of stepwise
overall haemostasis. The initial fibrin formation can be deter-
enzymatic conversions was described as early as 1964, under
mined easily by routine laboratory tests such as PT and aPTT,
the headings of the intrinsic pathway and the extrinsic pathway,
supplemented by thrombin time, fibrinogen (functional), and
culminating in the conversion of fibrinogen to fibrin [1, 2] (see
platelet count, to assess the coagulation status of the patient (see
E Figure 34.1A).
E Figure 34.1A).
Many clinicians have adopted this easily conceptualized view
These methods have been widely utilized for diagnosing and
of haemostasis; however, it is not applicable to in vivo haemo-
monitoring patients with coagulation abnormalities. However,
stasis, although the concept is a valuable scheme for diagnostic
the value of standard coagulation tests has been questioned,
purposes. The current view of in vivo coagulation is that the co-
due to a number of drawbacks—​delays from blood sampling to
agulation process can be divided into three phases:  initiation,
obtaining the results (30–​60 minutes); the tests are determined in
amplification, and propagation (see E Figure 34.1B) [3]‌.
plasma, rather than whole blood; and no information is available
In the initiation phase, exposure of subendothelial tissue factor
on platelet function.
leads to the formation of a catalytic complex with factor (F) VIIa,
In the operating room, the ACT is often used before and during
and small amounts of FIXa, FXa, and thrombin are formed.
cardiopulmonary bypass. The ACT may be used before the pro-
Besides being a cofactor for FVII, tissue factor serves as a re-
cedure to assess heparin requirements, during the procedure
ceptor with signal transduction, resulting in the induction of
to ensure adequate anticoagulation, and finally after the pro-
genes involved in inflammation, apoptosis, and cell migration
cedure to monitor the reversal of heparin [9]‌. ACT is also used
[4]‌. Tissue factor is expressed by many extravascular tissues, es-
in the catheterization laboratory for guidance of anticoagulation
pecially perivascular tissues [5], and importantly tissue factor ex-
therapy with UFH.
pression can also be induced on the endothelium, in response to
The introduction of point-​of-​care coagulation monitoring ad-
inflammatory stimuli such as sepsis. Thus, coagulation and in-
dresses some of the above-​mentioned limitations [10] and may
flammation are strongly integrated processes.
provide a useful supplement to standard coagulation analyses.
During amplification, low concentrations of thrombin acti-
vate platelets and a positive feedback loop is initiated, causing Thromboelastometry/​thromboelastography—​a
increasing amounts of thrombin to be formed. In the propagation
dynamic whole blood coagulation profile
phase, this thrombin burst results in the formation of physiolo-
gically relevant amounts of cross-​linked fibrin, leading to a stable Thromboelastometry (or thromboelastography) (TE) is a diag-
haemostatic clot. Fibrinolysis is essential for removal of the clot. nostic POCT that measures initial clotting, platelet interaction,
The principal mediator of fibrinolysis is plasmin, which cleaves and fibrinolysis in a sample of whole blood. TE was introduced
fibrin to fibrin degradation products. more than 60 years ago to assess primary and secondary haemo-
stasis [11]. After the development of PT and aPTT, the utility
Acute cardiac care and cardiac surgery of TE became limited in clinical settings. With an increasing
number of complex surgical procedures, such as cardiac bypass,
The widespread use of potent antithrombotic therapy in cardiac
TE has been revisited due to a need for rapid assessment of the
care often challenges sufficient haemostasis in these patients.
global haemostatic function.
Coagulation management in patients undergoing cardiac sur-
TE is performed using whole blood and thus allows in vivo
gery is difficult, because of the delicate balance between sufficient
interaction between the coagulation system, platelets, and RBCs.
anticoagulation during cardiopulmonary bypass and the need for
A  major advantage is that the analysis has a short turnaround
sufficient haemostasis afterwards. During cardiopulmonary by-
time (15 minutes) and clot development can be visually displayed
pass, activation of coagulation occurs, because of contact with the
in real time. Furthermore, the use of TE provides a basis for tar-
non-​endothelial surface of the extracorporeal circuit and because
geted therapy and a reduced need for blood products after cardiac
of tissue factor release in the late phase of cardiopulmonary by-
surgery [12–​14].
pass [6]‌. Thus, anticoagulation with heparin is required during
the procedure to inhibit the coagulation cascade, in order to pre-
Evaluation of the response to antiplatelet
vent thrombus formation and microvascular consumption of co-
agulation factors.
therapy
Characterization of the haemostatic defects responsible for Finding the optimal balance between adequate haemostasis and
bleeding is crucial for optimal clinical management of these a beneficial degree of platelet inhibition is a growing challenge,
 Haemostatic disorders in acu te cardiac care and cardiac surgery: p oint-of-care t e sts 427

(a) Intrinsic pathway Extrinsic pathway

(aPTT) (PT)
XII VII

XI

XIIa IX VIIa

XIa

VIII VIIIa + IXa Protein S

Protein C

X Xa + Va V

Common pathway
Antithrombin Fibrinogen (I)
Prothrombin (II) Thrombin (IIa)

Antithrombin
XIII XIIIa

Fibrin clot

(b) Initiation Amplification Propagation

Prothrombin Free vWF Fibrinogen

X Xa XIII
Thrombin VIII/vWF
Va Thrombin
IIa

Prothrombin
-V
TF

XI V
IXa XIIIa
X
TF - VIIa Vllla
XIa IXa
IX Va Vllla Xa
Va
XIa
Activated platelet
P-selectin GP IIb/IIIa Fibrin
CD4OL PAR 1;4
P2Y12/ADP

Figure 34.1  (A) The intrinsic pathway (contact activation pathway) and extrinsic pathway (tissue factor pathway), as described in the cascade model of
coagulation, reflected by the laboratory measurements of aPTT and PT. (B) Current concepts on the coagulation process. TF, tissue factor; vWF, von Willebrand
factor.
Reproduced from De Caterina R, Husted S, Wallentin L, et al. Anticoagulants in heart disease: current status and perspectives. Eur Heart J 2007;28(7):880–​913. doi:10.1093/​eurheartj/​
ehl492 with permission from Oxford University Press.

as more and more patients are receiving antiplatelet therapy [15]. The traditional platelet aggregation test was developed by
Evidence suggests that not all patients respond uniformly to Born [22] and O’Brien [23], and for many years, it was the gold
antiplatelet agents, with some being low-​responders (‘resistant’) standard. This test measures platelet aggregation by turbidimetry,
[16]. This is the case for aspirin and, in particular, for clopidogrel in response to an agonist in platelet-​rich plasma. It has several
[16]. A  low response to antiplatelet therapy may be associated drawbacks, including poor reproducibility, a high sample volume,
with an increased risk of thrombosis [17–​20]. However, a recent the requirement for sample preparation with potential loss of
study did not find that a reduced antiplatelet effect of aspirin pre- large and dense platelets, the length of assay time, the require-
dicted cardiovascular events in patients with stable CAD [21]. As ment of a skilled technician, and high costs [24].
pointed out by the ESC Working Group on Thrombosis [16], the Newly developed POCTs have advantages, including use of
main problem with ‘resistance’ is the lack of a clear definition, due anticoagulated whole blood (no need for sample preparation),
to a lack of standardized methods of platelet function monitoring usage of disposable cartridges or cups (no cleaning required), a
and evidence-​based cut-​off values for platelet function measure- low sample volume, no requirement for a skilled technician, and
ments to classify patients as ‘responders’ or ‘non-​responders’. rapid availability of results.
428 CHAPTER 34   B io m a rkers of   c oagu l at ion a n d  thro m b o si s

A number of POCTs exist, including the platelet function ana- [31]. Furthermore, the utility of these analysers for predicting
lyser 100 (PFA-​100®, new version PFA-​200®), VerifyNow®, and the clinical outcomes has not yet been fully established.
multiple platelet function analyser (Multiplate® Analyzer) [25].
The PFA-​100/​200® assay draws an anticoagulated blood sample Laboratory determination of direct
through a 150-​ micron diameter, collagen-​ coated aperture, in oral anticoagulants
the presence of adenosine diphosphate (ADP) or adrenaline, DOACs are used for prophylaxis, treatment, and secondary
thus mimicking arterial high-​shear conditions. Shear stress and prevention of venous thromboembolism (VTE), non-​valvular
platelet agonists lead to platelet plug formation, and the time until AF, and other cardiac indications [32]. They include the direct
closure of the capillary is recorded [26]. The PFA-​100/​200® might thrombin inhibitor dabigatran etexilate (termed dabigatran) and
be regarded as an in vitro bleeding time recorder. However, this the direct FX inhibitors rivaroxaban, apixaban, and edoxaban.
method has shown considerable variability in evaluating aspirin Regular laboratory monitoring is not considered necessary [33],
low responsiveness [27]. but determination of the anticoagulant activity is important in
The VerifyNow® device is based on the ability of platelets acute situations such as trauma, suspicion of intoxication, or prior
to aggregate with fibrinogen. The system measures changes to acute surgery. For this purpose, specific coagulation tests have
in light transmission, as a result of platelet aggregation been introduced to measure DOAC levels indirectly. These tests
[28]. Three VerifyNow® assays are currently available:  the largely comprise dilute thrombin time (dTT; commercially avail-
VerifyNow® IIb/​ IIIa Assay [sensitive to glycoprotein (GP) able as the Hemoclot®) and the ecarin clotting time for dabigatran
IIb/​IIIa antagonists], the VerifyNow® Aspirin Assay (sensi- and DOAC-​calibrated anti-​Xa activity assays for the Xa inhibitors
tive to aspirin), and the VerifyNow® P2Y12 Assay (sensitive to [32]. Neither standard coagulations tests such as aPTT or PT nor
clopidogrel, prasugrel, and ticagrelor, for example). The vari- TE have proven efficient to monitor DOACs [32], and therefore,
ability of the VerifyNow® Aspirin Assay has been reported to the specific DOAC tests should be preferred.
be low [29].
The Multiplate® Analyzer is based on whole blood impedance
aggregometry [30]. The device has five channels with test cells for
parallel testing. Each test cell contains a stirring magnet and two
Thrombophilia
pairs of electrodes on which activated platelets adhere and aggre- Thrombophilia is an inherited or acquired coagulation defect,
gate, resulting in increased electrical resistance. Several agonists which predisposes to thrombosis. Importantly, most individ-
are available for the stimulation of different platelet receptors or uals with thrombophilia do not develop thrombosis. When
activation of signal transduction pathways, in order to detect thrombophilia presents clinically, the predominant manifestation
changes induced by drugs, as well as by acquired or hereditary is VTE.
platelet disorders. Strong risk factors are deficiencies of the natural anticoagu-
It is not possible to estimate the exact prevalence of ‘resistance’ lants antithrombin, protein C, and protein S.  Deficiencies of
to antiplatelet drugs, due to the lack of a univocal definition [16]. antithrombin, protein C, and its cofactor protein S are found in
As suggested by the ESC Working Group on Thrombosis, the re- <1% of the population [34, 35]. A 10-​fold increased risk of throm-
commended test is a measurement of aggregation induced by ara- bosis has been reported among heterozygous carriers [36].
chidonic acid and the determination of serum thromboxane B2 Factor V Leiden and prothrombin 20210A are less strong risk
for the assessment of aspirin-​specific effects [16]. For assessment factors. In the white population, the prevalence of factor V Leiden
of P2Y12-​specific effects, the recommended test is an aggrega- is approximately 5% [37]. This variant leads to resistance to ac-
tion induced with ADP or vasodilator-​stimulated phosphopro- tivated protein C (APC) [38], and the risk of VTE is increased
tein (VASP) phosphorylation. However, routine determination of 2-​to 5-​fold in heterozygotes and at least 7-​fold in homozygotes
platelet function, while on antiplatelet therapy, is currently not [39, 40].
recommended, due to a lack of evidence on how to use the results A mutation in the prothrombin gene (prothrombin 20210A)
in a clinical setting. leads to increased prothrombin levels, which are associated with a
1.5-​fold increased risk of venous thrombosis [41]. The prevalence
Limitations of point-​of-​care coagulation tests of this mutation is about 2% among whites.
POCTs are difficult to standardize. The blood collection site, pro- Several genetic factors are known to have a weak effect on the
cessing of the sample (e.g. native versus anticoagulated samples, risk of thrombosis, with relative risks between 1.0 and 1.5. The
time delay between collection and measurement), patient age, variant in the gene encoding methylenetetrahydrofolate reductase
and gender may significantly affect test results [10]. The equip- (MTHFR) results in elevated levels of homocysteine. Around 10%
ment and activators will alter the assay specificity, and currently of the general population are carriers, but the effect on homo-
no single point-​of-​care platelet function analyser has conclusively cysteine levels are small and conflicting results exist on the risk of
been shown to be highly reproducible and superior to other tests. thrombosis [42, 43].
Notably, the predictive value in non-​bleeding patients is as low for The antiphospholipid syndrome is an acquired condition de-
whole blood POCTs as it is for conventional coagulation analyses fined by thrombotic and/​or obstetric events, together with the
 Di s sem i nated i n tr avas cu l a r c oag ul at i on 429

presence of antiphospholipid antibodies. Antiphospholipid degree of platelet activation and consumption of coagulation fac-
antibodies can currently be detected using three different as- tors. The extent of fibrin formation can be indirectly evaluated by
says:  lupus anticoagulants, IgG/​ IgM β2 glycoprotein I  anti- measurements of fibrin D-​dimers. A reduced level of the natural
bodies, and IgG/​ IgM cardiolipin antibodies [44,  45]. The anticoagulant antithrombin indicates consumption of natural
presence of lupus anticoagulants consistently shows the highest anticoagulants during the process of DIC.
strength of association with both arterial and venous throm- Repeated determinations of platelet counts are essential when
botic complications [46]. DIC is suspected. A  clear downward trend at repeated meas-
Currently, there is no single laboratory assay or simple set of urements is a sensitive sign of DIC. Thrombocytopenia is seen
assays to identify thrombophilia. Consequently, a battery of com- in up to 98% of patients with DIC. In only around 50% of these
plex and expensive assays is usually required. patients, the platelet count is below 50 × 109/​L [49]. Importantly,
a single determination of platelet count is not sufficient, as the
original platelet count may remain within the normal range of
Disseminated intravascular 150–​400 × 109/​L. A low or decreasing platelet count is not spe-
cific for DIC, as many of the underlying conditions associated
coagulation with DIC, such as sepsis, may also cause a low platelet count
DIC is a clinical pathological syndrome characterized by systemic per se [50].
activation of the coagulation system, leading to widespread vas- PT and aPTT are prolonged in about half of patients with DIC
cular deposition of fibrin and resulting in multiple organ dysfunc- at some point during the course of the disease [47]. This is mainly
tion. Continuous activation of coagulation causes consumption caused by the consumption of coagulation factors. However, re-
of platelets and coagulation factors, which may lead to overt clin- duced liver function, and thereby an impaired synthesis of co-
ical bleeding (see E Figure 34.2). DIC is always secondary to agulation factors, may also contribute to the reduced level of
an underlying disorder that causes activation of the coagulation coagulation factors and a prolongation of PT and aPTT [47].
system, e.g. sepsis. (See also E Chapter 68.) Importantly, normal PT and/​or aPTT do not exclude an activa-
tion of the haemostatic system and repeated measurements are
Diagnosis and laboratory tests required.
Sequential measurements of fibrinogen may also be useful in the
The diagnosis of DIC should be based on appropriate clinical sus-
diagnosis of DIC, although several limitations must be considered.
picion, supported by laboratory tests. There is no gold standard
Fibrinogen is an acute phase reactant, and despite an ongoing
for the diagnosis of DIC, and no single laboratory test exists to
consumption, the plasma levels of fibrinogen may remain within
establish or rule out DIC. A combination of tests can be used to
the normal range for a long period. Thus, hypofibrinogenaemia is
support the diagnosis with reasonable certainty, when under-
mainly seen in very severe cases of DIC [48].
taken in patients with a condition known to be associated with
Plasma levels of antithrombin, the most important inhibitor
DIC [47, 48].
of thrombin, are reduced during DIC, due to consumption, in-
Screening tests for haemostatic function, such as PT, aPTT,
creased degradation, and impaired synthesis. A  reduction of
functional plasma fibrinogen, and platelet count, reflect the
another natural anticoagulant protein C further compromises
adequate regulation of coagulation. Accordingly, the levels of
Underlying disorder antithrombin and protein C are often reduced in DIC, and these
associated with DIC markers have prognostic significance [51, 52]. Repeated measure-
ments are needed, as single determinations are neither sensitive
nor specific for DIC.
A definition and a diagnostic scoring system for overt DIC
Systemic activation of
coagulation
have been proposed by the Subcommittee of the Scientific and
Standardization Committee on DIC of the ISTH [53]. These ISTH
criteria suggest a five-​step diagnostic algorithm to calculate a DIC
score, utilizing laboratory tests available in almost every hospital
Widespread fibrin Consumption of platelets
deposition and coagulation factors laboratory (see E Table 34.1). Using this system, overt DIC is
identified by a score of 5 or more [53, 54]. The overt DIC score is
Thrombocytopenia and
useful for the diagnosis of DIC resulting from infective and non-​
Vascular thrombosis infective aetiologies [55].
coagulation factor deficiency
Treating the underlying triggering condition is the cornerstone
of DIC management [55], but supportive treatment, specifically
Organ failure Bleeding
aimed at coagulation and platelet abnormalities, may be required
[55]. For further information on treatment, see E Chapter 68.
Figure 34.2  The process in DIC.
430 CHAPTER 34   B io m a rkers of   c oagu l at ion a n d  thro m b o si s

Table 34.1  Diagnostic scoring system from the ISTH for DIC

Risk assessment:
Does the patient have an underlying disorder known to be associated with overt DIC?
◆
If yes: proceed.
◆
If no: do not use this algorithm.
◆

Order global coagulation tests: ◆  Platelet count, PT, aPTT, fibrinogen, fibrin D-​dimera.
Score the test results:
Platelet count >100 × 109/​L = 0 50–​100 × 109/​L = 1 <50 × 109/​L = 2
Prolonged PT <3 s = 0 3–​6 s = 1 >6 s = 2
Fibrinogen >1 g/​L = 0 <1 g/​L = 1
Fibrin D-​dimer No increase = 0 Moderate increase = 2 Strong increase = 3
Calculate score:
≥5: compatible with overt DIC; repeat score daily.
◆
<5: suggestive for non-​overt DIC; repeat next 1–​2 days.
◆

aPTT, activated partial thromboplastin time; DIC, disseminated intravascular coagulation; ISTH, International Society on Thrombosis and
Haemostasis; PT, prothrombin time.
a
In most prospective validation studies, a fibrin D-​dimer assay was used as a fibrin-​related marker. A value above the upper limit of normal (0.4
micrograms/​L) was considered moderately elevated, whereas a value >10 times the upper limit of normal (4.0 micrograms/​L) was considered a
strong increase.
Source data from Taylor FB Jr, Toh CH, Hoots WK et al. Towards definition, clinical and laboratory criteria, and a scoring system for disseminated
intravascular coagulation. Thromb Haemost 2001;86(5);1327–​30.

with a laboratory test for HIT provides the highest predictivity

Heparin-​induced thrombocytopenia for HIT [61].
HIT is unlikely if: (1) the platelet counts decrease between days
HIT is an immunological adverse effect of treatment with heparins,
1 and 5 of heparin treatment; (2) the patient shows overt bleeding;
associated with an increased thrombotic risk. Antibody-​mediated
(3) the patient receives GP IIb/​IIIa inhibitors; or (4) the patient is
platelet activation causes thrombin generation, resulting in the
septic.
paradox that, despite thrombocytopenia induced by heparin, the
Laboratory tests can confirm or refute a clinical suspicion of
major clinical consequence of HIT is an enhanced risk of venous
HIT. A rapid HIT assay may be used initially, as the NPV is very
and/​or arterial thrombosis. A prompt diagnosis, discontinuation
high [62]. However, a positive result has to be further investigated
of heparin, and initiation of non-​heparin anticoagulants are es-
by extended laboratory investigations. Currently, these laboratory
sential to prevent further complications.
tests fall into one of two categories:  antigen assays (i.e. platelet
HIT typically occurs 5–​14 days after the start of heparin treat-
factor 4/​polyanion immunoassay) and functional (platelet acti-
ment [56]. In cases of re-​exposure to heparin within 1–​2 months,
vation) assays [e.g. platelet serotonin release assay (14C-​SRA) or
HIT may occur on day 1 of heparin treatment (rapid-​onset HIT).
heparin-​induced platelet activation (HIPA) assay]. Both types of
Delayed-​onset HIT begins several days, and up to a few weeks, after
tests are excellent to rule out HIT, as the NPV is close to 99%
heparin exposure and is caused by antibodies activating platelets,
[63]. However, the specificity is limited, and therefore, these tests
independently of heparin, thus mimicking an autoimmune dis-
only have a moderate PPV. The optimal laboratory diagnostic ap-
ease. HIT enhances the risk of both venous and arterial throm-
proach is a combination of both functional and antigen assays
bosis, but thromboembolic complications predominantly affect
[59, 64].
the venous system.
When HIT is strongly suspected, it is recommended to stop
If a new, unusual thrombotic event occurs during or after hep-
heparin treatment, investigate for HIT antibodies, and initiate
arin therapy, the diagnosis of HIT should be considered. The risk
non-​heparin anticoagulant treatment in therapeutic doses, even
of HIT is influenced by the heparin preparation (bovine UFH >
in patients without thrombosis. For further information on treat-
porcine UFH > LMWH), the duration of heparin exposure, pa-
ment, see E Chapter 68.
tient gender (female > male), and patient category (post-​surgical
> medical > obstetric) [57]. (See also E Chapter 68.)

Diagnosis and laboratory tests Conclusion

The diagnosis should be based on both clinical symptoms and de- Cardiac surgery and antithrombotic treatment of cardiac patients
tection of platelet-​activating HIT antibodies [58, 59]. predispose to bleeding, whereas thrombophilia and the acute
The ‘4 Ts’ score is a standardized tool to assess the probability medical conditions DIC and HIT mainly predispose to thrombo-
of HIT (see E Table 34.2) [60]. Combining the clinical score embolic disease. Furthermore, a reduced antiplatelet effect of
 Per s ona l  pe r spe c t i v e 431

Table 34.2  Standardized clinical assessment of the probability of HIT

Probability score
Clinical features (4 Ts) 2 1 0
Thrombocytopenia Platelet count fall >50% and platelet Platelet count fall 30–​50% or platelet nadir 10–​19 Platelet count fall <30% or
nadir ≥20 platelet nadir ≤10
Timing of fall in platelet count Onset days 5–​10 or <1 day if heparin >10 days or timing unclear Platelet count fall <4 days,
or other sequelae exposure within 30 days without recent heparin
exposure
Thrombosis or other sequelae New thrombosis; skin necrosis; post-​ Progressive or recurrent thrombosis; erythematous None
heparin bolus acute systemic reaction skin lesions; suspected thrombosis—​not confirmed
Other causes of No other cause of platelet count fall Possible other cause is evident Definite other cause is present
thrombocytopenia is evident
HIT, heparin-​induced thrombocytopenia.
Score 0–​3: HIT is very unlikely; no further testing is needed and heparin treatment can be maintained.
Score 4–​5: a minority of patients have HIT.
Score 6–​8: HIT is likely and these patients usually require substitution with a non-​heparin anticoagulant.
Reproduced from Lo GK, Juhl D, Warkentin TE, Sigouin CS, Eichler P, Greinacher A. Evaluation of pretest clinical score (4 T's) for the diagnosis of heparin-​induced thrombocytopenia in
two clinical settings. J Thromb Haemost 2006;4(4):759–​765. doi:10.1111/​j.1538-​7836.2006.01787.x with permission from John Wiley and Sons.

aspirin and/​or clopidogrel (‘resistance’) might increase the risk of Thrombophilia is an inherited or acquired coagulation de-
thromboembolic events in patients with CAD. fect, which predisposes to thrombosis. Currently, there is
In acute bleeding, coagulation is evaluated by standard coagu- no single laboratory assay or simple set of assays to identify
lation analyses, often supplemented by TE. A major advantage of thrombophilia, so a battery of complex and expensive assays is
TE is a short turnaround time (15 minutes) and visual real-​time usually required.
display of clot development. In addition, the use of TE provides DIC is characterized by microthrombosis and is often fol-
guidance for targeted haemostatic intervention. Neither standard lowed by clinically overt bleeding. DIC is always secondary to
coagulation tests nor TE are capable of predicting the risk of an underlying disorder that causes activation of the coagulation
bleeding, e.g. prior to surgery. system, e.g. sepsis. In patients with a condition known to be as-
A number of tests for evaluation of platelet function and the sociated with DIC, a combination of tests can be used to support
efficacy of antiplatelet therapy are currently being investigated. the diagnosis with reasonable certainty. The cornerstone of DIC
However, routine measurements of platelet function in patients management is treatment of the underlying triggering condition.
on antiplatelet therapy is not recommended, due to a lack of evi- Besides thrombocytopenia, the major clinical consequence of
dence on how to interpret the results in a clinical setting. HIT is an enhanced risk of thrombosis. The diagnosis is based on
Specific assays for detection of DOACs have emerged and can the clinical picture and detection of platelet-​activating HIT anti-
be used prior to acute surgery, in the management of trauma, or bodies. Rapid laboratory assays with a high NPV have emerged
in cases of bleeding in patients treated with DOACs. and may be used as an acute first-​line test.

Personal perspective
Many new antithrombotic drugs are more effective in individually tailored therapy into practice. Novel classes of
preventing ischaemic events but are also likely to increase antithrombotic drugs will be developed, including dual-​
bleeding complications. As bleeding increases cardiovas- function drugs inhibiting several platelet-​activating path-
cular mortality, present and future strategies will focus on ways or drugs combining antiplatelet and anticoagulant
reducing bleeding complications. By tailoring a specific activity.
therapy to individual patients, such strategies may hope- The scoring system for DIC will be further validated, and
fully improve the benefit–​risk ratio of oral antithrombotic similar approaches for capturing coagulopathy through readily
drugs. These strategies are likely to include individual drug available and future assays will be developed. Potentially
dosing, individual duration of therapy, and identification new therapies used for the treatment of DIC will be further
of risk factors and patient subgroups with an increased risk evaluated.
of bleeding. These points are already major research areas. Future studies performed to understand the immunobiology
In particular, efforts to develop simple and reliable platelet of HIT may help to explain why host defences can result in
function tests and to identify polymorphisms in key re- autoimmunity. Prospective studies will be required to test the
ceptors and metabolic enzymes may put the concept of clinical utility and safety of pretest clinical scores for HIT.
432 CHAPTER 34   B io m a rkers of   c oagu l at ion a n d  thro m b o si s

Further reading
Grove EL, Storey RF, Würtz M. Platelet function testing in Levi M, Toh CH, Thachil J, Watson HG. Guidelines for the diagnosis
atherothrombotic disease. Curr Pharm Des 2012;18:5379–​491. and management of disseminated intravascular coagulation.
Hoffman M, Monroe DM. Coagulation 2006:  a modern view of British Committee for Standards in Haematology. Br J Haematol
hemostasis. Hematol Oncol Clin North Am 2007;21:1–​11. 2009;145:24–​33.
Hvas AM, Grove EL. Platelet function tests:  preanalytical variables, Taylor FB Jr, Toh CH, Hoots WK, Wada H, Levi M. Towards definition,
clinical utility, advantages, and disadvantages. Methods Mol Biol clinical and laboratory criteria, and a scoring system for disseminated
2017;1646:305–​20. intravascular coagulation. Thromb Haemost 2001;86:1327–​30.
Kuliczkowski W, Witkowski A, Polonski L, et  al. Interindividual Watson H, Davidson S, Keeling D. Guidelines on the diagnosis and
variability in the response to oral antiplatelet drugs: a position paper of management of heparin-​induced thrombocytopenia: second edition.
the Working Group on antiplatelet drugs resistance appointed by the Br J Haematol 2012;159:528–​40.
Section of Cardiovascular Interventions of the Polish Cardiac Society, Würtz M, Grove EL. Interindividual variability in the efficacy of oral
endorsed by the Working Group on Thrombosis of the European antiplatelet drugs:  definitions, mechanisms and clinical importance.
Society of Cardiology. Eur Heart J 2009;30:426–​35. Curr Pharm Des 2012;18:5344–​61.

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 CHAPTER 35

Biomarkers of renal and

hepatic failure
Mario Plebani, Monica Maria Mion, and
Martina Zaninotto

Contents Summary
Summary  434
In the last years, major advances have been achieved in the understanding of the
The cardiorenal syndrome  434
molecular and pathophysiological mechanisms which underlie the complex inter-
Pathophysiological mechanisms  434
Biomarkers  435 actions between the heart and the kidney, as well as between the heart and the liver.
Creatinine  435 According to these new insights, new biomarkers have been proposed for better
Creatinine clearance and glomerular
filtration rate  435
evaluating and monitoring patients affected by cardiovascular diseases. In add-
Estimated glomerular filtration ition, some biomarkers should be used as risk factors and for early identification
rate  435 and treatment of these severe diseases. This chapter reviews the most important
Cystatin C  435
Cystatin C and prediction of biomarkers for evaluating the ‘cardiorenal syndrome’, in particular the measure-
cardiovascular outcome  436 ment of serum creatinine and its use for calculating the glomerular filtration rate
Urinary proteins and albumin/​creatinine
ratio  436
which, with a new and more efficient equation, namely the Chronic Kidney Disease
Proteinuria  436 Epidemiology Collaboration, still remains the most widely used biomarker. The
Albuminuria  437 role of newer biomarkers will be explored. The measurement of cystatin C, rep-
Neutrophil gelatinase-​associated
lipocalin  438 resenting additional information, particularly in paediatric age groups and in
Acute kidney injury  438 the early phase of kidney disease, plays an increasing role. Neutrophil gelatinase-​
The heart and liver connection: associated lipocalin is a recently developed, but largely used, biomarker for early
background  438 diagnosis of acute kidney injury, while the well-​known albumin/​creatinine ratio
Acute liver diseases: background  439
Cardiogenic ischaemic hepatitis: definition has been re-​evaluated as a simple and useful tool for early identification of kidney
and diagnosis  439 disease. Regarding liver diseases, a growing body of evidence demonstrates the
Oxygen free radicals and usefulness of non-​invasive markers of hepatic fibrosis that may avoid the need for
scavengers  439
Leucocytes and inflammatory a liver biopsy in most patients. A  promising field of research is represented by
mediators  439 the role of non-​alcoholic fatty liver disease in the pathogenesis of cardiovascular
Laboratory tests to be used in clinical
practice  439 disease.
Chronic liver diseases: background  439
Biochemical markers of liver fibrosis  439
Direct markers of fibrogenesis  439
Indirect markers  439
Enhanced Liver Fibrosis Test®  439
Cirrhotic cardiomyopathy: background  439
Biomarkers  440
Risk of cardiovascular disease in liver
The cardiorenal syndrome
disease: background  440
Diagnosis and biomarkers  440 Pathophysiological mechanisms
Conclusion  440 The term ‘cardiorenal syndrome’ (CRS) [1, 2] can be generally defined as bidirectional
Personal perspective  441 disorders of the heart and kidney, whereby an acute or chronic dysfunction in one organ
Further reading  441 may induce an acute or chronic dysfunction in the other organ.
References  441 The pathophysiological mechanism [3]‌seems to be primary via the circulatory system
(haemodynamic factors), or secondary to underlying endogenous humoral or exogenous
factors that are associated with disease of either organ, or a combination of both.
 The ca rdi orena l   sy n dro m e 435

This interaction can occur in normal organs (acute dysfunc- Creatinine clearance and glomerular filtration rate
tion) or diseased organs (acute or chronic dysfunction) and in Because creatinine is endogenously produced and released into
one or both organs, or a combination. The cause and temporality body fluids at a constant rate, its clearance has been proposed
of this interaction, in terms of kidney damage and subsequent as an indicator of the GFR. Historically, creatinine clearance has
clinical deterioration, are unpredictable. been seen as more sensitive for the detection of renal dysfunc-
In order to include the vast array of interrelated derangements tion than the measurement of plasma creatinine, but it requires
and to stress the bidirectional nature of the heart–​kidney inter- a timed urine collection, which introduces its own inaccuracies.
actions, the proposed classification includes five subtypes, the Furthermore, in adults, the intraindividual day-​to-​day creatinine
etymology of which reflects the primary and secondary path- clearance may exceed 25%, and this further devalues the use of
ology, the time frame, and the simultaneous cardiac and renal creatinine clearance as a measure of the GFR. Creatinine clear-
co-​dysfunction secondary to systemic disease [4]‌, in particular: ance and the GFR are not equivalent; as the kidney function de-
◆ Type I: acute CRS. clines, creatinine clearance becomes significantly higher, due to
◆ Type II: chronic CRS. preserved tubular secretion of creatinine, and may be twice the
◆ Type III: acute renocardial syndrome. true GFR when the GFR is severely reduced. The best overall
◆ Type IV: chronic renocardial syndrome. measure of kidney function is the GFR measured as the urinary
◆ Type V: secondary CRS. or plasma clearance of an ideal filtration marker, such as inulin,
or of alternative exogenous markers such as iothalamate or ethyl-
Biomarkers enediamine tetraacetic acid (EDTA) [7]‌.
Quantitation of overall renal function is based on the assump- Estimated glomerular filtration rate
tion that all functioning nephrons are performing normally and Several formulae have been derived to estimate GFR, using
that a decline in renal function is due to a loss of functioning plasma creatinine corrected for some, or all, of gender, body
nephrons quantitatively related to the decline. Thus, in nearly size, race, and age. Indeed, the National Kidney Foundation has
all types of renal disease, impaired function is attributed to a recommended [8]‌the Chronic Kidney Disease Epidemiology
diminished number of nephrons, rather than to compromised Collaboration (CKD-​ EPI) creatinine equation that uses four
function of individual nephrons. Because glomerular filtration variables, as well as the known Modified Diet in Renal Disease
is the initiating phase of all nephron functions, a quantitative (MDRD) study equation, but shows high accuracy, particularly
or qualitative assessment of filtration generally provides the at high GFRs. As a consequence, the CKD-​EPI formula is widely
most useful indices to assess the severity and progress of kidney used because it has been demonstrated to perform well also in
damage. elderly patients (>65 years).
The biochemical markers that have been proved to be the most The improvement in accuracy is attributable to a substantial
practical and useful to diagnose and monitor impaired kidney decrease in systematic differences between the measured GFR
function are the following. (mGFR) and the eGFR, especially for subjects with an eGFR of
>60 mL/​min/​1.73 m2. In particular, there was an improvement
Creatinine in bias in subgroups at low risk of CKD, for which an underesti-
Creatinine is the most widely used endogenous marker of the mation of the mGFR may have led to an overestimation of the
GFR, produced at fairly constant rates and freely filtered at the CKD prevalence, including those aged younger than 65  years,
glomerulus; a distal tubular secretion may account, however, for women, and whites. For eGFR of up to >90 mL/​min/​1.73 m2, bias
up to 10–​40%. As a GFR marker, it is convenient and cheap to is negligible—​unbiased GFR estimations in groups at increased
measure, but the concentrations are affected by age, sex, exercise, risk of CKD, such as the elderly, blacks, patients with diabetes,
certain drugs, muscle mass, nutritional status, and meal intake. organ transplant recipients, and the overweight and obese, have
Plasma creatinine remains within the reference interval, until sig- important implications in public health and clinical care [9]‌.
nificant renal function has been lost, showing an unsatisfactory On the basis of eGFR values obtained with the CKD-​EPI equa-
sensitivity in the early diagnosis of kidney insufficiency. tion, five GFR categories have been defined:
The most relevant limitation in the clinical sensitivity of cre- ◆ G1—​normal or high: >90 mL/​min/​1.73 m2.
atinine lies in the evaluation of the circulating concentration on
◆ G2—​mildly decreased: 60–​89 mL/​min/​1.73  m2.
the basis of a general reference interval; creatinine concentra-
◆ G3a—​mildly to moderately decreased: 45–​59 mL/​min/​1.73 m2.
tion shows, in fact, a high variability between subjects, making
◆ G3b—​moderately to severely decreased: 30–​44 mL/​min/​1.73  m2.
the adoption of a general reference interval not adequate to
evaluate small changes [5]‌. The knowledge of the biological vari- ◆ G4—​severely decreased: 15–​29 mL/​min/​1.73  m2.
ability and usefulness of the reference change value (RCV) rep- ◆ G5—​kidney failure: <15 mL/​min/​1.73  m2.
resents a fundamental tool in clinical chemistry [6]. However, Cystatin C
because of all the described limitations, it is recommended
that plasma creatinine measurement alone is not used to assess Cystatin C, a 13-​kDa endogenous cysteine proteinase inhibitor, is
kidney function. a member of a family of proteins having an important role in the
436 CHAPTER 35   B io m a rkers of   renal and h epati c fa i lu re

intracellular catabolism of several peptides and proteins [10]. It Several studies have highlighted the significant association be-
is synthesized at a constant rate by all nucleated cells in the body. tween cystatin C concentrations and heart failure incidence and
With regard to renal function, due to free filtration of cystatin C outcomes. In particular, it was shown that cystatin C, but not cre-
by the glomerulus, its complete reabsorption, and its catabolism atinine, was a predictor of heart failure, independently of other
without secretion in the renal tubule, serum cystatin C circulating risk factors [26, 32]. High concentrations of cystatin C were re-
concentration has been thought to depend almost exclusively on lated to LV hypertrophy and diastolic dysfunction in patients with
the GFR [11, 12]. Cystatin C represents an alternative blood bio- no previous cardiac failure [33–​35]. In patients with heart failure,
marker of kidney function [13, 14], and several GFR-​estimating cystatin C concentration increases with severity of the disease,
equations have been developed in the past [15–​18]. The influence as defined by the NYHA classification [36]. Several studies have
of body composition and other non-​renal factors on cystatin C documented cystatin C to be an independent predictor of mor-
serum concentrations seems less than that on creatinine, and tality in heart failure patients [37–​43]. The association between
cystatin C correlates with true GFR more accurately than cre- higher cystatin C concentrations and increased rates of CVD
atinine [19]. An international certified cystatin C primary refer- and/​or adverse outcomes has been reported in different cohorts
ence material (ERM®-​DA471/​IFCC) was prepared and released in of subjects without CKD or with normal kidney function [26, 29,
2010 by the International Federation of Clinical Chemistry and 44,  45]. In CKD patients, higher cystatin C values significantly
Laboratory Medicine (IFCC) [20], and a standardized assay of predicted mortality and progression to renal transplantation or
cystatin C traceable to that reference material is available. Recently, dialysis [46]. In populations of older adults, cystatin C predicted
the CKD-​EPI developed new equations, based on standardized CKD or renal function decline, associated with an increased risk
cystatin C and cystatin C, in combination with standardized cre- of all-​cause and cardiovascular death [26, 47, 48].
atinine [21]. Cystatin C measurement is recommended when a In summary, cystatin C is a useful blood biomarker of kidney
confirmation of CKD is required for patients with a creatinine-​ function that accurately reflects the renal GFR in various popu-
based eGFR of 45–​59 mL/​min/​1.73 m2 and no albuminuria; in lations of healthy and diseased subjects. In CRS, cystatin C is an
these patients, a cystatin C-​based eGFR of <60 mL/​min/​1.73 m2 interesting biomarker in the evaluation of kidney function, as well
confirms a diagnosis of CKD [8]‌. Cystatin C-​based eGFRs seem as in the risk stratification of patients with cardiac failure or CVD,
more powerful predictors of patient clinical outcomes, particu- reflecting even a modest impairment in renal function not de-
larly CVD, than those based on creatinine [22] among patients tected by traditional routine markers such as creatinine.
showing a GFR of >45 mL/​min/​1.73 m2. Moreover, measuring
cystatin C, in addition to creatinine, can improve the accuracy of Urinary proteins and albumin/​creatinine ratio
GFR estimation and CKD classification [8]. Proteinuria
Proteinuria refers to the presence of increased amounts of
Cystatin C and prediction of cardiovascular outcome
protein in the urine. It may reflect an abnormal loss of serum
Given that the kidney function is tightly correlated with cardio- proteins being attributable to:  (1) increased permeability of
vascular risk, due to the strong impact of renal dysfunction on glomeruli to high-​molecular weight proteins (glomerular pro-
impaired survival and CVD progression, cystatin C might prove teinuria or albuminuria); (2) incomplete tubular reabsorption of
a useful predictor of cardiovascular risk (see E Figure 35.1). usually filtered low-​molecular weight proteins (tubular protein-
Several studies have shown cystatin C to be a powerful risk marker uria); and (3) increased serum concentration of low-​molecular
for adverse cardiovascular events in different cohorts of subjects. weight proteins [overproduction proteinuria, e.g. immuno-
Decreased eGFR calculated with cystatin C has a higher predictive globulin (Ig) light chains]. Similarly, proteinuria may reflect an
value in terms of cardiovascular morbidity and mortality in hyper- abnormal loss of proteins from the kidney (renal tubular damage
tensive population than creatinine-​based eGFR in patients with a causing a leak of tubular cell constituents), as well as from the
moderate to severe reduction in renal function [23]. Furthermore, lower urinary tract. Albuminuria, tubular proteinuria, and the
patients having the highest cystatin C values showed higher rates presence of renal tubular cell constituents in urine samples are
of MI and stroke (median follow-​up 7.4 years) [24], particularly in pathognomonic of kidney damage [8]‌. Moreover, proteinuria
elderly patients without renal insufficiency at baseline, resulting appears to play a significant role in the pathogenesis of disease
in cystatin C being a better predictor of cardiovascular events and progression of CKD [49]. The recently published KDIGO clinical
death than creatinine [25, 26]. practice guideline for the evaluation and management of CKD
A recently published meta-​analysis [27] demonstrated that in recommends, as diagnostic criteria for CKD, a GFR threshold
patients with stable CAD, high cystatin C concentrations were as- of <60 mL/​min/​1.73 m2 or the detection of kidney injury (albu-
sociated with an increased risk of death, cardiovascular events, minuria, urine sediment abnormalities, electrolyte and other ab-
and hospitalization in both patients with and those without normalities due to tubular disorders, abnormalities detected by
kidney insufficiency at baseline. In patients without CKD, higher histology, structural abnormalities detected by imaging, a history
cystatin C levels were correlated with a higher rate of stroke, MI, of kidney transplantation). A  CKD classification, based on the
and angina pectoris [28]. In ACS patients, including both STEMI cause, GFR, and albuminuria, is promoted (see E Chapter 66).
and NSTEMI, cystatin C concentrations predicted the subsequent As a matter of fact, albumin is the main component of urinary
incidence of death, MI, and heart failure hospitalization [29–​31]. protein in most kidney diseases and a strong graded relationship
 The ca rdi orena l   sy n dro m e 437

Figure 35.1  Proposed mechanisms linking renal dysfunction, inflammation, atherogenesis, and cardiovascular events.

exists between urinary albumin concentrations and the risk of threshold for the urinary AER in the timed urine sample is ≥30
kidney disease and/​or CVD [8]. mg/​24 hours sustained for >3  months, a value approximately
Albuminuria equivalent to an ACR of ≥30 mg/​g measured in a random urine
Albuminuria refers to the presence of an abnormal loss of al- sample [8]. These values are >3 times the normal levels found in
bumin in the urine. Albumin is the most abundant protein meas- young adults (AER 10 mg/​24 hours; ACR 10 mg/​g) and associ-
ured in serum, contributing significantly to maintain a normal ated with an increased risk of CKD complications, as well as with
serum oncotic pressure. Despite the high concentration of al- a subsequent risk of all-​cause mortality, cardiovascular mortality,
bumin in serum, only small quantities of this protein appear in AKI, kidney failure, and CKD progression in the general popu-
the urine of normal subjects, due to the size and charge select- lation and in subjects with cardiovascular risk factors [51–​53].
ivity of the glomerular filtration barrier, in addition to reabsorp- Different studies showed evidence that urine samples collected
tion of filtered albumin by the renal tubuli [50]. Even if albumin in the first morning void provide lower albuminuria values than
is one of the serum proteins measured in the urine of normal a random urine sample collected throughout the day (urinary
subjects, it is a common, but not uniform, finding in CKD. AER is normally higher during the day due to physical exercise
Albuminuria is the earliest biomarker of glomerular diseases, and/​or body posture). Moreover, albuminuria levels measured
appearing generally before a reduction in the GFR (e.g. diabetic in a first morning void urine sample correlate better with results
glomerulosclerosis). On the other hand, it is also a biomarker of obtained from a 24-​hour collected urine sample than with re-
hypertensive nephrosclerosis, in which it may rise after a reduc- sults obtained from a random urine sample [54, 55]. According
tion of the GFR. Albuminuria is also associated with underlying to these observations, sequential testing is recommended, fol-
hypertension, obesity, and vascular disease where the underlying lowing an increased ACR obtained from a random urine sample
kidney disease is not overt [8]‌. Albuminuria, as well as protein- with testing on a first morning void urine sample. If a more ac-
uria, is expressed as the urinary loss rate: albumin excretion rate curate estimate of albuminuria (or proteinuria) is required, it is
(AER) and protein excretion rate (PER), respectively. Three main recommended to measure the AER (or PER) in a timed urine
albuminuria categories have been identified, on the basis of daily sample [8]. Albuminuria is a well-​established diagnostic and
urinary albumin loss, generally detected as the albumin/​cre- prognostic biomarker in diabetic nephropathy, and it is associ-
atinine ratio (ACR): A1 (normal to mildly increased), <30 mg/​24 ated with glomerulonephritis, hypertension, hyperlipidaemia,
hours or <30 mg/​g; A2 (moderately increased), 30–​300 mg/​24 obesity, smoking, the metabolic syndrome, and a previous history
hours or 30–​300 mg/​g; A3 (severely increased), >300 mg/​24 of stroke or MI [56–​59]. Across every category of eGFR, higher
hours or >300 mg/​g [8]. To indicate CKD, the clinical decision levels of albuminuria define an increased risk of death, CVD, and
438 CHAPTER 35   B io m a rkers of   renal and h epati c fa i lu re

kidney disease progression [60]. Due to its additional predictive are necessary, given rapid and accurate identification of the early
ability, above and beyond that of the eGFR, albuminuria has been phase of AKI is a major challenge in clinical laboratories; an ideal
proposed as an additional biomarker to classify the CKD stages biomarker should be non-​invasive to measure, using urine or
[60]. Supporting data are lacking to definitively recommend al- blood, rapid and inexpensive, and on automated assay platforms,
buminuria reduction as a surrogate clinical target [61]. Albumin allowing to report results with a turnaround time adequate for
represents a major urinary protein in many severe glomerular in- clinical needs. From a clinical point of view, it should be associ-
juries, being, for example, the recommended marker for early dia- ated with a known mechanism of renal injury, sensitive to estab-
betic nephropathy. However, the determination of albuminuria, lish an early diagnosis, and able to identify tubular damage and
rather than total proteinuria, may underdiagnose kidney disease differentiate AKI from CKD [71].
associated with multiple myeloma, in which filtered light chains In guidelines published some years ago by the Acute Dialysis
may be the main protein in the urine sample [51]. Indeed, if sig- Qualitative Initiative (ADQI), only NGAL and cystatin C have
nificant non-​albumin proteinuria is suspected, analytical assays been proposed as novel biomarkers with the potential to be
to measure specific urinary proteins (e.g. monoclonal heavy or integrated into clinical practice [4]‌ . Recently, in association
light chains, α1-​microglobulin) should be used [8]. with NGAL measurement, new plasmatic and urinary bio-
In summary, the AER is strongly recognized as a convenient, markers [kidney injury molecule 1 (KIM-​1), tissue inhibitor of
cheap, and helpful tool in routine clinical practice to assess the metalloproteinase (TIMP)-​2, insulin-​like growth factor-​binding
onset, as well as the progression, of renal disease. Albuminuria or protein (IGFBP)-​7), microRNA] have been proposed and evalu-
proteinuria adds significantly to the risk stratification of subjects ated in several studies, providing relevant information on risk
with, or at risk of, CKD. stratification and prognosis of AKI patients [71].
Several studies in homogenous (adult and paediatric cardiac
Neutrophil gelatinase-​associated lipocalin surgery), as well as heterogenous (intensive care and ED) [72],
NGAL, also known as lipocalin 2 or siderocalin, is a small molecule populations have further demonstrated the utility of NGAL meas-
(178 amino acids) that belongs to the superfamily of lipocalins, urement for the early diagnosis of AKI and for the prediction of
which are proteins specialized in binding and transporting severity of the acute disease and the need for RRT.
small hydrophobic molecules. It is expressed by neutrophils and A multicentre pooled analysis of prospective studies carried out
various human tissues, with the loop of Henle and the collecting on critically ill children and adults with CRS [73] demonstrates
ducts as main production sites in the kidney [62], and may have that approximately 20% of patients display an early increase in
an important role not only in defending against bacterial strains NGAL concentrations, without any increase in creatinine con-
depending on siderophores through iron sequestration [63], but centrations, during monitoring. In this subgroup of patients, a
also in kidney development, as a growth factor, in renal regener- significant increase in the rate of adverse clinical events, such as
ation and repair after ischaemic injury, and in kidney protection mortality, dialysis requirement, and ICU and overall hospital stay,
[64]. Human NGAL was identified and isolated from secondary has been observed, suggesting that early NGAL measurements
granules of neutrophils and is detectable in the serum and urine as may allow to identify patients with subclinical AKI.
three main forms: a 25-​kDa monomer; a 45-​kDa disulfide-​linked In conclusion, the described results indicate that NGAL repre-
homodimer; and a 135-​kDa heterodimer where the protein is cova- sents an earlier and more sensitive marker of renal injury, com-
lently bonded to matrix metalloproteinase (MMP)-​9. According to pared to creatinine, and that the concept and definition of AKI
experimental data, the monomer may be predominantly released (currently still based on the measurement of serum creatinine and
by tubular cells, whereas the homodimer may be synthesized by urinary flow) might need reassessment. More recently, TIMP-​2
neutrophils [65]. This aspect seems to be relevant in the configur- and IGFBP-​7 have been proposed as valuable biomarkers for early
ation and performance of measurement assays [66,  67]. The ex- identification of AKI [74].
pression of NGAL rises 1000-​fold in humans, in response to renal
tubular injury, and it appears so rapidly in the urine and serum that
it is useful as an early biomarker of renal failure. Therefore, from
a clinical point of view, the use of the NGAL assay is particularly
The heart and liver connection:
useful for the diagnosis and prognosis of patients suffering from background
AKI, including patients with CRS related to heart failure [68]. Chronic, as well as acute, heart diseases can affect the function of
Acute kidney injury the liver, and vice versa liver dysfunction affects the heart [75, 76].
AKI represents a serious and frequent clinical complication Liver injury encountered in patients suffering from CVDs is ar-
among hospitalized patients [69] that has been shown to correlate bitrarily divided into acute and chronic, based on the duration or
with adverse patient outcome (see E Chapter  66). Serum cre- persistence of the process.
atinine, as well as BUN or other urinary markers of kidney injury, Acute insults may arise from transient deprivation of blood
reflects functional alteration when a significant amount of renal flow and O2 and the return of blood flow during reperfusion (e.g.
function has been lost, thus limiting their usefulness in the early in AMI and CS). Chronic heart disease, namely haemodynamic
detection of AKI [70]. Consequently, more reliable biomarkers changes due to right or left cardiac failure, can lead to reduced
 The hea rt a n d l i ver c on n ecti on : bac kg roun d 439

liver perfusion and secondarily to impairment of liver function. there has been increasing interest in identifying and describing
In particular, liver damage in congestive heart failure may further liver fibrosis by using non-​invasive biochemical markers meas-
progress to liver fibrosis and cirrhosis [77]. urable in peripheral blood.

Acute liver diseases: background Biochemical markers of liver fibrosis

Ischaemia and reperfusion injury (IRI) represents a complex Biochemical markers of liver fibrosis may be classified into two
series of events that result in cellular and tissue damage of the broad groups that are:  (1) direct markers of fibrogenesis which
liver. In particular, cardiogenic ischaemic hepatitis (CIH) is often are the direct expression of either the deposition or the removal
seen in the face of acute CS. (See also E Chapter 15.) of the extracellular matrix (ECM) in the liver; and (2)  indirect
markers that are single or combined haematological or biochem-
Cardiogenic ischaemic hepatitis: definition and diagnosis ical parameters that reflect the stage of liver disease.
CIH is defined as a rapid and marked increase of serum trans- Direct markers of fibrogenesis
aminases and is diagnosed when there are extremely high levels These include several glycoproteins (hyaluronan, laminin, YKL-​
of ALT and/​or AST (>1000 U/​L), acute arterial hypertension is 40), the collagen family (procollagen III, type IV collagen),
present, and primary liver failure is excluded [78]. The liver en- collagenases and their inhibitors, and a number of cytokines as-
zymes fall rapidly to normal levels, once the circulation is re- sociated with the fibrogenic process [transforming growth factor
stored. Oxygen free radicals (OFRs), NO, and several chemokines (TGF)-​β1, TNF-​β]. While some of these biochemical markers,
and cytokines may mediate and modulate this process [79, 80]. namely hyaluronan and type III procollagen, have demonstrated
Oxygen free radicals and scavengers good accuracy in excluding cirrhosis, their performance in
OFRs are considered one of the most significant components of defining the stage of liver fibrosis greatly varies from one study
cell and tissue damage during ischaemia and reperfusion. Among to another, with a wide range of sensitivity and specificity [87].
OFRs, hydrogen peroxide, superoxide anion, and hydroxyl rep- Indirect markers
resent the main aggressive components, while among OFR scav- The first indirect markers of liver fibrosis are the transamin-
engers and inhibitors, superoxide dismutase (SOD) represents an ases, particularly when reported as the AST-​ to-​
ALT ratio
important, and even measurable, biomarker [81]. (AAR). A  further evolution of this index is the so-​called AST-​
Leucocytes and inflammatory mediators to-​platelet ratio index (APRI). In the last few years, many other
Leucocytes are highly involved in liver IRI and function both to test panels have been proposed, but the most widely investigated
amplify the molecular pathways and to directly cause cellular combination set of non-​invasive markers of liver fibrosis is the
damage [82,  83]. A  number of mechanisms may account for FibroTest®. This is a combination of five blood tests, including
leucocyte infiltration during liver IRI:  P-​selectin, phosphatidyl gamma glutamyltransferase (GGT), bilirubin, haptoglobin,
serine, and various cytokines/​chemokines (CXCL10, RANTES, apolipoprotein A1, and α2-​macroglobulin, adjusted for gender
MCP-​1, MIP-​1, MIP-​MMP, namely MMP-​9) [84]. and age by using a patent algorithm [88]. The FibroTest® has been
Moreover, NO plays a significant role in microcirculation and extensively tested in chronic hepatitis, namely virus C hepatitis,
organ IRI, exerting both beneficial and harmful effects [85]. where the AUC resulted to be around 0.85 for significant fibrosis.
Recently, a new combination algorithm of non-​invasive markers
Laboratory tests to be used in clinical practice
of liver fibrosis in chronic hepatitis C has been proposed, with
The new insights and experimental evidence previously described
high diagnostic accuracy (>94%), allowing a 50% reduction in the
have not been translated into clinical practice, and currently none
number of liver biopsies [89].
of the described mediators, other than transaminases, are used
as valuable biomarkers for detecting acute liver damage in CVD. Enhanced Liver Fibrosis Test®
The Enhanced Liver Fibrosis Test® (ELF®) is an algorithm con-
Chronic liver diseases: background sisting of direct markers of fibrogenesis, namely hyaluronic acid,
the amino terminal propeptide of type III collagen, and TIMP-​1.
The distinction between acute and chronic liver injury is a
A  systematic review has shown comparable results for the ELF®
mechanistic oversimplification. Chronic liver injury reflects, in
and FibroTest®, with an AUC of 0.90 for cirrhosis and 0.82 for >
part, continuous acute liver injury extended over time; how-
stage 2 fibrosis [90, 91].
ever, it leads to progressive fibrosis that can eventually result in
cirrhosis, liver failure, or hepatocellular carcinoma [86]. Liver
fibrosis represents a hallmark of chronic liver diseases and cir-
Cirrhotic cardiomyopathy: background
rhosis, and staging of hepatic fibrosis is of paramount clinical Cirrhotic cardiomyopathy is defined as ‘a cardiac dysfunction
importance for prognostic assessment in the individual patient. in patients with cirrhosis that is characterized by impaired con-
Liver biopsy still represents the gold standard for evaluating the tractile responsiveness to stress and/​or altered diastolic relaxation
presence, type, and stage of liver fibrosis, but this procedure is with electrophysiological abnormalities in the absence of other
invasive, costly, and difficult to standardize [87]. In recent years, known cardiac disease’ [92].
440 CHAPTER 35   B io m a rkers of   renal and h epati c fa i lu re

Biomarkers the presence of insulin resistance and the metabolic syndrome.

BNP and NT-​proBNP elevations correlate with the severity of cir- Fibrinogen and CRP are increased in NAFLD patients, particu-
rhosis and with the degree of cardiac dysfunction, as well as with larly those with steatohepatitis [non-​ alcoholic steatohepatitis
intraventricular septal and LV wall thickness [93]. A possible role (NASH)]. In the last few years, the importance of adiponectin has
for ADM, a hormone involved in the regulation of vascular tone been increasingly recognized, and hypoadiponectinaemia is in-
and natriuresis, was also reported [94]; ADM may contribute to dependently associated with NASH and with more severe hepatic
myocardial dysfunction in cirrhosis, via the negative inotropic ef- steatosis and necroinflammation [96]. Measurement of these bio-
fect of NO. Serum levels of this hormone are higher in cirrhotic, chemical markers should be suggested to allow an early diagnosis
particularly ascitic, than non-​ascitic patients. and effective treatment of these diseases.

Risk of cardiovascular disease in liver

disease: background Conclusion
Recent cross-​sectional and prospective studies on the association The discovery of molecular and pathophysiological mechanisms
between non-​alcoholic fatty liver disease (NAFLD) and inter- underlying the complex interactions between the heart, kidney,
mediate markers of CVD or clinical outcomes indicate not only a and liver paved the way to the development and implementa-
link, but also a causal role of NAFLD in the pathogenesis of CVD tion of new biomarkers. In particular, a body of evidence has
[95]. Current understanding of the pathogenesis of NAFLD im- been collected to recommend the reporting of eGFR, as well as
plies that lipids accumulate in hepatocytes in the presence of in- the inclusion of cystatin C assay, for cardiovascular risk predic-
sulin resistance and that multiple factors, including non-​esterified tion. The ACR, a very simple and inexpensive test, is associated
fatty acids (NEFAs), hormones, pro-​inflammatory cytokines, and with an increased risk of CKD complications, as well as with a
adipocytokines, are involved in the atherogenic process, as shown subsequent risk of cardiovascular mortality, and NGAL rep-
in E Figure 35.2. resents a very promising marker in AKI. Concerning the heart
and liver interaction, the measurement of simple tests, such as
Diagnosis and biomarkers
serum transaminases, is still of value in acute liver diseases, while
The liver is central to the production of classical biomarkers a promising field of translational research is in the development
of inflammation and endothelial dysfunction, the secretion of of non-​invasive markers of fibrosis.
which depends, at least in part, on factors that are upregulated in

Expanded and inflamed

Genetic variability abdominal adipose tissue
Environmental factors

Inflammatory cytokines
Insulin resistance
NEFA
Inflammatory cytokines
Insulin resistance

Pure steatosis NASH

Oxidative stress
Atherosclerosis Inflammation
Lipotoxicity

C-reactive protein
Fibrinogen
Plasminogen activator inhibitor-1
Oxidative stress
Triacylglycerol-rich VLDL, small dense LDL
HDL2
Postprandial lipaemia
Glucose dysregulation
Insulin resistance

Figure 35.2  Biochemical and genetic mechanisms linking NAFLD to the pathogenesis of CVD.
Reproduced from Targher G, Marra F, Marchesini G. Increased risk of cardiovascular disease in non-​alcoholic fatty liver disease: causal effect or epiphenomenon? Diabetologia
2008;51(11):1947–​1953. doi:10.1007/​s00125-​008-​1135-​4 with permission from Springer Nature.
 RE F E RE N C E S 441

Personal perspective
Recently published recommendations by scientific societies particularly in paediatric age groups and in the early phase of
confirm the fundamental role of new biomarkers in early disease. Among other recently developed and promising new
identification of patients suffering from CRS. Measurement biomarkers, NGAL is expected to play a fundamental role in
of serum creatinine and its use for calculating the eGFR the early diagnosis of AKI, while the well-​known ACR has
still remain the most widely used biomarker. However, the been re-​evaluated as a simple and useful tool for early identifi-
cystatin C assay provides relevant additional information, cation of kidney disease.

Further reading
Boudoulas KD, Triposkiadis F, Parissis J, et  al. The cardio-​ renal Di Lullo L, Bellasi A, Russo D, et  al. Cardiorenal acute kidney injury:
interrelationship. Prog Cardiovasc Dis 2017;59:636–​48. epidemiology, presentation, causes, pathophysiology and treatment.
Sivalingam Z, Larsen SB, Grove EL, et al. Neutrophil gelatinase-​associated Int J Cardiol 2017;227:143–​50.
lipocalin as a risk marker in cardiovascular disease. Clin Chem Lab Boursier J, Vergniol J, Guillet A, et  al. Diagnostic accuracy and
Med 2018;56:5–​18. prognostic significance of blood fibrosis tests and liver stiffness
Inker LA, Eckfeldt J, Levey AS, et al. Expressing the CKD-​EPI (Chronic measurement by FibroScan in non-​alcoholic fatty liver disease. J
Kidney Disease Epidemiology Collaboration) cystatin C equations Hepatol 2016;65:570–​8.
for estimating GFR with standardized serum cystatin C values. Am J Stevens LA, Coresh J, Greene T, Levey SA. Assessing kidney function—​
Kidney Dis 2011;58:682–​4. measured and estimated glomerular filtration rate. N Engl J Med
Ketteler M, Block GA, Evenepoel P, et al. Executive summary of the 2017 2006;354:2473–​83.
KDIGO Chronic Kidney Disease-​Mineral and Bone Disorder (CKD-​ Bjork J, Back SE, Ebert N, et al. GFR estimation based on standardized
MBD) Guideline Update: what’s changed and why it matters. Kidney creatinine and cystatin C:  a European multicenter analysis in older
Int 2017;92:26–​36. adults. Clin Chem Lab Med 2018;56:422–​35.
Peralta CA, Shlipak MG, Judd S, et al. Detection of chronic kidney disease Bukabau JB, Yayo E, Gnionsahé A, et al. Performance of creatinine-​or
with creatinine, cystatin C, and urine albumin-​to-​creatinine ratio and cystatin C-​based equations to estimate glomerular filtration rate in
association with progression to end-​stage renal disease and mortality. sub-​Saharan African populations. Kidney Int 2019;95:1181–​9.
JAMA 2011;305:1545–​52.

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 SECTION VI

Acute coronary
syndromes

36 Atherosclerosis and thrombosis  447

Lina Badimon and Gemma Vilahur
37 The universal definition of myocardial infarction  463
Kristian Thygesen, Joseph S Alpert, Allan S Jaffe, and Harvey D White
38 ST-​segment elevation myocardial infarction  479
Borja Ibanez and Stefan James
39 Fibrinolytic, antiplatelet, and anticoagulant drugs in acute coronary syndromes  494
Sigrun Halvorsen, Giuseppe Gargiulo, Marco Valgimigli, and Kurt Huber
40 Mechanical complications of myocardial infarction  513
Elena Puerto and Héctor Bueno
41 Non-​ST-​segment elevation acute coronary syndromes  531
Héctor Bueno and José A Barrabés
42 Percutaneous coronary interventions in acute coronary syndromes  549
Andreas Mitsis and Marco Valgimigli
43 Coronary artery bypass graft surgery  565
Piroze M Davierwala and Michael A Borger
44 Sex considerations in acute coronary syndromes  585
Eva Swahn, Joakim Alfredsson, and Sofia Sederholm Lawesson
 CHAPTER 36

Atherosclerosis
and thrombosis
Lina Badimon and Gemma Vilahur

Contents
Summary  447
Summary
Introduction  448 Atherosclerosis is the main underlying cause of ischaemic heart disease.
Atherosclerosis  448 Continuous exposure to cardiovascular risk factors induces endothelial activation/​
Initial changes in the arterial wall  448 dysfunction which enhances the permeability of the endothelial layer and the ex-
Dysfunctional endothelium and
lipoprotein infiltration and
pression of cytokines/​chemokines and adhesion molecules. This results in the ac-
retention  448 cumulation of lipids (low-​density lipoprotein particles) in the intimal layer and
Vascular smooth muscle cell the triggering of an inflammatory response. Accumulated low-​density lipoprotein
response  449
Effects of flow and geometry  450 particles attached to the extracellular matrix suffer modifications and become pro-​
Progression of vascular lesions  450 atherogenic, enhancing leucocyte recruitment and further transmigration across
Innate and adaptive immunity
responses  450
the endothelium into the intima. Infiltrated pro-​atherogenic monocytes (mainly
Fibroproliferative changes and vascular CD14+/​CD16–​) differentiate into macrophages which acquire a specialized pheno-
remodelling  451 typic polarization, depending on the stage of atherosclerosis progression. Once
Fatty streaks  451
Complex vulnerable atheroma and differentiated, macrophages upregulate pattern recognition receptors capable of
calcification  452 engulfing modified low-​density lipoprotein, leading to foam cell formation. Foam
Systemic and local risk factors for plaque cells release growth factors and cytokines that promote vascular smooth muscle
complications and event presentation  452
Atherosclerotic plaque burden and plaque cell phenotypic switch and further migration into the intima, which then in-
imaging  453 ternalize low-​ density lipoproteins via low-​ density lipoprotein receptor-​ related
Thrombosis  453 protein-​1 receptors, becoming foam cells. As the plaque evolves, the number of
Cellular and molecular mechanisms in
thrombus formation  453
vascular smooth muscle cells decline, whereas the number of fragile/​haemor-
Platelets  453 rhagic neovessels and calcium deposits increases, promoting plaque destabiliza-
Coagulation  454 tion. Disruption of this atherosclerotic lesion exposes thrombogenic surfaces rich
Platelet–​coagulation interplay  455
Fibrinolysis  455 in tissue factor that initiate platelet adhesion, activation, and aggregation, as well
Regulation of thrombus growth by local and as thrombin generation. Platelets also participate in leucocytes and progenitor cell
systemic factors  456
Extracellular vesicles  456
recruitment are likely to mediate atherosclerosis progression. Recent data attribute
Lifestyle and therapeutic implications in to extracellular vesicles (mainly microvesicles) a modulatory effect in the overall
atherothrombosis  456 atherothrombotic process and provide evidence for their potential use as systemic
Conclusion  457 biomarkers of thrombus growth and/​or thrombotic burden.
Personal perspective  457 This chapter reviews our current understanding of the pathophysiological mech-
Acknowledgements  457 anisms involved in atherogenesis, highlights platelet contribution to thrombosis and
Further reading  457 atherosclerosis progression, and provides new insights into how atherothrombosis
References  457 may be prevented and modulated.
448 CHAPTER 36   Atherosclerosis and t h romb o si s

cell recruitment and transmigration [6–​9]. Indeed, NO modulates

Introduction leucocyte trafficking by blocking the expression of nuclear factor
(NF) κB-​regulated cytokines/​chemokines and vascular adhesion
Atherosclerotic disease is a pathological inflammatory process
molecules.
characterized by the deposition of lipid and other blood-​borne
Endothelial NO is produced through enzymatic conversion
materials within the arterial wall. Deposition of these materials
of L-​arginine to L-​citrulline by eNOS. However, continuous ex-
and subsequent thickening of the wall may significantly com-
posure of the endothelial layer to cardiovascular risk factors
promise the residual lumen, leading to plaque erosion or rup-
(e.g. hyperlipidaemia, hypertension, smoking, obesity, insulin
ture and subsequent thrombus formation (atherothrombosis).
resistance, or inflammation, among others) leads to endothelial
Atherothrombosis is a major cause of AMI which, in turn, is
cell dysfunction and eNOS impairment. We demonstrated that
the leading cause of mortality and morbidity in Western coun-
atherogenic concentrations of native unmodified LDL and low
tries [1]‌. From a clinical point of view, this disease is seen as a
concentrations of minimally modified LDL (mmLDL) suffice to
single diffuse pathological entity (affecting almost all vascular
decrease NO bioavailability, either via a reduction of eNOS ac-
territories), but with local manifestations. Until recently, athero-
tivity or via a decrease in mRNA and protein eNOS expression
sclerosis development was seen as a constantly progressing pro-
[10]. Furthermore, oxidized LDL (oxLDL) has also been shown to
cess, irreversibly associated to ageing. However, within the last
impair acetylcholine-​induced eNOS activation. Hence, increased
decade, evidence indicates that atherosclerotic plaque homeo-
plasma levels of LDL particles damage the endothelium, enhan-
stasis is not necessarily a constantly progressing process. There
cing vascular permeability and favouring circulating LDL entry
are wide data showing that atherosclerotic plaque formation can
into the arterial wall. In fact, arterial deposition of cholesterol has
be slowed, stopped, or even reversed. A better understanding of
been shown to be directly proportional to the concentration of
the underlying mechanisms involved in the dynamics of athero-
circulating plasma lipoproteins.
genesis will allow the development of interventions aimed at
Subendothelial retention and modification of LDL particles
halting, and even regressing, the atherosclerotic process. In fact,
and subsequent accumulation of LDL-​derived lipids in the intima
novel imaging technology has allowed the accurate evaluation
are the central pathogenic event that promotes atherosclerotic
of plaque evolution and composition, vital to the assessment of
lesion formation [11, 12]. LDL transports cholesterol and other
intervention efficacy.
lipids in the circulation where it is in native non-​oxidized form,
In this chapter, we discuss the processes and players involved in
because plasma antioxidant molecules protect against oxidation.
the formation and progression of atherosclerotic lesions, highlight
However, once these apolipoprotein-​B-​rich particles have entered
the contribution of platelets to thrombosis and atherosclerosis
the intimal space, they become modified and retained by ECM
progression, and provide new insights into how atherothrombosis
components of the intima such as proteoglycans. Chondroitin
progression may be modulated.
sulfate proteoglycans, such as versican, a main structural proteo-
glycans of the ECM, can strongly interact with, retain, and ag-
gregate LDLs. The length and number of proteoglycan-​related
Atherosclerosis glycosaminoglycan chains, as well as their degree of sulfation, de-
termine their capacity to retain LDL particles within the arterial
Initial changes in the arterial wall intima [13]. Once sequestered in this intimal microenvironment,
Dysfunctional endothelium and lipoprotein infiltration lipoprotein–​proteoglycan complexes are susceptible to modifi-
and retention cations (aggregation/​fusion, enzymatic cleavage, and hydrolysis)
The vascular endothelium is a semi-​permeable barrier that con- and oxidative changes. During the initial stages of in vitro LDL
trols the diffusion of plasma molecules and regulates vascular oxidation, oxidative modifications of LDL lipids can occur in the
tone, inflammation, and haemostasis [2,  3]. The endothelial absence of changes, or little change, in apolipoprotein-​B. Such
antithrombotic properties are maintained through the continuous modified LDLs are called mmLDLs, which retain the affinity to
release of NO and PGI2, and by the expression of transmembrane the LDL receptor, have a negative charge, activate anti-​apoptotic
proteins, including thrombomodulin and heparan-​ like mol- signalling, and enhance chemokine and cytokine release [12].
ecules (see E Figure 36.1). The endothelial transcription factors This results in the recruitment of inflammatory cells which
Kruppel-​like factor 2 and 4 (KLF4) have been shown to contribute promote continued LDL oxidation, thereby affecting the LDL
to maintaining the antithrombotic endothelial surface by inducing apolipoprotein-​B component (oxLDL). oxLDLs lose their recog-
endothelial nitric oxide synthase (eNOS) and thrombomodulin nition by the LDL receptor and shift to a recognition by pattern
expression [4]‌. Besides, the endothelium blocks coagulation by the recognition receptors [toll-​like receptors (TLRs) and scavenger
expression of tissue factor pathway inhibitor (TFPi) and the activa- receptors] (see E Figure 36.1). In this regard, oxLDLs have
tion of tissue plasminogen activator (tPA) which enhances spon- been shown to induce inflammasome activation through TLR
taneous fibrinolysis (see E Figure 36.1) [5]. Endothelial-​derived stimulation. Inflammasomes are intracellular complexes able to
NO also exerts other vasoprotective effects such as vascular relax- convert pro-​IL1β and pro-​IL18 into their mature forms, thereby
ation (in concurrence with endothelium-​derived hyperpolarizing contributing to a pro-​inflammatory innate immune response.
factor), endothelial regeneration, and inhibition of inflammatory Among the various inflammasome complexes, inflammasome
 Athero s c l e ro si s 449

KLF2/4

– – –
ICAM
Electrostatic
LFA-1 Thrombomodulin
Heparan sulfate – – – repulsion
Healthy
NO proteoglycan TFPi TPa
CX3CR1 endothelium
PG12 Platelet
TF-FVIIa
Monocyte Fibrinolysis Antithrombotic endothelium
Platelet Thrombin
(CD14+/CD16++)
aggregation Blood
coagulation
Monocyte P-selectin
Aggregated
(CD14+/CD16–) Neutrophil platelets
CXCL-2
LDL EVs
MCP-1
Lymphocyte
EVs EVs Thrombus formation
(Th1)
RBC
Activated
platelets GPIIb/IIIa
vWF Atherosclerotic
CD40L GPIb
ICAM VCAM ↑ ICAM ↑ VCAM VCAM TF lesion
↑IL-6 ↑ IL-1 ↑ IL-1β
EC
ECM
Macrophage (M1) Foam cell Necrosis
mmLDL oxLDL LOX-1 Haemorrhage
EVs
Intima

M-CSF
Lipid-laden
EVs Angiogenesis
SRA SRA VSMC MMPs
CD36 CD36
EVs TF
IL-1β, IL6, IL8,
TNF-α, ROS
Media

Contractile VSMC
Synthetic VSMC

Figure 36.1  This figure illustrates the complexity of events that drive the atherosclerotic process. The first step in atherosclerosis is the internalization of lipids
in the intima that induces the endothelial secretion of chemotactic substances and the expression of adhesion receptors that favour monocyte recruitment,
adhesion, and transmigration into the arterial wall. Once there, macrophages accumulate lipids, leading to foam cell formation. Foam cells aggravate the
atherogenic process by releasing growth factors, cytokines, metalloproteinases, and reactive oxygen species, all of which perpetuate and amplify the vascular
remodelling process and activate VSMC migration. On the other hand, continuous exposure of risk factors damages the endothelium, which loses its
antithrombotic features (green circles), which, in conjunction with endothelial dysfunction/​disruption, induces platelet activation. Activated platelets, through
the release of chemokines, cytokines, and a number of immunomodulatory ligands, mediate the inflammatory response. Indeed, activated platelets have a
large arsenal of mediators that interact with both leucocytes and endothelial cells, promoting atherogenesis progression and further complications. Finally, EVs
derived from platelets, leucocytes, macrophages, and endothelial cells are suggested to contribute to all stages of atherosclerosis development by promoting
endothelial activation, inflammation, VSMC migration, and eventual thrombus formation through TF. CD40L, CD40 ligand; CXCL-​2, chemokine (C-​X-​C motif)
ligand 2; EV, extracellular vesicle; IL, interleukin; KLF, Kruppel-​like factor; LDL, low-​density lipoprotein; LFA-​1, lymphocyte-​associated antigen-​1; MCP-​1, monocyte
chemoattractant protein-​1; M-​CSF, macrophage colony-​stimulating factor; mLDL, modified LDL; MMP, matrix metalloproteinase; NO, nitric oxide; PGI2,
prostacyclin; PSGL-​1, P-​selectin glycoprotein ligand-​1; ROS, reactive oxygen species; TF, tissue factor; TNF-​α, tumour necrosis alpha; VCAM, vascular cell adhesion
molecule.

NLRP3 is associated with the pathogenesis of multiple inflam- Transmigration of monocytes preferably occurs in areas where
matory diseases. As such, recent studies have evidenced the pres- the basal lamina is enriched with modified LDL particles [18].
ence of NLRP3 in the cytoplasm of macrophages and foam cells
[14] and have identified the microRNAs (miRNAs) that modu- Vascular smooth muscle cell response
late NLRP3 activation. Moreover, NLRP3 has been correlated Vascular smooth muscle cells (VSMCs) reside in the medial layer
with the severity and prognosis of coronary atherosclerosis in and exhibit a contractile phenotype with low proliferative rates.
ACS patients [15, 16]. oxLDL also enhances the endothelial ex- However, the effect of atherogenic stimuli results in the activa-
pression of adhesion molecules [vascular cell adhesion molecule tion and dedifferentiation of VSMCs to a synthetic phenotype.
1 (VCAM-​1), intercellular adhesion molecule 1 (ICAM-​1), and This phenotypic switch permits VSMC migration into the intima
selectin] and monocyte chemoattractant protein 1 (MCP-​1) ex- where VSMCs proliferate and deposit ECM and release a number
pression, favouring the recruitment and influx of monocytes of enzymes responsible for the balance between ECM synthesis
through interendothelial gaps into the subendothelial region [17]. (lysyl oxidase) and degradation (MMPs, plasminogen activators)
450 CHAPTER 36   Atherosclerosis and t h romb o si s

[19]. Hence, the migration of VSMCs from the vascular media to endothelial renewal (through small G-​proteins) [33]. However,
the vascular intima (see E Figure 36.1) is a key process in intimal in regions with flow perturbances and low shear stress, such as
thickening and further vascular remodelling (detailed later). occurring at branches and bends of the arterial tree, flow acti-
Both adenosine monophosphate (AMP)-​activated protein kinase vates intracellular signalling cascades that induce reactive oxygen
(AMPK) and KLF-​4 have been reported as powerful negative species production and enhancement of a matricellular protein
regulators of VSMC phenotypic switching, favouring atheroscler- (CCN1) and its receptor (integrin α6 β 1), both involved in NF-​
otic plaque stability [20, 21], whereas platelet-​derived miRNA-​223 κB activation. NF-​κB, in turn, not only sustains CCN1 and α6β1
has been demonstrated recently to reverse VSMC dedifferenti- expression through a positive feedback loop but also primes pro-​
ation [22]. In the intima, VSMCs express a variety of receptors inflammatory molecules such as ICAM-​1 and MCP-​1 [34,  35].
for cholesterol uptake, mainly LDL receptor-​related protein 1 Recent data also suggest that low shear rates may prevent the
(LRP-​1) receptors, thereby participating in early accumulation of washout of senescent endothelial cells, hindering their replace-
lipids within the plaque. Whereas VSMCs account for 90–​95% of ment [36]. In contrast, arterial regions that are exposed to rela-
the cell component in initial lesions, this proportion decreases to tively higher time-​averaged shear stress and pulsatile laminar
50% in advanced atherosclerotic lesions, making those plaques flow are less susceptible to plaque formation.
more vulnerable to rupture [23]. Indeed, unstable plaques con-
tain a substantial lipid core, little collagen, and a small number Progression of vascular lesions
of VSMCs. These data reflect the importance of identifying and
Innate and adaptive immunity responses
elucidating the cellular mechanisms that lead to VSMC loss in
advanced lesions. In normal arteries, VSMC apoptosis is rare. In Several monocyte subsets have been described to contribute to
fact, recent data have attributed to the transmembrane receptor atherogenesis, depending on the local stimulus. In particular, the
CD98 and kinase Akt-​1 a key role in preventing VSMC apoptosis 2010 nomenclature document acknowledged the existence of three
and maintaining VSMC proliferation [24, 25]. Moreover, over the subsets based on their membrane expression of specific receptors,
last few years, emerging data have supported that activation of the including cluster of differentiation 14 (CD14) and CD16. As such,
Wnt pathway (essential for embryogenesis and development) also they were standardized as classical monocytes (CD14++CD16–​),
contributes to regulating VSMC proliferation, migration, and sur- intermediate monocytes (CD14++CD16+), and non-​ classical
vival [26] and that VMSC autophagy and mitophagy (degradation monocytes (CD14+CD16++). A  recent consensus document has
of damaged mitochondria by autophagy) represent safeguard proposed a more simplified numerical assignment of Mon1,
mechanisms to protect against apoptosis [27,  28]. Nevertheless, Mon2, and Mon3 for classical, intermediate, and non-​classical
increased apoptosis occurs in unstable atherosclerotic plaques monocyte subsets, respectively [37]. Experimental evidence has
[29]. In vitro data showed that macrophages can directly trigger suggested that non-​ classical monocytes exert endothelial sur-
apoptosis in VSMCs by activating their Fas apoptotic pathway veillance (patrolling), which is intensified under hyperlipaemic
and secreting pro-​apoptotic TNF-​α [30]. On the other hand, conditions in order to prevent endothelial damage. This patrol-
atherogenic concentrations of LDL have been shown to signifi- ling behaviour is dependent on the integrin lymphocyte associ-
cantly reduce the migratory capacity of human VSMCs, thus re- ated antigen-​1 (LFA-​1) and the chemokine receptor CX(3)CR1. In
ducing the number of VSMCs, thereby contributing to increasing contrast, classical monocytes, or Mon1, highly respond to inflam-
the vulnerability of these advanced-​stage plaques. In this regard, matory signals, early invade the atherosclerosis-​prone region, and
we have shown, using proteomic approaches and confocal mi- become pro-​inflammatory macrophages, likely favouring foam
croscopy, that LDL particles affect the expression and phenotypic cell formation and plaque development (see E Figure 36.1) [38].
profile of different cytoskeleton-​related proteins, including the Interestingly, classical monocytes that differentiate into CD16–​
myosin light chain in both essential and regulatory isoforms [31]. macrophages do not express LRP5; instead, human monocytes
As such, atherogenic concentrations of LDLs inhibit myosin regu- expressing LRP5 differentiate into CD16+ macrophages with anti-​
latory light chain phosphorylation, a key event in the formation inflammatory activity [39]. Despite their widely accepted pro-​
of actin–​myosin complexes during cell migration and in the dy- inflammatory profile, a study on patients with established carotid
namics of actin fibre formation [31], a process highly regulated by artery disease has reported no association between circulating
gelsolin and heat shock protein 27 (HSP-​27) [32]. CD14++CD16–​ cells and specific vulnerable plaque features [40].
In addition to monocytes, lymphocytes have also been recognized
Effects of flow and geometry to play an important role in atherogenesis. T-​lymphocytes enter
Despite systemic exposure of the arterial vascular system to car- the intima by binding to VCAM-​1 where they are activated by
diovascular risk factors, plaques are located in geometrically interferon (IFN)-​γ, recognize modified autoantigens (oxLDL and
predisposed arterial regions where the local haemodynamic HSP-​60), and start releasing inflammatory cytokines. As occurs
environment determines plaque initiation and progression. with monocytes, the Th1 lymphocyte subtype appears to be pro-​
Endothelial cells contain mechanosensing molecules that de- inflammatory, while the Th2 subtype and Treg appear to inhibit
tect blood flow forces (e.g. shear stress) and underlaminar flow inflammation. A  recent study has identified CD69 as an oxLDL
activates intracellular processes aimed at maintaining vascular receptor in T-​lymphocytes that contributes to the regulatory ac-
health, including NO synthesis (likely through KLF-​ 4) and tion of the adaptive immune system, preventing atherosclerosis
 Athero s c l e ro si s 451

development. Moreover, the expression of CD69 inversely correl- distinct macrophage subtypes M2 and M1, with different pro-
ated with the presence and extension of subclinical atherosclerosis tective or pathogenic functions, respectively, have been suggested
and remained associated with the risk of subclinical atherosclerosis to exist, based on in vitro models. However, whether a pure M1/​
[41]. The anti-​inflammatory cytokine TGF-​β has also been shown M2 phenotype is present in atherosclerotic lesions remains to be
to be a powerful modulator of T-​cell-​related immune response by determined since macrophages are exposed to multiple stimuli
inhibiting the proliferation of naive and activated T-​cells and also that may modulate their function and cell surface receptors [58].
by mediating T-​cell differentiation [42]. While the role of T-​cells
in atherosclerosis has been studied extensively, the role of B-​cells Fibroproliferative changes and vascular remodelling
is less understood, probably because they accumulate in small Remodelling of the arterial wall takes place during plaque de-
numbers in atherosclerotic plaques. Among B-​cell subsets, B1 velopment. The flow-​ limiting potential of the intimal plaque
have shown to be atheroprotective by secreting antibodies against may change in two directions; it may be attenuated (expansive—​
modified LDL, with the aim to favour oxLDL clearance, while B2 outward or positive remodelling) or accentuated (constrictive—​
cells have been shown to exert both atherogenic (B2 cells formed inward or negative remodelling) by reactive changes in the
in the follicular region) and atheroprotective (B2 cells formed in underlying vessel wall. Human studies, using intravascular ultra-
the marginal zone) effects [43]. Several studies also support the sound, have shown that an outward arterial expansion, caused
contribution of vascular dendritic cells (DCs), mast cells, and neu- by positive remodelling, is more common at culprit lesion sites
trophils on atherogenesis progression. Although the role of vas- in UA, whereas an inward or negative remodelling is more
cular DCs is less understood, data suggest that they are thought common in stable angina [59, 60]. Moreover, positive remodel-
to present antigens to naive T-​cells, accelerating lymphocyte re- ling has been considered as a potential surrogate marker of plaque
cruitment into the atherosclerotic vessel, thereby modulating both vulnerability [61].
cellular and humoral immunity [44–​46]. Vascular remodelling involves modification of the ECM com-
As for mast cells, they are thought to orchestrate both innate position and structure. In this regard, it is critical to balance
and acquired immunity, via TLR activation and ensuing cytokine between collagen synthesis (by VSMCs) and collagen fibril
release. Neutrophils seem to be recruited to the atherosclerotic breakdown (by MMPs, collagenases, membrane-​ type MMPs,
lesion, in a partially platelet-​dependent manner (via CCL5), and gelatinases, and stromelysins). Several lines of evidence suggest
captured by the engagement of P-​and E-​selectins where they that inflammatory cytokines are responsible for this balance,
become activated [47]. Upon activation, neutrophils can release since these inflammatory mediators not only induce endothelial
web-​like filamentous structures of decondensed chromatin [so-​ cells, macrophages, and VSMC apoptosis [62], but also markedly
called neutrophil extracellular traps (NETs)] which are com- enhance MMP expression [63]. Importantly, the death of these
posed of deoxyribonucleic acid (DNA), histones, and granular cells results in the continuous release of certain MMPs that may
components [myeloperoxidase (MPO)], neutrophil elastase, and be particularly active in destabilizing plaques and thus predispose
cathepsin G.  Some experimental studies have supported that them to rupture [64–​66]. In fact, quantification of certain MMPs
NETs directly enhance coagulation through activation of the con- and their inhibitors in blood has been correlated with the degree
tact/​intrinsic pathway. In fact, studies in human thrombectomy of atherogenesis in humans [67].
specimens have suggested a potential contribution of NETs in the
Fatty streaks
culprit coronary thrombus through activation of the extrinsic co-
agulation pathway through tissue factor (TF)-​dependent mechan- On differentiation, macrophages display high levels of surface
isms [48–​49]. However, other studies have failed to demonstrate a pattern recognition receptors which have the ability to take up
role for neutrophils in thrombogenesis [50]. modified LDLs (see E Figure 36.1). We have demonstrated that
NETs have also been shown to contribute to atherosclerosis for- internalization of aggregated LDLs is mainly driven by LRP-​1
mation. As such, cholesterol crystals have been shown to trigger [68]. In contrast, oxLDL are mainly recognized by scavenger re-
NET release, priming macrophages for cytokine production and ceptors (SRs), including SR class A, CD36, and lectin-​like oxLDL
eventually amplifying immune cell recruitment in atherosclerotic receptor 1 (LOX1) [69,  70]. LOX1 has consistently shown pro-​
plaques [51]. atherosclerotic effects on other cells types, including VSMCs
Once monocytes reach the intimal space, they differentiate into where it also contributes to foam cell formation, and on endo-
macrophages (an irreversible process) (see E Figure 36.1). The thelial cells where it induces endothelial dysfunction and arterial
major driver of monocyte–​macrophage differentiation is macro- denudation through pro-​inflammatory activation and induction
phage colony-​ stimulating factor (M-​ CSF). However, this dif- of apoptosis [71].
ferentiation process is also driven by various factors, including After internalization, lipids are delivered to late endosomes/​
cell–​cell contact, components of the ECM, the platelet chemokine lysosomes where lysosomal acid lipase digests cholesterol esters
CXCL4, oxLDL [52, 53], and native LDL [54]. Macrophages are (CEs), releasing free cholesterol. To prevent free cholesterol-​
also very versatile, and it has been hypothesized that depending associated cell toxicity, released free cholesterol is re-​esterified on
on the local lesional microenvironment, they can assume dif- the endoplasmic reticulum by ACAT1 and stored in cytoplasmic
ferent phenotypes and functional characteristics, referred to as lipid droplets. In addition, excess cholesterol accumulated in
‘polarization’ (a reversible process) [55–​57]. In this context, two macrophages is removed from macrophages by ATP-​ binding
452 CHAPTER 36   Atherosclerosis and t h romb o si s

cassette (ABC) transporters (mediating cholesterol efflux) in enhance the inflammatory response and oxidative stress and
a process partly regulated by sphingosine-​ 1-​phosphate (S1P) contribute to the expansion of the lipid core, thereby increasing
[72–​74]. plaque vulnerability. In rupture-​prone and ruptured plaques, the
However, if this persistently occurs, the efflux mechanisms microvessel density is 2-​to 4-​fold higher than in stable plaques,
become eventually overwhelmed; excessive CEs accumulate in in both carotid and coronary arteries [59, 60]. In line with these
macrophages, thereby becoming foam cells [75]. During the early observations, we have reported that, in coronary atherosclerotic
stages of atherogenesis, many of these lipid-​laden macrophage lesions excised from patients’ hearts, the highest neovessel con-
cells undergo apoptosis and are cleared by neighbouring M2 tent is associated with the most advanced-​stage plaques and, in
macrophages (a process called efferocytosis) [76]. However, the turn, is linked with the highest rate of thrombotic episodes [23].
uptake of excessive apoptotic cells by macrophages induces endo- Moreover, using laser dissection microscopy approaches, we
plasmic reticulum stress and an unfolded protein response, re- have deciphered novel angiogenic factors that may contribute to
sulting in an impaired efferocytosis. Failure of efferocytosis leads plaque vascularization and vulnerability [86–​88], as well as dem-
to necrosis, in which macrophages die and release their cellular onstrated a critical role for TF in angiogenesis regulation via cyto-
contents, including debris, oxidized lipids, and pro-​inflammatory/​ plasmic domain signalling [89–​93].
prothrombotic mediators (see E Figure 36.1). This necrotic pro- Ca2+ deposition within the intimal layer is a common mani-
cess amplifies the inflammatory response and leads to the de- festation in atherosclerosis and is thought to result from the con-
velopment of a necrotic core in the plaque, increasing plaque vergence of a number of inflammatory-​based signalling pathways
susceptibility to erosion or rupture and subsequent thrombus for- that work to activate an osteogenic gene programme in the dif-
mation [77, 78]. ferent vascular cells. A recent study has reported that the amount
of Ca2+ accumulated in the arterial wall is strongly and grad-
Complex vulnerable atheroma and calcification ually associated with an increased risk of cardiovascular events
The risk of suffering a thrombotic complication depends more in atherosclerotic CVD patients [94,  95]. Moreover, it has been
on the biochemical and cellular composition of the lesions, ra- suggested that the density of the accumulated Ca2+ is inversely as-
ther than on their stenotic severity. Pathologic studies performed sociated with an increased risk of coronary and CVD, regardless
on patients dying from cardiovascular events showed the exist- of the total Ca2+ volume [96]. In fact, large and dense calcifica-
ence of an acute thrombus anchored on the disrupted areas of tions are considered to stabilize atherosclerotic plaques, whereas
atherosclerotic lesions in the majority of patients [79]. The same small and scattered calcifications appear to contribute to plaque
evidence has associated plaque characteristics with lesion vulner- destabilization.
ability. At the histological level, these lesions are mildly stenotic;
they have a significant lipid-​rich necrotic core, separated from the
Systemic and local risk factors for plaque
circulating blood by a thin fibrotic cap. Interestingly, the presence
of a large necrotic core has been associated with the inability of
complications and event presentation
the vessel to dilate, likely predisposing to ischaemia and impaired ACS may be caused by plaque rupture or erosion. Rupture of vul-
microvascular perfusion, regardless of the degree of luminal sten- nerable plaques is responsible for approximately 75% of coronary
osis [80]. At the cellular level, high-​risk lesions show a higher con- thrombi, leading to MI or death [97], and around 90% of throm-
tent of macrophages and inflammatory cells; the core is acellular, bosed carotid plaques, causing ischaemic stroke [98]. Much less
without the mechanical support of collagen fibres, and delimited is known about non-​rupture-​related thrombosis, among which
by macrophages and cholesterol-​loaded cells [81]. In addition, in the so-​called erosion-​prone plaque dominates [11, 99]. However,
disrupted lesions, inflammatory cells seem to selectively concen- endothelial cell erosion/​disruption is not a necessary prerequisite
trate in ruptured areas. for functionally relevant interactions of platelets with vascular
Another feature recently associated with lesion vulnerability endothelial cells. For instance, platelets may be activated by local
is an increase in lesion neovascularization [82]. Atherosclerotic haemodynamics in the atherosclerotic vessels. Indeed, high shear
plaque progression results in hypoxia and the accumulation stress induces the exposure of platelet receptors and the triggering
of a vast array of cells which trigger vessel formation, in order of the aggregation cascade [100]. We have shown that GRP78,
to provide nutrients to the developing and expanding intima. an endoplasmic reticulum chaperone, is exposed on the resting
The resulting neovessel and vasa vasorum network grows as platelet membrane and is translocated to the cytosol, after shear-​
the plaque evolves and prevents cellular death, contributing induced platelet activation, to allow platelet aggregation [101].
to plaque growth and stabilization [10]. However, in more ad- On the other hand, chronic exposure to systemic risk factors also
vanced plaques, inflammatory cell infiltration and concomitant induces platelet interaction with the intact, but dysfunctional,
production of numerous pro-​angiogenic cytokines result in the endothelial layer, because of impairment of antithrombotic/​
induction of uncontrolled neointimal microvessel proliferation, thrombolytic properties, in addition to the exposure of platelet
resulting in the production of immature and fragile neovessels adhesion molecules, such as fibronectin, ICAM-​1, P-​selectin,
that are easily broken and that can lead to intraplaque haemor- E-​selectin, integrin αvβ3, and von Willebrand factor (vWF), on
rhage (see E Figure 36.1) [79, 83–​85]. Moreover, the released their surface. However, all these stimuli induce limited platelet
lipid-​
rich red blood cell membranes and free haemoglobin deposition that most likely intervenes in the progression of
 T h ro m b o si s 453

atherosclerosis, rather than in the ultimate thrombotic compli- does not mediate irreversible adhesion but keeps platelets in close
cations. In contrast, both endothelial erosion and/​or atheroscler- contact with the endothelium, constantly moving towards flow
otic plaque rupture expose the components of the vascular matrix directions [107]. Two well-​ established platelet collagen recep-
(mainly collagen types I and III, vWF, fibronectin, laminin, fibulin, tors [GPIa/​IIa (integrin α2β1) and GPVI] further promote firm
and thrombospondin) to the bloodstream, which triggers exten- platelet adhesion and induce activation/​aggregation. It has been
sive platelet adhesion, activation, and aggregation [102, 103]. In established that whereas GPIa/​ IIa mediates platelet adhesion,
addition, TF may also enter in contact with the blood flow, trig- GPVI is essential for platelet activation and aggregation [108].
gering thrombin generation, which converts fibrinogen to fibrin In addition to GPIa/​IIa, fibronectin, laminin, vitronectin, and
and potently activates platelets, eventually leading to thrombus thrombospondin also contribute to platelet adhesion by binding
mass formation (detailed later). to GPIc-​IIa, GPIc’-​IIa, vitronectin receptors, and GPIV, respect-
ively, although to a lesser extent.
Atherosclerotic plaque burden and Of interest, CRP has also been shown to induce platelet adhe-
plaque imaging sion to endothelial cells under high shear conditions [109]. In this
Over the past few years, the great advances in imaging tech- regard, we have demonstrated that the monomeric form of CRP
niques have allowed the visualization and characterization of exerts a significant effect on platelet adhesion [110]. As such, na-
atheromatous plaques, as well as the monitoring of their progres- tive or circulating CRP (pentameric form) does not affect platelet
sion or regression [104]. As per the invasive imaging modalities deposition, whereas monomeric CRP displays a prothrombotic
most widely employed, intravascular ultrasound virtual histology phenotype, enhancing not only platelet deposition, but also
(IVUS-​VH) enables the assessment of plaque morphology and thrombus growth [110]. Furthermore, we have recently demon-
composition, although optical coherence tomography (OCT), strated the ability of monogenic CRP to induce pro-​angiogenic
because of its higher resolution, allows a more detailed assess- effects by upregulating TF signalling [111].
ment of vulnerable plaque morphology, such as the presence of Platelet adhesion and further activation, in concurrence with
macrophages, neovascularization, and microcalcifications, as RBC lysis, lead to the local release of platelet agonists [ADP and
well as a better estimation of fibrous cap thickness. Regarding thromboxane A2 (TXA2)] which, in combination with thrombin
non-​invasive-​based approaches, computed tomography coronary generated upon atherosclerotic plaque exposure of TF, recruit
angiography (CTCA) facilitates the assessment of coronary ath- additional platelets (see E Figure 36.2).
erosclerosis and provides 3D pictures of the arterial tree; however As to the intracellular signalling pathways mainly involved in
its radiation hazard has limited its use. MRI, in contrast, is safe platelet activation, GPIb and GVI activate protein kinases that
and effectively assesses plaque morphology on the carotid artery, enable the activation of phospholipase C (PLC)-​γ2, whereas en-
but its reliability is questioned in the coronary tree. Finally, mo- gagement of soluble platelet agonists with Gq-​protein-​coupled
lecular imaging using PET detects inflammation and metabolic receptor triggers PLC-​β activation. Once activated, PLC-​γ2/​β in-
processes within atherosclerotic lesions [105]. duces the generation of the second messengers inositol triphos-
phate (IP3) and diacylglycerol (DAG), which induce cytoskeleton
rearrangements (shape change), extrusion of platelet granules,
and conversion of GPIIb/​IIIa receptor into a high-​affinity state
Thrombosis (‘inside-​out’ signalling) [106].
Cellular and molecular mechanisms Platelet shape change is a prerequisite for optimal granule se-
cretion and supports platelet–​platelet and platelet–​matrix inter-
in thrombus formation
actions and tethering [112]. Platelet granule secretion leads to
Platelets the local release of ADP/​ATP, serotonin, Ca2 + adhesion proteins
Platelets are released into the circulation as cytoplasmic fragments (e.g. fibrinogen, fibronectin, vWF, thrombospondin, vitronectin,
(2–​5 microns), originating from bone marrow megakaryocytes, P-​selectin, integrin αIIbβ3), and coagulation factors [e.g. FV, FXI,
and circulate in blood for 7–​10 days. They play a pivotal role in plasminogen activator inhibitor type 1 (PAI-​ 1), plasminogen,
maintaining vascular integrity and haemostasis; yet, the disrup- protein S], all of which contribute to amplify the thrombotic
tion of an atherosclerotic plaque triggers uncontrolled platelet response. On the other hand, activated platelets externalize
recruitment and thrombin production, leading to thrombus for- phosphatidylserine, becoming a substrate for the coagulation
mation. The initial tethering of platelets at sites of injured vessels cofactor/​enzyme complexes VIIa/​IXa and Va/​Xa, thereby being
is mainly driven by the interaction of the collagen-​anchored A3 of critical importance for driving procoagulant reactions [113].
domain of vWF with the platelet glycoprotein (GP) GPIbα re- Moreover, several reports have demonstrated that distinct platelet
ceptor (the major binding region of GPIb/​IX/​V platelet complex), surface receptors (e.g. GPIb-​IX-​V) may also contribute to coagu-
via the vWF A1 domain (see E Figure 36.2). GPIbα also con- lation factor recruitment in a highly coordinated manner [114].
tains binding sites for the leucocyte integrin macrophage antigen 1 Regardless of the trigger, platelet aggregation is regulated in the
(MAC-​1) and P-​selectin, which favours further platelet and leuco- final part of the pathway by activation of the platelet heterodimer
cyte recruitment, thus further perpetuating both the thrombotic GPIIb/​IIIa receptor (αIIbβ3), the most abundant protein on the
and the atherosclerotic process [106, 107]. GPIbα–​vWF, however, platelet surface. Fibrinogen (of plasma or platelet origin) is the
454 CHAPTER 36   Atherosclerosis and t h romb o si s

ATP Thromboxane
Ticlopidine Cangrelor
ADP receptor
P2X1 PAF
Clopidogrel Ticagrelor receptor blockade
Prasugrel antagonists
Terutroban
Sulotroban
GLS-409
PDE inhibitors ADP
P2Y12 PLATELET TP
Dipyridamole ADP
Cilostazol P2Y1 ACTIVATION TXA2
TX
A
PGH2synth
PGG2 ase
PDE AMPc Platelet TXA2

PG
Co /PG
Serotonin Rc PLATELET LOX ML-355

H2
x-1 G 2
Serotonin

5-HT2 ACTIVATION AA
antagonists A1 Thromboxane
vWF A3 RGD

APD791 pathway inhibitors

Fibrinogen
Aspirin
PAR-4
Rc GPIIb/IIIa
Parmodulins, PLATELET a2
BMS-986120 PAR-1 ACTIVATION
GPIIb/IIIA inhibitors Adrenaline
Thrombin
Abciximab Eptifibatide
Tirofiban
PAR inhibitors PZ-128
BI1002494 Syk
Vorapaxar

GPIb-IX-V
GPIa/IIa Caplacicumab, ARC1799
GPIc/IIa GPVI
RGD
FVW A1 A3
Laminin Collagen
Subendothelium
Fibronectin Collagen
Revacept, 9012Fab

Figure 36.2  This figure depicts the key mediators involved in thrombus formation upon atherosclerotic plaque rupture and molecular targets for antiplatelet
agents. It highlights the main vascular and platelet receptors involved (blue) and details the antiplatelet agents currently in clinical use (red) or under
development (green). AA, arachidonic acid; ADP, adenosine diphosphate; Fg, fibrinogen; GP, glycoprotein; PAR, protease-​activated receptor; SyK: spleen tyrosine
kinase; TF, tissue factor; TP, thromboxane receptor; TXA2, thromboxane A2; vWF, von Willebrand factor.

main ligand for the GPIIb/​IIIa receptor (see E Figure 36.2). The potential markers or modulator. As such, ADAM (a disintegrin
dimeric structure of fibrinogen allows its interaction with two and metalloprotease with thrombospondin motif) mediates the
platelets at the same time, thereby favouring platelet aggregation. cleavage of GPIbα, GPV, GPVI, CD40L, and semaphorin 4D, and
Hence, the thrombus grows as active GPIIb/​IIIa captures new concretely ADAMTS-​13 cleaves the platelet-​bound multimeric
platelets by means of fibrinogen (see E Figure 36.2). Other ligands vWF, downregulating platelet reactivity [118–​120].
for GPIIb/​IIIa that participate in platelet aggregation (although to
a lesser extent) include vWF, fibronectin, and vitronectin (see E Coagulation
Figure 36.2). Ligand interaction with GPIIb/​IIIa not only bridges A fibrin monolayer is the first circulation-​derived response to
platelets together but also triggers ‘outside-​in’ signalling that or- atherosclerotic plaque damage [121–​123]. This fibrin monolayer,
chestrates cytoskeletal rearrangements for platelet spreading and triggered by TF-​dependent thrombin formation [124,  125], is
clot stabilization through the PI3K/​PDK1/​Akt/​GSK3 axis. In this immediately followed by a platelet deposition reaction that may
latter regard, in the last stage of thrombus formation, fibrinogen is even occlude the lumen of the vessel [126, 127]. Later real-​time
converted to fibrin by thrombin, also contributing to clot stabiliza- thrombus formation studies in damaged mouse arterioles have
tion, Finally, besides further platelet recruitment, other circulating shown that the first traces of fibrin appear already soon after
cells, including RBCs and leucocytes, are trapped within the ex- vascular damage, which implies a rapid onset of thrombin gen-
panding thrombus, contributing to its growth [115–​117]. eration close to the damaged vessel wall [128]. However, most
In contrast to platelets found in the inner layers of the growing importantly, thrombin generation is dependent upon the ex-
thrombus, the outer platelets, which are in direct contact with posure of atherosclerotic-​related TF (extracellular domain) to the
the flowing blood, are easily accessible to modifying plasma flowing blood, activating the extrinsic coagulation pathway by
enzymes, and therefore susceptible to changing their surface. binding the clotting factors FVII/​VIIa [129, 130] (see E Figure
In this regard, several plasma proteases have been described to 36.3). Because of the proximity of TF and lipid-​rich areas in ad-
cause extracellular proteolysis of receptors, irreversibly inacti- vanced atherosclerotic lesions, a link between LDL particles, TF
vating receptor-​ mediated adhesion and signalling, as well as expression, and thrombotic risk has been established. Indeed,
to release soluble fragments into the plasma where they act as studies of the relative thrombogenicity of the various components
 T h ro m b o si s 455

Extrinsic pathway

Natural coagulant inhibitors

Reduces hepatic synthesis
Anticoagulant drugs Antisense oligonucleotide Contact pathway
TF (INOIS-416858)
Novel anticoagulant compounds
FXIIa
TFPi FVII/FVIIa FXI
Kallikrein/HMWK
FX FIX VKA FXIIa

FXIa
APC VIIIa FIXa AT

Block FXI activity

– Monoclonal antibody (BAY1213790)
AT FXa Direct FXa inhibition
– Aptamer
Rivaroxaban – Small molecule (BMS-986177/EP-7041/ONO-
Va Apixaban 6560598
Edoxaban
FII VKA

(Poly)phosphates
Thrombin
(FIIa) ATIII Indirect via thrombin
Low molecular weight heparin Platelet
Unfractioned heparin activation
Direct thrombin inhibitors
Fibrinogen
Fibrin Dabigatran etexilate
Argatroban
Hirudin
Bivalirudin

Fibrin polymers Clot retraction

Figure 36.3  Diagram of the coagulation cascade (extrinsic and intrinsic/​contact pathway) and potential anticoagulants [physiological anticoagulants (purple),
anticoagulant drugs in clinical use (red), and anticoagulants under development (orange)]. APC: activated protein C; AT: antithrombin; HMWK: high-​molecular
weight kininogen; TF, tissue factor; TFPi, tissue factor pathway inhibitor type-​1; VKA, vitamin K antagonist.

of atherosclerotic plaques have demonstrated that the lipid-​rich through the four PARs present on the surface of different athero-
nucleus is up to six times more thrombogenic than all other sclerotic cell types. Specifically, PAR1 and PAR2 are present on
components [126]. In addition, we have reported that inhib- VSMCs and favour their proliferation; PAR1, PAR2, and PAR4
ition of TF by local administration of TFPi effectively reduces ar- are present on macrophages and induce inflammatory pathways;
terial thrombosis in atherosclerotic lesions [131]. In this regard, and PAR1 and PAR4 are present on human platelets, and their
LDL-​laden foam cells have been shown to release TF, increasing signalling culminates in the activation of the GPIIb/​IIIa receptor
plaque susceptibility to thrombus formation. On the other hand, (see E Figure 36.2). Therefore, thrombin, through PARs, influ-
we have reported that the interaction between LRP-​1 and LDL ences a wide variety of responses that favour the development of
aggregates is one of the mechanisms that induce VSMC TF ex- atherothrombosis.
pression, in a process that depends on RhoA translocation to
the membrane and the release of microparticles (MPs), enriched Platelet–​coagulation interplay
in active TF, to the ECM [132, 133]. According to our observa- Activated platelets play a pivotal procoagulant role through
tions, VSMCs might therefore not only contribute to increasing at least two mechanisms. First, activated platelets externalize
the thrombogenicity of the atherosclerotic plaque, but also to phosphatidylserine, becoming a substrate for the coagulation
increasing circulating TF-​enriched MPs. In any case, as a result of cofactor/​enzyme complexes VIIIa/​ IXa and Va/​ Xa, leading to
initiating the coagulation cascade, thrombin is produced, which thrombin formation (see E Figure 36.3) [113]. Second, activated
cleaves fibrinogen to fibrin and results in the formation of com- platelets release inorganic polyphosphates from their dense gran-
plex thrombi which are platelet-​and fibrin-​rich (see E Figure ules, which trigger the activation of the contact/​intrinsic pathway
36.3). At a later stage, once a full fibrin network is formed, this (FXII, prekallikrein), enhancing FXI-​related thrombin activation.
consolidates the thrombus not only passively, but also in an ac-
tive way, as fibrin provides a substrate for platelets to contract. Fibrinolysis
Additionally, thrombin, by interacting with protease-​activated re- The stability of the resulting thrombus is governed by the activity of
ceptors (PARs), amplifies platelet activation and participates in various elements with a thrombus-​specific lytic action, including
the overall atherothrombotic process. Thrombin signalling occurs tPA and/​or urokinase-​type plasminogen activator activation. tPA,
456 CHAPTER 36   Atherosclerosis and t h romb o si s

stimulated either by thrombus-​bound fibrin or by ECM proteins, partly, by decreased NO synthesis [141, 142]. Moreover, plaque-​
initiates fibrinolysis by converting plasminogen to the fibrin-​ derived MPs have been shown to favour local inflammation—​by
degrading protease plasmin [134]. However, in stable thrombi, augmenting the expression of adhesion molecules and promoting
cross-​linking of fibrin masks tPA binding sites, protecting fibrin monocyte recruitment—​as well as to increase thrombus forma-
from degradation. However, these prothrombolytic actions are tion at the time of rupture. Besides, we have demonstrated that
counterbalanced by PAI-​ 1 (plasminogen activator inhibitor), both circulating and platelet MPs enhance thrombosis on athero-
which is activated by phospholipid membrane components re- sclerotic plaques [143]. In fact, the platelet MP surface presents an
leased at sites of vascular injury and inhibits fibrinolysis. array of platelet-​derived adhesion and chemokine receptors, such
as P-​selectin, GPIIb/​IIIa, GPIbα, and PF4 receptor, that induce
Regulation of thrombus growth by local and monocyte and endothelial cytokine production and an increase
systemic factors in leucocyte aggregation and recruitment, via P-​selectin/​PSGL-​1-​
A wide range of factors have been identified in prospective dependent interactions, likely contributing to the atherosclerosis
epidemiological studies to have a systemic effect on blood progression [144]. Interestingly, we have also demonstrated that
thrombogenicity. Certainly, there is increasing evidence of a erythrocyte-​derived MPs are continuously released from evolving
close relationship between traditional cardiovascular risk fac- growing thrombi and are likely to be a potential novel systemic
tors, such as diabetes mellitus, hypertension, or hyperlipid- biomarker of ongoing thrombosis [145]. In addition, we have re-
aemia, and increased thrombogenicity, which is characterized cently reported that circulating and platelet-​and leucocyte-​related
by hypercoagulability, hypofibrinolysis, or increased platelet MPs are found to be increased in patients with complete coronary
reactivity [135]. Other cardiovascular risk factors, such as lipo- thrombotic occlusion (i.e. STEMI patients), as compared to those
protein (a) [Lp(a)], have also been shown to directly increase the with partial coronary thrombotic occlusion (i.e. non-​ STEMI
risk of thrombosis. Lp(a) consists of a lipoprotein moiety indis- patients), thus serving as a marker of thrombus burden [146].
tinguishable from LDL and a plasminogen-​related glycoprotein Furthermore, we have also found that MPs are further increased in
apo(a). Because of its homology with plasminogen, Lp(a) not STEMI patients complicated with cardiogenic shock and that their
only interferes with plasminogen functions, but also has been levels are directly associated with a worse outcome [147].
shown to exert direct procoagulant/​antifibrinolytic effects [136]. Platelet MPs have also been described to intervene in the in-
Importantly, however, improvements of these cardiovascular hibition of fibrinolysis by promoting PAI-​ 1 activation [148].
risk factors have been associated with a lower prothrombotic Interestingly, despite the pro-​atherogenic potential of MPs, we
tendency [137]. have recently demonstrated that statin treatment diminishes
the number of circulating and platelet MPs carrying markers
Extracellular vesicles of activated cells, suggesting a protection against vascular
Vascular and circulating cells secrete, upon activation or apop- activation [149].
tosis, membrane vesicles into the extracellular space, the so-​
called extracellular vesicles (EVs). EVs include apoptotic bodies,
exosomes, and microvesicles (previously known as microparticles) Lifestyle and therapeutic implications
that carry proteins (e.g. ICAM, VCAM, IL-​6, IL-​1β), lipids (e.g.
prostaglandins, leukotrienes, fatty acids, and eicosanoids), and
in atherothrombosis
nucleic acids (miRNA, circular RNA, and long non-​coding RNA), Atherosclerosis prevention is mainly focused on the management
known to contribute to cellular intercommunication [138]. EVs of so-​called ‘cardiovascular risk factors’. Indeed, abundant studies
derived from platelets, leucocytes, macrophages, and endothe- have reported on the effect of healthy lifestyle habits, such as exer-
lial cells have been shown to enhance endothelial cell activation, cise [150], body weight [151], a Mediterranean diet [152], light to
promote inflammation, induce VSMC migration, and favour moderate alcohol consumption [153], smoking [154], and stress
thrombus formation (particularly platelet-​derived microvesicles), [155], not only on limiting the atherosclerosis progression, but
thereby regulating each stage of plaque development [139] (see also on reducing blood thrombogenicity. As for the mechanisms
E Figure 36.1). behind the benefits afforded by healthy dietary habits, systems
MPs are characterized by the loss of plasma membrane asym- biology studies, by combining several ‘-​omics’ disciplines (mainly
metry, resulting in the exposure of phosphatidylserine on their genomics/​ transcriptomics, proteomics, and metabolomics),
outer leaflet. Although MP formation represents a physiological have demonstrated the key role of bioactive food components
phenomenon, over the past decade, numerous studies have shown in preventing CVD [156] by decreasing low-​grade inflamma-
that circulating MP levels increase in a wide range of CVDs, tion and oxidation, leucocyte activation, platelet aggregation, or
including uncontrolled cardiovascular risk factors, atheroscler- microparticle shedding [157]. At a pharmacological level, there
otic lesion progression, heart failure, thrombosis, arrhythmias, are several lipid-​lowering agents available to prevent hyperlipid-
and inflammatory vascular disease [140]. Within the last years, aemia and atherosclerosis [158, 159] and a wide armamentarium
a large number of studies have proposed that MPs impair the of antiplatelet and anticoagulant drugs to prevent and/​or treat
atheroprotective function of the vascular endothelium, at least thrombosis-​related complications (see E Figures 36.2 and 36.3)
 RE F E RE N C E S 457

[160–​162]. Yet, despite implementation of these therapeutic strat- prevalent in thrombosis that will guide in the development of
egies and the progressive reduction in morbidity and mortality new antithrombotic therapies.
due to CVD, treatment goals are still unmet, since 20% of MI pa-
tients suffer from a recurrent event. Efforts are currently focused
on reducing this residual cardiovascular risk either by combined Personal perspective
targeting of different pathological pathways or by developing and
testing new drugs. Understanding the mechanisms that drive the formation of
atheromatous plaques and induce thrombus formation is of
critical importance for identifying the best therapeutic treat-
ment out of an extensive therapeutic arsenal and to search for
Conclusion new opportunities capable of reducing the burden of heart
Throughout this chapter, we have reviewed the diversity and disease. Although many challenges remain, the emergence of
complexity of the cellular/​molecular interactions that underlie ‘-​omics’ technologies (lipidomics, metabolomics, genomics,
the development and progression of atherosclerosis. The role and proteomics) applied to this area may hopefully generate
of LDL in atherogenesis is well established, but much more novel insights into the bioactive mediators, signalling cas-
has been learnt recently about how LDL drives the vascular in- cades, and gene/​protein modifications that govern the patho-
flammatory response and the role of the inflammatory reaction genesis of the atherothrombotic process, as well as open new
per se. In this regard, the Canakinumab Anti-​Inflammatory therapeutic venues for the prevention and treatment of CVD.
Thrombosis Outcomes Study (CANTOS) trial has recently
demonstrated that diminishing the innate immune response
by blocking the pro-​inflammatory cytokine IL-​1β reduces the
risk of future cardiovascular events, even in the absence of lipid-​
lowering effects [163]. More research is needed to determine
the environmental local signals that mediate the leucocyte and
Acknowledgements
VSMC phenotypic switch during atherosclerosis progression. This review has been supported by SAF2016-​76819R (to LB) and
Besides, while the role of platelets in thrombus formation is PGC2018-094025-B-I00 (to GV) from the Spanish Ministry of
well known, the engagement of platelets with immune and pro- Science and Innovation and funds FEDER ‘Una Manera de Hacer
genitor cells and their role in atherosclerosis progression is more Europa’ and CiberCV, Institute Carlos III. We are grateful to the
complex, and new concepts continue to emerge. Undoubtedly, Generalitat of Catalunya (Secretaria d’Universitats i Recerca del
new insights at the -​omic and cellular levels will help to under- Departament d’Economia i Coneixement de la Generalitat, 2017
stand the pathological events that take place during the course SGR 1480) and the Fundación Investigación Cardiovascular-
of atherosclerosis, as well as unveil the molecular interactions Fundación Jesus Serra for their continuous support.

Further reading
Arbab-​Zadeh A, Fuster V. The myth of the ‘vulnerable plaque’: transitioning Ridger VC, Boulanger CM, Angelillo-​Scherrer A, et al. Microvesicles in
from a focus on individual lesions to atherosclerotic disease burden for vascular homeostasis and diseases. Position Paper of the European
coronary artery disease risk assessment. J Am Coll Cardiol 2015;65:846–​55. Society of Cardiology (ESC) Working Group on Atherosclerosis and
Badimon L, Vilahur G. Thrombosis formation on atherosclerotic lesions Vascular Biology. Thromb Haemost 2017;117:1296–​316.
and plaque rupture. J Intern Med 2014;276:618–​32. Weber C, Badimon L, Mach F, van der Vorst EPC. Therapeutic strategies
Patrono C, Morais J, Baigent C, et al. Antiplatelet agents for the treatment for atherosclerosis and atherothrombosis:  past, present and future.
and prevention of coronary atherothrombosis. J Am Coll Cardiol Thromb Haemost 2017;117:1258–​64.
2017;70:1760–​76.

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 CHAPTER 37

The universal definition

of myocardial infarction
Kristian Thygesen, Joseph S Alpert,
Allan S Jaffe, and Harvey D White

Contents
Summary  463 Summary
Introduction  463 Myocardial infarction is defined by the presence of myocardial injury detected by
Pathological characteristics of myocardial abnormal cardiac biomarkers in the setting of acute clinical myocardial ischaemia.
ischaemia and infarction  464 These conditions are met when there is a detection of a rise and/​or fall of cardiac
Biomarker detection of myocardial injury biomarkers, preferably cardiac troponins, with at least one value above the 99th
and infarction  464
percentile of the upper reference limit, together with evidence of acute clinical
Clinical presentations of myocardial
infarction  464 myocardial ischaemia, as recognized by at least one of the following: symptoms of
Clinical classification of myocardial
ischaemia, ECG changes of new ischaemia, development of pathological Q waves,
infarction  465 imaging evidence of new loss of viable myocardium or new regional wall motion
Myocardial infarction type 1  465 abnormality, or identification of an intracoronary thrombus by angiography or
Myocardial infarction type 2  466 autopsy.
Myocardial infarction type 2 and myocardial
injury  467
Myocardial infarction type 3  467
Coronary procedure-​related myocardial
injury  468
Myocardial infarction associated with PCI
(type 4a MI)  469
Stent/​scaffold thrombosis associated with Introduction
PCI (type 4b MI)  469
Restenosis associated with PCI (type 4c MI)  470 When MI was redefined in 2000, it was stated that acute myocardial injury detected by
Myocardial infarction associated with CABG
(type 5 MI)  470 a rising or falling pattern of cardiac biomarkers in the setting of acute clinical myocar-
Myocardial injury and infarction associated dial ischaemia should be labelled as myocardial infarction [1]‌. Since then, this prin-
with cardiac procedures other than ciple has remained a fundamental component of the Universal Definition of Myocardial
revascularization  470
Myocardial injury and infarction associated Infarction, including the Fourth Universal Definition of Myocardial Infarction Consensus
with non-​cardiac procedures  470 Document [2].
Myocardial injury or infarction associated
with heart failure  471 Even though myocardial injury is a prerequisite for the diagnosis of MI, it is also an
Myocardial injury and/​or infarction entity in itself and is now considered a separate condition. Myocardial injury is present
associated with kidney disease  471 when blood levels of cTn are increased above the 99th percentile upper reference limit
Recurrent myocardial infarction  471
Reinfarction  471 (URL). The injury may be acute, as evidenced by a newly detected dynamic rising and/​or
Biochemical approach for diagnosing a falling pattern of cTn values above the 99th percentile URL, or chronic in the setting of
myocardial injury and infarction  472 persistently elevated cTn levels [2]‌.
Electrocardiographic detection of
myocardial infarction  473
Prior or silent/​unrecognized myocardial
infarction  474
Imaging techniques  474
Echocardiography  474
Cardiac magnetic resonance imaging  474
Personal perspective  475
Further reading  475
References  475
464 CHAPTER 37   The u niversal def init ion of m yo ca rdia l  i n fa rcti on

No myocardial injury
Clinical criteria for myocardial infarction
The clinical definition of MI denotes the presence of acute myo-
Increased cTn =
cardial injury detected by abnormal cardiac biomarkers in the Hypoxaemia myocardial injury Anaemia
setting of clinical evidence of acute myocardial ischaemia.

Clinical evidence
Criteria for myocardial injury of acute ischaemic
Detection of an elevated cTn value above the 99th percentile Hypotension/ myocardial Ventricular
shock injury = tachyarrhythmia
URL is defined as myocardial injury. The injury is considered myocardial
acute if there is a rise and/​or fall of cTn values. infarction

Kidney Heart
Pathological characteristics of disease failure

myocardial ischaemia and infarction

MI is defined pathologically as myocardial cell death due to Figure 37.1  Spectrum of myocardial injury, ranging from no injury
prolonged ischaemia. Diminished cellular glycogen and re- to myocardial infarction. a No myocardial injury = cTn values ≤99th
laxed myofibrils and sarcolemmal disruption are the first percentile URL or not detectable. b Myocardial injury = cTn values >99th
percentile URL. c Myocardial infarction = clinical evidence of myocardial
ultrastructural changes and are seen as early as 10–​15 minutes
ischaemia and a rise and/​or fall of cTn values >99th percentile URL. Various
after the onset of ischaemia [3]‌. Mitochondrial abnormalities clinical entities may involve these myocardial categories, e.g. ventricular
are observed as early as 10 minutes after coronary occlusion by tachyarrhythmia, heart failure, kidney disease, hypotension/​shock,
electron microscopy and are progressive [4]. It can take hours hypoxaemia, and anaemia.
before myocyte necrosis can be identified by post-​mortem
examination in humans; this is in contrast to animal models, mechanisms and can arise following preload-​induced mechanical
in which biochemical evidence of myocardial cell death due to stretch or physiological stresses in otherwise normal hearts [16–​
apoptosis can be detected within 10 minutes of induced myo- 19]. Various causes have been suggested for the release of struc-
cardial ischaemia in association with myocyte death [5]. tural proteins from the myocardium, including normal turnover
of myocardial cells, apoptosis, cellular release of cTn degradation
products, increased cellular wall permeability, formation and re-
Biomarker detection of myocardial lease of membranous blebs, and myocyte necrosis [12, 20]. Yet,
it is not possible clinically to distinguish which increases of cTn
injury and infarction levels are due to which mechanisms [21]. However, acute myo-
Cardiac troponin I (cTnI) and T (cTnT) are components of the cardial injury, when associated with a rising and/​or falling pattern
contractile apparatus of myocardial cells and are expressed al- of cTn values, with at least one value above the 99th percentile
most exclusively in the heart [6, 7]. Increases in cTnI values have URL and caused by myocardial ischaemia, regardless of the
not been reported to occur following injury to non-​cardiac tis- mechanism, is designated as an AMI [2]‌. Histological evidence of
sues. The situation is more complex for cTnT. Biochemical data myocardial injury with myocyte death can be detected in clinical
indicate that injured skeletal muscle expresses proteins that are conditions associated with non-​ischaemic mechanisms of myo-
detected by the cTnT assay, leading to some situations where cardial injury as well [22, 23] (see E Figure 37.1).
elevations of cTnT could emanate from skeletal muscle [8–​12]. Myocardial ischaemic or non-​ischaemic conditions associ-
Recent data suggest that the frequency of such elevations in ated with increased cTn values are presented in E Box 37.1. The
the absence of ischaemic heart disease may be higher than ori- complexity of clinical circumstances may sometimes make it dif-
ginally thought [13, 14]. cTnI and cTnT are the preferred bio- ficult to discriminate specific individual mechanism(s) of myo-
markers for the evaluation of myocardial injury, and hs-​cTn cardial injury. In this situation, the multi-​factorial contributions
assays are recommended for routine clinical use [2, 7, 15]. Other resulting in myocardial injury should be described in the patient
biomarkers, e.g. CK-​MB, are less sensitive and less specific [16]. record.
Myocardial injury is defined to be present when blood levels of
cTn are increased above the 99th percentile URL [2]‌. The injury
may be acute, as evidenced by a newly detected dynamic rising Clinical presentations of myocardial
and/​or falling pattern of cTn values above the 99th percentile
URL, or chronic in the setting of persistently elevated cTn levels.
infarction
Although elevated cTn values reflect injury to myocardial Onset of myocardial ischaemia is the initial step in the develop-
cells, they do not indicate the underlying pathophysiologic ment of MI and results from an imbalance between O2 supply
 Cl i n i ca l cl as si fi cati on of m yo ca rdia l i n fa rc t i on 465

ischaemia and can be observed in other conditions such as GI,

Box 37.1  Reasons for elevation of cardiac troponin values
because of myocardial injury neurological, pulmonary, or musculoskeletal complaints. MI
may occur with atypical symptoms such as palpitations or cardiac
Myocardial injury related to acute myocardial ischaemia arrest, or even without symptoms. In these situations, imaging,
◆ Atherosclerotic plaque disruption with thrombosis including echocardiography, may have an important role [2]‌.
Very brief episodes of ischaemia too short to cause necrosis can
Myocardial injury related to acute myocardial ischaemia be- also cause cTn release and elevations. The involved myocytes can
cause of oxygen supply/​demand imbalance
subsequently die due to apoptosis [24].
◆ Reduced myocardial perfusion, e.g.: If myocardial ischaemia is present clinically or detected by
• Coronary artery spasm, microvascular dysfunction ECG changes together with myocardial injury, manifested by a
• Coronary embolism rising and/​or falling pattern of cTn values, a diagnosis of AMI
• Coronary artery dissection is appropriate. If myocardial ischaemia is not present clinically,
• Sustained bradyarrhythmia then elevated cTn levels may be indicative of acute myocardial
• Hypotension or shock injury if the pattern of values is rising and/​or falling, or related
• Respiratory failure to more chronic ongoing injury if the pattern is unchanging
• Severe anaemia [2]‌. Similar considerations are relevant when evaluating events
potentially related to procedures that may cause myocardial in-
Increased myocardial oxygen demand, e.g.:
◆
jury and/​or MI. Additional evaluations may lead to the need
• Sustained tachyarrhythmia
for the initial diagnosis to be revised. Patients with suspected
• Severe hypertension with or without left ventricular ACS that rule out MI with normal cardiac biomarker values
hypertrophy (≤99th percentile URL) may have UA or an alternative diag-
Other causes of myocardial injury nosis [2, 25].
◆ Cardiac conditions, e.g.:
• Heart failure
• Myocarditis Clinical classification of myocardial
• Cardiomyopathy (any type)
• Takotsubo syndrome
infarction
• Coronary revascularization procedure For the sake of immediate treatment strategies, such as reperfusion
• Cardiac procedure other than revascularization therapy, it is usual practice to designate MI as STEMI in patients
• Catheter ablation with chest discomfort or other ischaemic symptoms who de-
velop new ST-​segment elevations in two contiguous leads or new
• Defibrillator shocks
bundle branch blocks with ischaemic repolarization patterns. In
• Cardiac contusion
contrast, patients without ST-​segment elevation at presentation
Systemic conditions, e.g.:
◆
are usually designated NSTEMI. The categories of patients with
• Sepsis, infectious disease STEMI, NSTEMI, or UA are customarily included in the concept
• Chronic kidney disease of ACS. In addition to these categories, MI may be classified into
• Stroke, subarachnoid haemorrhage various types, based on pathological, clinical, and prognostic dif-
• Pulmonary embolism, pulmonary hypertension ferences, along with different treatment strategies [2, 26, 27].
• Infiltrative diseases, e.g. amyloidosis, sarcoidosis
• Chemotherapeutic agents Myocardial infarction type 1
• Critically ill patients MI caused by athero-​thrombotic CAD and usually precipitated
• Strenuous exercise by atherosclerotic plaque disruption (rupture or erosion) is des-
ignated as type 1 MI. The relative burden of atherosclerosis and
thrombosis in the culprit lesion varies greatly, and the dynamic
and demand. Myocardial ischaemia in a clinical setting can thrombotic component may lead to distal coronary embolization
most often be identified from the patient’s history and from the resulting in myocyte necrosis. Plaque rupture may be compli-
ECG. Possible ischaemic symptoms include various combin- cated not only by intraluminal thrombosis, but also by haem-
ations of chest, upper extremity, mandibular, or epigastric dis- orrhage into the plaque through the disrupted surface [28,  29]
comfort during exertion or at rest or an ischaemic equivalent (see E Figure 37.2). It is essential to integrate the ECG findings
such as dyspnoea or fatigue. Often, the discomfort is diffuse and with the aim of classifying type 1 MI into STEMI or NSTEMI, in
not localized, nor positional or affected by movement of the re- order to establish the appropriate treatment according to current
gion. However, these symptoms are not specific to myocardial guidelines [30, 31].
466 CHAPTER 37   The u niversal def init ion of m yo ca rdia l  i n fa rcti on

for type 1 MI patients in most, but not all, studies due to an in-
creased prevalence of comorbid conditions [33–​41]. Coronary
atherosclerosis is a common finding in type 2 MI patients selected
for coronary angiography. In general, these patients have a worse
prognosis than those without CAD [38–​41]. Prospective evalu-
Plaque rupture/erosion with ations of the importance of CAD with type 2 MI using consistent
occlusive thrombus definitions and approaches are needed.
It has been shown that the frequency of ST-​segment elevation
in type 2 MI varies from 3% to 24% [37]. In some cases, coronary
embolism caused by thrombi, Ca2+, or vegetation from the atria
Plaque rupture/erosion with or ventricles or acute aortic dissection may result in type 2 MI.
non-occlusive thrombus
Spontaneous coronary artery dissection with or without intra-
mural haematoma is another non-​atherosclerotic condition that
Figure 37.2  Myocardial infarction type 1.
may occur, especially in young women. It is defined as spontan-
eous dissection of the coronary artery wall with accumulation of
Criteria for type 1 MI blood within the false lumen which can compress the true lumen
to varying degrees [42] (see E Figure 37.3).
Detection of a rise and/​or fall of cTn with at least one value above
All of the clinical information available should be considered
the 99th percentile URL and with at least one of the following:
in distinguishing type 1 from type 2 MI. The context and mech-
• Symptoms of acute clinical myocardial ischaemia.
anisms of type 2 MI should be considered when establishing this
• New ischaemic ECG changes.
diagnosis (see E Figure 37.4) [43]. The myocardial O2 supply/​
• Development of pathological Q waves. demand imbalance attributable to acute myocardial ischaemia
• Imaging evidence of loss of viable myocardium that is pre- may be multi-​factorial, related either to reduced myocardial per-
sumed to be new or new regional wall motion abnormality in fusion due to fixed coronary atherosclerosis without plaque rup-
a pattern consistent with an ischaemic aetiology. ture, coronary artery spasm, coronary microvascular dysfunction
• Identification of plaque disruption and coronary thrombus by (which includes endothelial dysfunction, smooth muscle cell
angiography, including intracoronary imaging or by autopsy.* dysfunction, and dysregulation of sympathetic innervation),
*
Post-​mortem demonstration of an athero-​thrombus in the artery supplying coronary embolism, coronary artery dissection with or without
the infarcted myocardium or macroscopically a large circumscribed area of
intramural haematoma, or other mechanisms that reduce O2
necrosis with or without intramyocardial haemorrhage meets the type 1 MI
criteria, regardless of cTn values. supply such as severe bradyarrhythmia, respiratory failure
with severe hypoxaemia, severe anaemia, and hypotension/​
shock; or to increased myocardial O2 demand due to sustained
tachyarrhythmia or severe hypertension with or without LV hyper-
Myocardial infarction type 2 trophy. In patients who undergo timely coronary angiography,
The pathophysiological mechanism leading to ischaemic myocar- the finding of a ruptured plaque with thrombus in the
dial injury in the context of a mismatch between O2 supply and
demand has been classified as type 2 MI [2, 26,  27]. By defin-
ition, acute athero-​thrombotic plaque disruption is not a feature
of type 2 MI. In patients with stable known or presumed CAD,
an acute stressor, such as an acute GI bleed with a precipitous
drop in Hb, or a sustained tachyarrhythmia with clinical mani- Atherosclerosis and oxygen
festations of myocardial ischaemia may result in myocardial in- supply/demand imbalance

jury and type 2 MI. These effects are due to insufficient blood flow
to the ischaemic myocardium to meet the increased myocardial
O2 demand of the stressor. Ischaemic thresholds may vary sub- Vasospasm or coronary
microvascular dysfunction
stantially in individual patients, depending on the magnitude of
the stressor, the presence of non-​cardiac comorbidities, and the
extent of underlying CAD and cardiac structural abnormalities.
Non-atherosclerotic
Studies have shown variable occurrences of type 2 MI, coronary dissection
depending on the criteria used for diagnosis. Some reports rely
on specific predetermined O2 mismatch criteria [32, 33], whereas
others apply more liberal criteria. Most studies show a higher fre- Oxygen supply/demand
imbalance alone
quency of type 2 MI in women. The short-​and long-​term mor-
tality rates for patients with type 2 MI are generally higher than Figure 37.3  Myocardial infarction type 2.
 Cl i n i ca l cl as si fi cati on of m yo ca rdia l i n fa rc t i on 467

Secondary to another illness or process

Context
Main reason leading to clinical presentation (e.g. chest pain)

Fixed coronary atherosclerosis

Type 2 Coronary spasm
myocardial Coronary microvascular dysfunction
infarction
Coronary embolism
Coronary artery dissection +/–
Intramural haematoma
Oxygen supply Sustained tachyarrhythmia
Mechanisms and demand
Severe hypertension +/–
imbalance
Left ventricular hypertrophy
Severe bradyarrhythmia

Respiratory failure

Severe anaemia

Hypotension/shock

Figure 37.4  Framework for type 2 MI considering the clinical context and pathophysiological mechanisms attributable to acute myocardial ischaemia.
a
Ischaemic thresholds vary substantially in relation to the magnitude of the stressor and the extent of underlying cardiac disease.
Reproduced from Januzzi JL, Sandoval Y. The Many Faces of Type 2 Myocardial Infarction. J Am Coll Cardiol 2017;70(13):1569–​1572. doi:10.1016/​j.jacc.2017.07.784 with permission
from Elsevier.

infarct-​related artery is helpful in making the diagnosis of type Myocardial infarction type 2 and myocardial
1 MI, differentiating from type 2 MI, but angiography is not al- injury
ways definitive, clinically indicated, or required to establish the
diagnosis of type 2 MI. Type 2 MI and myocardial injury are frequently encountered
It appears advisable in the acute setting to treat the under- in clinical practice and both are related to a poor outcome [33,
lying cause of the ischaemic imbalance of O2 supply and de- 35, 40, 44,  45]. A  conceptual model to facilitate the clinical
mand. This treatment may include volume adjustment, blood distinction between acute ischaemic myocardial injury with
pressure management, administration of blood products, heart or without an acute athero-​thrombotic event (type 1 or type
rate control, and respiratory support [31, 32]. Depending on the 2 MI) versus conditions without acute ischaemic myocardial
clinical situation, coronary evaluations may be indicated to as- injury is displayed in E Figure 37.5. AMI requires a rising
sess the likelihood of CAD. If that is present, the MI guidelines and/​or falling pattern of cTn values. Acute myocardial injury
may be applied in accordance with the ECG findings of STEMI may also manifest such a pattern, but if the injury is related to
or NSTEMI [30, 31]. However, if CAD is absent, the benefit of structural heart disease, cTn values may be stable and unchan-
cardiovascular risk reduction strategies with type 2 MI remains ging. Type 2 MI and non-​ischaemic myocardial injury may co-
uncertain. exist. It should be recognized that some disease entities could
be on both sides of the diagram, e.g. AHF that may occur in
the context of acute myocardial ischaemia. Nevertheless, ab-
normal cTn values in the setting of acute and/​or chronic heart
failure are often better categorized as a myocardial injury con-
Criteria for type 2 MI
dition. Few studies have compared the incidence and clinical
Detection of a rise and/​or fall of cTn with at least one value above
features of type 2 MI versus myocardial injury without acute
the 99th percentile URL and evidence of an imbalance between
myocardial ischaemia.
myocardial O2 supply and demand unrelated to coronary artery
plaque disruption and thrombosis, requiring at least one of the Myocardial infarction type 3
following:
The detection of cardiac biomarkers in blood is fundamental
• Symptoms of acute myocardial ischaemia.
for establishing the diagnosis of MI [2]‌. However, patients can
• New ischaemic ECG changes.
manifest a typical presentation of myocardial ischaemia/​infarc-
• Development of pathological Q waves.
tion, including presumed new ischaemic ECG changes or VF,
• Imaging evidence of new loss of viable myocardium or new
and die before it is possible to obtain blood for cardiac bio-
regional wall motion abnormality in a pattern consistent with
marker determination; or the patient may succumb soon after
an ischaemic aetiology.
the onset of symptoms before elevation of biomarker values
468 CHAPTER 37   The u niversal def init ion of m yo ca rdia l  i n fa rcti on

Elevated cardiac troponin value(s) >99th percentile URL

Troponin rise and/or fall Troponin level stable

With Without
acute ischaemia acute ischaemia

Acute Acute Chronic

myocardial infarction myocardial injury myocardial injury

Oxygen supply
Atherosclerosis
and demand
+ thrombosis
imbalance

Type 1 MI: triggers Type 2 MI: examples Examples Examples

• Plaque rupture • Severe hypertension • Acute heart failure • Structural heart disease
• Plaque erosion • Sustained tachyarrhythmia • Myocarditis • Chronic kidney disease

Figure 37.5  A model for interpreting myocardial injury. a Stable denotes ≤20% variation in troponin values in the appropriate clinical context. b Ischaemia
denotes signs and/​or symptoms of clinical myocardial ischaemia.

has occurred. Such patients are designated as having type 3 Coronary procedure-​related myocardial
MI, when suspicion for an acute myocardial ischaemic event injury
is high, even when cardiac biomarker evidence of MI is lacking
[2]. This category allows the separation of fatal MI events from Cardiac procedural myocardial injury related to coronary
the much larger group of sudden death episodes that may be revascularization procedures, whether PCI or CABG, may be tem-
cardiac (non-​ischaemic) or non-​cardiac in origin. When type 3 porally related to the procedure itself, reflecting periprocedural
MI is diagnosed, and a subsequent autopsy reveals recent evi- issues, or may occur later reflecting the complications of a device
dence of an MI, with a fresh or recent thrombus in the infarct-​ such as early or late stent thrombosis or in-​stent restenosis for
related artery, the type 3 MI should be reclassified to type 1 MI. PCI or graft occlusion or stenosis with CABG. Late gadolinium
Original investigations addressing the incidence of type 3 MI enhancement cardiac magnetic resonance (LGE-​CMR) allows as-
are sparse, but a study showed an annual incidence of below sessment of procedural myocardial injury [47–​49]. When quan-
10/​100  000 person-​years and a frequency of 3–​4% among all tifying procedural injury using LGE-​CMR before and shortly
types of MI [46]. after PCI or CABG, it was found that 32% of patients had evi-
dence of procedural myocardial injury [49]. Furthermore, it
has been shown that patients with elevation of cTnI values after
PCI or CABG have evidence of procedural myocardial injury
on CMR imaging [47, 48]. For that reason, increased cTn values
detected following a coronary revascularization procedure may
Criteria for type 3 MI
reflect procedural myocardial injury. Of importance, if the base-
Patients who suffer cardiac death, with symptoms suggestive of line value before the procedure is above the 99th percentile URL,
myocardial ischaemia accompanied by presumed new ischaemic
it is essential that cTn levels are stable (≤20% change) prior to
ECG changes or VF, but die before blood samples for biomarkers
the evaluation in order to reliably establish the presence of acute
can be obtained or before increases in cardiac biomarkers can be
procedural myocardial injury. It is not possible to determine,
identified or MI detected by autopsy examination.
when intervening in a patient with an AMI event resulting in an
 Cl i n i ca l cl as si fi cati on of m yo ca rdia l i n fa rc t i on 469

increased cTn level, how much of any given increase is related to assays to diagnose type 4a MI (and type 5 MI) is an area of ac-
the MI and how much is due to the procedure. tive research. Many hs-​cTn assays are available, which have wide
dynamic ranges. Different criteria may be required for different
assays. However, it has recently been shown that the optimal
Criteria for cardiac procedural myocardial injury
hs-​cTnT threshold to predict cardiovascular events at 30  days
Cardiac procedural myocardial injury is arbitrarily defined by and 1  year was very close to the fivefold increase suggested by
increases in cTn values (>99th percentile URL) in patients with
the Third Universal Definition of MI [27, 52, 53]. These criteria
normal baseline values (≤99th percentile URL) or a rise in cTn
are therefore retained because of a lack of new scientific evidence
values >20% of the baseline value when it is above the 99th per-
that identifies superior criteria for defining this MI subtype.
centile URL but is stable or falling.
Other criteria that meet the definition of type 4a MI, regard-
less of hs-​cTn or cTn values, are the development of new patho-
A large proportion of patients have abnormal values of cTn logical Q waves or autopsy evidence of recent procedure-​related
after PCI, ranging from approximately 20–​40% in stable CAD thrombus in the culprit artery [2]‌.
to 40–​50% in MI [50]. The occurrence of procedural myocardial
injury can be detected by measurement of cTn before the pro-
Criteria for PCI-​related MI ≤48 hours after the index procedure
cedure and repeated 3–​6 hours later. Where the second value is (type 4a MI)
rising, further sampling should be performed to document the
Coronary intervention-​related MI is arbitrarily defined by ele-
peak cTn value. Increasing levels after the procedure can only be
vation of cTn values >5 times the 99th percentile URL in pa-
attributed with certainty to procedural myocardial injury when
tients with normal baseline values. In patients with elevated
the preprocedure cTn values are normal (≤99th percentile URL) preprocedure cTn in whom the cTn level is stable (≤20% vari-
or if they are stable or falling. For patients who present with ation) or falling, the post-​procedure cTn must rise by >20%.
an ACS and undergo a prompt coronary revascularization pro- However, the absolute post-​procedural value must still be at least
cedure resulting in only a single preprocedural baseline value five times the 99th percentile URL. In addition, one of the fol-
that is normal or mildly elevated, followed by subsequent post-​ lowing elements is required:
procedural values that continue to increase, the post-​procedural • New ischaemic ECG changes.
increase should be attributed to the index event. Recent data • Development of new pathological Q waves.*
corroborate the importance of elevated preprocedural cTn
• Imaging evidence of new loss of viable myocardium or new
values as a prognostic marker in patients who have values that
regional wall motion abnormality in a pattern consistent with
rise after the procedure [51]. To diagnose procedural myocar- an ischaemic aetiology.
dial injury in the clinical setting of only a single preprocedure
• Angiographic findings consistent with a procedural
cTn value, the cTn values would need to be stable or falling post-​
flow-​limiting complication such as coronary dissection,
procedure, followed by a subsequent increase that exceeds the occlusion of a major epicardial artery or a side branch oc-
99th percentile URL, and if the value has not returned to base- clusion/​thrombus, disruption of collateral flow, or distal
line, the increase should be >20% with an absolute value above embolization.**
the 99th percentile URL. *
Isolated development of new pathological Q waves meets the type 4a
MI criteria if cTn values are elevated and rising, but <5 times the 99th
Myocardial infarction associated with PCI percentile URL.
(type 4a MI) **
Post-​mortem demonstration of a procedure-​related thrombus in the
culprit artery or macroscopically a large circumscribed area of necrosis
Standalone post-​procedural increases of cTn values are sufficient with or without intramyocardial haemorrhage meets the type 4a MI
to establish a diagnosis of procedural myocardial injury, but not criteria.
for the diagnosis of type 4a MI. Type 4a MI requires an elevation
of cTn values >5 times the 99th percentile URL in patients with
normal baseline values or in patients with elevated preprocedure
Stent/​scaffold thrombosis associated with PCI
cTn values in whom the cTn levels are stable (≤20% variation) or (type 4b MI)
falling and the post-​procedure cTn must rise >20% to an abso- A subcategory of PCI-​related MI is stent/​scaffold thrombosis,
lute value >5 times the 99th percentile URL. In addition, there type 4b MI, as documented by angiography or autopsy using the
should be evidence of new myocardial ischaemia, either from same criteria utilized for type 1 MI. It is important to indicate the
ECG changes or from imaging evidence, or procedure-​related time of the occurrence of the stent/​scaffold thrombosis in rela-
complications associated with reduced coronary blood flow such tion to the timing of the PCI procedure. The following temporal
as coronary dissection, occlusion of a major epicardial artery or categories are suggested: acute 0–​24 hours; subacute >24 hours to
a side branch occlusion/​thrombus, disruption of collateral flow, 30 days; late >30 days to 1 year; and very late >1 year after stent/​
slow flow or no reflow, or distal embolization. The use of hs-​cTn scaffold implantation [2, 54].
470 CHAPTER 37   The u niversal def init ion of m yo ca rdia l  i n fa rcti on

Restenosis associated with PCI (type 4c MI) evidence of MI, indicates prognostically significant cardiac pro-
cedural myocardial injury [58].
Occasionally MI occurs, and at angiography, in-​stent restenosis
or restenosis following balloon angioplasty in the infarct territory
is the only angiographic explanation, since no other culprit le- Criteria for  CABG-​related MI ≤48 hours after  the index
sion or thrombus can be identified. This PCI-​related MI type is procedure (type 5 MI)
designated as type 4c MI, defined as focal or diffuse restenosis or CABG-​related MI is arbitrarily defined as elevation of cTn values
a complex lesion associated with a rise and/​or fall of cTn values >10 times the 99th percentile URL in patients with normal base-
above the 99th percentile URL, applying the same criteria utilized line cTn values. In patients with elevated preprocedure cTn in
for type 1 MI [2]‌. whom cTn levels are stable (≤20% variation) or falling, the post-​
procedure cTn must rise by >20%. However, the absolute post-​
procedural value still must be >10 times the 99th percentile URL.
Myocardial infarction associated with CABG
In addition, one of the following elements is required:
(type 5 MI) • Development of new pathological Q waves.*
Numerous factors can lead to procedural myocardial injury • Documented angiographic new graft occlusion or new native
during a CABG procedure. Many of them are related to the de- coronary artery occlusion.
tails of cardiac preservation and the extent of the direct trau- • Imaging evidence of new loss of viable myocardium or new
matic injury to the myocardium, as well as to any potential regional wall motion abnormality in a pattern consistent with
ischaemic injury. For that reason, increases in cTn values should an ischaemic aetiology.
be expected after all CABG procedures [55, 56], which need to *
Isolated development of new pathological Q waves meets the type 5
be taken into account when comparing the extent of procedural MI criteria if cTn values are elevated and rising, but <10 times the 99th
myocardial injury after cardiac surgery to that associated with percentile URL.
less invasive approaches. Depending on whether it is off-​pump
or on-​pump surgery, procedural myocardial injury is observed
among 32–​44% of CABG patients when quantified by LGE-​CMR Myocardial injury and infarction
[47, 49]. The AUC and routine cTn sampling have demonstrated associated with cardiac procedures other
an excellent linear relationship with the mass of the new injury, than revascularization
as defined by LGE-​CMR. The AUC for CK-​MB is also good, al-
Cardiac procedures such as transcatheter valve interventions may
though clearly inferior to cTnI [55]. However, these relationships
cause myocardial injury, both by direct trauma to the myocardium
vary, depending on the nature of the procedure, the nature of the
and by creating regional ischaemia secondary to coronary ob-
cardioplegia, and the specific assay used to measure cTn. Very
struction or embolization. Ablation of arrhythmias involves con-
high cTn values are most often associated with coronary artery-​
trolled procedural myocardial injury by application of warming
related events [47, 49,  55]. Thus, although cardiac biomarkers,
or cooling of the tissue. The extent of procedural myocardial in-
and especially cTn, appear robust for the detection of procedural
jury can be assessed by serial cTn measurements. Increases in cTn
myocardial injury and also, in the presence of new myocardial is-
values in this context should be considered as procedural myocar-
chaemia, for the detection of type 5 MI, a specific cut-​off value for
dial injury, and not labelled as MI unless the biomarker criteria
all procedures and all cTn assays is difficult to define. However,
and one of the ancillary criteria for acute myocardial ischaemia
in order to ensure consistency with the analogous standards of
listed for type 5 MI are present [59, 60].
the preceding definition of type 5 MI [27] and because of the
lack of new scientific evidence that identifies superior criteria for
defining this MI subtype, it is suggested to apply a cTn value >10
Myocardial injury and infarction associated
times the 99th percentile URL as the cut-​point during the first 48 with non-​cardiac procedures
hours following CABG, occurring from a normal baseline cTn Perioperative MI is one of the most important complications in
value (≤99th percentile URL), for diagnosing type 5 MI [2]‌. It is major non-​cardiac surgery, and it is associated with a poor prog-
important that the post-​procedural elevation of cTn values is ac- nosis [61,  62]. Most patients who have a perioperative MI will
companied by ECG and angiographic evidence of graft occlusion not experience ischaemic symptoms due to anaesthesia, sedation,
or new native coronary artery occlusion or imaging evidence or pain-​relieving medications. Nevertheless, asymptomatic peri-
of new myocardial ischaemia/​new loss of myocardial viability operative MI is as strongly associated with 30-​day mortality as
[2, 57]. The higher cut-​off of MI after CABG than that after PCI symptomatic MI [61, 62]. Knowledge about hs-​cTn values at base-
(ten times versus five times 99th percentile URL) has been arbi- line can help to identify patients having chronic cTn elevation be-
trarily selected due to the occurrence of more unavoidable myo- fore surgery, as well as those at increased risk during and after
cardial injury during surgery than during PCI. Marked isolated the procedure [63, 64]. Measurement of hs-​cTn in post-​operative
elevation of cTn values within the 48-​hour post-​operative period, samples reveals that as many as 35% of patients have levels above
even in the absence of ECG/​angiographic or other imaging the 99th percentile URL and 17% have an elevation and a rising
 Cl i n i ca l cl as si fi cati on of m yo ca rdia l i n fa rc t i on 471

pattern of values indicative of evolving myocardial injury [65]. with evidence of myocardial injury [5]‌. Recently, a minor effect
Those with a rising pattern of elevated hs-​cTn values are at par- on renal clearance of cTn has been shown when levels are low, but
ticular risk—​the greater the rise, the greater the risk [66, 67]. not in response to acute episodes of myocardial injury [80]. The
The pathophysiologic mechanism of perioperative MI is sub- mechanisms include increased ventricular pressure, small vessel
ject to debate. It is recognized that the perioperative period is coronary obstruction, anaemia, hypotension, and possibly direct
characterized by increased cardiac metabolic demand that may toxic effects on the myocardium associated with the uraemic state
lead to MI in patients with otherwise stable CAD [68, 69]. Thus, [73]. Cardiomyocyte apoptosis and autophagy due to acute wall
an angiographic investigation has identified demand myocar- stretch have been demonstrated experimentally [3]. Thus, base-
dial ischaemia as the predominant aetiology of perioperative MI line elevation of cTn values is common, and because they reflect
[68,  69], which, together with a rise and/​or fall of cTn values, myocardial injury, such elevations are highly prognostic [74].
indicates type 2 MI. However, other angiographic studies have Diagnosing MI in patients with CKD and elevated cTn levels
detected coronary plaque rupture in approximately 50–​60% of may be difficult if symptoms or ECG changes indicating myo-
patients with perioperative MI [70, 71], which qualifies as type 1 cardial ischaemia are absent. However, studies suggest that serial
MI. On the other hand, perioperative myocardial injury without changes in cTn levels are equally effective in diagnosing MI in
ancillary ischaemic evidence indicative of MI is a common patients with CKD and in those with normal renal function [81].
complication after non-​cardiac surgery and is associated with If the level of elevated cTn values is unchanging and the timing
substantial short-​and long-​term mortality on a level with peri- of the event makes a rising and/​or falling pattern unlikely, the
operative MI [67]. elevated level, even if substantial, is likely a reflection of chronic
myocardial injury. This does not imply that these patients are
Myocardial injury or infarction associated free of CAD, since renal dysfunction and CAD are correlated.
with heart failure However, if a rising and/​or falling pattern is present, then the
Depending on the assay used, detectable to clearly elevated cTn aetiology of the abnormal cTn values could be acute volume over-
values being indicative of myocardial injury may be seen in pa- load, congestive heart failure, or MI. If a rising and falling pattern
tients with heart failure, both with reduced EF and with preserved is seen and it is accompanied by ischaemic symptoms, new is-
EF [72]. Using hs-​cTn assays, measurable hs-​cTn concentrations chaemic ECG changes, or loss of viable myocardium on imaging,
may be present in nearly all patients with heart failure, with a sig- a diagnosis of AMI is likely.
nificant percentage exceeding the 99th percentile URL, particu-
larly in those patients with more severe heart failure syndromes Recurrent myocardial infarction
such as in ADHF [73]. Incident MI is defined as the individual’s first MI. When features
Beyond type 1 MI, multiple mechanisms have been proposed of MI occur in the first 28 days after an incident event, the second
to explain measurable to pathologically elevated cTn concentra- event is not counted as a new MI for epidemiological purposes. If
tions in patients with heart failure [72, 73]. For example, type 2 characteristics of MI occur after 28 days following an incident MI,
MI may result from increased transmural pressure, small vessel it is considered to be a recurrent MI [2]‌.
coronary obstruction, endothelial dysfunction, anaemia, or hypo-
tension. Besides type 1 or type 2 MI, cardiomyocyte apoptosis and Reinfarction
autophagy due to wall stretch have been experimentally demon- The term reinfarction is used clinically for an AMI that occurs
strated. Direct cellular toxicity related to inflammation, circu- within 28 days of an incident or recurrent MI [2]‌. The ECG diag-
lating neurohormones, and infiltrative processes may present with nosis of suspected reinfarction following the initial MI may be
heart failure and abnormal cTn measurements indicating myo- confounded by the initial evolutionary ECG changes. Reinfarction
cardial injury. Finally, exocytosis of the early releasable cytosolic should be considered when ST-​segment elevation of ≥1 mm re-
troponin pool into the bloodstream from stressed cardiomyocytes curs or new pathognomonic Q waves appear in at least two
has also been suggested as a cause of elevated cTn values [73]. contiguous leads, particularly when associated with ischaemic
symptoms. Re-​elevation of the ST-​segment can, however, also be
Myocardial injury and/​or infarction associated seen in threatened myocardial rupture or in cases of pericarditis
with kidney disease and should lead to additional diagnostic evaluation.
Many patients with CKD have elevation of cTn values [74,  75]. In patients where reinfarction is suspected from clinical signs
With hs-​cTn assays, the majority of patients with end-​stage renal or symptoms following the initial MI, an immediate measurement
disease will have elevation of hs-​cTn values above the 99th per- of cTn is recommended. A second sample should be obtained 3–​6
centile URL [74,  76]. This is particularly the case for hs-​cTnT hours later or earlier with more sensitive cTn assays. If the cTn
which is more often elevated, compared to hs-​cTnI [74, 77]. It has concentration is elevated, but stable or decreasing at the time of
been shown, using hs-​cTn assays, that renal dysfunction is com- suspected reinfarction, the diagnosis of reinfarction requires a
monly associated with cardiovascular abnormalities [77–​79]. In >20% increase of the cTn value in the second sample. If the initial
autopsy studies, elevation of cTn values was invariably associated cTn concentration is normal, the criteria for a new AMI apply [2]‌.
472 CHAPTER 37   The u niversal def init ion of m yo ca rdia l  i n fa rcti on

For that reason, this percentage has been suggested for use
Biochemical approach for diagnosing when initial baseline values are ≤99th percentile URL [83].
myocardial injury and infarction However, for individuals with an initial value >99th percentile
URL, a lesser degree of change during serial measurements is
cTnI and cTnT are the preferred biomarkers recommended to necessary to achieve improved clinical sensitivity (as compared
both rule in and rule out myocardial injury, and thus to define MI to individuals with initial values ≤99th percentile URL). Thus,
and each specific subtype of MI [2]‌. Detection of a rise and/​or fall an expert consensus group has recommended serial changes of
of cTn values is essential and a key early component, along with >20% be used in this situation [2]‌. Absolute changes are assay-​
other elements of the clinical evaluation, to establish the diagnosis dependent but appear superior to relative percentage changes
of AMI. Criteria for determining a pathological rise between two with hs-​cTn assays [84], and in some studies, this is especially the
serial cTn values are assay-​dependent and continue to evolve. An case when the initial value is increased [85]. The use of a fixed
idealized view of troponin kinetics in patients with AMI is shown absolute value change criteria translates into a smaller percentage
in E Figure 37.6. or relative change as absolute values rise and therefore provides
It should be appreciated that because biomarker release is greater sensitivity. The use of a changing pattern is important in
substantially dependent on blood flow [82], there is significant allowing clinicians to differentiate an acute from a chronic cTn
variability in the time to peak value (velocity), the time when increase above the 99th percentile URL [83–​85]. Using criteria
a normal value may become >99th percentile URL, or when a less than conjoint analytical and biological variation will reduce
changing pattern of values can be observed. The ability to de- the clinical specificity of hs-​cTn assays [83, 86]. An imprecision of
fine a changing pattern will also depend on timing. For example, ≤10% CV at the 99th percentile URL is also mandatory for hs-​cTn
around peak values, it may be difficult to observe a chan- assays. The use of non-​hs-​cTn assays that do not have imprecision
ging pattern of values. Similarly, the downslope of the time–​ (≤10% CV at the 99th percentile URL) makes determination of
concentration curve is much slower than the upslope. These a significant serial change more difficult but does not cause false
issues need to be taken into account when defining whether or positive results. Assays with CVs between 10% and 20% are ac-
not a changing pattern is present. In addition, it is important ceptable for clinical use. However, assays with CVs >20% at the
to make sure that a given change is greater than can be antici- 99th percentile URL should not be used [87].
pated by variability alone. This is defined for conventional cTn False positive elevations of cTn are unusual [11]. Almost all in-
assays as a change ≥3 times the standard deviation around the creases reflect myocardial injury and herald a worse prognosis
measurement of the individual assay at relevant values. For than for otherwise similar patients without cTn elevations. An
hs-​cTn assays, biological variation also needs to be considered. elevated cTn level even indicates a worse prognosis in asymp-
In most studies, conjoint analytical and biological variation is in tomatic people without known CVD [88]. Even those with higher
the range of 50–​60% [2, 7]. values within the normal range in whom MI is excluded have an

Very early
sampling Early sampling Later sampling Very late sampling

Rising cTn values

from below to
>99th percentile
Delta is
detectable
cTn values
>99th percentile
Delta may not Acute
be seen over a
short period
cTn values myocardial
>99th percentile
Cardiac Declining delta
infarction
troponin Chronic
(cTn) myocardial
Low injury
cTn
values
Hard to
detect
delta
99th
percentile
URL
Time from onset of symptoms (hours)

Figure 37.6  Conceptual illustration of early cTn kinetics in patients after acute myocardial injury, including acute myocardial infarction. The timing of
biomarker release into the circulation is dependent on blood flow and how soon after the onset of symptoms samples are obtained. Thus, the ability to consider
small changes as diagnostic can be problematic. In addition, many comorbidities increase cTn values, in particular hs-​cTn values, so that elevations can be present
at baseline, even in those with myocardial infarction who present early after the onset of symptoms. Changes in cTn values or deltas can be used to define acute,
compared to chronic, events and the ability to detect these is indicated in the figure. Increased cTn values can often be detected for days after an acute event.
 Elect ro ca rdi o g r a phi c detecti on of m yo ca rdia l  i n fa rc t i on 473

increased long-​term risk [89]. Due to its high sensitivity, hs-​cTn is

Box 37.2  Electrocardiographic manifestations suggestive
more useful for risk stratification of acute myocardial injury and of acute myocardial ischaemia (in the absence of left ventricular
infarction, compared to conventional cTn [90,  91]. In addition, hypertrophy and bundle branch block)
strong associations between chronic circulating concentrations
of hs-​cTn and the incidence of cardiovascular death or congestive ST-​segment elevation
heart failure were first reported in patients with stable CAD and New ST-​segment elevation at the J-​point in two contiguous
subsequently confirmed in several large population-​based studies leads with the cut-​point of ≥1 mm in all leads other than leads
[92]. Changes in values over time and sex-​specific cut-​off values are V2 and V3 where the following cut-​points apply: ≥2mm in men
invariably found to augment risk prediction in these studies [93]. ≥40 years; ≥2.5 mm in men <40 years; or ≥1.5 mm in women,
regardless of age.*
ST-​segment depression and T-​wave changes
New horizontal or downsloping ST-​ segment depression of
Electrocardiographic detection ≥0.5  mm in two contiguous leads and/​ or T-​
wave inversion
of myocardial infarction of >1  mm in two contiguous leads with prominent R wave or
R/​S ratio of >1.
The ECG is an integral part of the diagnostic work-​up of pa-
*
When the magnitudes of J-​point elevation in leads V2 and V3 are recorded
tients with suspected MI and should be acquired and interpreted
from a prior ECG, new J-​point elevation of ≥1 mm (as compared to an earlier
promptly (i.e. target within 10 minutes) after first medical con- ECG) should be considered as an ischaemic response. For bundle branch
tact (FMC) [31, 94]. Pre-​hospital ECGs reduce the time to diag- block, see E Box 37.3.
nosis and treatment and can facilitate triage of STEMI patients
to hospitals with PCI capability if within the recommended time
interval (120 minutes from STEMI diagnosis) [95]. Acute myo- ischaemia is typical T-​wave and ST-​segment changes. Increased
cardial ischaemia is often associated with dynamic changes in hyperacute T-​wave amplitude, with prominent symmetrical T-​
ECG waveform, and serial ECG acquisition can provide critical waves in at least two contiguous leads, is an early sign that may
information, particularly if the ECG at initial presentation is non-​ precede the elevation of the ST-​segment. In general, the develop-
diagnostic. Recording several standard ECGs with fixed electrode ment of new Q waves indicates myocardial necrosis, which starts
positions at 15-​to 30-​minute intervals for the initial 1–​2 hours in minutes/​hours after the myocardial insult. Transient Q waves
or use of continuous computer-​assisted 12-​lead ECG recording, may be observed during an episode of acute ischaemia or (rarely)
if available, to detect dynamic ECG changes are reasonable for during AMI with successful reperfusion. E Box 37.2 lists ST-​
patients with persistent or recurrent symptoms or an initial non-​ segment–​T-​wave (ST-​T) criteria suggestive of acute myocardial
diagnostic ECG [96]. ischaemia that may or may not lead to MI. The J-​point (junction
More profound ST-​segment shift or T-​wave inversion involving between QRS termination and ST-​segment onset) is used to de-
multiple leads/​territories are associated with a greater degree of termine the magnitude of the ST-​segment shift, with the onset of
myocardial ischaemia and a worse prognosis. For example, ST-​ the QRS serving as the reference point. In patients with a stable
segment depression of ≥1  mm in six leads that may be associ- baseline, the TP segment (isoelectric interval) is a more accurate
ated with ST-​segment elevation in leads aVR or lead V1 and method to assess the magnitude of the ST-​segment shift and to
haemodynamic compromise is suggestive evidence of multivessel distinguish pericarditis (PTa depression) from acute myocardial
disease or left main disease. Pathologic Q waves increase the prog- ischaemia. Tachycardia and baseline shift are common in the
nostic risk. Other ECG signs associated with acute myocardial acute setting and can make this determination difficult. Therefore,
ischaemia include cardiac arrhythmias, intraventricular bundle QRS onset is recommended as the reference point for J-​point de-
branch blocks, AV conduction delays, and loss of precordial R termination (see E Figure 37.7).
wave amplitude, a less specific finding. The ECG by itself is often
insufficient to diagnose acute myocardial ischaemia or infarction,
since ST-​segment deviation may be observed in other conditions
such as acute pericarditis, LV hypertrophy, LBBB, Brugada syn-
drome, Takotsubo syndrome, and early repolarization patterns
1
[97]. A prior ECG is often helpful in distinguishing a new from a
chronic finding but should not delay the decision for treatment.
Prolonged new convex ST-​segment elevation, particularly when
associated with reciprocal ST-​segment depression, usually reflects 2
acute coronary occlusion and results in myocardial injury with
necrosis. Reciprocal changes can help to differentiate STEMI from Figure 37.7  ECG example of ST-​segment elevation. The initial onset of the
Q wave, shown by arrow 1, serves as the reference point, and arrow 2 shows
pericarditis or early repolarization changes. As in cardiomyopathy, the onset of the ST-​segment or J-​point. The difference between the two
Q waves may also occur due to myocardial fibrosis in the ab- identifies the magnitude of displacement. Measurements of both arrows
sence of CAD. One of the earlier manifestations of myocardial should be made from the top of the ECG line tracing.
474 CHAPTER 37   The u niversal def init ion of m yo ca rdia l  i n fa rcti on

New J-​point elevation of ≥1 mm (1 mm = 0.1 mV) is required

Criteria for prior or silent/​unrecognized myocardial infarction
in all leads, other than V2 and V3, as an ischaemic response. In
Any one of the following criteria meets the diagnosis for prior or
healthy men under age 40, J-​point elevation can be as much as
silent/​unrecognized  MI:
2.5 mm in leads V2 or V3, but it decreases with increasing age. Sex
differences require different cut-​points for women, since J-​point • Pathological Q waves as described in E Box 37.3, with or
without symptoms, in the absence of non-​ischaemic causes.
elevation in healthy women in leads V2 and V3 is less than in men
[2]‌. The criteria in E Box 37.2 require that the ST-​segment shift • Imaging evidence of loss of viable myocardium in a pattern
be present in two or more contiguous leads. For example, ≥2 mm consistent with ischaemic aetiology.
of ST-​segment elevation in lead V2 and ≥1 mm in lead V1 would • Pathological findings of a prior MI.
meet the criteria of two abnormal contiguous leads in a man
≥40 years old. However, ≥1 mm and <2 mm of ST-​segment ele-
vation, seen only in leads V2–​V3 in men (or <1.5 mm in women),
may represent a normal finding.
Imaging techniques
Commonly used imaging techniques in acute and prior MI are
echocardiography, MPS using SPECT or PET, CMR, and possibly
Prior or silent/​unrecognized CT [100]. There is considerable overlap in their capabilities, and
each of the techniques can assess myocardial viability, perfusion,
myocardial infarction and function to a greater or lesser extent. Only the radionuclide
Q wave criteria associated with MI and increased relative risk techniques provide a direct assessment of myocyte viability be-
of death are illustrated in E Box 37.3 and contained in Q wave cause of the inherent properties of the tracers used. Other tech-
coding algorithms such as the Minnesota Code and the WHO niques provide indirect assessments of myocardial viability such
MONItoring of trends and determinants in CArdiovascular dis- as contractile response to dobutamine by echocardiography
ease (MONICA) code [98, 99]. The specificity of ECG diagnosis or increased extracellular space secondary to myocyte loss by
for MI is greatest when Q waves occur in several leads or lead CMR or CT.
groupings or are >0.04 seconds. When the Q waves are associ-
ated with ST-​segment deviations or T-​wave changes in the same Echocardiography
leads, the likelihood of MI is increased; for example, minor Q The strength of echocardiography is the combined assessment of
waves of ≥0.02 seconds and <0.03 seconds that are ≥1 mm deep cardiac structure and function, in particular myocardial thick-
are suggestive of prior MI if accompanied by inverted T-​waves ness, thickening/​thinning, and motion. Regional wall motion
in the same lead group. Non-​invasive imaging techniques also abnormalities induced by ischaemia can be detected by echo-
provide important supportive evidence of prior MI. In the ab- cardiography almost immediately after onset when >20% of
sence of non-​ischaemic causes, regional myocardial thinning, transmural myocardial thickness is affected [101–​103]. These
scar, or new reduced wall motion abnormality, as shown by abnormalities, when new and without an alternative aetiology,
echocardiography, MPS with SPECT or PET, or MRI provide support the diagnosis of MI when cTn values show a rising and/​
strong evidence for prior MI, particularly when the ECG criteria or falling pattern. Echocardiography also allows detection of
are equivocal. non-​coronary cardiac pathologies known to cause CP, e.g. acute
pericarditis, severe aortic stenosis, hypertrophic cardiomyo-
pathy, and Takotsubo syndrome, among others. The technique
Box 37.3  Electrocardiographic changes associated with prior is useful in diagnosing mechanical complications in patients
myocardial infarction (in the absence of left ventricular with MI and haemodynamic compromise (shock) or other po-
hypertrophy and left bundle branch block) tentially fatal entities such as acute aortic dissection or massive
PE where the clinical presentation might be similar to that seen
● Any Q wave in leads V2 and V3 of >0.02 seconds or QS com-
with AMI.
plex in leads V2 and V3.
Q wave of ≥0.03 seconds and ≥1 mm deep or QS complex
●
Cardiac magnetic resonance imaging
in leads I, II, aVL, aVF, or V4–​V6, in any two leads of a con-
tiguous lead grouping (I, aVL; V1–​V6; II, III, aVF).* The high tissue contrast and resolution of CMR provides
R wave of >0.04 seconds in leads V1 and V2 and R/​S of
●
an accurate assessment of myocardial structure and func-
>1 with a concordant positive T-​wave in the absence of tion. Although less commonly used in the acute setting, it
conduction defect. has similar capability to echocardiography in suspected MI.
* Paramagnetic contrast agents can be used to assess myocar-
The same criteria are used for supplemental leads V7–​V9.
dial perfusion and the increase in extracellular space that is
 RE F E RE N C E S 475

associated with fibrosis of prior MI (detected by LGE-​C MR). to be as little as 1 g [106]. CMR also has the ability to identify
These techniques have been used in the setting of AMI the presence and extent of myocardial oedema/​inflamma-
[104,  105], and localized delay in contrast enhancement is tion, allowing the distinction of acute versus chronic myo-
able to detect even small areas of subendocardial MI, thought cardial injury.

Personal perspective
The process that led to the fourth revision of the Universal practice and is now included in the codes of the tenth revi-
Definition of Myocardial Infarction is an ongoing activity sion of the International Statistical Classification of Diseases
involving cardiologists from all over the world. The cur- and Related Health Problems. The Universal Definition of
rent chapter reflects the updates to the Universal Definition Myocardial Infarction has changed clinical practice, resulted in
of Myocardial Infarction that were published simultaneously a large number of publications, and has fostered a new area of
in European Heart Journal, Circulation, Journal of American clinical investigation in cardiology. The Task Force continues
College of Cardiology, and Global Heart. Since its incep- to monitor all new research concerning the now well-​known
tion in 2000, and through its three further updates in 2007, Universal Definition of Myocardial Infarction, and revisions to
2012, and 2018, the Universal Definition of Myocardial the definition will be prepared in the future, based on investi-
Infarction has been widely employed in daily clinical gations currently ongoing throughout the world.

Further reading
Thygesen K, Alpert JS, Jaffe AS, et al.; the Executive Group on behalf of the of Myocardial Infarction. Fourth universal definition of myocardial
Joint ESC/​ACC/​AHA/​WHF Task Force for the Universal Definition infarction (2018). Eur Heart J 2019;40:237–​69.

References
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European Society of Cardiology/​American College of Cardiology troponin T, but not cardiac troponin I, in patients with neuromus-
Committee for the redefinition of myocardial infarction. Eur Heart J cular diseases: implications for the diagnosis of myocardial infarc-
2000;21:1502–​13. tion. J Am Coll Cardiol 2014;63:2411–​20.
2. Thygesen K, Alpert JS, Jaffe AS, et  al.; the Executive Group on be- 9. Jaffe AS, Vasile VC, Milone M, et  al. Diseased skeletal muscle:  a
half of the Joint ESC/​ACC/​AHA/​WHF Task Force for the Universal noncardiac source of increased circulating concentrations of cardiac
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 CHAPTER 38

ST-​segment elevation
myocardial infarction
Borja Ibanez and Stefan James

Contents
Summary  479
Summary
Introduction  479 Acute myocardial infarction with ST-​segment elevation (STEMI) is a common and
Initial diagnosis and management  480 dramatic manifestation of coronary artery disease. The diagnosis of ST-​segment ele-
Challenging ECGs  480 vation is based on a syndrome of ischaemic chest pain symptoms, associated with
Complementary investigations  480
typical ST-​segment elevation on the electrocardiogram and an eventual rise in bio-
Pre-​hospital logistics  480
Delays of initial management  480
markers of myocardial necrosis. Treatment of STEMI is focused on re-​establishing
Emergency medical system  481 blood flow in the coronary artery involved, preferably by percutaneous coronary
Organization of ST-​segment elevation intervention or by pharmacological thrombolysis in the case of expected lengthy
myocardial infarction treatment in
networks  481 time delays or lack of availability of facilities. Early mortality from STEMI can be
Selection of reperfusion strategy: primary attributed to the sequelae or complications of myocardial ischaemia or to complica-
PCI versus fibrinolysis  482 tions related to therapy. The former includes arrhythmias such as ventricular tachy-
Primary PCI  483 cardia or fibrillation; mechanical complications such as ventricular free wall, septal,
Procedural aspects of primary PCI  483 and mitral chordal rupture; and pump failure leading to cardiogenic shock. The
Arterial access route during
primary PCI  483 latter includes haemorrhagic complications and coronary stent thrombosis. Given
Primary PCI technique  483 that myocardial necrosis is a critically time-​dependent process, organization of an
Management of multivessel disease in stable STEMI elevation care system and adherence to the latest clinical trial evidence and
STEMI patients  484
Management of multivessel disease in STEMI guidelines are crucial to ensure that patients are treated in an optimal manner.
patients in shock  484
Rescue PCI  484
Adjunctive antithrombotic
treatments  484
Anticoagulation  485
Heparins  485
Bivalirudin  485 Introduction
Antiplatelet therapy  485
GPIIb/​IIIa inhibitors  485 Over the last 50  years, treatment of acute STEMI has been improved considerably. The
Fibrinolytic treatment  485 widespread implementation of reperfusion (initially pharmacological and later mechan-
Fibrinolytic agents 485 ical) resulted in a magnificent reduction in the rates of in-​hospital mortality from about
Pre-​hospital fibrinolysis  486
Hazards of fibrinolysis  486 25% in the 1970s to 5% in the late 2010s [1]‌. Mortality in real life, however, is higher than
Routine angiography after fibrinolytic these figures shown in clinical trials. There is compelling evidence showing an association
therapy  486
Adjunctive anticoagulant and antiplatelet
between the duration of ischaemia and mortality. This is the basis for timely reperfusion
therapy  486 in STEMI. All actions should be made to reduce all components of the ischaemic time.
Coronary bypass surgery in STEMI Despite these advances, STEMI survivors are still at high risk of developing repetitive events,
patients  487 including reinfarctions, heart failure, and sudden death. Evolving therapies beyond timely
Adjunctive therapy in the acute reperfusion are contributing to further reduce the morbidity associated with STEMI [1].
phase  487
Early beta-​blockers  487
Nitrates  487 Maintenance after STEMI  489 Mitral regurgitation  490
Specific types of infarction and Acute complications of ST-​segment Arrhythmias and conduction
subgroups  487 elevation myocardial infarction  489 disturbances  490
Right ventricular infarction  487 Pericarditis  490
Pump failure  489
Patients on chronic anticoagulation  489 Cardiogenic shock  489 References  490
Management during STEMI  489 Cardiac rupture  489
480 CHAPTER 38   ST- se g ment elevat ion myo ca rdia l  i n fa rcti on

previously known. In patients with RBBB, it may be difficult to detect

Initial diagnosis and management transmural ischaemia. Therefore, a primary PCI strategy (emergent
coronary angiography and PCI if indicated) should be considered
Management of STEMI starts from the point of FMC, the time
when persistent ischaemic symptoms occur in the presence of RBBB.
point when the patient is initially assessed by health care per-
Some patients with an occluded artery may have an initial ECG
sonnel who can obtain and interpret the ECG and deliver initial
without ST-​segment elevation, sometimes because they are seen
interventions (e.g. defibrillation). A working diagnosis of STEMI
very early after symptom onset (in which case, one should look
(called the ‘STEMI diagnosis’) must be made first. This is usually
for hyperacute T-​waves, which may precede ST-​segment eleva-
based on symptoms consistent with myocardial ischaemia and
tion). It is important to repeat the ECG. Some patients with acute
signs (mainly ECG). Some patients may present with less typical
occlusion of a coronary artery and ongoing MI, such as those with
symptoms and/​or non-​diagnostic ECG. In cases of symptom re-
an occluded circumflex coronary artery, acute occlusion of a vein
lief after nitroglycerin administration, another 12-​lead ECG must
graft, or left main disease, may present without ST-​segment ele-
be obtained. Complete normalization of the ST-​segment eleva-
vation. In any case, suspicion of ongoing myocardial ischaemia is
tion after nitroglycerin administration, along with complete relief
an indication for a primary PCI strategy, even in patients without
of symptoms, is suggestive of coronary spasm, with or without
diagnostic ST-​segment elevation.
associated MI (see management of these patients in subsequent
In AMI of the inferior and basal portions of the heart, often cor-
sections).
responding to the left circumflex territory, isolated ST-​segment
It is recommended to initiate ECG monitoring as soon as pos-
depression of ≥0.5 mm in leads V1–​V3 represents the dominant
sible to detect life-​threatening arrhythmias and allow prompt de-
finding. These should be managed as STEMI. The use of additional
fibrillation if indicated. When STEMI is suspected, a 12-​lead ECG
posterior chest wall leads [elevation V7–​V9 ≥0.5 mm (≥1 mm in
must be acquired and interpreted as soon as possible to facilitate
men, 40 years old)] is recommended to detect ST-​segment eleva-
early STEMI diagnosis and triage (goal <10 minutes from FMC).
tion consistent with inferior and basal MI.
O2 is indicated only in hypoxic patients with arterial O2 satur-
The presence of ST-​segment depression of ≥1 mm in ≥8 sur-
ation (SaO2) of <90%, since the DETO2X trial showed no clinical
face leads (inferolateral ST-​segment depression), coupled with
benefits when SaO2 is ≥90% in MI patients [2]‌and a meta-​
ST-​segment elevation in aVR and/​or V1, suggests multivessel is-
analysis demonstrated that in acutely ill adults, liberal O2 therapy
chaemia or left main coronary artery obstruction.
increases mortality without improving other patient-​important
As a general rule, patients with a clinical suspicion of ongoing
outcomes [3]. A  mild tranquillizer (usually a benzodiazepine)
myocardial ischaemia and non-​diagnostic ECGs should undergo
should be considered in anxious patients.
a primary PCI strategy (emergent coronary angiography and PCI
In patients with a clinical suspicion of myocardial ischaemia
if indicated).
and an equivocal ECG, this should be repeated and, when pos-
sible, compared with previous recordings. If interpretation of
pre-​hospital ECG is not possible on site, field transmission of the
Complementary investigations
ECG is recommended. In the proper clinical context, ST-​segment Blood sampling for serum markers is indicated in the acute phase
elevation (measured at the J-​point) is considered suggestive of but should not delay the reperfusion strategy. If in doubt regarding
ongoing coronary artery acute occlusion in the following cases: ≥2 the possibility of acute evolving MI, emergency echocardiogram
contiguous leads with ST-​segment elevation of ≥2.5 mm in men aids the provision of timely reperfusion therapy to these patients.
<40 years, ≥2 mm in men ≥40 years, or ≥1.5 mm in women in If this is not available or if doubts persist after echocardiography,
leads V2–​V3 and/​or ≥1 mm in the other leads. In patients with a primary PCI strategy is indicated. Use of CT should be confined
inferior MI, it is recommended to record right precordial leads to selected cases where acute aortic dissection or PE is suspected,
(V3R and V4R) to identify concomitant RV infarction. Likewise, but if STEMI diagnosis is likely, CT is not recommended.
ST-​segment depression in leads V1–​V3 suggests myocardial is-
chaemia, and confirmation by concomitant ST-​segment eleva-
tion of ≥0.5 mm recorded in leads V7–​V9 should be considered Pre-​hospital logistics
as a means to identify posterior MI. The presence of a Q wave on
the ECG should not necessarily change the reperfusion strategy Treatment delays and system delays are the most easily audited
decision. index of quality of care in STEMI; they should be recorded in
every system providing care to STEMI patients and be reviewed
Challenging ECGs regularly, to ensure that simple quality-​of-​care indicators are met
In the presence of LBBB, including paced patients, the presence of and maintained over time.
concordant ST-​segment elevation (i.e. in leads with positive QRS
deflections) appears to be one of the best indicators of ongoing MI Delays of initial management
with an occluded infarct artery. Patients with a clinical suspicion of Components of ischaemic time are presented in E Figure 38.1.
ongoing myocardial ischaemia and LBBB should be managed in a To minimize patient delay, it is recommended to increase public
way similar to STEMI patients, regardless of whether the LBBB is awareness of how to recognize common symptoms of AMI and to
 Pre- ho spi ta l   l o g i st i c s 481

call the emergency services. In hospitals and EMS participating to enhance early initial diagnosis, triage, and treatment. It is in-
in the care of STEMI patients, the goal is to reduce the delay dicated that all ambulances in the EMS are equipped with ECG
between FMC and STEMI diagnosis to ≤10 minutes. STEMI recorders, defibrillators, and at least one person trained in ALS.
diagnosis refers to the time when the ECG is interpreted as ST-​ The quality of care provided depends on the training of staff in-
segment elevation or equivalent and it is the time zero to guide volved. It is indicated that all ambulance personnel are trained to
appropriate therapy. System delay is more readily modifiable by recognize the symptoms of an AMI.
organizational measures than is patient delay, and it is a predictor
of outcomes. When STEMI diagnosis is made in the pre-​hospital Organization of ST-​segment elevation
setting (EMS), immediate activation of the catheterization labora- myocardial infarction treatment in networks
tory and bypassing EDs is recommended. For patients presenting Optimal treatment of STEMI should be based on implementation
in a non-​PCI centre, a door-​in to door-​out time, defined as the of networks between hospitals (‘hub’ and ‘spoke’) with various
duration between arrival of the patient at the hospital to discharge levels of technology, linked by a prioritized and efficient ambu-
of the patient in an ambulance en route to the PCI centre, of ≤30 lance service. The goal of these networks is to provide optimal care,
minutes is recommended. while minimizing delays, thereby improving clinical outcomes.
Cardiologists should actively collaborate with all stakeholders,
Emergency medical system particularly emergency physicians, in establishing such networks.
An EMS with an easily recalled and well-​publicized unique med- The main features of such a network are: (1) a clear definition of
ical dispatching number (112 for most medical emergencies geographic areas of responsibility; (2)  shared written protocols;
across Europe) is important to speed up activation. The ambu- (3) pre-​hospital triage of STEMI patients to the appropriate insti-
lance system is not only a mode of transport, but also a system tution, bypassing non-​PCI hospitals or hospitals without a 24/​7

Total ischaemic time

Patient delay EMS delay System delay

FMC: EMS
+

<10’ Primary <90’

Reperfusion
≤120 min PCI
(wire crossing)
STEMI strategy
diagnosis Time
to PCI?
<10’ Fibrinolysis <10’ Reperfusion
>120 min
strategy (lytic bolus)

FMC: non-PCI centre

<10’ Primary <60’ Reperfusion

PCI
(wire crossing)
STEMI strategy
FMC: PCI centre diagnosis

Patient delay System delay

Total ischaemic time

Figure 38.1  Modes of patient presentation, components of ischaemia time, and flow chart for reperfusion strategy selection. A system delay for patients
alerting the EMS starts at the time of phone alert, although FMC occurs when EMS arrives to the scene. EMS, emergency medical system; FMC, first medical
contact; PCI, percutaneous coronary intervention; STEMI, ST-​segment elevation myocardial infarction. ′ denotes minutes. a Patients with fibrinolysis should be
transferred to a PCI centre immediately after administration of the lytic bolus.
Reproduced from Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-​Ducci C, Bueno H, Caforio ALP, Crea F, Goudevenos JA, Halvorsen S, Hindricks G, Kastrati A, Lenzen MJ,
Prescott E, Roffi M, Valgimigli M, Varenhorst C, Vranckx P, Widimsky P, Group ESCSD. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting
with ST-​segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-​segment elevation of the European Society of
Cardiology (ESC). Eur Heart J 2018;39(2):119–​177 with permission from Oxford University Press.
482 CHAPTER 38   ST- se g ment elevat ion myo ca rdia l  i n fa rcti on

primary PCI programme; (4)  bypassing EDs; (5)  attending pa-

tients presenting to a non-​PCI-​capable hospital in an appropriate
monitored and staffed area, while awaiting transportation; and
(6) ambulance crew awaiting the diagnosis to be made/​ruled out Symptoms 0 Primary
onset PCI
for patients without a clear STEMI diagnosis brought to a non-​
I A I A
PCI centre. If a diagnosis is made, the same crew should continue

Early phase of STEMI

Fibrinolysis
to a PCI-​capable hospital. (only if PCI cannot be performed
Primary PCI centres should perform the procedure on a 24/​7 within 120 min from STEMI diagnosis)
3 hours
basis. Other models, although not ideal, may include weekly or
Primary
daily rotation of primary PCI centres or multiple primary PCI PCI
centres in the same region. Hospitals that cannot offer a 24/​7 I A I A
service for primary PCI should be allowed to perform primary Fibrinolysis
(only if PCI cannot be performed
PCI in patients already admitted for another reason who develop within 120 min from STEMI diagnosis)
STEMI during their hospital stay. These hospitals should, how- 12 hours
ever, be discouraged from initiating a service limited to daytime Primary PCI Primary PCI
(if symptoms, (asymptomatic
or within-​hours primary PCI. It is therefore indicated that the haemodynamic instability, stable patients)

Evolved STEMI
or arrhythmias)
EMS transports STEMI patients to hospitals with an established
interventional cardiology programme available 24/​7.
Geographic areas where the expected transfer time to a pri-
mary PCI centre makes it impossible to achieve the maximal al- IIa B
lowable delays (see E Selection of reperfusion strategy: primary 48 hours
I C
PCI versus fibrinolysis, p.  482) should develop systems for on-​ Routine PCI
(asymptomatic III A
scene immediate fibrinolysis, with subsequent immediate transfer
Recent
STEMI
stable patients)

to the primary PCI centre.

Figure 38.2  Reperfusion strategies in IRA according to the time from

Selection of reperfusion strategy: symptom onset. In early presenters (i.e. those with STEMI diagnosis within 3
hours of symptom onset), a primary PCI strategy is the reperfusion strategy
primary PCI versus fibrinolysis of choice. If the anticipated time from STEMI diagnosis to PCI-​mediated
reperfusion is >120 minutes, then immediate fibrinolysis is indicated. After 3
E Figure 38.2 shows the reperfusion strategy recommended hours (and up to 12 hours) of symptom onset, the later the patient presents,
according to patient characteristics. There is ample evidence the more consideration should be given to a primary PCI strategy, as opposed
showing that, head-​to-​head, primary PCI is superior to fibrin- to administering fibrinolytic therapy. In evolved STEMI (12–​48 hours after
olysis in reducing mortality, reinfarction, or stroke [4]‌. However, symptom onset), a routine primary PCI strategy (urgent angiography and
subsequent PCI if indicated) should be considered in all patients. After 48
in some circumstances, primary PCI is not an immediate op- hours (recent STEMI), angiography should be performed, but routine PCI
tion (e.g. patients diagnosed in the out-​of-​hospital setting) and of a totally occluded IRA is not recommended. Regardless of the time from
fibrinolysis could be initiated instantly. The extent to which a symptom onset, the presence of ongoing symptoms suggestive of ischaemia,
PCI-​related time delay diminishes the advantages of PCI over fi- haemodynamic instability, or life-​threatening arrhythmias is an indication for
brinolysis has been widely debated. Despite the fact that no spe- a primary PCI strategy. PCI, percutaneous coronary intervention; STEMI, ST-​
segment elevation myocardial infarction.
cifically designed study has addressed this issue and there are Reproduced from Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-​Ducci C, Bueno
heterogenous data, there is consensus that a PCI-​related time H, Caforio ALP, Crea F, Goudevenos JA, Halvorsen S, Hindricks G, Kastrati A, Lenzen MJ,
delay potentially mitigating the benefit of the mechanical inter- Prescott E, Roffi M, Valgimigli M, Varenhorst C, Vranckx P, Widimsky P, Group ESCSD.
2017 ESC Guidelines for the management of acute myocardial infarction in patients
vention is 120 minutes [5]. presenting with ST-​segment elevation: The Task Force for the management of acute
In STEMI patients without persistent symptoms 12–​48 hours myocardial infarction in patients presenting with ST-​segment elevation of the European
after symptom onset, a small (n = 350) randomized study showed Society of Cardiology (ESC). Eur Heart J 2018;39(2):119–​177 with permission from
Oxford University Press.
improved myocardial salvage and 4-​ year survival in patients
treated with primary PCI, compared with those on conservative
treatment alone [6]‌. Thus, in these patients, primary PCI should Therefore, routine PCI of an occluded IRA in asymptomatic pa-
be considered. However, in stable patients with persistent occlu- tients >48 hours after symptoms onset is not indicated.
sion of infarct-​related arteries (IRAs) 3–​28 days after MI, the large Patients presenting with transient ST-​ segment elevation
(n = 2150) Occluded Artery Trial revealed no clinical benefit from (angina and ST-​ segment elevation whose ECG completely
routine coronary intervention with medical management, be- normalizes and symptoms disappear) have a high probability of
yond that from medical management alone [7]. A meta-​analysis having a coronary spasm (with or without MI). In these patients,
of trials, testing whether late recanalization of an occluded in- early coronary angiography within 24 hours is recommended [5]‌.
farct artery is beneficial, showed no benefit of reperfusion [8]. A recent clinical trial enrolled patients with transient ST-​segment
 Pri m a ry   P C I 483

elevation and randomized them into immediate versus delayed improved residual LV function, and, most importantly, a better
(24-​hour) angiography. Infarct size and clinical outcomes were clinical outcome with primary PCI [4]‌.
not different between groups [9].
E Figure 38.3 shows the maximum target times according to Procedural aspects of primary PCI
the reperfusion strategy. Arterial access route during primary PCI
The Minimizing Adverse Haemorrhagic Events by Transradial
Access Site and Systemic Implementation of Angiox (MATRIX)
Primary PCI trial [11] recruited 8400 MI patients who were randomly allo-
cated to transradial or transfemoral access. The radial access site
Primary PCI is defined as an urgent coronary angioplasty was associated with lower risks of access site bleeding, vascular
(with or without stenting) performed in the context of STEMI. complications, need for transfusion, and a lower 30-​day mortality.
Fibrinolytic therapy is not used in primary PCI. Primary PCI is At 1 year follow-​up, MACEs did not differ between patients as-
the preferred therapeutic option when it can be performed exped- signed to radial, compared with, femoral access, but net adverse
itiously by an experienced team, including interventional cardi- clinical events were fewer with radial access [12]. Therefore, radial
ologists and skilled supporting staff. Lower mortality rates among access is recommended over femoral access.
patients undergoing primary PCI are observed in centres with
a high volume of PCI procedures [10]. Primary PCI is effective Primary PCI technique
in securing and maintaining coronary artery patency and avoids Stenting is the technique of choice during primary PCI. DES re-
some of the bleeding risks of fibrinolysis. Randomized clinical duce the risk of repeated target vessel revascularization, compared
trials comparing timely performed primary PCI with in-​hospital with BMS, in STEMI [13]. A meta-​analysis of randomized trials of
fibrinolytic therapy in high-​volume, experienced centres have newer-​generation DES even showed improved safety, with a lower
shown more effective restoration of patency, less reocclusion, risk of stent thrombosis and cardiac mortality, compared with

Strategy
clock
Time to PCI?
ECG:
STEMI
0 ≤120 min >120 min
diagnosis

Alert and transfer Primary PCI Fibrinolysis

to PCI centre strategy strategy

10 min Bolus of
fibrinolytic

Transfer to
60–90 min

PCI centre

Wire crossing IV
90 min
120 min

(reperfusion)

Rescue Meet reperfusion

No Yes
PCI criteria?

2 hours
Routine PCI
strategy
24 hours

Figure 38.3  Maximum target times according to reperfusion strategy selection in patients presenting via EMS or in a non-​PCI centre. STEMI diagnosis is time
zero for the strategy clock. Target times from STEMI diagnosis represent the maximum time to do specific interventions. a If fibrinolysis is contraindicated, direct
for primary PCI strategy, regardless of the time to PCI. b10 minutes is the maximum target delay time from STEMI diagnosis to fibrinolytic bolus administration;
however, it should be given as soon as possible after STEMI diagnosis (after ruling out contraindications). ECG, electrocardiogram; PCI, percutaneous coronary
intervention; STEMI, ST-​segment elevation myocardial infarction.
Reproduced from Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-​Ducci C, Bueno H, Caforio ALP, Crea F, Goudevenos JA, Halvorsen S, Hindricks G, Kastrati A, Lenzen MJ,
Prescott E, Roffi M, Valgimigli M, Varenhorst C, Vranckx P, Widimsky P, Group ESCSD. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting
with ST-​segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-​segment elevation of the European Society of
Cardiology (ESC). Eur Heart J 2018;39(2):119–​177 with permission from Oxford University Press.
484 CHAPTER 38   ST- se g ment elevat ion myo ca rdia l  i n fa rcti on

BMS [14]. In the clinical Evaluation of the Xience-​V stent in Acute [27]. In summary, revascularization of non-​IRA lesions should
Myocardial INfArcTION (EXAMINATION) trial (n = 1500), use be considered in stable STEMI patients with multivessel disease
of everolimus-​eluting stents in patients with STEMI was associ- before hospital discharge. In the absence of a face-​to-​face clinical
ated with lower risks of target vessel revascularization and stent trial, the optimal timing of revascularization (immediate versus
thrombosis [15], and with a 5-​year reduction in all-​cause mor- staged) cannot be ascertained, albeit immediate non-​IRA PCI in
tality, compared with BMS [16]. In the Norwegian Coronary Stent selected cases might be the best strategy.
Trial (NORSTENT) trial [17], 9000 patients undergoing PCI (26%
with STEMI) were randomized to DES or BMS. There were no Management of multivessel disease in STEMI
differences in incidence of the primary endpoint (composite of patients in shock
death from any cause or non-​fatal spontaneous MI) after a median Up to 80% of STEMI patients presenting in shock have multivessel
follow-​up of 5 years, but DES were associated with lower rates of disease [28]. Despite the fact that there was controversy, the con-
definite stent thrombosis and repeat revascularizations [17]. sensus from observational and non-​randomized studies was that
Delaying stenting in primary PCI is not recommended in multivessel PCI during the index procedure was beneficial in
STEMI since in the DANish Study of Optimal Acute Treatment STEMI patients presenting in shock [28, 29]. The only random-
of Patients With ST-​elevation Myocardial Infarction (DANAMI ized clinical trial prospectively testing the benefits of multivessel
3)  trial [18] (n  =  1200), deferred stenting had no effect on the PCI in this population is the Culprit Lesion Only PCI versus
primary clinical outcome (composite of all-​cause mortality, non-​ Multivessel PCI in Cardiogenic Shock (CULPRIT-​SHOCK) trial
fatal MI, or ischaemia-​driven revascularization of non-​IRA le- [30]. In this contemporaneous trial, 700 MI patients in shock
sions) over a median follow-​up of 42 months. (62% with STEMI) with multivessel disease were randomized to
Routine thrombus aspiration is not recommended in STEMI IRA-​only PCI during the index procedure (18% of these patients
since two large RCTs showed no benefit on clinical outcomes of the underwent staged non-​IRA PCI) or multivessel PCI during the
routine aspiration strategy overall or in any subgroup of patients index procedure. At 1  month, all-​cause mortality was signifi-
indicating high thrombotic risk [19, 20]. A safety concern emerged cantly higher in the ‘multivessel PCI during the index procedure’
in one of these trials, with an increase in risk of stroke [21]. group (51.5% versus 43.3%). Results were consistent across pre-​
specified subgroups, including presence/​absence of chronic total
Management of multivessel disease in stable occlusion of the non-​IRA. The crossover rate was not high. At 1-​
STEMI patients year follow-​up, mortality did not differ significantly between the
Multivessel disease is common in patients with STEMI. Evidence two groups [50.0% and 56.9%, RR 0.88 (0.76–​1.01)]. However, the
supporting immediate (preventive) revascularization of additional rates of repeat revascularization were significantly higher in the
significant coronary stenoses was lacking until recently. One IRA-​only PCI group than in the multivessel PCI group (32.3%
small study published in 2010 allocated 214 STEMI patients with versus 9.4%, respectively), as were the rates of rehospitalization
multivessel disease to three arms: IRA angioplasty only, simultan- for heart failure (5.2% versus 1.2%, respectively) [31]. From these
eous treatment of non-​IRA lesions, and staged revascularization data, the recommendation for STEMI patients with multivessel
of the non-​IRA. At a mean follow-​up of 2.5  years, patients al- disease presenting in shock is to perform IRA-​only PCI during the
located to IRA angioplasty only had more MACEs than those index procedure. Later on, when the patient is stable, staged non-​
treated with other strategies [22]. More recently, four larger ran- IRA PCI before hospital discharge seems a reasonable approach.
domized clinical trials have compared PCI of the IRA only versus
complete revascularization:  Preventive Angioplasty in Acute
Rescue PCI
Myocardial Infarction (PRAMI) trial (n  =  450) [23]; Complete Rescue PCI is defined as PCI performed on a coronary artery which
Versus Lesion-​Only Primary PCI trial (CvLPRIT) trial (n = 300) remains occluded despite prior fibrinolytic therapy. Compared to
[24]; Third DANish Study of Optimal Acute Treatment of Patients a conservative strategy, rescue PCI is associated with improved
With STEMI: PRImary PCI in MULTIvessel Disease (DANAMI-​ clinical outcomes (less heart failure and reinfarction and a trend
3–​PRIMULTI) trial (n  =  600) [25]; and Compare-​Acute trial towards lower all-​cause mortality) at the cost of an increased risk
(n  =  900) [26]. Design of trials in terms of timing of non-​IRA of stroke and bleeding complications [32]. Therefore, rescue PCI
PCI (immediate or staged) and indication for non-​ IRA PCI is indicated when ST-​segment resolution is <50% within 90 min-
(angiography-​or FFR-​guided) was heterogenous, making it diffi- utes of thrombolytic administration [33].
cult to draw definite conclusion on these issues. In terms of clinical
benefits, results of these trials are, however, homogenous; primary Adjunctive antithrombotic treatments
outcome (composite of different endpoints) was significantly re- Patients undergoing primary PCI should receive a parenteral
duced in the complete revascularization group in all four trials. anticoagulant and DAPT, a combination of aspirin and a P2Y12
Total mortality was not statistically different in any of the four inhibitor, in all cases. Routine GPIIb/​IIIa inhibitors have not been
trials. Repeat revascularization was significantly reduced in all consistently associated with a clinical benefit and thus are left for
trials but CvLPRIT. Recent meta-​analyses have shown that com- bailout in cases of high thrombus burden upon the decision of the
plete revascularization reduces the incidence of hard endpoints interventional cardiologist.
 Fi b ri n oly ti c  t re atm e n t 485

Anticoagulation or IV (150 mg) after STEMI diagnosis. There is limited evidence in

Anticoagulant options for primary PCI include UFH as the de- regard to when the P2Y12 inhibitor should be initiated in STEMI
fault strategy, with enoxaparin as an alternative in some cases. patients. The Administration of Ticagrelor in the Cath Lab or in
Bivalirudin may be considered, but its use is mostly restricted the Ambulance for New ST Elevation Myocardial Infarction to
to patients with heparin-​ induced thrombocytopenia. Use of Open the Coronary Artery (ATLANTIC) trial is the only ran-
fondaparinux in the context of primary PCI was associated domized study testing the safety and efficacy of different timings
with potential harm in the Organization for the Assessment of of P2Y12 inhibitor initiation in STEMI. In this trial, patients were
Strategies for Ischemic Syndromes 6 (OASIS 6)  trial and is not randomized to receive ticagrelor either during transfer to a pri-
therefore recommended [34]. mary PCI centre or immediately before angiography [42]. This
study failed to meet the pre-​specified primary endpoint in terms
Heparins of improved ST-​segment elevation resolution or TIMI flow before
There have been no placebo-​controlled trials evaluating UFH intervention. While the evidence of a clinical benefit of P2Y12 in-
in primary PCI, but there is a large body of experience with this hibitor pre-​treatment in this setting is lacking, early initiation of
agent. UFH is the anticoagulant of choice during primary PCI. a P2Y12 inhibitor is common practice in Europe and consistent
Dosage should follow standard recommendations for PCI (i.e. with the pharmacokinetic data for oral antithrombotic agents. In
initial bolus of 70–​100 U/​kg). Enoxaparin [0.5 mg/​kg IV, followed all, the data suggest that the earliest administration may be prefer-
by subcutaneous (SC) treatment] was compared with UFH in one able to achieve early efficacy, particularly for long delays.
randomized, open-​label trial [the Acute Myocardial Infarction The preferred P2Y12 inhibitors are prasugrel (60 mg loading
Treated with primary angioplasty and intravenous enoxaparin Or dose, 10 mg maintenance dose once daily PO) or ticagrelor (180
unfractionated heparin to Lower ischemic and bleeding events at mg PO loading dose, 90 mg maintenance dose twice daily). These
short-​and Long-​term follow-​up (ATOLL) trial, 900 STEMI pa- drugs have a more rapid onset of action and greater potency, and
tients] [35]. The primary composite endpoint of 30-​day death, are superior in clinical outcomes [37, 43]. When neither of these
MI, procedural failure, or major bleeding was not significantly agents is available (or if they are contraindicated), clopidogrel 600
reduced by enoxaparin, but there were reductions in the com- mg PO should be given.
posite main secondary endpoint of death, recurrent MI or ACS, Cangrelor is a potent IV reversible P2Y12 inhibitor with a rapid
or urgent revascularization. Importantly, there was no indication onset and offset of action. It has been assessed in three RCTs enrol-
of increased bleeding from use of enoxaparin [35]. In the per-​ ling patients with PCI for stable angina or ACS against clopidogrel
protocol analysis of the ATOLL trial (<87% of the study popu- loading or placebo [44]. A  pooled analysis of these three trials
lation), IV enoxaparin was superior to UFH in reducing the showed that cangrelor reduced periprocedural ischaemic com-
primary endpoint, ischaemic endpoints, mortality, and major plications at the expense of an increased risk of bleeding [45].
bleedings [36]. Based on these considerations and on the substan- A significant reduction in ischaemic events was only observed in
tial clinical experience with enoxaparin in other PCI settings [37], the most recent Cangrelor versus Standard Therapy to Achieve
enoxaparin is a valid alternative to UFH during primary PCI. Optimal Management of Platelet Inhibition (CHAMPION
Bivalirudin PHOENIX) trial [44]. Based on these data, cangrelor may be con-
There have been several trials comparing bivalirudin with UHF sidered in patients not pre-​treated with oral P2Y12 receptor in-
(with or without GPIIb/​IIIa), with mixed results [38,  39]. The hibitors at the time of PCI.
most recent Bivalirudin versus Heparin in ST-​ Segment and GPIIb/​IIIa inhibitors
Non–​ST-​Segment Elevation Myocardial Infarction in Patients Routine use of GPIIb/​ IIIa inhibitors during primary PCI is
on Modern Antiplatelet Therapy in the Swedish Web System not recommended. Their use (either intracoronary or IV) as
for Enhancement and Development of Evidence-​based Care in bailout therapy in the event of angiographic evidence of a large
Heart Disease Evaluated according to Recommended Therapies thrombus, slow or no reflow, and other thrombotic complica-
Registry Trial (VALIDATE-​SWEDEHEART) enrolled 6000 MI tions is reasonable, although this strategy has not been tested in a
patients (3000 with STEMI) undergoing PCI under potent P2Y12 randomized trial.
inhibitors without GPIIb/​IIIa to bivalirudin or heparin during the
index procedure. The rate of the combined endpoint of all-​cause
death, MI, or major bleeding was not different among groups Fibrinolytic treatment
[40]. Despite the fact that bivalirudin may be considered as an al-
ternative to UFH during primary PCI, its main indication during Fibrinolytic therapy is a valid reperfusion strategy when PCI
primary PCI is for patients with HIT [41]. cannot be offered in a timely manner (see E Figure 38.3).

Antiplatelet therapy Fibrinolytic agents
DAPT (aspirin plus P2Y12 inhibitor) is the standard of care for Streptokinase was the first fibrinolytic agent available. The
STEMI patients for the year following the event. Aspirin should Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto
be given orally (PO) (preferably 150–​300 mg), including chewing, Miocardico (GISSI) and International Study of Infarct Survival
486 CHAPTER 38   ST- se g ment elevat ion myo ca rdia l  i n fa rcti on

(ISIS) trials are major landmark studies of fibrinolytic therapy,

Box 38.1  Contraindications for fibrinolysis
demonstrating a 23% reduction in 30-​day mortality among pa-
tients randomized to streptokinase, compared to those on control Absolute
therapy [46]. Fibrinolysis with this agent was also associated with
Previous ICH or stroke of unknown origin at any time
◆
a small, but significant, excess of ICH (0.4% versus 0.1%). Today, a
Ischaemic stroke in the preceding 6 months
◆
fibrin-​specific agent should be preferred. In the Global Utilization
Central nervous system neoplasms or arteriovenous
◆
of Streptokinase and Tissue Plasminogen Activator for Occluded
malformation
Coronary Arteries (GUSTO) trial [47], an accelerated infusion of
Recent major trauma/​surgery/​head injury (within the
◆
the fibrin-​specific agent tPA alteplase with concomitant IV hep-
preceding month)
arin resulted in ten fewer deaths per 1000 patients treated, when
compared to streptokinase at the cost of three additional strokes. Known bleeding disorder (excluding menses)
◆

Single-​bolus weight-​adjusted tenecteplase (TNK-​tPA) is equiva- Aortic dissection

◆

lent to accelerated tPA with respect to 30-​day mortality and is as- Non-​compressible punctures in the past 24 hours (e.g. liver
◆

sociated with a significantly lower rate of non-​cerebral bleeding biopsy, lumbar puncture)
and less need for blood transfusion. A  recent meta-​ analysis Relative
showed that there are significant differences between various fi-
Transient ischaemic attack in the preceding 6 months
◆
brinolytic regimens. TNK-​tPA and tPA with an accelerated in-
Oral anticoagulant therapy
◆
fusion regime should be considered over streptokinase and a
Pregnancy or within 1 week postpartum
◆
non-​accelerated infusion of tPA [48].
Refractory hypertension (SBP >180 mmHg and/​or DBP
◆

Pre-​hospital fibrinolysis >110 mmHg)
Advanced liver disease
◆
An analysis of studies including overall >6000 patients has shown
Infective endocarditis
◆
a significant reduction (17%) in early mortality with pre-​hospital,
compared to in-​hospital, lysis initiation [49]. In a meta-​analysis Active peptic ulcer
◆

of 22 trials, a much larger mortality reduction was found in pa- Prolonged or traumatic resuscitation
◆

tients treated within the first 2 hours than in those treated later DBP, diastolic blood pressure; SBP, systolic blood pressure.
[50]. These and more recent data support pre-​hospital initiation
of fibrinolytic treatment if this reperfusion strategy is indicated
[51]. The STREAM trial showed that pre-​hospital fibrinolysis fol- shown to be beneficial. Even if it is likely that fibrinolysis was suc-
lowed by routine early angiography and PCI if indicated was as- cessful, a strategy of routine early angiography is recommended
sociated with a similar outcome as transfer for primary PCI in if there are no contraindications. Several randomized trials and
STEMI patients presented within 3 hours after symptom onset contemporary meta-​analyses [53] have shown that early routine
who could not undergo primary PCI within 1 hour after FMC angiography with subsequent PCI (if indicated) after fibrinolysis
[33]. It is therefore recommended to initiate fibrinolytic therapy reduced the rates of reinfarction and recurrent ischaemia. Routine
in the pre-​hospital setting. angiography should be performed 2–​24 hours after successful
fibrinolysis.
Hazards of fibrinolysis
Fibrinolytic therapy is associated with a small, but significant, excess Adjunctive anticoagulant and
of strokes, largely attributable to cerebral haemorrhage, appearing antiplatelet therapy
on the first days after treatment. Advanced age, lower weight, fe- Tenecteplase, enoxaparin, aspirin, and clopidogrel comprise
male gender, prior cerebrovascular disease, and hypertension on the antithrombotic combination that has been most extensively
admission are significant predictors of ICH [52]. In the most re- studied as part of a fibrinolysis and early routine PCI strategy
cent STREAM trial, the initial excess in ICH (1% incidence) was [33, 54].
reduced to 0.5% after protocol amendment to reduce the dose of Convincing evidence of the effectiveness of aspirin was dem-
tenecteplase by 50% in patients >75 years [33]. Major non-​cerebral onstrated in the ISIS-​2 trial, in which the benefits of aspirin and
bleeds can occur in 4–​13% of patients [33]. Contraindications to streptokinase were additive—​with a first dose of 150–​300 mg
fibrinolytic therapy are shown in E Box 38.1. (chewed) and a lower oral dose (75–​100 mg) daily thereafter.
If oral ingestion is not possible, aspirin can be given IV (250–​
Routine angiography after fibrinolytic therapy 500 mg). The benefit of clopidogrel added to aspirin in patients
E Figure 38.3 shows treament strategies in patients undergoing fi- treated with fibrinolysis was demonstrated in the ClOpidogrel
brinolysis. If there is evidence of persistent occlusion, reocclusion, and Metoprolol in Myocardial Infarction Trial (COMMIT) and
or reinfarction with recurrence of ST-​segment elevation after fi- Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)
brinolysis, immediate angiography and rescue PCI are indicated. trials [55,  56]. Accordingly, clopidogrel should be added to as-
In this setting, re-​ administration of fibrinolysis has not been pirin as an adjunct to lytic therapy in the acute phase. The recent
 Speci fi c t y pes of i n fa rcti on a n d   sub g roup s 487

Ticagrelor in Patients With ST Elevation Myocardial Infarction to continue aspirin [62]. The first aspirin administration post-​
Treated With Pharmacological Thrombolysis (TREAT) trial en- CABG is recommended 6–​24 hours after surgery in the absence
rolled 3800 STEMI patients undergoing fibrinolysis and random- of ongoing bleeding events.
ized them to clopidogrel or ticagrelor (both with loading dose)
at a mean time of 11 hours after lytic therapy [57]. There were
no differences in the rate of the combined outcome of cardiovas- Adjunctive therapy in the acute
cular mortality, MI, or stroke at 1 year. The rates of major, fatal,
and intracranial bleeding were similar between the ticagrelor and phase
clopidogrel groups [57]. Despite this trial being neutral, it pro- Early beta-​blockers
vides strong evidence for the safety of using ticagrelor in patients
In patients undergoing thrombolysis, early IV β-​blocker treat-
who underwent fibrinolysis. There is no evidence that adminis-
ment reduces the incidence of acute malignant ventricular ar-
tration of GPIIb/​IIIa inhibitors improves myocardial perfusion or
rhythmias, although there is no clear evidence of long-​ term
outcomes in patients treated with fibrinolysis [58], and a recent
clinical benefit [63–​65].
meta-​analysis showed that addition of GPIIb or GPIIIa inhibitors
In patients undergoing primary PCI, information on the effi-
to fibrinolytic therapy increases the risk of major bleeding and
cacy and safety of early IV β-​blocker administration is limited.
should be discouraged [48].
The Effect of Metoprolol in Cardioprotection During an Acute
Heparin has been extensively used during and after fibrinolysis.
Myocardial Infarction (METOCARD-​ CNIC) trial (n  =  270)
Heparin does not improve immediate clot lysis, but coronary pa-
showed that administration of IV metoprolol (3 × 5 mg bo-
tency evaluated in the hours or days following fibrinolytic therapy.
luses = 15 mg) at the time of diagnosis in patients with anterior
Heparin infusion after fibrinolytic therapy may be discontinued
STEMI, no signs of heart failure, and systolic blood pressure of
after 24–​48 hours. Treatment with the low-​ molecular weight
>120 mmHg was associated with a significant reduction in infarct
enoxaparin is associated with a significant reduction in the risk of
size measured by CMR at 5–​7 days and significantly higher LVEF at
death and reinfarction at 30 days, compared to a weight-​adjusted
6 months by CMR, compared with control treatment [66]. A sub-
heparin dose [59]. This is, however, achieved at the cost of a signifi-
group analysis of the trial suggested that the sooner IV metoprolol
cant increase in non-​cerebral bleeding complications. The net clin-
was administered in the course of infarction, the smaller was the
ical benefit favours enoxaparin. When the dose is adjusted for age
infarct size [67]. In the Early-​Beta blocker Administration before
and renal function, this benefit was observed, regardless of the type
reperfusion primary PCI in patients with ST-​elevation Myocardial
of fibrinolytic agent and the age of the patient. Fondaparinux has
Infarction (EARLY-​BAMI) trial [68], early IV metoprolol admin-
been shown to be superior to placebo or heparin in preventing death
istration did not show any benefit in reducing CMR-​based infarct
and reinfarction, especially in patients receiving streptokinase [60].
size, but it reduced the rate of malignant ventricular arrhythmias.
Based on the current available evidence, early administration of
IV β-​blockers at the time of presentation should be considered in
Coronary bypass surgery in STEMI haemodynamically stable patients undergoing primary PCI. Oral
β-​blockers should be initiated within 24 hours after STEMI.
patients
Emergent CABG should be considered for patients with a patent Nitrates
IRA, but with an unsuitable anatomy for PCI, and with either a Routine use of nitrates in STEMI was of no benefit in a trial against
large myocardial area at jeopardy or CS. In STEMI patients with placebo and is therefore not recommended [69]. IV nitrates may
failed PCI or coronary occlusion not amenable to PCI, emergent be useful during the acute phase in patients with hypertension or
CABG is infrequently performed because the benefits of surgical heart failure.
revascularization in this setting are uncertain. In the absence of E Figure 38.4 shows the most important therapies to be used
randomized data, optimal timing for non-​emergent CABG in in STEMI patients.
stabilized post-​STEMI patients should be determined individu-
ally. A  review of California discharge data compared patients
who underwent early (<3 days) versus delayed (≥3 days) post-​MI
CABG [61]. Patients who underwent early CABG had a higher
Specific types of infarction
mortality rate, with the highest mortality observed in those who and subgroups
were operated on the day of the MI. Patients with haemodynamic
Right ventricular infarction
deterioration or who are at high risk of recurrent ischaemic
events should be operated on as soon as possible, without waiting The recognition of RV infarction is important because it may
for the full recovery of platelet function following discontinu- manifest itself as CS, but the appropriate treatment strategy is
ation of DAPT. For all other patients, a waiting period of at least quite different from that in shock due to severe LV dysfunction.
3 days following interruption of ticagrelor (5 days for clopidogrel RV infarction may be suspected by the specific, but insensitive,
and 7 days for prasugrel) is reasonable, while it is recommended clinical triad of hypotension, clear lung fields, and raised JVP
488 CHAPTER 38   ST- se g ment elevat ion myo ca rdia l  i n fa rcti on

Strategy
clock
0 STEMI ECG Alert
diagnosis monitoring Cath lab &
Aspirin Oxygen when
I B bypass ED loading1 sat <90% I C IV
I B IV opioids/
I B β-blocker tranquillizer
Prasurgel IIa A IIa C
or ticagrelor
loading2
I A
Radial
access3 Unfractionated
I A heparin4 I C
Cath lab

Wire
90 min
crossing GP IIb/IIa New-gen
(reperfusion) bailout IIa C DES
I A

Non-IRA
Transfer back to High-dose
PCI
non-PCI centre statin
IIa A
IIa C I A
Oral β-blocker ACE inhibitor
LVEF ≤40% or HF I A LVEF ≤40% or HF I A
Hospital admission

LVEF >40%, no HF IIa B LVEF >40%, no HF IIa A

24 hours
Routine DAPT MRA (if LVEF
echo ≤40% and HF)
Aspirin5 Prasugrel or
I B ticagrelor6 I B
I A
I A

Hospital
discharge

Echo
6–12 (LVEF)
weeks I C

I year
b

Figure 38.4  ‘Do not forget’ interventions in STEMI patients undergoing a primary PCI strategy. Mostly prescribed interventions (Class I, green; Class IIa,
yellow) are presented, along with the expected timing of delivery. Solid lines represent recurrent (daily) intervention. Double-​arrowed dashed lines represent a
time window in which the intervention can be delivered. 1 Aspirin loading dose: 150–​300 mg chewed or 75–​250 mg IV (in patients not already on an aspirin
maintenance dose). 2 Prasugrel loading dose: 60 mg. Ticagrelor loading dose: 180 mg. If there are contraindications for prasugrel/​ticagrelor or these are not
available, a loading dose of clopidogrel (600 mg) is indicated. 3 If the interventional cardiologist is not an expert in radial access, the femoral route is then
preferred. 4 Enoxaparin or bivalirudin are alternatives to UFH (Class IIa A). 5 Aspirin maintenance dose: 75–​100 mg PO. 6 Prasugrel maintenance dose: 10 mg once
daily. Ticagrelor maintenance dose: 90 mg twice daily. If there are contraindications for prasugrel/​ticagrelor or these are not available, clopidogrel maintenance (75
mg daily) is indicated. a 90 minutes represents the maximum target time to PCI-​mediated reperfusion. For patients presenting to a PCI-​centre, this target time
is 60 minutes. b Prolongation of ticagrelor (60 mg twice daily), in addition to aspirin. ACE, angiotensin-​converting enzyme; DAPT, dual antiplatelet therapy; DES,
drug-​eluting stent; ECG, electrocardiogram; echo, echocardiogram; ED, emergency department; HF, heart failure; IV, intravenous; IRA, infarct-​related artery; LVEF,
left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; PCI, percutaneous coronary intervention; STEMI, ST-​segment elevation myocardial
infarction; UFH, unfractionated heparin.
Reproduced from Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-​Ducci C, Bueno H, Caforio ALP, Crea F, Goudevenos JA, Halvorsen S, Hindricks G, Kastrati A, Lenzen MJ,
Prescott E, Roffi M, Valgimigli M, Varenhorst C, Vranckx P, Widimsky P, Group ESCSD. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting
with ST-​segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-​segment elevation of the European Society of
Cardiology (ESC). Eur Heart J 2018;39(2):119–​177 with permission from Oxford University Press.
 Acu t e c omplicat i on s of ST- seg m en t el evati on m yo ca rdia l   i n fa rc t i on 489

in a patient with inferior STEMI. ST-​segment elevation in V4R of myocardial dysfunction and possible complications such as MR
is very suggestive of the diagnosis. Echocardiography may con- and VSD. Patients with pulmonary congestion and SaO2 of <90%
firm the diagnosis. When RV infarction can be implicated in require O2 therapy, with a target of 95%, and may require periodic
hypotension or shock, it is important to maintain RV preload. It blood gas control. In severe heart failure and shock (Killip III/​IV),
is desirable to avoid (if possible) vasodilator drugs such as opi- CPAP or intubation with ventilatory support may be required.
oids, nitrates, diuretics, and ACE-​Is/​ARBs. IV fluid loading is ef- Inotropic agents may be of value in severely hypotensive patients.
fective in many cases; initially, it should be administered rapidly.
Revascularization should be performed as soon as possible, as it Cardiogenic shock
may result in rapid haemodynamic improvement [70]. CS is defined as persistent hypotension (systolic blood pres-
sure ≤90  mmHg) with signs of hypoperfusion. It complicates
Patients on chronic anticoagulation 6–​10% of all cases of STEMI and remains a leading cause of
Management during STEMI death, with in-​hospital mortality rates approaching 50% [72].
Oral anticoagulation is a relative contraindication for fibrinolysis. Haemodynamically, it is characterized by cardiac index ≤2.2 L/​
Therefore, patients should be triaged for primary PCI strategy, min/​m2, wedge pressure ≥18  mmHg, and diuresis usually <20
regardless of the anticipated time to PCI-​mediated reperfusion. mL/​hour. Shock is also considered to be present if IV inotropes
Patients should receive additional parenteral anticoagulation, and/​or mechanical support are needed to maintain a systolic
regardless of the timing of the last dose of oral anticoagulant blood pressure of >90 mmHg. LV function and associated mech-
and INR. Loading of aspirin should be done as in all STEMI pa- anical complications should be evaluated urgently by 2D Doppler
tients, and clopidogrel is the P2Y12 inhibitor of choice (it is not echocardiography.
recommended to use prasugrel/​ ticagrelor). Ideally, a chronic The first step in the treatment of patients with CS is to identify
anticoagulation regimen should not be stopped during admis- the mechanism and to correct any reversible cause (hypovolaemia,
sion. Gastric protection with a PPI is recommended. drug-​induced hypotension, or arrhythmias) or alternatively to
initiate treatment of potential specific causes such as mechan-
Maintenance after STEMI ical complications or tamponade. Management of CS in STEMI
While triple therapy (in the form of oral anticoagulation, as- patients includes immediate reperfusion and haemodynamic
pirin, and clopidogrel) for 6 months has been the default strategy stabilization with medical therapy or mechanical circulatory sup-
for these patients, recent evidence from the Open-​Label, 2 × 2 port. IV inotropic agents or vasopressors are usually required to
Factorial, Randomized, Controlled Clinical Trial to Evaluate maintain a systolic blood pressure of ≥90 mmHg and to increase
the Safety of Apixaban vs Vitamin K Antagonist and Aspirin vs the cardiac output and renal perfusion. Dobutamine is the ini-
Aspirin Placebo in Patients with Atrial Fibrillation and Acute tial therapy for patients with predominantly low cardiac output,
Coronary Syndrome and/​or Percutaneous Coronary Intervention while noradrenaline is preferred over dopamine in patients with
(AUGUSTUS) trial [71] suggests that dual therapy in the form of CS [73].
P2Y12 inhibitor plus oral anticoagulation results in lower bleeding IABP counterpulsation does not improve outcomes in pa-
rates without an increase in ischaemic events. This trial enrolled tients with STEMI and CS without mechanical complications
4600 patients with AF undergoing PCI (38% ACS) who were [74]. Therefore, routine IABP counterpulsation is not recom-
planning to take a P2Y12 inhibitor (>90% clopidogrel) to receive mended but may be considered for haemodynamic support in
apixaban or a vitamin K antagonist (VKA) and to receive aspirin selected patients. Mechanical LVADs have been used in patients
or matching placebo for 6 months (2 × 2 factorial design). Major not responding to standard therapy, including inotropes, fluids,
or clinically relevant non-​major bleeding rates were significantly and IABP, but evidence regarding their benefits is limited [75].
higher in the VKA group, compared to apixaban, and in patients Therefore, short-​term mechanical circulatory support may be
receiving triple therapy, compared to those receiving dual therapy considered to stabilize patients and preserve organ perfusion
(i.e. no aspirin). Ischaemic events were not different among (oxygenation) as a bridge to recovery of myocardial function, car-
groups [71]. In general, non-​vitamin K new oral anticoagulants diac transplantation, or even LVAD destination therapy on an in-
(NOACs), with the lowest effective tested dose for stroke preven- dividual basis [76].
tion, are preferred over VKAs for any combination [41].
Cardiac rupture
Acute free wall rupture is characterized by cardiovascular collapse
Acute complications of ST-​segment with electromechanical dissociation, i.e. continuing electrical ac-
elevation myocardial infarction tivity with a loss of cardiac output and pulse. Echocardiography is
not always able to show the site of rupture, but it can demonstrate
Pump failure pericardial fluid with or without signs of tamponade. However, the
Heart failure during the acute phase of STEMI is associated with presence of pericardial fluid alone is not sufficient to diagnose a
poor short-​and long-​term prognosis. Echocardiography is the subacute free wall rupture, because effusion is relatively common
key diagnostic tool and should be performed to assess the extent after STEMI. The typical finding is an echo-​dense mass in the
490 CHAPTER 38   ST- se g ment elevat ion myo ca rdia l  i n fa rcti on

pericardial space consistent with a clot (haemopericardium). Arrhythmias and conduction disturbances

Immediate surgery is the treatment of choice. Ventricular septal
Life-​threatening arrhythmias, such as VT, VF, and complete AV
rupture must be considered in cases of sudden severe clinical de-
block, may be the first manifestation of ischaemia and require im-
terioration. Intra-​aortic balloon counter pulsation is the most ef-
mediate correction. VF occurring early after STEMI (≤48 hours)
fective method of providing circulatory support, while preparing
has only been associated with increased in-​hospital (but not long-​
for further therapy. Even if there is no haemodynamic instability,
term) mortality. Use of prophylactic β-​blockers in the setting of
early surgery is usually indicated, because the defect may increase
STEMI reduces the incidence of VF [80]. AF complicates 10–​20%
[77]. However, there is still no consensus on the optimal timing of
of STEMIs where it is associated with higher stroke rates and in-​
surgery because early surgical repair is difficult due to friable nec-
hospital mortality [81].
rotic tissue. Therefore, percutaneous closure of the defect using
an occluder device may be an option, either as a bridge to subse-
Pericarditis
quent surgery or as definite therapy [78].
Pericarditis associated with STEMI may cause chest pain that can
Mitral regurgitation be easily misinterpreted as recurrent infarction or post-​infarction
angina. However, contrary to these entities, pericarditis-​induced
MR is common and occurs usually after 2–​7 days. There are four
pain is usually of a sharp nature and related to posture and res-
mechanisms of acute MR in this setting: (1) mitral valve annulus
piration. It is often accompanied by a pericardial rub. Anti-​
dilatation due to LV dilatation; (2) papillary muscle dysfunction
inflammatory therapy is recommended in post-​STEMI pericarditis
usually due to inferior MI; (3)  concomitant LA infarction [79];
to hasten symptom remission and reduce recurrences. Aspirin
and (4) rupture of the trunk or tip of the papillary muscle. In most
is recommended as the first-​choice anti-​inflammatory therapy
patients, acute MR is secondary to papillary muscle dysfunc-
post-​STEMI [82]. Colchicine is recommended as the first-​line
tion, rather than rupture. Most patients with acute MR should
therapy as an adjunct to aspirin/​non-​steroidal anti-​inflammatory
be operated early because they may deteriorate suddenly. CS and
drugs (NSAIDs) therapy (3 months) and is also recommended for
pulmonary oedema with severe MR require emergency surgery.
the recurrent forms (6 months) [82]. Echocardiography should be
Most patients need IABP placement during preparation for cor-
regularly performed in order to diagnose complicating pericar-
onary angiography and surgery.
dial effusions early.

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 CHAPTER 39

Fibrinolytic, antiplatelet,
and anticoagulant drugs in
acute coronary syndromes
Sigrun Halvorsen, Giuseppe Gargiulo,
Marco Valgimigli, and Kurt Huber

Contents
Summary  494 Summary
Introduction  494 Antithrombotic therapy is a major cornerstone in the treatment of acute cor-
Fibrinolytic agents  495 onary syndromes, as thrombus formation upon a plaque rupture or an erosion
Streptokinase  495 plays a pivotal role in non-​ST-​segment elevation, as well as ST-​segment elevation,
Alteplase  495
Reteplase  496 acute coronary syndromes. Both acute and long-​term oral antiplatelet therapies,
Tenecteplase  497 targeting specific platelet activation pathways, have demonstrated significant
Antiplatelet agents  498 short-​and long-​term benefits. The use of anticoagulants is currently largely con-
Aspirin  498
P2Y12 inhibitors  498
fined to the acute setting, except in patients with a clear indication for long-​term
Clopidogrel  498 treatment, including atrial fibrillation or the presence of intraventricular thrombi.
Prasugrel  499 Despite the benefit of primary percutaneous coronary intervention in ST-​segment
Ticagrelor  500
Cangrelor  501 elevation myocardial infarction, fibrinolytic therapy continues to play an im-
Genetic and platelet function testing for portant role throughout the world. In this chapter, fibrinolytic, antiplatelet, and
P2Y12 inhibitors  501
anticoagulant agents used in the management of acute coronary syndrome pa-
Glycoprotein IIb/​IIIa inhibitors  502
tients are discussed.
Thrombin receptor (PAR-​1)
antagonists  503
Anticoagulant agents  503
Unfractionated heparin  503
Low-​molecular weight heparins  504
Intravenous direct thrombin inhibitors  504
Bivalirudin  504
Indirect (subcutaneous) factor Xa
Introduction
inhibitors  505 The ACS are, in essence, triggered by spontaneous atherosclerotic plaque rupture or ero-
Fondaparinux  505
Oral anticoagulants in ACS  506 sion, followed by thrombus formation, due to platelet activation and activation of the
Vitamin K antagonists  506 coagulation cascade, as well as imbalances in the endogenous fibrinolytic system [1, 2].
Oral direct thrombin inhibitors  506 Antithrombotic treatment has been shown to decrease the risk of ischaemic complica-
Oral factor Xa inhibitors  506
tions in ACS [3, 4]. Despite the proven efficacy of antiplatelet and anticoagulant therapy,
Antiplatelet therapy in ACS patients
with an indication for oral however, acute risks and long-​term residual morbidity and mortality remain consider-
anticoagulation  506 able. Improvements in patient outcomes could be achieved by developing agents that act
Antithrombotic agents and bleeding faster and more reliably and inhibit other platelet activation pathways, or new, safer, and
complications  507 more convenient anticoagulants.
Thienopyridines and proton pump In this chapter, fibrinolytic, antiplatelet, and anticoagulant agents used today are dis-
inhibitors  507 cussed. The agents are listed in E Table 39.1, and the mechanisms of action of the most
New antithrombotic agents on the commonly used drugs are illustrated in E Figure 39.1.
horizon  508
Conclusion  508
References  508
 Fi b ri n oly t i c   ag e n ts 495

Table 39.1  Current fibrinolytic, antiplatelet, and anticoagulant fibrinolytics. Time lost between symptom onset and treatment
drugs in ACS initiation remains a crucial factor for treatment delay in MI with
STEMI. In a meta-​analysis of six randomized trials (n  =  6434),
Fibrinolytic agents
pre-​hospital fibrinolysis reduced early mortality by 17%, com-
Fibrin-​specific Alteplase pared with in-​hospital fibrinolysis [5]‌, particularly when admin-
Reteplase
Tenecteplase istered in the first 2 hours of symptom onset [6]. In addition, the
recent STREAM trial showed that pre-​hospital fibrinolysis, fol-
Non-​fibrin-​specific Streptokinase
lowed by an early PCI strategy, was associated with a similar out-
Antiplatelet agents come as transfer for primary PCI in STEMI patients presenting
Oral Aspirin within 3 hours after symptom onset who could not undergo pri-
P2Y12 inhibitors: mary PCI within 1 hour after FMC [7]. Based on these findings,
Clopidogrel
◆ the ESC guidelines on management of STEMI recommend to ini-
Ticlopidine
◆
tiate fibrinolysis in the pre-​hospital setting [8]. Following initi-
Prasugrel
◆
Ticagrelor
◆
ation of lytic therapy, it is recommended to transfer the patients
to a PCI centre as soon as possible, for rescue PCI in case of failed
Thrombin receptor inhibitor:
Vorapaxar
◆
fibrinolysis or for early angiography with subsequent PCI, if indi-
cated, in cases of successful fibrinolysis [8, 9].
Intravenous Glycoprotein inhibitors:
Abciximab
◆
Contraindications for fibrinolytic therapy are listed in E
Tirofiban
◆ Table 39.3, and antithrombotic co-​therapies in E Table 39.4.
Eptifibatide
◆ Fibrinolytic drugs need 30–​45 minutes, on average, to recanalize
P2Y12 inhibitor: the IRA, and complete patency is only achieved in 60–​80% of pa-
Cangrelor
◆ tients. Unfortunately, reocclusion occurs in 5–​15% of previously
Anticoagulant agents recanalized arteries [10]. Furthermore, even when blood flow to
Oral Vitamin K antagonists:
the IRA is restored, microcirculatory reperfusion can still be ab-
Warfarin
◆ sent (‘no-​reflow’ phenomenon) [11]. Finally, bleeding complica-
Acenocoumarol
◆ tions, especially intracranial haemorrhage (ICH), are a concern.
Phenprocoumon
◆

Direct thrombin inhibitor: Streptokinase

Dabigatran
◆
Streptokinase is a non-​fibrin-​specific fibrinolytic agent that indir-
Factor Xa inhibitors: ectly activates plasminogen. Because of its lack of fibrin specifi-
Rivaroxaban
◆
city, streptokinase induces a systemic lytic state. Although newer
Apixaban
◆
Edoxaban
◆
fibrin-​specific fibrinolytics have theoretical and clinical advan-
tages, streptokinase remains widely used, in part, because of its
Subcutaneous or intravenous Unfractionated heparin
low cost. Administration of streptokinase invariably induces anti-​
Low-​molecular weight heparins: streptokinase antibodies, precluding readministration.
◆ Enoxaparin
◆ Dalteparin The first large trial to show a significant reduction in mor-
◆ Nadroparin tality with a fibrinolytic agent was the landmark GISSI-​1 trial
◆ Fraxiparin [12]. In this study, 11  806 patients with an acute STEMI, pre-
Direct thrombin inhibitors: senting within 12 hours of symptom onset, were randomized to
◆ Bivalirudin either reperfusion therapy with streptokinase or standard non-​
◆ Argatroban fibrinolytic therapy. In-​hospital mortality was 10.7% in patients
◆ Lepirudin
treated with IV streptokinase versus 13.1% in control subjects.
Factor Xa inhibitor: This benefit in mortality was preserved after 1-​year and 10-​year
Fondaparinux
◆
follow-​up [13]. Another landmark trial, the ISIS-​2, corroborated
these results [14]. A total of 17 187 STEMI patients received ei-
ther streptokinase or aspirin daily for 1 month, both treatments,
or neither. Treatment with aspirin or streptokinase alone resulted
Fibrinolytic agents in a significant reduction in mortality (23% and 24%, respect-
Fibrinolytic agents are categorized as fibrin-​specific and non-​ ively). The effect was additive, as demonstrated by a 43% reduc-
fibrin-​specific agents (see E Table 39.2). Fibrin-​specific drugs tion in the combination group.
are more efficient in dissolving thrombi and do not deplete the
systemic coagulation factors, in contrast to non-​fibrin-​specific Alteplase
agents. Contemporary lytic strategies in patients with STEMI Recombinant tPA (or alteplase) is a single-​chain tissue-​type plas-
consist of IV bolus administration of second-​or third-​generation minogen activator molecule. It has a considerably greater fibrin
496 CHAPTER 3 9   Fibrinolytic, antiplatelet, and anticoagulant drugs in acu te coronary syndromes

Anticoagulant Antiplatelet
drugs drugs

Tissue factor

Rivaroxaban Aspirin

Plasma clotting ADP

Fondaparinux cascade

Cangrelor
Thromboxane A Clopidogrel
Prasugrel
Prothrombin
Ticagrelor

Antithrombin
LMWH Conformational
Factor activation of GPIIb/IIIa
UFH Xa
GPIIb/IIIA
Inhibitors
Thrombin

Bivalirudin

Vorapaxar

Fibrinogen Fibrin
PAR-I receptor

GPIIb/IIIa receptor Thrombin FXa

Collagen

Clot-bound thrombin/factor Xa

Figure 39.1  Targets of antithrombotic agents in ACS. ADP, adenosine diphosphate; GP, glycoprotein; LMWH, low-​molecular weight heparin; TX, thromboxane;
UFH, unfractionated heparin. Vorapaxar is a protease-​activated receptor 1 (PAR-​1) blocker.
Reproduced from Roffi M, Patrono C, Collet JP, et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-​segment
elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-​Segment Elevation of the European Society of Cardiology (ESC).
Eur Heart J 2016;37(3):267–​315. doi:10.1093/​eurheartj/​ehv320 with permission from Oxford University Press.

specificity than streptokinase but nevertheless induces mild sys- with streptokinase (P  =  0.001). The 1% lower mortality rate at
temic fibrinogen depletion. Because of its short half-​life, alteplase 30 days with front-​loaded alteplase corresponded with a signifi-
requires a continuous infusion. cantly higher TIMI flow grade 3 rate at 90 minutes (54% versus
In the ISIS-​3 and GISSI-​2 trials, alteplase given as a 3-​hour con- only 32% with streptokinase) [18].
tinuous infusion was not superior to streptokinase with respect
to mortality [15, 16]. The question of which of the two fibrino-
lytic drugs was the most effective in terms of mortality reduction Reteplase
was nevertheless answered in the first GUSTO trial [17]. In this Reteplase, a second-​generation fibrinolytic agent, was a first at-
trial, a ‘front-​loaded’ 90-​minute dosing regimen of alteplase was tempt to improve on the shortcomings of alteplase. It is a mutant
used, which had been shown earlier to achieve higher patency of alteplase, in which the finger, kringle-​1, and epidermal growth
rates than the 3-​hour scheme. The 30-​day mortality was 6.3% in factor domains are removed. This results in decreased plasma
patients receiving alteplase, compared to 7.4% in patients treated clearance, allowing bolus administration.

Table 39.2  Fibrinolytic agents

Streptokinase Alteplase Reteplase Tenecteplase

Fibrin specificity –​ ++ + +++
Half-​life (minutes) 18–​23 3–​4 18 20
Administration 1-​hour infusion 90-​minute infusion Double bolus Single bolus
Antigenicity +++ –​ –​ –​
 Fi b ri n oly t i c   ag e n ts 497

Table 39.3  Contraindications for fibrinolysis

Absolute Relative
Previous intracranial haemorrhage or stroke of unknown origin at any time Transient ischaemic attack in preceding 6 months
Ischaemic stroke in preceding 6 months Refractory hypertension (systolic blood pressure >180 mmHg and/​or
diastolic blood pressure >110 mmHg)
Central nervous system damage or neoplasms or arteriovenous malformation Prolonged or traumatic resuscitation
Recent major surgery or trauma (including head trauma) within 4 weeks Oral anticoagulant therapy
Non-​compressible punctures in past 24 hours (e.g. liver biopsy, lumbar puncture) Infective endocarditis
Active internal bleeding Pregnancy or within 1 week postpartum
Gastrointestinal bleeding within the past month Active peptic ulcer
Known bleeding disorder Advanced liver disease
Suspected aortic dissection

In the GUSTO-​III trial, which was designed as a superiority In the Assessment of the Safety and Efficacy of a New
trial, 15 059 patients were randomized to double-​bolus reteplase Thrombolytic (ASSENT-​2) trial, 16 949 patients were randomized
given 30 minutes apart or to front-​loaded alteplase [19]. Mortality either to weight-​adjusted, single-​bolus TNK-​tPA or to standard
at 30 days was similar in both treatment arms (7.47% versus 7.24%, front-​loaded alteplase [21]. Specifically designed as an equiva-
respectively), as was the incidence of haemorrhagic stroke or lency trial, this study showed that TNK-​tPA and alteplase had
other major bleeding complications. Similar mortality rates were equivalent 30-​day mortality rates (6.18% versus 6.15%, 90% CI
maintained for both treatment groups at 1-​year follow-​up [20]. 0.92–​1.10). Mortality rates remained similar at 1-​year follow-​up
[22]. Although the rates of ICH were similar for TNK-​tPA (0.93%)
Tenecteplase and alteplase (0.94%), female patients, the elderly aged >75 years,
TNK-​tPA is derived from alteplase, after mutations in three places and patients weighing <67 kg tended to have lower rates of ICH
(T103, N117, KHRR296-​299), increasing fibrin binding and speci- after treatment with TNK-​tPA [23]. During the recent STREAM
ficity, the plasma half-​life, and resistance to PAI-​1. Its slower clear- trial, the TNK-​tPA dose was decreased in patients ≥75 years after
ance allows single-​bolus administration. TNK-​tPA leads to faster the occurrence of three ICHs in the first 37 elderly patients ran-
recanalization, compared to alteplase, and also has higher fibrino- domized; after this dose reduction, no ICH occurred in the sub-
lytic potency on platelet-​rich clots than its parent molecule. sequent 97 randomized patients ≥75 years [7]‌. Coronary patency

Table 39.4  Doses of fibrinolytic agents and antithrombotic co-​therapies

Antiplatelet co-​therapy Aspirin: starting dose of 150–​300 mg PO (or 75–​250 mg IV if PO ingestion is not possible), followed by a maintenance dose of
75–​100  mg/​day
Clopidogrel: loading dose of 300 mg PO, followed by a maintenance dose of 75 mg/​day. In patients ≥75 years: 75 mg loading dose,
followed by 75 mg maintenance dose
Fibrinolysis Tenecteplase Reteplase Streptokinase
Single weight-​adjusted IV bolus Double bolus: 1.5 million units over
If <75 years: 10 U + 10 U IV bolus, given 30 minutes apart 30–​60 minutes IV
<60 kg: 30 mg
60 to <70 kg: 35 mg
70 to <80 kg: 40 mg
80 to <90 kg: 45 mg
≥90 kg: 50 mg
It is recommended to reduce to half-​dose in
patients aged ≥75 years
Anticoagulation Enoxaparin Fondaparinux
In patients <75 years: 30 mg IV bolus, followed by 1 mg/​kg SC every 12 hours until revascularization 2.5 mg IV bolus,
The first two SC doses should not exceed 100 mg per injection followed by SC dose of
In patients ≥75 years: no IV bolus; start with 0.75 mg/​kg SC, with a maximum of 75 mg per injection for 2.5 mg once daily
the first two SC doses
UFH
60 IU/​kg IV bolus (max 4000 IU)
12 IU/​kg/​hour (max 1000 U/​hour)
Target aPTT: 50–​70 seconds; first measurement at 3 hours
498 CHAPTER 3 9   Fibrinolytic, antiplatelet, and anticoagulant drugs in acu te coronary syndromes

rates were similar to those found in patients below 75 years. The full pharmacodynamic effect but accommodate some degree of
2017 ESC STEMI guidelines recommend using a half-​dose of interindividual variability. Large evidence accumulated during
TNK-​tPA in patients ≥75 years (IIa B recommendation) [8]. the last years shows that higher dosages, which were commonly
prescribed in the past, were only associated with increased risks
of GI bleeding, while not being more effective in the prevention
Antiplatelet agents of ischaemic events [1]‌. Current guidelines recommend the use of
low-​dose aspirin [30].
Aspirin
Aspirin irreversibly inhibits cyclo-​oxygenase (COX), blocking the P2Y12 inhibitors
formation of TXA2, a promoter of platelet aggregation. Numerous P2Y12 receptor inhibitors inhibit ADP-​ induced platelet acti-
studies have clearly shown that low-​dose aspirin reduces cardio- vation by binding to the platelet P2Y12 ADP receptor. P2Y12
vascular morbidity and mortality in patients with ACS or previous receptor inhibitors include clopidogrel and prasugrel, which
MI and confers a durable long-​term benefit [24–​26]. A  meta-​ are thienopyridine pro-​ drugs that are converted to active
analysis of 287 trials, involving 135 000 patients in comparisons metabolite(s), as well as ticagrelor and cangrelor, which are ac-
of antiplatelet therapy versus control and 77 000 patients in com- tive drugs that do not require metabolism and are reversible (see
parisons of different antiplatelet regimens by the Antithrombotic E Table 39.5).
Trialists’ Collaboration (ATC), showed a 22% reduction in vas-
cular events with aspirin [26]. This benefit was mainly driven by
Clopidogrel
a 34% reduction in MI and a 25% reduction in stroke. Currently, In 1996, the Intracoronary Stenting and Antithrombotic Regimen
however, the role of aspirin as secondary prevention is under in- (ISAR) trial suggested benefits of DAPT over anticoagulation
vestigation in more contemporary trials [24, 27–​29]. by reducing both cardiovascular and haemorrhagic events after
The optimal maintenance dose of aspirin after an ACS has placement of coronary stents [31]. This evidence was then con-
long been a matter of debate. Low doses of aspirin are suffi- firmed by other trials [Stent Anticoagulation Restenosis Study
cient to inhibit platelet TXA2; thus, typical regimens of 75–​100 (STARS), Full ANTicoagulation versus ASpirin and TIClopidine
mg daily clearly exceed the minimal effective dose required for a (FANTASTIC), and Multicenter Aspirin and Ticlopidine Trial

Table 39.5  P2Y12 receptor antagonists

Clopidogrel Prasugrel Ticagrelor Cangrelor

Chemical class Thienopyridine Thienopyridine Cyclopentyl-t​ riazolopyrimidine Stabilized ATP analogue
Administration PO PO PO IV
Dose 300–​600 mg, then 75 mg/​day 60 mg, then 10 mg/​day (5 180 mg, then 90 mg twice 30 micrograms/​kg bolus,
mg in selected cases) daily then 4 micrograms/​kg/​min
infusion
Binding to P2Y12 Irreversible Irreversible Reversible Reversible
2
eGFR 15–​60 mL/​min/​1.73 m No adjustment No adjustment No adjustment No adjustment
2
eGFR <15 mL/​min/​1.73 m Use only for selected Not recommended Not recommended No adjustment
indications (stent thrombosis
prevention)
Activation/​pro-​drug Pro-​drug, with variable liver Pro-​drug, with predictable Active drug, plus active Active drug
metabolism liver metabolism metabolite
Onset of action (load) 2–​6 hours 30 minutes to 4 hours 30 minutes to 4 hours 2 minutes
Duration of effect 3–​10 days 7–​10 days 3–​5 days 1–​2 hours
Withdrawal before surgery 5 days 7 days 3 days 1 hour
Plasma half-​life of active P2Y12 30–​60 minutes 30–​60 minutes 6–​12 hours 5–​10 minutes
inhibitor
Inhibition of adenosine No No Yes Yes (inactive metabolite
reuptake only)
Contraindication Hypersensitivity, active Prior CVA, hypersensitivity, Prior ICH, hypersensitivity, high Prior CVA, hypersensitivity,
bleeding high bleeding risk bleeding risk, severe hepatic high bleeding risk
dysfunction
Approval indication ACS (managed invasively or PCI in ACS ACS (managed invasively or PCI in patients with or
not) and PCI in spontaneous not) without ACS
coronary artery dissection
 A n ti pl ate l et   ag e n ts 499

after Intracoronary Stenting (MATTIS)] [31]. The most relevant the coronary anatomy was defined by angiography, patients were
evidence that adding clopidogrel to aspirin in patients with ACS randomized to a standard regimen of clopidogrel or a loading
and in those undergoing PCI was safe and more effective than dose of 60 mg prasugrel, followed by a 10 mg daily dose. The
aspirin alone came from the Clopidogrel in Unstable Angina to primary efficacy endpoint of cardiovascular death, MI, or stroke
Prevent Recurrent Events (CURE) study and its PCI substudy was in favour of prasugrel over the 15-​month follow-​up period
[32, 33]. In this trial, 12 562 patients with NSTE-​ACS received as- (9.9% versus 12.1%; P <0.001). This benefit was more pro-
pirin (75–​325 mg daily) and were randomized to either clopidogrel nounced (30%) in patients with diabetes versus those without
(300 mg loading dose, followed by 75 mg daily) or placebo for a (14%) [38]. In the 12 844 patients who received at least one cor-
mean duration of 9 months [32]. Clopidogrel resulted in a 20% onary stent, prasugrel significantly reduced the primary endpoint
reduction in the primary composite endpoint of cardiovascular by 18%. Stent thrombosis was also remarkably reduced with
death, MI, and stroke (9.3% versus 11.5%; P <0.001). The benefit prasugrel—​overall 1.13% versus 2.35% (HR 0.48; P <0.0001),
of clopidogrel occurred very early (<24 hours) in the course of especially in patients with DES (0.84% versus 2.34%, HR 0.36;
treatment and was consistent among low-​, intermediate-​, and P <0.0001). A  total of 2.4% of patients receiving prasugrel had
high-​risk patients. Although patients in the clopidogrel arm had major bleeding versus 1.8% of patients who received clopidogrel.
an increase in major bleeding, compared to aspirin alone (3.7% Moreover, significantly more patients treated with prasugrel
versus 2.7%), there was no significant difference in fatal bleeding. had fatal bleeding (0.4% versus 0.1% for clopidogrel). In those
In the Percutaneous Coronary Intervention-​ Clopidogrel in with STEMI, prasugrel was also significantly more effective than
Unstable angina to prevent Recurrent Events (PCI-​CURE) trial, clopidogrel (HR 0.68; P = 0.002), but without an increased risk
patients undergoing PCI who were pre-​treated with clopidogrel of life-​threatening or major bleeding [39]. In the 346 patients
for a median of 10 days also had a significantly lower rate of the who underwent isolated CABG and received prasugrel before
primary endpoint of cardiovascular death, MI, or urgent target the procedure, the bleeding risk was significantly higher than in
vessel revascularization within 30  days of PCI (4.5% versus those receiving clopidogrel [40].
6.4%) [33]. Later, prasugrel has been studied in ACS patients who did not
Because of the intricate hepatic metabolism from the pro-​ undergo revascularization. In the Targeted Platelet Inhibition
drug to its active compound, the onset of action of clopidogrel to Clarify the Optimal Strategy to Medically Manage Acute
is delayed. This issue has been partially overcome by the use of a Coronary Syndrome (TRILOGY) trial, 9326 high-​risk ACS pa-
600 mg loading dose which was found to accelerate the onset tients were randomized to prasugrel or clopidogrel, if they were
of action and increase the proportion of patients with sufficient selected for a final strategy of medical management within
antiplatelet response, compared with a loading dose of 300 mg. 10 days of the event [41]. Angiography was not compulsory, but
The CLARITY trial examined whether the addition of if such a procedure was planned, it needed to be done before ran-
clopidogrel (300 mg bolus, followed by 75 mg daily) was associ- domization. The loading dose of prasugrel was reduced to 30 mg,
ated with higher rates of IRA patency in patients ≤75 years treated followed by a maintenance dose of 10 mg daily, except for patients
with a fibrinolytic agent [34]. Patients treated with clopidogrel ≥75 years who received 5 mg. At 30-​month follow-​up, there was
had improved patency rates at angiography and also 20% reduced no significant difference between prasugrel and clopidogrel in the
risk of ischaemic complications. primary efficacy endpoint.
Recently, the TREAT trial showed that among patients The optimal timing of the initiation of P2Y12 inhibition in re-
<75 years with STEMI, administration of ticagrelor after fibrino- lation to invasive management in ACS patients (generally known
lytic therapy did not significantly reduce the rate of cardiovascular as ‘pre-​treatment’) remains controversial. Pre-​treatment could
events, when compared with clopidogrel, up to 12 months [35]. be associated with some theoretical advantages for the patient,
Today, clopidogrel (600 mg loading dose, 75 mg daily dose), including more time for the oral P2Y12 inhibitor to achieve full
on top of aspirin, is recommended in stable CAD patients under- antiplatelet effects, more ischaemic protection while waiting to
going coronary stent implantation and in ACS patients who undergo coronary angiography, less periprocedural thrombotic
cannot receive ticagrelor or prasugrel, including those with prior complications, and less need for bailout use of GPIs in cases of
ICH or an indication for oral anticoagulant, while clopidogrel PCI. Conversely, pre-​treatment may increase bleeding, is useless
(300 mg loading dose in patients aged ≤75, 75 mg daily dose) is in patients without CAD, and is possibly harmful in a small pro-
recommended on top of aspirin in STEMI patients receiving fi- portion of those who are referred for immediate CABG. Even
brinolysis [8, 36]. when CABG may be safely delayed to allow for washout from
P2Y12 inhibition, pre-​treatment leads to prolonged hospital stay
Prasugrel and increased overall costs.
Compared to clopidogrel, prasugrel requires one step fewer Because of the faster onset of action of prasugrel, compared
during metabolism to the active metabolite and hence in- to that of clopidogrel, however, it is reasonable to assume that
hibits platelets faster and more consistently. The Trial to Assess delaying its loading dose to the time of intervention could avoid
Improvement in Therapeutic Outcomes by Optimizing Platelet unnecessary exposure to DAPT, while avoiding early thrombotic
Inhibition with Prasugrel (TRITON) trial included patients with complications. This hypothesis was tested in the Comparison of
NSTE-​ACS and STEMI who were scheduled for PCI [37]. After Prasugrel at the Time of Percutaneous Coronary Intervention
500 CHAPTER 3 9   Fibrinolytic, antiplatelet, and anticoagulant drugs in acu te coronary syndromes

(PCI) or as Pretreatment at the Time of Diagnosis in Patients with in patients with a prior TIA or stroke, the efficacy and bleeding
Non-​ST Elevation Myocardial Infarction (ACCOAST) study in risk of ticagrelor, compared to clopidogrel, appeared to be con-
patients with NSTE-​ACS but was stopped prematurely because of sistent with the overall population in these high-​risk patients [46].
a lack of efficacy and excess bleeding in the preloading arm [42]. The ATLANTIC trial evaluated whether pre-​hospital admin-
Current ESC guidelines state that in patients with ACS under- istration of ticagrelor improved coronary reperfusion, compared
going PCI, prasugrel (60 mg loading dose, 10 mg daily dose) on to in-​hospital initiation, in 1862 STEMI patients undergoing pri-
top of aspirin is recommended for P2Y12 inhibitor-​naive patients mary PCI [47]. While pre-​hospital administration of ticagrelor
with NSTE-​ACS or in STEMI patients undergoing immediate cor- appeared to be safe, it did not improve the primary endpoints of
onary catheterization unless there is a high risk of life-​threatening ST-​segment elevation resolution or TIMI grade 3 flow rates. Stent
bleeding or other contraindications (Class I, LoE B) [36]. In pa- thromboses were significantly lower with pre-​hospital ticagrelor
tients with a body weight of <60 kg, a maintenance dose of 5 mg is administration, however (0.0% versus 0.8% with in-​hospital ad-
recommended. In patients aged >75 years, prasugrel is generally ministration; P = 0.008).
not recommended, but a dose of 5 mg should be used if treatment The value of ticagrelor beyond 12  months of therapy in pa-
is deemed necessary. Additionally, in stable patients undergoing tients with prior ACS has been investigated in the Prevention of
PCI, prasugrel or ticagrelor on top of aspirin may be considered Cardiovascular Events in Patients with Prior Heart Attack Using
instead of clopidogrel, taking into account the ischaemic (e.g. Ticagrelor Compared to Placebo on a Background of Aspirin–​
high SYNTAX score, prior stent thrombosis, location and number Thrombolysis in Myocardial Infarction 54 (PEGASUS-​ TIMI
of implanted stents) and bleeding [e.g. according to Predicting 54) trial in which treatment with ticagrelor significantly reduced
Bleeding Complication in Patients Undergoing Stent Implantation the risk of cardiovascular death, MI, or stroke and increased the
and Subsequent Dual Antiplatelet Therapy (PRECISE-​DAPT) risk of major bleeding in 21 162 patients who had MI 1–​3 years
score] risks (Class  IIb, LoE C) [30,  36]. Prasugrel is not recom- earlier [48]. For this purpose, the dose of 60 mg twice daily was as
mended in NSTE-​ACS patients in whom the coronary anatomy effective as, but safer than, the 90 mg twice daily dose.
is not known (Class III, LoE B), in medically managed ACS pa- More recently, the role of ticagrelor monotherapy was investi-
tients (Class III, LoE B), or in patients under oral anticoagulation gated in the GLOBAL LEADERS trial, in which the hypothesis
(Class III, LoE C) [30, 36]. was tested that ticagrelor in combination with aspirin for 1 month,
followed by ticagrelor alone, improved outcomes after PCI, com-
Ticagrelor pared with standard antiplatelet regimens [27]. Specifically,
Ticagrelor is a reversible oral P2Y12 inhibitor that does not require 15 968 patients undergoing PCI with a Biolimus A9™-​eluting stent
hepatic metabolism. Compared to clopidogrel, its peak antiplatelet for stable CAD or ACS were randomly assigned either to 75–​100
effect is therefore considerably faster (see E Table 39.5); its re- mg aspirin daily plus 90 mg ticagrelor twice daily for 1 month,
versibility also allows more flexibility for surgical procedures. followed by 23 months of ticagrelor monotherapy, or to standard
Ticagrelor was tested in the Study of Platelet Inhibition and DAPT with 75–​100 mg aspirin daily plus either 75 mg clopidogrel
Patient Outcomes (PLATO) trial, in which 18  624 patients daily (for patients with stable CAD) or 90 mg ticagrelor twice
with NSTE-​ ACS or STEMI were randomized to clopidogrel daily (for patients with ACS) for 12 months, followed by aspirin
(300–​600 mg loading dose, 75 mg daily) or ticagrelor (180 mg monotherapy for 12 months. The primary endpoint at 2 years was
loading dose, 90 mg twice daily) [43]. At 12 months, the primary a composite of all-​cause mortality or non-​fatal new Q-​wave MI.
endpoint (cardiovascular death, MI, or stroke) was significantly The key secondary safety endpoint was site-​reported bleeding
lower with ticagrelor (9.8%), compared to clopidogrel (11.7%). [Bleeding Academic Research Consortium (BARC) criteria grade
All-​cause mortality, cardiovascular death, and MI were also sig- 3 or 5]. At 2 years, the primary endpoint had occurred in 3.81%
nificantly lower in patients randomized to ticagrelor. Moreover, of the experimental group versus 4.37% of the control group
the risk of stent thrombosis was 33% lower with ticagrelor, com- (rate ratio 0.87, 95% CI 0.75–​1.01; P = 0.073). BARC grade 3 or
pared to clopidogrel. Importantly, the superiority of ticagrelor 5 bleeding occurred in 2.04% versus 2.12% (rate ratio 0.97, 95%
over clopidogrel with respect to the primary endpoint, as well CI 0.78–​1.20; P  =  0.77). Thus, the experimental group was not
as to cardiovascular death or overall mortality, was consistent superior to standard therapy. However, it is important to note
across management strategies, i.e. in patients undergoing PCI, that all study endpoints were investigator-​reported and not sub-
those medically managed, and those who underwent CABG. ject to formal adjudication by an independent Clinical Event
The overall rate of major bleeding was similar in both groups, al- Committee (CEC), which may introduce detection, reporting,
though ticagrelor was associated with a significantly higher risk or ascertainment bias. Accordingly, the GLOBAL LEADERS
of bleeding unrelated to CABG. There was no difference in fatal Adjudication Sub-​Study (GLASSY) was designed to perform an
bleeding. The most common side effect of ticagrelor was dys- independent adjudication process of reported and unreported
pnoea (13.8% versus 7.8% for clopidogrel), although this rarely potential endpoints, using standardized CEC procedures, in al-
led to study drug discontinuation and did not affect the efficacy most 50% of trial patients [28]. This study showed that ticagrelor
[44]. Another off-​target effect of ticagrelor is an increased risk of monotherapy after 1  month of DAPT was non-​inferior to con-
bradyarrhythmias, probably related to its effect on adenosine me- ventional DAPT in the prevention of all-​cause death, non-​fatal
tabolism [45]. In contrast to prasugrel, which is contraindicated MI, non-​fatal stroke, or urgent target vessel revascularization at
 A n ti pl ate l et   ag e n ts 501

2 years, suggesting that discontinuation of aspirin after 30 days, patients taking clopidogrel and scheduled for CABG. Overall
while continuing ticagrelor, does not expose patients to a higher results were positive, but due to the use of a surrogate primary
ischaemic risk. endpoint (platelet reactivity), this small trial must be interpreted
Like prasugrel, ticagrelor (180 mg loading dose, 90 mg twice with caution [53].
daily) on top of aspirin is recommended over clopidogrel in ACS When cangrelor is used, a switch from cangrelor to an oral
patients and can also be considered in stable patients under- P2Y12 inhibitor will be needed [54]. Because cangrelor is of a
going complex PCI, but it should not be used in patients on oral different class than oral P2Y12 inhibitors, all switches involving
anticoagulation [8, 30, 36]. Differently from prasugrel, ticagrelor cangrelor are, by definition, interclass. Transitioning from
can be used in patients with an unknown coronary anatomy and cangrelor to a thienopyridine (clopidogrel and prasugrel), but
in medically managed patients, and it may be considered for not ticagrelor, can be associated with a drug–​drug interaction,
longer than 12 months (preferred over prasugrel or clopidogrel) and this is concerning because it can result in reduced platelet
in patients with MI and high ischaemic risk who have tolerated inhibition and subsequent lack of protection from thrombotic
DAPT without a bleeding complication. In this latter case, the 60 complications in the periprocedural period [54]. The active me-
mg twice-​daily dose should be used on top of aspirin (Class IIb, tabolite of both clopidogrel and prasugrel cannot bind to P2Y12
LoE B) [36]. receptors if already largely occupied by cangrelor; thus, these two
agents must be administered when cangrelor infusion is stopped
Cangrelor [54]. In contrast to what is observed for the thienopyridines, no
Cangrelor is an IV ATP analogue that reversibly inhibits the interaction exists for the transition from cangrelor to ticagrelor,
P2Y12 receptor. It effectively inhibits platelets to a high degree a which can be administered concomitantly to cangrelor, providing
few minutes after bolus administration and has a very short half-​ a fast antiplatelet effect, as recently demonstrated in STEMI pa-
life, so platelet recovery occurs rapidly after infusion discontinu- tients undergoing primary PCI in the CANgrelor and Crushed
ation (see E Table 39.5). TICagrelor in STEMI Patients Undergoing Primary Percutaneous
The cangrelor phase III programme Cangrelor versus Standard Coronary Intervention (CANTIC) study [55].
Therapy to Achieve Optimal Management of Platelet Inhibition The ESC guidelines indicate that periprocedural cangrelor may
(CHAMPION) originally consisted of two randomized, double-​ be considered in ACS patients undergoing PCI who have not yet
blind trials CHAMPION PCI and CHAMPION PLATFORM that received P2Y12 inhibitors (Class IIb, LoE A) [30].
tested the hypothesis that cangrelor given during PCI in ACS pa-
tients could reduce thrombotic events, compared with clopidogrel
Genetic and platelet function testing for
administered at the beginning or at the end of PCI, respectively,
with an acceptable safety profile [49, 50]. The primary endpoint
P2Y12 inhibitors
(death, MI, or ischaemia-​driven urgent revascularization) at 48 Both clopidogrel and prasugrel are pro-​drugs and require hep-
hours after PCI was not different between the two groups in both atic metabolism by the cytochrome P450 system to form their
studies. The subsequent CHAMPION PHOENIX trial was de- active compound. Functional variants of CYP2C19 reduce the
signed differently from the two previous studies and accounted availability of the active metabolite of clopidogrel, but not that of
for relevant aspects:  (1) updated definition of MI as endpoint; prasugrel [56]. As a consequence, carriers of these genetic variants
(2)  the comparator arm was clopidogrel 300 or 600 mg, at the have a higher risk of adverse cardiovascular events on clopidogrel,
investigator’s discretion; (3) the primary endpoint was the com- but not on prasugrel [57–​60]. With respect to ticagrelor, there is
posite of death, MI, ischaemia-​driven revascularization, or stent no interference of P450 variants on the antiplatelet effect [61].
thrombosis (including intraprocedural) at 48 hours; and (4) the Genotype-​based choice of the type of antiplatelet agent might im-
population of interest was restricted to clopidogrel-​naive patients prove an individual’s risk of adverse ischaemic events. However,
[51]. Here the primary efficacy endpoint was significantly lower to date, no randomized trial has ever demonstrated any clinical
with cangrelor, compared to clopidogrel (4.7% versus 5.9%, re- benefit of such an approach and only 6–​12% of the variability in
spectively; P = 0.005), driven by a decrease in acute periprocedural on-​clopidogrel platelet reactivity can be explained by the differ-
MI and stent thrombosis, and there were no differences in the ences in genotype.
primary safety endpoint. The pre-​specified pooled analysis of There is evidence that high and low platelet reactivity on
patient-​level data from these three cangrelor trials confirmed P2Y12 antagonist treatment may predict ischaemic and bleeding
the lower rates of PCI periprocedural thrombotic complica- risks, respectively, thus leading to the rationale for individual-
tions (3.8% versus 4.7%; P = 0.0007) and stent thrombosis (0.5% ized antiplatelet therapy based on platelet function monitoring
versus 0.8%; P  =  0.0008), with no relevant differences in major [62]. However, randomized trials have failed to demonstrate any
bleeding [52]. benefit of platelet function monitoring to adjust therapy [63–​65].
Based on its pharmacologic profile, cangrelor might be useful The recent ANTARCTIC (The Platelet Function Monitoring to
also as a bridging agent in patients requiring surgery. The Adjust Antiplatelet Therapy in Elderly Patients Stented for an
Maintenance of Platelet inihiBition With cangRelor After dIs- Acute Coronary Syndrome) trial selected only ACS patients at
continuation of ThienopyriDines in Patients Undergoing sur- high risk of both ischaemic and bleeding events (based on age
GEry (BRIDGE) study tested the efficacy of this strategy in 210 ≥75 years) and with accurate thresholds reflecting optimal P2Y12
502 CHAPTER 3 9   Fibrinolytic, antiplatelet, and anticoagulant drugs in acu te coronary syndromes

inhibition [66]. Clopidogrel was replaced by prasugrel using the include eptifibatide, tirofiban, and abciximab, which have rele-
recommended daily dose of 5 mg for the elderly, with the pos- vant differences in structure, binding, and pharmacokinetic/​
sibility of up and down adjustment according to individual re- pharmacodynamic profiles (see E Table 39.6).
sponse. Platelet function monitoring performed 14  days after GPIs have been extensively tested in ACS patients. Evidence
discharge and later, if needed, led to a change of treatment in 45% coming from the most recent trials in NSTE-​ ACS patients
of patients. However, this strategy did not improve ischaemic undergoing PCI [Intracoronary Stenting and Antithrombotic
or safety outcomes. In the Testing Responsiveness to Platelet Regimen: Rapid Early Action for Coronary Treatment 4 (ISAR-​
Inhibition on Chronic Antiplatelet Treatment for Acute Coronary REACT 4), Early Glycoprotein IIb/​IIIa Inhibition in Non-​ST-​
Syndromes (TROPICAL-​ACS) trial, de-​escalation of antiplatelet Segment Elevation Acute Coronary Syndrome (EARLY-​ACS)]
treatment guided by platelet function testing was non-​inferior to did not support an important role for GPIs, particularly if ad-
standard treatment with prasugrel at 1 year after PCI in terms of ministered before PCI (upstream). Therefore, even in this setting,
net clinical benefit [67]. ESC guidelines allow for bailout use only (Class IIa, LoE C) [30].
Current ESC guidelines state that neither genetic testing nor Today, the most relevant clinical setting for the use of GPIs re-
platelet function testing can be recommended for tailoring DAPT mains that of STEMI. In the era before thienopyridine preloading,
but may be considered in specific situations (e.g. patients suf- numerous studies demonstrated that GPIs, mostly abciximab,
fering from recurrent AEs) if the results may change the treat- added to UFH, improved outcomes after primary PCI, but also
ment strategy [36]. De-​escalation guided by platelet function that high-​dose tirofiban was non-​inferior to abciximab in this set-
testing might be considered as an alternative to 12 months of po- ting [Multicentre Evaluation of Single High-​Dose Bolus Tirofiban
tent platelet inhibition, especially for patients deemed unsuitable vs Abciximab With Sirolimus-​Eluting Stent or Bare Metal Stent
for maintained potent platelet inhibition (Class IIb, LoE B) [30]. in Acute Myocardial Infarction Study (MULTISTRATEGY) trial]
[68]. Even in the most recent era of routine use of thienopyridines,
GPIs could be useful. The Facilitation through Aggrastat By
Glycoprotein IIb/​IIIa inhibitors drOpping or shortening Infusion Line in patients with ST-​
segment elevation myocardial infarction compared to or on top of
Binding of fibrinogen to the integrin αIIbβ3 (GPIIb/​IIIa) receptor PRasugrel given at loading dOse (FABOLUS-​PRO) study showed
on activated platelets represents the final common pathway of that a tirofiban bolus after pre-​treatment with prasugrel offered
platelet aggregation and the formation of platelet-​rich thrombi. the best platelet inhibition and that in patients pre-​treated with
By preventing the interaction of GPIIb/​IIIa receptors with fi- clopidogrel, a bolus followed by a 2-​hour infusion was neces-
brinogen, GPIs prevent platelet aggregation and subsequent sary [69]. Nevertheless, subsequent trials (FINESSE, On-​TIME2,
thrombus formation, regardless of the agonist. Available GPIs BRAVE 3, INFUSE-​MI) provided contrasting results on clinical

Table 39.6  Glycoprotein IIb/​IIIa inhibitors

Abciximab Eptifibatide Tirofiban

Type Fab fragment of chimeric human–​murine Synthetic cyclic heptapeptide Synthetic non-​peptide
monoclonal antibody
Molecular weight Large molecule Small molecule Small molecule
(47 515 Da) (832 Da) (496 Da)
Antigenicity Present Absent Absent
Inhibition Non-​competitive Competitive Competitive
Binding Irreversible Competitive Competitive
Plasma half-​life 10–​30 minutes 2.5–​2.8 hours 1.2–​2 hours
Receptor binding Minutes Seconds Seconds
Recovery of platelet function 24–​48 hours Approximately 4 hours Approximately 4 hours
Elimination route Spleen Renal (60–​75%) Renal (65–​75%)
Dosage recommended Bolus of 0.25 mg/​kg IV, followed by 0.125 Bolus of 180 micrograms/​kg IV over High-​dose bolus 25 micrograms/​kg
micrograms/​kg/​min infusion (maximum 10 1–​2 minutes, a second bolus of 180 IV, then 0.15 micrograms/​kg/​min
micrograms/​min) and can be continued for micrograms/​kg 10 minutes later, and an
12 hours after PCI infusion of 2 micrograms/​kg/​min
Dose adjustment in CKD No dose adjustment needed Infusion should be reduced by Bolus and infusion should be
half if eGFR <50 mL/​min/​1.73 m2. reduced by 50% if eGFR 15–​30 mL/​
Not recommended if <30 or on min/​1.73 m2. Not recommended if
haemodialysis <15 mL/​min/​1.73 m2
 A n ti c oag u l a n t   ag e n ts 503

Table 39.7  Dosing scheme for UFH

Indication Bolus Infusion Target aPTT/​ACT

NSTE-​ACS 60 U/​kg 12–​15 U/​kg/​hour aPTT 50–​70 seconds
(max 5000) (1000 U/​hour max)
NSTE-​ACS 50–​85 U/​kg after initial use 12–​15 U/​kg/​hour aPTT 50–​70 seconds
of fondaparinux (1000 U/​hour max)
STEMI 70–​100  U/​kg –​ ACT 250–​300 or 200–​250 if GPIIb/​IIIa
(with primary PCI) 50–​70 U/​kg if GPIIb/​IIIa

benefits. Therefore, routine use of GPIs in primary PCI cannot (8898) or placebo (8881) and maintenance therapy with vorapaxar
be supported, particularly in current practice when prasugrel or (2.5 mg daily) at a median follow-​up of 2.5 years. It was associ-
ticagrelor is used, and the value of starting upstream treatment re- ated with a reduction of cardiovascular death, MI, or stroke, but
mains uncertain. Regarding the intracoronary administration of which was counterbalanced by a higher risk of moderate to se-
abciximab, instead of IV, small studies suggested potential bene- vere bleeding [71]. However, the Thrombin Receptor Antagonist
fits of the intracoronary route, but they were not confirmed in for Clinical Event Reduction in Acute Coronary Syndrome
large randomized trials or in a meta-​analysis of five randomized (TRACER) trial, which randomized 12 944 patients with NSTE-​
trials [70]. ACS to vorapaxar or placebo, was prematurely interrupted due
The main concern related to GPI use is an increase of bleeding to safety concerns—​adding vorapaxar to standard therapy did
complications, but this was mainly observed in old studies using not significantly reduce the primary composite endpoint (death
prolonged post-​PCI infusions. To reduce this risk and provide from cardiovascular causes, MI, stroke, recurrent ischaemia
similar efficacy, studies have shown that a bolus only or short-​ with rehospitalization, or urgent coronary revascularization)
term infusion is feasible [69]. but significantly increased the risk of major bleeding, including
The most recent ESC guidelines state that in STEMI patients, ICH [72].
GPIs can be used as bailout but may also be considered in P2Y12 Today, vorapaxar is approved by the European Medicines
inhibitor-​naive patients undergoing PCI (Class IIb, LoE C) [30]. Agency (EMA) for the reduction of thrombotic events in patients
with previous MI or peripheral arterial disease, but there is no
dedicated recommendation for its use in the ESC guidelines [36].
Thrombin receptor (PAR-​1)
antagonists
Anticoagulant agents
Despite optimal secondary prevention, including high-​ dose
statins and DAPT, the risk of recurrent events remains consid- Although platelet activation and adhesion are essential in
erable, especially in high-​risk patients. DAPT primarily targets atherothrombosis, thrombin also plays a pivotal role in thrombus
pathways associated with TXA2 and ADP-​mediated platelet acti- formation [73]. In addition, the coagulation system remains con-
vation. Thus, other pathways, such as thrombin-​mediated platelet siderably activated for months after an ACS [74]. Anticoagulants
activation, remain unaffected, which might account for the re- are used to inhibit thrombin generation and/​or activity, thereby
sidual risk of atherothrombotic events. As the coagulation system reducing thrombus-​related events. Several anticoagulants, acting
often remains activated long after the initial event, long-​term at different levels of the coagulation cascade, have been approved
additional platelet inhibition at the interplay of the coagulation for use in ACS (see E Figure 39.1).
cascade and platelets might be a more subtle, and perhaps safer,
approach than adding anticoagulation per se. Unfractionated heparin
Given that thrombin levels are known to be elevated after an Traditionally, UFH has been the standard antithrombin for use
ACS, and thrombin is the most potent platelet activator, targeting in the acute setting. UFH is a preparation of heparin molecules
thrombin-​mediated effects has been an important area of clin- that are heterogenous with respect to the molecular weight. The
ical investigation. Vorapaxar acts by inhibiting protease-​activated anticoagulant effect of UFH is mediated by binding to circulating
receptor 1 (PAR-​1), leading to prevention of thrombin-​mediated antithrombin III, which augments its inhibitory activity towards
platelet activation. It is the only PAR-​1 antagonist that has com- several coagulation factors, primarily activated thrombin (FIIa)
pleted phase III clinical investigations and is available for clinical and activated factor X (FXa). Multiple studies have consistently
use. Based on the Thrombin Receptor Antagonist in Secondary demonstrated the benefit of UFH as an adjunct to aspirin in pa-
Prevention of Atherothrombotic Ischemic Events–​Thrombolysis tients with ACS. In a meta-​analysis comprising 17  157 patients
in Myocardial Infarction 50 (TRA 2P-​TIMI 50) trial, vorapaxar with NSTE-​ACS from 12 trials, heparin use was associated with a
was approved in May 2014 [71]. Patients with prior MI on main- 47% reduction in death or MI, representing 29 events prevented
tenance antiplatelet therapy were randomized 1:1 to vorapaxar per 1000 patients treated [75]. Although there are no RCTs, UFH
504 CHAPTER 3 9   Fibrinolytic, antiplatelet, and anticoagulant drugs in acu te coronary syndromes

is also considered standard therapy during primary PCI, mainly during PCI and particularly in patients undergoing primary PCI
because of the strong belief that anticoagulation is necessary for STEMI [81]. Yet, this meta-​analysis was largely based on non-​
during the intervention. randomized comparisons.
The effectiveness of UFH is highly variable in patients, because of The ESC guidelines recommend that enoxaparin should be
low bioavailability and variable clearance. The anticoagulant effect considered for primary PCI [8]‌and should also be considered
is usually monitored in the cardiac catheterization laboratory with during PCI in NSTE-​ACS patients pre-​treated with enoxaparin
ACT and elsewhere with aPTT [76]. Higher aPTT values are associ- SC [30].
ated with bleeding; for every 10-​second increase in aPTT, the prob- In fibrinolysis studies, a significant improvement in the pri-
ability of major bleeding was increased by 7% [77]. Binding of UFH mary combined efficacy and safety endpoint was seen with
to platelet factor 4 on the surface of platelets can result in HIT [78]. TNK-​tPA and enoxaparin, when compared to TNK-​tPA and
Despite its limitations, UFH remains a widely used anti- UFH [82, 83]. Unfortunately, a significant increase in ICH was
coagulant and is still the primarily recommended anticoagulant seen in the ASSENT-​3 PLUS trial using the same combination
by the ESC for use during PCI in stable CAD and ACS (see E [84]. The excess of intracranial bleeding complications was pre-
Table 39.7) [30]. dominantly observed in elderly patients. Using an age-​adjusted
dose (see E Table 39.8), enoxaparin did not increase the risk
Low-​molecular weight heparins of ICH after fibrinolytic therapy, while still reducing the risk of
LMWHs are preparations comprising heparin molecules of lower ischaemic complications in the Enoxaparin and Thrombolysis
molecular weight. Similarly to UFH, LMWHs bind and acti- Reperfusion for Acute Myocardial Infarction Treatment–​
vate antithrombin III, although the relative inhibitory activity of Thrombolysis in Myocardial Infarction 25 (ExTRACT-​ TIMI
LMWHs towards FXa is greater than that of thrombin, resulting 25) study [85].
in greater inhibition of thrombin generation. LMWHs have
several advantages over standard UFH, including greater bio- Intravenous direct thrombin inhibitors
availability, better resistance to inhibition by activated platelets, Unlike UFH and LMWH, direct thrombin inhibitors (DTIs) (e.g.
lower incidence of HIT, and higher anti-​FXa activity. LMWHs lepirudin, bivalirudin, argatroban) exert their anticoagulant effect
are also easier to administer and have a more stable and pre- by binding directly to thrombin. DTIs do not require monitoring
dictable anticoagulant response that eliminates the need for and have not been associated with thrombocytopenia. DTIs in-
aPTT monitoring. A  better anti-​Xa:IIa ratio than that of UFH hibit thrombin activity better than heparin do and present an im-
more efficiently promotes the inhibition of thrombin generation. proved protection against thrombin reactivation after cessation or
Furthermore, SC administration and a longer half-​life greatly fa- discontinuation of therapy [86].
cilitate administration.
Several trials have evaluated the efficacy and safety of Bivalirudin
enoxaparin versus UFH in ACS patients. A meta-​analysis of 12 The efficacy and safety of bivalirudin was evaluated in the
trials testing enoxaparin versus UFH in ACS (n = 49 088) showed Acute Catheterization and Urgent Intervention Triage Strategy
a significant reduction in the combined endpoint of death (ACUITY) trial, an open-​label study that randomized 13  819
or MI at 30  days in favour of enoxaparin, but a significant in- patients with NSTE-​ACS to UFH or enoxaparin plus a GPI,
crease in major bleeding [79]. The net clinical benefit in favour bivalirudin plus a GPI, or bivalirudin alone with provisional
of enoxaparin was evident among the STEMI population and was GPI [87]. Bivalirudin alone, when compared with heparin plus a
neutral among the NSTE-​ACS population. In the ATOLL trial, GPI, was associated with a non-​inferior 30-​day rate of the com-
IV enoxaparin, compared to UFH, did not reduce the primary posite ischaemia endpoint and significantly less major bleeding
endpoint of the study but significantly reduced the secondary (3.0 versus 5.7%, respectively; P <0.001). The net clinical out-
endpoint of death, recurrent ACS, or urgent revascularization in come endpoint was significantly lower with bivalirudin alone
patients undergoing primary PCI for STEMI [80]. Importantly, (10.1 versus 11.7%, respectively; P  =  0.02). The reduction of
bleeding complications were similar to those for enoxaparin and in-​
hospital bleeding associated with bivalirudin appeared to
UFH. A more recent meta-​analysis including 23 trials and 30 966 improve long-​term outcome [88]. In patients not pre-​treated
patients with ACS undergoing PCI showed that enoxaparin was with clopidogrel, however, bivalirudin alone appeared to be in-
superior to UFH in reducing mortality and bleeding outcomes ferior to the combination of UFH/​LMWH plus a GPI. Similarly,

Table 39.8  Dosing scheme for enoxaparin

Indication Dose Duration

NSTE-​ACS 1 mg/​kg SC twice daily 2–​8 days
(in cases of PCI, no additional bolus is necessary if the last dose has been administered <8 hours before;
a 0.3 mg/​kg bolus is required if the last dose was given >8 hours before)
STEMI (primary PCI) 0.5 mg/​kg IV bolus (additional 0.25 mg/​kg in cases of prolonged procedure)
 A n ti c oag u l a n t   ag e n ts 505

abciximab plus UFH was not found to be superior to bivalirudin Indirect (subcutaneous) factor Xa inhibitors
alone in the subsequent ISAR-​REACT 4 trial in NSTEMI pa-
Fondaparinux
tients who received a 600-​mg loading dose of clopidogrel [89].
A combined analysis of these two trials confirmed similar effi- Fondaparinux, a synthetic pentasaccharide, is a selective indirect
cacy of bivalirudin, but better safety, compared to the combin- antithrombin-​ dependent FXa inhibitor. The pentasaccharide–​
ation of UFH plus a GPI [90]. antithrombin complex is active against FXa, but not against
Bivalirudin also significantly reduced the risk of the 30-​day com- thrombin, resulting in inhibition of thrombin generation, without
bined endpoint of major bleeding and adverse ischaemic events by direct inhibition of thrombin activity [100]. Compared to UFH
24%, when compared to UFH plus a GPI, in primary PCI patients and LMWHs, fondaparinux is associated with less biological
in the Harmonizing Outcomes with Revascularization and Stents variability, immunogenic reactivity, and risk of contamination.
in Acute Myocardial Infarction (HORIZONS-​AMI) trial [91]. As with LMWHs, fondaparinux does not need monitoring of
This benefit was largely driven by a reduction in bleeding com- its anticoagulant effect. Also, in contrast with UFH or LMWHs,
plications; no difference was observed in the rates of MI, stroke, fondaparinux does not bind to platelet factor 4.
or revascularization. Importantly, mortality was also significantly The efficacy and safety of fondaparinux were evaluated in
lower in the bivalirudin arm (2.1% versus 3.1% for UFH plus a the Fifth Organization to Assess Strategies in Acute Ischemic
GPI). The mortality benefit even appeared to be sustained for Syndromes (OASIS-​5) trial, in which 20 078 patients with NSTE-​
up to 3 years after randomization (5.9 versus 7.7%, respectively; ACS were randomized to receive either fondaparinux (2.5 mg/​day
P = 0.03) [92]. A low bridging dose of heparin pre-​randomization SC) or enoxaparin [101]. The rate of the primary outcome (death,
was shown to be safe, and even efficacious, in a subanalysis of MI, or refractory ischaemia) at 9  days was comparable in the
HORIZONS [93]. In the European Ambulance Acute Coronary fondaparinux and enoxaparin groups (5.8% versus 5.7%, respect-
Syndrome Angiography (EUROMAX) study, bivalirudin given ively), satisfying the non-​inferiority criteria. However, the rate of
during emergency transport for primary PCI reduced the 30-​ major bleeding at 9 days was significantly lower with fondaparinux
day combined ischaemic endpoint, when compared to UFH or versus enoxaparin. At 30 days, the rate of the primary endpoint
LMWH with an optional GPI (in 70% of patients), but increased was comparable between groups (8.0% versus 8.6%, respectively),
the risk for stent thrombosis in STEMI patients on contemporary while the rate of death was significantly lower with fondaparinux
antiplatelet regimens [94]. (2.9% versus 3.5%, respectively). Remarkably, the majority of ex-
Since the HORIZONS-​AMI and EUROMAX trials, bivalirudin cess deaths in the enoxaparin group occurred in patients who ex-
has been compared to UFH without systematic use of a GPI and perienced bleeding [102]. In addition, fondaparinux appeared to
in a contemporary setting of preferred radial access in three large-​ be particularly effective and considerably safer in patients with
scale clinical trials: How Effective Are Antithrombotic Therapies renal dysfunction.
in Primary PCI (HEAT-​PPCI) (in primary PCI), MATRIX, and In patients undergoing PCI, additional UFH was administrated
VALIDATE-​ SWEDEHEART [95–​ 97]. Taken together, these in OASIS-​5 to prevent catheter-​related thrombus formation, and
three trials did not show a benefit over UFH monotherapy—​there this did not negate the benefit of fondaparinux over enoxaparin
was no benefit in ischaemic risk or the risk of bleeding. A meta-​ [103]. As a consequence, additional UFH (60–​85 IU/​kg bolus)
analysis updated for the results of these three trials showed that during the procedure is recommended. The Fondaparinux with
bivalirudin, compared with heparin, was associated with a similar UnfracTionated heparin dUring Revascularization in Acute cor-
incidence of all-​cause death and ischaemic events after PCI for onary syndromes (FUTURA OASIS-​8) trial failed to prospect-
ACS [98]. A  significant association of bivalirudin with a de- ively settle the optimal periprocedural UFH dose in addition to
creased risk of bleeding was only found with unbalanced use of fondaparinux, as there appeared to be no significant difference
GPIs in conjunction with heparin. in the bleeding risk between the 50-​and 85-​IU/​kg boluses [104].
Based on the above-​mentioned trials, the ESC guidelines pri- Due to the systematic additional use of UFH in all patients, how-
marily recommend UFH as the anticoagulant of choice for PCI ever, the rate of catheter thrombosis was very low overall and did
(Class IA) [30]. Due to its short half-​life and favourable results in not differ between the two groups.
some of the studies, bivalirudin may be considered as an alterna- Fondaparinux was also evaluated in STEMI patients. In the
tive to UFH in selected cases (Class IIb A) [30]. OASIS-​6 trial, fondaparinux was compared to UFH or placebo
The optimal regimen of bivalirudin has been highly debated for in 12 092 patients with STEMI [101]. Lytic therapy was given to
years. In the MATRIX trial, randomized comparison of post-​PCI 45% of patients (n = 5436), most of whom received a non-​fibrin-​
bivalirudin infusion versus no infusion failed to show benefits specific agent, while 37% underwent primary PCI. In the lytic-​
of the post-​PCI infusion. However, a recent subanalysis showed treated patients, fondaparinux was associated with a significant
that post-​PCI full-​dose infusion was associated with improved 21% lower risk of death or MI, compared to standard heparin or
outcomes when compared with no or low-​dose post-​PCI infu- placebo [105]. The risk of bleeding was also considerably lower.
sion or heparin [99]. This provides support for the American and In contrast, in PCI patients, fondaparinux was associated with a
European guidelines and FDA label stating that when bivalirudin non-​significant 1% higher incidence of death or MI. In patients
is used, a regimen with a post-​PCI infusion at full dose (1.75 mg/​ not receiving any reperfusion therapy, fondaparinux was again
kg/​hour) for 4 hours should be preferred. found to be superior to UFH [106].
506 CHAPTER 3 9   Fibrinolytic, antiplatelet, and anticoagulant drugs in acu te coronary syndromes

Because of its excellent efficacy/​safety profile, fondaparinux Syndrome (ATLAS ACS 2) trial, stabilized ACS patients were ran-
is recommended by the ESC guidelines for use in patients with domized to placebo or twice-​daily doses of either 2.5 mg or 5 mg
NSTE-​ACS (Class  IA) [76]. In STEMI patients, the ESC guide- rivaroxaban, a quarter to half of the daily dose tested in AF pa-
lines recommend fondaparinux as adjunctive therapy in patients tients [111]. Rivaroxaban significantly reduced the risk of death,
treated with streptokinase (Class IIa, LoE B) and for conservatively MI, or stroke. When assessed separately, both doses significantly
treated patients, but recommend against the use of fondaparinux reduced the primary efficacy endpoint, but only the 2.5 mg twice-​
in primary PCI (Class III, LoE B)  [8]‌. daily dose significantly reduced the risk of cardiovascular (HR
0.66, 95% CI 0.51–​0.86) and all-​cause death. Conversely, MI, but
not death, was significantly lower with the 5 mg twice-​daily dose
Oral anticoagulants in ACS versus placebo. Major bleeding complications, although infre-
quent, were almost four times more frequent with rivaroxaban,
Anticoagulation therapy beyond the acute phase might be an especially with the 5 mg twice-​daily dose, and consistent across
attractive approach to improve outcome, and several oral anti- the key subgroups.
coagulants have been studied for long-​term treatment after ACS. Low-​dose rivaroxaban (2.5 mg twice daily) was directly
compared to low-​ dose aspirin in 3037 ACS patients on ei-
Vitamin K antagonists ther clopidogrel or ticagrelor in the Safety of Rivaroxaban
Oral VKAs were tested in several ACS trials in the pre-​clopidogrel Versus Acetylsalicylic Acid in Addition to Either Clopidogrel
era. These studies suggested that a moderate to high dose of VKAs, or Ticagrelor Therapy in Participants With Acute Coronary
on top of aspirin, further reduced the risk of ischaemic complica- Syndrome (GEMINI ACS 1)  trial [112]. Major bleeding com-
tions [107, 108]. Unfortunately, there was a price to pay—​VKAs plications were similar in both groups (5%, HR 1.09, 95% CI
were associated with up to 3-​fold increase in bleeding complica- 0.80–​1.09), as were the rates of ischaemic events. After these
tions. As a consequence, VKAs are rarely used in standard care disappointing results, there are currently no plans for further
for ACS patients without a formal indication for chronic oral studies with the combination of low-​dose rivaroxaban with a
anticoagulation. P2Y12 inhibitor (without aspirin).
Taken together, the trials assessing NOACs after ACS invari-
Oral direct thrombin inhibitors ably demonstrated a dose-​dependent increase in bleeding com-
The oral thrombin inhibitor dabigatran was studied in stabilized plications [113]. Only very low-​ dose rivaroxaban appeared
ACS patients on DAPT in the phase II Randomised Dabigatran to have an acceptable efficacy/​safety balance [111]. Low-​dose
Etexilate Dose Finding Study in Patients With Acute Coronary rivaroxaban, but not apixaban, has been approved for secondary
Syndromes (REDEEM) trial [109]. A total of 1861 patients were prevention in ACS patients. The ESC guidelines suggest that low-​
randomized to placebo or 50, 75, 110, or 150 mg dabigatran twice dose rivaroxaban (2.5 mg twice daily for approximately 1  year)
daily at a mean of 7.5 days after their initial event. Although the may be considered in ACS patients with no prior stroke/​TIA
overall incidence of major bleeding events was relatively low, there and at high ischaemic risk, as well as at low bleeding risk, re-
was a dose-​dependent 2-​to 4-​fold increase in the risk of major or ceiving aspirin and clopidogrel after discontinuation of parenteral
clinically relevant minor bleeding events. Ischaemic events were anticoagulation [30].
infrequent overall and numerically lower with the two highest
doses, compared to the 50 mg dose arm. To date, a large phase III
trial to evaluate outcomes with dabigatran in this setting has not Antiplatelet therapy in ACS
been planned.
patients with an indication for oral
Oral factor Xa inhibitors anticoagulation
Two oral FXa inhibitors on the market (apixaban and rivaroxaban) When patients with AF or other indications for oral
have been evaluated in patients with a recent ACS. In the Apixaban anticoagulation experience an ACS, the need for adding one or
for Prevention of Acute Ischemic Events 2 (APPRAISE-​2) trial, two antiplatelet agents to oral anticoagulation arises. There is a
apixaban 5 mg twice daily was tested in high-​risk ACS patients, wide variety of possible strategies, not only with regard to the
a dose similar to that tested in AF patients [110]. The trial was number and type of agents, but also the duration of the combin-
terminated prematurely because of an increase in major bleeding, ation treatment. Adding antiplatelet agents to oral anticoagulants
with no counterbalancing benefit in ischaemic events. Major evidently increases the bleeding risk and there appears to be no
bleeding complications were more than twice as frequent with safe therapeutic window [114]. The difficulty lies in balancing
apixaban than with placebo; there were also more fatal bleeding the thromboembolic versus the bleeding risk in the individual
and ICH with apixaban. The increased risk of bleeding and lack patient.
of benefit were consistent among all key subgroups of patients. Several randomized trials have shown that in stable and
In the Anti-​Xa Therapy to Lower Cardiovascular Events in unstable patients with AF undergoing PCI ± stenting, dual
Addition to Standard Therapy in Subjects with Acute Coronary antithrombotic therapy with a P2Y12 inhibitor (clopidogrel) and
 Thi en op y ri di n es a n d proton pum p  i n h i b i tor s 507

either a VKA [What is the Optimal antiplatElet & Anticoagulant risk of 30-​day mortality [120,  121]. Vice versa, lower rates of
Therapy in Patients With Oral Anticoagulation and Coronary in-​hospital bleeding complications with newer antithrombotic
StenTing (WOEST)] [115] or a NOAC (PIONEER AF-​ PCI agents appear to be associated with improved outcome after
with rivaroxaban, REDUAL PCI with dabigatran, AUGUSTUS discharge [102, 122]. Age, low body weight, and renal impair-
with apixaban) [29, 116, 117] was safer with respect to bleeding ment appear to be strong predictors of bleeding complications
than triple antithrombotic therapy. Furthermore, the incidence in ACS [123]. Overdosing of antithrombotic agents also plays a
of ischaemic events was similar with dual and triple therapy major role, certainly in the elderly [124], as well as use of mul-
[29, 116,  117]. However, none of these studies were sufficiently tiple antithrombotic drugs [125]. Transfusions are independ-
powered for efficacy and the populations studied were a mixture ently associated with poorer outcome after ACS and need to be
of stable CAD and ACS patients. Data of the Edoxaban-​Based avoided, if possible [124]. Finally, the risk of procedure-​related
Antithrombotic Regimen in Patients With Atrial Fibrillation bleeding can be minimized by using a transradial approach
(ENTRUST-​AF) PCI trial are expected soon and will demon- [126, 127].
strate the safety (and efficacy) of edoxaban in a dual-​therapy
strategy versus conservative triple therapy and add to the current
knowledge. Thienopyridines and proton
The most recent ESC guidelines still recommend that for most
patients, triple therapy in the form of oral anticoagulation, as- pump inhibitors
pirin, and clopidogrel should be considered for 1–​6 months after GI haemorrhage is the most common serious bleeding compli-
an ACS [36, 118]. The optimal duration of such triple therapy de- cation from the use of long-​term antiplatelet therapy, and PPIs
pends on the patient’s ischaemic and bleeding risks. In patients might reduce this risk. Both clopidogrel and prasugrel are pro-​
with a high ischaemic risk and a low bleeding risk, triple therapy drugs and require hepatic metabolism by the cytochrome P450
is still the recommended treatment for the first month after an system to form their active compounds. A few clinical and mech-
ACS; it may also be extended to 3 (in rare cases also to 6) months anistic studies indicated that the formation of the active metab-
[36]. After this period of triple therapy, oral anticoagulation plus olite of clopidogrel could be hampered by some (but not all) PPIs
aspirin or clopidogrel should be considered up to 12  months [128–​131]. In contrast, other studies have not found any clin-
after PCI. Neither prasugrel nor ticagrelor have been sufficiently ical evidence of an interaction between PPIs and clopidogrel or
tested in the above-​mentioned trials and are therefore not recom- prasugrel [132–​134].
mended to date [118] for this indication. After 1  year, it is in- Importantly, drug–​ drug interaction studies showed that
dicated to maintain oral anticoagulation alone. In cases of high omeprazole and esomeprazole would appear to have the highest
bleeding risk, dual therapy (oral anticoagulation plus a P2Y12 propensity for clinically relevant interactions, while lansoprazole
inhibitor) may be considered from the time of discharge and has an intermediate probability and pantoprazole and rabeprazole
continued for 1  year, and thereafter oral anticoagulation alone have the lowest [135]. No interaction between concomitant use of
[36,  118]. When NOACs are used, in general, a dose reduction PPIs and prasugrel or ticagrelor has been described.
below the approved dose is not recommended [118]. The dose The Clopidogrel and the Optimization of Gastrointestinal
intensity of VKAs should be carefully monitored with INRs in the Events Trial (COGENT) was a randomized, double-​ blind,
lower part of the recommended range (2–​2.5). double-​dummy, placebo-​controlled phase III study of the efficacy
Interestingly, there are different perspectives in Europe [36, 118] and safety of a fixed-​dose combination of clopidogrel (75 mg) and
and North America [119] on when, and in which patients, dual omeprazole (20 mg), as compared with clopidogrel alone [136].
therapy should be initiated. From the North American perspec- Patients were eligible if the use of clopidogrel therapy with con-
tive, it is suggested that triple therapy should be used in-​hospital comitant aspirin was anticipated for at least the next 12 months.
but de-​escalated to dual therapy (with oral anticoagulation and Patients at high risk of GI bleeding were excluded. The study was
clopidogrel) at hospital discharge for 6–​12 months, depending on prematurely stopped with a total of 3761 patients, instead of the
the bleeding risk, followed by oral anticoagulation alone in most planned 5000, due to financial reasons. The pre-​specified primary
of the cases [119]. GI efficacy endpoint occurred in 1.1% of patients on omeprazole
and in 2.9% of those on placebo at 180 days after randomization
(HR 0.34, 95% CI 0.18–​0.63; P <0.001). Furthermore, there was
Antithrombotic agents and no significant increase in the risk of cardiovascular events with
concomitant use of clopidogrel and omeprazole, and the rate of
bleeding complications serious AEs or overall AEs did not differ significantly between the
Bleeding complications appear to be inherent to antithrombotic two groups [136].
therapy, especially when several agents are combined. It is in- Based on this background, current ESC guidelines include
creasingly clear, however, that not only major, but also non-​life-​ the use of PPI among strategies to minimize the risk of bleeding
threatening, bleeding has an impact on outcome. In-​hospital under DAPT by stating that a PPI in combination with DAPT is
bleeding complications are associated with up to 5-​fold higher recommended (Class 1, LoE B) and underline that pantoprazole
508 CHAPTER 3 9   Fibrinolytic, antiplatelet, and anticoagulant drugs in acu te coronary syndromes

and rabeprazole might have the lowest propensity for clinically

relevant drug–​drug interactions [36]. Conclusion
Antithrombotic therapy remains a major cornerstone in short-​
and long-​term management of ACS. With so many antiplatelet
New antithrombotic agents and anticoagulant agents from which to choose, deciding
on the horizon upon the most effective combination of drugs, while at the
same time also the safest, as well as the most optimal timing
An ideal antithrombotic agent would combine optimal efficacy and duration of therapies, may appear to be a bewildering task
with minimal bleeding diathesis. The search for such an ideal for the practising cardiologist. Fortunately, the frequently up-
agent is still ongoing, and new antiplatelet agents that select- dated ESC guidelines are here to guide us through this pro-
ively inhibit arterial thrombosis without interfering with normal cess. Nevertheless, only a well-​informed bedside physician can
haemostasis are on the horizon. They interfere with the inter- make a balanced decision for the individual patient, taking
action of vWF with GPIbα or are directed against GPVI, GPIIb/​ into account his or her risk of ischaemic events [141], risk of
IIIa (integrin αIIbβ3), the thrombin receptor PAR-​1, and the ADP bleeding, comorbidities, and preferences, as well as the charac-
receptor P2Y12, respectively [137]. teristics of the different drugs.
The development of new anticoagulant drugs is also rapidly ex- Despite the proven efficacy of antithrombotic therapy, residual
panding, targeting other factors in the coagulation cascade such morbidity and mortality in ACS remain considerable. A  con-
as FXI and FXII [138]. FXI has emerged as a particularly prom- tinuous challenge for antithrombotic strategies in ACS is to fur-
ising target for new anticoagulants that may be even safer than ther reduce the risk of ischaemic complications without increasing
the NOACs [139]. the risk of bleeding. One attractive approach is the development
Recently, GPVI-​mediated platelet adhesion and activation have of new drugs with a better benefit/​risk profile. As important as
been shown to be important in atherothrombotic diseases like MI developing new agents, however, is the need to continue ques-
and stroke, while they do not play an important role in physio- tioning the existing agents, treatment strategies, or patterns that
logic haemostasis. Inhibition of this pathway seems promising might have become less effective or less safe with the arrival of
and is currently under clinical evaluation [140]. newer drugs or interventional approaches over time.

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 CHAPTER 40

Mechanical complications
of myocardial infarction
Elena Puerto and Héctor Bueno

Contents
Summary  513 Summary
Introduction  514 Mechanical complications of acute myocardial infarction are those caused by rup-
Mechanical complications caused by tures or geometrical distortions of cardiac structures. Cardiac ruptures are cur-
cardiac rupture  514 rently rare complications, with <1% in the era of reperfusion therapy, but often
Epidemiology: incidence and mortality  514
Pathophysiology  514 with catastrophic consequences, and include free wall rupture (the most frequent),
Risk factors  514 interventricular septal rupture, and papillary muscle rupture. The clinical pres-
Management  514 entation may vary from unusually milder presentations to sudden presentation
Free wall rupture  515
with severe hypotension, cardiogenic shock, or electromechanical dissociation.
Introduction  515
Epidemiology: incidence and mortality  515 Therefore, immediate diagnosis is key, generally by echocardiography, followed by
Forms of presentation: pathophysiology and resuscitation and/​or haemodynamic support (pharmacological or mechanical). In
clinical presentation  515
Acute rupture  515
the majority of cases, these complications require urgent surgical repair. In some
Subacute rupture  515 cases, percutaneous therapies may be a valid alternative.
Pseudoaneurysm  515 Mechanical complications due to geometrical distortion include functional is-
Management of acute and subacute
ruptures  516 chaemic mitral regurgitation, ventricular aneurysms, and intraventricular throm-
Diagnosis  516 bosis. These complications are more frequent than ruptures and, in general, less
Echocardiography  516
Diagnostic pericardiocentesis  516
severe, ranging from accidental findings by imaging techniques in asymptomatic
Ventriculography  516 patients to advanced heart failure. Most often, these complications can be treated
Right heart catheterization  516 medically and occasionally may need surgical therapy.
Treatment  516
Preventive measures  516
Supportive treatment  516
Medical treatment  516
Pericardiocentesis  516 Support treatment  521 Functional ischaemic mitral
Surgical repair  517 Medical treatment  521 regurgitation  525
Timing of surgery  517 Mechanical circulatory support  521 Introduction  525
Surgical technique  517 Intra-​aortic balloon pump  521 Epidemiology  525
Outcomes after surgery  517 Impella®  521 Pathophysiology  525
Management strategy for FWR  517 Veno-​arterial extracorporeal Clinical presentation  526
Management of pseudoaneurysms  517 membrane oxygenator  521 Diagnosis  526
Management strategy for VSR  522 Treatment  526
Ventricular septal rupture  517 Left ventricular aneurysm  526
Papillary muscle rupture  523
Introduction  517 Introduction  526
Epidemiology: incidence and mortality  518 Introduction  523
Epidemiology  526
Pathophysiology  518 Epidemiology: incidence and mortality  523
Clinical presentation  527
Clinical presentation  518 Pathophysiology  523
Diagnosis  527
Diagnosis  519 Clinical presentation  523
Treatment  527
Treatment  519 Diagnosis  523
Intraventricular thrombi  527
Type of repair  519 Treatment  524
Introduction  527
Surgical therapy  519 Support treatment  524
Epidemiology  527
Surgical technique  519 Type of repair  524
Clinical presentation  527
Outcomes after surgery  520 Surgical repair  524
Diagnosis  527
Technique  524
Percutaneous septal defect Treatment  527
closure  520 Timing of surgery  524
Outcomes after surgery  524 Acknowledgements  527
Devices and technique  520
Selection of candidates  521 Percutaneous repair  524 References  528
Outcomes after percutaneous Mechanical complications caused by Additional online material  530
closure  521 geometrical distortion  525
514 CHAPTER 40   Me c ha nical c omplicat ions of m yo ca rdia l  i n fa rcti on

ECM proteins are deposited, increasing the tensile strength of the

Introduction necrotic area again. Late reperfusion with fibrinolysis may cause
intramyocardial haemorrhage and increase the risk of CR in the
There is no uniform definition of mechanical complication (MC)
elderly.
after AMI. The more strict definition includes only cardiac rup-
Some authors postulated that genetic variations in the
ture (CR), according to the approach used in the last ESC STEMI
metalloproteinase system may contribute to develop myocardial
guidelines [1]‌. In this chapter, we use a wider classification of
rupture following AMI [13], but this has not been confirmed.
MCs, including CR and complications caused by geometric ven-
The renin–​angiotensin system is activated during the remodel-
tricular distortion:
ling process [14], with an upregulation of angiotensin-​converting
1. MCs caused by CR: enzyme (ACE) activity, producing local angiotensin II that stimu-
(i) Free wall rupture (FWR). lates fibrogenesis.
(ii) Ventricular septal rupture (VSR). The timing of presentation is probably determined by the histo-
(iii) Papillary muscle rupture (PMR). logical changes occurring in the myocardium [15, 16]:
2. MCs caused by geometric distortion: ◆ Early (within the first 24–​48 hours after onset of AMI): roughly
(i) Functional ischaemic mitral regurgitation (FIMR). half of CRs occur within the early phase, before the inflam-
(ii) Ventricular aneurysm. matory process starts, when weakening of the myocardium is
(iii) Intraventricular thrombi. caused by apoptosis of cardiomyocytes.
◆ Late (beyond 24–​ 48 hours):  erosion of the infarcted area,
occurring within the first 2 weeks when neutrophilic infiltration
and coagulation necrosis predominate, as a result of the infarct
Mechanical complications caused expansion and/​or defective cellular and ECM remodelling.
by cardiac rupture ◆ Very late: perforation of thinned areas taking place beyond the
first 2 weeks.
Epidemiology: incidence and mortality
CR is a major and catastrophic complication of AMI. Although Risk factors
the incidence of MCs is not high, their extremely high lethality
MCs occur more often during first-​time AMIs with transmural
makes them the second leading cause of mortality in patients
necrosis [17] and persistent coronary occlusion [18,  19], unless
with AMI, after pump failure [2]‌. CR is more common in patients
collateral circulation is present [20]. The risk of MCs increases
with STEMI (0.9%) than in those with non-​STEMI (0.17%) or UA
with age [3, 21,  22] and in women [3, 21,  22]. Situations that
(0.25%) [3], but its incidence has decreased in STEMI patients
increase LV wall stress in the early phase, such as high blood
in parallel with increased use of reperfusion therapy, particularly
pressure, physical activity, or physical efforts for vomiting or defe-
after the widespread use of primary PCI, falling from 6% to <1%
cation or agitation, increase the risk of FWR [16, 23]. The use of
[3–​5]. The most common type of CR is LV FWR (0.5–​2% of MIs)
anti-​inflammatory drugs in the early phase of MI has been de-
[3, 4, 6]. VSR and PMR occur less often (0.17–​0.31% [2, 3, 7–​9]
scribed as a risk factor [24, 25], while in the pre-​reperfusion era,
and 0.25% [2, 10], respectively). In the last years, mortality due to
the early use of β-​blockers reduced the risk of rupture [26] (see
MCs has shown a significant decrease in hospital [3], at 30 and
E Table 40.1). The presence of collateral circulation [20] and the
90 days [2], with a significant drop in fatality (from 94% to 75%
achievement of early and sustained reperfusion reduce the risk
between 1997 and 2008) in the general population [4], but no sig-
of MCs [2, 27]. Primary PCI reduces the risk of CR, compared to
nificant change in the oldest patients (from 87% to 82% between
thrombolysis, in patients with AMI [5, 28]. Although thrombo-
1988 and 2008) [11].
lytic therapy promotes reperfusion and, in general, reduces the
risk of CR, it may increase its risk in certain situations, particu-
Pathophysiology larly with late fibrinolysis [28,  29], especially in patients older
A persistent myocardial ischaemic insult triggers cardiomyocyte than 75 years [30]. Delayed admission (>24 hours) also increases
death [12,  13], initially via the apoptotic pathway and later by the risk of CR [31].
coagulative necrosis, both activating cardiac healing, which in-
cludes infiltration of inflammatory cells, ECM degradation, fun- Management
damentally by MMPs, and new collagen synthesis. Over this
In general, the abrupt development of hypotension or CS in pa-
process, the combination of extensive myocardial damage with a
tients without preceding heart failure or of cardiac arrest due
high collagenolytic activity can result in a temporary loss of the
to electromechanical dissociation must be a call to rule out CR.
structural support and wall thinning, which, added to increased
Immediate auscultation searching for new-​onset murmurs or
wall stress, may favour the occurrence of myocardial disruption.
pericardial rub, with immediate bedside echocardiographic
This usually occurs at the transition zone between the infarcted
examination, is mandatory to rule out cardiac tamponade, VSD,
myocardium and the adjacent hyperkinetic non-​necrotic areas
or severe MR after haemodynamic deterioration. CPR and/​or
where shear stress is maximal. Two or 3  days after AMI, new
haemodynamic stabilization are often needed. When any type of
 Free wa l l   rup t ure 515

Table 40.1  Factors associated with the incidence of cardiac rupture

Factors associated with increased risk Factors associated with reduced risk
Baseline characteristics Advanced age
Female sex
Presentation First episode of AMI
Transmural necrosis
Persistent ST-​segment elevation
Early Q wave development
Myocardial circulation Total occlusion of culprit artery (TIMI flow 0) Past history of MI or angina
Lack of collateral circulation Extensive collateral circulation
Reperfusion therapy Ineffective reperfusion (TIMI flow <2–​3) Complete, sustained reperfusion
Late reperfusion (≥24 hours after symptom onset) Early reperfusion
Thrombolytic therapy in older patients*
Wall stress High blood pressure during early phase
Physical efforts in the early phase (physical activity,
agitation, vomiting, defecation)
Drugs Early use of steroidal and non-​steroidal anti-​ Early use of β-​blockers?
inflammatory drugs
*
Only for FWR.

CR is confirmed, interventional cardiology and cardiothoracic extremely high in-​hospital mortality rate of over 80–​90% [3, 35].
surgery consults are indicated to plan the timing (emergent, ur- By contrast, patients who can reach surgical treatment had ac-
gent, and occasionally elective) and technique of repair (surgical ceptable long-​term survival (40–​50%) [36].
or percutaneous) of the ruptured structure. The clinical course,
diagnosis, and specific treatment of each type of CR are described Forms of presentation: pathophysiology and
in detail in the following sections. clinical presentation
Acute rupture
An acute rupture is a catastrophic presentation, which implies
Free wall rupture an abrupt tear of the myocardium and a massive pericardial ef-
fusion, causing sudden death due to electromechanical dissoci-
Introduction ation or acute cardiac tamponade and CS within minutes. This
FWR is a spontaneous perforation through an infarcted area in is accompanied by cyanosis of the neck and face and intense
the myocardial wall, which implies penetration of blood into the jugular venous congestion. Sometimes, severe CP shortly pre-
pericardial cavity. FWR is most commonly located at the LV wall, cedes haemodynamic collapse and death.
but other rare locations, such as RV or atrial rupture, have been
described [32, 33].
Subacute rupture
FWRs can be divided into: In about one-​third of patients with LV FWR, the course is sub-
acute [32,  37]. It means that FWR is partially contained by a
◆ Complete FWRs: disruption of the three layers of the ventricular
haematoma, with slow bleeding into the pericardium over hours
wall (endocardium, myocardium, and epicardium). They com-
or days [32], which produces a progressive pericardial effusion,
prise acute rupture, subacute rupture, and pseudoaneurysms.
better tolerated, with less severe haemodynamic compromise and
◆ Incomplete FWRs:  intramyocardial haematoma or dissection
progressive hypotension, while evolving to cardiac tamponade.
of the myocardium while keeping the integrity of the endocar-
This clinical course is associated with transient, prolonged, or re-
dium and/​or epicardium, without direct communication with
current CP with pericarditic characteristics as blood irritates the
the pericardial cavity. Up to 5% of post-​mortem studies after MI
present these findings [34]. pericardium. Advanced stages are characterized by hypotension,
transient bradycardia, and syncope. Alarming symptoms that
Epidemiology: incidence and mortality may shortly precede the event are repetitive emesis and agitation.

FWR is the second cause of death in hospitalized patients with Pseudoaneurysm

AMI. The incidence was higher in the pre-​reperfusion era. In the Pseudoaneurysm is a chronic contained FWR, resulting after the
era of primary PCI, LV FWR occurs in 0.5–​2% of patients with sealing of the tear, initially by a haematoma and later by fibrin
MI [3, 4,  6], although the incidence may be higher due to the deposits and pericardial adhesions. Old series estimated the inci-
unknown contribution of out-​of-​hospital sudden death. Among dence in 25% of AMIs [38, 39], but this complication is much less
all CRs, FWR has the poorest prognosis, associated with an frequent in the reperfusion therapy era. These false aneurysms
516 CHAPTER 40   Me c ha nical c omplicat ions of m yo ca rdia l  i n fa rcti on

have a tendency to burst but also can enlarge significantly, gen- Occasionally, leaking into the pericardial space can be observed
erally allocating thrombi inside that may cause systemic embol- using contrast agents with echocardiography [41].
ization [39]. Pseudoaneurysms are usually accidental findings in Diagnostic pericardiocentesis
imaging techniques of the heart in asymptomatic patients, even This procedure is usually performed as a therapeutic strategy, but
months or years after an AMI. In some cases, they can be sus- in stable patients in whom clinical and echocardiographic find-
pected by the presence of a persistent loud pericardial friction rub ings are inconclusive for FWR and the indication for surgery is
and occasionally pansystolic murmurs. uncertain, pericardiocentesis constitutes a pillar diagnostic tool
to confirm the presence of a haemopericardium. Extraction of
Management of acute and subacute ruptures haemorrhagic fluid, with a haematocrit of >25%, strongly sug-
Diagnosis gests the definitive diagnosis.
Patients who present with an acute catastrophic rupture usually Ventriculography
die immediately presenting with electromechanical dissociation Ventriculography is only useful when leakage through a myo-
and are diagnosed by the presence of massive pericardial effusion cardial tear is ongoing, but this technique is not recommended if
by echocardiography during CPR or on post-​mortem examin- FWR is suspected due to the risk of completing the rupture as a
ation. Otherwise, the diagnostic approach can be made using dif- result of the sudden increase in intraventricular pressure or local
ferent techniques as follows. manipulation with the catheter.
Echocardiography
Right heart catheterization
After the development of abrupt hypotension, bradycardia, RHC has been relegated by echocardiography, because it is less
or loss of consciousness, bedside TTE should be performed sensitive and the typical findings of cardiac tamponade (deep
immediately. negative X wave, blunted Y waveforms, and equalization of dia-
Findings that suggest ventricular FWR on echocardiography stolic pressures between cardiac chambers) can be absent due
(see E Figure 40.1) include [32]: to selective chamber compression by clots or early compression
◆ Pericardial effusion of >10  mm (sensitivity 100% and spe- of the RV can occur because of a significant increase in LV end-​
cificity 77%). A  differential diagnosis of pericardial effu- diastolic pressure.
sion after MI must be established with post-​MI pericarditis
and haemopericardium after thrombolysis (approximately Treatment
1%) [40]. Preventive measures
◆ Echo-​dense masses overlying the heart, corresponding to an or- In addition to procuring the earliest and sustained reperfusion,
ganized thrombus. ideally with primary PCI, blood pressure should be controlled
◆ Signs of echocardiographic compromise:  right atrial or ven- with ACE-​Is and β-​blockers. Limitation of physical activity and
tricular wall compression and inferior vena cava distension prevention of undue efforts (e.g. laxatives for constipation, seda-
without respiratory variation. tives for anxiety) during the first 48 hours should be promoted,
particularly in patients with a high risk of rupture. Steroidal and
◆ Identification of the exact site of the myocardial tear, which is
non-​steroidal anti-​inflammatory agents, except aspirin, should be
hard to find but a pathognomonic finding.
avoided.
Supportive treatment
Medical therapy and pericardiocentesis are aimed at achieving
haemodynamic stability as a bridge to surgery.
Medical treatment
Recovery of severe haemodynamic compromise should start with
rapid fluid replacement with saline or colloidal solutions until ur-
gent pericardiocentesis and surgical repair can be performed.
Pericardiocentesis
Immediate pericardiocentesis has a therapeutic role in relieving
life-​threatening cardiac tamponade, thus allowing enough time
for surgical intervention. It is recommended to drain a small
quantity of pericardial fluid (10–​50 mL), sufficient to achieve
haemodynamic recovery, but at the same time keeping high
pressure inside the pericardial cavity to promote sealing of the
bleeding point. It is a temporal measure because bleeding can
Figure 40.1  Subcostal view of 2D echocardiography showing severe echo-​ recur rapidly or blood clotting inside the drainage tubing may
dense pericardial effusion, suggestive of haemopericardium, in a patient with prevent further evacuation of pericardial fluid and more than one
confirmed subacute LV FWR on autopsy. procedure may be needed.
 Ven tri cu l a r sep ta l   rup t ure 517

Surgical repair ◆ Cardiac tamponade with haemodynamic collapse or severe CS. In

Timing of surgery patients with severe CS, urgent pericardiocentesis must be per-
Urgent surgical closure of acute and subacute wall rupture needs formed, accompanied by a rapid IV infusion of fluids as prepar-
to be considered as soon as diagnosed (see E Figure 40.2). ation for emergent surgery.
Surgical technique ◆ Cardiac tamponade with moderate haemodynamic compromise.
Occasionally, in patients with hypotension without systemic
Surgical techniques to repair ruptured myocardium have evolved
hypoperfusion, stabilization can be achieved with fluid over-
over years, currently including less aggressive approaches [42]:
load and eventually vasoactive drugs. In these cases, it is re-
◆ Repair of the ventricle tear using a direct pledgeted suture commended to avoid pericardiocentesis, as it may precipitate
technique. further bleeding into the pericardial space and progression
◆ Infarctectomy and patching with Teflon™ or Dacron™. to severe cardiac tamponade, and proceed to urgent surgical
◆ Covering the ventricular perforation with a synthetic or peri- repair.
cardium patch adhered with biologic glue or sutures. ◆ Haemopericardium without haemodynamic compromise. In
haemodynamically stable patients, blood pressure control is es-
In cases of active major bleeding, CPB should be used and sential (systolic blood pressure target: <100–​120 mmHg), as well
sutureless procedures must be avoided to prevent detachment of as absolute rest, avoiding of any physical exercise and proceeding
the patch. CABG or percutaneous reperfusion might be estab- to urgent surgery.
lished, depending on the emergency of the repair. Since under-
going coronary angiography and CPB might delay reconstruction, Management of pseudoaneurysms
in terms of survival, indication is controversial.
Pseudoaneurysms are usually incidental findings in elective
Outcomes after surgery echocardiographic studies. MRI has superior image quality and
Re-​rupture has been described in 17%, especially after sutureless higher spatial resolution than echocardiography and may be
repair [43]. Despite advances in surgical techniques, post-​ useful for the confirmation of ventricular pseudoaneurysms [46].
operative in-​hospital mortality ranges from 12% to 35% [37, 42, Disruption of the epicardial fat layer, absence of parietal myo-
44, 45], being higher in acute ruptures. Nevertheless, among sur- cardial tissue, with sharp discontinuity of the myocardium at the
vivors after successful repair, 5-​and 10-​year survival is 81% and connection site, and a relatively narrow neck help to differentiate
76%, respectively [37]. a pseudoaneurysm from a true aneurysm. Surgical repair may be
considered in these cases due to the risk of re-​rupture.
Management strategy for FWR
Management of patients will depend on the clinical presentation
and haemodynamic compromise (see E Figure 40.3). Ventricular septal rupture
◆ Cardiac arrest due to electromechanical dissociation. In case
of cardiac arrest, immediate cardiac massage and ALS must
Introduction
be initiated to restore ROSC, in combination with rapid VSR is a disruption of the interventricular septum due to is-
volume loading and bedside emergent pericardiocentesis. chaemic necrosis, causing an acute left-​to-​right shunt. According
Endotracheal intubation and mechanical ventilation can be re- to the morphology, VSRs are classified as:
quired. Anecdotal survivors must go to emergent surgery. ◆ Simple:  a single straight defect with its orifices situated ap-
proximately at the same level on both sides of the septum (see
E Figure 40.4).
◆ Complex: a tortuous tear of the necrotic myocardial tissue, with
openings located at different levels or a set of sinuous intercon-
nected channels.
The area where the defect occurs is related to the culprit ar-
tery. Anterior and apical ruptures are more usual after occlu-
sion of the LAD artery, whereas inferior ruptures, traditionally
named as posterior, are often secondary to thrombosis of the pos-
terior descending artery. In most series, the incidence of VSRs is
similar in anterior and non-​anterior MI [47]. Inferior VSRs (see
E Figure 40.5) have a notably worse prognosis [48], since they
are larger, anatomically more complex, usually located in the
basal segment, and more difficult to repair due to difficult sur-
gical access. Inferior VSRs are more frequently associated with
Figure 40.2  Surgical view of subacute LV FWR during reconstruction. FWR [7]‌or RV systolic dysfunction [9].
518 CHAPTER 40   Me c ha nical c omplicat ions of m yo ca rdia l  i n fa rcti on

Free wall
rupture

CPR ± Yes Cardiac No Haemodynamic

pericardiocentesis arrest? instability?

Profound No

Yes

Pericardiocentesis Medical support

(volume load, etc.)

Emergent Urgent
surgery surgery

Figure 40.3  Algorithm for the management of LV FWR.

Epidemiology: incidence and mortality Pathophysiology

Before the implementation of reperfusion therapy, the incidence The immediate effect of VSR is shunting of oxygenated blood
of VSRs was roughly 1–​2% of AMIs [49]. However, since the from the LV, the highest-​pressure chamber, to the RV [52]. The
introduction of fibrinolysis, its incidence decreased to 0.2% [9]‌ magnitude of the shunt determines the haemodynamic com-
and ranges between 0.17% and 0.31% in the primary PCI era [2, promise of the patient, which, in turn, depends on the size of
3, 7–​9]. Overall, in-​hospital mortality varies widely according to the defect and the pressure gradient between the two chambers,
the therapeutic strategy. As evidenced in the GUSTO-​I trial, mor- mainly conditioned by the SVR and the LV afterload. Since the
tality after conservative treatment is extremely high at 94–​96% shunt occurs mainly in systole, RV volume overload is prefer-
[9]. The most important mortality predictors are CS (roughly entially directed to the pulmonary circulation, contributing to
100% of mortality) [3], the location of AMI, and the gap between pulmonary congestion and the increase of the LV end-​diastolic
the onset of VSR and repair [50, 51]. RV dysfunction has a signifi- volume and pressure, which, in turn, contribute to the deterior-
cant impact on prognosis due to its influence on haemodynamic ation of LV dysfunction already caused by the extension of the
stability and post-​operative survival. infarct. As a consequence of the shunt, the anterograde systemic
flow is reduced, resulting in systemic hypoperfusion, CS, and re-
fractory multiple organ failure.

Clinical presentation
Patients may present with CP and ST-​segment re-​elevation at the
moment when VSR actually occurs. In such instance, ausculta-
tion of a new harsh pansystolic murmur along the left sternal
border, present in 90% of patients, should trigger clinical sus-
picion. Differential diagnosis should include acute papillary
muscle dysfunction or rupture. Signs of pulmonary congestion
with rales over the lung fields, systemic congestion with dis-
tended jugular veins, and signs of shock may be evidenced. From
then, clinical presentation will depend on the volume of the
shunt and biventricular function, ranging from asymptomatic,
haemodynamically stable patients to those with progressively
Figure 40.4  Subcostal four-​chamber view of 2D echocardiography showing increasing dyspnoea that rapidly deteriorates haemodynamically
simple posterior VSR. or sudden-​onset CS.
 Ven tri cu l a r sep ta l   rup t ure 519

(a) (b)

Figure 40.5  (A) Short-​axis subcostal view of 2D echocardiography showing posterior basal VSR. (B) Doppler colour echocardiography showing left-​to-​right
shunt through the anatomical defect.

Diagnosis healthy lungs to be fully oxygenated at 100%. Transpulmonary

aortic thermodilution measurement of cardiac output, such as
Doppler echocardiography is the gold standard diagnostic tech-
the lithium dilution cardiac output (LiDCO) (London, UK) or
nique for VSR, with a reported sensitivity and specificity close to
pulse-​induced contour cardiac output (PiCCO) (Pulsion AG,
100% [53]. It allows the location of the perforation site, charac-
Munich, Germany) systems, may be more accurate [54].
terization of the morphology of the rupture, and estimation of
the degree of left-​to-​right shunt by assessing the flow across the
pulmonary and aortic valves (see E Figure 40.6). Integration of Treatment
these data with simultaneous quantification of RV and LV func- After confirming the diagnosis, prompt attempts should be made
tion helps plan the therapeutic strategy and specific repair tech- to stabilize the patient and plan septal repair by a multidiscip-
nique. In cases of poor acoustic window or inaccessible defects, linary heart team.
suspicion of VSR can be confirmed through 2D or 3D TOE or
with microbubble contrast agents (see z Video 40.1).
Type of repair
If echocardiographic data are unclear, alternative procedures The technique of repair choice will depend on two factors:
that can provide the definitive diagnosis are ventriculography, ◆ Operability of the patient.
which shows the contrast crossing through the septum, and ◆ Anatomic characteristics of the VSR.
RHC with evidence of a ‘step-​up’ in O2 saturation between blood
samples taken from the right atrium and pulmonary artery. An Currently, open surgical repair of a VSR is the treatment
oximetric gap of >7–​10% is suggestive of VSR. Graduation of of choice. If the patient is rendered unsuitable for surgical
the shunt can be calculated by the ratio between pulmonary flow closure, percutaneous device therapy should be considered in
(Qp) and systemic flow (Qs), based on the excess of pulmonary selected cases.
flow that represents the amount of blood passing through the de- Surgical therapy
fect. A Qp/​Qs of >2 suggests a large shunt, which is usually poorly Surgical technique
tolerated by patients. This ratio can be obtained in two ways [52]: Initially, surgical septal repair consisted of infarctectomy and re-
1. Echocardiography: (Qp = VTI pulmonary tract·π·r2; Qs = VTI construction of the septum and ventricular walls with Dacron™
aortic tract·π·r2). patches [55], but the ‘infarct exclusion’ technique has become
the current standard procedure since first described in 1990 [56].
2. Swan–​Ganz catheter and O2 saturation. PAC values in the pres- Exposure of the rupture area is made through an incision in the
ence of a VSR may overestimate right heart cardiac output using infarcted LV myocardium, parallel to the LAD artery or posterior
thermodilution because the measurement includes LV forward descending artery, respectively (see E Figure 40.7). Later, the de-
cardiac output plus blood flow coming from the left-​to-​right fect is covered with an oversized patch (bovine pericardial or pros-
shunt. Thus, calculation of the cardiac output and Qp/​Qs ratio is thetic patch), anchored with reinforced sutures to the adjacent
more accurate using the Fick equation [Qp/​Qs = (SaO2 –​ ScvO2)/​ non-​ischaemic myocardium, excluding the infarcted myocardium
(SpvO2 –​ SvO2)]. Samples are taken from the right atrium (ScvO2), from the high pressure of the LV cavity to prevent tearing of
pulmonary artery (SvO2), and systemic artery (SaO2), repre- endocardial tissue. In cases of anterior VSR, the patch can remain
senting aortic saturation. O2 saturation from the pulmonary veins intraventricular or brought out through the ventriculotomy and
(SpvO2) are not usually measured but assumed in a patient with incorporated in the closure line. Reconstruction of an inferior
520 CHAPTER 40   Me c ha nical c omplicat ions of m yo ca rdia l  i n fa rcti on

(a) (b)

Figure 40.6  (A) Apical four-​chamber view of 2D echocardiography showing anteroapical VSR. (B) Doppler colour echocardiography showing left-​to-​right
shunt through the anatomical defect.

VSR is even more challenging for several reasons: (1) inferobasal (the most important—​88% mortality versus 29%), location (an-
segments are hardly accessible; (2)  there is usual collateral in- terior 25–​29% versus posterior 42–​50%), time interval to surgery
volvement of the ventricular wall; and (3) there is possible com- (54.1% if within 7 days from MI versus 18.4% if >7 days following
promise of the papillary muscle, the function of which can be MI) [50], preoperative dialysis, age, female sex, preoperative
impaired due to its location in the ischaemic area or on the suture IABP, mitral insufficiency, and RV failure [9, 58]. Residual shunts
line, needing concomitant reconstruction or replacement of the after surgery are common (37%), and VSD recurrence occurs (be-
mitral valve. Once surgical repair of the VSR is complete, CABG tween 10% and 40%) due to perioperative failure of the repair,
is performed if necessary. However, there is controversy about the especially in the posterior location [64].
advantages of concomitant myocardial revascularization in the Percutaneous septal defect closure
surgical literature, with some studies suggesting a decrease in op- Given the high mortality rate and the technical complexity of sur-
erative mortality and improved long-​term survival [57–​59] and gical repair, percutaneous closure of VSR emerged as an alterna-
others showing no significant benefit [60]. tive to surgery in high-​risk patients with VSD [65–​67]. Initially,
Outcomes after surgery transcatheter closure post-​AMI was performed experimentally
Despite advances in surgical care, operative mortality remains with devices for atrial septal defect (Amplatzer) and later with
high (36.2–​42.9%) [50] and the 30-​day mortality rate is 41% VSD occluders that currently have been improved to specific
[50, 61,  62]. The European System for Cardiac Operative Risk post-​infarction VSR devices.
Evaluation (EuroSCORE II) score [63] allows predicting opera- Devices and technique
tive mortality in patients with post-​MI VSR. Several factors are Ventricular septal occluders are self-​expandable, double-​umbrella
associated with higher operative mortality risk, including CS devices with a long and wide waist, which accommodates the
muscular ventricular septum. The device is linearly placed in-
side a small sheath, and after delivery, it returns to its original
configuration. The two flat discs extend radially beyond the cen-
tral waist to provide secure anchorage. Catheterization and VSR
closure are performed under sedation and guided by fluoroscopy
and, in most cases, with additional TOE guidance, which is used
for a detailed assessment of the device delivery.
The procedure consists of crossing a wire from the LV side dir-
ected to the pulmonary artery where it is snared for exteriorizing
across a central vein, creating a railway loop that allows the de-
ployment and complete expansion of the device. Two approaches
to the LV are described: the arteriovenous loop (transaortic) and
the veno-​venous loop (trans-​septal puncture). After intervention,
LV angiography is performed usually to assess the position of the
Figure 40.7  Surgical view in a patient with VSR, showing forceps crossing device and assess for residual intracardiac shunt, valve interfer-
through the defect. ence, and device position.
 Ven tri cu l a r sep ta l   rup t ure 521

Selection of candidates left-​to-​right shunt; and (3)  to improve biventricular function,

Anatomically, the currently available devices are only suitable for scaling up progressively from simple medical therapies to MCS,
simple and small to medium VSRs (<15  mm) [62], and its an- including IABP, Impella device, and VA-​ECMO.
chorage is conditioned by the existence of a large rim and the Medical treatment
absence of interference with the mitral valvular apparatus or the Pharmacological strategies are focused on [72]:
aortic valve, occurring particularly after device deployment in an
◆ Reducing LV afterload with vasodilators; opting for IV drugs,
inferior VSR [68].
such as sodium nitroprusside or nitroglycerin, in critically ill
From a patient perspective, closure devices for post-​MI VSR
patients or oral pharmacological agents, such as ACE-​Is or
are used for:
hydralazine, in more stable patients. However, the effect of
◆ Inoperable patients with high surgical risk. vasodilators requires very close clinical tolerance monitoring
◆ Operable patients in a combined approach as: because they may be associated with marked hypotension and
A bridge to definitive surgery to provide haemodynamic sta-
●
reduced coronary perfusion.
bilization in the acute setting. Treating volume overload with diuretics or haemofiltration.
◆
Residual defects after surgical repair.
●
◆ Enhancing ventricular function with vasoactive drugs,
Outcomes after percutaneous closure preferentially with inodilators, such as dobutamine or
Successful device implantation rates of over 80% have been re- phosphodiesterase-​3 inhibitors, since they increase myocardial
ported [69], although publication bias may be relevant. Residual contractility, as well as produce vasodilatation.
shunt after discharge is frequent (55%), but only 11% are mod- Respiratory compromise in these patients may require mech-
erate to large [66]. Occasionally, multiple devices are implanted anical ventilation, non-​invasive or with intubation.
in the first procedure, but additional device implantation in new
Mechanical circulatory support
procedures is required in 16.5% of patients. The rupture site can
Intra-​aortic balloon pump
expand abruptly, resulting in a recurrence of large-​volume shunts
Insertion of IABP in unstable patients with VSR is generally re-
and sudden haemodynamic collapse in previously stable patients.
commended because it reduces LV afterload, thereby increasing
During and after the procedure, major complications have been
cardiac output and decreasing left-​to-​right shunting [73,  74].
described [69]:
However, IABP seems to provide only partial and short-​term
◆ Iatrogenic left or right wall ventricular rupture. haemodynamic benefit (markedly within the first 24 hours) and
◆ Occluder-​related haemolysis. progression to more powerful devices or corrective therapy may
◆ Device malpositioning. be needed [75].
◆ Embolization to the pulmonary artery. Impella®
◆ Entrapment in the subvalvular apparatus, tricuspid leaflet injury. Initial experience of the use of Impella® CP or 5.0 reducing left-​to-​
◆ Malignant arrhythmias and conduction disturbances. right shunting and increasing cardiac output has been reported in
However, procedural success is not related to an increase in 30-​ some cases with inferior VSR. This location interferes very min-
day survival (25–​35%), especially if performed in the acute phase imally with suction of the catheter tip and the probability of aspir-
[69]. The overall mortality rate of percutaneous VSD closure was ation of necrotic material is very low, while insertion into anterior
below or similar to several surgical VSD repair series reporting VSR is more likely associated with tissue damage and emboliza-
mortality rates ranging between 36% and 81% [69]. However, a tion. The most frequent complications associated with Impella®
direct comparison is not possible owing to the absence of a non-​ CP utilization are major bleeding at the vascular access site
randomized design and inherent selection bias, since percutan- (33.3%), haemolysis (5–​10%), and limb ischaemia [76]. Further
eous closure may have been carried out earlier and in simpler clinical experience is needed to confirm these early results.
cases. The Model for End-​stage Liver Disease eXcluding INR Veno-​arterial extracorporeal membrane oxygenator
(MELD-​XI) score (adapted version of MELD score), used as a In a substantial proportion of patients who are haemodynam-
tool to predict outcomes in patients suffering from liver disease, is ically unstable with refractory CS despite inotropic support and
also a strong predictor of 30-​day survival in these patients (score IABP, early surgical repair recommended by current guidelines
>20 associated with 30-​day mortality of 62%). Most series iden- can be unfeasible. Specifically in those cases, VA-​ECMO may
tified as significant 30-​day and in-​hospital mortality predicting provide haemodynamic stabilization, improve organ perfusion,
factors: the presence of CS, large shunt or residual defect, the time and prolong time to surgery, allowing consolidation of the freshly
from AMI to VSR diagnosis, and time delay between VSR diag- infarcted myocardium [75].
nosis and percutaneous closure [70, 71]. Once inserted, the timing of definitive treatment must be cus-
tomized, as prolonged duration of circulatory support increases
Support treatment the potential for complications, including coagulopathy, bleeding,
The three main targets for early treatment are: (1) to reduce LV and infections [77]. It is important to highlight that use of per-
filling pressures; (2)  to reduce LV afterload, and consequently ipheral VA-​ECMO increases LV afterload and wall stress, with a
522 CHAPTER 40   Me c ha nical c omplicat ions of m yo ca rdia l  i n fa rcti on

risk of inadequate unloading, LV distension, aggravation of left-​ suturing of the patch [51, 78]. Elective procedures increase the
to-​right shunting, and VSR expansion. IABP may prevent inad- chance of operative success, but this is explained, to a large ex-
equate decompression. tent, by selection bias, in which only the most favourable cases,
i.e. the lowest-​risk cases, would survive to surgery, excluding
Management strategy for VSR therefore the highest-​risk cases from surgical results. Thus, the
Current guidelines recommend immediate surgical treatment timing for VSR closure should be based on the haemodynamic
for patients with VSR, regardless of haemodynamic status at the situation of the patient and the severity of the condition, as fol-
time of diagnosis. However, the timing of VSD closure remains lows (see E Figure 40.8):
controversial, balancing the risk of emergent repair to prevent ◆ Haemodynamically stable patients. Reconstruction may be per-
the establishment of CS and MOF with the advantage of delaying formed after 3–​4 weeks of medical optimization, with careful
surgery to enhance scarring of the necrotic tissue and facilitate watching for instabilization [51].

Ventricular septal
rupture

Profound Yes Haemodynamic No

cardiogenic
instability?
shock?

No Yes

Medical treatment VA-ECMO

+/– IABP Refractory
Watchful waiting
with close clinical
and haemodynamic
monitoring

Successful
stabilization?

No Yes

Consider emergent Urgent Elective

rupture repair rupture repair rupture repair

Heart team

Prohibitive surgical
risk?
Yes No

Favourable Favourable
anatomy for percutaneous anatomy for percutaneous
closure?* closure ?*
No Yes Yes No

Conservative/ Consider
Failure Surgical * Favourable anatomy for percutaneous closure:
palliative percutaneous
repair • Simple rupture
treatment closure • Small-medium size (<15 mm)
• Large rim
• No interference with mitral valvular apparatus
• No interference with aortic valve

Figure 40.8  Algorithm for the management of VSR.

 Pa pi l l a ry m u s c l e   rup t ure 523

◆ Haemodynamically unstable patients [Interagency Registry for the effective forward flow, leading to low cardiac output, hypoten-
Mechanically Assisted Circulatory Support (INTERMACS) 2–​3]. sion, and CS.
In patients with hypotension or tachyarrhythmia, use of ino-
tropic agents or placement of an IABP must be considered. In Clinical presentation
these patients, urgent repair must be considered. PMR should be suspected in patients with sudden acute left-​sided
◆ Haemodynamically unstable patients (INTERMACS 1). In cases heart failure symptoms or signs, such as rapidly progressive pul-
of refractory CS, with mortality approaching 100%, immediate monary oedema and hypoxia, and/​or CS. Although a mid-​, late-​, or
percutaneous ECLS might be necessary. holo-​systolic murmur can be heard in the parasternal edge or apical
location, rapid equalization of pressures between the atrium and the
ventricle can make the murmur inaudible, hindering the diagnosis.
Papillary muscle rupture
Diagnosis
Introduction
TTE has been well established as the initial diagnostic tool to
PMR is an acute tear in the mitral papillary muscle as a con- identify PMR, with a diagnostic sensitivity of 65–​85% [86]. TOE
sequence of prolonged ischaemia, resulting in acute severe provides superior imaging of the mitral apparatus and papillary
MR, although involvement of the tricuspid papillary muscle structures for unequivocal TTE results, as its sensitivity has been
after RV infarction has been also reported [79]. Classically, the reported as high as 92–​100% [87] and it is more precise in eviden-
posteromedial papillary muscle is more commonly injured than cing the location of the ruptured structure. The following analysis
the anterior papillary muscle (75% versus 25%, respectively) due must be performed with echocardiography (see z Video 40.2):
to its single blood irrigation from the posterior descending cor-
onary artery [branch of either the RCA or the left circumflex ar- 1. Identification of the ruptured papillary muscle segment.
tery (LCX)], in contrast to the dual blood supply that arises to the Visualization of the head of the papillary muscle attached to
anterolateral papillary muscle (LAD or LCX) [80, 81]. the chordae tendinea as a highly mobile, echo-​intense mass
Rupture of the papillary muscle is classified as: prolapsing into the LA during systole and returning to the LV
in diastole. Very large fragments can remain confined in the LV
◆ Complete: disruption is located at the papillary trunk, usually cavity, as they are unable to cross the mitral valve orifice.
occurring within 1 week post-​infarction and leading to rapid
clinical deterioration. 2. Visualization of flail mitral valve segments. Each mitral papillary
muscle supplies chordae to the ipsilateral half of both anterior
◆ Partial: including disruption of only one of the heads of the pap-
and posterior leaflets [86]. Disruption of the posteromedial
illary muscle or an incomplete tear at the body of the muscle,
with a high risk of progressing to complete rupture. Partial rup-
papillary muscle usually causes flailing of the medial commis-
tures may occur up to 3 months after infarction and are haemo- sure scallops (A3–​P3), generating a horizontal eccentric jet
dynamically better tolerated because they are associated with directed laterally before turning superiorly towards the upper
fewer scallops of leaflets flailing and less valvular regurgitation. pulmonary veins. By contrast, anterolateral papillary muscle
tear affects the lateral commissure (A1–​P1) and the resultant jet
Epidemiology: incidence and mortality crosses the surface of the mitral valve towards the atrial septum.
Prior to the era of reperfusion therapy, the incidence of PMR after 3. Evaluation of direction and severity of MR (see E Figure 40.9). MR
MI was approximately 3%, but with thrombolytic therapy and caused by PMR is usually severe, although assessment can be com-
primary PCI, the frequency has decreased to 0.2% [2, 10]. In the plex because regurgitant jets are usually eccentric and horizontal
presurgical era, in-​hospital mortality was estimated to be 70–​90% and colour Doppler flow signal can underestimate the severity due
[82, 83]. In modern series, overall mortality ranges from 27% to to reduced MR aliasing in the context of a large regurgitant orifice
60% [2,  84]. However, in surgically treated patients, in-​hospital area, elevated LA pressure, and hypotension. Moreover, the brief
mortality has dramatically fallen to 10–​27% [2, 85]. duration of regurgitation, caused by rapid equalization of LV and
LA pressures, may further render the MR colour flow. Evidence of
Pathophysiology pulmonary vein systolic flow reversal can be present or absent in
Acute severe MR involves a large volume overload on the LA and each vein, depending on the direction of the jet.
LV. Since compensatory mechanisms, such as atrial distension 4. Assessment of regional and global LV systolic function. About
and enlargement, cannot occur over a short period of time, the 50% of cases of PMR have a relatively small infarction, and
acute volume overload is translated into a steep rise in LA pres- their EF is preserved. Hyperdynamic contractility of non-​
sure, resulting in pulmonary venous congestion and pulmonary infarcted segments may cause underestimation of the true se-
oedema. According to the Frank–​Starling law, the increase of the verity of regional wall motion abnormalities.
LV end-​diastolic volume increases LV stroke volume, but as the Contrast ventriculography is useful in the diagnosis of MR.
regurgitant flow to the LA faces a much lower resistance, most of However, given the high performance of echocardiography, ven-
the ejected blood therefore moves backwards to the LA through triculography is not required and, in general, not recommended
the incompetent mitral valve, resulting in a marked reduction in due to the risk of worsening pulmonary oedema.
524 CHAPTER 40   Me c ha nical c omplicat ions of m yo ca rdia l  i n fa rcti on

(a) (c)

(b) (d)

Figure 40.9  Three-​chamber view of 2D TOE showing anterior PMR. (A) Head of the papillary muscle attached to the anterior leaflet, billowing into the LA
during systole. (B) Severe systolic MR with a posterolateral jet with Coanda effect. (C) Head of the papillary muscle attached to the anterior leaflet, moving
across the LV during diastole. (D) Diastolic severe MR. An additional eccentric jet directed to the anterior wall of the LV can be observed.

Treatment after surgery [83], a lower risk of endocarditis, and a lack of

need for long-​term oral anticoagulation [89]. It is mostly per-
The treatment of choice for PMR is surgical mitral valve repair
formed as the first option after partial PMR where healthy tissue
or replacement (see E Figure 40.10). In addition to acute valve
is present. In contrast, in the presence of necrotic and friable
surgery, coronary revascularization has shown improvement in
myocardium, prosthetic valve replacement may be the only op-
short-​and long-​term survival [88].
tion [83, 90], and therefore, it is the most common intervention
Support treatment after complete PMR.
Initial medical therapy can be instituted with O2 therapy, often Timing of surgery
with non-​invasive or invasive mechanical ventilation, diuretics, Urgent intervention is proposed as the optimal timing for sur-
and vasodilators to reduce LV afterload. IABP may be necessary gery in cases of abrupt haemodynamic deterioration [83,  88],
for severely unstable patients. Patients presenting with refractory more typically observed after complete PMR, but a relative delay
CS should be considered for VA-​ECMO support. This may serve (>7 days) [91] may be considered for stable patients, mostly pre-
as a temporal measure for haemodynamic stabilization, organ senting with partial PMR, to avoid suture dehiscence in friable
dysfunction recovery, and preparing surgical treatment. necrotic tissue or retraction of the scar and improve outcomes.

Type of repair Outcomes after surgery

Surgical repair Perioperative mortality rate of PMR ranges between 18.5% and
The selection of tecwhnique and timing of surgery is conditioned 27% [85,  88], although more recently, mortality has markedly
by the type of rupture and the patient’s haemodynamic situation decreased to close to 10% for patients undergoing surgical valve
[72] (see E Figure 40.11). therapy with concomitant CABG [85, 88].
Percutaneous repair
Technique
Election of the surgical technique is controversial. Valve repair Many patients may be considered to be at high surgical risk
is usually preferred due to better preservation of LV function and thus not eligible for surgical treatment. In these acutely ill
 Mechani ca l c o m pl i cati on s cau sed b y  g eo m etri ca l  di stort i on 525

Papillary muscle
rupture

Profound Yes Haemodynamic No

cardiogenic instability?
shock?
No Yes

Medical treatment Refractory VA-ECMO

+/-IABP

Successful
stabilization?

No Yes

Consider emergent Urgent valve Non-urgent

valve replacement repair/replacement valve repair/replacement

Prohibitive
surgical risk?

No Yes

Favourable
Partial rupture? anatomy for
MitraClip?*
No Yes Yes No

Valve Failure Try valve Consider Conservative/

replacement repair MitraClip palliative
treatment
* Favourable anatomy for percutaneous edge-
to-edge repair (MitraClip): EVEREST criteria

Figure 40.10  Algorithm for the management of PMR.

patients with refractory heart failure, transcatheter edge-​to-​edge and the subvalvular apparatus remain structurally preserved, but
repair with the MitraClip device [92] may be a solution as bailout there exists an alteration between the tethering and closing forces
therapy if the anatomy is favourable [Endovascular Valve Edge-​ acting over the valve.
to-​Edge Repair Study (EVEREST) criteria].
Epidemiology
With the progressive implementation of early reperfusion, the
incidence of FIMR after AMI (PMR excluded) has decreased to
Mechanical complications caused 26%, but of which only 3% are severe [93]. Severe FIMR is most
by geometrical distortion common in inferior wall MIs [23]. In contrast to PMR, patients
with FIMR have a higher prevalence of prior MI and multivessel
Functional ischaemic mitral regurgitation
disease [23].
Introduction
Functional ischaemic mitral regurgitation (FIMR) is a type of Pathophysiology
functional regurgitation caused by pathological remodelling of In the context of MI, we can find two different scenarios,
the LV after MI or chronic CAD. This implies that both the valve depending on the reversibility of the ischaemia:
526 CHAPTER 40   Me c ha nical c omplicat ions of m yo ca rdia l  i n fa rcti on

(a) (b)

Figure 40.11  (A) Three-​chamber view of 2D TOE showing rupture of the posterior papillary muscle. The head of the papillary muscle is attached to the
posterior leaflet, billowing into the LA during systole. (B) Resected valve with the attached papillary muscle head after mitral valve replacement.

◆ Acute post-​MI functional MR (reversible ischaemia). In the acute antagonists), palliate symptoms (vasodilators and diuretics),
phase of MI, the papillary muscles and underlying myocardial and prevent myocardial ischaemia. In the presence of viable
segments may become stunned and present with transient func- myocardium, coronary revascularization (percutaneous or sur-
tional loss, causing mitral insufficiency. Once reperfusion is re-​ gical) must be pursued. In cases of severe adverse remodelling
established, functionality may be recovered and MR reverts. in NYHA functional class III and IV patients who remain symp-
◆ Chronic post-​ MI functional MR (irreversible ischaemia). tomatic despite optimal heart failure medical therapy and have
Irreversible ischaemia may trigger regional or global adverse LV an LVEF ≤35% and a prolonged QRS duration (>130–​150 ms),
remodelling. Consequently, outward apical displacement of one or CRT may have a beneficial effect [96]. In the majority of non-​
both papillary muscles generates tethering over the leaflets, which, responders with moderate to severe FIMR and recurrent heart
in addition to restriction of closure forces over the valve due to failure, a concomitant mitral valve procedure is recommended,
hypocontractility, dilation of the annulus, and loss of synchron- with a variety of techniques including suture, band, or ring
icity, causes incomplete coaptation of the leaflets and MR [94, 95]. annuloplasty, versus replacement [97]. Percutaneous mitral valve
Clinical presentation repair may be a less invasive approach for patients with FIMR at
high surgical risk.
FIMR may be asymptomatic or cause any degree of pulmonary
congestion, depending on the severity and speed of development.
Dynamic behaviour is a typical feature of FIMR, conditioned by Left ventricular aneurysm
haemodynamic factors or triggers of myocardial ischaemia. For in- Introduction
stance, situations associated with increased demands of O2, such as A true LV aneurysm is a dilatation of a portion of the LV wall
exercise, may set off transitory reversible ischaemia of the papillary that is structurally thin, fibrotic, and functionally characterized
muscles and reproduce the MR. In chronic post-​MI functional MR, by akinetic or dyskinetic motion, generally as a consequence
hypertension and hypervolaemia can aggravate the degree of regur- of the healing process after transmural AMI. An LV aneurysm
gitation and provoke recurrent episodes of acute pulmonary oedema. distorts the normal geometry of the LV, impairing its con-
Diagnosis tractile and filling capacities. In contrast to pseudoaneurysms
or false aneurysms, the three layers of the ventricular wall are
The diagnosis is typically made by echocardiography. The pattern
preserved, with loss of thickness at the expense of a necrotic
of FIMR is usually asymmetric with an eccentric posterolateral
myocardium and areas of fibrosis. An anteroapical location is
jet, since deformation predominantly affects the posteromedial
four times more common than involvement of the inferior pos-
PM after lateral or inferior MI. However, as FIMR is often vari-
terior wall. Although unusual, RV aneurysms may occur after
able, MR may not be evidenced by TTE in a resting state and
RV infarction.
exercise TTE may be needed to unveil severe FMR, which may
explain intermittent symptoms.
Epidemiology
Treatment Before the reperfusion era, the incidence of LV aneurysms was
Medical treatment is directed to prevent LV remodelling de- 30% [98] but has decreased importantly in the reperfusion era,
velopment (ACE-​ Is, β-​blockers, mineralocorticoid receptor although current accurate estimations are lacking.
 Ack n ow l e d g e m e n ts 527

Clinical presentation
LV aneurysms may be asymptomatic or present as heart failure,
ventricular arrhythmias, or arterial embolism. A dyskinetic im-
pulse of the aneurysm area can occasionally be palpated.

Diagnosis
Persistent ST-​segment elevation on the ECG may suggest the pres-
ence of LV aneurysm, but the definitive diagnosis must be confirmed
with imaging techniques. The first approach is usually by echocardio-
graphy (see z Video 40.3). Characteristically, the endocardial sur-
face is smooth and non-​trabeculated, with an echo-​dense contour,
and the neck of the dilatation is wider than that in pseudoaneurysm.
The dilated segments can be filled with organized thrombi in >50% of
cases, most of which are of long-​term evolution, well endothelialized,
and even calcified, and related to a low risk of embolization. Cardiac
MRI is useful to obtain 3D views, assess the viability of the territory,
and distinguish from pseudoaneurysms [99]. Figure 40.12  Four-​chamber view of 2D echocardiography showing apical
thrombus after anterior MI.
Treatment
Early and complete reperfusion is the most effective method of
preventing the development of LV aneurysms. Use of ACE-​Is, Diagnosis
β-​
blockers, and eventually mineralocorticoid receptor antag-
Initial screening by TTE should be done to rule out intraventricular
onists in patients with LV dysfunction prevents adverse LV re-
thrombosis, especially in patients with severe LV dysfunction or
modelling. In the case of the presence of fresh thrombus inside
LV aneurysm. IV contrast agents may be needed to define the
the aneurysm, oral anticoagulation is indicated. In the Surgical
endocardial border in cases of suboptimal acoustic window.
Treatment for Ischemic Heart Failure (STICH) trial [100], sur-
Characteristics of LV thrombus include a mural or pedunculated
gical aneurysmectomy did not show an impact on survival or
mass, often with acoustic properties similar to those of normal
rehospitalization. However, it is reasonable to consider surgical
myocardium (see E Figure 40.12). In patients with uncertain
reconstruction in cases of refractory heart failure, ventricular ar-
diagnosis, cardiac MRI with gadolinium offers high diagnostic
rhythmias not amenable to ablation, or recurrent systemic embol-
accuracy [103, 108].
ization despite chronic anticoagulation [101, 102].

Intraventricular thrombi Treatment
Introduction Patients with LV thrombus should receive long-​ term
anticoagulation, in addition to DAPT, unless the bleeding risk is
Akinetic or dyskinetic wall motion disorders of the infarcted
extremely high. Initially, parenteral therapy is preferred until ef-
area cause stasis of blood in the LV, promoting the formation of
fective anticoagulation with warfarin has been achieved (target
thrombi in the cardiac cavity, usually involving apical aneurysms.
INR 2–​3). Clinical experience with direct-​acting oral anticoagu-
Epidemiology lants in this setting is limited. There are no prospective studies
to assess the optimal length of therapy, but treatment should be
In recent modern series of STEMI patients treated with primary PCI,
prolonged for up to 3–​6 months from AMI, guided by repeated
the incidence of LV thrombi is 2.4–​7% [93, 103–​106), but with more
echocardiography.
sensitive diagnostic tests, such as cardiac MRI, the frequency in pa-
tients with ischaemic cardiomyopathy increases to up to 9% [107].

Clinical presentation
The natural history of LV thrombi includes complete resolution
Acknowledgements
or re-​endothelialization, but embolization may occur along these We thank Dr Carmen Jiménez López-​Guarch and Dr Fernando
processes. The incidence of embolic cerebrovascular events is Guillén for their contribution in providing echocardiographic
around 5.6% [103]. and surgical images.
528 CHAPTER 40   Me c ha nical c omplicat ions of m yo ca rdia l  i n fa rcti on

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M oxfordmedicine.com/ESCIACC3e)).
 CHAPTER 41

Non-​ST-​segment elevation
acute coronary syndromes
Héctor Bueno and José A Barrabés

Contents
Summary  531 Summary
Introduction  531 Non-​ ST-​segment elevation acute coronary syndromes (NSTE-​ ACS) are life-​
Epidemiology  532 threatening disorders, usually caused by acute coronary thrombosis and sub-
Pathophysiology  532 sequent myocardial ischaemia and presenting without persistent ST-​ segment
Diagnosis  533 elevation in the initial electrocardiogram. According to the occurrence of myo-
Clinical presentation  533 cardial necrosis, NSTE-​ACS are divided into non-​ST-​segment myocardial in-
Electrocardiogram  533
Cardiac biomarkers  534 farction or unstable angina. Management of NSTE-​ACS requires early diagnosis
Stress tests and other imaging and risk stratification, urgent hospitalization, monitoring, and medical treatment,
techniques  535 including antithrombotic therapy with dual antiplatelet therapy (aspirin plus
Risk stratification  535
one P2Y12 inhibitor) and parenteral anticoagulation, anti-​ischaemic treatment,
Biomarkers  536
Risk scores for prognosis assessment in acute and preventative therapies. After initial medical therapy is established, an inva-
coronary syndrome patients  536 sive strategy, consisting of coronary angiography with coronary revascularization
Treatment  536 (either percutaneous coronary intervention or coronary bypass graft surgery), as
General management  536
Initial treatment  536
appropriate, should be decided. The timing of the invasive strategy should be ad-
Antithrombotic therapy  537 justed according to the patient’s risk. Given the high event rate of patients with
Antiplatelet therapy  537 NSTE-​ACS after hospital discharge, an aggressive long-​term preventative therapy
Anticoagulation  539
Antithrombotic therapy in patients should be put in place to improve prognosis.
needing oral anticoagulation  539
Anti-​ischaemic therapy  539
Nitrates  539
Beta-​blockers  540
Calcium channel blockers  540
Other treatments  540
Invasive strategy  540
Timing of invasive strategy  541
Introduction
Coronary revascularization  541
Planning secondary prevention and ACS encompass a wide spectrum of clinical presentations derived from acute myo-
follow-​up  542 cardial ischaemia, ranging from one short episode of self-​limited mild chest discom-
Indicators for assessing quality of acute fort to cardiogenic shock or cardiac arrest, and constitute a major cause of emergent
care  542
Long-​term prognosis  543 medical care and hospitalization. NSTE-​ACS include NSTEMI and UA. The former
Personal perspective  543
is defined by the occurrence of myocardial injury secondary to acute myocardial is-
chaemia, usually detected by a rise and fall of cTns [1]‌, without persistent (i.e. 20
Further reading  544
minutes or less) elevation of the ST-​segment on the ECG, while diagnosis of UA relies
References  544
on the presence of symptoms consistent with myocardial ischaemia without necrosis,
often, but not always, accompanied by changes in repolarization (i.e. ST-​segment de-
pression or T-​wave inversion). NSTE-​ACS are usually caused by chronic atheroscler-
otic CAD with acute local thrombosis. Early diagnosis and treatment are needed, first
to rule out STEMI, which requires a strategy of immediate reperfusion, as well as
other potentially severe diseases causing the symptoms, such as aortic dissection or
PE, and second to reduce the increased risk of short-​and long-​term cardiac death and
532 CHAPTER 41   N on - ST -segment elevat ion acu te c orona ry  sy n dro m es

300
Pathophysiology
(no. of cases/100 000 person-year)
MI
250
Most ACS are the result of a thrombotic complication of coronary
200
Incidence rate

atherosclerosis [7–​9] (see E Chapter  36). Thrombosis usually

Non-STEMI
150 occurs in response to plaque rupture or, less frequently, erosion
[10, 11]. After plaque rupture, exposure of TF and other compo-
100
nents of the lipid core triggers platelet adhesion, activation, and
50
STEMI aggregation and initiates the extrinsic pathway of coagulation,
leading to fibrin generation [7–​9, 12–​14].
0
1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 Rupture-​prone plaques are characterized, among other fac-
tors, by a large lipid-​rich core and by a thin and inflamed fi-
Figure 41.1  Temporal trends in the age-​and sex-​adjusted incidence of AMI.
MI, myocardial infarction; STEMI, ST-​segment elevation myocardial infarction. brous cap (see E Figure 41.2), whereas factors predisposing to
Reproduced from Yeh RW, Sidney S, Chandra M, Sorel M, Selby JV, Go AS. Population plaque erosion are largely unknown [10, 11]. A prospective study,
trends in the incidence and outcomes of acute myocardial infarction. N Engl J using multimodality intracoronary imaging, in ACS patients
Med 2010;362(23):2155–​2165. doi:10.1056/​NEJMoa0908610 with permission from
Massachusetts Medical Society.
showed that most non-​culprit lesions that caused new coronary
events were angiographically mild and identified a thin-​capped
subsequent MI associated with this syndrome with appropriate fibroatheroma, a larger plaque burden, and a smaller minimal lu-
medical therapy and a timely invasive strategy. minal area as predictors of plaque complication [15]. Vulnerability
to coronary thrombosis not only depends on plaque-​related fac-
tors, but also on systemic factors enhancing thrombosis or in-
flammation, as suggested by the observation in autopsy studies of
Epidemiology ruptured plaques without thrombosis [16, 17] or by the finding of
The incidence of NSTE-​ACS in developed countries is three times multiple complicated lesions in some ACS patients [18, 19]. Much
as high as that of STEMI [2, 3]. Moreover, while STEMI incidence less frequently, ACS occurs in the absence of atherosclerosis and
is declining (see E Figure 41.1), probably in relation to a better may be caused by coronary spasm, embolization, spontaneous
control of coronary risk factors in the general population, the in- dissection, or arteritis [11].
cidence of NSTE-​ACS remains stable and is even expected to in- In contrast to STEMI, where a totally occlusive intracoronary
crease, mainly because of progressive ageing of the population, an thrombosis is the paradigm at early angiography, patients with
increase in the number of patients who survive an acute event and NSTE-​ACS have a relatively low prevalence of occlusive throm-
are thus exposed to recurrent events, and the increasing number of bosis [20]. Angiographically visible collaterals are not uncommon
diabetic people [3]‌. In addition, incorporation of high-​sensitivity and might be protective in these patients [21]. Transient cor-
biochemical assays to the standards for the diagnosis of AMI [4, 5] onary occlusion, increased vasoreactivity, microembolization,
will result in the reclassification of CAD patients who would not and platelet-​mediated damage, alone or in combination, may
have previously qualified for NSTE-​ACS. The rates of in-​hospital have a particularly significant contribution to myocardial injury
mortality and complications are lower for NSTE-​ACS than for in NSTE-​ACS patients [10, 22–​24]. Finally, a non-​neglibible pro-
STEMI patients [2, 6]; however, long-​term outcomes are poorer. portion of NSTE-​ACS are not caused by plaque complication but

(a) (b)

fl nc
th

Figure 41.2  Human coronary arteries with different types of atherosclerotic lesion. (A) Vulnerable complex atherosclerotic plaque, with large necrotic centre
(nc) and a fine fibrous layer (fl). (B) Eroded plaque with a superimposed thrombus (th). Haematoxylin–​eosin staining.
Reproduced from Badimón L, Vilahur G, Padró T. Lipoproteins, platelets and atherothrombosis. Rev Esp Cardiol 2009;62(10):1161–​1178. doi:10.1016/​s1885-​5857(09)73331-​6 with
permission from Elsevier.
 Diag n o si s 533

are due to an imbalance between demand and supply of O2 in the family history—​increases the probability that the symptoms are
myocardium [25]. due to NSTE-​ACS [31, 32]. Ongoing cardiovascular medications,
major comorbidities, and potential contraindications to therapy
should be recorded.
Physical examination is often normal. Heart rate, blood pres-
Diagnosis sure, and Killip class are strongly associated with prognosis and
Correct identification of patients with NSTE-​ACS is critical, not must be assessed on admission. A fourth heart sound is common.
only to start management as soon as possible, but also to iden- Auscultation of a third heart sound or a systolic murmur of
tify patients with other potentially life-​threatening illnesses and MR during CP episodes usually reflects extensive ischaemia
to safely discharge those with trivial causes for their symptoms. and a worse prognosis. History and physical examination may
Patient misclassification may have serious consequences if an help differentiate between NSTE-​ACS and other diagnoses (see
ACS is not detected or conversely may lead to unnecessary ad- ETable 41.1).
missions and use of resources [26, 27]. Given the heterogenous
presentation of NSTE-​ACS, this diagnosis may be challenging. It Electrocardiogram
is based on clinical data, the ECG, and cardiac biomarkers, with An ECG should be recorded within 10 minutes of FMC and re-
additional tests being needed in selected patients. Since these peated during the first hours, after 24 hours, and during recur-
items are also the pillars of early risk stratification, diagnosis and rence of symptoms. It is useful to compare tracings obtained
risk assessment can usually be made in parallel. with and without CP and also to assess changes with respect
to previous tracings, if available, particularly in the presence of
Clinical presentation intraventricular conduction disturbances or signs of left ven-
Most patients present with chest pain (CP), in the form of pro- tricular (LV) hypertrophy or myocardial necrosis [33].
longed, new-​onset, or crescendo angina. Angina is often reported The ECG in NSTE-​ACS can show ST-​segment depression,
as intermittent or persistent substernal or precordial pressure, or transient ST-​segment elevation, or T-​wave inversion or can be
heaviness radiating, or not, to the shoulders, arms, neck, or jaw completely normal, especially if obtained when the patient is
that may worsen during exercise, can be accompanied by sweating, asymptomatic (see E Figure 41.3). Ongoing ischaemia fre-
nausea, or vomiting, and usually alleviates with nitroglycerin [28]. quently causes ST-​segment deviation, whereas negative T-​waves
Other presentations that may be associated with chest discomfort or typically appear once ischaemia has resolved.
appear in isolation include epigastric pain, dyspnoea, fatigue, syn- ECG may help to identify patients with an acute coronary oc-
cope, or even cardiac arrest. Atypical presentations without CP or clusion, despite lacking a significant ST-​segment elevation, which
with atypical pain are more frequent among the elderly, in women, could benefit from immediate reperfusion therapy. Persistent ST-​
and in patients with diabetes mellitus or renal failure [29, 30]. segment depression in leads V1–​V4 must point to the diagnosis of
History and physical examination can detect the precipitating an acute posterior (inferobasal) MI [34, 35], due to occlusion of the
causes of ACS such as arrhythmias, anaemia, infection, or thyro- circumflex artery or one of its branches, and is often considered
toxicosis. The existence of previous CAD, vascular disease in other an STEMI equivalent. More rarely, posterior transmural ischaemia
territories, or risk factors of CAD—​especially diabetes or a strong does not cause ST-​segment deviation on the 12-​lead ECG and

Table 41.1  Main clues to differentiate NSTE-​ACS from other major causes of chest pain

Clinical presentation ECG Troponins Others

Acute aortic syndrome Sudden onset of sharp pain Normal/​non-​specific Normal/​may be Mediastinal enlargement on
Frequent hypertension on admission elevated chest radiograph may be
AR murmur may be present present
Pulse asymmetry (infrequent)
Myopericarditis Prolonged pain Frequent diffuse ST-​segment Normal or Concomitant pleural effusion
Pain worsens with inspiration and alleviates elevation without reciprocal elevated may be present
by sitting up and leaning forward ST-​segment depression
Fever, flu-​like symptoms Depression of PR segment
Pericardial rub
Pulmonary embolism Dyspnoea is predominant symptom Often normal Normal or Hyperventilation
Hypoxaemia S1Q3T3 pattern elevated Echocardiography: RV
Signs of thrombophlebitis may be present RBBB/​right axis deviation dilatation, signs of PH
Often tachycardia with clear lungs
AR, aortic regurgitation; PH, pulmonary hypertension; RBBB, right bundle branch block; RV, right ventricle.
Source data from Barrabes JA, Inserte J, Mirabet M, Quiroga A, Hernando V, Figueras J, et al. Antagonism of P2Y12 or GPIIb/​IIIa receptors reduces platelet-​mediated myocardial injury
after ischaemia and reperfusion in isolated rat hearts. Thromb Haemost 2010 Jul;104(1):128–​35.
534 CHAPTER 41   N on - ST -segment elevat ion acu te c orona ry  sy n dro m es

CHEST PAIN
or symptoms consistent with myocardial ischaemia

ECG

ST elevation Repolarization not interpretable ST/T abnormalities Normal ECG

(persistent) (i.e. LBBB, pacemaker...)

Pain resolves with

Yes 1st hs-cTn
nitroglycerin

No hs-cTn>ULN hs-cTn<ULN
STEMI Potential
non-cardiac
likely cause for Pain onset <3 h Pain onset >3 h
abnormal Tn

hs-cTn high Re-test hs-cTn

(i.e. >×5 ULN (1–3 h later)
or clinical diagnosis
evident)
∆ hs-cTn hs-cTn
(1 value >ULN) no change
STEMI
Work-up
NSTEMI Unstable angina differential diagnoses

Figure 41.3  Diagnostic algorithm for patients with chest pain (or other symptoms consistent with myocardial ischaemia) and suspected ACS. ACS, acute
coronary syndromes; ECG, electrocardiogram; hs-c Tn, high-​sensitivity cardiac troponin; LBBB, left bundle branch block; NSTEMI, non-​ST-​segment elevation
myocardial infarction; STEMI, ST-​segment elevation myocardial infarction; ULN, upper limit of normal;Δ, delta.
Reproduced from Bueno H. Non-​ST-​segment elevation acute coronary syndromes. In: Bueno H, Vranckx P, eds. The Acute Cardiovascular Care Association Clinical Decision-​Making
Toolkit, 2018 Edition. ESC Editions, Nice 2018 with permission from European Society of Cardiology.

might be detected by the non-​standard V7–​V9 leads. An upsloping sensitivity with a reasonable specificity for NSTEMI diagnosis (see
ST-​segment depression, with tall, positive T-​waves in the precordial E Figure 41.4). However, these algorithms probably should be
leads, is a rare feature of an acute proximal occlusion of the LAD interpreted cautiously in patients presenting very early after the
coronary artery [36]. Finally, minor ST-​segment elevation in any onset of symptoms [47, 48]. Integrating high-​sensitivity troponin
territory has been related to a high frequency of acute, complete
coronary occlusion [37]. Immediate coronary angiography should
be strongly considered in a patient with persistent angina and any Suspected NSTEMI
of these ECG features.

Cardiac biomarkers 0h <A ng/I or

0h <B ng/I
and Other
0h ≥D ng/I
or
Blood troponin levels are essential for diagnosis and risk stratifica- ∆0–h <C ng/I ∆0–h ≥E ng/I
tion and should be measured in all patients. Abnormal troponins
reflect myocardial damage and, in the setting of myocardial is-
Rule-out Observe Rule-in
chaemia, allow differentiating between MI and UA. Troponins
are more sensitive and specific than other markers of cardiac
damage such as CK or its MB fraction (CK-​MB) or myoglobin. A B C D E
Troponins I  and T have similar kinetics and can be used indis- hs-cTnT (Elecsys)* 5 12 3 52 5
tinctly. Troponins become abnormal approximately 4–​6 hours hs-cTnI (Architect)* 2 5 2 52 6
hs-cTnI (Dimension vista)* 0.5 5 2 107 19
after symptom onset and peak at 24–​48 hours. Serial sampling
is recommended, with a second determination at 3 hours after Figure 41.4  One-​hour rule-​in, rule-​out tests for the diagnosis of non-​ST-​
symptom onset [33]. Troponin measurement by high-​sensitivity segment elevation myocardial infarction (NSTEMI). * NSTEMI can be ruled
assays allows an earlier detection of AMI, with a higher sensitivity out at presentation if hs-​cTn concentration is very low or by the combination
and NPV, although with a somewhat lower specificity than by of low baseline levels and the lack of a relevant increase within 1 hour.
NSTEMI is highly likely if initial hs-​cTn concentration is at least moderately
conventional assays [38–​42]. If these tests are used and the first
elevated or hs-​cTn concentrations show a clear rise within the first hour.
determination is normal, a second determination after 3 hours al- Reproduced from Roffi M, Patrono C, Collet JP, et al. 2015 ESC Guidelines for the
lows to rule out MI, with a sensitivity approaching 100% (see E management of acute coronary syndromes in patients presenting without persistent
Figure 41.3) [40,  41]. It has been shown that 1-​hour algorithms ST-​segment elevation: Task Force for the Management of Acute Coronary Syndromes
in Patients Presenting without Persistent ST-​Segment Elevation of the European
[43, 44], or even a single determination of very low or undetectable Society of Cardiology (ESC). Eur Heart J 2016;37:267–​315 with permission from Oxford
levels of high-​sensitive troponins [45, 46], maintain an excellent University Press.
 Ri sk  str at i f i c at i on 535

concentration at presentation, its dynamic change during serial ischaemia and the myocardial mass at risk, the baseline cardiac
sampling, and the time between obtention of samples has been situation, and the patient’s clinical profile (age and comorbidities).
shown to reliably estimate the probability of MI at presentation As risk may change over time, depending on the evolution of the
and 30-​day outcomes [49]. Although high-​sensitivity troponin causal factors (coronary thrombosis), myocardial dysfunction—​
assays have significantly increased the sensitivity for AMI detec- spontaneously or as a response to treatment—​or the development
tion over standard assays, whether their implementation translates of complications, risk assessment is a dynamic process that starts at
into improved outcomes has been questioned [50]. In addition, it the time of FMC and must be updated over time. Several of the de-
should be kept in mind that a careful clinical assessment is still terminants of risk cannot be measured directly; therefore, several
necessary in the era of high-​sensitive troponins to rule out UA, a indirect markers are used for risk stratification. These include clin-
diagnosis associated with a non-​negligible risk [51]. ical factors, ECG signs, and biomarker levels, which may be used
Given that troponin levels may remain elevated for up to 2 isolated or in combinations that are more or less structured (i.e.
weeks after infarction, their usefulness to detect reinfarction or risk scores). Given the risk of secondary effects due to treatments,
periprocedural MI is a matter of controversy and CK-​MB might mostly bleeding, risk factors for such complications have also been
be better for these purposes [42, 52]. identified and specific tools for risk calculation developed.
Troponin elevation, by itself, does not diagnose AMI. Troponins Simple risk stratifications based on the presence or absence of
can be elevated in multiple cardiac and extracardiac conditions, one or more key prognostic factors have been proposed. Clinical
different from ACS—​some of them associated with CP such as findings associated with a higher risk may be related either to the
PE, aortic dissection, stroke, myocarditis, apical ballooning syn- severity of the acute event due to greater ischaemic instability
drome, heart failure, arrhythmias, or hypertensive crisis—​or in (such as CP at rest, longer duration, and with recurrences, par-
cardiac damage of any cause, as well as in renal failure [33]. With ticularly after treatment initiation) or greater myocardial im-
the newer high-​sensitivity assays, troponin elevations above the pairment, including haemodynamic or electrical instability
99th percentile of the URL have been detected in patients with (tachycardia, hypotension, acute heart failure, cardiogenic
stable CAD or even in apparently healthy individuals. (See also shock, new mitral regurgitation, or ventricular arrhythmias) or
E Chapter 32.) to the patient’s baseline characteristics such as older age, dia-
betes, and renal insufficiency (see E Table 41.2). Individual
Stress tests and other imaging techniques factors predicting very high short-​ term risk, such as severe
The presence of dynamic ST–​T changes or a significant eleva- haemodynamic or electrical instability or refractory CP, are so
tion of cardiac biomarkers in a patient with symptoms compat-
ible with myocardial ischaemia allows establishing a working
diagnosis of NSTE-​ACS—​that should be confirmed by early cor- Table 41.2  Key prognostic factors in ACS
onary angiography—​and starting medical management. There Risk factors for ischaemic events Risk factors for bleeding events
are patients, however, who present with symptoms suggestive
Older age Older age
of, or compatible with, angina, in whom the ECG is normal or
shows non-​specific changes and troponins are negative. To de- Diabetes Diabetes
tect those with a true NSTE-​ACS—​that may represent about 10–​ Renal failure Renal failure
20% of these patients [53]—​further non-​invasive tests are often Anaemia Anaemia, thrombocytopenia
needed. Performing an exercise ECG reasonably allows ruling out Elevated cardiac troponin levels Elevated cardiac troponin levels
an ACS in most cases [54] and has become standard practice in
ST-​segment deviation ST-​segment deviation
this subgroup in many CPUs. Stress imaging with echocardiog-
Haemodynamics on presentation
raphy (see E Chapter 18.1), nuclear MPI, or CMR imaging (see
(systolic blood pressure, heart rate)
E Chapter  20) may be of help, especially in the presence of a
Clinical instability (shock, ventricular
non-​interpretable ECG or in patients unable to exercise [55–​57].
arrhythmias)
Finally, a multidetector CT may accurately detect coronary le-
Heart failure (past or present)
sions and has proven useful for the non-​invasive evaluation of CP
patients in the emergency room [58]. Prior vascular/​CAD Liver cirrhosis
A rest echocardiogram allows a rapid assessment of ventricular History of prior bleeding
function and helps identify other causes of CP and should be Intensity of antithrombotic
available in the emergency room [33]. treatment (number of drugs, excess
dosing)
Invasive cardiac procedures
Risk stratification Female gender
Need for oral anticoagulation
Early risk assessment is essential to identify patients at highest
short-​term risk, who benefit from an earlier invasive strategy Chronic use of oral NSAIDs or
[33,  59]. The risk of ACS relates to the severity of myocardial steroids
536 CHAPTER 41   N on - ST -segment elevat ion acu te c orona ry  sy n dro m es

important that should lead to a shift in the management strategy which are incorporated into a continuous model. The risk calcula-
towards an emergent invasive strategy. tion is complex and requires a specific calculator (available from:
The ECG contains important prognostic information on M https://​www.outcomes-​umassmed.org/​grace/​acs_​risk2/​index.
NSTE-​ACS patients. A new ST-​segment depression—​even as low html).
as 0.5 mV—​is strongly associated with higher mortality, more Given the risk of secondary effects due to antithrombotic
severe coronary disease, and a greater benefit of an early inva- therapies and invasive strategies—​key steps in the management
sive strategy [60–​62]. The magnitude and extent of ST-​segment of NSTE-​ACS—​mostly bleeding, and the increased mortality
depression provide additional prognostic information [63]. ST-​ risk associated with bleeding [33, 80–​83], risk factors for such
segment depression in the lateral leads, with elevation in aVR, complications have also been identified (see E Table 41.2) and
predicts extensive subendocardial ischaemia, often due to left specific tools developed. Several bleeding scores have been de-
main or multivessel disease, and a particularly poor prognosis veloped for patients with ACS [78, 82, 84] or who have under-
[64, 65]. The prognostic implications of negative T-​waves are less gone PCI [85–​88]. However, a pragmatic approach for defining
important [60,  61], although evolving deep, symmetrical, nega- high bleeding considering the main factors related to this (age,
tive T-​waves in the anterolateral leads usually indicate a proximal comorbidities, laboratory results, prior CNS damage, bleeding
LAD involvement. history, and prescribed drugs—​DAPT, oral anticoagulation, or
NSAIDs) may be preferable [89].
Biomarkers While assessment of ischaemic and bleeding risk should be
helpful to tailor antithrombotic therapy, including drugs and dur-
Cardiac troponin is the key biomarker for diagnosis and risk
ation, there is considerable overlap between predictors of high is-
stratification, as it is not only needed for the modern definition
chaemic risk and high bleeding risk (see E Table 41.2). However,
of MI [1]‌, but it also indicates the patients with NSTE-​ACS with
when concordant, bleeding risk should be considered more im-
an increased thrombotic burden, as well as with higher short-​
portant than ischaemic risk in guiding DAPT duration, at least in
and long-​term mortality and reinfarction rates [66–​68]. This
patients who had undergone complex PCI, because these derive
increased risk is independent of that predicted by clinical evalu-
benefit from long-​term DAPT only if high bleeding risk features
ation and ECG. Other biomarkers (E see Chapter  32), such
were not present [90].
as BNP, NT-​proBNP [69, 70], high-​sensitivity CRP, or copeptin,
are also associated with long-​term prognosis [69, 71–​74] but
are not used in routine practice, due to their marginal incre-
mental value in predicting short-​term outcomes and lack of help Treatment
in selecting the initial management over standard evaluation.
Other haematological or biochemical determinations, such as General management
white blood cell count, creatinine, or glycaemia on admission Treatment of ACS should be integrated in the clinical man-
or in the first fasting sample, provide prognostic information agement of patients with CP/​ suspected ACS, as shown in
as well [33]. Finally, it is essential to assess renal function—​ E Figure 41.5. As soon as ACS is suspected, an ECG must
preferably by calculating the creatinine clearance or eGFR—​not be performed immediately to rule out ST-​segment elevation
only because it is related to long-​term mortality, but also to or STEMI equivalent (see E Figure 41.3). If there is no ST-​
help select the pharmacological treatment and adjust doses, if segment elevation in an ECG with interpretable repolarization
necessary [33]. (ST-​segment level may not be interpretable in the presence of
LBBB, pacemaker stimulation, or major QRS abnormalities
Risk scores for prognosis assessment in acute such as pre-​excitation), the diagnosis of NSTE-​ACS should be
coronary syndrome patients confirmed and, at the same time, early risk stratification per-
While qualitative risk stratification is simple and helps select formed. When NSTE-​ACS is confirmed, treatment with anti-​
patients with an elevated risk of adverse cardiovascular events, ischaemic and antithrombotic drugs should be started and
it does not allow to estimate the absolute risk for each patient, coordinated with the planned strategy of coronary angiography
precluding from weighing the individual patient’s risk with the and revascularization (see E Figure 41.5).
potential benefits and risks associated with the use of available
therapies. Quantitative risk estimations are more helpful than Initial treatment
qualitative risk stratifications in guiding therapy for ACS patients. Ongoing CP should be treated with sublingual or IV nitrogly-
The GRACE risk score is the most discriminative tool for risk pre- cerin to relieve ischaemia and discomfort. Morphine may be
diction, with external validation and ability to predict in-​hospital, used in refractory cases but should not be used routinely, given
6-​month, 1-​ year, and 3-​ year outcomes (death or death/​ MI) the risk of reducing gastric absorption of oral antithrombotic
[75–​79] using eight items:  (1) age; (2)  heart rate on admission; drugs [91, 92]. However, when morphine is needed, occlusion of
(3) systolic blood pressure on admission; (4) Killip class; (5) ini- a large coronary artery with low ECG expression (i.e. posterior
tial serum creatinine concentration; (6) cardiac arrest at admis- or posterolateral infarcts due to circumflex occlusion) should be
sion; (7) ST-​segment deviation; and (8) elevated cardiac markers, suspected and immediate coronary angiography performed. O2
 T re atm e n t 537

1 2 3 4 5
Clinical ECG Diagnosis/ Medical Invasive
evaluation (<10 min) risk assessment treatment strategy

Primary
STEMI PCI
(<90 min)
Thrombolysis
If primary PCI not
timely available Emergent
<2 hours

Quality of • hs-cTn level and evolution

chest pain • Clinical presentation Anti-ischaemic Urgent
Clinical (BP, HR) therapy 2–24 hours
context • ECG presentation Antiplatelet
ECG NSTE-ACS • Past history
Probability therapy
of CAD • Ischaemic and bleeding risk Early
• Additional information Anticoagulation 24–72
Physical
(labs, imaging...) hours
examination

No or
ACS unclear elective
Chest pain
(rule out ACS)
unit

No ACS Rule out non-cardiac

causes

Figure 41.5  General approach to the patient with chest pain/​suspected ACS. * Three to 12 hours after thrombolysis. ACS, acute coronary syndromes; BP, blood
pressure; CAD, coronary artery disease; HR, heart rate; PCI, percutaneous coronary intervention; STEMI, ST-​segment elevation myocardial infarction.
Reproduced from Bueno H. Non-​ST-​segment elevation acute coronary syndromes. In: Bueno H, Vranckx P, eds. The Acute Cardiovascular Care Association Clinical Decision-​Making
Toolkit, 2018 Edition. ESC Editions, Nice 2018 with permission from European Society of Cardiology.

should only be used in patients with dyspnoea and/​or SpO2 of patients or with one glycoprotein IIb/IIIa inhibitor (GPI), usually
<90% [93, 94]. as rescue therapy. In the absence of contraindications, all patients
with ACS should receive initially a loading dose of 150–​300 mg of
Antithrombotic therapy chewed plain aspirin [96], followed by a daily maintenance dose of
Given the pathophysiology of NSTE-​ACS, most frequently based 75–​100 mg [95]. For patients with an aspirin allergy, rapid desensi-
on intracoronary thrombosis triggered by platelet aggregation, tization protocols have been shown to be effective. Aspirin should
antiplatelet therapy plays an essential role in the treatment of this be combined with one oral P2Y12 inhibitor, preferably one of the
disease. Temporary anticoagulation is also required to stabilize two more rapid, potent, and predictable oral antiplatelet agents—​
the process. ticagrelor (180 mg loading dose, followed by 90 mg twice daily)
or prasugrel (60 mg loading dose, followed by 10 mg once daily)
Antiplatelet therapy (see E Figure 41.6)—​as they improve clinical outcomes, com-
Platelet activation and subsequent aggregation play a key role in the pared with clopidogrel. Ticagrelor showed superiority, compared
pathophysiology of ACS. Therefore, antiplatelet therapy should be with clopidogrel [97], regardless of the revascularization type or
instituted as early as possible when the diagnosis of ACS is made, in strategy, including treatment with PCI [98], CABG [99], or medical
order to reduce the risk of progression or recurrence of ischaemic management [100], while prasugrel is superior to clopidogrel only
complications. Platelets can be inhibited by three classes of drugs when used in the catheterization laboratory in patients undergoing
with distinct mechanisms of action (see E Chapter 39): aspirin PCI [101], as early treatment with prasugrel before coronary angi-
(acetylsalicylic acid), P2Y12 platelet receptor inhibitors (oral such ography [102] or its use for medically managed patients [103] pro-
as clopidogrel, prasugrel, and ticagrelor; or IV such as cangrelor), vides no clinical benefit and increases major bleeding. All P2Y12
and GPIs (tirofiban, eptifibatide, and abciximab). inhibitors increase the risk of bleeding, more often the two more
In general, patients with NSTE-​ACS should be treated with potent drugs. Additionally, ticagrelor causes dyspnoea and ven-
dual antiplatelet therapy (DAPT), combining aspirin with one oral tricular pauses. Therefore, prasugrel or ticagrelor are preferred first
P2Y12 inhibitor. Specific recommendations for the use of DAPT and if not available or for patients at high bleeding risk, clopidogrel
have been published [95]. Occasionally, patients may need IV (300 mg loading dose, followed by a 75 mg dose once daily) [104] is
platelet inhibition during PCI, either with cangrelor in P2Y12-​naive indicated, regardless of the management strategy.
538 CHAPTER 41   N on - ST -segment elevat ion acu te c orona ry  sy n dro m es

Non ST-segment elevation ACS

Pharmacological Myocardial
treatment revascularization

Antithrombotic Anti-ischaemic Other preventative

therapy therapy therapies
• Nitrates • Statins
• β-blockers • ACE inh. (or ARB)
• Calcium antagonists • Other specific
therapies
Anticoagulation Antiplatelet PCI
One of the following: Aspirin + one CABG
• Fondaparinux P2Y12 inhibitor:
• Enoxaparin • Ticagrelor
• UFH • Prasugrel
• Clopidogrel

Figure 41.6  General overview of the treatment of NSTE-​ACS. ACE, angiotensin-​converting enzyme; ACS, acute coronary syndromes; ARB, angiotensin receptor
blocker; CABG, coronary artery bypass grafting; PCI, percutaneous coronary intervention; UFH, unfractionated heparin.
Reproduced from Bueno H. Non-​ST-​segment elevation acute coronary syndromes. In: Bueno H, Vranckx P, eds. The Acute Cardiovascular Care Association Clinical Decision-​Making
Toolkit, 2018 Edition. ESC Editions, Nice 2018 with permission from European Society of Cardiology.

The benefits of treatment with clopidogrel are limited by a Two strategies for DAPT can be used in patients with NSTE-​
number of factors such as a slow beginning of its antiplatelet ef- ACS (see E Figure 41.7). An early initiation strategy, commonly
fect, a reduced and hardly predictable maximal level of platelet called ‘pre-​treatment’ (but incorrectly as it does not precede the
inhibition, and a wide variability in the pharmacodynamic re- pathophysiological situation or the clinical event), is defined by
sponse to clopidogrel, influenced by genotype polymorphisms of routine initiation of DAPT with aspirin plus one P2Y12 inhibitor,
enzymes needed for its intestinal absorption or its conversion to early after NSTE-​ACS diagnosis and before knowing the coronary
its active metabolite, and the interactions produced by drugs that anatomy and therefore the revascularization plan. This was the
activate or inhibit cytochrome P450. All interventions directed approach used when clopidogrel or ticagrelor were tested for the
to overcome these limitations, such as use of higher loading and management of ACS and showed their efficacy, compared with
maintenance doses of clopidogrel [84], use of genetic testing, or placebo and clopidogrel, respectively, in all patients, regardless of
ex vivo platelet function to guide changes in DAPT, failed to im- the management strategy, including those who underwent PCI
prove outcomes. or CABG or those medically managed, at the price of increasing

Strategy 1: Early DAPT initiation

CABG
Pharmacological
treatment
• Aspirin + ticagrelor
(or clopidogrel) Coronary PCI
NSTE-ACS angiography
• Anticoagulation
• Anti-ischaemic drugs
• Other therapies
Medical
management

Strategy 2: Delayed DAPT initiation

PCI
Pharmacological
treatment Prasugrel
NSTE-ACS • Aspirin Coronary
• Anticoagulation angiography Alternative
• Anti-ischaemic drugs antiplatelet
• Other therapies strategy CABG or
medical
management

Figure 41.7  Strategies for DAPT in patients with NSTE-​ACS. ACS, acute coronary syndrome; AP, antiplatelet; CABG, coronary artery bypass grafting; PCI,
percutaneous coronary intervention.
 T re atm e n t 539

major bleeding [97, 105]. Early DAPT treatment initiation is con- of 5000 IU. Bivalirudin may be considered as an alternative op-
troversial for a number of reasons. The first reason is the lack of tion for anticoagulation in patients at high bleeding risk, but the
evidence on the trade-​off in efficacy and safety of the use of these risk/​benefit ratio and cost-​effectiveness of this option is unclear.
drugs with an early versus a delayed strategy (which proved to be Fondaparinux at a 2.5 mg fixed daily SC dose is the preferred pre-​
ineffective and associated with more bleeding when tested with procedural anticoagulation regime in patients with NSTE-​ACS
prasugrel) [102]. Although this evidence is still lacking, a recent not requiring full anticoagulation for another reason (i.e. AF)
open-​label randomized trial comparing an early strategy with and not undergoing an urgent invasive strategy. It is as effective
ticagrelor versus a delayed strategy with prasugrel in 4018 patients as enoxaparin in preventing ischaemic events but halves major
with ACS with an invasive strategy planned showed a superiority bleeds and reduces 30-​day mortality [112], although it is not an
of prasugrel over ticagrelor in the primary endpoint of death, MI, adequate anticoagulation to be used alone for coronary angiog-
or stroke at 1 year (6.9% versus 9.3%, HR for ticagrelor 1.36, 95% raphy, when additional anticoagulation with UFH during the pro-
CI 1.09–​1.70; P = 0.006), with no increase in major BARC scale cedure is needed [113]. Enoxaparin may be used if fondaparinux
bleedings (5.4% for ticagrelor versus 4.8% for prasugrel, HR 1.12, is not available, at an SC dose of 1 mg/​kg twice a day, which should
95% CI 0.83–​1.51; P = 0.46) [106]. The second limitation of an be reduced to 0.75 mg/​kg/​12 hours in patients >75 years of age or
early DAPT strategy is the possibility that the patient becomes to 1 mg/​kg once daily in patients with a creatinine clearance of
a candidate for surgical coronary revascularization, given that <30 mL/​min, due to a severe increase in bleeding risk [114], but it
both clopidogrel and ticagrelor increase the rate of post-​operative is associated with a higher rate of bleeding.
bleeding and the need for blood transfusion and reoperation Antithrombotic therapy in patients needing oral anticoagulation
after CABG, which often leads to delays in surgery to prevent Approximately 6–​ 8% of patients admitted with NSTE-​ ACS
these complications. However, despite this increase in bleeding, have an indication for oral anticoagulation such as AF, mech-
early DAPT with ticagrelor or clopidogrel showed better clin- anical heart valves, or VTE. Because a combination of oral
ical outcomes in surgically treated patients [99, 107], essentially anticoagulation with antiplatelet therapy increases significantly
preventing events before surgery (see E Chapter 43). Therefore, the risk of bleeding, management of these patients is challen-
either the early use of an early DAPT strategy in very high-​or ging [95,  115]. In these patients, it is especially important to
high-​risk patients who may be surgical candidates and the deci- minimize the risk of PCI-​related complications. In this respect,
sion to interrupt DAPT before CABG, when this has been decided radial access is always preferred and it is recommended that
to prevent perioperative bleeding need to be carefully balanced. PCI be performed without interrupting oral anticoagulation
A third limitation of an early strategy is the possibility of treating therapy, unless overdosing is suspected; GPIs should, in gen-
DAPT patients in whom this therapy may be dangerous if an al- eral, be avoided and, among P2Y12 platelet inhibitors, only
ternative disease is the cause of the clinical situation (i.e. aortic clopidogrel should be used [30]. The duration of triple therapy
dissection) or in patients with no significant CAD. should be kept as short as possible, and PPIs are recommended.
At the present time, with fast and potent oral antiplatelet treat- In patients receiving VKAs, the INR should be carefully main-
ment available and routinely used, upstream IV antiplatelet tained close to the lower limit of the recommended target range.
therapy has no role, although it may be required during PCI. Four major trials have compared the safety of a regimen of
Cangrelor, a fast and potent IV P2Y12 receptor inhibitor, may NOACs plus a P2Y12 inhibitor with that of VKAs plus dual or
help reduce periprocedural ischaemic complications and post-​ single antiplatelet therapy in AF patients undergoing PCI (one
procedural stent thrombosis, particularly in patients without pre- of the trials also included patients with medically managed
vious P2Y12 inhibition [108–​111]. However, despite its two major ACS) [116–​119]. According to their results, the combination of
advantages—​being reversible and having a very short plasma VKAs plus DAPT should generally be avoided and a regimen of
half-​life, it does increase major bleeds. Glycoprotein IIb/​IIIa re- NOACs plus a P2Y12 inhibitor—​with or without a short period
ceptor inhibitors—​tirofiban, eptifibatide, and abciximab—​may be of concomitant aspirin—​may be the preferred option for most
useful for bailout situations or difficult procedures due to large of these patients.
thrombus burden or acute thrombotic complications.

Anticoagulation Anti-​ischaemic therapy
Anticoagulation, in addition to platelet inhibition, reduces is- Anti-​ischaemic drugs decrease myocardial O2 demand and/​or
chaemic events in patients with NSTE-​ACS (see E Chapter 39). increase O2 supply and, in NSTE-​ACS, are mainly aimed at pro-
In general, anticoagulation should be initiated after the diagnosis viding symptomatic relief.
has been established and stopped after completion of coronary
revascularization, unless another indication for anticoagulation Nitrates
is present. If coronary angiography is planned in a very short Sublingual nitroglycerin can abrogate anginal crises. IV nitro-
time (i.e. a few hours), anticoagulation may be delayed until glycerin is more effective but needs blood pressure monitoring,
initiation of the procedure. For the procedure, anticoagulation as it may cause significant hypotension. There is no indication
with UFH is the standard of care, using a weight-​adjusted dose, for nitrates beyond symptom control, as there is no evidence of
with an initial IV UFH bolus of 70–​100 IU/​kg and a maximum outcome improvement unless there is concomitant LV failure or
540 CHAPTER 41   N on - ST -segment elevat ion acu te c orona ry  sy n dro m es

vasospastic angina. Nitrates should be avoided in hypotensive pa- interventions carrying a high risk of bleeding avoided if possible.
tients and in those on phosphodiesterase-​5 inhibitors. Blood transfusions may be harmful and should be restricted to pa-
tients with haemodynamic compromise or severe anaemia (haem-
Beta-​blockers atocrit value <25% or Hb level <7 g/​dL). Iron supplements are
Beta-​blockers reduce myocardial O2 consumption by lowering indicated if iron deficiency is detected, but erythropoietin or its de-
heart rate, blood pressure, and contractility and may reduce the rivatives must be avoided in the acute setting, because their use has
rates of recurrent ischaemia or reinfarction and improve prognosis been associated with an increased rate of thrombotic events.
in NSTE-​ACS patients [120]. Oral β-​blockers are often initiated PPIs are recommended in patients with a previous indication
in NSTE-​ACS patients and are mandatory in those with LV dys- or in those at increased risk of GI haemorrhage, including those
function, in the absence of contraindications (bradycardia or AV with a prior history of bleeding or peptic disease and patients
conduction disturbances, bronchospasm, decompensated heart needing oral anticoagulation and DAPT.
failure, or a history of asthma). IV β-​blockers are rarely needed but
can be useful in patients with severe hypertension or tachycardia, Invasive strategy
provided that they do not have significant heart failure. Recent The performance of invasive coronary angiography (see
studies suggest that the use of β-​blockers in patients without heart E Chapter 43) during the acute phase, with the objective to at-
failure or LV dysfunction may produce no long-​term benefit [121]. tempt coronary revascularization whenever feasible, defines an
A number of randomized trials are currently testing this indication. invasive strategy. As coronary revascularization improves prog-
nosis, relieves symptoms, and shortens hospital stay in patients
Calcium channel blockers with NSTE-​ACS, deciding a strategy for coronary angiography
CCBs are vasodilators with varying effects on cardiac contractility, and revascularization is one of the key steps in their management
heart rate, and AV conduction. Short-​acting nifedipine may in- (see E Figure 41.4) and is recommended in the majority of pa-
duce tachycardia and hypotension and should be avoided. In con- tients. Only low-​risk patients or those who are not candidates for
trast, verapamil or diltiazem have an anti-​ischaemic effect, similar coronary revascularization for any given reason are not candidates
to that of β-​blockers, and may reduce the risk of adverse events. for an invasive strategy. Thus, risk stratification should be per-
CCBs are usually indicated in patients with contraindications to formed early to identify intermediate-​to high-​risk patients who
β-​blockers or, in combination with other anti-​ischaemic drugs, in are candidates for an invasive approach, to select the timing, and
those with refractory angina, and they are the preferred therapy in to decide on the antithrombotic strategy accordingly. The man-
the subset of patients with vasospastic angina. agement of NSTE-​ACS patients without coronary angiography
and revascularization is called a conservative, non-​invasive, or
Other treatments selective invasive strategy, and patients not undergoing coronary
Secondary prevention therapy should be initiated early during revascularization are often defined as medically managed. These
admission. High-​ dose statins are always indicated with LDL patients tend to have a worse prognosis [125, 126].
cholesterol target according to risk [122]. As mentioned earlier, The invasive strategy may be routine or selective. A  routine
β-​blockers are recommended in patients with LV dysfunction invasive strategy consists of a systematic approach with invasive
and/​or heart failure. ACE-​Is or, if not tolerated, ARBs are recom- coronary angiography in all patients with NSTE-​ACS without
mended for patients with an LVEF of ≤40% and in those with contraindications. This is in contrast with a selective invasive
heart failure, diabetes, hypertension, or chronic renal failure, in strategy, in which only patients with specific high-​risk features,
the absence of contraindications, and can protect also against vas- such as the presence of inducible myocardial ischaemia in non-​
cular events in all other patients. invasive tests or recurrence of symptoms, undergo coronary
Acute management of glycaemia, as well as long-​term treatment angiography. Several RCTs have compared the clinical efficacy of
of diabetes mellitus, is important in NSTE-​ACS. Hyperglycaemia a routine invasive versus a conservative or selective invasive ap-
(see E Chapter 67) is associated with a worse prognosis in NSTE-​ proach, with contradictory results in individual trials [127–​132],
ACS, both in diabetic patients and in those without known dia- as well as in the results of a number of meta-​analyses evaluating
betes. SC or IV insulin should be administered to these patients the effect on short-​term and long-​term outcomes [133–​138].
to avoid severe hyperglycaemia (>180 mg/​dL or 10 mmol/​L), with This inconsistency may be explained by differences in the rou-
care not to induce hypoglycaemia which has been proven to be tine pharmacological therapy that the patients received, changes
dangerous, especially in critically ill patients [123]. The recom- in the use of technical advances for coronary revascularization,
mendations for the management of diabetes mellitus in patients including coronary stents, and the variable definitions of what
at high cardiovascular risk have been updated recently [124] is a true conservative strategy. In general, a routine invasive
and now, in addition to metformin, early use of sodium–​glucose strategy reduces ischaemic recurrences and the need for future
cotransporter-​2 inhibitors or glucagon-​ like peptide-​
1 receptor coronary revascularization without reducing mortality, at the
agonists should be incorporated into routine therapies, given the price of an increased risk of periprocedural complications, par-
magnitude of clinical cardiovascular benefits (see E Chapter 67). ticularly in troponin-​negative women [135], and is recommended
Hb levels should be measured on admission (see E Chapter 68). for patients at intermediate to high risk, particularly those with
In patients with anaemia, the cause should be investigated, and troponin elevation [33]. This is also true for older patients [139].
 T re atm e n t 541

By contrast, it is not recommended for low-​risk patients. It is im- renal insufficiency, an LVEF of <40%, early post-​infarction angina,
portant that, whenever possible, radial access is used to reduce recent PCI, and prior CABG, an early routine invasive strategy (be-
the risk of bleeding and mortality [140]. tween 24 and 72 hours) is recommended. Other patients should
undergo further risk stratification with non-​invasive testing be-
Timing of invasive strategy fore hospital discharge, and coronary angiography performed if
Based on the very high short-​term risk, but with no clinical evi- there is evidence of significant myocardial ischaemia [33] (see
dence, it is recommended that patients with clinical or haemo- E Figure 41.8).
dynamic instability (refractory angina, severe heart failure, CS,
severe MR) or presenting with life-​threatening ventricular ar- Coronary revascularization
rhythmias should undergo an emergent invasive approach (within Coronary angiography reveals the absence of significant CAD
2 hours), regardless of the ECG or biomarker findings [33]. The in 15–​20% of patients [126], more frequently women [145], who
optimal timing for a routine invasive strategy is not well estab- are not candidates for revascularization. In such patients, using a
lished [141]. Observations from two randomized trials found provocation test to detect coronary vasospasm may be advisable.
that high-​risk patients, those with a GRACE risk score of >140, or Single-​vessel disease is found in approximately one-​third of pa-
those with troponin elevation may obtain a long-​term mortality tients, and multivessel disease in half of them [146, 147], a more
benefit if coronary angiography and revascularization are per- frequent finding than in patients with STEMI. Despite the lack
formed in the first 24 hours [142, 143]. However, there is no solid of RCTs comparing revascularization versus medical therapy or
evidence to suggest that an urgent routine invasive strategy (within revascularization with PCI versus CABG specifically in patients
24 hours) is appropriate for all patients [144]. The ESC guidelines with NSTE-​ACS, coronary revascularization is recommended,
recommend to consider this strategy for patients with a GRACE whenever feasible, if significant CAD is present, given the high
risk score value of >140, troponin elevation, or dynamic ECG risk of recurrent events in these patients. In general, PCI is the
changes (symptomatic or silent). For patients with GRACE risk preferred technique for the majority of patients with NSTE-​
score values of <140, but with the presence of diabetes mellitus, ACS, while CABG is indicated in 4–​10% of cases [129]. Different

Symptom onset

First medical contact NSTE-ACE diagnosis

PCI centre EMS or non-PCI centre

Immediate transfer to PCI centre

Very high Very high

Same-day transfer
Risk stratification

High High

Transfer
Intermediate Intermediate

Transfer
optional
Low Low
Therapeutic
strategy

Immediate Early Non-invasive

Invasive
invasive invasive testing if
(<72 hour)
(<2 hour) (<24 hour) appropriate

Figure 41.8  Timing of invasive strategy for NSTE-​ACS patients according to the ESC Guidelines. EMS, emergency medical services; PCI, percutaneous coronary
intervention.
Reproduced from Roffi M, Patrono C, Collet JP, et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-​segment
elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-​Segment Elevation of the European Society of Cardiology (ESC).
Eur Heart J 2016;37:267–​315 with permission from Oxford University Press.
542 CHAPTER 41   N on - ST -segment elevat ion acu te c orona ry  sy n dro m es

revascularization strategies can be used in patients with multivessel CABG to prevent perioperative bleeding has been discussed pre-
disease: multivessel PCI (either complete revascularization at one viously. (See also E Chapters 42 and 43.)
time or PCI of the culprit lesion and scheduled PCI of pending
lesions), combined revascularization (i.e. PCI of the culprit le- Planning secondary prevention and follow-​up
sion and later surgical revascularization of the rest of the cor- Patients must receive education about the disease, the risk factors,
onary arteries), or CABG only. The decision to use one or another and the importance of self care, including counselling regarding
revascularization mode depends on the coronary anatomy, the healthy diet, physical activity, smoking cessation, vaccination, and
patient’s clinical profile, the estimated risk, and preferences. Local reinitiation of sexual activity after discharge, as well as additional
availability and results may be considered as additional infor- advice and psychological support. Formal rehabilitation and sec-
mation. For PCI, complete revascularization offers better long-​ ondary prevention programmes integrated in the hospital and
term results than culprit lesion revascularization only [148]. The outpatient care continuum should be made available for these pa-
decision in complex patients should be taken by heart teams, tients [151] (see E Figure 41.9) After discharge, patients should
including clinical cardiologists, interventionalists, and cardiac be followed up to re-​evaluate compliance with lifestyle and medi-
surgeons. Technical issues regarding coronary revascularization cation recommendations, adequate control of risk factors, and
are discussed elsewhere [149] (see E Chapter 4). In patients with psychosocial factors, and, if needed, secondary prevention ther-
surgical indication who can be stabilized without PCI and whose apies should be adjusted with dose changes or other therapies.
immediate risk is not very high (i.e. critical thrombotic stenosis),
CABG can be delayed for some days [150], but in general, patients Indicators for assessing quality of acute care
with left main or three-​vessel disease involving the proximal LAD Systematic assessment of the quality of care during the man-
artery should be submitted for surgery during initial hospitaliza- agement of AMI has been recommended by the ESC [152]. For
tion. The risk–​benefit of withdrawing P2Y12 inhibitors before this, a set of quality indicators covering different dimensions of

NSTE-ACS
Hospitalization

1. Acute care
• Medical therapy
• Coronary revascularization
2. Search for unknown/suboptimal controlled risk factors
3. Initiate standard secondary prevention

Plan and schedule Education and advice Standard secondary

cardiac rehabilitation prevention therapy

• Risk factor control (weight

control, smoking cessation,
blood pressure, and lipid Antithrombotic Lipid lowering BP/LVD/HF control Glucose control
control) therapy
• Diet/nutritional counselling
• Physical activity Aspirin + P2Y12 High-intensity statin ACEI/ARB*, β- SGLT2i*, GLP-1ra*,
counselling/exercise inhibitor [12 mo] therapy blockers*, MRA* metformin, insulin*
training
• Psychological management
Cardiac rehabilitation • Sexual advice
programme • Vocational advice

Re-evaluate lifestyle, control of risk factors, psychosocial factors, and compliance with medications
Adjustment of secondary prevention therapies

Reinforce education After 12 mo consider*: Consider adding Dose adjustment, Consider

Psychosocial support ticagrelor 60 mg bid or ezetimibe* consider SGLT2i*, GLP-1ra*,
After discharge rivaroxaban 2.5 mg bid PCSK9 inhibitor* sacubitril/valsartan* insulin*

Figure 41.9  Comprehensive secondary prevention plan for patients with NSTE-​ACS in a care continuum. ACE-​I, angiotensin-​converting enzyme inhibitor;
ARB, angiotensin receptor blocker; BP, blood pressure; GLP1-​ra, glucagon-​like peptide-​1 receptor agonist; HF, heart failure; LVD, left ventricular dysfunction; MRA,
mineralocorticoid receptor antagonist; PCSK9, proprotein convertase subtilisin kexin 9; SGLT2i, sodium–​glucose cotransporter-​2 inhibitors. * When individually
indicated and without specific contraindications.
Reproduced from Cortés-​Beringola A, Fitzsimons D, Pelliccia A, Moreno G, Martín-​Asenjo R, Bueno H. Planning secondary prevention: Room for improvement. Eur J Prev Cardiol
2017;24(3_​suppl):22–​28. doi:10.1177/​2047487317704954 with permission from SAGE.
 PER S ONA L PE R SPE C T I V E 543

Box 41.1  Quality indicators for the acute management of NSTE-​ACS

Structural conditions Patient satisfaction
◆ Centre organization: belonging to a structured network ◆ Feedback regarding the patient’s experience:
organization Pain control
●

Performance measures Quality of explanations received about CAD, benefit/​risk of

●

Invasive
◆ strategy: discharge therapies, and medical follow-​up
● Coronary angiography in high-​ischaemic risk patients without Discharge information regarding what to do in case of
●

contraindications symptom recurrence, recommendation to attend a cardiac

rehabilitation programme (including smoking cessation and
◆ In-​hospital risk assessment:
diet counselling)
Assessment of ischaemic and bleeding risk (i.e. use of GRACE
●

and CRUSADE risk scores) Outcomes

Assessment of LVEF before discharge
● ◆ GRACE 2.0 risk score-​adjusted 30-​day mortality rate
Antithrombotic treatment during hospitalization:
◆ Composite pharmacology quality indicator
Low-​
● dose aspirin (unless high bleeding risk or oral ◆ All-​or-​none prescriptions based on three components (or five
anticoagulation) components if LVEF ≤0.40):
Proportion of patients with ‘adequate’ P2Y12 inhibition
●
Low-​dose aspirin
●

Secondary prevention—​discharge treatments:

◆
P2Y12 inhibitor (unless documented contraindication)
●

● High-​intensity statins (i.e. atorvastatin ≥40 mg or rosuvastatin High-​intensity statins

●

≥20 mg) prescribed at discharge unless contraindicated And if clinical evidence of heart failure or LVEF ≤0.40:
◆
ACE-​I (or ARB if intolerant of ACE-​I) prescribed at dis-
●
ACE-​I (or ARB if intolerant of ACE-​I)
●
charge in patients with clinical evidence of heart failure or
LVEF ≤0.40 unless contraindicated β-​blockers
●

β-​blockers prescribed at discharge in patients with clinical evi-

●

dence of heart failure or LVEF ≤0.40 unless contraindicated

ACS care have been described, including structural conditions, discharge are more frequent in patients with NSTE-​ACS. Thus,
performance measures, outcomes, and patient satisfaction (see there is catch-​up in the mortality risk of patients with NSTE-​
E Box 41.1). Higher compliance with these quality indicators ACS, compared with those with STEMI, after 6–​12  months
by treating centres has been shown to be associated with lower of the initial event [59,  155]. The higher incidence of recur-
mid-​and long-​term mortality [153, 154]. rent events is mostly explained by their older age, more ex-
tensive CAD, and a greater prevalence of comorbidities than
in STEMI patients [2, 6, 60, 155]. Identification of higher-​risk
Long-​term prognosis patients and intensive secondary prevention measures are
In general, the long-​term prognosis after an NSTE-​ACS is not warranted in this population. For that, risk scores have been
benign. In contrast to the early phase, recurrent events after developed [156].

Personal perspective
NSTE-​ ACS are potentially life-​ threatening disorders, most therapy, and a timely invasive strategy, guided by an initial risk
frequently caused by acute thrombotic complications com- stratification assessing ischaemic and bleeding risk. Coronary
plicating chronic coronary atherosclerotic lesions. Early revascularization is warranted in the majority of patients, ei-
diagnosis, including clinical evaluation of symptoms and the ther with PCI or CABG, according to the coronary anatomy
patient’s cardiovascular risk, ECG interpretation and evalu- and other clinical factors, as well as aggressive secondary pre-
ation of repolarization changes, assessment of troponin levels in vention therapy, including strict control of risk factors and
time, and a differential diagnosis, should be made in the initial treatment with statins and drugs to prevent the progression of
phase. After the diagnosis is established, optimal management LV dysfunction or heart failure, such as ACE-​Is or ARBs, when
of NSTE-​ACS includes early antithrombotic treatment, with these are present, which should be planned and started in hos-
oral DAPT and temporary anticoagulation, anti-​ ischaemic pital and re-​evaluated and updated after discharge.
544 CHAPTER 41   N on - ST -segment elevat ion acu te c orona ry  sy n dro m es

Further reading
Adlam D, Alfonso F, Maas A, Vrints C; Writing Committee. European Kaski JC, Crea F, Gersh BJ, Camici PG. Reappraisal of ischemic heart
Society of Cardiology, acute cardiovascular care association, SCAD disease. Circulation 2018;138:1463–​80.
study group:  a position paper on spontaneous coronary artery Scalone G, Niccoli G, Crea F. Pathophysiology, diagnosis and
dissection. Eur Heart J 2018;39:3353–​68. management of MINOCA:  an update. Eur Heart J Acute Cardiovasc
Gallone G, Baldetti L, Pagnesi M, et  al. Medical therapy for long-​ Care 2019;8:54–​62.
term prevention of atherothrombosis following an acute coronary Szummer K, Jernberg T, Wallentin L. From early pharmacology to recent
syndrome: JACC state-​of-​the-​art review. J Am Coll Cardiol 2018;72(23 pharmacology interventions in acute coronary syndromes:  JACC
Pt A):2886–​903. state-​of-​the-​art review. J Am Coll Cardiol 2019;74:1618–​36.

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Disease), ICTUS (Invasive Versus Conservative Treatment in Coronary Treatment and Intervention Outcomes Network Registry-​
Unstable Coronary Syndromes), and RITA-​3 (Intervention Versus Get With The Guidelines). JACC Cardiovasc Interv 2010;3:419–​27.
Conservative Treatment Strategy in Patients With Unstable 151. Cortés-​Beringola A, Fitzsimons D, Pelliccia A, et al. Planning sec-
Angina or Non-​ST Elevation Myocardial Infarction) Trials. JACC ondary prevention:  room for improvement. Eur J Prev Cardiol
Cardiovasc Interv 2012;5:191–​9. 2017;24:22–​8.
139. Tegn N, Abdelnoor M, Aaberge L, et  al. Invasive versus conser- 152. Schiele F, Gale CP, Bonnefoy E, et al. Quality indicators for acute
vative strategy in patients aged 80  years or older with non-​ST-​ myocardial infarction: a position paper of the Acute Cardiovascular
elevation myocardial infarction or unstable angina pectoris (After Care Association. Eur Heart J Acute Cardiovasc Care 2017;6:34–​59.
Eighty study):  an open-​label randomised controlled trial. Lancet 153. Bebb O, Hall M, Fox KAA, et al. Performance of hospitals according
2016;387:1057–​65. to the ESC ACCA quality indicators and 30-​day mortality for acute
140. Valgimigli M, Gagnor A, Calabro P, et  al. Radial versus femoral myocardial infarction:  national cohort study using the United
access in patients with acute coronary syndromes undergoing Kingdom Myocardial Ischaemia National Audit Project (MINAP)
invasive management:  a randomised multicentre trial. Lancet register. Eur Heart J 2017;38:974–​82.
2015;385:2465–​76. 154. Schiele F, Gale CP, Simon T, et al. Assessment of quality indicators
141. Jobs A, Mehta SR, Montalescot G, et  al. Optimal timing of an for acute myocardial infarction in the FAST-​MI (French Registry
invasive strategy in patients with non-​ ST-​elevation acute cor- of Acute ST-​Elevation or Non-​ST-​Elevation Myocardial Infarction)
onary syndrome:  a meta-​ analysis of randomised trials. Lancet Registries. Circ Cardiovasc Qual Outcomes 2017;10:e003336.
2017;390:737–​46. 155. Fox KAA, Anderson FAJ, Goodman SG, et al. Time course of events
142. Mehta SR, Granger CB, Boden WE, et al. Early versus delayed in- in acute coronary syndromes: implications for clinical practice from
vasive intervention in acute coronary syndromes. N Engl J Med the GRACE registry. Nat Clin Pract Cardiovasc Med 2008;5:580–​9.
2009;360:2165–​75. 156. Pocock SJ, Huo Y, Van de Werf F, et al. Predicting two-​year mortality
143. Sorajja P, Gersh BJ, Cox DA, et al. Impact of delay to angioplasty from discharge after acute coronary syndrome: an internationally-​
in patients with acute coronary syndromes undergoing invasive based risk score. Eur Heart J Acute Cardiovasc Care 2019;8:727–​37.
 CHAPTER 42

Percutaneous coronary
interventions in acute
coronary syndromes
Andreas Mitsis and Marco Valgimigli

Contents
Summary  549 Summary
Introduction  549 Acute coronary syndromes (ACS) remain the most common disease in acute
Percutaneous coronary intervention for cardiovascular care. Historically, two groups of patients should be differentiated,
ST-​segment elevation myocardial
based on initial electrocardiographic features: patients with ongoing chest pain and
infarction  550
Primary percutaneous coronary persistent ST-​segment elevation and those with acute chest pain but no persistent
intervention  551 ST-​segment elevation. The first condition is defined as ST-​segment elevation myo-
Rescue percutaneous coronary cardial infarction and requires immediate reperfusion by primary angioplasty or
intervention  552
Facilitated percutaneous coronary fibrinolytic therapy. The second condition is defined as non-​ST-​segment elevation
intervention (and the pharmaco-​invasive acute coronary syndrome and consists of a wide spectrum of cases ranging from
approach)  552
Late percutaneous coronary
patients free of symptoms at presentation to individuals with ongoing ischaemia,
intervention  552 electrical or haemodynamic instability, or cardiac arrest. The different types of ACS
Adjunctive antithrombotic must be differentiated, as their prognosis and therapeutic strategy vary. However,
medication  553
Microvascular obstruction—​definition, over the last years, early and broad use of percutaneous coronary intervention and
prevention, and therapy  554 innovations in adjunctive antithrombotic therapy, including more effective P2Y12
Adjunctive devices  554
Drug-​eluting or bare-​metal stents in
inhibitors and new-​generation drug-​eluting stents, have resulted in a dramatic im-
ST-​segment elevation myocardial provement of prognosis across the whole spectrum of ACS patients.
infarction?  555
Radial or femoral approach?  555
How to treat multivessel disease in
ST-​segment elevation myocardial
infarction patients  555
Specific situations (cardiac arrest,
cardiogenic shock, post-​coronary artery
bypass grafting, no clear culprit lesion
Introduction
identified)  556 Percutaneous transluminal balloon coronary angioplasty (PTCA) was first performed by
Cardiac arrest  556 Andreas Grüntzig in 1977. Over the next 15 years, it developed into an effective treat-
Percutaneous coronary intervention and
mechanical circulatory support in ment method for chronic stable CAD. The Zwolle group demonstrated in 1993 the su-
cardiogenic shock  556 periority of PTCA over standalone fibrinolysis in the treatment of AMI. The combination
Primary percutaneous coronary intervention
in patients after coronary artery bypass of aspirin and thienopyridines was shown to considerably reduce the risk of thrombosis
grafting  556
Patients referred for primary percutaneous
coronary intervention with no clear culprit
lesion  557
Percutaneous coronary intervention Percutaneous coronary intervention or Bleeding post-​percutaneous coronary
for non-​ST-​segment elevation acute coronary artery bypass grafting in non-​ intervention: importance, definition, and
coronary syndromes  557 ST-​segment elevation acute coronary prevention  559
Routine invasive or early conservative (i.e. syndromes?  558 Contrast nephropathy  559
selective invasive) strategy  557 Special situations and conditions  559 Conclusion  559
Timing of angiography  558 The elderly patient  559 References  560
550 CHAPTER 42   Pe rc u taneou s c oronary interven ti on s i n  acu te c orona ry  sy n dro m es

and bleeding, as compared to aspirin and oral anticoagulation, re- undergo coronary angiography before discharge; the ideal
sulting in the widespread use of stenting, instead of plain balloon timing is within 24 hours after admission for high-​risk groups,
angioplasty. As a result, PCI—​the new name for the procedure that and within 72 hours for intermediate-​risk groups.
emerged after stents became a routine part of it—​was more and 4. Other patients with recurrent symptoms or at least one high-​
more used for the treatment of ACS, including STEMI. In 2002, risk criterion should undergo coronary angiography within 72
the PRimary Angioplasty in patients transferred from General hours of first presentation.
community hospitals to specialized PTCA Units with or without
5. Low-​risk NSTE-​ACS patients may be treated conservatively,
Emergency thrombolysis 2 (PRAGUE-​2) and DANAMI-​2 trials
and the indication for an invasive evaluation can be done based
proved that PCI (after immediate transport to a PCI-​capable
on the evidence of myocardial ischaemia during a non-​invasive
hospital) should be used as the primary reperfusion therapy of
stress testing.
STEMI also for patients presenting initially to non-​PCI hospitals.
Many large trials proved that very early coronary angiography, 6. Stent implantation is recommended at the time of PCI proced-
usually followed by immediate PCI or, in some cases, by CABG, ures, whenever technically feasible. Second-​generation DES do
was the best management strategy for moderate-​to high-​risk pa- not increase stent thrombosis and should be routinely used in
tients with NSTE-​ACS. Thus, modern therapy for all forms of STEMI and NSTE-​ACS settings.
ACS involves PCI as the most effective treatment method saving 7. Triple pharmacotherapy, consisting of aspirin, P2Y12 inhibitor,
many lives and improving symptoms for most survivors. The and parenteral anticoagulation, should be used in all PCI pro-
more severe the clinical presentation of a patient with ACS, the cedures, with GPIs to be selectively added in patients with a
higher the benefit from urgent coronary angiography/​PCI. high thrombus burden and low bleeding risk or as a bailout
Three different guidelines of the ESC cover the field of PCI [1–​ option.
3]. Their main recommendations are as follows:
1. All patients with an STEMI presenting within 12 hours from
symptom onset, or later but with evidence of ongoing is- Percutaneous coronary intervention
chaemia, should undergo immediate coronary angiography
and PCI as soon as possible after FMC. Fibrinolysis can be used for ST-​segment elevation myocardial
as an alternative reperfusion therapy if the time delay to pri- infarction
mary PCI is >2 hours.
Reperfusion therapy is indicated in all STEMI patients with
2. Patients with very high-​risk NSTE-​ACS (recurrent or ongoing symptoms of ischaemia of <12 hours’ duration and persistent ST-​
CP, profound or dynamic ECG changes, major arrhythmias, segment elevation (see E Table 42.1) [4]‌. In patients with time
or haemodynamic instability) should undergo urgent cor- from symptom onset of >12 hours, a primary PCI strategy is in-
onary angiography within <2 hours after the initial hospital dicated if there are high-​risk features like ongoing symptoms sug-
admission. gestive of ischaemia, haemodynamic instability, or life-​threatening
3. All intermediate-​to high-​risk (GRACE score >140 or at least arrhythmias [5]. A primary PCI strategy is recommended over fi-
one primary high-​risk criterion) NSTE-​ACS patients should brinolysis within indicated time frames (see E Figure 42.1) [6]. If

Table 42.1  Definitions of terms related to reperfusion therapy

Term Definition
FMC The time point when the patient is initially assessed by a physician, paramedic, nurse, or other trained EMS personnel
who can obtain and interpret the ECG and deliver initial interventions (e.g. defibrillation). FMC can be either in the pre-​
hospital setting or upon patient arrival at the hospital
STEMI diagnosis The time at which the ECG of a patient with ischaemic symptoms is interpreted as presenting ST-​segment elevation or
equivalent
Primary PCI Emergent PCI with balloon, stent, or other approved device performed on the IRA, without previous fibrinolytic treatment
Rescue PCI Emergent PCI performed as soon as possible in the case of failed fibrinolytic treatment
Routine early PCI strategy after Coronary angiography, with PCI of the IRA if indicated, performed between 2 and 24 hours after successful fibrinolysis
fibrinolysis
Pharmaco-​invasive strategy Fibrinolysis combined with rescue PCI (in case of failed fibrinolysis) or routine early PCI strategy (in case of successful
fibrinolysis)
ECG, electrocardiogram; EMS, emergency medical system; FMC, first medical contact; IRA, infarct-​related artery; PCI, percutaneous coronary intervention; STEMI, ST-​segment
elevation myocardial infarction.
Reproduced from Ibanez B, James S, Agewall S, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-​segment elevation: The
Task Force for the management of acute myocardial infarction in patients presenting with ST-​segment elevation of the European Society of Cardiology (ESC). Eur Heart J
2018;39(2):119–​177. doi:10.1093/​eurheartj/​ehx393 with permission from Oxford University Press.
Perc u tan eou s c oronary interventi on for  ST- seg m en t el evati on m yo ca rdia l i n fa rc t i on 551

Total ischaemic time

Patient delay EMS delay System delay

FMC: EMS
+

<10’ Primary <90’

Reperfusion
≤120 min PCI
(wire crossing)
STEMI strategy
diagnosis Time
to PCI?
<10’ Fibrinolysis <10’ Reperfusion
>120 min
strategy (lytic bolus)

FMC: non-PCI centre

<10’ Primary <60’ Reperfusion

PCI
(wire crossing)
STEMI strategy
FMC: PCI centre diagnosis

Patient delay System delay

Total ischaemic time

Figure 42.1  Modes of patient presentation, components of ischaemia time, and flow chart for reperfusion strategy selection. The recommended mode of
patient presentation is by alerting the EMS (call the national emergency number 112 or similar number according to region). When an STEMI diagnosis is made
in the out-​of-​hospital setting (via EMS) or in a non-​PCI centre, the decision for choosing a reperfusion strategy is based on the estimated time from the STEMI
diagnosis to PCI-​mediated reperfusion (wire crossing). System delay for patients alerting the EMS starts at the time of the phone alert, although FMC occurs
when the EMS arrives at the scene. Patients with fibrinolysis should be transferred to a PCI centre immediately after administration of the lytic bolus. EMS,
emergency medical system; FMC, first medical contact; PCI, percutaneous coronary intervention; STEMI, ST-​segment elevation myocardial infarction.
Reproduced from Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-​Ducci C, Bueno H, Caforio ALP, Crea F, Goudevenos JA, Halvorsen S, Hindricks G, Kastrati A, Lenzen MJ,
Prescott E, Roffi M, Valgimigli M, Varenhorst C, Vranckx P, Widimsky P, Group ESCSD. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting
with ST-​segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-​segment elevation of the European Society of
Cardiology (ESC). Eur Heart J 2018;39(2):119–​177 with permission from Oxford University Press.

timely primary PCI cannot be performed after STEMI diagnosis, PCI procedures [7, 8]. Randomized clinical trials in high-​volume
fibrinolytic therapy is recommended within 12 hours of symptom centres have shown that primary PCI is superior to fibrinolysis
onset in patients without contraindications. In the absence of ST-​ in reducing mortality, reinfarction, or stroke [9–​11]. This benefit
segment elevation, a primary PCI strategy is indicated in patients is mainly derived from a very high success rate in the opening of
with suspected ongoing ischaemic symptoms suggestive of MI and the IRA by angioplasty (>90%), compared to a 50–​60% success
at least one of the following criteria present:  (1) haemodynamic rate with fibrinolysis, which also comes at a cost of a 1–​2% rate
instability or CS; (2) recurrent or ongoing CP refractory to med- of intracranial bleeding [12]. Long-​term 5-​year follow-​up dem-
ical treatment; (3) life-​threatening arrhythmias or cardiac arrest; onstrated a highly significant 46% reduction in mortality in fa-
(4) mechanical complications of MI; (5) AHF; and (6) recurrent vour of primary balloon angioplasty [9]‌. Nowadays widespread
dynamic ST-​segment or T-​wave changes, particularly with inter- use of stents, and especially new-​generation DES, have improved
mittent ST-​segment elevation [1]. the outcomes of primary percutaneous interventions and made
PCI the first-​line therapy in patients with STEMI, irrespective of
Primary percutaneous coronary intervention presentation delay, as long as the procedure can be delivered in a
Primary PCI is the indicated reperfusion strategy in patients with timely manner by an expert team [13, 14].
STEMI within 12 hours of symptom onset, provided it can be per- Most patients with STEMI present to hospitals not equipped
formed quickly (i.e. 120 minutes from STEMI diagnosis) by an for primary PCI, but an urgent transfer to a tertiary centre for
experienced team. Lower mortality rates among patients under- primary PCI was proven to be effective and safe, which extended
going primary PCI are observed in centres with a high volume of the availability of a primary PCI strategy [9,  15]. The time of
552 CHAPTER 42   Pe rc u taneou s c oronary interven ti on s i n  acu te c orona ry  sy n dro m es

symptom onset is reported by the patient; first medical contact cooperation between EMS, local hospitals, and PCI centres is vital
(FMC) is defined as the first contact with the emergency med- in avoiding time delays and has justified the creation of local net-
ical system (EMS), a GP, or a hospital. A 12-​lead ECG is the key works for the management of STEMI patients and those with se-
to diagnosis and should be obtained and interpreted as soon as vere acute cardiac conditions.
possible. Management of STEMI starts from the point of FMc,
and STEMI diagnosis should occur within 10 minutes from FMC. Rescue percutaneous coronary intervention
Coordination between the EMS and hospitals with common Rescue PCI is defined as an urgent PCI performed on a coronary
protocols is crucial in the management of STEMI. The EMS artery which remains occluded, despite fibrinolytic therapy.
should alert the PCI centre immediately and transfer patients to Indications include <50% of ST-​segment resolution in the lead(s)
24/​7 high-​volume PCI centres, irrespective of whether the pri- with the highest ST-​segment elevations 60–​90 minutes after the
mary treatment strategy is PCI or pre-​hospital fibrinolysis [1]‌. start of fibrinolysis, the presence of haemodynamic or electrical
The next important step is wire passage into the IRA; subse- instability, worsening ischaemia, or persistent CP [24]. A  clin-
quent balloon dilatation typically results in restoration of blood ical suspicion is confirmed at angiography by demonstrating a
flow (recanalization). The absolute time from STEMI diagnosis culprit lesion in an epicardial artery with impaired flow (TIMI
to PCI-​mediated reperfusion with wire crossing of the IRA is set <3). A randomized study and a meta-​analysis showed that rescue
to 120 minutes. Given the maximum limit of 10 minutes from PCI is associated with a significant reduction in heart failure and
STEMI diagnosis to a bolus of fibrinolytics, the 120-​minute ab- reinfarction and a trend towards lower all-​cause mortality, when
solute time would correspond to a PCI-​related delay in the range compared with a conservative strategy, at the cost, however, of an
of 110–​120 minutes, being in the range of the times identified in increased risk of stroke and bleeding complications [25]. A rou-
old studies and registries as the limit delay to choose PCI [16–​19]. tine early PCI strategy is indicated after successful fibrinolysis
Fibrinolytic therapy is more effective when the clot is fresh, i.e. (preferably 2–​24 hours after fibrinolysis).
the time from onset of symptoms to FMC is <3 hours, and if the
reperfusion strategy is fibrinolysis, the goal is to inject the bolus Facilitated percutaneous coronary
of fibrinolytics within 10 minutes of STEMI diagnosis. It must intervention (and the pharmaco-​invasive
be emphasized that, although fibrinolysis can be administered approach)
faster, its onset of action is not immediate—​reperfusion occurs
Facilitated PCI is defined as a pharmacological reperfusion
after 30–​60 minutes [10]. Thus, the only situation where fibrin-
treatment delivered prior to an emergent planned PCI, in order
olysis might be better is if the patient presents early (ischaemia
to optimize antithrombotic therapy during the PCI-​ related
<3 hours) to a non-​PCI hospital, with an estimated time to PCI-​
time delay. Full-​ dose fibrinolytic therapy, half-​ dose fibrino-
mediated reperfusion of over 120 minutes. The main reason
lytic therapy with a GPI, and GPI alone have all been tested
favouring primary PCI, even in this setting, would be the pre-
for this indication. There is no clear evidence of a significant
vention of intracranial bleeding—​stroke is reduced from 2% to
clinical benefit with any of these agents [10, 26–​29]. Although
1% by primary PCI [20]. Other benefits of primary PCI over fi-
pre-​PCI patency rates were higher with fibrinolytic-​based treat-
brinolytic therapy include the fact that early (3 days) discharge of
ments, no mortality benefits and bleeding complications were
low-​risk patients (defined as age <70 years, LVEF >45%, one-​or
observed with this regimen. Pre-​PCI patency rates with upfront
two-​vessel disease, successful PCI, no persistent arrhythmias) is
abciximab or a bolus dose of tirofiban alone were not higher
safe and cost-​effective [21].
than with placebo. Facilitated PCI, as it has been tested so far,
In conclusion, primary PCI is the preferred therapeutic option
cannot be recommended.
in STEMI cases when it can be performed expeditiously by an
The so-​called pharmaco-​invasive approach is defined as a
experienced team. Only hospitals with an established interven-
first-​line treatment with fibrinolytic agents (half-​or full-​dose fi-
tional cardiology programme (open 24 hours/​7 days) should use
brinolysis), followed by rescue PCI, if needed, or routine non-​
primary PCI as a routine treatment option. There are significant
emergent coronary arteriography with PCI (if needed) within
financial and geographical limitations to the widespread use of
24 hours of the administration of the fibrinolytic treatment. This
primary PCI and large variations in treatment availability between
approach showed that pre-​hospital fibrinolysis followed by an
European countries. Currently, primary PCI is widely available
early PCI strategy was related to a similar outcome as transfer for
in rich, densely populated countries with well-​organized health
primary PCI in STEMI patients presenting within 3 hours after
care systems. In Europe, the uptake of primary PCI varies, but
symptom onset who could not undergo primary PCI within 1
within the last years, many countries have implemented primary
hour after FMC [30].
PCI and established STEMI centres [22]. In 2008, the Stent for
Life (SFL) initiative was launched by the European Association
of Percutaneous Cardiovascular Interventions and Euro PCR, Late percutaneous coronary intervention
in partnership with the ESC Working Group on Acute Cardiac Some patients present late, >12 hours after the onset of symp-
Care and country-​specific national cardiac societies [23]. This toms. There is consensus that a primary PCI strategy should also
initiative aims to improve the delivery of care to STEMI patients be delivered for patients with symptoms lasting >12 hours in the
and access to the lifesaving indications of primary PCI. Excellent presence of: (1) ECG signs of ongoing ischaemia; (2) ongoing or
Perc u tan eou s c oronary interventi on for  ST- seg m en t el evati on m yo ca rdia l i n fa rc t i on 553

recurrent pain and dynamic ECG changes; and (3)  ongoing or is indicated in ACS patients in whom the coronary anatomy is
recurrent pain, symptoms, and signs of heart failure, shock, or known, when the indication for PCI has been established [38].
malignant arrhythmias. However, there is no agreement as to Ticagrelor is recommended for all ACS patients, regardless of
whether PCI is also beneficial in patients presenting >12 hours the initial treatment strategy, including those pre-​treated with
from symptom onset in the absence of clinical and/​or ECG evi- clopidogrel. Administration of ticagrelor or clopidogrel should
dence of ongoing ischaemia. The open artery hypothesis sug- be started as early as possible. Cangrelor is a reversible ATP ana-
gested that late patency of an infarct artery would prevent adverse logue, with a short half-​life, administered IV; it has been com-
LV remodelling, increase electrical stability, and provide collat- pared to clopidogrel in three CHAMPION trials [39] and might
eral vessels to other coronary beds for protection against future be clinically useful in bridging of DAPT to cardiac, or even non-​
events. In asymptomatic patients without persistent symptoms cardiac, surgery.
12–​48 hours after symptom onset, a small (n = 347) randomized STEMI patients undergoing primary PCI should receive as-
study showed improved myocardial salvage and 4-​year survival pirin and a P2Y12 receptor inhibitor as soon as the diagnosis
in patients treated with primary PCI, compared with conser- of STEMI is established. Randomized data on a comparison of
vative treatment alone [31,  32]. However, the larger (n  =  2166) ticagrelor versus prasugrel in STEMI patients are limited, but the
Occluded Artery Trial (OAT), which evaluated the perform- recently published randomized trial Comparison of Prasugrel
ance of routine PCI at least 24 hours from symptom onset on and Ticagrelor in the Treatment of Acute Myocardial Infarction
a totally occluded IRA, showed that there was no benefit, com- (PRAGUE-​ 18) found similar safety and efficacy profiles of
pared to medical therapy alone, with even a trend towards excess ticagrelor and prasugrel in the setting of primary PCI [40]. If
reinfarction, during 4 years of follow-​up [33]. The OAT exclusion the new P2Y12 inhibitors are not available or contraindicated,
criteria included NYHA class III or IV of heart failure, rest an- clopidogrel should be given for primary PCI.
gina, left main or three-​vessel disease, clinical instability, and se- For NSTE-​ACS patients, DAPT including aspirin and a po-
vere inducible ischaemia on stress testing if the infarct zone was tent P2Y12 receptor inhibitor (prasugrel or ticagrelor) is recom-
not akinetic or dyskinetic. A recent meta-​analysis testing whether mended [41, 42]. Clopidogrel should only be used when prasugrel
late recanalization is beneficial showed no benefit of reperfusion or ticagrelor are not available or are contraindicated. Based on
[34]. Therefore, routine PCI of an occluded IRA in asymptom- the results of the ACCOAST trial, it is not recommended that
atic patients >48 hours after onset of symptoms is not indicated. prasugrel is administered in patients in whom the coronary
These patients should be managed like all patients with chronic anatomy is not known [38]. Pre-​treatment with ticagrelor can be
total occlusion, in whom revascularization should be considered used and it is associated with early benefit over clopidogrel [42].
in the presence of symptoms or objective evidence of viability/​ The duration of DAPT should be driven by bleeding and is-
ischaemia in the territory of the occluded artery. chaemic risks. Six-​month therapy duration should be considered
in high bleeding risk patients, whereas >12-​month therapy may
Adjunctive antithrombotic medication be considered in ACS patients at low bleeding risk, especially if
This topic is discussed in detail in E Chapter 39, and we there- additional high-​risk features are present, including prior multiple
fore briefly describe here a practical approach to antithrombotic MIs or multivessel disease/​intervention [43].
management, as recommended by current ESC guidelines. The Anticoagulation is recommended for all patients, in addition
combination of parenteral anticoagulation and DAPT (aspirin to antiplatelet therapy, during primary PCI or PCI for NSTE-​
and a P2Y12 inhibitor) is indicated in patients with ACS under- ACS [44]. In general, a crossover between anticoagulants should
going PCI, and the most recent data support the superiority of be avoided (especially between UFH and LMWH), apart from
ticagrelor and prasugrel over clopidogrel in this setting. Hence, adding UFH to fondaparinux when a patient proceeds to PCI
clopidogrel should be regarded as a second-​line option in patients [45, 46]. UFH is primarily recommended as an anticoagulant for
with ACS, irrespective of the final revascularization strategy. PCI. Anticoagulation with UFH is ideally administered in 50–​70
Aspirin 150–​300 mg is usually administered as soon as pos- IU/​kg as an initial dose to allow the safe use of GPIs, if needed, in
sible, after confirmation of the diagnosis, either PO or IV, and the catheterization laboratory. Regarding other anticoagulant op-
oral therapy with a 75–​100 mg dose is recommended lifelong. tions, fondaparinux did not show any benefit in the setting of pri-
The preferred P2Y12 inhibitors in ACS are nowadays prasugrel mary PCI and is therefore not recommended in STEMI patients
and ticagrelor. Both drugs have a more rapid onset of action [47] but is recommended in NSTEMI patients [48]. Enoxaparin
and a greater antiplatelet efficacy than clopidogrel, and they (0.5 mg/​kg IV) showed, in one randomized study, a trend to-
have proved to be superior to clopidogrel in large outcome trials wards a net clinical benefit, without an increase in bleeding,
[35,  36]. Prasugrel is contraindicated in patients with previous and is therefore an alternative to UFH [49]. With regard to
stroke or TIA, and its use is generally not recommended in pa- bivalirudin, a large meta-​analysis showed no mortality advantage
tients aged >75 years or in those with lower body weight (<60 kg), with bivalirudin and a reduction in the risk of major bleeding,
as it was not associated with a net clinical benefit in these subsets. but at the cost of an increased risk of acute stent thrombosis [50].
In cases where prasugrel is used in these patients, a reduced dose In the recent MATRIX trial including 7213 ACS patients (56%
(5 mg) is generally recommended [37]. In NSTEMI patients, with STEMI), bivalirudin did not reduce the incidence of the pri-
pre-​treatment with prasugrel is not recommended. Prasugrel mary endpoint (composite of death, MI, or stroke), compared to
554 CHAPTER 42   Pe rc u taneou s c oronary interven ti on s i n  acu te c orona ry  sy n dro m es

UFH [51]. However, major bleeding, both access-​site and non-​

Box 42.2  Doses of medications used to prevent or treat
access site-​related, was reduced. The most recent VALIDATE-​ the no-​reflow phenomenon
SWEDEHEART study compared UFH versus bivalirudin and
illustrated similar risk patterns for both ischaemia and bleeding Prevention
when comparing the two drugs [52]. Thus, the latest ESC guide- Tirofiban IV 25 micrograms/kg bolus and 0.15 micrograms/kg/
lines on revascularization have downgraded the recommendation min IV infusion for 12–18 hours
for bivalirudin as an anticoagulant during primary PCI [3]‌. All Treatment
anticoagulation agents should be discontinued after PCI, except
Adenosine IV infusion 70 mg/​kg/​min for 3 hours
in specific clinical settings such as the presence of an LV aneurysm
Adenosine intracoronary bolus 30–​60 mg
with thrombus or AF requiring anticoagulation or prophylactic
Verapamil intracoronary bolus 0.5–​1 mg
doses for the prevention of VTE in patients requiring prolonged Papaverine intracoronary bolus 10–​20 mg
bed rest. Nicorandil intracoronary bolus 2 mg
Most of the trials evaluating GPIs in PCI-​treated patients are Nitroprusside intracoronary bolus 50–​200 micrograms
old and came before the establishment and routine use of the
novel oral P2Y12 inhibitors. In a setting of potent platelet in-
hibition with ticagrelor or prasugrel, where randomized data on
GPI use are limited, routine use of these agents cannot be recom- associated with a significantly increased risk of clinical compli-
mended. However, it should be considered for bailout situations cations [56, 58–​60].
or thrombotic complications and may be used for high-​risk PCI Intracoronary administration of vasodilators, such as ad-
in patients without pre-​treatment with P2Y12 inhibitors. enosine, verapamil, nicorandil, papaverine, ciclosporin, and
nitroprusside (see E Box 42.2), during and after primary PCI has
Microvascular obstruction—​definition, been shown to improve flow in the infarct-​related coronary artery
prevention, and therapy and myocardial perfusion and/​or to reduce the infarct size, but
large prospective randomized trials with hard clinical outcomes
The ‘no-​reflow’ phenomenon in STEMI patients is characterized are lacking [53]. In some cases, distal injection of vasodilating
by inadequate myocardial reperfusion at the microcirculatory medication with an aspiration catheter or a microcatheter may
level, after successful reopening of the epicardial IRA, without improve flow in an IRA with the no-​flow phenomenon. Using
evidence of a persistent mechanical obstruction. The mechan- GPIs as bailout therapy in the event of angiographic evidence of a
isms of no-​reflow are not fully understood—​distal thrombotic large thrombus, slow or no-​reflow, and other thrombotic compli-
microembolization, vascular reperfusion injury, adrenergic cations is reasonable, although this strategy has not been tested in
microvascular constriction, and myocardial oedema may con- a randomized trial. The reduction of microvascular obstruction
tribute [53]. Depending on the definitions used, 10–​40% of pa- remains an important unmet need awaiting further research.
tients undergoing reperfusion therapy for STEMI may show
evidence of no-​reflow [54–​56]. A grading system was developed Adjunctive devices
by the TIMI study group for assessing epicardial flow in infarct-​
The presence of a coronary thrombus creates special challenges
related coronary arteries [57] (see E Box 42.1). However, a
in the performance of primary PCI. A large thrombus burden is
substantial number of patients with TIMI 3 flow have per-
associated with an increased incidence of distal embolization and
sistent ST-​segment elevation on the post-​angioplasty ECG, and
no-​reflow and may limit reperfusion at the microvascular level.
the primary objective of reperfusion therapies is not only the
Several adjunctive strategies have been tried. Unfortunately, the
restoration of blood flow in the epicardial coronary artery, but
use of sophisticated mechanical thrombectomy systems was as-
also the reperfusion of the infarcted myocardium. This can be
sociated with a larger infarct size and an unexpected increase
judged angiographically by the ‘myocardial blush grade’ (MBG)
in mortality. Consequently, mechanical thrombectomy is now
which uses myocardial contrast density as a measure of the
used infrequently with primary PCI [61]. Distal protection de-
functional integrity of the microvascular bed [58]. No-​reflow
vices are represented by filters or proximal balloon occlusion sys-
can cause prolonged myocardial ischaemia, may result in severe
tems. There are nine randomized trials comparing primary PCI
arrhythmia and critical haemodynamic deterioration, and is
with distal protection using filters or balloon occlusion, com-
pared with primary PCI alone; they found that distal protection
Box 42.1  TIMI flow grades did not improve myocardial reperfusion or clinical outcomes.
Distal protection is not thought to be beneficial with primary PCI
TIMI 0: no antegrade flow beyond the point of obstruction for STEMI, except in saphenous vein graft lesions [61]. Simple
TIMI 1: slow flow with contrast material not reaching the distal manual aspiration catheters have two lumens—​one for passage of
coronary bed in one cine run
the catheter over a coronary wire, and the other for aspiration of
TIMI 2:  antegrade flow opacifies all coronary bed, but more
the thrombus and atheromatous debris. The Thrombus Aspiration
slowly than in another coronary artery
during Percutaneous Coronary Intervention in Acute Myocardial
TIMI 3: normal flow
Infarction Study (TAPAS) and Thrombectomy With EXPort
Perc u tan eou s c oronary interventi on for  ST- seg m en t el evati on m yo ca rdia l i n fa rc t i on 555

Catheter in Infarct-​Related Artery During Primary Percutaneous stent sizing is of paramount importance. The presence of IRA
Coronary Intervention (EXPIRA) trials together randomized spasm or a thrombus may lead to significant stent undersizing,
over 1200 STEMI patients to aspiration thrombectomy followed which is a frequent cause of restenosis and/​or stent throm-
by stenting versus stenting alone [62, 63]. Aspiration was success- bosis. Bioresorbable vascular scaffolds represent a very intuitive
fully performed in 90% of patients; a thrombus or an atheroma idea and initial experience in the STEMI setting is available.
was retrieved in 72% of patients, and direct stenting (without However, there is clear evidence of an increased thrombosis rate
predilatation) was performed in 59% of patients. The frequency and routine clinical use of this technology is not recommended.
of high MBG (the primary endpoint) and complete ST-​segment Deferred stenting as an attempt to preserve distal microcircu-
resolution on ECG (the secondary endpoint) was significantly lation cannot be routinely recommended, based on the Third
higher with aspiration thrombectomy. These improved results in DANish Study of Optimal Acute Treatment of Patients with
myocardial reperfusion were associated with a clinical benefit at ST-​segment Elevation Myocardial Infarction:  DEFERred stent
1 year, with a lower incidence of cardiac death and cardiac death implantation in connection with primary PCI (DANAMI 3-​
or MI [62]. However, the recent and much larger randomized DEFER) study [76].
trials TASTE (7244 patients) [64] and TOTAL (10 732 patients)
[65, 66] did not show any mortality benefit with routine use of Radial or femoral approach?
thrombectomy. Furthermore, the incidence of stroke was in- Cardiac catheterization using radial artery access has become
creased in the TOTAL trial [67]. In the TASTE [64] and TOTAL routine in many centres. The radial approach results in quick mo-
trials [66], 1–​5% of randomized patients crossed over from PCI bilization of the patient and minimizes the risk of local bleeding
alone to thrombus aspiration. Based on these data and the results complications, which makes it especially attractive in the setting
of a recent meta-​analysis [68], routine thrombus aspiration is not of ACS, with aggressive antithrombotic and antiplatelet medica-
recommended. However, in cases of a large residual thrombus tions. Recently, several trials have compared radial versus fem-
burden after opening the vessel with a guidewire or a balloon, oral access in a randomized fashion. The Minimizing Adverse
thrombus aspiration may be considered. Haemorrhagic Events by TRansradial Access Site and Systemic
Implementation of angioX (MATRIX) trial recruited 8404
Drug-​eluting or bare-​metal stents in ST-​segment ACS patients (48% STEMI) who were randomly allocated to
elevation myocardial infarction? transradial or transfemoral access. Radial access was associated
Coronary stenting is the technique of choice during primary PCI. with lower risks of access site bleeding, vascular complications,
Compared with balloon angioplasty alone, stenting with a BMS and the need for transfusion. Importantly, there was significant
is associated with a lower risk of reinfarction and target vessel mortality benefit in patients allocated to the transradial access
revascularization but is not associated with a reduction in mor- site [77]. These findings extend observations from previous trials,
tality rate [69,  70]. In primary PCI, DES reduce the risk of re- including RadIal Vs femorAL access for coronary intervention
peated target vessel revascularization, compared with BMS [71]. (RIVAL) [78], Radial Versus Femoral Randomized Investigation
Newer generations of DES (everolimus, zotarolimus, or in ST-​ Elevation Acute Coronary Syndrome (RIFLE-​ STEACS)
biolimus-​ eluting) have been tested recently in patients with [79], and ST Elevation Myocardial Infarction treated by RADIAL
STEMI, with encouraging results, and have been shown to be or femoral approach (STEMI-​RADIAL) [80], and support the
superior to BMS in patients with AMI, mostly in terms of need ESC guideline recommendations that for patients with ACS, ra-
for reintervention. The Comparison of Biolimus Eluted from dial access should be considered over femoral access if performed
an Erodible Stent Coating with Bare-​ Metal Stents in Acute by an experienced radial operator [1]‌. There is 2–​7% conversion
ST-​Elevation Myocardial Infarction (COMFORTABLE AMI) to femoral access, and there seems to be no increase in radiation
trial demonstrated a reduction of the 1-​year composite clinical exposure in experienced centres.
endpoint by implantation of a biolimus-​eluting stent, in com-
parison with a BMS [72]. Implantation of everolimus-​eluting How to treat multivessel disease in ST-​segment
stents (EXAMINATION trial) did not lower the combined elevation myocardial infarction patients
clinical patient-​oriented endpoint, but it reduced target vessel As many as 50% of STEMI patients have multivessel disease
revascularization and stent thrombosis rate [73] and clinical [81]. The IRA should be treated during the initial intervention.
benefit was confirmed at 5-​year follow-​up [74]. In the NORSTENT However, revascularization of non-​IRA lesions is still being de-
trial, 9013 patients undergoing PCI (26% with STEMI) were ran- bated. Randomized clinical trials addressing this issue have been
domized to either DES or BMS. There were no differences in the small. The most important of these—​PRAMI [82], CvLPRIT
incidence of the primary endpoint of death after a median follow-​ [83], DANAMI-​ 3–​PRIMULTI [84], and the Comparison
up of 5  years. However, DES were associated with lower rates Between FFR Guided Revascularization Versus Conventional
of definite stent thrombosis and of target lesion and any repeat Strategy in Acute STEMI Patients With Multivessel disease
revascularization [75]. (COMPARE-​ ACUTE) trial [85]—​ have compared PCI of the
In summary, there are enough data to support the rou- IRA only versus complete revascularization. Primary outcome
tine use of second-​generation DES in primary PCI. Optimal (composite of different endpoints) was significantly reduced in
556 CHAPTER 42   Pe rc u taneou s c oronary interven ti on s i n  acu te c orona ry  sy n dro m es

the complete revascularization group in all four trials. Total mor- 30-​day risk of the composite of all-​cause mortality or severe
tality was not statistically different in any of the four trials. Repeat renal failure, compared with immediate multivessel PCI. This
revascularization was significantly reduced in the complete was driven by a significant risk reduction in 30-​day all-​cause
revascularization arm in the PRAMI, DANAMI-​3–​PRIMULTI, mortality by the culprit lesion-​only strategy, compared with im-
and Compare-​Acute trials. Non-​fatal MI was reduced in the non-​ mediate multivessel PCI [95]. Based on these findings, the latest
IRA PCI group only in PRAMI. Several subsequent meta-​analyses guidelines on myocardial revascularization recommend culprit
confirmed the lack of significant treatment effect of non-​IRA le- lesion-​only PCI as the default strategy in patients with AMI
sion intervention on death or MI [86–​88]. Based on these data, with CS [3]‌.
preventive revascularization of non-​IRA lesions should be con- In the setting of CS, MCS devices that are currently available
sidered in STEMI patients with multivessel disease before hospital are the IABP, VA-​ECMO, and percutaneous left ventricular assist
discharge. As the optimal timing of revascularization (immediate devices (pLVADs). Real-​life utilization of IABP during primary
versus staged) has not been adequately investigated, no recom- PCI for CS is low (20–​39%) [96]. A  recently published meta-​
mendation in favour of immediate versus staged multivessel PCI analysis of IABP in CS did not show any efficacy benefit, and in
can be formulated. a large randomized trial, the use of IABP resulted in a significant
increase in bleeding complications and stroke [97]. Many studies
regarding IABP in the setting of CS are importantly hampered by
Specific situations (cardiac arrest, bias and confounding, and randomized trials were recently per-
formed to clarify the situation. The Counterpulsation to Reduce
cardiogenic shock, post-​coronary Infarct Size Pre-​PCI Acute Myocardial Infarction (CRISP-​AMI)
artery bypass grafting, no clear study randomized patients with a large anterior MI to primary
culprit lesion identified) PCI, with or without IABP, and did not find any reduction in in-
farct size [98]. The Intra-​Aortic Balloon Pump in Cardiogenic
Cardiac arrest Shock II (IABP-​ SHOCK II) randomized trial (600 patients)
Patients with ST-​segment elevation on post-​resuscitation ECG showed that in patients with CS complicating AMI, the use of
should undergo an immediate primary PCI strategy [89]. In cases IABPs did not reduce 30-​day mortality and there was no evidence
without ST-​segment elevation on post-​resuscitation ECG, but of long-​term benefit [99, 100]. In summary, routine use of IABP
with a high suspicion of ongoing myocardial ischaemia, urgent cannot be recommended [3]‌.
angiography should be considered within 2 hours after a com- Recently available pLVADs, such as TandemHeart® or Impella®,
prehensive assessment to exclude possible non-​coronary causes are technically feasible and provide superior haemodynamic sup-
[90, 91]. More recent data suggest that almost one-​quarter of pa- port but, so far, have not been proven to improve clinical out-
tients, resuscitated from cardiac arrest but without ST-​segment comes [101]. Mechanical ventilation with high PEEP should be
elevation, show a culprit lesion (either vessel occlusion or an ir- considered early for patients with hypoxia; it is helpful to stabilize
regular lesion) [91–​93]. In all cases, the decision to perform ur- patients prior to PCI [101, 102]. The role of ECMO is currently
gent coronary angiography should consider factors associated studied. In patients with cardiac arrest, evidence from obser-
with poor neurological outcome. vational trials supports better survival in patients treated with
VA-​ECMO, compared with those without [103]. When com-
Percutaneous coronary intervention pared with IABP, VA-​ECMO provides superior circulatory sup-
and mechanical circulatory support port [104,  105]. Furthermore, a meta-​analysis of observational
in cardiogenic shock studies suggested that in patients with CS post-​ACS, VA-​ECMO
showed 33% higher 30-​day survival, compared with IABP [103].
(See E Section VII.) Emergency PCI in the setting of CS may
However, the low number of patients included in the analysed
be lifesaving and should be considered at an early stage and
studies and non-​random treatment allocation are important limi-
performed as soon as possible. The Should We Emergently
tations. In conclusion, despite significant efforts, CS affects 6–​10%
Revascularize Occluded Coronaries for Cardiogenic Shock
of patients with STEMI and remains a leading cause of in-​hospital
(SHOCK) trial randomized 300 patients to medical therapy or
mortality. More details on this emerging topic are discussed in
revascularization (PCI or surgery); 86% of patients received IABP.
E Section VII.
The 6-​month mortality rate was lower in the revascularization
group than in the medical therapy group (50.3% versus 63.1%,
Primary percutaneous coronary intervention
respectively; P = 0.027) [94]. The revascularization strategy for
patients with CS and multivessel disease seems to be in favour
in patients after coronary artery bypass
of the IRA only. The recently published CULPRIT-​SHOCK grafting
trial showed that in the case of patients with multivessel dis- Patients presenting with STEMI after CABG are challenging
ease and AMI with CS, a strategy with PCI of the culprit lesion with a larger thrombus load. Angiographic and clinical out-
only with possible staged revascularization determined a lower comes after primary PCI are, however, like those observed in
Percutaneous coronary intervention for non-​S T-​s egment elevation acute coronary syndromes 557

non-​post-​ CABG patients, despite a larger thrombus burden Finally, non-​coronary conditions (e.g. PE, aortic dissection,
[106]. Information on the number and type of graft is not always acute pericarditis) should always be taken under consideration
available, and this could result in a high contrast and radiation in the differential diagnosis of STEMI because some of them
dose. Saphenous vein graft disease behaves quite differently from are potentially life-​threatening. A  PE can result in ST-​segment
native coronary atheroma. Fibrinolytic therapy has poor efficacy elevation in the anterior leads [116]. Haemodynamically un-
in thrombotic vein graft occlusions. The risk of no-​reflow is high, stable patients with a clinical suspicion of PE might benefit from
and there is a higher probability of vessel rupture. Embolic pro- RHC, pulmonary angiography, and possibly local thrombolytic
tection devices—​both proximal balloon occlusion systems and therapy. Aortic dissection may present with ST-​segment eleva-
distal filter-​based systems—​have demonstrated a reduced rate of tion, and CT aortography or echocardiography should be per-
periprocedural complications. GPIs have not shown any benefit formed when this diagnosis is suspected. Pericarditis may also be
in vein graft PCI. Based on data from a small number of ran- mistaken for STEMI. However, ST-​segment elevations are wide-
domized trials, implantation of DES in saphenous vein graft le- spread, with no reduction of the R wave, and echocardiography
sions is associated with a lower risk of repeat revascularization is often diagnostic.
than with BMS at 1-​year follow-​up [107–​110]. In the only trial
powered for a clinical endpoint—​the Is Drug-​Eluting-​Stenting
Associated with Improved Results in Coronary Artery Bypass
Grafts (ISAR-​CABG) trial—​the primary endpoint of death, MI,
Percutaneous coronary intervention
and target lesion revascularization was significantly reduced with for non-​ST-​segment elevation acute
DES versus BMS [107]. However, at 5-​year follow-​up, the advan- coronary syndromes
tage of DES over BMS was lost due to a higher incidence of target
lesion revascularization between years 1 and 5 in patients treated Routine invasive or early conservative
with DES [108]. (i.e. selective invasive) strategy
Approximately one-​third of patients with unstable coronary syn-
Patients referred for primary percutaneous dromes have single-​vessel disease, and 44–​59% have multivessel
coronary intervention with no clear disease [117, 118]. The decision for invasive coronary angiography
culprit lesion should carefully evaluate the risks of the procedure and the advan-
A relatively large proportion of STEMI patients do not present tages with regard to the diagnosis, risk stratification, and treatment.
with significant coronary artery stenosis on urgent angiography The role of coronary angiography and revascularization in pa-
[111, 112]. It is important to perform additional diagnostic tests in tients with NSTE-​ACS was first studied in 1994 in the randomized
these patients to identify the aetiology and adapt the appropriate trial TIMI IIIB, which hypothesized that early angiography and
therapy, which may be different from typical STEMI. The term revascularization would be beneficial in preventing subsequent
MINOCA has been used over the last years to describe all these cardiac events [118]. Since then, numerous trials have addressed
different causes, characterized by clinical evidence of MI with this question, with—​at first sight—​conflicting results. There was
normal or near-​normal coronary arteries on angiography [113]. significant crossover; the selection of patients may have been biased
Clinical history, ECG, cardiac biomarkers, echocardiography, cor- towards lower-​risk groups. After adjusting for real difference in
onary angiography, and LV angiography are the first-​level diag- coronary revascularization, there appears to be a direct relation-
nostic investigations to identify the causes of MINOCA. The most ship between higher use of revascularization and lower mortality
common causes of MINOCA include coronary plaque disease, [119]. There are several meta-​analyses comparing a routine inva-
coronary dissection, coronary artery spasm, coronary micro- sive strategy with a selective invasive one, some of which included
vascular spasm, Takotsubo cardiomyopathy, myocarditis, cor- studies with out-​of-​date PCI techniques [120–​122]; the most re-
onary thromboembolism, other forms of type 2 MI, and MINOCA cent analysis (which included well-​conducted trials with 5-​year
of uncertain aetiology [114]. Coronary artery spasm may result follow-​up) revealed a significant absolute reduction in cardiovas-
in temporary coronary artery occlusion, with ST-​segment eleva- cular death or MI at 5 years in favour of a routine over a selective
tion on ECG; serial ECGs are usually helpful, and intracoronary invasive strategy [123]. The most pronounced difference was ob-
imaging techniques might be helpful by excluding significant cor- served in high-​risk patients. Nowadays, there is a clear consensus
onary atheroma. Stress-​induced cardiomyopathy of the Takotsubo that most of the benefit is in biomarker-​positive patients and those
type is easily diagnosed with left ventriculography or echocardi- with high-​risk characteristics (see E Box 42.3). In a sex-​specific
ography, demonstrating a dyskinetic segment which typically does analysis, biomarker-​positive women had a clear benefit from a rou-
not correspond to the vascular territory of a single coronary artery. tine invasive approach, but there was no benefit, and even a trend
The onset of Takotsubo syndrome is often triggered by intense to more events, in a group of low-​risk, troponin-​negative female
emotional or physical stress. The LV function usually recovers, and patients. Thus, the old belief that percutaneous revascularization
the recovery time varies from hours to several weeks [115]. does not improve mortality in coronary disease, but just improves
558 CHAPTER 42   Pe rc u taneou s c oronary interven ti on s i n  acu te c orona ry  sy n dro m es

symptoms, is no longer true. There is a clear mortality benefit for

Box 42.3  Recommendations for invasive coronary angiography
patients with NSTE-​ACS. and revascularization in non-​ST-​segment elevation ACS

Timing of angiography Immediate invasive strategy (<2 hours)

The issue of timing has been extensively studied and is closely At least one of the following very high-​risk criteria:
linked to risk stratification. Coronary angiography should be per- Haemodynamic instability or CS
◆

formed urgently (<2 hours), in the same regime as for STEMI, Recurrent or ongoing CP refractory to medical treatment
◆
in very high-​risk patients with at least one of the following very Life-​threatening arrhythmias or cardiac arrest
◆
high-​risk criteria:  haemodynamic instability or CS, recurrent Mechanical complications of MI
◆
or ongoing CP refractory to medical treatment, life-​threatening Recurrent dynamic ST-​segment or T-​wave changes
◆
arrhythmias or cardiac arrest, mechanical complications of MI,
and recurrent dynamic ST-​segment or T-​wave changes [2]‌. These Early invasive strategy (<24 hours)
patients represent 2–​15% of patients admitted with NSTE-​ACS; At least one of the following high-​risk criteria:
in fact, some of them will have acute occlusion of the LCX cor- GRACE score >140
◆

onary artery [124, 125]. In patients without the above-​mentioned Rise or fall in cTn compatible with MI
◆

life-​
threatening features, the ideal timing of coronary angio- Dynamic ST-​segment or T-​wave changes (symptomatic or
◆
graphy was debated from two perspectives: (1) early intervention silent)
to prevent ischaemic events that could occur while the patient
Late invasive strategy (<72 hours)
awaits a delayed procedure; or (2) with intensive antithrombotic
At least one of the following intermediate-​risk criteria:
therapy from the start and angiography delayed by a few days,
procedure-​related complications might be avoided by intervening Diabetes mellitus
◆

on a more stable plaque. Results of the Early or Late Intervention Renal insufficiency (eGFR <60 mL/​min/​1.73 m2)
◆

in unStable Angina (ELISA) [126], Intracoronary Stenting With LVEF <40% or congestive heart failure
◆

Antithrombotic Regimen Cooling-​ Off (ISAR-​ COOL) [127], Early post-​infarction angina

◆

Timing of Intervention in Acute Coronary Syndrome (TIMACS) Recent PCI, prior CABG

◆

[128], OPTIMA [129], and Angioplasty to Blunt the Rise of GRACE risk score >109 and <140
◆
Troponin in Acute Coronary Syndromes Randomized for an Reproduced from Roffi M, Patrono C, Collet JP, et al. 2015 ESC Guidelines
Immediate or Delayed Intervention (ABOARD) [130] studies for the management of acute coronary syndromes in patients presenting
can be summarized as: (1) high-​risk patients, defined as having a without persistent ST-​segment elevation:  Task Force for the Management
of Acute Coronary Syndromes in Patients Presenting without Persistent ST-​
GRACE risk score [131] of >140, derive benefit from early angio- Segment Elevation of the European Society of Cardiology (ESC). Eur Heart
graphy within the first 24 hours; (2)  very early (e.g. <2 hours) J 2016;37(3):267–​315. doi:10.1093/​eurheartj/​ehv320 with permission from
angiography does not add any incremental benefit but probably Oxford University Press.
does no harm; and (3) the timing of angiography is not crucial
in low-​to intermediate-​risk patients but should be performed
during the same hospital stay; a strategy may be chosen individu-
Percutaneous coronary intervention or coronary
ally, according to the patient’s, physician’s, or institution’s pref-
erence (e.g. efficiency, cost savings, etc.). In conclusion, an early
artery bypass grafting in non-​ST-​segment
invasive strategy (<24 hours) is recommended in patients with elevation acute coronary syndromes?
at least one of the following high-​risk criteria: (1) GRACE score There are no randomized data specifically comparing PCI
>140; (2) rise or fall in cTn compatible with MI; and (3) dynamic with CABG in the setting of NSTE-​ACS. Approximately one-​
ST-​segment or T-​wave changes (symptomatic or silent). An inva- third of patients will have single-​vessel disease and these
sive strategy with maximal delay of <72 hours is recommended patients should undergo ad hoc PCI of the culprit lesion.
in patients without recurrence of symptoms but with at least one Multivessel disease is present in half of these patients [133].
intermediate-​risk criterion (diabetes mellitus, renal insufficiency The revascularization strategy in an individual NSTE-​ACS
with eGFR <60 mL/​min/​1.73 m2, LVEF 40% or congestive heart patient with multivessel CAD should be discussed in the con-
failure, early post-​infarction angina, recent PCI, prior CABG, text of a heart team and be based on the clinical status, as
GRACE risk score >109 and <140). Finally, patients with no re- well as on the severity and distribution of the CAD and lesion
currence of CP, no signs of heart failure, no abnormalities in the characteristics. The SYNTAX score was found to be useful
initial or subsequent ECG, and no increase in (preferably high-​ in the prediction of death, MI, and revascularization among
sensitivity) cTn level are at low risk of subsequent cardiovas- NSTE-​ ACS patients undergoing PCI and may help guide
cular events. In this setting, a non-​invasive stress test (preferably the choice between revascularization strategies [134]. FFR
with imaging) for inducible ischaemia is recommended before measurements will help to determine the functional signifi-
deciding on an invasive strategy [132] (see E Box 42.3). cance of moderate coronary stenoses. A sequential approach,
 C on c lusi on 559

consisting of treating the culprit lesion with PCI followed by have been developed in order to assess the haemorrhagic risk in
elective CABG, with proof of ischaemia and/​or FFR of the ACS patients [147]. The choice of arterial approach, early sheath
non-​c ulprit lesions, may be advantageous in selected patients. removal, very careful arterial puncture site management, and
However, the prognostic role of FFR and in guiding myocar- properly adjusted dosing of antithrombotic medications are crit-
dial revascularization in the setting of an ACS needs add- ical issues. Persistent hypotension with no obvious explanation
itional clarification. after a femoral artery puncture is suspicious of retroperitoneal
haemorrhage and urgent CT is indicated. Possible indications for
a transfusion should be cautious and judged more on clinical, ra-
Special situations and conditions ther than laboratory, parameters. Antiplatelet medications should
be restarted as soon as the risk of bleeding allows. Widespread
The elderly patient preference of the radial approach will reduce bleeding, but we
A large observational study of patients with ACS (both STEMI should keep in mind that not all bleeding is related to an arterial
and NSTE-​ACS) showed that 30-​day mortality rates were higher puncture site, with GI bleeding being the most common [148].
in older age groups (65–​69 years: 10.9%; 70–​74 years: 14.1%; 75–​ Advances in stent design may allow a shorter treatment time with
79 years: 18.5%; 80–​84 years: 23.2%; ≥85 years: 31.2%; P = 0.001 DAPT and therefore lower the risk of bleeding. Novel risk scores,
for trend) [135]. Elderly patients (>75  years) are frequently ex- such as PRECISE-​DAPT, offer us a prediction algorithm for out-
cluded from RCTs, and therefore, evidence-​based medicine is of-hospital bleeding in patients treated with DAPT [149].
lacking. Primary PCI seems to be safe also in elderly patients
[136]. GPIs are associated with an increased risk of bleeding. As Contrast nephropathy
far as stent selection is concerned, one randomized trial tended to Contrast medium-​induced nephropathy (CIN) is a recognized
favour DES in the elderly population [137]. complication of PCI, defined as an increase in serum creatinine
concentration of ≥25% from baseline to up to 3 days. It may lead
Bleeding post-​percutaneous coronary to acute renal failure and is associated with a significantly in-
intervention: importance, definition, creased mortality rate. Patients with STEMI treated with primary
and prevention PCI are at higher risk of CIN (possibly up to 20% of patients)
Previously, bleeding was considered an inevitable consequence than those undergoing elective interventions, possibly due to im-
of an effective antithrombotic therapy, and avoidance of bleeding paired systemic perfusion, a large volume of contrast medium,
therefore received little attention. However, recently, it has be- and the impossibility of starting renal prophylactic therapies be-
come clear that approximately 5% of patients presenting with fore exposure to contrast medium [150]. So far, the only strat-
ACS experience major bleeding during the next 30  days and egies that are proven effective in preventing CIN are meticulous
this is associated with a 3.5-​fold increased mortality risk, which patient hydration (possibly guided by patient’s haemodynamic
is prolonged and steady throughout 1 year [138–​141]. Different status), minimizing the volume of contrast agent, stopping the in-
classifications of bleeding scales for severity have been devel- take of nephrotoxic drugs, and avoiding short intervals between
oped, with some based on laboratory values (e.g. TIMI bleeding procedures. High-​dose statins, as indicated for secondary pre-
score) and some clinical such as the GUSTO definition of vention, irrespective of the risk of CIN, are also beneficial [151].
bleeding—​ life-​
threatening (fatal, intracranial, or resulting in N-​acetylcysteine is not effective in CIN prevention and should
haemodynamic compromise), moderate (requiring transfu- not be used [152, 153].
sion), and mild [142,  143]. The BARC was established in 2011,
but the resulting classification is rather complicated [144]. The
possible mechanisms responsible for the association between
bleeding and mortality include bleeding itself, discontinuation of
Conclusion
antiplatelet or antithrombotic medications, and anaemia with re- ACS are the leading cause of morbidity and mortality in Western
duced O2 delivery. There are also previously unforeseen possible countries. With regard to patients with STEMI, early reperfusion
consequences of blood transfusion like NO depletion, resulting therapy is crucial and constitutes a lifesaving treatment. Primary
in vasoconstriction or decreased O2 tissue delivery. All data re- PCI is the preferred method of reperfusion. For patients with
garding the consequences of bleeding in the setting of ACS are NSTE-​ACS, early diagnosis and risk stratification are mandatory
obviously not randomized, but observational, with many po- as the prognosis and therapeutic strategy usually vary. New diag-
tential confounders, and therefore require a cautious interpret- nostic methods with the introduction of a rapid rule-​out protocol
ation. Older age, female sex, renal insufficiency, baseline anaemia, by use of high-​sensitive troponin assays, new risk stratification
LMWH administration in the last 48 hours, and use of GPIs and scores, novel antithrombotic agents, and new-​generation DES
IABP are among the known factors predicting bleeding [145, 146]. have nowadays dramatically improved the immediate and long-​
Importantly, specific risk scores (such as the CRUSADE score) term results of PCI in ACS.
560 CHAPTER 42   Pe rc u taneou s c oronary interven ti on s i n  acu te c orona ry  sy n dro m es

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 CHAPTER 43

Coronary artery bypass

graft surgery
Piroze M Davierwala and Michael A Borger

Contents
Summary  565 Summary
Introduction  565 Surgical management of acute coronary syndromes still remains a challenge for
Indication and timing of the operation  566 the cardiac surgeon. Although most patients can be managed by percutaneous cor-
Unstable angina and non-​ST-​segment
onary intervention, for patients with complex multivessel or left main coronary ar-
elevation myocardial infarction  566
ST-​segment elevation myocardial tery disease (high SYNTAX score), in whom percutaneous coronary intervention
infarction  567 is not possible or is unsuccessful, urgent or emergent coronary artery bypass graft
Gender-​related characteristics  568
Heart team approach  568 surgery is the only available option. It is very important for surgeons to determine
Surgical considerations in acute coronary the optimal timing of surgical intervention, which is usually based on the clinical
syndrome patients  569 presentation, coronary anatomy, and biomarkers. Surgeons should be conversant
Operative risk assessment  569 with the different operative techniques, whether off-​or on-​pump coronary artery
Choice of approach  569
Choice of operative technique  570 bypass graft surgery, that would help in achieving the best possible outcomes in
Choice of conduits  570 such situations. Early and late survival of patients depends not only on an efficiently
Management of complications associated executed operation, but also on the competency of post-​operative care delivered.
with acute coronary syndrome  571
Cardiogenic shock  571 Modern perioperative management is reinforced by the availability of a variety of
Acute mechanical complications  571 mechanical cardiopulmonary assist devices, such as the intra-​aortic balloon pump,
Perioperative care  572
Mechanical circulatory support  572 extracorporeal membrane oxygenation, and an array of ventricular assist devices,
Coagulation management  574 which aid us in managing very sick patients presenting with cardiogenic shock.
Results of coronary artery bypass The results of coronary artery bypass graft surgery for acute coronary syn-
graft procedures in acute coronary
syndrome  574 dromes, as published in the literature, vary significantly, because of the heterogen-
Unstable angina and non-​ST-​elevation eity of patient populations, operative timing, and haemodynamic status, making
myocardial infarction  575
ST-​segment elevation myocardial
comparison of surgical outcomes almost impossible. Only one randomized trial
infarction  575 has been conducted to that effect, to date. A  heart team approach, involving an
Cardiogenic shock  576 interventional cardiologist and a cardiac surgeon, is mandatory to determine the
Salvage CABG  576
Techniques of coronary artery bypass graft best treatment strategy and achieve the best possible outcomes in patients with
surgery  576 acute coronary syndromes.
Conclusion  577
Personal perspective  577
Further reading  577
References  578
Additional online material  583
Introduction
An expeditious diagnosis and the earliest possible implementation of treatment in patients
with UA/​NSTEMI (see E Chapter 41), and STEMI (see E Chapter 38) can lead to con-
finement of further irreversible myocardial damage, with beneficial effects on early and
long-​term outcomes. In order to achieve early and successful revascularization, the treat-
ment of ACS requires an interdisciplinary, integrated approach between family physicians,
intensivists, non-​invasive and invasive cardiologists, and cardiac surgeons. When urgent
or emergent revascularization is deemed appropriate, PCI (see E Chapter  42) is most
566 CHAPTER 43   C oronary art ery bypass gra ft su rg ery

commonly used as the first-​line therapy in patients with ACS, due and haemodynamic stability of the patient and, to a lesser extent,
to its immediate and widespread availability, its lesser degree of on the need for routine and/​or additional diagnostic tests (see
invasiveness, and the major advances in stent technology [1,  2]. E Table 43.1). There are no randomized trials conducted to date,
However, in certain situations, such as complex CAD (i.e. left main comparing an early with a delayed CABG strategy for patients
stem or bifurcation stenosis, in-​stent restenosis, or stenosis of the with NSTEMI. One of the largest cohort studies analysing the ef-
proximal LAD coronary artery), chronic total coronary artery oc- fect of timing of CABG in patients with NSTEMI found surgery
clusion, or unsuccessful or complicated PCIs, urgent or emergent <6 hours from NSTEMI as an independent predictor of mortality
coronary artery bypass graft (CABG) becomes necessary in patients [9]. Contrarily, evaluation of the CRUSADE and Acute Coronary
with STEMI [3]‌. For patients with UA/​NSTEMI, the selection of Treatment and Intervention Outcomes Network Registry—​Get
PCI or CABG, as the means of revascularization, should generally With The Guidelines (ACTION Registry–​GWTG) databases re-
be based on the same considerations as those for patients without garding the timing of CABG for NSTEMI and in-​hospital out-
ACS [4]. Due to this difference in the urgency and type of therapy re- comes revealed that, although patients operated on >48 hours
quired in patients with or without ST-​segment elevation, the ESC [1, after the acute event had a higher risk profile, hospital mortality,
5, 6] and AHA guidelines [2–​4] have also been structured separately stroke, MI, and congestive heart failure were similar to those op-
for the two different manifestations of ACS. erated on within 48 hours [10]. Braxton and colleagues similarly
CABG can be carried out either conventionally on an arrested showed that non-​Q wave MI patients may receive CABG surgery
heart with CPB support or on a beating heart with the mainten- at any time, with similar outcomes to non-​MI patients [11]. Our
ance of native coronary perfusion, with or without CPB support. group evaluated 758 consecutive patients with NSTEMI under-
Mechanical assist device systems for short-​to mid-​term circula- going CABG and showed no difference in in-​hospital mortality
tory support offer an excellent option to bridge the crisis period and long-​term outcomes in patients operated within 24 hours of
in patients with impending or existing CS. This chapter discusses infarct, compared to those operated after 3 days, despite a higher
the indications, surgical techniques, results, and future prospects risk profile. In contrast, CABG performed between 24 and 72
of CABG in patients with ACS. hours showed a non-​significant trend towards poorer long-​term
outcomes [12].
In the Alberta Provincial Project for Outcome Assessment in
Coronary Heart Disease (APPROACH) study, the time from ad-
Indication and timing of the mission to CABG in patients operated on beyond 48 hours (non-​
operation emergent) after the index admission was not associated with an
increased risk of short-​term mortality [13].
Unstable angina and non-​ST-​segment elevation Hence, we believe that, for patients with NSTEMI, decision-​
myocardial infarction making about the timing of surgery is dependent more on the
For patients with UA/​ NSTEMI, the indications that favour clinical presentation and status of the patient, rather than the
a CABG procedure over PCI are the same as those for pa- time elapsed since the acute event. A  post hoc analysis of the
tients without ACS [4,  7]. In the wake of a lack of RCTs com- Treatment of Acute Coronary Syndrome with Otamixaban (TAO)
paring the outcomes of PCI and CABG in patients with left trial revealed that coronary angiography performed within 12
main and/​or multivessel disease suffering from UA/​NSTEMI, hours after admission to hospital in patients with NSTEMI was
Chang et  al. analysed the 5-​year results of a pooled database associated with a lower risk of death and MI at 6 months than
of patients with UA/​NSTEMI enrolled in the SYNTAX, the in those undergoing angiography after 12 hours or more [14].
Premier of Randomized Comparison of Bypass Surgery versus Patients with persistent or recurrent chest pain (CP)/​angina
Angioplasty Using Sirolimus-​ Eluting Stent in Patients with equivalent, ECG changes, and/​or rising cardiac biomarker levels
Left Main Coronary Artery Disease (PRECOMBAT), and the refractory to medical therapy, with ventricular arrhythmias, sub-
Randomized Comparison of Coronary Artery Bypass Surgery total non-​collateralized or severe distal left main coronary artery
and Everolimus-​Eluting Stent Implantation in the Treatment of stenoses, inducible ischaemia or inadequate flow reserve meas-
Patients with Multivessel Coronary Artery Disease (BEST) trials urements, and/​or haemodynamic instability with impending or
who underwent PCI and CABG. The primary outcome of death, manifested cardiogenic shock (CS) should be operated on an
MI, and stroke occurred significantly more often following emergent basis, i.e. before the beginning of the next workday (see
PCI than CABG (18% versus 13.4%; P = 0.036) and was driven E Figure 43.1). Our study demonstrated that delaying surgery
chiefly by a significantly higher rate of MI (7.5% versus 3.8%; in such patients, with the intent of stabilizing them, may worsen
P = 0.0006). In addition, the rate of repeat revascularization was their clinical status with time, resulting in poorer outcomes,
significantly lower in the CABG group than in the PCI group which could probably explain the non-​significant trend towards
(HR 0.56; P <0.001) [8]‌. Once a consensus has been reached by inferior results in patients undergoing CABG between 24 and
the heart team (see E Chapter  4) that CABG is the choice of 72 hours after NSTEMI [12]. Additionally, patients who have
revascularization, the timing of surgery should be primarily de- undergone a failed or complicated PCI should undergo emergent
termined, based on the symptom complex, coronary pathology, CABG. Furthermore, CABG should be considered on an urgent
 I n di cati on a n d ti m i n g of the ope r at i on 567

Table 43.1  Preoperative diagnostic tests performed in patients undergoing CABG surgery

Examination Mandatory Indications, if not mandatory Impact on treatment

Cardiac catheterization:
Coronary angiography
◆ Yes Heart valve disease
◆ Additional heart valve surgery
◆
Levocardiography
◆ Cardiomyopathy
◆ Assessment for ECMO/​cardiac assist devices
◆
RHC
◆ PH
◆

Echocardiography:
TTE
◆ Yes Heart valve disease
◆ ◆ Exclusion of heart valve disease, assessment of ventricular
TOE
◆ CS
◆ function
Suspected intracardiac thrombus
◆ Additional heart valve surgery may be required
◆
Preoperative assessment of VSDs, PMR, and contained FWRs
◆
Surgical thrombus removal should be performed
◆

12-​lead ECG Yes Left atrial or biatrial ablation surgery indicated in patients with AF
CXR Yes
Duplex US: Not essential before emergency CABG
Carotid arteries
◆ Yes Clinical signs of stenosis
◆ ◆ Suspicious carotid lesions warrant further diagnostic
Subclavian arteries
◆ Pathological Allen test, diabetes
◆ tests. Perioperative carotid artery stenting or
Radial arteries
◆ thromboendarterectomy, as per guidelines
LITA use, consideration to perform preoperative subclavian
◆
artery stent
Vessel quality and collateralization
◆

CT Redo cardiac surgery

◆ ◆ Imaging of adhesions, examination of relations between
Unclear findings on CXR
◆ thoracic structures
PH
◆ Identification of thoracic tumours
◆
Aortic aneurysms
◆ Exclusion of PE
◆
Decipher length and diameter of aortic aneurysms
◆

Pulmonary function tests Yes Not essential before emergency CABG

Cardiac scintigraphy Patients with suspected hibernating/​ Identification of viable myocardium and assessment of reversibility
scarred myocardium of ischaemia
Nuclear MRI Patients with suspected hibernating/​ Identification of viable myocardium
◆
scarred myocardium and/​or Assessment of ventricular and valve function
◆
cardiomyopathy Identification of LV aneurysms
◆

Abdominal sonography Patients with previous abdominal Mandatory

◆ in patients with advanced liver cirrhosis
surgery or abdominal organ disease ◆ Exclusion of hepatobiliary disease
Gastroscopy History of peptic ulcer
◆ Exclusion of active ulcer, malignant lesions, bleeding foci
◆
History of gastric surgery
◆ Grading of oesophageal varices
◆
Liver cirrhosis
◆

Laboratory tests Yes ◆ Haemogram, full coagulation profile, serum electrolytes, liver
and renal function tests
Blood grouping and cross-​matching tests, serological tests for
◆
HIV, and hepatitis A, B, and C
AF, atrial fibrillation; CABG, coronary artery bypass grafting; CS, cardiogenic shock; CT, computerized tomography; CXR, chest X-​ray; ECG, electrocardiogram; ECMO, extracorporeal
membrane oxygenation; FWR, free wall rupture; HIV, human immunodeficiency virus; LITA, left internal thoracic artery; LV, left ventricular; MRI, magnetic resonance imaging; PE,
pulmonary embolism; PH, pulmonary hypertension; PMR, papillary muscle rupture; RHC, right heart catheterization; TOE, transoesophageal echocardiography; TTE, transthoracic
echocardiography; US, ultrasound; VSD, ventricular septal defect.

basis (within the same hospital stay) in patients with left main completion of the necessary routine diagnostic procedures is es-
or three-​vessel disease involving the proximal LAD artery and sentially the preferred strategy.
those with a large area of the myocardium at risk. Conversely,
patients with long-​standing, well-​collateralized coronary lesions, ST-​segment elevation myocardial infarction
with stable haemodynamic parameters, usually respond favour- Previous studies showed an increase in the risk of mortality after
ably to medical therapy and do not require immediate surgery. emergency CABG early after STEMI. A review of the New York
Such patients can undergo an early elective operation (within 3–​ State Cardiac Surgery Registry [15], which investigated the effect
4 weeks). In hospitals without the availability of cardiac surgery, of timing of CABG after a transmural AMI, reported an overall
transfer to a tertiary care centre with cardiac surgical facility after mortality of 3.3%, which decreased as the timing of CABG
568 CHAPTER 43   C oronary art ery bypass gra ft su rg ery

Coronary angiography patients undergoing CABG within and after 24 hours following
STEMI [18]. Grothusen and colleagues recently reported ex-
Depending on CA findings cellent outcomes in patients undergoing early surgery (mean 5
and/or SYNTAX scores
CABG PCI
hours) following STEMI. The significantly lower 30-​day and 5-​
If PCI unsuccessful or eventful
and 10-​year mortality in STEMI than in NSTEMI patients (2.7%
versus 6.6%, P = 0.04; 87% versus 73%, P <0.001; 74% versus 57%,
P <0.001) undergoing CABG was probably due to younger age,
lower risk profiles and earlier timing of surgery in the STEMI
patients [19]. A  more recent study revealed that the haemo-
Emergent Urgent Elective
dynamic profile of patients is more important in determining
post-​operative outcomes than the timing of surgery itself [20]. An
analysis of STEMI patients undergoing CABG from the ACTION
In patients with: In patients with: Registry–​GWTG showed that utilization of CABG in STEMI pa-
• Persistent angina • Resolving angina/symptoms tients has declined over the years. However, when used, CABG
• Mechanical complications • Low-risk UA/non-ST-segment
• Cardiogenic shock elevation MI was performed as the primary reperfusion therapy or following
• Critical coronary pathology • Stable haemodynamic parameters primary PCI in the vast majority of patients and was performed
• Uncritical coronary pathology
within 1–​3 days after angiography. The observed mortality rates
Figure 43.1  Flow chart for decision-​making in patients with ACS. CA, were low and comparable to those in STEMI patients not treated
coronary angiography; CABG, coronary artery bypass graft; MI, myocardial with CABG, suggestive of the safety of early CABG in a select
infarction; PCI, percutaneous coronary intervention; UA, unstable angina. group of STEMI patients [21]. An RCT would be justified in the
present era to answer this question.
increased after a transmural AMI. Multivariate analysis showed
that CABG within 3 days of a transmural AMI was an independent
Gender-​related characteristics
predictor of mortality. Thielmann and colleagues [16], in a retro- It is well known that women are less likely to receive diagnostic
spective review of 138 patients with STEMI undergoing CABG, coronary angiography and subsequent revascularization than
identified the time to operation as a major predictor of mor- men, even in patients with ACS [22]. A recently published Danish
bidity and mortality on unadjusted univariable and risk-​adjusted study including 52 565 patients, which comprised 36% women,
multivariable logistic regression analysis. Similarly, Weiss and col- found that women underwent diagnostic coronary angiography
leagues [17], in a retrospective review of the California Discharge less frequently than men, both within 1 day (31% versus 42%; P
Data, identified 9746 patients with STEMI undergoing CABG. <0.001) and 60 days (67% versus 80%; P <0.001) of hospital ad-
Patients undergoing early CABG (0–​2 days post-​AMI) had sig- mission [23]. Additionally, women were less likely to undergo
nificantly higher mortality than the late CABG group (day 3 or PCI (58% versus 72%; P <0.001) and CABG (6% versus 11%; P
later) (5.6% versus 3.8%; P <0.001). The authors suggested that <0.001) within 60  days of hospitalization than men. The differ-
CABG may best be deferred for at least 3 days after admission for ences, which remained constant over the period of this study
an AMI. Hence, emergency surgical revascularization in STEMI from 2005 to 2011, could probably be explained by several fac-
is confined to a very select group of patients. These include pa- tors such as physicians’ tendency to underestimate the risk of ACS
tients with symptoms and signs of ongoing ischaemia, who have a [24] in women, lack of benefit from an early invasive strategy in
coronary anatomy unsuitable for PCI or who have already under- women [25], the greater possibility of non-​obstructive CAD in
gone an unsuccessful PCI or developed severe heart failure or CS women (22% of women; more than twice as frequent as in men)
[3]‌. Patients developing complications of STEMI, such as acute [23], caused by coronary artery spasms, rupture, or erosion of ec-
MR, VSD, or PMR or free VWR, also need emergent surgery [3]. centric plaques, microvascular disease, including Takotsubo syn-
Not uncommonly, the IRA can be successfully acutely re- drome observed more often in women, and the higher likelihood
opened, but it unmasks accompanying multivessel CAD during of unfavourable periprocedural factors such as small vessel size,
angiography, which essentially requires CABG. In this situation, tortuosity, and potential complications in women. The impact of
an urgent CABG is recommended after a few days of cooling off this sex-​related discrepancy in the management of ACS on clin-
following the acute infarct or earlier in the case of recurrent is- ical outcomes should be the focus of future research.
chaemia, haemodynamic instability, or critical coronary anatomy.
Nevertheless, no RCTs assessing the optimal timing of CABG Heart team approach
after STEMI exist in the literature, and the above-​mentioned Although a ‘heart team’, first introduced by the SYNTAX trial
studies are also almost a decade old. Advancements in opera- [26], may not be required for STEMI or unstable NSTEMI pa-
tive and anaesthesia techniques and the ever improving post-​ tients who primarily undergo culprit-​lesion PCI [27], the never-​
operative ICU care could definitely have a positive impact on ending debate about the choice of revascularization technique,
the outcomes of emergent CABG following STEMI. Khan et al. whether CABG or PCI, for haemodynamically stable patients
demonstrated no difference in 1-​month and 1-​year mortality in with UA/​NSTEMI still exists [1, 28, 29] and warrants a heart team
 Su rgical c on si der ati on s i n  acu te c orona ry sy n dro me   pat i e n ts 569

approach. This is especially true in patients with isolated prox- which performs better in predicting the operative morbidity and
imal LAD disease, which is involved in as many as 15% of patients mortality after an isolated CABG [41] (see Appendices I and
presenting with ACS [30] and is associated with worse prognosis II in Additional online material).
[31]. An analysis of 842 patients undergoing revascularization Another score recently introduced is the age, creatinine, and
of the proximal LAD culprit lesion in the ACUITY trial ejection fraction (ACEF) score, which uses just the age, serum
(PCI: n = 562, 66.7%; CABG: n = 280, 33.3%) revealed no dif- creatinine, and LVEF and appears to be as good as more complex
ferences in rates of death, MI, MACE, and stroke for the two scores in predicting mortality in patients undergoing an elective
revascularization strategies, but PCI patients had significantly CABG [42].
higher revascularization rates at 1 month and 1 year, which was With the expanding use of PCI to treat CAD, new risk stratifica-
mainly driven by target lesion failure. In contrast, CABG was as- tion scores have been recently developed to predict the long-​term
sociated with higher periprocedural major bleeding (8.1% versus AE rates, according to the type of therapy used. The SYNTAX
54.4%; P <0.001) [32]. The same applies to patients with left main score, which is a lesion-​based scoring system used to quantify the
disease, with low-​to intermediate-​risk SYNTAX scores (available coronary anatomical complexity [33, 43], is used for short-​and
from:  M http://www.syntaxscore.com/calculator/syntaxscore/ long-​term risk stratification of patients undergoing PCI, but not
framesetss2.htm) [33]. A  definite algorithm, based on the so much for CABG [26]. Second, the SYNTAX score alone has
SYNTAX score [34], should be drafted by the heart team at each been found to be inadequate in predicting mortality, when com-
institution, delineating the criteria for selection of the appropriate pared with clinical-​based scoring systems. Clinical variables cor-
therapy. In fact, the development of definite algorithms, based relate well with clinical endpoints such as death or MI [44]. As a
on the SYNTAX score [34], drafted by heart teams, or on risk result, a number of scoring systems that combine the SYNTAX
stratification scores, by combining the SYNTAX score with rele- score with preoperative clinical characteristics have been devel-
vant preoperative clinical parameters (logistic Clinical SX Score, oped. Two such scores are the Global Risk Classification (GRC),
SYNTAX II score, Global Risk Approach), to aid in determining which is a combination of the EuroSCORE and SYNTAX score
the ideal revascularization strategy in haemodynamically stable strata, and the Clinical SYNTAX Score (CSS), which is a combin-
patients with NSTEMI could be the foreseeable future [35]. ation of the SYNTAX score and the ACEF score [45, 46] (see
Appendices I and II in Additional online material).
The GRC substantially enhances the identification of low-​risk
Surgical considerations in acute patients who could safely and efficaciously be treated with CABG
or PCI [47]. However, the most recently developed SYNTAX
coronary syndrome patients score II, which contains eight predictors, i.e. the anatomical
Operative risk assessment SYNTAX score, age, creatinine clearance, LVEF, the presence of
unprotected left main CAD, peripheral vascular disease, female
The operative risks of patients can be fairly assessed by scoring
sex, and COPD, was found to be a better guide for decision-​
systems, which render as valuable prognostic tools to predict
making between CABG and PCI than the original anatomical
early and late outcomes of the procedure for a particular patient.
SYNTAX score, with regard to long-​term mortality in patients
The two most commonly used risk stratification systems in pa-
with complex CAD [48] (see Appendix III in Additional on-
tients undergoing CABG are the STS score and the EuroSCORE,
line material).
which allow online and offline operative risk calculations of
Surgeons should be aware that these risk stratification scores
an individual patient (available from:  M http://​riskcalc.sts.org/​
have not been validated in patients undergoing emergent proced-
STSWebRiskCalc273/​de.aspx and M http://​www.euroscore.org)
ures for ACS. However, these scores are the best guides available
[36–​38]. Several preoperative parameters are recorded into a
at the present time to predict early and long-​term outcomes in
computer-​based system before the operation to calculate the
patients with CAD undergoing PCI or CABG.
actual percentage of the predicted risk. These include timing
of surgery, age, gender, prior heart surgery, race (only for STS
score), LVEF, haemodynamic status, percentage of stenosis of the Choice of approach
left main coronary artery, and the number of major epicardial A median sternotomy continues to be the standard approach used
coronary arteries with >70% stenosis (only for STS score). Long-​ to perform CABG in patients with multivessel CAD. This is par-
standing comorbidities, like diabetes (only for STS score), per- ticularly true in patients with borderline haemodynamic stability
ipheral vascular disease, chronic renal insufficiency, and COPD, undergoing urgent or emergent surgery for ACS. It not only en-
are also included in the calculation. Whereas the STS score reli- ables the surgeon to have an excellent approach to, and vision of,
ably allows for an estimation of the procedural risk for mortality all epicardial coronary arteries, but also facilitates quick and easy
and morbidity, it is widely accepted that the EuroSCORE over- access to all cardiac structures, in case an emergent implemen-
estimates the procedural risk by a factor of approximately 2.5 tation of CPB is required. In addition, haemodynamic situation
[39]. Hence, the EuroSCORE investigators recently developed a permitting, the internal thoracic arteries (ITAs) can also be har-
modified version of this risk scoring method called EuroSCORE vested in a short time through this approach. As these patients are
II (available from:  M http://​www.euroscore.org/​calc.html) [40], operated on an emergency basis, routine antiseptic preparation of
570 CHAPTER 43   C oronary art ery bypass gra ft su rg ery

these patients may frequently not be possible and thus represents OPCABG is that, in the era of DAPT, surgery can be executed with
a potential risk for the development of post-​operative wound in- minimal blood loss and transfusion requirements, even in patients
fections, not only at the sternotomy site, but also, more frequently, on DAPT close to surgery [64, 65].
at the site of graft harvest. Thus, harvesting the ITAs in a skelet- In haemodynamically unstable patients, the heart may not
onized fashion and other conduits using minimally invasive tech- tolerate manipulations to expose the coronary arteries. In such
niques, with the preservation of multiple skin bridges, or through situations, preoperative implantation of an IABP followed
endoscopic techniques, particularly in diabetic patients, when by OPCABG enables achievement of acceptable periopera-
time and haemodynamic stability permit, leads to a lower inci- tive outcomes and excellent mid-​to long-​term survival [66]. If
dence of post-​operative wound infections [49, 50]. haemodynamic stability is not accomplished following IABP
In haemodynamically stable patients with ACS due to prox- implantation, CABG can be performed on-​pump, without ar-
imal or mid-​LAD lesions not amenable to PCI or failed PCI, a resting the heart (beating heart). In a study comparing CPB-​
minimally invasive direct coronary artery bypass (MIDCAB) [51] supported beating-​heart surgery to conventional CABG with
could be considered a potential option, as long as the indication is cardioplegic arrest in ACS patients, not only was mortality in the
semi-​elective or at the most urgent. This procedure is performed CPB-​supported beating-​heart group lower (6.5% versus 8.0%),
through a small left anterior thoracotomy, through the fourth or but the occurrence of perioperative MI, excessive post-​operative
fifth intercostal spaces. The LITA is harvested and anastomosed to bleeding, and confusion states were also significantly lower [60].
the LAD. Performance of this operation in emergency situations,
like an iatrogenic dissection of the LAD in the catheterization la- Choice of conduits
boratory, in ACS patients with haemodynamic instability or in The LITA is the best conduit available to graft the LAD artery
those in CS should be strictly avoided. Furthermore, this oper- [7]‌. The endothelium of the ITA releases NO and prostacyclin,
ation should be performed by an experienced surgeon who can which are potent vasodilators and inhibitors of platelet function
expedite the procedure efficiently. [67–​69] and as a result, has a good response to vasodilators and
is less spastic in the presence of vasopressors used in the post-​
Choice of operative technique operative period [70–​72]. The ITA flow characteristics are com-
With the ever growing expertise and experience in performing parable to those of normal coronary arteries. Elami et  al. have
off-​pump CABG (OPCABG), it has also become a valuable option proven that non-​use of the ITA is one of the most significant in-
in patients undergoing CABG in the acute phase of MI [52, 53]. dependent predictors of a low cardiac output after CABG for an
Although OPCABG is often criticized for the inferior quality of AMI [73]. It is speculated that the ITA could be more resistant to
anastomoses, hence lower graft patency and higher incomplete low-​flow situations, like the no-​reflow phenomenon, than other
revascularization rates, when compared to conventional CABG arterial conduits, which represents a major reason why the LITA
performed on cardiopulmonary bypass with an arrested heart [54], remains a very important option for these patients. In addition,
there is enough evidence to show that there is a uniform reduction LITA bypass to the LAD artery not only improves the survival
in myocardial trauma and the release of markers of myocardial rate, but also reduces the incidence of late MI, hospitalization for
necrosis in patients undergoing OPCABG [55, 56], through avoid- cardiac events, the need for reoperation, and recurrence of angina
ance of ischaemic cardiac arrest and reperfusion injury. In add- [74, 75]. Caceres and co-​workers recently proved that ITA grafting
ition, earlier revascularization of the culprit lesion, attenuation of was independently associated with a lower risk of mortality and
the no-​reflow phenomenon, and a reduction of myocardial oe- did not seem to compromise outcomes in patients with ACS [76].
dema curtail the extent of myocardial necrosis. Even though these The only possible drawback of using the LITA in patients with
subtle benefits of OPCABG are not evident in patients under- ACS is that its preparation requires an additional 10–​20 minutes.
going elective CABG, it can be assumed that patients with ACS Although this should not pose a problem in most patients with
undergoing OPCABG will specifically profit from the preserva- ACS, surgery in patients in CS should be expedited as quickly as
tion of native coronary perfusion and a correspondingly lesser possible. In such patients, the surgeon must either forego the use
ischaemia–​reperfusion injury. To date, only a few retrospective of the LITA or harvest the LITA after the establishment of CPB.
studies [57–​63] and one RCT comparing the results of OPCABG Under emergency conditions, it would also be faster to harvest
and conventional CABG in ACS patients have been published. the LITA as a pedicle, rather than in a skeletonized fashion.
‘Time is myocardium’ is a terminology common to interventional Due to the excellent short-​and long-​term outcomes of CABG
cardiologists. OPCABG achieves quick revascularization of the performed with the LITA, one would expect that use of the right
target vessel, thus keeping the ischaemic time of the jeopardized ITA (RITA), in addition, would further improve the results. This
myocardium as short as possible [60]. In this context, the coronary fact has been confirmed by a number of studies published in the
artery supplying the ischaemic territory, which is commonly the literature [77–​79]. However, the use of bilateral ITAs (BITAs) is
LAD territory, is grafted first and reperfused. As a result, not only recommended only in those patients with ACS, who are haemo-
is the infarct-​associated ischaemic time shortened, but it also im- dynamically stable with a good LV function and in whom one
proves the tolerance of the heart to ensuing manipulations re- does not expect the use of high-​dose inotropes post-​operatively.
quired to graft the lateral and inferior walls. Another advantage of ITAs also require a higher perfusion pressure to maintain an
 Su rgical c on si der ati on s i n  acu te c orona ry sy n dro me   pat i e n ts 571

adequate myocardial blood flow. Hence, BITAs would be more almost up to 60% [88]. Acute coronary revascularization posi-
commonly harvested in stable patients with UA/​NSTEMI, as op- tively influences short-​and long-​term outcomes in patients with
posed to those with STEMI. ischaemia-​related CS [89, 90]. The window period between FMC
The third most popular arterial graft used in CABG is the radial and PCI has been liberalized to 12 hours, even for multivessel PCI
artery. It is a muscular artery and is therefore highly susceptible [1, 91]. Emergency CABG in patients with a coronary anatomy
to spasm, especially in the presence of high-​dose vasopressor sup- not suitable for PCI, or those undergoing an unsuccessful or a
port [80, 81]. Second, the chances of graft failure are higher if it complicated PCI, has to be most often performed on CPB to en-
is used to graft a coronary artery that is not severely stenosed, i.e. sure the maintenance of adequate end-​organ perfusion. However,
<70% for left-​sided and <90% for the right coronary artery [82]. our strategy, for the past decade, to perform bypass grafts on CPB
The overall long-​term patency of the radial artery is excellent without clamping the aorta, i.e. on a beating heart [58, 92], was
but is highly influenced by the site of the proximal anastomosis associated with lower perioperative morbidity and mortality, with
and competitive flow [83]. The indications for its use in patients similar long-​term results to conventional CABG with ischaemic
with ACS are similar to those for the use of a second ITA graft, arrest [60]. In contrast to PCI, CABG on CPB offers:  (1) acute
although there are reports about the safety of its use in patients volume unloading of the LV until revascularization is achieved;
with moderate to severe LV dysfunction [84]. A recent report on (2) a higher possibility of complete revascularization; and (3) the
the use of total arterial revascularization in ACS patients demon- option of implanting an assist device for hearts which require
strated that experienced surgeons could expedite the procedure a longer recovery period for the hibernating myocardium and
efficiently without an increase in additional risks, but with the reperfusion injury.
possibility of better long-​term survival [85]. Apart from inotropic medications and early revascularization,
The saphenous vein is one of the most commonly used con- mechanical haemodynamic support can also be used to help the
duits in CABG, especially in emergency situations, because it is heart and other organs recover from CS.
easy and quick to harvest and graft and is resistant to vasospasm,
thus potentially being a safe option in patients on high doses of Acute mechanical complications
vasopressors. It can be harvested easily by using open, semi-​open Most mechanical complications, described in E Chapter  40,
(bridged), or endoscopic techniques [86]. occur in the first 24 hours after an AMI but may ensue even 1
week thereafter. They include free left ventricular wall rupture
Management of complications associated (LVWR), post-​infarct VSD, and acute MR and have been dis-
with acute coronary syndrome cussed in greater detail in E Chapter 40. Prompt repair (with or
without CABG) is indicated in most cases.
ACS can result in the development of some deadly complications,
FWR leads to acute pump failure within minutes, electromech-
which are life-​threatening in nature. This section will focus primarily
anical dissociation, and death [93]. A lifesaving operation is pos-
on CS and acute mechanical complications like VSR, PMR causing
sible only in selected cases, as a very small number of patients are
severe mitral regurgitation (MR), and FWR of the left ventricle (LV).
capable of reaching the hospital, with mortality rates approaching
Cardiogenic shock 60% [94].
CS (see E Figure 43.2), which is discussed in detail in E Post-​infarct VSD is seen in approximately 1% of AMI patients
Chapter 47, is one of the most common causes of death in patients and has 1-​year mortality of >90%, if not operated upon. Definitive
presenting with ACS [87], with hospital case fatality rates being treatment consists of an urgent/​emergent closure of the VSD with
a patch (Dacron® or bovine pericardium), which should be per-
formed, even in haemodynamically stable patients, because the
Inotropes AMI + CS rupture site can expand abruptly, resulting in sudden haemo-
PDE inhibitors dynamic collapse in previously stable patients [95]. Although
IABPvv Emergency coronary angiography
the appropriate timing of surgical repair is elusive, patients in CS
- Off-pump
PCI
CABG
- On-pump due to a large left-​to-​right shunt volume should undergo emer-
• Beating heart
• Cardioplegic arrest
gent surgery. In haemodynamically stable patients, surgery can
be delayed for 3–​4 weeks, during which the patient can be opti-
Assist device ECMO/ECLS mized with inotropic and mechanical support [96]. Despite sur-
gery, hospital mortality still ranges from 20% [97] to up to around
Recovery the 50% mark [98, 99], although it did reduce in the last decade
of the twentieth century [100]. Alternatively, there are reports of
Heart transplant Destination therapy transcatheter VSD closure using interventional occluder devices,
but with equally bad outcomes [101].
Figure 43.2  Flow chart for decision-​making in patients with ACS and Acute MR develops due to: (1) papillary muscle rupture or dys-
cardiogenic shock. AMI, acute myocardial infarction; CABG, coronary artery
bypass surgery; CS, cardiogenic shock; ECLS, extracorporeal life support;
function; and (2)  dilatation of the mitral valve annulus due to
ECMO, extracorporeal membrane oxygenation; IABP, intra-​aortic balloon infarct-​related LV dysfunction. Treatment of patients with acute
pump; PCI, percutaneous coronary intervention. MR with associated pulmonary oedema and/​or CS incorporates
572 CHAPTER 43   C oronary art ery bypass gra ft su rg ery

emergent mitral valve surgery. Surgical treatment most com- the same subjects at different time points that are often influenced
monly involves mitral valve replacement to keep the aortic clamp by different clinical conditions [111]. Additionally, the prevalence
time as short as possible. Alternatively, mitral valve repair can be of aspirin resistance, which hinders platelet inhibition, appears
attempted in more suitable valve pathologies and stable haemo- to increase significantly in the early post-​operative period [112],
dynamic conditions, using chordal transfer or replacement tech- probably as a result of CPB-​induced inflammation and platelet
niques, in combination with a ring annuloplasty. However, valve hyperactivity, leading to an increase in the potential for occur-
repairs in these patients always bear a higher-​than-​average risk rence of adverse ischaemic events. DAPT, with the addition of a
of failure. Overall 30-​day mortality still remains higher than 25% P2Y12 inhibitor such as clopidogrel in patients with aspirin re-
[102,  103]. There have been recent case reports describing suc- sistance, has not been found to reduce the incidence of adverse
cessful percutaneous mitral valve repair in such patients with the ischaemic events or death, at least after elective primary CABG
MitraClip system [104]. [113]. Moreover, DAPT has demonstrated no impact on saphe-
nous vein graft intimal hyperplasia or patency at 1-​year follow-​up
[114]. A recently published review reported that only 12 studies
Perioperative care concerning the efficacy of the use of DAPT after CABG existed
Perioperative care of patients undergoing emergency CABG is vir- in the literature [115], of which only one was an RCT [114].
tually similar to that of any other patient undergoing an elective Furthermore, the outcomes revealed by them were variable, most
CABG or heart operation (as outlined in E Chapter 75), with a likely because of inadequate cohort sizes, poor study design, and
few points that need to be alluded to. Patients with ACS (especially heterogenous surgical populations, which lead to conflicting
STEMI) need to be aggressively monitored and stabilized preopera- conclusions. The authors recommended that DAPT can be com-
tively in the ICCU, so that the haemodynamics are adequately op- menced in the post-​operative period once the possibility of major
timized at the time of surgery. Bedside routine invasive monitoring bleeding is unlikely. Once implemented, a P2Y12 inhibitor should
with peripheral and pulmonary artery catheters, mechanical sup- preferably be maintained over 12 months, unless there are contra-
port with IABP, and/​or ECMO (see E Chapter 28) for patients indications such as an excessive risk of bleeding [6]‌. This is obvi-
in frank CS are some of the ardent measures that may have to be ously a matter of concern in patients requiring emergency CABG.
taken for preoperative optimization in this patient subset (see E The use of mechanical circulatory support (MCS) and peri-
Chapter 28). Ischaemia–​reperfusion injury is a well-​known phe- operative coagulation management, which have been comprehen-
nomenon in patients undergoing on-​pump CABG, especially as sively reviewed in E Chapters 28 and 68, respectively, warrant a
emergency procedures for ACS. Even in OPCABG, short periods brief mention here.
of regional myocardial ischaemia are produced during target
vessel anastomosis, resulting in myocardial injury, the severity of Mechanical circulatory support
which varies, according to the area of distribution of the vessel and IABP counterpulsation (see E Figure 43.3), a Class IC recom-
the extent of collateralization. Obviously, increasing the number mendation for use in CS in the ESC guidelines [6]‌, can also be
of grafts performed for multivessel CAD could theoretically put used for haemodynamic support during catheterization and/​or
greater myocardium at risk of injury, particularly in patients with angioplasty, before high-​risk surgery, for mechanical complica-
evolving MI, UA, or both. The beneficial effect of glucose–​insulin–​ tions of MI, or for refractory post-​MI UA. In many critical situ-
potassium (GIK) solution, as a cardioprotective agent after cardiac ations, it also enables the surgeon to perform OPCABG. However,
surgery, has been controversial [105, 106]. However, a recent meta-​ the scientific evidence for the benefits of IABP in STEMI and CS
analysis addressing the effects of GIK solution in adult cardiac sur- still remains controversial [116–​ 118]. The recently published
gical patients [107] and an RCT in patients undergoing OPCABG large multicentre prospectively randomized IABP-​ SHOCK II
for ACS [108] revealed a significant reduction in myocardial in- trial reported that the use of IABP (E see Chapter 47) did not
jury and an improvement in haemodynamic performance when reduce 30-​day mortality in patients with CS complicating AMI,
the GIK solution was initiated during surgery and continued for for whom an early revascularization strategy was planned [119].
6 hours after reperfusion. The majority of patients with ACS also Nevertheless, IABP implantation, at least in the context of CABG,
receive aggressive antiplatelet therapy, which has been detailed in remains a Class  I  indication [13]. With regard to the timing of
E Chapter 39. The use of aspirin following CABG is associated implantation, some reports and meta-​analyses [120–​123] dem-
with a significant decline in non-​fatal MI, non-​fatal stroke, or vas- onstrated a significantly lower mortality rate in high-​risk patients
cular death in patients with UA and AMI [109] and a 40% reduc- treated with preoperative IABP. We usually implant an IABP pre-
tion in bypass graft occlusions [110]. As per the ESC guidelines, operatively in patients with STEMI and CS and at the first sign
aspirin should be given to all patients without contraindications, of cardiac failure in NSTEMI patients in our institution. This is
at an initial loading dose of 150–​300 mg and at a maintenance dose supported by a study by Ranucci and co-​workers who proved that
of 75–​100 mg daily long-​term, regardless of the treatment strategy postponing the use of IABP may be deleterious in patients with
(see E Chapter 39). However, these effects are subject to the pa- drug-​refractory heart failure [124].
tients’ platelet inhibitory responses to antiplatelet therapy, which Patients in CS with severe LV dysfunction commonly cannot be
not only demonstrate diversity between subjects, but also within weaned from CPB after completion of revascularization, despite
 Su rgical c on si der ati on s i n  acu te c orona ry sy n dro me   pat i e n ts 573

(a) (b)
Blood pressure
(mmHg) Dicrotic notch
120

100

80
Systole Diastole

Coronary blood
flow (mL/min)

300
Left
200 coronary artery

100 Right
coronary artery
0
Systole Diastole

Figure 43.3  Intra-​aortic balloon pump (IABP). (A) Position in the descending aorta. (B) Arterial and coronary blood flow waveforms recorded during a
functioning IABP.

maximum inotropic therapy and IABP support. In such cases, a function [125], which allows the heart team to decide about fur-
temporary MCS device may be considered as a bridge to recovery ther lines of therapy, especially in patients with an unknown
or as a bridge to other procedures like LVADs or heart transplant- medical history, comorbidities, and neurological status. When
ation (HTx). Use of these devices is a Class IIa recommendation, warranted, the implantation of a permanent assist device (see E
according to the ESC guidelines [6]‌. One option is implantation Chapter 50) may serve as a bridge to heart transplant or as destin-
of a VA-​ECMO or an isolated blood pump to support left and/​or ation therapy (see E Figure 43.3). In general, non-​pulsatile assist
right heart function. The main advantages of these systems are the devices (see E Figure 43.4) are associated with acceptable long-​
ease of implantation and maintenance of an adequate end-​organ term survival rates [126].

Figure 43.4  Assist device in operation on the ICU showing the system monitor (yellow arrow), the power module (yellow hatched arrow), the battery charger
(orange arrow), the system controller (brown arrow), the modular cable (red arrow), and driveline (red hatched arrow).
574 CHAPTER 43   C oronary art ery bypass gra ft su rg ery

Coagulation management in emergent situations [137]. In contrast, short-​acting agents, like

Emergent CABG procedures in patients with ACS require a tirofiban and eptifibatide, should be discontinued only 2–​4 hours
more aggressive coagulation management protocol, because the [138, 139] before surgery. The performance of extended coagulation
overwhelming majority are acutely treated with platelet aggregation profile tests or thromboelastography is recommended immediately
inhibitors. Acetylsalicylic acid (see E Chapter 39), not being asso- after protamine antagonization in such patients. This allows for the
ciated with an increased risk of bleeding [127], should not be with- specific substitution of coagulation factors, platelets, protamine, or
held before urgent CABG [3,  128]. It is common knowledge that antifibrinolytic agents, as deemed necessary [140]. The use of cell-​
P2Y12 inhibitors, like clopidogrel, ticagrelor, or prasugrel, should savers cannot be overemphasized in these patients.
be withheld, ideally for 5 days preceding surgery [129] and at least
3 days when the benefits of urgent revascularization outweigh the
Results of coronary artery bypass graft
risks associated with excessive post-​operative bleeding [130, 131]. procedures in acute coronary syndrome
Among 20 304 NSTEMI patients in the Acute Coronary Treatment Real-​life data from large databases are not consistent with respect
and Intervention Outcomes Network (ACTION) Registry (2009–​ to the percentage of AMI patients undergoing CABG. Analysis
2014) who underwent catheterization within 24 hours of admis- of data from the Research Data Centers of the Federal and State
sion and CABG during the index hospitalization, 32.9% received Statistical Offices of Germany for the years 2005, 2007, and 2009
a pre-​catheterization P2Y12 inhibitor and the time from catheter- demonstrated an increase in the number of CABGs performed in
ization to CABG was longer among patients who received a pre-​ AMI patients [2005: 9402 (4.6%); 2007: 10 296 (4.9%); 2009: 10 501
catheterization P2Y12 inhibitor than those who did not (median (5.2%)]. The rate of CABG in STEMI and NSTEMI patients in 2009
69.9 hours versus 43.5 hours; P <0.0001), and longer for patients was 4.3% and 5.7%, respectively [141]. Contrarily, a serial cross-​
treated with prasugrel (114.4 hours) or ticagrelor (90.4 hours), com- sectional analysis of hospitalizations from 2001 through to 2011,
pared with clopidogrel (69.3 hours; P <0.0001). P2Y12 inhibitor use using the Healthcare Cost and Utilization Project Nationwide
was associated with higher risks of post-​CABG bleeding (OR 1.33, Inpatient Sample (NIS) in the United States revealed a reduction
95% CI 1.22–​1.45), post-​CABG blood transfusion (OR 1.51, 95% CI in CABG use for both STEMI (39% decrease; Ptrend  <0.001) and
1.41–​1.62), and the need for surgical or procedural intervention for NSTEMI (14% decrease; Ptrend = 0.005) over the study period [142].
treatment of bleeding (34% versus 23%; P <0.001). Furthermore, the Perioperative mortality in patients undergoing CABG during the
rates of post-​CABG bleeding and transfusion were higher in those acute phase of MI is much higher than that in patients with stable
undergoing CABG within 5 days of the pre-​catheterization dose of angina, in whom 30-​day mortality rates of approximately 1% have
a P2Y12 inhibitor than those undergoing CABG after 5 days [132]. been reported [28]. In-​hospital mortality reported from Germany
Similarly, a Swedish observational study including 2244 ACS patients for the year 2009 was 11.6% in STEMI and 7.5% in NSTEMI pa-
on acetylsalicylic acid and either ticagrelor (n = 1266) or clopidogrel tients [141]. Despite this fact, early CABG after ACS is justified if the
(n  =  978) within the last 14  days before acute or urgent CABG benefits of an emergent operation outweigh the risks. The timing of
(99.3% with CPB) demonstrated that the difference in incidence of emergent CABG after the onset of ACS, the type of MI, and the
major bleeding complications between the two P2Y12 inhibitors was presence of CS have a major impact on mortality and morbidity.
mainly driven by a significant reduction in major bleeding compli- Comparing various studies is difficult, because patient popula-
cations in the ticagrelor group when clopidogrel/​ticagrelor was dis- tions vary enormously, with respect to age, the timing of surgery,
continued 3–​5 days before surgery (unadjusted OR 0.39; P = 0.006). haemodynamic stability, and, most importantly, the type of ACS,
Discontinuation of ticagrelor at 3–​5 or >5 days before surgery did i.e. whether STEMI or NSTEMI. Analyses portraying excellent re-
not affect perioperative major bleeding rates (unadjusted OR 0.93; sults often exclude patient subsets at highest risk. As a result, the
P = 0.80), whereas discontinuation at 0–​3 days was associated with reported operative mortality in patients with ACS varies between
a significantly higher rate of major bleeding, compared with both 1.6% and 32% [9, 10, 15–​17, 124, 125, 143–​146] (see E Table 43.2).
3–​5 days (unadjusted OR 5.17; P <0.0001) and >5 days (unadjusted Management of diabetic patients presenting with ACS has also
OR 4.81; P <0.0001) [133]. In contrast, clopidogrel-​treated patients evoked interest in recent times. A  propensity-​matched analysis of
had a higher incidence of major bleeding complications when dis- 21  681 diabetic patients with NSTEMI comparing an early (<48
continued 3–​5  days, compared with >5  days, before surgery (un- hours) invasive strategy with an initial conservative strategy revealed
adjusted OR 1.71; P = 0.033). However, if the P2Y12 inhibitors could lower in-​hospital mortality in patients undergoing early intervention
not be discontinued before surgery, ticagrelor was associated with (2.2% versus 3.8%, OR 0.57, 95% CI 0.50–​0.63; P <0.0001) [147].
a higher risk for severe bleeding than with clopidogrel, probably A population-​based, retrospective cohort study of diabetic pa-
due to its stronger antiplatelet effect [134]. Nevertheless, OPCABG, tients included in the British Columbia Province-​wide registry
being associated with a lower risk of bleeding [135, 136], can be per- demonstrated that 30-​day MACCE rates were significantly lower
formed even within 24 hours of stopping the P2Y12 inhibitors [3]‌. in ACS patients undergoing CABG, compared with those under-
Our study also demonstrated a long-​term beneficial effect of con- going PCI (adjusted OR 0.49, 95% CI 0.34–​0.71; inverse prob-
tinuation of P2Y12 inhibitors till the day of surgery [12]. Abciximab, ability of treatment weight [IPTW] adjusted analysis:  OR 0.52,
an IV GP IIb/​IIIa receptor antagonist with biological effects for up 95% CI 0.37–​0.73). A  similar result was observed at the 5-​year
to 48 hours, given to patients has to be discontinued at least 12 hours follow-​up mark as well (HR 0.67, 95% CI 0.55–​0.81; IPTW-​based
before CABG or can only be antagonized by platelet transfusion model: HR 0.74, 95% CI 0.62–​0.89) [148].
 Su rgical c on si der ati on s i n  acu te c orona ry sy n dro me   pat i e n ts 575

Unstable angina and non-​ST-​elevation CABG in patients with NSTEMI does not really impact the risk
myocardial infarction of surgery. Dayan and co-​workers have written a best evidence
Although several studies have shown that adoption of an early topic, according to a structured protocol [154]. They could find
invasive strategy for the treatment of patients with UA/​NSTEMI, only seven articles in the literature that were of any relevance.
especially those with higher risk scores, is more beneficial [149–​ A  recent publication reported an acceptable  30-​day mortality
152], very few studies, depicted in E Table 43.2, have analysed of 2% in patients with NSTEMI undergoing immediate CABG
the benefits of early CABG in patients with NSTEMI [153]. [155]. (See also E Chapter  41.) A  US study by Sugiyama and
Second, the exact timing of early CABG in patients with NSTEMI colleagues showed a significant reduction in in-​hospital mortality
has also not been adequately investigated. This could probably be after CABG for NSTEMI, from almost 5% in 2001 to 2.9% in 2011
due to the fact that, unlike STEMI patients, the timing of early (Ptrend <0.001) [142].

Table 43.2  Results of CABG in patients presenting with ACS

Authors (reference) Number of Type of ACS Early mortality Remarks

patients
Lee et al. [8]‌ 44 365 Transmural: 22 983; HM: 3.1% for each type HM: according to time interval between CABG and MI: 11.8%,
non-​transmural of ACS 9.5%, and 2.8% (P <0.001) for <6 hours, 6 hours to 1 day, and
MI: 21 382 >1 day, respectively
Weiss et al. [17] 40 159 All types of MI HM: 4.7%, 8.2%, and 3% in Early CABG was an independent predictor of mortality (OR
those operated on on day 1.43; P = 0.003)
0 and 3, respectively
Creswell et al. [144] 2296 All types of MI OM: 8.4 and 4.3% in Independent predictors of OM: urgency of operation
those operated on <48 (P = 0.0001), increasing patient age (P = 0.0001), renal
and >48 hours after AMI, insufficiency (P = 0.0001), number of previous MIs (P = 0.001),
respectively and hypertension (P = 0.013). MI to CABG time interval was
not a significant predictor
Kaul et al. [145] 642 All types of MI Early mortality: 5.9% Independent predictors of early mortality were LVEF <30%, age
>70 years, and CS
Sergeant et al. [146] 269 All types of MI 30-​day mortality: 13.8% 1-​and 10-​year survival: 84% and 66%, respectively. CS and CPR
were incremental risk factors for early, but not late, risk
Tomasco et al. [135] 444 All types of MI HM: ranged from 7.4% Predictors: LVEF (P = 0.02), aortic cross-​clamp time (P = 0.10)
to 31.7%, according to for the urgent group; and CS (P = 0.001), preoperative ischaemic
urgency interval (P = 0.001), aortic cross-​clamp time (P = 0.018), and non-​
use of blood cardioplegia (P = 0.01) for the emergent group
Caceres et al. [76] 44 141 All types of MI OM: 7.9% Emergency/​salvage status (OR 6.4), age >80 years (OR 4.1),
dialysis (OR 3.1), and CS (OR 2.8) were independent mortality
predictors
Senanayake et al. [153] 304 NSTEMI HM: 1.6% 6-​month survival: 2%, 1.9%, and 20% for low-​, medium-​, and
high-​risk groups, respectively
Parikh et al. [10] 2647 NSTEMI HM: 3.6% versus 3.8% for Composite outcome of death, MI, congestive heart failure, or
patients operated on <48 CS (12.6% versus 12.4% for early and late CABG, respectively)
and >48 hours after MI,
respectively
Braxton et al. [11] 116 Q and non-​Q HM, non-​Q wave MI: 3.4% Non-​Q wave MI patients may receive CABG surgery at any
wave MI time, with similar outcomes in non-​MI patients
Khaladj et al. [155] 127 STEMI: 41; 30-​day mortality, EuroSCORE II was an independent risk factor for mortality
NSTEMI: 86 STEMI: 15%; NSTEMI: 2% (P <0.001). Results of emergency CABG for patients presenting
(P = 0.01) with NSTEMI can be compared with those of elective
revascularization
Lee et al. [15] 32 099 STEMI HM: 3.3%; 14.2%, and 2.7% Revascularization within 3 days of transmural AMI is
for CABG <6 hours and independently associated with mortality
>15 days, respectively
Filizcan et al. [156] 150 STEMI HM: 22% Age, preoperative cTn levels, and preoperative IABP use were
predictive factors of HM
ACS, acute coronary syndrome; AMI, acute myocardial infarction; CABG, coronary artery bypass grafting; CPR, cardiopulmonary resuscitation; CS, cardiogenic shock; HM, hospital
mortality; IABP, intra-​aortic balloon pump; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NSTEMI, non-​ST-​segment elevation myocardial infarction; OM, operative
mortality; OR, odds ratio; STEMI, ST-​segment elevation myocardial infarction.
576 CHAPTER 43   C oronary art ery bypass gra ft su rg ery

ST-​segment elevation myocardial infarction Salvage CABG

PCI being the first option for revascularization in patients with Some patients require CPR en route to the operating theatre or
STEMI, emergency CABG is performed only in very specific prior to induction of anaesthesia [33]. Such CABG procedures,
situations (already discussed earlier) and is therefore relatively known as salvage operations, are relatively rare [163] and are as-
uncommon. This is chiefly due to the higher in-​hospital mor- sociated with high mortality [143, 164]. A multicentre study from
tality rate associated with emergent CABG [9, 17,  156], which the Nordic countries evaluated 38 patients undergoing salvage
seems to vary with the timing of surgery after STEMI (see E CABG procedures. Hospital mortality was 41% and 1-​and 5-​year
Table 43.2). Contrary to this, DeWood et al. reported an overall survival rates were 50% and 46%, respectively [165]. Of the nine
in-​hospital mortality rate of 5.2% for early CABG after STEMI patients who received cardiac massage during sternotomy, only
and showed that CABG performed within 6 hours after symptom one survived. Although salvage CABG patients have high peri-
onset had a lower in-​hospital and long-​term (10 years) mortality operative mortality, mid-​term survival of patients who can be sal-
rate than CABG performed beyond 6 hours after symptom onset vaged is encouraging.
[157]. The recently published US study by Sugiyama et al. demon- However, patients with AMI who have been successfully re-
strated no change in in-​hospital mortality for CABG in patients suscitated following a cardiac arrest may have a better prog-
with STEMI. It ranged between 4.5% and 6.2% [142]. Rohn et al., nosis. A very recent study reported on 129 patients, the majority
in a series of 135 patients undergoing CABG within 24 hours of of whom with three-​vessel disease following STEMI underwent
STEMI, reported that acute CABG in patients with STEMI can CABG within a median period of 4 hours after cardiac arrest. The
be performed with good results. They demonstrated no signifi- 30-​day mortality rate was 23%. Hypoxic brain injury occurred
cant difference in 30-​day mortality between patients operated on in 12% of patients, with patients resuscitated for >20 minutes
within 6 hours and those between 6 and 24 hours after STEMI being the most vulnerable. Most patients (79%) discharged alive
(5.7% versus 9%; P = 0.45). They, however, found poor haemo- showed good neurological outcomes according to the cerebral
dynamic status of patients, such as LVEF (HR 1.103; P = 0.0024), performance category scale [166].
preoperative ventilation (HR 13; P = 0.00076), preoperative ino-
tropic support (HR 8.6; P = 0.0074), CS (HR 28.7; P = 5.8 x 10-6), Techniques of coronary artery bypass graft surgery
and Killip class at admission (HR 6.9; P = 0.00038), to be inde- To date, there are only a few non-​randomized retrospective
pendent predictors of 30-​day mortality [20]. studies that compare beating-​heart (with or without CPB) and
cardioplegic arrest techniques in this patient subset [59, 60, 62,
Cardiogenic shock 167–​170]. In most studies, one encounters comparable hospital
For patients in CS, the mortality rate ranges between 21.3% and mortality between both groups, although a trend favouring
46.7% [89, 135, 146]. However, the SHOCK trial showed that early OPCABG procedures is often evident [59]. OPCABG was
revascularization was beneficial and that patients undergoing CABG found to be beneficial with respect to perioperative MI [70],
had similar survival rates to those undergoing PCI, despite the former IABP implantation [68,  71], reoperation rates [60,  170], ino-
group more likely to be diabetic and to have a more complex coronary tropic requirement [60, 159], AKI [157, 161], stroke rates [58],
anatomy [158, 159]. Additionally, mortality after CABG in such pa- and duration of intensive care and hospital stays [60, 167–​170].
tients has significantly declined over the first decade of this century. The ACUITY trial showed that patients undergoing OPCABG
A  retrospective analysis of 508 patients in CS undergoing CABG had fewer events of bleeding MI, but higher reintervention
demonstrated a reduction in in-​hospital mortality from 42.2% to rates at 30 days, than those undergoing an on-​pump procedure.
24.6% over a 15-​year period. Factors that most commonly impacted However, at 1 year, there was no difference between the groups
mortality were serum lactate >4  mmol/​L (OR 4.78; P < 0.0001), in death, total MIs, reinterventions, strokes, or MACEs, but
STEMI (OR 2.10; P = 0.001), age >75 years (OR 2.01; P = 0.03), and there was a lower rate of non-​Q wave MI in the OPCABG group
LVEF <30% (OR 1.83; P = 0.01). Moreover, hospital survivors had [171]. In haemodynamically unstable patients or those in frank
good long-​term outcomes (5-​and 10-​year survival was 64.3 ± 3.0% CS, our group revealed beneficial effects of CPB-​supported
and 49.8 ± 3.0%, respectively), which justifies the use of surgical beating-​heart surgery, in terms of lower hospital mortality
revascularization in patients not suitable for PCI [160]. Furthermore, (19.3% versus 33.3%), less bleeding, transfusion requirement,
high-​risk STEMI patients with CS appear to have better outcomes and inotropic support, shorter ventilation time, lower stroke
after CABG, compared to PCI, when the latter cannot achieve com- rates, and shorter ICU stay than CABG with cardioplegic
plete revascularization [91, 161]. (See also Chapter 47.) arrest [60].
Therefore, patients in CS, who have severe multivessel or left main Long-​term outcomes in patients undergoing emergency CABG
disease, should be discussed ad hoc in the catheterization labora- are determined not only by the quality of surgery and the occur-
tory by the heart team. Several factors such as coronary anatomy rence of post-​operative complications, but also by the severity of
and associated procedural risks, patient comorbidities, potential coronary atherosclerosis, LV function, age, gender, overall health
treatment delays, local expertise, patient preference, and the pres- status, and the presence and severity of associated comorbidities
ence or absence of additional mechanical complications of infarc- [58]. The occurrence of ischaemic clinical events, stroke, or renal
tion should be taken into consideration by the heart team, before failure after CABG has a significant negative impact on long-​term
making a final decision regarding the best therapy option [162]. survival [172].
 FU RTH E R RE A DI N G 577

One of the most important prerequisites for a successful out-

Conclusion come in patients needing emergency surgery is an expeditious
diagnosis and an immediate referral to a cardiac surgery-​capable
Adherence to treatment guidelines is associated with a gradual
centre. The cardiac surgeon should be included in the decision-​
lowering of both short-​and long-​term mortality [173]. Based
making process (heart team approach) in cases of patients dir-
on current guidelines, the indications for performing an urgent/​
ectly referred or transferred to a tertiary care centre and who are
emergent CABG in patients with NSTEMI remain the same as for
potential surgical candidates. It is now a Class I recommendation
patients with stable angina. On the other hand, CABG should be
[7]‌. This also holds true for patients undergoing a high-​risk PCI
performed on an emergency basis in patients with STEMI when-
procedure. Surgical backup and collaboration between the car-
ever PCI has failed or is not amenable, as in some chronic total
diologist and the cardiac surgeon is mandatory to reduce delay
occlusive or complex bifurcation or trifurcation lesions. Patients
in management and to obtain the best outcome possible. The
with multivessel disease in CS should also undergo emergent
technique of CABG should ideally be left to the discretion of the
CABG if complete revascularization is not possible with PCI.
operating surgeon, although it should be noted that outcomes are
Although it would be ideal to follow the guidelines strictly for
probably more favourable in patients undergoing beating-​heart
every case, there are, however, many factors that influence
CABG, with or without CPB. Several studies have demonstrated
decision-​making in the ‘real-​world scenario’. The indications for
that early mortality still continues to remain the Achilles heel for
coronary revascularization ultimately depend on individual pa-
emergency CABG, especially in STEMI patients, even though
tient factors such as the general condition, life expectancy, age,
long-​term outcomes are comparable to those in patients under-
and associated comorbidities.
going elective surgery (see E Table 43.2).

Personal perspective
We believe that the outcomes of emergency coronary artery by- randomized clinical trials to determine the optimal timing of
pass surgery during the acute phase of MI can be improved if surgery, particularly after STEMI, are warranted in the future.
performed within the so-​called ‘golden period’ of 6 hours after Furthermore, we suppose that post-​operative results could be
symptom onset, especially in patients with complex multivessel positively impacted by using the appropriate surgical strategy
disease (high SYNTAX score) not amenable to PCI, before (off-​pump versus on-​pump CABG, with or without ischaemic
the onset of haemodynamic instability and CS. In addition, arrest), which anyway needs further evaluation.

Further reading
Anderson JL, Adams CD, Antman EM, et al. 2012 ACCF/​AHA focused Practice Guidelines (Committee to Update the 1999 Guidelines for
update incorporated into the ACCF/​AHA 2007 guidelines for the Coronary Artery Bypass Graft Surgery). Circulation 2004;110:e340–​437.
management of patients with unstable angina/​ non-​ST-​elevation Gelfand E, Cannon CP (editors). Management of Acute Coronary
myocardial infarction. A report of the American College of Cardiology Syndromes, first edition. Wiley-​Blackwell: Chichester; 2009.
Foundation/​ American Heart Association Task Force on Practice George I, Williams M. Myocardial revascularization after acute
Guidelines. Circulation 2013;127:e663–​828. myocardial infarction. In: Cohn LH (editor). Cardiac Surgery in The
Antman EM, Hand M, Armstrong PW, et al. 2007 focused update of the Adult, fourth edition. McGraw-​Hill: New York, NY; 2012. pp. 535–​52.
ACC/​AHA 2004 guidelines for the management of patients with ST-​ Hamm CW, Bassand JP, Agewall S, et  al. ESC Guidelines for the
elevation myocardial infarction. Circulation 2008;117:296–​329. management of acute coronary syndromes in patients presenting
Antman EM, Morrow DA. ST-​ segment elevation myocardial without persistent ST-​segment elevation. Guidelines for the diagnosis
infarction: management. In: Bonow RO, Mann DL, Zipes DP, Libby and treatment of non-​ST-​segment elevation acute coronary syndromes.
P (editors). Braunwald’s Heart Disease: A Textbook of Cardiovascular Eur Heart J 2011;32:2999–​3054.
Medicine, ninth edition. Saunders Elsevier: Philadelphia, PA; 2012. Hamm CW, Möllmann H, Bassand JP, Van de Werf. Acute coronary
pp. 1111–​77. syndrome. In:  Camm AJ, Luescher TF, Serruys PW (editors). The
Cannon CP, Braunwald E. Unstable angina and non-​ ST elevation ESC Textbook of Cardiovascular Medicine, second edition. Oxford
myocardial infarction:  management. In:  Bonow RO, Mann University Press: New York, NY; 2009. pp. 535–​96.
DL, Zipes DP, Libby P (editors). Braunwald’s Heart Disease:  A Hillis LD, Smith PK, Anderson JL, et al. 2011 ACCF/​AHA guideline for
Textbook of Cardiovascular Medicine, ninth edition. Saunders coronary artery bypass graft surgery. A report of the American College
Elsevier: Philadelphia, PA; 2012. pp. 1178–​209. of Cardiology Foundation/​American Heart Association Task Force on
Eagle KA, Guyton RA, Davidoff R, et al. ACC/​AHA 2004 guideline update Practice Guidelines. Circulation 2011;124:e652–​735.
for coronary artery bypass graft surgery:  a report of the American Kouchoukos N, Blackstone EH, Hanley FL, Kirklin JK (editors). Part
College of Cardiology/​ American Heart Association Task Force on II: Ischemic heart disease. In: Kouchoukos N, Blackstone EH, Hanley
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FL, Kirklin JK (editors). Kirklin/​Barratt-​Boyes Cardiac Surgery, fourth in patients presenting with ST-​segment elevation: The Task Force for
edition. Saunders Elsevier: Philadelphia, PA; 2013. pp. 353–​469. the management of acute myocardial infarction in patients presenting
Kushner FG, Hand M, Smith SC Jr, et  al. 2009 focused updates:  ACC/​ with ST-​segment elevation of the European Society of Cardiology
AHA guidelines for the management of patients with ST-​elevation (ESC). Eur Heart J 2018;39:119–​77.
myocardial infarction. Circulation 2009;120:2271–​306. Silber S, Albertsson P, Avilés FF, et  al. Guidelines for percutaneous
Lemmer JH Jr, Vlahakes GJ (editors). Handbook of Patient Care coronary interventions. The Task Force for Percutaneous Coronary
in Cardiac Surgery, seventh edition. Lippincott Williams and Interventions of the European Society of Cardiology. Eur Heart J
Wilkins: Philadelphia, PA; 2010. 2005;26:804–​47.
O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/​AHA Guideline Sousa-​Uva M, Neumann FJ, Ahlsson A, et al.; ESC Scientific Document
for the management of ST-​elevation myocardial infarction:  a report Group. 2018 ESC/​EACTS Guidelines on myocardial revascularization.
of the American College of Cardiology Foundation/​American Heart Eur J Cardiothorac Surg 2019;55:4–​90.
Association Task Force on Practice Guidelines. J Am Coll Cardiol van de Werf F, Bax J, Betriu A, et al. Management of acute myocardial
2013;61:485–​510. infarction in patients presenting with persistent ST-​ segment
Patel MR, Dehmer GJ, Hirshfeld JW, et al. ACCF/​SCAI/​STS/​AATS/​AHA/​ elevation: the Task Force on the Management of ST-​Segment Elevation
ASNC 2009 Appropriateness criteria for coronary revascularization. J Acute Myocardial Infarction of the European Society of Cardiology.
Am Coll Cardiol 2009;53:530–​3. Eur Heart J 2008;29:2909–​45.
Roffi M, Patrono C, Collet JP, et  al. 2015 ESC Guidelines for the Windecker S, Kolh P, Alfonso F, et  al. 2014 ESC/​EACTS Guidelines
management of acute coronary syndromes in patients presenting on myocardial revascularization:  The Task Force on Myocardial
without persistent ST-​ segment elevation:  Task Force for the Revascularization of the European Society of Cardiology (ESC) and
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154. Dayan V, Soca G, Parma G, et al. Does early coronary artery bypass 171. Ben-​Gal Y, Stone GW, Smith CR, et al. On-​pump versus off-​pump sur-
surgery improve survival in non-​ST acute myocardial infarction? gical revascularization in patients with acute coronary syndromes: ana-
Interac Cardiovasc Thorac Surg 2013;17:140–​2. lysis from the Acute Catheterization and Urgent Intervention Triage
155. Khaladj N, Bobylev D, Peterss S, et al. Immediate surgical coronary Strategy trial. J Thorac Cardiovasc Surg 2011;142:e33–​9.
revascularisation in patients presenting with acute myocardial in- 172. Wahl GW, Swinburne AJ, Fedullo AJ, et  al. Long-​term outcome
farction. J Cardiothorac Surg 2013;8:167–​73. when major complications follow coronary artery bypass graft sur-
156. Filizcan U, Kurc E, Cetemen S, et  al. Mortality predictors in ST-​ gery. Recovery after complicated coronary artery bypass graft sur-
elevated myocardial infarction patients undergoing coronary artery gery. Chest 1996;110:1394–​8.
bypass grafting. Angiology 2011;62:68–​73. 173. Jernberg T, Johanson P, Held C, et al.; SWEDEHEART/​RIKS-​HIA.
157. DeWood MA, Spores J, Berg R Jr, et  al. Acute myocardial infarc- Association between adoption of evidence-​based treatment and
tion:  a decade of experience with surgical reperfusion in 701 pa- survival for patients with ST-​ Elevation Myocardial Infarction.
tients. Circulation 1983;68:II8–​16. JAMA 2011;305:1677–​84.
158. Hochman JS, Sleeper LA, Webb JG, et  al. Early revascularization
in acute myocardial infarction complicated by cardiogenic shock.
SHOCK Investigators:  Should We Emergently Revascularize ADDITIONAL ONLINE MATERIAL
Occluded Coronaries for Cardiogenic Shock. N Engl J Med
1999;341:625–​34. For additional multimedia materials, please visit the online
159. White HD, Assmann SF, Sanborn TA, et al. Comparison of percu- version of the book (M
M oxfordmedicine.com/ESCIACC3e).
taneous coronary intervention and coronary artery bypass grafting
after acute myocardial infarction complicated by cardiogenic
shock:  results from the Should We Emergently Revascularize
Occluded Coronaries for Cardiogenic Shock (SHOCK) trial. Appendix I
Circulation 2005;112:1992–​2001.
160. Davierwala PM, Leontyev S, Verevkin A, et al. Temporal trends in
Global Risk Classification (GRC)
predictors of early and late mortality after emergency coronary ar- The GRC is a combination of both the EuroSCORE and SYNTAX
tery bypass grafting for cardiogenic shock complicating acute myo- score.
cardial infarction. Circulation 2016;134:1224–​37.
The EuroSCORE is stratified into three risk categories: low risk,
161. Chiu FC, Chang SN, Lin JW, et al. Coronary artery bypass graft sur-
gery provides better survival in patients with acute coronary syn- 0–​3; intermediate risk, 4–​5; high-​risk, ≥6.
drome or ST-​segment elevation myocardial infarction experiencing The SYNTAX score is stratified into three tertiles: lowest tertile,
cardiogenic shock after percutaneous coronary intervention: a pro- <28; intermediate tertile, 28–​38; highest tertile, >38.
pensity score analysis. J Thorac Cardiovasc Surg 2009;138:1326–​30. The GRC system is classified into three risk groups as shown in
162. Desch S. Revascularization strategies in cardiogenic shock after Table 43.3.
acute myocardial infarction. Curr Opin Crit Care 2019;25:379–​83.
163. Haan CK, O’Brien S, Edwards FH, et al. Trends in emergency cor-
onary artery bypass grafting after percutaneous coronary interven-
tion, 1994–​2003. Ann Thorac Surg 2006;81:1658–​65. Appendix II
164. Sezai A, Hata M, Yoshitake I, et al. Results of emergency coronary
artery bypass grafting for acute myocardial infarction: importance
Clinical SYNTAX Score (CSS)
of intraoperative and postoperative cardiac medical therapy. Ann
Thorac Cardiovasc Surg 2012;18:338–​46. CSS = (SYNTAX score ) × ( modified ACEF score )
165. Axelsson TA, Mennander A, Malmberg M, et  al. Is emergency
and salvage coronary artery bypass grafting justified? The Nordic The SYNTAX score for each patient is calculated retrospect-
Emergency/​Salvage coronary artery bypass grafting study. Eur J ively by scoring all coronary lesions with a diameter stenosis of
Cardiothorac Surg 2016;49:1451–​6. >50%, in vessels of ≥1.5 mm, using the SYNTAX Score algorithm,
166. Grothusen C, Friedrich C, Attmann T, et al. Coronary artery bypass which is available on the SYNTAX Score website (M M http://​www.
surgery within 48 hours after cardiac arrest due to acute myocardial
syntaxscore.com).
infarction. Eur J Cardiothorac Surg 2017;52:297–​302.
167. Karthik S, Musleh G, Grayson AD, et al. Effect of avoiding cardio-
The modified ACEF score (ACEFCrCl) is calculated, using the
pulmonary bypass in non-​elective coronary artery bypass surgery: a formula:  age/​ejection fraction + 1 point for every 10 mL/​min
propensity score analysis. Eur J Cardiothorac Surg 2003;24:66–​71. reduction in the creatinine clearance (CrCl) below 60 mL/​min/​
168. Kerendi F, Puskas JD, Craver JM, et al. Emergency coronary artery 1.73 m2 (up to a maximum of 6 points). Therefore, a creatinine
bypass grafting can be performed safely without cardiopulmonary clearance of between 50 and 59 mL/​min/​1.73 m2, 40–​49 mL/​
bypass in selected patients. Ann Thorac Surg 2005;79:801–​6. min/​1.73 m2, and 30–​39 mL/​min/​1.73 m2 would receive 1, 2, and
169. Onorati F, DeFeo M, Mastroroberto P, et  al. Unstable angina and
3 points, respectively. The LVEF used is the value recorded be-
non-​ST segment elevation: Surgical revascularization with different
strategies. Eur J Cardiothorac Surg 2005;27:1043–​50. fore CABG and, in the event of multiple available values, is the
170. Stamou SC, Hill PC, Haile E, et al. Clinical outcome of non-​elective lowest recorded figure. Creatinine clearance is calculated using
coronary revascularization with and without cardiopulmonary by- the Cockcroft–​Gault equation, using the patient’s age, weight, and
pass. J Thorac Cardiovasc Surg 2006;131:28–​33. serum creatinine recorded before CABG.
584 CHAPTER 43   C oronary art ery bypass gra ft su rg ery

When serum creatinine is measured in mg/​dL: ◆ CSSLOW ≤15.6

◆ CSSMID ≥15.6 to ≤27.5
eCrCr = (140 − age ) × mass (in kg ) × (0.85 if female ) /72
◆ CSSHIGH >27.5
× serum creatinine

When serum creatinine is measured in micromoles/​L:

Appendix III
eCrCr = (140 − age ) × mass (in kg ) × constant/serum creatinine SYNTAX Score II
(where the constant is 1.23 for men and 1.04 for women) Figure 43.5 shows the SYNTAX Score II nomogram for bed-
Patients can be divided, according to their CSS, into tertiles, side application.
defined as:
 CHAPTER 44

Sex considerations in acute

coronary syndromes
Eva Swahn, Joakim Alfredsson, and
Sofia Sederholm Lawesson

Contents
Summary  585 Summary
Introduction  585 It is a very important issue to enlighten on sex differences and similarities re-
Epidemiology  586 garding the management of patients with acute coronary syndromes (ACS). It is
Pathophysiology  586 a fact that women have not been included in clinical trials in numbers equal to
Risk factors  586 men, for whatever reason. In the future, it will be necessary to individualize, as
Risk stratification  587 much as possible, the management of patients, regardless of sex. To get there, it is
Clinical presentation and symptoms  588 necessary to have sufficient numbers of patients from both sexes included in trials,
Medical treatment  588 or otherwise it is not possible to draw proper conclusions. Until now, most results
Beta-​blockers  588 regarding women and ACS have been based on substudy analyses with inadequate
Lipid-​lowering treatment  588
Angiotensin-​converting enzyme inbibitors,
statistical power. If sex differences have become evident in studies with sex-​mixed
angiotensin receptor blockers, populations, it seems obvious that the calculated power to show significant differ-
and mineralocorticoid receptor ences is also inadequate for men.
antagonists  588
Antithrombotic treatment  588 There is an urgent need for more research in this area, in order not to harm our
Acetylsalicylic acid  588 patients with our treatment because of a paucity of knowledge. It is also as im-
P2Y12 inhibitors  589
Glycoprotein IIb/​IIIa inhibitors  589
portant not to withdraw proper treatment from certain individuals when they can
Low-​molecular weight heparin  589 benefit from it.
Direct thrombin inhibitors  589
Factor Xa inhibitors  590
Reperfusion therapy in ST-​segment
elevation myocardial infarction  590
Sex differences in benefit from invasive
treatment in non-​ST-​segment elevation
acute coronary syndromes  590 Introduction
Complications  591 In both women and men, CVDs remain the leading cause of death in Europe (see
Outcome  591 E Chapters 38 and 41).
ACS-​mimicking syndromes  592 This is despite a continuous decrease in MI morbidity, as well as mortality, during
Takotsubo syndrome  592 the last decades. The most common manifestations of ischaemic heart disease (IHD)
Spontaneous coronary artery dissection  592
Personal perspective  593 are ACS which include sudden cardiac death (SCD), STEMI, NSTEMI, and UA. Due to
References  593 similarities in pathophysiology and treatment, NSTEMI and UA are often referred to as
NSTE-​ACS.
The ACS population is very heterogenous, with wide variations in the risk of death
and new ischaemic events, and early risk stratification is therefore a key part of treat-
ment. Although in-​hospital mortality is higher in STEMI than in NSTE-​ACS, long-​term
mortality rates are comparable. During the last decades, the incidence of NSTE-​ACS has
increased, whereas the incidence of STEMI has decreased [1]‌.
Women and men with ACS differ in several aspects. Women are older, with a higher
prevalence of comorbidities such as hypertension, diabetes, COPD, heart failure, and
586 CHAPTER 44   Se x c onsiderations in acu t e c orona ry  sy n dro m es

CKD, whereas men are more often smokers [2]‌. Female patients
are more likely to present with UA versus MI and NSTEMI versus Pathophysiology
STEMI, compared to men [3, 4]. Numerous trials have shown that
The pathogenesis of ACS involves two different processes: (1) a
women with ACS, even after adjustment for their higher age and
slow atherosclerotic process, with a low degree of reversibility
more frequent comorbidities, are less intensively investigated and
that lasts for decades; and (2) a fast, dynamic, and potentially re-
treated [5–​11]. On the other hand, we do not know if all aspects
versible process, characterized by plaque rupture or erosion, with
of EBM of today are equally applicable to both sexes, as fewer
subsequent thrombus formation [18]. Before menopause, ACS is
women than men have been included in most randomized clin-
uncommon in women; those who do get affected have a higher
ical studies regarding CVDs [12]. Whether the lower inclusion
IHD risk factor burden, compared to their male counterparts [5]‌,
rates reflect a lower incidence in women or an actual exclusion of
and the vast majority are smokers [19–​21]. Young women have
women from the trials has been debated.
plaque erosions, instead of plaque ruptures, more often than older
The clinical challenge today is to identify and treat patients
women and men with ACS [22], and they have more often single-​
with the highest risk of ischaemic events, without an unreason-
vessel disease, compared to men of similar age [ 21].
ably elevated early risk of complications with treatment. For ex-
Several studies have shown less obstructive CAD in women
ample, actions to minimize bleeding complications, including
with ACS [23], even in patients with elevated myocardial damage
dose adjustments according to renal function, weight, and age,
markers [24]. In a study of 95  849 MI patients registered in
are of utmost importance, particularly for women, with their
the Swedish Coronary Angiography and Angioplasty Register
known higher risk of bleeding complications. However, an indi-
(SCAAR), non-​obstructive disease was found in 6% of men and
vidually tailored treatment strategy to balance early procedural
10% of women with STEMI, and in 11% of men and 28% of
risk with long-​term reduction of cardiac events will benefit both
women with NSTEMI [23]. If only MI patients with completely
men and women with ACS.
normal coronaries, according to ICA, are included the majority
In this chapter, we aim to focus on sex-​specific similarities and
(75%) are women [25]. MINOCA patients, defined as MI with
differences that are of importance to identify and learn, in order
<50% stenosis on coronary angiography [26, 27], constitute 6% of
not to harm the patient in front of us.
all MI cases, with 40% being women [26]. The pathogenic mech-
anisms of MINOCA are multifactorial, including endothelial dys-
function, coronary vasospasm, and thromboembolic disease, with
Epidemiology or without underlying plaque disruption [28,  29]. Studies with
IVUS and coronary vascular reactivity assessment have demon-
CVDs remain the most common cause of death, accounting for strated more microcirculation disturbances in women, compared
approximately one-​third of all deaths worldwide. While IHD to men, with CAD [30]. On the other hand, when a cohort of
mortality decreased by about 50% during the last decades in most 50 women with MINOCA were examined with IVUS, 38% were
industrialized countries, it increased by almost 20% worldwide found to have plaque disruption. Approximately one-​fifth of cases
[13]. Over a 30-​year period, a 50% reduction in CVD-​related initially diagnosed as MINOCA will turn out to be myocarditis.
deaths has been observed in Western Europe, whereas the decline Thus, MINOCA should be regarded as a working diagnosis, and
in Eastern Europe has been more modest [14]. The explanations further evaluation with intracoronary imaging, such as IVUS
are a combination of improved risk factor situation, acute treat- or optical coherence tomography (OCT), as well as use of CMR
ment, and prevention. Despite this decline, >4 million people died imaging, has been suggested [27].
from CVDs in Europe, accounting for 45% of all deaths [15]. The
overall number of CVD deaths was higher in women (2.2  mil-
lion) than in men (1.8 million), accounting for 49% and 40% of
all deaths, respectively [15]. IHD accounted for approximately as
Risk factors
many deaths per year in women as in men—​about 900 000 (20% Early longitudinal studies revealed that there are sex differences
of all deaths). However, premature IHD death was more than in risk factor prevalence, especially in young and middle ages.
twice as common in men than in women before the age of 75 and Although there are differences between men and women in the
three times more common before the age of 65 [15]. This reflects impact of a certain risk factor, there is a striking similarity be-
the fact that the incidence of ACS is 3–​4 times higher in men than tween the sexes in the relative risk associated with most of the
in women below the age of 60 years, but after the age of 75, women classical risk factors [31]. The INTERHEART study, a case control
represent the majority of patients in some reports [16]. However, study of 52 populations from all over the world, investigated the
in the extended long-​term follow-​up of the Tromsø Study, 33 997 association of nine potentially modifiable risk factors for a first
individuals were followed from 1979 to 2012. The incident risk MI [32, 33]. The six factors positively associated with an increased
of MI was about doubled in men, compared to women, in all age risk of a first MI were hyperlipidaemia, smoking, hypertension,
groups. Adjustment for differences in classical risk factors had diabetes, abdominal obesity, and psychosocial stress. The three
little impact on the result [17]. The reasons for these differences factors negatively associated with MI (i.e. protection from MI)
in MI incidence remain largely unknown. were physical activity, a low-​risk diet (daily vegetables and fruits),
 Ri sk  str at i f i c at i on 587

and moderate alcohol consumption. The study confirmed that Table 44.1  ECG manifestations of acute myocardial inschaemia (in
CAD determinants were the same in women and men, and these absence of LV hypertrophy and LBBB)
nine factors accounted for 90% of the population-​attributable
ST-​segment elevation:
risk in men and 94% in women. However, there were small dif- New ST-​segment elevation at the J-​point in two contiguous leads with
◆
ferences between the sexes in the strength of specific risk factors. the cut-​point of ≥0.1 mV in all leads other than in leads V2 and V3 where
Hypertension, diabetes, physical inactivity, and lack of alcohol in- the following cut-​points apply: ≥0.2 mV in men aged ≤40 years; ≥0.25 mV
take were more strongly associated with MI in women than in in men aged <40 years; or ≥0.15 mV in women
men. Regarding smoking, several longitudinal studies have indi- ST-​segment depression and T-​wave changes:
cated that this is a more powerful risk factor in women than in New horizontal or downsloping ST-​segment depression of ≥0.05 mV
◆
in two contiguous leads and/​or T-​wave inversion of ≥0.1 mV in two
men [31, 34]. This was confirmed in a recent cohort study from contiguous leads with prominent R wave or R/​S ratio >1
the UK Biobank on 471 998 participants without a CVD history,
which showed that hypertension, smoking, and diabetes were all
associated with higher HRs for MI in women than in men, with intensive treatment [47]. In the same way, troponins are estab-
the highest HRs for type 2 diabetes (HR 1.47, 95% CI 1.16–​1.87), lished markers for the prediction of death and MI and benefit
smoking (1.55, 95% CI 1.32–​1.83), and type 1 diabetes (2.91, 95% from an invasive strategy [48]. In a meta-​analysis of seven clinical
CI 1.56–​5.45). With the exception of type 1 diabetes, the inci- trials and 19 cohort studies of patients with NSTE-​ACS, patients
dence of MI was higher in men than in women for all risk fac- with elevated troponin had higher mortality [49].
tors [35]. Contrasting previous data, a subgroup analysis from the No sex differences have been observed with the Minnesota code
large Trial Evaluating Cardiovascular Outcomes with Sitagliptin or Novacode ECG for prognostication of IHD. Little is known
(TECOS) trial (comparing sitagliptin to placebo in 4297 women about the differences between men and women in the prognostic
and 10 374 men with type 2 diabetes and established CVD) indi- value of ECG changes in NSTE-​ACS, but sex-​specific cut-​offs are
cated that female sex may be associated with a protective effect advocated in STEMI (see E Table 44.1) [50].
also among diabetic patients, in a contemporary setting. Women In patients with suspected ACS, sex differences in troponin
had a lower incidence of the composite endpoint of cardiovas- levels have been observed and sex-​specific cut-​off values ad-
cular death, MI, stroke, or hospitalization for UA (9.7% versus vocated [51]. However, a recent study assessing diagnostic and
12.3%; P <0.0001). In addition, women had a lower risk of sec- prognostic performance with troponin indicated minor influence
ondary cardiovascular outcomes and all-​cause death [36]. using sex-​specific cut-​offs [52, 53]. Since ACS is a complex event,
In addition to the classical risk factors, there are reproductive different markers may reflect different pathophysiological aspects
factors specifically associated with CVDs in women such as of the disease. Combining markers for myocardial necrosis, in-
polycystic ovary syndrome (PCOS), and pregnancy-​related fac- flammation, neurohormonal activation, and renal dysfunction in
tors such as gestational diabetes, pre-​eclampsia, and pregnancy a multimarker approach has been proposed, and studies have dem-
loss (i.e. stillbirth and miscarriage) [37–​40]. However, it is un- onstrated that such an approach improves risk stratification from
certain whether these conditions are independently related to a gender perspective [54]. Wiviott et al. reported, in a substudy
CVD beyond the classical risk factors or if the associations may from the Treat Angina with Aggrastat and Determine Cost of
be confounded, mediated, or modified by other factors [41–​43]. Therapy with an Invasive or Conservative Strategy–​Thrombolysis
Anyhow, it is of importance that women affected with PCOS or in Myocardial Infarction 18 (TACTICS TIMI 18)  including pa-
pregnancy-​related complications linked to CVD do get a proper tients with NSTE-​ACS, that a multimarker approach identified a
follow-​up, including evaluation of any present classical CVD risk higher proportion of high-​risk women, but the lack of any marker
factors that ought to be treated. elevation also identified very low-​risk women. Men were more
likely to have elevated CK-​MB or troponin, while women were
more likely to have elevated CRP or BNP. Of note, hs-​Tn was not
used in the study [55].
Risk stratification A number of clinical risk scores have been constructed,
The ACS population is very heterogenous, with a large variation among them, the GRACE score, the TIMI score, and the Fast
in the risk of future ischaemic events or death. Therefore, strati- Revascularisation in InStability in Coronary disease (FRISC)
fication of patients, according to risk for future cardiac events, score. In one small study, the TIMI score was shown to correctly
but also identification of patients with the highest benefit from predict 30-​ day death/​ MI/​ revascularization in both men and
intensive treatment have become an integrated part of the man- women [56]. The GRACE risk score has been validated in >14 000
agement of NSTE-​ACS patients [44]. patients with MI. A similar overall discrimination for the predic-
The two most established single objective findings used in risk tion of in-​hospital mortality was found for men and women. In
stratification are ECG changes (in NSTE-​ACS, mainly ST-​segment one study comparing a routine invasive strategy with a conserva-
depression) and elevation of myocardial damage markers (today tive strategy in men and women with NSTE-​ACS, there was no
preferably troponins). Several studies have confirmed ST-​segment difference between the sexes in mortality within the same FRISC
depression as a marker of risk of death and MI [45, 46] and as a score class. Notably, validation of the score was not the primary
marker to identify patients with the highest benefit from a more purpose of the study [57, 58].
588 CHAPTER 44   Se x c onsiderations in acu t e c orona ry  sy n dro m es

Lipid-​lowering treatment
Clinical presentation and symptoms
Statin therapy improves long-​term outcome [80] and is recom-
In a CP population, a substantially higher proportion of men, mended to be initiated early in all patients with ACS [81, 82]. Men
compared to women, have ACS [59]. Gender differences in were in majority in most statin trials, and sex-​specific data are
symptoms in ACS have been debated for a long time. In more limited, with somewhat contradictory results. There are studies
recent studies, CP has been present in 80–​90% of included MI reflecting secondary prevention [83], primary prevention in high-​
patients, with small gender differences, although the majority risk individuals [84], and primary prevention in individuals with
of these have been based on data from medical records with an low cholesterol but elevated CRP [85], with no apparent differences
inherent risk of a certain information bias [60–​65]. Two meta-​ in effect between the sexes. With a lower event rate in women, the
analyses of ACS studies reporting on symptom data showed a benefit was more uncertain. However, a meta-​analysis including
somewhat higher prevalence of CP in men [66, 67], but a higher 18 randomized trials found a similar effect in women and men (P
prevalence of fatigue, neck pain, jaw pain, and nausea in women for interaction = 0.45) [86]. In a pre-​specified subgroup analysis
[67]. There are several confounders that may contribute to to the large Improved Reduction of Outcomes: Vytorin Efficacy
these differences, the most important being age and diabetes. International Trial (IMPROVE-​IT), comparing a combination of
Anyhow, female sex seems to persist as a predictor of atypical ezetimibe and simvastatin to simvastatin alone, there was no sig-
presentation of MI also after multivariable adjustments. In a nificant interaction between the sexes [87]. Regarding other lipid-​
large American registry study, female sex was an independent lowering therapy such as proprotein convertase subtilisin/​kexin
predictor of MI presenting without CP, after adjustment, type 9 (PCSK9) inhibitors, sex-​specific data are scarce.
including age, type of MI, smoking, diabetes, and hypertension
[62]. In a Swedish multicentre survey study on STEMI patients, Angiotensin-​converting enzyme inbibitors,
CP was less prevalent in women (74% versus 93%; P <0.001) and angiotensin receptor blockers, and
female sex was the strongest independent predictor of non-​CP mineralocorticoid receptor antagonists
presentation (OR 5.29, 95% CI 2.85–​9.80). On the other hand,
Several studies have shown that ACE-​Is are beneficial in reducing
symptoms such as shoulder pain, throat/​neck pain, back pain,
remodelling and improving survival in patients with reduced LV
and nausea were more prevalent in women. Similar findings
systolic function post-​MI [88–​90]. In patients who are intolerant
were done in the STEMI subgroup in the US study Variation in
of ACE-​Is, ARBs are indicated [91]. Treatment is indicated in all
Recovery: Role of Gender on Outcomes of Young AMI Patients
ACS patients with LV dysfunction, diabetes, or hypertension [88–​
(VIRGO) on young MI patients [68]. In acute coronary occlu-
90]. A  meta-​analysis (based on 10  267 men and 2396 women)
sion, women have been shown to react with more vagal activa-
indicated similar effects in men and women [92].
tion than men [69]. This could be one explanation why nausea
Mineralocorticoid receptor antagonists (MRAs) are recom-
and dizziness are more common symptoms in women than in
mended in patients with LV dysfunction (LVEF ≤40%) and heart
men with MI.
failure after STEMI [82]. Broad use of spironolactone has been
Several studies have found a longer patient delay in women,
limited by the adverse effect of gynaecomastia. The more modern
compared to men [68, 70–​72], partly due to failure to recognize
MRA eplerenone was developed to bind selectively to mineralo-
the symptoms as an evolving MI [68, 72]. There are also studies
corticoid receptors in order to minimize binding to progesterone
indicating a longer system delay for female MI patients, including
and androgen receptors, and it is better tolerated with less sex-​
getting lower priority when calling the EMS [73], longer time
related adverse effects [93].
from admission to the first ECG [74], to thrombolytic therapy,
[75, 76] or to PCI [77]. It has been proposed that difficulties in
Antithrombotic treatment
proper identification and interpretation of symptoms in female
patients, by both patients and health care professionals, could Antithrombotic therapy is fundamental in the acute treatment of
cause this delay [78]. ACS to prevent the progression of the thrombotic process in the
afflicted coronary artery, and it is also essential in the long-​term
treatment to prevent new ischaemic events (see E Chapter 39).
Antithrombotic treatment is especially important in clinical set-
Medical treatment tings involving PCI.
Beta-​blockers Acetylsalicylic acid
Evidence for β-​blockers in the context of ACS is based on a very Randomized trials of aspirin, compared with placebo, already
limited amount of randomized trial data, and most of the studies in the 1980s, showed consistent benefit for patients with NSTE-​
were performed more than two decades ago. Although there is ACS by reducing the risk of non-​fatal MI by approximately 50%
a paucity of sex-​specific data, no obvious differences in effect [94, 95]. An indirect comparison of maintenance doses has shown
between the sexes have been shown [79]. β-​blockers are recom- a similar effect over a broad range (75–​1500 mg), but a dose-​
mended for secondary prevention, in the absence of contraindi- dependent increase in bleeding [96]. Hence, a maintenance dose
cations, without difference between the sexes. of 75–​162 mg/​day is recommended. A meta-​analysis by Baigent
 M edi ca l   t re atm e n t 589

et al. revealed a similar effect in men and women in secondary reduction, compared to those who were not revascularized [103].
prevention, driven by a reduction in ischaemic stroke in women While men had significant benefit in reduction of death/​MI by
and MI in men and a similar degree of bleeding [97]. 30 days, harm was indicated in women (OR 0.81 versus 1.15; P
for interaction <0.0001).
P2Y12 inhibitors
Inhibition of platelets is a cornerstone treatment both in the Low-​molecular weight heparin
acute phase and as secondary prevention after MI, including Trials of LMWH added to treatment with aspirin have generally
DAPT with aspirin and a P2Y12 inhibitor. In the Clopidogrel shown favourable results for the combination in the acute phase,
in Unstable Angina to Prevent Recurrent Events (CURE) study, but extended treatment after hospital discharge has been less con-
clopidogrel added to aspirin was more effective, compared to vincing [104]. The FRISC trial comparing dalteparin with placebo
aspirin alone, in NSTE-​ACS, with a 20% risk reduction in the in NSTE-​ACS showed a significantly lower rate of death/​MI at
composite endpoint of cardiovascular death, MI, or stroke. Risk 6 days in women. The effect was less pronounced, and not statis-
reduction was directionally the same in both sexes, but lower tically significant, in men [105].
and not statistically significant in women [98]. A meta-​analysis
of all blinded RCTs by Berger et al., comparing clopidogrel and Direct thrombin inhibitors
placebo, did not show any significant sex differences in treat- The synthetic hirudin analogue bivalirudin was compared to
ment effect, reducing CVD by 14%, or in safety, increasing the UFH/​LMWH in ACS patients (65% NSTE-​ACS) in the ACUITY
bleeding risk by 42% [99]. trial. Bivalirudin alone was non-​inferior to bivalirudin plus GPI
In the TRITON-​TIMI 38 trial, patients with ACS (74% NSTE-​ or UFH/​LMWH plus GPI in the composite ischaemic endpoint,
ACS) planned for PCI were randomized to either prasugrel or but with a lower rate of bleeding [106]. A subgroup analysis ac-
clopidogrel. The primary efficacy outcome of cardiovascular cording to sex showed no difference in effect, but a higher rate of
death, MI, or stroke was lower with prasugrel, but with a higher net clinical AEs, due to more bleeding complications in women
bleeding risk. In a subgroup analysis, the primary outcome was than men. However, the relative decrease in bleeding events asso-
not statistically significant in women alone, but directionally the ciated with a non-​GPI strategy (i.e. bivalirudin alone) was similar
same as in men [100]. In the PLATO trial, the reversible P2Y12 in women and men [107, 108].
inhibitor ticagrelor was proved superior to clopidogrel in ACS In the HORIZONS-​ AMI trial, patients undergoing pri-
(38% STEMI), with a lower rate of cardiovascular death/​MI or mary PCI were randomly assigned to bivalirudin or UFH
stroke. A  subgroup analysis revealed a similar, and statistically plus GPI. Bivalirudin reduced the rates of net adverse clinical
significant, benefit in both men and women [101]. events, driven by a reduction in major bleeding at 1  year; no
The IV P2Y12 inhibitor cangrelor may be considered at the sex analyses were performed [109,  110]. In the EUROMAX
catheterization laboratory in patients who have not received PO trial, a pre-​specified sex analysis was performed, with results
P2Y12 inhibitors. A collaborative meta-​analysis regarding sex dif- consistent with those from the overall intention-​to-​treat ana-
ferences in the effect and safety of all modern P2Y12 inhibitors, lysis [111]. In the UK HEAT-​PPCI study, UFH monotherapy
using data from large randomized trials on prasugrel, ticagrelor, was found to be superior to bivalirudin in lowering the rate of
and cangrelor, showed similar results in men and women for both MACE in primary PCI patients, with no increase in bleeding
efficacy and safety. These potent P2Y12 inhibitors significantly re- [112]. Opposite results were found in the Chinese Bivalirudin
duced the risk of MACE by 14% in women (HR 0.86, 95% CI in Acute Myocardial Infarction versus Heparin and GPI Plus
0.78–​0.94) and by 15% in men (HR 0.85, 95% CI 0.80–​0.90), Heparin (BRIGHT) trial showing fewer bleeding events in the
while the risk of major bleeding was increased in both sexes (HR bivalirudin arm, compared to the UFH or UFH plus GPI arms,
1.28, 95% CI 0.87–​1.88 in women; HR 1.52, 95% CI 1.12–​2.07 in in a mixed MI population [113]. None of these trials reported
men) [102]. outcome according to sex. The MATRIX trial randomized ACS
patients planned for PCI to bivalirudin versus UFH, without
Glycoprotein IIb/​IIIa inhibitors any difference in MACE and with no interaction according to
GPIs are potent platelet inhibitors, blocking platelet aggregation sex [114, 115]. In the Swedish register-​randomized VALIDATE-​
by inhibiting fibrinogen binding to platelet GPIIb/​IIIa receptors. SWEDEHEART study, comparing bivalirudin and UFH in ACS
Today, if patients are treated with the modern P2Y12 inhibitors patients undergoing PCI, a borderline significant interaction
ticagrelor or prasugrel, GPIs are only recommended as bailout (P  =  0.05) according to sex and the primary endpoint (death
therapy during PCI [44, 82]. from any cause, MI, or major bleeding) was found. Whereas
A meta-​analysis of six large randomized GPI trials in patients bivalirudin tended to be better in women (HR 0.78, 95% CI
with UA/​NSTEMI not routinely scheduled to undergo coronary 0.60–​1.00), no difference was found in men (HR 1.06, 95% CI
angiography showed a modest benefit by reducing the combined 0.89–​1.26) [116]. The observed difference was primarily due
endpoint of death/​MI by 30  days (11.8 versus 10.8%, OR 0.91, to a lower risk of major bleeding associated with bivalirudin
95% CI 0.84–​0.98). The effect was mainly restricted to patients in women (HR 0.74, 95% CI 0.54–​1.01), but not in men (HR
with high-​risk features such as elevated troponin or ST-​segment 1.16, 95% CI 0.94–​1.43; P for interaction = 0.02) [117]. In add-
depression. Patients undergoing PCI or CABG had a greater risk ition, a pooled analysis of the Randomized Evaluation in PCI
590 CHAPTER 44   Se x c onsiderations in acu t e c orona ry  sy n dro m es

Linking Angiomax to Reduced Clinical Events 2 (REPLACE-​2), men more often have multivessel or left main disease, whereas
ACUITY, and HORIZONS-​AMI trials found a greater advan- women more often have one-​vessel disease [127].
tage of bivalirudin in women than in men. This study found a
similar safety benefit of bivalirudin in men and women in re-
ducing bleeding, but women had a more pronounced benefit of Sex differences in benefit from
bivalirudin in reducing 12-​month mortality [118].
invasive treatment in non-​ST-​
Factor Xa inhibitors segment elevation acute coronary
In the OASIS-​5 and OASIS-​6 trials, it was shown that fondaparinux
reduced mortality, ischaemic events, and major bleeding across
syndromes
the full spectrum of ACS, in comparison with a heparin-​based Today, an early invasive treatment strategy with coronary angio-
strategy, and was associated with a more favourable net clinical graphy and revascularization, if feasible, has become the treat-
outcome in patients undergoing either an invasive or a conser- ment strategy of choice in patients with NSTE-​ACS [44].
vative management strategy [6, 119, 120]. Subgroup analyses re- Gender differences in benefit from an invasive strategy have
garding the net clinical benefit revealed no sex interaction. been debated, and data are conflicting. Three earlier random-
ized trials, comparing a routine invasive with a selective invasive
strategy in NSTE-​ACS, have reported outcomes separately for
Reperfusion therapy in ST-​segment women and men.
In the FRISC II and Randomized Intervention Trial of Unstable
elevation myocardial infarction Angina 3 (RITA 3) trials, in contrast to a clear favourable outcome
Several studies have shown that women with STEMI present at with a routine invasive strategy in men, there was no benefit in
the hospital after a significantly longer delay from symptom onset, women [133, 134]. The TACTICS-​TIMI 18 trial indicated similar
compared to their male counterparts [2, 6, 121]. This could be one benefit in men and women with a routine invasive strategy, but
reason why women with STEMI have been treated with thrombo- mainly restricted to those with elevated markers [9]‌. Finally, in
lytic therapy more seldom than men during the thrombolytic era the OASIS-​5 trial, a substudy included women only and showed
[6, 122], as the time from symptom to treatment is crucial when no difference between routine invasive and selective invasive
using this type of reperfusion therapy. Thrombolytic therapy for strategies in the primary outcome of death/​MI/​stroke or the sec-
treatment of STEMI has been associated with a higher risk of ondary outcome of death/​MI during 1  year. However, a higher
stroke and bleeding in women, compared to men, but also with a rate of death was indicated with a routine invasive strategy [135].
greater relative reduction in mortality [123]. A meta-​analysis, presented together with data from the OASIS-​5
Primary PCI has been shown to significantly improve the sur- WSS, suggested a clear benefit for death/​MI with a routine in-
vival of patients with STEMI and to be superior to thrombolytic vasive strategy, compared to a selective invasive strategy, in men
therapy in both men and women [124]. PCI studies have also that could not be seen in women [135]. Another meta-​analysis
shown a longer symptom-​to-​door time in women, compared to including eight trials showed no significant difference in outcome
men [125–​127], in spite of public education programmes. In the with a routine invasive versus a selective invasive strategy in the
primary PCI era, a higher percentage of STEMI patients, both endpoint of death/​MI, either for men or women [136]. Finally, a
men and women, are offered reperfusion therapy [6,  128] and pooled analysis on individual patient data from three random-
the sex gap has diminished [128]. Still, after adjusting for age, ized trials with long-​term follow-​up (5 years) confirmed benefit
comorbidity, and later arrival, there are several studies showing a of a routine invasive, compared to a selective invasive, strategy in
lower rate of reperfusion therapy in women than in men [6, 129–​ men, but not in women. The risk-​adjusted HR for the combin-
131]. Even if the time to treatment is even more crucial regarding ation of cardiovascular death/​MI was 0.73 (95% CI 0.63–​0.86) for
thrombolytic therapy, there is clear evidence that time is crucial men and 1.13 (95% CI 0.89–​1.43), with a significant interaction
also for primary PCI. In a Danish study on 6209 STEMI patients (P = 0.01) [137, 138].
who underwent primary PCI within 12 hours of symptom onset, There are several possible reasons for less benefit from an inva-
system delay was the strongest covariate independently associ- sive strategy in women with NSTE-​ACS and for the difference in
ated with long-​term mortality (HR 1.10, 95% CI 1.04–​1.16) per outcome between earlier studies.
1-​hour increase [132]. A common finding in the three randomized trials that reported
The success rate of PCI in STEMI is not different between the sex differences was that women have less obstructive CHD. In
sexes [127], but MACEs, such as bleeding, occur more often the FRISC II trial, patients without significant stenosis had an
in women than in men [125]. The use of intracoronary stents excellent prognosis, with no death during the 1-​year follow-​up.
has been significantly lower in women than in men [126], but The relative paucity of obstructive coronary disease may obvi-
stenting in the setting of primary PCI has been shown to be asso- ously dilute the treatment benefit with a routine invasive strategy
ciated with a reduction in MACEs also in women [125]. The lower [133]. In both the FRISC II and TACTICS-​TIMI 18 trials, men
stenting incidence is, at least in part, due to the sex difference in were significantly more likely to have elevated troponin, com-
the underlying CAD severity. In STEMI, as well as in NSTE-​ACS, pared to women. In a subgroup analysis of high-​risk patients in
 Ou tc o m e 591

the TACTICS TIMI-​18 trial, there was a similar benefit in the have been published. In the DAPT trial, patients treated with PCI
primary endpoint of death/​ MI/​revascularization in troponin-​ were randomized after 12  months of DAPT to placebo or ex-
positive female and male patients. These data were further sup- tended treatment during another 18 months. There was no sig-
ported in a meta-​analysis by O’Donoghue et al. showing benefit nificant difference between the sexes in bleeding complications
with an invasive strategy in women with elevated markers [135]. and sex is therefore not included in the bleeding risk score [157].
In a large registry analysis of 46  455 consecutive patients with In the TRILOGY trial, patients with NSTE-​ACS were randomized
NSTE-​ACS reflecting daily clinical practice, there was a similar to receiving either clopidogrel or prasugrel for up to 30 months
mortality reduction in men and women with an invasive strategy (mean 14.8 months). By study design, a large proportion of the
[58]. Importantly, based on the collected evidence, the ESC clin- patients were >75 years old. Non-​CABG-​related GUSTO severe,
ical guidelines for the management of patients presenting with life-​threatening, or moderate bleeding occurred in 158 patients
NSTE-​ACS recommend no difference in treatment strategy be- (3.0%), and 48 of the bleeding events were determined to be se-
tween the sexes. vere or life-​threatening bleeds. Non-​CABG-​related TIMI major
or minor bleeding occurred in 174 patients (3.3%), and 105 of the
bleeding events were determined to be major bleeds. A risk score
Complications was developed to predict bleeding complications, and female sex
was significantly associated with lower long-​term bleeding risk
Female sex has been associated with bleeding events in sev- (HR 0.67, 95% CI 0.47–​0.96 for non-​CABG-​related GUSTO se-
eral ACS and PCI trials with different anticoagulation strat- vere/​life-​threatening/​moderate bleeding; HR 0.59, 95% CI 0.41–​
egies [139–​ 142], and several established short-​ term bleeding 0.84 for non-​CABG-​related TIMI major/​minor bleeding) [158].
risk scores include sex among the factors that predict bleeding Finally, in the PLATO trial, there was no difference between men
complications [143,  144]. Data from real-​life management in and women in non-​CABG-​related bleeding complications during
the GRACE registry showed rates of a major bleed of between 1-​year follow-​up. When procedure-​related and non-​procedure-​
2.7% (in UA) and 4.7% (in NSTEMI). Independent predictors of related bleeding complications were analysed separately, female
major bleeding included female sex, age, renal dysfunction, his- sex was positively associated with (increased) procedure-​related
tory of bleeding, and use of GPIs. In a multivariate analysis, the bleeds (HR 2.245, 95% CI 1.416–​3.559) and negatively associated
adjusted OR for bleeding was 1.71 (95% CI 1.35–​2.17) in women, with (decreased) non-​procedure-​related bleeds (HR 0.765, 95%
compared to men [143]. In a study based on the SWEDEHEART CI 0.587–​0.996). This may explain the apparently contradictory
registry, including >50 000 hospitalized MI patients, female sex results in short-​and long-​term bleeding risk in women versus
was a predictor of bleeding (OR 1.17, 95% CI 1.01–​1.37). The as- men. Actions to minimize bleeding, including individual treat-
sociation was stronger in STEMI (OR 1.46, 95% CI 1.10–​1.94) ment decisions, are warranted and use of clinical risk scores to
and in invasively treated patients (OR 1.80, 95% CI 1.45–​2.24) assess bleeding risk is advocated in clinical guidelines.
[145]. In-​hospital bleeding was associated with a higher risk of
mortality in men (OR 1.35, 95% CI 1.04–​1.74), but not in women
(OR 0.97, 95% CI 0.72–​1.31) [145]. The reasons for a difference
in prognostic impact of a bleeding complication may be related to
Outcome
the observation that women more often have procedure-​related Short-​term mortality in MI is reported to be approximately twice
(especially access site) bleeding, while men more often have as high in women, compared to men. The higher mortality rate in
spontaneous bleeding. The latter are more associated with worse women is largely explained by differences in age and comorbidities
long-​term outcome [146–​148]. A  report from the PLATO trial between men and women [2–​4, 75, 123, 159–​164). However, an
confirmed a higher risk of PCI-​related bleeding complications age–​sex interaction has been identified whereby younger women
in women, but a significantly lower risk of spontaneous non-​ are at particularly high risk, relative to men, even after adjustment
procedure-​related bleeding through 12 months’ follow-​up [147]. for other prognostic factors [19, 159, 165, 166]. One reason for
A higher in-​hospital bleeding risk in women was also supported higher short-​term mortality in women in hospital-​based cohorts
in a recent report on 6.6 million PCI procedures in the US [149]. could be higher pre-​hospital mortality in men [167, 168]. In an
Increased bleeding risk in women may also be explained by renal analysis of Swedish MI patients, including deaths occurring be-
insufficiency, since the risk of bleeding events increases as cre- fore hospital admission, short-​(28 days) and long-​term (1 year)
atinine clearance declines, and female sex is a strong independent mortality was assessed in 658  110 patients (35.7% women).
risk factor for renal insufficiency in MI [150–​154]. Women and Women had lower short-​term mortality in all age groups when
patients with renal insufficiency are more likely to receive excess pre-​hospital deaths were included in the adjustment model [169].
dosing of antithrombotic therapy for ACS, which may increase Other possible explanations could be differences in the under-
bleeding complications [141]. lying anatomy and pathophysiology, such as reduced collateral
Longer-​term bleeding risk is less studied, but studies have in- circulation due to single-​vessel CAD, but also fewer typical symp-
dicated a similar risk, or even a lower risk, in women [155, 156]. toms and less awareness about MI among young women, com-
More recently, two risk scores for extended treatment with DAPT pared to same-​age men.
592 CHAPTER 44   Se x c onsiderations in acu t e c orona ry  sy n dro m es

Earlier studies focusing on sex differences in outcome have often characterized by sudden CP and/​or dyspnoea and signs of
usually included both STEMI and NSTE-​ACS patients. Not only AHF. The most frequent finding on the ECG is ST-​segment ele-
do the pathophysiology and initial management differ between vation in the precordial leads mimicking STEMI, but absence of
these two conditions [44], but an interaction between sex and the occlusive CAD in ICA. The typical echocardiography appear-
type of ACS regarding outcome also seems to be present [3, 170]. ance (80–​90%) is apical LV ballooning, but also other patterns
In STEMI, most studies during the fibrinolytic era found around of ventricular dysfunction are recognized such as basal, mid-​
20% higher risk of short-​term mortality after multivariable ad- ventricular, and focal patterns [186]. In the acute phase, high
justment [4, 6, 161,  171]. During the primary PCI era, there is amounts of catecholamine are released from the adrenal medulla
conflicting evidence [6, 125, 172–​176]. The relative benefit of and simultaneously noradrenaline is released from sympathetic
primary PCI, compared to thrombolytic therapy, seems to be at nerve terminals. This leads to a combination of catecholamine
least as good in women as in men [126], and in selected primary toxicity, vasoconstriction, and/​or spasm of epicardial and micro-
PCI populations, many studies have not found a significant sex vascular vessels, resulting in increased cardiac workload [187].
difference in short-​term outcome [174, 175,  177]. Nevertheless, In one-​third of Takotsubo syndrome cases, no stressful trigger
a meta-​analysis performed by Panchole et al. including 35 studies can be identified [186]. The cause and pathogenesis of Takotsubo
with STEMI patients treated with primary PCI found twice as syndrome remain incompletely understood and more research is
high in-​hospital mortality in women, which was attenuated, but needed, including explaining the trigger in cases without precipi-
still significant, after multivariable adjustment (RR 1.48, 95% CI tating intense emotional events/​physical stress, as well as why the
1.07–​2.05). There was no significant difference in adjusted 1-​year vast majority of Takotsubo syndrome cases are post-​menopausal
mortality (RR 0.90, 95% CI 0.69–​1.17) [178]. In studies from the women. A  hypothesis for the latter is mediation of endothelial
same era including all-​comers, regardless of given reperfusion dysfunction by deprivation of oestrogen.
therapy or not, a sex difference still seems to be present [6]‌.
As regards long-​term outcome, there are limited data on pos- Spontaneous coronary artery dissection
sible sex differences in STEMI prognosis beyond 1 year. According Another pathophysiologic mechanism behind ACS which re-
to a study on 54 146 (34.9% women) STEMI patients registered in cently has got more attention is spontaneous coronary artery
SWEDEHEART between 1995 and 2006, with median follow-​up dissection (SCAD), a condition where >90% of the patients
of 4.6 years, women had 59% higher mortality (crude OR 1.59, are women [188–​190]. SCAD is defined as a spontaneous sep-
95% CI 1.55–​1.64), but this was explained by the age difference aration of part of the coronary artery wall which may com-
(age-​adjusted OR 0.98, 95% CI 0.95–​1.01). After adjusting for promise coronary flow, giving rise to acute cardiac ischaemia. It
differences in comorbidities and treatments, women had a lower is not linked to atherosclerosis, trauma, or invasive procedures.
long-​term risk of mortality (OR 0.92, 95% CI 0.89–​0.96) [2]‌.
According to a review on sex differences in long-​term prognosis
after MI (not separating STEMI from NSTE-​ACS) by Bucholz
et al., there appeared to be a slight downward trend over the last Box 44.1  Subtypes of spontaneous coronary artery
dissection [201]
decades in the adjusted risk ratios for women versus men, which
the authors attributed to improvements in MI management over ◆ Type 1 (evident arterial wall stain): the pathognomonic angio-
time [20]. graphic appearance of SCAD with contrast dye staining of
In contrast to STEMI, women with NSTE-​ACS seem to have arterial wall with multiple radiolucent lumen.
equal or better outcome, after adjustment for age and comorbidity Type 2 (diffuse stenosis of varying severity): absence of ob-
◆

[179–​183]. In a large cohort of patients with NSTE-​ACS, the structive CAD or angiographic diffuse stenosis of varying
impact of age on long-​term mortality was obvious, with sub- severity and length (typically >20 mm) and with appreciable,
stantially higher mortality with increasing age. There was no sig- but often subtle, abrupt changes in the arterial calibre from a
nificant difference in in-​hospital or 30-​day mortality, but at 1 year, normal diameter to diffuse smooth narrowing.
male sex was associated with higher mortality (OR 1.12, 95% CI Type 2A: diffuse narrowing is bordered by normal artery
◆

1.06–​1.19). segments that are proximal and distal to the intramural

haematoma.
Type 2B: diffuse narrowing extends to the apical tip of the
◆

artery.
ACS-​mimicking syndromes
Type 3 (mimics atherosclerosis): angiographic features that
◆

Takotsubo syndrome favour SCAD: (1) lack of atherosclerotic changes in other cor-

Intense emotional or physical, stressful events may trigger a cat- onary arteries; (2) long lesions (11–​20 mm); (3) hazy stenosis;
and (4) linear stenosis. Use of intracoronary imaging can be
echolamine overload, leading to stress-​induced cardiomyopathy
necessary to identify these cases.
mimicking STEMI—​the Takotsubo syndrome [184,  185]. The
vast majority (90%) of these patients are women, most often at Source data from Saw J. Coronary angiogram classification of spontaneous
coronary artery dissection. Catheter Cardiovasc Interv 2014;84(7):1115–​1122.
post-​menopausal age (80%) [186]. The clinical presentation is
 RE F E RE N C E S 593

Two hypotheses have been proposed on why this occurs. The (22–​35%) [188, 195–​197], with 43% of MIs occurring during
first is that an intimal rupture gives rise to a false lumen with pregnancy [198].
an intramural haematoma. The second is that disruption of The aetiology of SCAD is yet to be defined but seems to be multi-
a vasa vasorum within the arterial wall is the primary mech- factorial. There is often an underlying predisposing arteriopathy,
anism [189]. The population-​based incidence and prevalence the most common being fibromuscular dysplasia which is preva-
of SCAD are still uncertain due to underdiagnosis, and ICA is lent in 41–​86% of SCAD patients [189,  199]. SCAD is also as-
not always sufficient to identify SCAD. Hence, with clinicians sociated with pregnancy, especially the postpartum period [200].
not being aware of this entity, combined with complementary Other predisposing factors are connective tissue disorders, sys-
coronary imaging techniques still not widely used, many SCAD temic inflammatory diseases, and hormonal therapy [188]. There
cases are probably missed [188]. It is estimated from a couple are also studies showing that up to half of all SCAD cases have
of studies in the modern era that SCAD may constitute around been precipitated by an emotional stress trigger, but also intense
1–​4% of all ACS cases [191–​ 194], but in pre-​ menopausal exercise and use of certain drugs, such as cocaine, have been de-
women, studies are showing much higher percentages of SCAD scribed as potential triggers (see E Box 44.1) [188].

Personal perspective
There are differences between women and men, regarding be- with patients. One of the most logical places to introduce con-
haviour and disease, as well as the inequality of life conditions. cepts related to sex-​and gender-​based medicine is via the
Thus, sex is, and should be, an important factor for the treating curriculum of medical, pharmaceutical, public health, and
physician, especially as it relates to interpersonal interactions nursing schools [121].

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 SECTION VII

Acute heart
failure (including
cardiogenic shock)

45 Acute heart failure: epidemiology, classification, and pathophysiology  603

Dimitrios Farmakis and Gerasimos Filippatos
46 Acute heart failure: early pharmacological therapy  617
Kieran F Docherty, Jonathan R Dalzell, Mark C Petrie, and John JV McMurray
47 Low cardiac output states and cardiogenic shock  633
Holger Thiele and Suzanne de Waha-​Thiele
48 Non-​pharmacological therapy of acute heart failure: when drugs alone
are not enough  651
Jeroen Dauw, Wilfried Mullens, Johan Vijgen, and Pascal Vranckx
49 Heart failure surgery and transplantation  664
Felix Schoenrath, Jan Klages, and Volkmar Falk
50 Implanted cardiac support devices  680
Andrew C Morley-​Smith, André R Simon, and John Pepper
51 Donor organ management  691
Arne P Neyrinck, Patrick Ferdinande, Dirk Van Raemdonck, and Marc Van de Velde
52 Palliative care in the intensive cardiovascular care unit  706
Jayne Wood
 CHAPTER 45

Acute heart failure:

epidemiology,
classification, and
pathophysiology
Dimitrios Farmakis and Gerasimos Filippatos

Contents
Summary  603
Summary
Introduction  604 Acute heart failure is defined as the rapid development or change of symptoms
Epidemiology  604 and signs of heart failure that requires urgent medical attention and usually hos-
Epidemiological studies in acute heart pitalization. It represents the first reason for hospital admission in individuals
failure  604
Clinical profile  604 aged 65 or more and accounts for nearly 70% of the total health care expenditure
Outcomes and prognosis  604 for heart failure. It is generally characterized by an adverse prognosis, with an
In-​hospital and post-​discharge in-​hospital mortality rate of 4–​7%, a 2-​to 3-​month post-​discharge mortality rate
mortality  604
Readmission to hospital  604 of 7–​11%, and a 2-​to 3-​month readmission rate of 25–​30%. The majority of pa-
Prognostic indicators  606 tients have a previous history of heart failure and present with symptoms and/​
Classification  607 or signs of congestion and normal or increased blood pressure, while about half
Acute heart failure classifications  607
General heart failure classifications relevant
of the patients have preserved left ventricular ejection fraction. A  high preva-
to acute heart failure  610 lence of cardiovascular or non-​cardiovascular comorbidities is further observed,
Pathophysiology  611 including coronary artery disease, arterial hypertension, atrial fibrillation, dia-
Main pathogenetic mechanisms  611 betes mellitus, renal dysfunction, chronic lung disease, anaemia, and iron de-
Congestion  611
Low cardiac output  612 ficiency. Different classification criteria have been proposed for acute heart
‘Cardiac’ versus ‘vascular’ failure  612 failure, reflecting the clinical heterogeneity of the syndrome. Classifications ac-
Myocardial injury  612 cording to the past history of heart failure (acutely decompensated, chronic, or
Renal dysfunction  613
Conclusion  614 de novo), the systolic blood pressure upon presentation (hypertensive, normo-
Further reading  614 tensive, or hypotensive), and the presence or absence of congestion and per-
References  614
ipheral hypoperfusion are among the most widely used. The pathophysiology
of acute heart failure involves several mechanisms, including volume overload,
pressure overload, myocardial loss, and restrictive filling, while several cardio-
vascular and non-​cardiovascular precipitating factors lead to acute heart failure.
Regardless of the underlying mechanism, peripheral and/​or pulmonary conges-
tion is present in the vast majority of cases of acute heart failure, resulting from
fluid retention and/​or fluid redistribution, while a marked reduction in cardiac
output with peripheral hypoperfusion occurs in a minority of cases. Myocardial
injury and renal dysfunction are important factors involved in the precipitation
and progression of the syndrome.
604 CHAPTER 45   Ac u te h eart failu re: epidemi ol o g y, cl as si fi cati on , a n d pathophysi ol o g y

level of natriuretic peptides [18]. Most of these findings did not

Introduction differ whether a 40% or a 50% LVEF cut-​off was used for patient
AHF is generally defined as the rapid development or change of
classification.
symptoms and signs of heart failure that requires urgent med-
Patients presenting with AHF suffer from several other car-
ical attention [1]‌. AHF is a prevalent condition, as it represents
diovascular and non-​ cardiovascular conditions besides heart
the first reason for hospitalization in the elderly. It generally
failure. Cardiovascular comorbidities may often have a causal re-
bears an adverse prognosis, characterized by high mortality and
lationship with AHF, in contrast to extracardiac ones, which are
rehospitalization rates, while it further confers enormous health
rarely the cause of heart failure but may frequently affect its clin-
care expenditure. Despite the considerable public health and fi-
ical course and contribute to its worsening or progression. The
nancial burden related to AHF and the advances accomplished in
most prevalent comorbidities in patients with AHF are presented
chronic heart failure therapy, there has been only little progress in
in E Tables 45.2 and 45.3. Cardiovascular history comprises ar-
the medical management of those patients over the last years, as
terial hypertension in about 70% of patients, documented CAD in
most of the tested drugs have failed to improve prognosis.
50–​60%, and AF in 30–​40%. Non-​cardiovascular comorbidities
include diabetes mellitus in about 40% of patients, renal dysfunc-
tion in 20–​30%, COPD in 20–​30%, and anaemia in 15–​30%. It
Epidemiology should be stressed here the low prevalence of IHD in sub-​Saharan
African populations (7.7%) where the primary cause of heart
Epidemiological studies in acute heart failure failure is arterial hypertension [12].
AHF represents the first reason for hospitalization in individ-
uals aged 65 years or older in the Western world, accounting for Outcomes and prognosis
>1 million hospitalizations per year in the US [2]‌. Over the last In-​hospital and post-​discharge mortality
years, several heart failure registries from different parts of the
AHF is a syndrome with an ominous prognosis. In-​hospital mor-
world were published, providing us with an important bulk of evi-
tality ranges from 4% in American registries to 7% in European
dence on the epidemiology of the syndrome. Interestingly, these
surveys [3–​9,  14]. An in-​hospital mortality rate as high as 11%
registries do not concern only Europe and the US, as it was the
was reported by the ALARM-​HF registry, a survey that included,
case some time ago, but also different parts of Asia and Africa,
however, a much higher percentage of critically ill patients, i.e.
thus allowing a better understanding of the global epidemiology
those with CS [10]. Post-​discharge mortality rates during the first
of AHF. The main characteristics of the aforementioned surveys
3  months range between 7% and 11% [4, 7,  8], while mortality
are provided in E Table 45.1 [3–​17]. Several other smaller or
at 1  year after index hospitalization reaches 36% [4]‌. The me-
national registries have further contributed significantly to our
dian length of hospital stay was 5 days in American registries and
knowledge of AHF epidemiology.
6–​11 days in European surveys [19], while a much longer median
Clinical profile hospital stay of 21 days was reported by the Japanese registry [11].
The cause of death is not always directly related to heart failure. In
The mean age of patients presenting with AHF in the different fact, data from the EVEREST trial showed that death was directly
registries ranges between 70 and 73  years (see E Table 45.1). related to heart failure in only 41% of patients, while 13% of pa-
About half of the patients are male. The majority (65–​75%) have a tients died because of non-​cardiovascular causes (see E Figure
known history of heart failure. Most of these patients have normal 45.1) [20].
or increased blood pressure, while those presenting with hypo-
tension generally constitute <8%, including patients with CS that Readmission to hospital
represent <1% to 2% of cases. Discharged AHF patients suffer a considerably high readmission
A significant number of AHF patients do not have impaired rate. Registries have shown that the incidence of rehospitalization
LVEF. The prevalence of preserved LVEF ranges, in different ranges between 22% and 30% at 1–​3  months and reaches 65%
cohorts, from 25% in the Acute Heart Failure Global Survey at 1 year of the index AHF hospitalization [4, 7, 8]. It has been
of Standard Treatment (ALARM-​HF) registry to 55% in the shown that the risk of readmission follows a three-​phase pat-
EuroHeart Failure Survey I, depending apparently on the par- tern, with an early and a late peak, separated by a long plateau
ticular clinical features of each population and the applied LVEF phase of low incidence (see E Figure 45.2) [21]. According to
cut-​off (see E Table 45.1). A comparison of patients with pre- a Canadian cohort of 8500 patients hospitalized for heart failure
served and reduced LVEF in the Organized Program To Initiate and followed subsequently for 10 years, the incidence of recurrent
Lifesaving Treatment In Hospitalized Patients With Heart hospitalization was 30% during the first 2 months after discharge,
Failure (OPTIMIZE-​ HF) registry showed that patients with 50% during the last 2 months before death, and 20% during the
preserved LV systolic function were older and more frequently intercurrent period [22]. In >50% of patients, the reason for hos-
female, and had less frequently an ischaemic aetiology of heart pitalization is not heart failure itself. Data from the EVEREST
failure, a higher occurrence of risk factors and comorbidities trial in patients with known systolic heart failure showed that
such as arterial hypertension and diabetes mellitus, and a lower heart failure decompensation was the reason for hospitalization
 Epide m i ol o g y 605

Table 45.1  Main features and findings of large-​scale registries in acute heart failure

ADHERE OPTIMIZE-H
​ F EHFS I EHFS II ESC HF ATTEND CHINA-H
​ F Gulf CARE THESUS-​HF ALARM-​HF
Long-​Term
Study characteristics
Number of 105 388 48 612 11 327 3580 5039 4842 13 687 5005 1006 4953
patients
Region US Europe Asia Africa International
Number of 1 1 24 30 21 1 (Japan) 1 (China) 7 (Gulf 9 9
countries countries)
Time period 2001–​2004 2003–​2004 2000–​2001 2004–​2005 2011–​2013 2007–​2011 2012–​2015 2012 2007–​2010 2006–​2007
Patient characteristics
Age (mean, SD), 72 (14) 73.1 (14.2) 71 69.9 (12.5) 71 (median) 73 (13.8) 65 (15) 59 (15) 52.3 (18.3) 66–​70
years (median)
Gender, male 48 48 53 61 62.7 58 59.1 63 49.2 62
Known heart 75 87 65 63 54.5 36.2 45.5 55 64
failure, %
CS, % 2 <1 3.9 8 11.7
ICU/​CCU 19 7 51 8.5 75
admission, %
Preserved LVEF 40 (≥40) 51 (≥40) 55 (≥40) 34 (≥45) 32.8 (>45) 46.6 (>40) 36 (≥45) 31 (>40) 25 (≥45)
(cut-​off used), %
Outcomes
In-​hospital 4 4 6.9 6.7 4.9 6.4 4.1 6.3 4.2 11
mortality, %
Hospital stay, 4 4 11 9 21 10 7 7 6
median (days)
30-​ to 90-​day 11.2 9 (60–​90 days) 6.6 12.6 (90 days) 10.6
post-​discharge (30 days) (90 days) (60 days)
mortality, %
1-​year post-​ 36 23.6 20.2
discharge
mortality, %
Post-​discharge 22.1 30, 24, 22.2 (1 year) 18 (3 months) 9.1 (60 days)
readmission, % (30 days) (60–​90 days) (90 days) 40 (1 year)
(time period) 65.8 (1 year)
ADHERE, Acute Decompensated HEart Failure National Registry; ALARM-​HF, Acute Heart Failure Global Survey of Standard. Treatment; ATTEND, Acute decompensated heart
failure syndromes; CHINA-​HF, China Heart Failure; EHFS I, EuroHeart Failure Survey I; EHFS II, EuroHeart Failure Survey II; ESC HF Long-​Term, European Society of Cardiology Heart
Failure Long-​Term Registry; Gulf CARE, Gulf Acute Heart Failure; OPTIMIZE-​HF, Organized Program To Initiate Lifesaving Treatment In Hospitalized Patients With Heart Failure;
THESUS-​HF, The Sub-​Saharan Africa Survey on Heart Failure.

in only 46% of cases, while other cardiovascular reasons, such as ranging from 2.5 years in patients with one hospital admission to
ischaemia or arrhythmias, accounted for another 15% [20]. The 0.5 year in those with four admissions [24]. Regarding cost, it has
remaining 39% of patients were admitted for non-​cardiovascular been calculated that in the UK, 69% of the total health care ex-
reasons (see E Figure 45.3). penditure for heart failure is attributable to hospitalizations [25].
Recurrent hospital admissions affect both the clinical course In the US, this is translated into a total cost of $17 billion per year,
and the health care cost of the heart failure syndrome. It has been which represents more than half of the total health care cost for
postulated that each hospitalization is associated with a deteri- heart failure [2]‌. Given this situation, the US legislation has im-
oration of cardiac function that is not completely restored to the posed the reporting of readmission rates during the first 30 days
pre-​hospitalization state and the same seems to happen with renal after discharge and established a financial penalty for hospitals
function as well [23]. As a result, recurrent hospitalizations lead to with the highest readmission rates [26]. Therefore, strategies
a gradual worsening of the syndrome. This theory is supported by to prevent rehospitalization in AHF are warranted and involve
survival data, according to which median survival in heart failure better decongestion and training of patients during their hospital
patients decreases gradually with the number of hospitalizations, stay, timely institution and titration of oral medications, and close
606 CHAPTER 45   Ac u te h eart failu re: epidemi ol o g y, cl as si fi cati on , a n d pathophysi ol o g y

Table 45.2  Common comorbid conditions in patients with acute <120 mmHg to 5.4% when >161 mmHg (see E Figure 45.4). In
heart failure contrast, post-​discharge readmission rates did not differ signifi-
cantly according to admission SBP.
Common comorbid conditions
LVEF is considered as one of the main determinants of prog-
Cardiovascular CAD
◆
nosis in heart failure. Patients with preserved LVEF have several
Arterial hypertension
◆
clinical differences from those with established LV systolic dys-
Arrhythmias (i.e. AF)
◆
function, as stressed earlier (see E Table 45.1). However, the
Valvular heart disease (i.e. MR)
◆
prognosis is not quite different between these two subgroups
Non-​cardiovascular Diabetes mellitus
◆
of AHF patients. According to data from the OPTIMIZE-​HF
Renal dysfunction
◆
registry, although in-​hospital mortality was significantly better
COPD
◆
in patients with preserved systolic function (2.9% versus 3.9% in
Anaemia
◆
those with reduced LVEF; P <0.0001), there was no difference in
Depression
◆
post-​discharge mortality or hospital readmission at 2–​3 months
Cerebrovascular disease
◆
(see E Figure 45.5) [18]. Moreover, the use of neurohormonal
Sleep-​disordered breathing
◆
inhibitors (ACE-​ Is, ARBs, and β-​ blockers) at discharge was
Cachexia
◆
not associated with better mortality or readmission rates at
AF, atrial fibrillation; CAD, coronary artery disease; COPD, chronic obstructive 2–​3 months in patients with preserved LVEF [18]. This finding
pulmonary disease; MR, mitral regurgitation.
is in accordance with the neutral results of several randomized
trials on the use of classic heart failure therapies in patients with
post-​discharge monitoring for early identification and manage- preserved LVEF.
ment of decompensation [27, 28]. In the ALARM-​HF registry, in-​hospital mortality differed ac-
cording to the baseline characteristics and comorbid conditions
Prognostic indicators of patients [10]. For example, mortality ranged from 5% in pa-
Several clinical and laboratory variables are independent pre- tients who received RAAS antagonists before their hospitalization
dictors of outcome in the AHF syndrome. The most important to 14% in those aged 75 or higher and to 19% in those with renal
prognostic indicators are presented in E Table 45.4. dysfunction (see E Figure 45.6).
Systolic blood pressure (SBP) on admission is an important de- The precipitating factors that cause an AHF episode also have
terminant of patient outcome. Findings from the OPTIMIZE-​HF prognostic significance. Data from the OPTIMIZE-​HF registry
registry showed that both in-​hospital and post-​discharge mor- showed that in-​hospital mortality was relatively low, around 2%,
tality rates were significantly worse in patients with lower SBP when AHF had been caused by hypertension or lack of compli-
[29]. Thus, in-​hospital mortality ranged between 7.2% in patients ance with medications, increased to 4% in the case of myocardial
presenting with SBP of <120 mmHg and 1.7% in those presenting ischaemia, further to 6% when AHF had been provoked by pneu-
with SBP of >161 mmHg. Similarly, 2-​to 3-​month post-​discharge monia, and reached 8% when the precipitating factor had been
mortality ranged from 14% when SBP on admission was worsening renal function (see E Figure 45.7) [30].

Table 45.3  Medical history reported in patients with acute heart failure from large-​scale registries

ADHERE OPTIMIZE-​HF EHFS I EHFS II ESC-​HF ATTEND CHINA-​HF Gulf CARE THESUS ALARM-​HF
Long-​term
Number of patients 105 388 48 612 11 327 3580 5039 4842 13 687 5005 1006 4953
Arterial hypertension, 72 71 53 62.5 64.5 69.4 50.9 61 55.5 70.2
%
CAD, % 57 50 68 53.6 54 31.1 49.6 47 7.7 30.7
Diabetes mellitus, % 44 42 27 32.8 38.9 33.8 21 50 11.4 45.3
AF, % 31 31 43 38.7 44 39.6 24.4 12 18.3 24.4
Renal dysfunction, % 30 30 17 16.8 26.4 7.7 21.4
COPD, % 31 28 19.3 20.2 9.5 24.8
Anaemia, % 14.7 15.2 14.4
AF, atrial fibrillation; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease.
ADHERE, Acute Decompensated HEart Failure National Registry; ALARM-​HF, Acute Heart Failure Global Survey of Standard. Treatment; ATTEND, Acute decompensated heart
failure syndromes; CHINA-​HF, China Heart Failure; EHFS I, EuroHeart Failure Survey I; EHFS II, EuroHeart Failure Survey II; ESC HF Long-​Term, European Society of Cardiology Heart
Failure Long-​Term Registry; Gulf CARE, Gulf Acute Heart Failure; OPTIMIZE-​HF, Organized Program To Initiate Lifesaving Treatment In Hospitalized Patients With Heart Failure;
THESUS-​HF, The Sub-​Saharan Africa Survey on Heart Failure.
 Cl assi f i c at i on 607

Non-cardiovascular
Stroke 2.2%
13.2%
Acute myocardial
infarction
2.6% Non-cardiovascular
Heart failure 39% Heart failure
41% 46%

Sudden 26%
Other
cardiovascular
15%

Figure 45.1  Causes of death in patients hospitalized for acute heart failure Figure 45.3  Causes leading to hospitalization for acute heart failure in the
in the EVEREST trial. EVEREST trial.
Source data from O’Connor CM, Miller AB, Blair JE, Konstam MA, Wedge P, Bahit MC, Source data from O’Connor CM, Miller AB, Blair JE, Konstam MA, Wedge P, Bahit MC,
Carson P, Haass M, Hauptman PJ, Metra M, Oren RM, Patten R, Pina I, Roth S, Sackner-​ Carson P, Haass M, Hauptman PJ, Metra M, Oren RM, Patten R, Pina I, Roth S, Sackner-​
Bernstein JD, Traver B, Cook T, Gheorghiade M, Efficacy of Vasopressin Antagonism in Bernstein JD, Traver B, Cook T, Gheorghiade M, Efficacy of Vasopressin Antagonism in
heart Failure Outcome Study with Tolvaptan i. Causes of death and rehospitalization in heart Failure Outcome Study with Tolvaptan i. Causes of death and rehospitalization in
patients hospitalized with worsening heart failure and reduced left ventricular ejection patients hospitalized with worsening heart failure and reduced left ventricular ejection
fraction: results from Efficacy of Vasopressin Antagonism in Heart Failure Outcome fraction: results from Efficacy of Vasopressin Antagonism in Heart Failure Outcome
Study with Tolvaptan (EVEREST) program. Am Heart J 2010;159:841–​9  e1. Study with Tolvaptan (EVEREST) program. Am Heart J 2010;159:841–​9  e1.

◆ Acutely decompensated chronic heart failure (ADCHF), that oc-

Classification curs in patients with a heart failure history. As stated earlier,
ADCHF is far more frequent, representing about 65–​75% of
Acute heart failure classifications patients hospitalized for AHF, according to different registries
AHF constitutes a heterogenous group of patients and there have (see E Table 45.1). Several precipitating factors (see E Table
been several attempts to categorize the AHF syndrome using dif- 45.6) act as a trigger of worsening, leading usually to a gradual
ferent classification criteria (see E Table 45.5). disruption of patients’ cardiac function and haemodynamics.
Depending on whether patients have a past history of heart Besides cardiac and extracardiac conditions, the lack of com-
failure or not, AHF is classified into: pliance with prescribed medication is a common precipitating
factor, accounting for 22% of ADCHF cases in the EuroHeart
Failure Survey II [9]‌.
% rehospitalization
◆ De novo AHF, that occurs in individuals without a past history
50%
of heart failure. This is the case for the remaining one-​third or
less of AHF patients. These patients often have a history of risk
30% factors such as arterial hypertension, diabetes mellitus, or ad-
20% vanced age. The term de novo AHF has been used to describe
the AHF patient with a rapid development of symptoms and
signs of heart failure that requires immediate medical care. It
Post-discharge phase Plateau phase Palliation phase has been also incorrectly used interchangeably with the term
(2 months) (2 months) AHF with preserved EF. ACS are a frequent cause for the de-
velopment of the syndrome. In the community, patients could
Discharge ... Death also present with symptoms and signs of heart failure for the
first time (de novo); however, in these patients, the onset is
Figure 45.2  Time distribution of post-​discharge rehospitalization rate in
patients hospitalized for acute heart failure. The incidence of rehospitalization more gradual.
is characterized by two peaks following discharge (post-​discharge phase) According to the level of SBP at presentation, AHF is
and preceding death (palliation phase), separated by an intercurrent classified into:
plateau phase.
Source data from Desai AS, Stevenson LW. Rehospitalization for heart failure: predict or ◆ Hypertensive AHF, when SBP at presentation is >140 mmHg.
prevent? Circulation 2012;126:501–​6. These patients represent 50% or more of AHF cases and are
608 CHAPTER 45   Ac u te h eart failu re: epidemi ol o g y, cl as si fi cati on , a n d pathophysi ol o g y

Table 45.4  Prognostic factors in acute heart failure 30

29.9
29.2
Prognostic factors
Clinical Age
◆
Heart rate
◆ 25
SBP
◆
O2 saturation
◆
6-​minute walked distance
◆
Need of inotropic agents
◆
20
Ischaemic ECG changes
◆

Medical history Recurrent hospitalizations

◆
Renal dysfunction
◆
COPD
◆ 15
Anaemia
◆
Cerebrovascular events
◆
Peripheral vascular disease
◆

10 9.8 9.5
Laboratory Natriuretic peptides
◆
Cardiac troponins
◆
Serum urea or BUN
◆
Serum creatinine
◆
Serum Na+
◆ 5
3.9
Hb
◆
2.9
Liver function tests
◆
LVEF
◆
Restrictive physiology (ECHO-​Doppler)
◆
0
BUN, blood urea nitrogen; COPD, chronic obstructive pulmonary disease; Hb, In-hospital Post-discharge Readmission
haemoglobin; LVEF, left ventricular ejection fraction; Na+, sodium; SBP, systolic blood mortality (%) mortality (%) (%)
pressure.
LVEF <40% LVEF ≥40%

30.6 Figure 45.5  Outcome of acute heart failure patients with reduced or

29.9 30.3
30 preserved left ventricular ejection fraction (LVEF) in the OPTIMIZE-​HF
27.6 registry. Although in-​hospital mortality is significantly higher in patients with
reduced LVEF (P <0.0001), neither post-​discharge mortality nor readmission
rates at 2–​3 months differ significantly between the two subgroups.
25 Source data from Fonarow GC, Stough WG, Abraham WT, Albert NM, Gheorghiade M,
Greenberg BH, O’Connor CM, Sun JL, Yancy CW, Young JB, Investigators O-​H, Hospitals.
Characteristics, treatments, and outcomes of patients with preserved systolic function
hospitalized for heart failure: a report from the OPTIMIZE-​HF Registry. J Am Coll Cardiol
20 2007;50:768–​77.

15 14 Pre-hospital ACE-I/ARB 5%

Pre-hospital β-blocker 8%
10
8.4
7.2 Age >75 years 14%
6
5.4
5
3.6 Previous AHF <1 year 10%
2.5
1.7
Renal dysfunction 19%
0
In-hospital Post-discharge Readmission
mortality (%) mortality (%) (%) Overall 11%
<120 120–139 140–161 >161
Figure 45.6  In-​hospital mortality according to baseline characteristics in the
Figure 45.4  Outcome of acute heart failure patients according to the level ALARM-​HF registry.
of systolic blood pressure on admission in the OPTIMIZE-​HF registry. Both Source data from Follath F, Yilmaz MB, Delgado JF, Parissis JT, Porcher R, Gayat E,
in-​hospital and 2-​to 3-​month post-​discharge mortality rates are significantly Burrows N, McLean A, Vilas-​Boas F, Mebazaa A. Clinical presentation, management and
worse with lower systolic blood pressure (both P <0.001), while the post-​ outcomes in the Acute Heart Failure Global Survey of Standard Treatment (ALARM-​
discharge readmission rate does not differ significantly. HF). Intensive Care Med 2011;37:619–​26.
Source data from Gheorghiade M, Abraham WT, Albert NM, Greenberg BH, O’Connor
CM, She L, Stough WG, Yancy CW, Young JB, Fonarow GC, Investigators O-​H,
Coordinators. Systolic blood pressure at admission, clinical characteristics, and outcomes
in patients hospitalized with acute heart failure. JAMA 2006;296:2217–​26.
 Cl assi f i c at i on 609

Table 45.6  Proposed classifications of acute heart failure syndromes

Ischaemia 4.2%
according to different classification criteria
Arrhythmia 3.9% Acute heart failure classification
Past history of heart failure ADCHF
◆
Diet non-adherence 1.8%
De novo AHF
◆

Hypertension 1.7% Blood pressure upon presentation Hypertensive AHF

◆
Normotensive AHF
◆
Hypotensive AHF
◆
Medication non-adherence 2.0%
Congestion and peripheral perfusion Warm and dry
◆

Pneumonia 5.8% Warm and wet

◆
Cold and dry
◆
Cold and wet
◆
Worsening renal function 8.0%
Clinical scenario upon presentation Decompensated heart failure
◆

Overall 3.8% Pulmonary oedema

◆
CS
◆
Hypertensive heart failure
◆
Figure 45.7  In-​hospital mortality according to precipitating factors in the Right heart failure
◆
OPTIMIZE-​HF registry. AHF associated with ACS
◆
Source data from Fonarow GC, Abraham WT, Albert NM, Stough WG, Gheorghiade M,
Greenberg BH, O’Connor CM, Pieper K, Sun JL, Yancy CW, Young JB, Investigators O-​H, General heart failure classifications relevant to AHF
Hospitals. Factors identified as precipitating hospital admissions for heart failure and
clinical outcomes: findings from OPTIMIZE-​HF. Arch Intern Med 2008;168:847–​54. NYHA functional class NYHA I
◆
NYHA II
◆
NYHA III
◆

more likely to be elderly and female and to have preserved NYHA IV

◆

LVEF [31]. Their symptom development is usually abrupt and LVEF AHF
◆ with reduced LVEF
involves pulmonary congestion [32]. The mortality rates in this AHF with mid-​range LVEF
◆
AHF with preserved LVEF
◆
subgroup are significantly lower, with in-​hospital mortality
ACS, acute coronary syndrome; ADCHF, acute decompensated chronic heart failure;
AHF, acute heart failure; CS, cardiogenic shock; LVEF, left ventricular ejection fraction;
NYHA, New York Heart Association.

Table 45.5  Causes and precipitating factors leading to acute heart

failure
ranging from 1.7% to 2.5% and post-​discharge 2-​to 3-​month
Causes and precipitating factors mortality from 5.4% to 6% [29].
Cardiovascular ACS
◆
◆ Normotensive AHF, when SBP at presentation falls between
Tachycardias (i.e. AF)
◆ 90 and 140  mmHg. These patients represent 40% or more of
Bradycardias (i.e. third-​degree AV block)
◆ AHF cases and usually have ADCHF and reduced LVEF. Their
Uncontrolled hypertension or hypertensive crisis
◆ symptom development is usually gradual and involves signifi-
Myocarditis
◆
cant systemic congestion [32]. Their in-​hospital mortality ranges
Acute PE
◆
between 8% and 10% [31].
Acute valvular regurgitation (i.e. endocarditis, MI)
◆
Aortic dissection
◆ ◆ Hypotensive AHF, when SBP at presentation is <90  mmHg.
Cardiac tamponade
◆ These patients represent <8% of AHF cases [32]. Many of them
Non-​ Infections and febrile states
◆ have advanced or end-​stage heart failure and they present with
cardiovascular COPD exacerbation or asthma
◆ signs of low cardiac output and tissue hypoperfusion, while
Renal dysfunction
◆
some of them present with CS. The in-​hospital mortality is
Anaemia
◆
Hyperthyroidism
◆
>15%, reaching 30% or more in the case of CS [31].
Hypothyroidism
◆ Although the SBP cut-​off for hypertension is well defined
Strenuous exercise
◆
(140  mmHg), this is not the case for hypotension and different
Emotional stress
◆
Pregnancy and delivery (peripartum cardiomyopathy)
◆
cut-​offs have been proposed such as 90 or 85 mmHg. The latest
ESC guidelines propose 90 mmHg as the cut-​off to recommend
Patient-​related Poor compliance with medication
◆
or iatrogenic Increased salt or fluid intake
◆
the use of inotropes or vasopressors in AHF patients [1]‌. This
Surgery
◆ classification is clinically relevant as SBP on admission is a strong
Drugs (i.e. NSAIDs, thiazolidinediones, negative
◆ predictor of outcome, particularly of mortality, while it also
inotropic drugs) guides the initial therapeutic decisions (i.e. inotropes/​vasopres-
Alcohol abuse
◆
sors in hypotensive AHF or vasodilators in hypertensive AHF).
ACS, acute coronary syndrome; AF, atrial fibrillation; AV, atrioventricular; COPD, chronic However, the proposed SBP cut-​offs are arbitrary and a compre-
obstructive pulmonary disease; MI, myocardial infarction; NSAID, non-​steroid anti-​
inflammatory drug; PE, pulmonary embolism.
hensive clinical evaluation of patients is warranted.
610 CHAPTER 45   Ac u te h eart failu re: epidemi ol o g y, cl as si fi cati on , a n d pathophysi ol o g y

Another clinical classification of AHF is based on the haemo- ◆ CS.

dynamic condition of patients upon presentation. Patients are ◆ Hypertensive heart failure.
classified according to the presence or absence of symptoms and/​ ◆ Right heart failure.
or signs of congestion and peripheral hypoperfusion at rest [33]. ◆ AHF associated with ACS.
The patient is characterized as ‘wet’ or ‘dry’ in the presence or
According to the ESC Heart Failure Long-​Term Registry, 61% of
absence of congestion, respectively, and as ‘cold’ or ‘warm’ in the
AHF patients present with decompensated heart failure, 13% with
presence or absence of signs of hypoperfusion, respectively. Thus,
pulmonary oedema, 14.5% with ACS-​AHF, 5% with hypertensive
four categories are possible (see E Figure 45.8):
heart failure, 3.5% with right heart failure, and 3% with CS [35].
◆ Warm and dry (well perfused without congestion). One-​year mortality ranged between 13% in patients with decom-
◆ Warm and wet (well perfused but congested). pensated heart failure to 54% in those with CS. This classification is
◆ Cold and dry (hypoperfused without congestion). also clinically helpful as it stresses the need for specific management
◆ Cold and wet (hypoperfused and congested). in each subgroup such as cardiac catheterization in patients with
According to the ESC-​ EURObservational Research Program ACS. However, the above categories are often overlapping; for ex-
(EORP)-​Heart Failure Association (HFA) Heart Failure Long-​Term ample, ACS is the most common cause of CS, may be complicated
Registry, the ‘warm and wet’ category is the most prevalent one, rep- further by acute pulmonary oedema or right heart failure, and may
resenting almost 70% of patients admitted for AHF, followed by ‘cold also be a precipitating factor for decompensated heart failure.
and wet’ in 20%, ‘warm and dry’ in 10%, and ‘cold and dry’ in <1%
[34]. In-​hospital mortality ranged between 2% in ‘warm and dry’ General heart failure classifications relevant
patients to 12% in ‘cold and wet’ ones. This classification has been to acute heart failure
used in the past for patients with advanced heart failure and has been The following general heart failure classifications are also relevant
proposed for treatment guidance by the recent ESC heart failure to patients with AHF.
guidelines [1]‌. Its clinical significance lies in the fact that the initial The single universally accepted classification of patients with
management of patients depends largely on these criteria, with con- symptoms of heart failure is that proposed by the NYHA [36].
gested patients requiring diuretics and/​or vasodilators and those with Patients are classified into four categories, according to their
peripheral hypoperfusion often being in need of inotropic support. functional capacity and severity of symptoms:
An alternative classification is based on the clinical scenario ◆ NYHA class I: no limitation of physical activity. Ordinary phys-
underlying the development of AHF: ical activity does not cause symptoms of heart failure.
◆ Decompensated heart failure. ◆ NYHA class II: slight limitation of physical activity. Comfortable
◆ Pulmonary oedema. at rest, but ordinary physical activity results in symptoms of
heart failure.
◆ NYHA class  III:  marked limitation of physical activity.
Congestion Comfortable at rest, but less-​than-​ordinary activity causes symp-
toms of heart failure.
No Yes ◆ NYHA class  IV:  unable to carry out any physical activity
without symptoms of heart failure, or symptoms of heart
failure at rest.
Another classification [1]‌, also used in chronic heart failure, is
Warm and dry Warm and wet
No

based on LVEF and thus AHF is divided into:

Hypoperfusion

◆ Heart failure with reduced LVEF (HFrEF; LVEF <40%), for-

merly termed systolic heart failure.
◆ Heart failure with mid-​range LVEF (HFmrEF; LVEF 40–​49%).
The new classification of heart failure proposed by the ESC in
the latest guidelines may contribute to better comprehension
Yes

Cold and dry Cold and wet

and conception of this ‘grey area’ between 40% and 50%; it seems
that heart failure patients in this group bear several clinical fea-
tures in between HFrEF and HFpEF [37].
Figure 45.8  Classification of acute heart failure patients according to the ◆ Heart failure with preserved LVEF (HFpEF; LVEF >50%), for-
presence or absence of signs of congestion (‘wet’ and ‘dry’, respectively) and merly termed diastolic heart failure. This group represents
the presence or absence of signs of low cardiac output (‘cold’ and ‘warm’,
respectively). approximately half of AHF cases. As stressed earlier, these
Reproduced from Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/​AHA guideline patients are more likely to be older, female, hypertensive,
for the management of heart failure: a report of the American College of Cardiology and diabetic and to have a non-​ischaemic aetiology of heart
Foundation/​American Heart Association Task Force on Practice Guidelines. J Am Coll
Cardiol 2013;62(16):e147–​e239. doi:10.1016/​j.jacc.2013.05.019 with permission from
failure [18].
Elsevier.
 Pathoph ysi ol o g y 611

The AHA and the American College of Cardiology have pro- low cardiac output, that is, in turn, responsible for the clinical
posed the following classification of heart failure patients ac- manifestation of the AHF syndrome. Several cardiovascular and
cording to LVEF [33, 38]: non-​cardiovascular conditions lead to AHF through a single
◆ HFrEF: LVEF ≤40%. mechanism or a combination of the above four mechanisms.
◆ HFpEF: LVEF ≥50%. For example, the main mechanism causing heart failure during
ACS is myocardial loss, but volume overload or impaired filling
◆ HFpEF, borderline:  LVEF 41–​ 49%; studies have shown that
may also be involved if ACS is complicated with acute MR or
these patients may have intermediate features between HFrEF
and HFpEF but do not differ in outcome from those with tachyarrhythmia, respectively. These conditions or factors may
HFpEF [18]. either provoke a rapid deterioration of cardiac function and
haemodynamics in an individual without a previous history of
◆ HFpEF, improved:  LVEF >40%; patients with formerly re-
heart failure, hence leading to de novo AHF, or disrupt the pre-
duced LVEF who have had a recovery and thus may bear par-
vious steady state condition in a patient with pre-​existing chronic
ticular features, compared to those with persistently reduced
heart failure and cause ADCHF. The most frequent aetiologies
LVEF.
and precipitating factors that may cause AHF are presented in
This classification is also clinically relevant, as the indicated E Table 45.5. Their timely identification and treatment is an im-
long-​term oral medications differ significantly between reduced portant aspect of the management of AHF.
and preserved LVEF; AHF patients with reduced LVEF require
timely onset and proper titration of neurohormonal inhibi- Congestion
tors (RAAS inhibitors and β-​blockers), while those with pre- The hallmark of AHF is congestion, being present in the vast ma-
served LVEF are treated by risk factor control and symptomatic jority of patients [34]. Congestion is either peripheral (character-
therapies. ized by weight gain, peripheral oedema, jugular vein distension,
hepatic enlargement, right upper quadrant pain, hepatojugular
reflux, and ascites) or pulmonary (characterized by dyspnoea of
Pathophysiology varying severity and lung rales). Peripheral congestion usually
coexists with pulmonary congestion, but not always vice versa. The
Main pathogenetic mechanisms two main mechanisms leading to congestion are fluid retention and
Heart failure results from four main pathogenetic mechan- fluid redistribution (see E Figure 45.10). In the case of fluid reten-
isms:  (1) volume overload; (2)  pressure overload; (3)  myocar- tion, cardiac dysfunction activates neurohormonal compensatory
dial cell loss; and (4) impaired ventricular filling (see E Figure mechanisms, leading to an increased release of aldosterone and
45.9). These mechanisms lead to congestion, with or without AVP that causes Na+ and water retention in the kidneys and thus

• Increased salt and water • Uncontrolled

intake hypertension or
• Poor compliance with hypertensive crisis
therapy • Acute pulmonary
• Renal dysfunction embolism
• Acute valvular
regurgitation
• Fever Volume Pressure
• Hyperthyroidism overload overload

(increased (increased
preload) afterload)

Acute heart failure

Myocardial Impaired
loss ventricular
filling
(impaired (reduced
contractility) preload)

• Acute myocardial • Tachycardia

infarction • Pericardial diseases
• Drug toxicity

Figure 45.9  Main pathogenetic mechanisms leading to acute heart failure. Examples of causes or precipitating factors are provided for each mechanism.
612 CHAPTER 45   Ac u te h eart failu re: epidemi ol o g y, cl as si fi cati on , a n d pathophysi ol o g y

Acute heart failure Artery

Capillary

Low cardiac Vein

Vasoconstriction
output

Increased venous Increased Neurohormonal

return afterload activation ‘Cardiac’ failure ‘Vascular’ failure
Mechanism Fluid retention Fluid redistribution
Increased LV Renal sodium and Heart failure type ADCHF De novo
pressures water retention Onset Gradual Rapid
Signs Peripheral and Pulmonary congestion
pulmonary congestion
Fluid Fluid Blood pressure Normal or low Normal or increased
redistribution retention LV ejection fraction Reduced Preserved
Filling pressures Lower* High
Cardiac output Low Higher*
Pulmonary Peripheral Main therapy Diuretics Vasodilators
congestion congestion Mortality rate High Lower*
Rehospitalization rate High High
Figure 45.10  Pathophysiology of congestion. The two main pathogenetic
pathways of fluid redistribution and fluid retention are interrelated (dotted Figure 45.11  Clinical profile and pathophysiology of acute heart failure:
arrows). ‘cardiac’ versus ‘vascular’ failure. * Compared to ‘vascular’ or ‘cardiac’ failure.

peripheral and pulmonary congestion. On the other hand, fluid for the pathophysiology of AHF—​a central one termed ‘cardiac
redistribution results from peripheral vasoconstriction; venous failure’ and a peripheral one termed ‘vascular failure’ (see E
constriction causes an abrupt increase in venous return, and Figure 45.11) [39]. In the case of ‘cardiac failure’, AHF is caused by
thus preload, while arterial constriction increases afterload, both a deterioration of cardiac function per se, a mechanism that pre-
leading, in turn, to increased LV pressure and increased backward dominates in ADCHF patients with impaired LVEF and normal or
pressure in pulmonary capillaries, and thus pulmonary congestion. low arterial pressure; the main pathogenetic mechanism causing
congestion is fluid retention. In the case of ‘vascular failure’, in
Low cardiac output contrast, vasoconstriction leading to fluid redistribution is the
main cause of congestion, a mechanism seen, for example, in
In contrast, a marked reduction in cardiac output, leading to
acute pulmonary oedema and hypertensive peaks. These latter
symptoms and signs of peripheral hypoperfusion, seems to be the
patients have frequently preserved LVEF and normal or increased
case in 10% or less of AHF patients [34]. Low cardiac output leads
arterial pressure. This consideration of AHF pathophysiology is
to hypotension, narrow pulse pressure, cold and wet extremities
actually clinically relevant, as ‘cardiac failure’ requires treatment
due to sympathetic nervous system activation, renal dysfunction
mainly with diuretics and, in cases with concurrent peripheral
with oliguria (urine output <0.5 mL/​kg/​hour), mental disorders
hypoperfusion, inotropes, while ‘vascular failure’ requires pri-
with confusion and dizziness, impaired tissue oxygenation and
marily vasodilators. It should be kept in mind, however, that AHF
metabolism with metabolic acidosis, and elevated serum lactate
is a complex syndrome and the above two mechanisms coexist,
(>2  mmol/​L). These manifestations, when persistent, constitute
each one with different magnitude, in most patients.
the syndrome of CS that represents 3% or less of patients pre-
Two important mechanisms contributing to the pathophysi-
senting with AHF in the ESC Heart Failure Long-​Term Registry
ology of AHF are myocardial injury and renal dysfunction. They
[35]. It should be stressed, however, that the above symptoms and
may often be the cause or a precipitating factor for AHF, but
signs of peripheral hypoperfusion may also result from low intra-
they also constitute consequences of AHF that contribute to fur-
vascular volume (hypovolaemia), as in the case of significant fluid
ther deterioration of the syndrome. Other comorbid conditions,
loss or excessive diuresis, and not primarily from cardiac dysfunc-
such as anaemia and iron deficiency, play an important role in
tion, as in the case of CS. This is an important fact that should be
the pathophysiology and outcome of patients with chronic heart
recognized early for the proper management of patients. It should
failure, but their role in AHF has not yet been clarified.
also be kept in mind that the lack of hypotension does not pre-
clude the presence of peripheral hypoperfusion, as sympathetic
activation may lead to potent peripheral vasoconstriction, and
Myocardial injury
thus preservation of blood pressure for some period of time. ACS are a frequent cause of AHF. At the same time, AHF itself is
followed by myocardial ischaemia that leads to myocardial injury.
‘Cardiac’ versus ‘vascular’ failure Indeed, cTn elevation, a surrogate of myocardial injury, is an in-
dependent predictor of short-​and long-​term outcomes in AHF.
Taking under consideration the two aforementioned mechanisms
According to data on nearly 85 000 AHF patients from the Acute
causing congestion, two different profiles have been proposed
Decompensated HEart Failure National REgistry (ADHERE)
 Pathoph ysi ol o g y 613

registry, 6% of patients had a positive troponin test and those pa- Renal dysfunction
tients had a 2.6 times higher risk of in-​hospital mortality [40]. On the
A frequent and important component of AHF pathophysiology is
other hand, in RELAX-​AHF (Relaxin in Acute Heart Failure) trial,
renal dysfunction. Renal dysfunction is a prevalent abnormality in
in which the new-​generation hsTn assays were used, troponin levels
AHF. In the ADHERE registry, among 118 465 AHF patients, only
were higher than the URL in 93% of patients and were independently
9% had normal renal function on admission (GFR ≥90 mL/​min/​
associated with 180-​day mortality, while a further increase of ≥20%
1.73 m2); 71% had mild to moderate renal dysfunction (GFR 30–​
during the first 2 days nearly doubled the risk of death [41].
89 mL/​min/​1.73 m2), and 20% had severe dysfunction (GFR <30
In the context of AHF, ischaemia is caused by both a decrease in
mL/​min/​1.73 m2) [43]. The close interdependence of the heart and
myocardial O2 supply and an increase in myocardial O2 demand.
kidneys may lead to a vicious circle, in which heart failure causes
O2 supply may be impaired due to: (1) low diastolic arterial pressure
renal dysfunction that, in turn, promotes additional deterioration
and high LV diastolic pressure, the combination of which leads to a
of cardiac function that aggravates further renal impairment and
decrease in the coronary driving pressure, and thus impaired cor-
so on. The term ‘cardiorenal syndrome’ has been introduced to ex-
onary perfusion; (2) tachycardia that restricts the diastolic period,
press this complex bidirectional relationship [44]. The main mech-
and thus coronary perfusion time; and (3)  potentially coexisting
anisms linking cardiac with renal dysfunction are outlined in E
CAD. O2 demand, on the other hand, is increased because of high
Figure 45.12. In brief, heart failure affects renal function by three
LV wall stress, tachycardia, and use of inotropes [42].

Heart failure

Drug therapy

High central venous pressure Low cardiac output

(backward failure) (forward failure)

RAS inhibitors Diuretics

High intra-abdominal pressure Dilatation of

efferent arteriole

Low urine output Low pressure

High pressure on
Bowman’s capsule in afferent arteriole

Neurohormonal activation Risk factors

Inflammation
Ageing
Anaemia
Diabetes
Cell death
Hypertension
Fibrosis/remodelling Renal dysfunction

Figure 45.12  Pathogenetic interactions between cardiac and renal function in acutely decompensated heart failure.
Reproduced from Heywood JT, Fonarow GC, Costanzo MR, et al. High prevalence of renal dysfunction and its impact on outcome in 118,465 patients hospitalized with acute
decompensated heart failure: a report from the ADHERE database. J Card Fail 2007;13(6):422–​430. doi:10.1016/​j.cardfail.2007.03.011 with permission from Elsevier.
614 CHAPTER 45   Ac u te h eart failu re: epidemi ol o g y, cl as si fi cati on , a n d pathophysi ol o g y

main mechanisms [45]:  (1) low cardiac output (forward failure)

that leads to low perfusion pressure in the afferent arteriole of the Conclusion
glomerulus; (2)  high CVP (backward failure) that increases the
AHF represents the most common cause of hospital admission in
intra-​abdominal pressure, and thus the pressure on the Bowman’s
the elderly and the main contributor to the huge health care cost
capsule; and (3) drug therapy, mainly diuretics, that reduce intra-
of heart failure. Despite recent therapeutic advances, the prog-
vascular volume and thus cause a further decrease in glomerulus
nosis of the syndrome remains ominous, with 4–​7% of patients
perfusion pressure, and RAAS inhibitors that cause dilatation of
dying during index hospitalization and one-​third of them dying
the efferent arteriole. The combination of the above three mech-
or being readmitted to hospital within the following few months.
anisms leads to low filtration pressure in the glomerulus, and thus
The clinical profile of patients upon presentation is heterogenous
low urine output. At the same time, there are several additional fac-
and constitutes a significant determinant of in-​ hospital and
tors with an increased prevalence in heart failure that affect both
post-​discharge outcome. The pathophysiology of AHF is com-
cardiac and renal function such as neurohormonal and inflamma-
plex and involves several mechanisms provoked by cardiac or
tory activation, anaemia, necrosis, apoptosis, and fibrosis. Finally, a
extracardiac causes or precipitating factors leading to congestion
number of risk factors that are common to heart and renal failure
and other conditions contributing to the further progression of
are frequently present in heart failure patients such as diabetes mel-
the syndrome.
litus, hypertension, and ageing.

Further reading
Filippatos G, Zannad F. An introduction to acute heart failure diagnosis and treatment of acute and chronic heart failure of the
syndromes: definition and classification. Heart Fail Rev 2007;12:87–​90. European Society of Cardiology (ESC). Developed with the special
Gheorghiade M, Follath F, Ponikowski P, et  al.; European Society of contribution of the Heart Failure Association (HFA) of the ESC. Eur J
Cardiology, European Society of Intensive Care Medicine. Assessing Heart Fail 2016;18:891–​975.
and grading congestion in acute heart failure:  a scientific statement Yancy CW, Jessup M, Bozkurt B, et  al. 2013 ACCF/​AHA guideline
from the acute heart failure committee of the heart failure association for the management of heart failure:  executive summary:  a report
of the European Society of Cardiology and endorsed by the European of the American College of Cardiology Foundation/​ American
Society of Intensive Care Medicine. Eur J Heart Fail 2010;12:423–​33. Heart Association Task Force on practice guidelines. Circulation
Metra M, Ravera A, Filippatos G. Understanding worsening heart 2013;128:1810–​52.
failure as a therapeutic target: another step forward? Eur J Heart Fail Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/​AHA/​HFSA Focused
2017;19:996–​1000. Update of the 2013 ACCF/​AHA guideline for the management of heart
Ponikowski P, Voors AA, Anker SD, et al.; Authors/​Task Force Members, failure:  a report of the American College of Cardiology/​American
Document Reviewers. 2016 ESC Guidelines for the diagnosis and Heart Association Task Force on Clinical Practice Guidelines and the
treatment of acute and chronic heart failure:  The Task Force for the Heart Failure Society of America. J Card Fail 2017;23:628–​51

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 CHAPTER 46

Acute heart failure: early

pharmacological therapy
Kieran F Docherty, Jonathan R Dalzell,
Mark C Petrie, and John JV McMurray

Contents
Summary  617
Summary
Introduction  617 Acute heart failure syndromes consist of a spectrum of clinical presentations due
Immediate aims  618 to impairment of some aspect of cardiac function. They represent a final common
Further aims  618
Non-​shocked, congested, and well-​perfused
pathway for a vast array of pathologies and may be either a de novo presenta-
patients (‘wet and warm’)  618 tion or, more commonly, a decompensation of pre-​existing chronic heart failure.
Oxygen  618 Despite being one of the most common medical presentations, there are no defini-
Opiates  618 tively proven prognosis-​modifying treatments. The mainstay of current therapy is
Diuretics and aquaretics  619
Intravenous diuretics  619 oxygen and intravenous diuretics. However, within this spectrum of presentations,
Vasopressin receptor antagonists  622 there is a crucial dichotomy which governs the ultimate treatment approach, i.e.
Vasodilators  622
Nitroglycerin (glyceryl trinitrate)  622
the presence or absence of cardiogenic shock. Patients without cardiogenic shock
Sodium nitroprusside  623 may receive vasodilators, whereas shocked patients should be considered for treat-
Nesiritide  623 ment with inotropic therapy and/​or mechanical circulatory support when appro-
Ularitide  623
Seralaxin  623 priate and where available.
Cardiogenic shock  624
Inotropic therapy  624
Sympathomimetics  624
Dobutamine  624
Dopamine  625
Adrenaline (epinephrine)  625
Noradrenaline (norepinephrine)  625 Introduction
Dopexamine  625
Phosphodiesterase inhibitors  625 AHF is a common end-​result of a spectrum of acute and chronic cardiovascular path-
Milrinone  626
Enoximone  626
ologies that impair cardiac function. Its definition continues to evolve with the recent
Calcium sensitizers  626 ESC guidelines defining it as ‘the rapid onset of, or change in, symptoms and signs of
Levosimendan  626 heart failure’ [1]‌. This definition encompasses all presentations, from patients presenting
General considerations in patients with with mild ankle swelling and breathlessness to those in fulminant CS. Haemodynamic
acute heart failure  626
Pre-​existing pharmacotherapy  626
parameters (especially blood pressure and peripheral perfusion), ventricular function,
Thromboprophylaxis  627 respiratory function, end-​organ perfusion and function, and underlying precipitants can
Predischarge  627 vary widely across this spectrum of presentations, and treatment needs to be tailored
Emerging pharmacological therapies for to the individual patient. Although ‘acute heart failure’ has often been thought as syn-
acute heart failure  627
Omecamtiv mecarbil  627
onymous with acute pulmonary oedema and unplanned admission to hospital for heart
Sodium–​glucose cotransporter 2 failure, there is increasing evidence that many patients admitted to hospital have neither
inhibitors  627 experienced acute onset of symptoms/​signs of heart failure nor had pulmonary oedema.
Acetazolamide  628
Conclusion  628
Instead, patients have often experienced new-​onset or worsening symptoms/​signs for
days or weeks prior to hospital admission and more may present with peripheral oedema
Appendix: the evidence base  628
as the predominant manifestation, rather than breathlessness due to pulmonary conges-
Further reading  630
tion/​oedema.
References  630
618 CHAPTER 46   Ac u te h eart failu re:  early pha r m ac ol o g i ca l  ther a p y

The epidemiology of AHF is less well defined than that of ◆ To reduce inpatient mortality.
chronic heart failure but is becoming better understood following ◆ To reduce length of stay.
the publication of data from large contemporary registries,
including ADHERE, OPTIMIZE-​HF, the EuroHeart Surveys on Further aims
Heart Failure, the ESC-​HF Pilot Registry, and the ALARM-​HF
◆ To identify patients who may benefit from further non-​
registry [2–​8]. In the developed world, the majority of AHF is
pharmacological therapy in the short term (e.g. invasive venti-
due to CAD or its sequelae (i.e. myocardial ischaemia, MI, and
lation, ultrafiltration, PCI, MCS) and medium term (e.g. CRT,
consequent LV systolic dysfunction). The majority of patients
transplantation).
with AHF are normotensive or hypertensive [4]‌. In the UK, pa-
tients are usually over 70 years of age and most have a history of ◆ To optimize oral therapy for chronic heart failure [i.e. initiate,
add, or uptitrate one or more of ACE-​Is, ARBs, or angiotensin
chronic heart failure [9]. There is a 50–​50 split between the sexes,
receptor–​neprilysin inhibitors (ARNIs), β-​blockers, and MRAs]
but women are older at presentation and are more likely to have
once stable and prior to discharge.
preserved LVEF. In-​hospital mortality is reported to be between
4% and 11% but is much higher in patients with AHF secondary ◆ To improve medium-​to long-​term clinical outcomes (including
to AMI and higher still in the presence of CS (whether or not due rehospitalization, mortality, and quality of life).
to AMI) [7, 9–​11]. Predictors of a poor outcome are increasing Close monitoring of blood pressure, fluid balance, and urine
age, male sex, low SBP, and renal dysfunction [11]. Mortality fol- output is essential during the management of AHF. Regular blood
lowing discharge from hospital is high, with 1-​year estimates of sampling and monitoring measures of renal function (BUN, cre-
20–​36%, with little improvement over the last decade [4, 9]. atinine, and eGFR) and electrolytes (especially K+), in particular,
The symptoms of AHF are predominantly driven by low car- is required in the decompensated state. E Figure 46.2 describes
diac output and congestion, resulting in dyspnoea, peripheral oe- a crude and simplistic, but nonetheless useful, approach to clas-
dema, or poor tissue and organ perfusion, or some combination sifying patient subtypes. This approach identifies four haemo-
of these. The mechanism underpinning the development of pul- dynamic categories that the patient may present with: warm and
monary oedema is increased intravascular pulmonary pressures dry, warm and wet, cold and dry, and cold and wet. Patients pre-
with transudation of protein-​depleted plasma down a pressure senting wet and warm or wet and cold are at the highest risk of
gradient into the pulmonary interstitium and alveoli in severe death or, in selected cases, need to be assessed for urgent cardiac
cases. This can result in significant impairment of gas exchange transplantation or MCS.
and respiratory failure. In patients with pre-​existing chronic heart Within this spectrum of presentations exists a crucial di-
failure, this is compounded by systemic hyperactivation of the chotomy which governs the ultimate treatment approach—​the
sympathetic and RAAS systems which promote renal retention of presence or absence of CS (see E Tables 46.1 and 46.2). CS is
Na+ and water, as well as vasoconstriction. defined as hypotension and inadequate organ perfusion due to
To date, no pharmacological intervention has been shown to cardiac dysfunction. Alternative pharmacological therapies util-
improve survival in patients with AHF. This may be due to mul- ized in patients with CS are discussed later in this chapter.
tiple factors. One may be the heterogeneity of patients with AHF.
They comprise a diverse range of aetiologies, comorbidities, and
severities at presentation. It has been postulated that the time from Non-​shocked, congested, and
presentation to randomization may have been too long in earlier
studies, thereby diminishing any potential benefit. It may also have well-​perfused patients
been unrealistic to expect that short-​term infusions would impact (‘wet and warm’)
medium-​to long-​term clinical outcomes. Also, the sickest patients,
who may have the most to gain, are often too unwell to give fully Oxygen
informed consent and therefore are excluded from such trials. Supplemental O2 may be needed to treat hypoxaemia due to pul-
The overall aims of pharmacological interventions (see E monary congestion and/​or oedema, although there is no trial
Figure 46.1 and E Tables 46.1 and 46.2) in managing AHF are evidence base to support this approach. O2 should not be used
described below. routinely in patients who are not hypoxic, as this causes vaso-
constriction and a reduction in cardiac output, effects which are
Immediate aims likely to be detrimental in AHF [12].
◆ To relieve symptoms.
Opiates
◆ To optimize fluid volume status.
IV morphine (2.5–​10 mg IV bolus) can provide prompt symp-
◆ To restore respiratory function, gas exchange, and systemic
oxygenation. tomatic improvement due to several pharmacological properties.
First, opiates have a mild anxiolytic effect and reduce distress as-
◆ To improve haemodynamics and end-​organ function.
sociated with symptoms. They also have a mild venodilator ef-
◆ To address any underlying cause or precipitant (e.g. myocardial
fect, which can help reduce congestion and preload. However,
ischaemia, arrhythmias, infection, anaemia, iatrogenic, etc.).
 Non-sh o cked, c on g ested, a n d w el l - perfu sed pati en ts ( ‘ w et a n d   wa r m ’ ) 619

Patient with acute heart failure

Bedside assessment to identify haemodynamic profiles

Presence of congestion?

Yes No
(95% of all AHF patients) (5% of all AHF patients)

‘Wet’ patient ‘Dry’ patient

Adequate peripheral perfusion?

Yes No Yes No

‘Dry and warm’ ‘Dry and cold’

Adequately perfused Hypoperfused,
≈ compensated hypovolaemic
‘Wet and warm’ patient
(typically elevated Adjust oral Consider fluid challenge
normal systolic therapy Consider inotropic agent
blood pressure) if still hypoperfused

‘Wet and cold’ patient

Systolic blood pressure <90 mmHg

Vascular type – Cardiac type –
fluid redistribution fluid accumulation Yes No
Hypertension Congestion
predominates predominates • Inotropic agent • Vasodilators
• Consider vasopressor • Diuretics
in refractory cases • Consider inotropic
• Diuretic (when perfusion agent in refractory
• Vasodilator • Diuretic
corrected) cases
• Diuretic • Vasodilator
• Consider mechanical
• Ultrafiltration
circulatory support
(consider if diuretic
if no response to drugs
resistance)

Figure 46.1  Algorithm for management of acute heart failure based on clinical profile.
a
Symptoms/​signs of congestion: orthopnoea, paroxysmal nocturnal dyspnoea, breathlessness, bi-​basilar rales, abnormal blood pressure response to the Valsalva
manoeuvre (left-​sided); symptoms of gut congestion, jugular venous distension, hepatojugular reflux, hepatomegaly, ascites, and peripheral oedema (right-​sided).
Reproduced from Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis
and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the
ESC [published correction appears in Eur Heart J 2016 Dec 30]. Eur Heart J 2016;37(27):2129–​2200. doi:10.1093/​eurheartj/​ehw128 with permission from Oxford University Press.

opiates frequently induce nausea and require co-​prescription of Diuretics and aquaretics

antiemetic drugs, some of which have undesirable actions, e.g.
(See E Figure 46.3.)
vasoconstriction [13]. A  further unwanted side effect of opiate
therapy is potential depression of the respiratory drive which may Intravenous diuretics
precipitate the requirement for invasive ventilation. There is no These are the first-​line therapy in patients with AHF and con-
evidence base to support the use of opiates and there are some gestion. No randomized, placebo-​controlled data exist for these
non-​randomized, observational data suggesting that opiate use is agents, but extensive observational experience of rapid im-
associated with adverse outcomes [14]. provement in symptoms has led to these agents being endorsed
620 CHAPTER 46   Ac u te h eart failu re:  early pha r m ac ol o g i ca l  ther a p y

Table 46.1  ESC Guideline recommendations for the pharmacological treatment of acute heart failure

Recommendations Classa Levelb

Diuretics
IV loop diuretics are recommended for all patients with AHF admitted with signs/​symptoms of fluid overload to improve symptoms. It I C
is recommended to regularly monitor symptoms, urine output, renal function, and electrolytes during use of IV diuretics
In patients with new-​onset AHF or those with chronic decompensated heart failure not receiving oral diuretics, the initial I B
recommended dose should be 20–​40 mg IV furosemide (or equivalent); for those on chronic diuretic therapy, the initial IV dose
should be at least equivalent to the oral dose
It is recommended to give diuretics either as intermittent boluses or as a continuous infusion, and the dose and duration should be I B
adjusted according to the patient’s symptoms and clinical status
A combination of loop diuretic with either a thiazide-​type diuretic or spironolactone may be considered in patients with resistant IIb C
oedema or insufficient symptomatic response
Vasodilators
IV vasodilators should be considered for symptomatic relief in AHF with SBP >90 mmHg (and without symptomatic hypotension) IIa B
Symptoms and blood pressure should be monitored frequently during administration of IV vasodilators
In patients with hypertensive AHF, IV vasodilators should be considered as initial therapy to improve symptoms and reduce congestion IIa B
Inotropic agents—​dobutamine, dopamine, levosimendan, phosphodiesterase III (PDE III) inhibitors
Short-​term IV infusion of inotropic agents may be considered in patients with hypotension (SBP <90 mmHg) and/​or signs/​symptoms IIb C
of hypoperfusion despite adequate filling status, to increase cardiac output, increase blood pressure, improve peripheral perfusion, and
maintain end-​organ function
An IV infusion of levosimendan or a PDE III inhibitor may be considered to reverse the effect of β-​blockade if β-​blockade is thought to IIb C
be contributing to hypotension with subsequent hypoperfusion
Inotropic agents are not recommended unless the patient is symptomatically hypotensive or hypoperfused because of safety concern III A
Vasopressors
A vasopressor (noradrenaline preferably) may be considered in patients who have CS, despite treatment with another inotrope, to IIb B
increase blood pressure and vital organ perfusion
It is recommended to monitor ECG and blood pressure when using inotropic agents and vasopressors, as they can cause arrhythmia, I C
myocardial ischaemia, and, in the case of levosimendan and PDE III inhibitors, also hypotension
In such cases, intra-​arterial blood pressure measurement may be considered IIb C
Thromboembolism prophylaxis
Thromboembolism prophylaxis (e.g. with LMWH) is recommended in patients not already anticoagulated and with no I B
contraindication to anticoagulation, to reduce the risk of DVT and PE
Other drugs
For acute control of the ventricular rate in patients with AF:
1. Digoxin and/​or β-​blockers should be considered as the first-​line therapy IIa C
2. Amiodarone may be considered IIb B
Opiates may be considered for cautious use to relieve dyspnoea and anxiety in patients with severe dyspnoea, but nausea and IIb B
hypopnoea may occur
a
Class of recommendation.
b
Level of evidence.
Reproduced from Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis
and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the
ESC [published correction appears in Eur Heart J 2016 Dec 30]. Eur Heart J 2016;37(27):2129–​2200. doi:10.1093/​eurheartj/​ehw128 with permission from Oxford University Press.

by all major international guidelines [1, 15]. Generally, IV loop to achieve the most efficient diuresis. A small randomized trial—​
diuretics (e.g. furosemide or bumetanide) are used as first-​line the Diuretic Optimization Strategies Evaluation (DOSE) trial—​
therapy (see E Table 46.1) and recommended to be initiated at used patient global symptom assessment, as opposed to objective
the earliest opportunity. Furosemide also has a venodilator action measures of fluid loss, as a primary endpoint and reported that
which can result in a reduction of ventricular filling pressures and continuous infusion of furosemide is no more effective than IV
marked symptomatic improvement prior to the onset of an aug- boluses [18]. Despite this, the American College of Cardiology/​
mented diuresis [16, 17]. The peak diuretic effect is typically seen AHA guidelines recommend switching between diuretic strat-
between 1 and 2 hours, following IV administration, which sub- egies in resistant patients [15]. A  recent meta-​analysis of ten
sides by 6 hours. Multiple daily doses may therefore be necessary trials did not demonstrate any significant difference in safety or
 Non-sh o cked, c on g ested, a n d w el l - perfu sed pati en ts ( ‘ w et a n d   wa r m ’ ) 621

Table 46.2  ESC Guideline recommendations for the management of patients with cardiogenic shock

Recommendations Classa Levelb

In all patients with suspected CS, immediate ECG and echocardiography are recommended I C
All patients with CS should be rapidly transferred to a tertiary care centre which has a 24/​7 service of cardiac catheterization and a I C
dedicated ICU/​CCU with availability of short-​term MCS
Continous ECG and blood pressure monitoring are recommended I C
Invasive monitoring with an arterial line is recommended I C
Fluid challenge (saline or Ringer’s lactate, >200 mL/​15–​30 minutes) is recommended as the first-​line treatment if there is no sign of I C
overt fluid overload
IV inotropic agents (dobutamine) may be considered to increase cardiac output IIb C
Vasopressors (noradrenaline preferable over dopamine) may be considered if there is a need to maintain SBP in the presence of IIb B
persistent hypoperfusion
IABP is not routinely recommended in CS III B
Short-​term MCS may be considered in refractory CS, depending on patient age, comorbidities, and neurological function IIb C
CCU, coronary care unit; CS, cardiogenic shock; ECG, electrocardiogram; IABP, intra-​aortic balloon pump; ICU, intensive care unit; MCS, mechanical circulatory support; SBP, systolic
blood pressure.
a
Class of recommendation.
b
Level of evidence.
Reproduced from Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis
and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the
ESC [published correction appears in Eur Heart J 2016 Dec 30]. Eur Heart J 2016;37(27):2129–​2200. doi:10.1093/​eurheartj/​ehw128 with permission from Oxford University Press.

Congestion (–) Congestion (+)

Pulmonary congestion
Orthopnoea/paroxysmal nocturnal dyspnoea
Peripheral (bilateral) oedema
Jugular venous dilatation
Congested hepatomegaly
Gut congestion, ascites
Hepatojugular reflux

Hypoperfusion (–)

Warm-dry Warm-wet

Hypoperfusion (+)
Cold sweated extremities
Oliguria
Mental confusion
Dizziness
Narrow pulse pressure Cold-dry Cold-wet

Figure 46.2  Clinical profiles of patients with acute heart failure based on clinical assessment and haemodynamic profile. Hypoperfusion is not synonymous
with hypotension, but often it is accompanied by hypotension.
Reproduced from Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis
and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the
ESC [published correction appears in Eur Heart J 2016 Dec 30]. Eur Heart J 2016;37(27):2129–​2200. doi:10.1093/​eurheartj/​ehw128 with permission from Oxford University Press.
622 CHAPTER 46   Ac u te h eart failu re:  early pha r m ac ol o g i ca l  ther a p y

Efferent Glomerulus Distal tubule and renal dysfunction did not improve either diuresis or renal
arteriole
Thiazide diuretics function, compared to diuretic therapy alone [23]. Interestingly,
there was a trend towards both of these agents having a positive
Afferent effect in the subgroup of patients with reduced LVEF. A small
arteriole Potassium-sparing
diuretics RCT in patients hospitalized with ADHF with HFpEF reported
a neutral effect of low-​dose dopamine on renal function in
Proximal this group of patients [24]. These findings serve to highlight
tubule
the marked heterogeneity of the contemporary AHF popula-
tion and potentially question whether the efficacy of targeted
Carbonic anhydrase Collecting tubule
inhibitors pharmacotherapy can be accurately delineated in such a diverse
SGLT2 inhibitors Loop diuretics
population. The findings from the ROSE-​AHF trial should
prompt a similar study in AHF patients with reduced LVEF.
Close monitoring of blood pressure, fluid balance, renal func-
Ascending loop
Descending of Henle tion, and plasma electrolytes is strongly recommended in pa-
loop of Henle
tients receiving IV diuretics [1, 15].
V2 antagonists

Vasopressin receptor antagonists
Vasopressin (previously known as antidiuretic hormone) concen-
trations are sometimes inappropriately elevated in heart failure
Figure 46.3  The site of action of diuretics and aquaretics on the nephron. and may contribute to volume overload. A  large multicentre
Reproduced from Gardner, McDonagh, and Walker, Oxford Specialist Handbook in Heart
randomized, placebo-​ controlled trial of tolvaptan, a selective
Failure, 2007, with permission from Oxford University Press.
vasopressin-​2 (V2) receptor antagonist which promotes aquaresis,
in addition to standard therapy in AHF patients, failed to dem-
efficacy between boluses and continuous diuretic infusions in onstrate any mortality benefit [25]. Improvements were noted in
patients with ADHF [19]. In the DOSE trial, the use of a high-​ the secondary endpoints of day 1 patient-​reported dyspnoea, day
dose strategy (2.5 times the patient’s oral dose), compared to a 1 body weight, and day 7 oedema, and there were no short-​to
low-​dose strategy (equivalent to the patient’s oral dose), resulted medium-​term adverse outcomes. Although not approved to treat
in a non-​significant trend towards a greater improvement in pa- heart failure in Europe, the ESC Heart Failure 2016 Guidelines
tient global assessment of symptoms [18]. Patients randomized say ‘Tolvaptan may be used to treat patients with volume overload
to a high-​dose strategy had greater diuresis, weight loss, and re- and resistant hyponatraemia (thirst and dehydration are recog-
lief from dyspnoea, compared to a low-​dose strategy. Short-​term nized adverse effects)’ [1]‌.
deterioration in renal function was more frequently observed in
those receiving a high-​dose strategy. Both ESC and American Vasodilators
College of Cardiology/​AHA guidelines recommend the use of an
In general, vasodilator treatment is recommended for patients
IV dose of diuretics at least equal to the pre-​existing oral dose
with pulmonary congestion who are normo-​or hypertensive.
in those already receiving oral diuretics, and 20–​40 mg IV fur-
These agents should be avoided in patients with concurrent ob-
osemide (or equivalent) in those who are not on regular oral di-
structive valvular disease or restrictive physiology.
uretics [1, 15].
In patients with resistant oedema, dual treatment with a
loop diuretic and a thiazide (e.g. bendroflumethiazide 5–​10 Nitroglycerin (glyceryl trinitrate)
mg) or a thiazide-​like diuretic (e.g. metolazone 2.5–​5 mg) Nitroglycerin is predominantly a venodilator which reduces ven-
may be needed to achieve adequate diuresis (so-​called ‘se- tricular filling pressures and helps to relieve pulmonary conges-
quential nephron blockade’) [20, 21]. The American College of tion [26, 27]. At higher doses, it also exhibits arterial dilatation and
Cardiology/​AHA guidelines stand alone in stipulating a level is frequently used as an effective anti-​ischaemic therapy, which
of recommendation (Class IIb, LoE B) for the consideration of makes it attractive in patients with AHF and concomitant myo-
a low-​dose dopamine infusion in order to potentiate diuresis in cardial ischaemia. There are no robust data to suggest a significant
certain resistant patients [15]. One relatively small trial dem- improvement in either symptoms or mortality, as confirmed by
onstrated that the addition of dopamine to a diuretic regime a Cochrane systematic review [28]. It can have a marked hypo-
is as efficacious as increasing the diuretics alone but may have tensive effect, especially when preload is also lowered by concur-
a more favourable effect on renal function and plasma K+ con- rent therapy such as diuretics, so blood pressure monitoring is
centrations [22]. However, the much larger Renal Optimization essential. Exposure to nitrates results in the rapid development
Strategies Evaluation in Acute Heart Failure (ROSE-​AHF) trial of tolerance (particularly when given IV in high doses), limiting
suggested that the addition of dopamine or nesiritide (see E their effectiveness to 16–​24 hours. Other adverse effects include
Nesiritide, p. 623) to a diuretic regimen in patients with AHF resistance, headache, and abdominal bloating.
 Non-sh o cked, c on g ested, a n d w el l - perfu sed pati en ts ( ‘ w et a n d   wa r m ’ ) 623

Sodium nitroprusside Early work demonstrated the efficacy of nesiritide in reducing

ventricular filling pressures with variable effects on cardiac output
Sodium nitroprusside (SNP) is a potent vasodilator that acts
[31]. In the largest international randomized, placebo-​controlled
directly on vascular smooth muscle. It is not as widely used as
trial to date in patients with AHF, nesiritide had no effect on the
nitroglycerin and has equal effects on arterial and venous tone,
composite endpoint of rehospitalization for heart failure or death
including pulmonary circulation. As with nitroglycerin, SNP can
within 30 days [32]. There was a trend towards an improvement
improve the haemodynamic profile, but there are no robust data
in dyspnoea that did not reach the pre-​specified level of statistical
indicating a symptomatic or prognostic benefit from this therapy
significance. No impact was noted on renal function, but hypoten-
[29]. Indeed, there are some data suggesting that SNP may have a
sion was more common in patients receiving nesiritide therapy.
detrimental effect in patients following MI, an effect which may
Nesiritide is currently available in North America, but only in a
be due to coronary ‘steal’ [30]. It is administered by IV infusion
few European countries. The synthetic human ANP caperitide is
at 0.3–​5 micrograms/​kg/​min, uptitrating carefully with invasive
used in Japan to treat AHF, although it has never been evaluated
arterial monitoring. Likewise, SNP should also be downtitrated
in a large randomized, placebo-​controlled trial.
slowly to avoid rebound hypertension. SNP is rapidly metabol-
ized and excreted entirely as metabolites, principally thiocyanate.
Ularitide
The elimination half-​life of thiocyanate is 2.7–​7 days when renal
function is normal. Adverse effects include hypotension and, Ularitide is a synthetic analogue of the endogenous vasodilatory and
rarely, metabolite (i.e. cyanide or thiocyanate) toxicity, which is natriuretic peptide urodilatin. Urodilatin has an identical amino
more commonly seen with concomitant hepatic or renal dysfunc- acid sequence to ANP but has an additional four amino acid res-
tion. Plasma cyanide and thiocyanate levels should be monitored idues at the amino terminus, rendering it more resistant to degrad-
in such patients or those receiving a prolonged infusion (see E ation by neutral endopeptidase (neprilysin) than ANP. Following
Table 46.3). expression on the distal tubular cells, it is secreted luminally, and
downstream it binds to the natriuretic peptide receptor NPR-​A in
Nesiritide the collecting duct, resulting in cGMP activation and consequent
natriuresis. Phase I/​II trials in AHF showed that ularitide therapy
Nesiritide is a recombinantly produced synthetic analogue of
was associated with beneficial haemodynamic effects (reductions
human BNP. Endogenous BNP binds to the guanylyl cyclase re-
in PCWP, reduced SVR, and increased cardiac index), along with
ceptor of vascular smooth muscle and endothelial cells, leading
improvements in patient-​reported dyspnoea [33, 34]. A large inter-
to increased intracellular concentrations of cGMP and smooth
national phase III trial of ularitide versus placebo in 2157 patients
muscle cell relaxation. Thus, nesiritide causes dose-​dependent re-
with AHF and preserved blood pressure—​the TRial of Ularitide’s
ductions in PCWP and systemic arterial pressure by venous and
Efficacy and safety in patients with Acute Heart Failure (TRUE-​
arterial dilatation. Nesiritide has a half-​life of approximately 18
AHF)—​reported that treatment with ularitide did not reduce the
minutes and is administered via an IV infusion at a rate of 0.01–​
risk of death from cardiovascular causes, compared with placebo,
0.03 micrograms/​kg/​min.
or have any effect on a hierarchical clinical composite endpoint
[35]. Patients treated with ularitide had significantly greater reduc-
tions in NT-​proBNP levels. However, no difference in cTn levels
Table 46.3  Therapies as recommended by the major guidelines were observed between the two treatment groups.
ESC American College of
Cardiology/​AHA Seralaxin
Supplemental O2 IC –​ Relaxin is a 53-​amino acid endogenous peptide hormone which
is a member of the insulin-​like growth receptor family. It has an
Opiates IIb B –​
established role in pregnancy and parturition, and more recently,
IV diuretics IB IB
a putative role in cardiovascular regulation and pathophysiology
Vasopressin receptor antagonists –​ IIb B has been identified [36, 37]. In humans, relaxin produces dose-​
Nitroglycerin IIa B IIb A dependent vasodilatation in ex vivo peripheral resistance arteries,
SNP IIb B IIb A but not pulmonary arteries. In vivo, it increases renal blood flow
Nesiritide –​ IIb A
and has a modest natriuretic effect in healthy humans. A  small
randomized, placebo-​controlled trial of serelaxin (recombinant
Inotropes in CS IIb C IC
relaxin-​2), in addition to standard therapy, in patients with AHF
Thromboprophylaxis IB IB revealed a significant improvement in one of the co-​primary
AHA, American Heart Association; CS, cardiogenic shock; ESC, European Society of measures of dyspnoea and the safety endpoint of 180-​day mor-
Cardiology; IV, intravenous; O2, oxygen; SNP, sodium nitroprusside. tality in patients receiving serelaxin [38]. However, in the ad-
Level of recommendation: I, is recommended/​is indicated; IIa, should be considered; IIb,
may be considered; III, is not recommended. equately powered RELAX-​AHF-​2 RCT, treatment with seralaxin
Level of evidence: A, multiple randomized trials or meta-​analyses; B, single randomized did not reduce either of the co-​primary endpoints of 180-​day car-
trial or large non-​randomized trial, meta-​analysis; C, consensus expert opinion and/​or diovascular death or worsening heart failure through day 5 [39].
small studies, retrospective studies, or registries.
624 CHAPTER 46   Ac u te h eart failu re:  early pha r m ac ol o g i ca l  ther a p y

or as a bridge to more definitive non-​pharmacological therapy

Cardiogenic shock such as transplantation or MCS. All of the major international
guidelines currently recommend the use of inotropes in pa-
‘Shocked’ or ‘low-​output’ patients in whom cardiac output is in-
tients with CS. The ESC guidelines recommend this as the sole
sufficient to maintain organ perfusion and function represent a
indication, whereas American guidelines suggest an additional
minority of AHF patients. Congestion, as described, coexists in a
potential role in patients with end-​stage heart failure receiving
large majority of patients. An arbitrary cut-​off SBP defining CS is
palliative care [1,  15]. Despite reports of beneficial haemo-
often quoted in the literature. However, the measured blood pres-
dynamic effects, none of these agents have been shown to im-
sure needs to be interpreted in the context of the patient’s baseline
prove clinical outcomes and, in some cases, their use has been
blood pressure (if known). Other clinical signs providing infor-
shown to increase mortality. Agents of choice differ between
mation about end-​organ status, such as capillary refill time, cold
centres, let  alone countries, as no robust evidence base exists.
skin, reduced urine output, lactate, plasma pH (or elevated H+
Classes include sympathomimetics/​ synthetic catecholamines
ions), and impaired cognition, are crucial for the diagnosis of CS.
(e.g. dobutamine, adrenaline), phosphodiesterase inhibitors (e.g.
O2 and diuretic therapy, as discussed earlier, should be con-
milrinone, enoximone), and, more recently, Ca2+ sensitizers (e.g.
sidered in these patients; however, vasodilators are contraindi-
levosimendan). Agents are further categorized as to whether or
cated. The aim of pharmacological therapy in patients with CS is
not they have a vasodilating (inodilators) or vasoconstricting
to improve cardiac function by increasing contractility and car-
(inoconstrictors) effect. All of these agents improve myocardial
diac output, with consequent optimization of tissue perfusion and
contractility but, especially in the case of the sympathomimetics,
end-​organ function (see E Table 46.2).
also increase myocardial O2 consumption and can promote the
Certain patients with AHF are ‘wet and cold’ with ‘normal’
development of tachyarrhythmias. Dosages/​ infusion rates are
blood pressure, i.e. they do not meet the criteria for CS. This likely
guided by clinical status, blood pressure, and markers of end-​
represents a pre-​CS compensatory phase, with peripheral vaso-
organ perfusion, as discussed earlier (see E Table 46.4) [40]. All
constriction maintaining blood pressure. Initial therapy with di-
patients require close monitoring of cardiac rhythm and haemo-
uretics should be closely monitored (with invasive monitoring, if
dynamic parameters during treatment with these agents.
necessary, to assess PCWP and cardiac output). If blood pressure
subsequently falls, then these patients should be managed as CS,
as outlined below.
Sympathomimetics
Dobutamine
Inotropic therapy Dobutamine is a synthetic catecholamine with β1, β2, and α1
(See E Figure 46.4.) adrenergic activity, resulting in increased cyclic adenosine
Inotropic agents represent ‘rescue’ therapy. They are frequently monophosphate (cAMP) production. Its primary mode of ac-
used in patients with AHF in an attempt to stabilize and salvage, tion is via β1 activation, resulting in an increased cardiac output

Digitalis
β-receptor
agonist 2K 3Na+

β NCX
Ca2+
3Na+
Ca2+ RyR2 Ca2+

Ca2+ Ca2+ Ca2+ Ca2+

ATP PL
SERCA2a

AMP cAMP PKA Ca-sensitizer

Ca2+
PDE
TNT TNC TNI

Ca2+
PDE inhibitors

Figure 46.4  Inotropic mechanisms and current inotropic interventions. AMP, adenosine monophosphate; ATP, adenosine triphosphate; Ca2+, calcium; cAMP,
cyclic adenosine monophosphate; K, potassium; Na+, sodium; NCX, sodium–​calcium exchanger; PDE, phosphodiesterase; PL, phospholamban; RyR2, ryanodine
receptor 2; TNC, troponin C; TNI, troponin I; TNT, troponin T.
Reproduced from Hasenfuss G, Teerlink JR. Cardiac inotropes: current agents and future directions. Eur Heart J 2011;32(15):1838–​1845. doi:10.1093/​eurheartj/​ehr026 with permission
from Oxford University Press.
 Ca rdi o g e n i c   sh o c k 625

Table 46.4  Drugs used to treat acute heart failure that are positive Adrenaline (epinephrine)
inotropes or vasopressors, or both
Adrenaline is a direct-​acting sympathomimetic agent, exerting
Bolus Infusion rate its effect on β1, β2, and α1 adrenoreceptors. It is a potent ino-
Dobutaminea No 2–​20 micrograms/​kg/​min (β+) tropic, chronotropic, and vasoconstricting agent. Generally, it
does not have a role in the management of AHF and should only
Dopamine No 3–​5 micrograms/​kg/​min;
inotropic (β+) be administered in the critical care setting. It is known to increase
myocardial O2 demand and is proarrhythmic due to raised intra-
>5 pg/​kg/​min (β+); vasopressor
(α+) cellular cAMP and Ca2+ concentrations, as well as reduced plasma
K+ concentration.
Milrinonea,b 25–​75 micrograms/​kg 0.375–​0.75 micrograms/​kg/​min
over 10–​20 minutes Noradrenaline (norepinephrine)
Enoximonea 0.5–​1.0 mg/​kg over 5–​20 micrograms/​kg/​min Noradrenaline is an endogenous agonist at α1 and α2
5–​10 minutes
adrenoreceptors, with only very modest effects on β1
Levosimendana 12 micrograms/​ 0.1 micrograms/​kg/​min, which adrenoreceptors. It is a potent vasoconstrictor and so does not
kg over 10 minutes can be decreased to 0.05 or
(optional)c increased to 0.2 micrograms/​kg/​ generally have a role in the management of AHF, as SVR is usu-
min ally high in these patients. However, it can be useful in patients
Noradrenaline No 0.2–​1.0 micrograms/​kg/​min with heart failure who have concurrent septic shock and should
be administered via central venous access. It has a plasma half-​life
Adrenaline Bolus: 1 mg can 0.05–​0.5 micrograms/​kg/​min
be given IV during of 5–​10 minutes. It is rapidly metabolized in the liver and tissues
resuscitation, and excreted in the urine.
repeated every 3–​5 In the Sepsis Occurrence in Acutely Ill Patients II (SOAP II)
minutes trial, patients with shock (defined as SBP <100 mmHg or MAP
IV, intravenous. <70 mmHg) were randomized to receive dopamine or noradren-
a
Also a vasodilator. aline as a first-​line agent [44]. However, this was not a heart
b
Not recommended in acutely worsened ischaemic heart failure.
c
failure study, and no assessment of cardiac function was made.
Bolus not recommended in hypotensive patients.
Reproduced from Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for It primarily included patients with septic shock (62%), and al-
the diagnosis and treatment of acute and chronic heart failure: The Task Force for the though 16.7% were said to have ‘cardiogenic shock’, this group
diagnosis and treatment of acute and chronic heart failure of the European Society included patients with PE, tamponade, and VHD. Overall, there
of Cardiology (ESC). Developed with the special contribution of the Heart Failure
Association (HFA) of the ESC [published correction appears in Eur Heart J 2016 Dec 30]. was no difference in the rate of death between patients with shock
Eur Heart J 2016;37(27):2129–​2200. doi:10.1093/​eurheartj/​ehw128 with permission from who were treated with dopamine as the first-​line vasopressor
Oxford University Press.
agent and those treated with noradrenaline. A subgroup analysis
showed that dopamine, as compared with noradrenaline, was as-
and a reduction in pulmonary wedge pressure. As such, it is one sociated with an increased rate of death at 28 days among the 280
of the most widely used inotropic agents in AHF. Dobutamine patients with ‘cardiogenic shock’, but not among the 1044 patients
has a short half-​life of around 2 minutes, with peak effect after with septic shock or the 263 patients with hypovolaemic shock
10 minutes. It is renally cleared and should be administered via (P = 0.03). Dopamine was also associated with a greater number
central venous access. Unwanted effects of dobutamine are rela- of AEs, particularly arrhythmia (and primarily an increase in AF).
tively common and include sinus tachycardia, myocardial is-
Dopexamine
chaemia, arrhythmias, and hypotension at higher doses (due to
β2 stimulation). At high doses, a vasoconstrictor effect can be Dopexamine is a synthetic analogue of dopamine, which stimu-
seen due to some α-​receptor binding. Dobutamine has not been lates adrenergic β2-​receptors and peripheral dopamine receptors,
the subject of a robust RCT with clinically meaningful endpoints. as well as inhibits the neuronal reuptake of noradrenaline. It leads
However, smaller studies and meta-​analyses suggest a trend to- to an increase in cardiac output mediated by afterload reduction
wards increasing mortality in treated patients [41–​43]. (β2, DA1) and increases blood flow to the renal and mesenteric
beds (DA1). It does not cause vasoconstriction but can lead to
Dopamine tachyarrhythmia and hypertension.
Dopamine is an endogenous precursor of noradrenaline (nor-
epinephrine), with predominantly β1-​receptor activity (see E Phosphodiesterase inhibitors
Tables 46.4 and 46.5). However, at low doses, it acts on dopa- Inhibitors of phosphodiesterase III are frequently used in AHF.
mine receptors (DA1), causing dilation of smooth muscles in Phosphodiesterase III catabolizes cAMP and, as such, inhibition
renal arteries, which may augment diuresis in combination with of phosphodiesterase III results in increased cAMP levels, with
diuretics as discussed earlier. At higher doses, it has inotropic ef- consequent vasodilating (both pulmonary and systemic) and
fects through β1 receptors, and vasoconstrictor effects via α1 and inotropic effects. No chronotropic effect occurs at low to me-
5HT receptors (see E Table 46.5). It has a plasma half-​life of 9 dium doses. The main adverse effects seen are arrhythmias and
minutes.
626 CHAPTER 46   Ac u te h eart failu re:  early pha r m ac ol o g i ca l  ther a p y

Table 46.5  Dose-​dependent effects of dopamine

Dose 0.5–​3.0 micrograms/​kg/​min 3.0–​5.0 micrograms/​kg/​min >5.0 micrograms/​kg/​min

Predominant action DA1 β1 5HT and α1
Cardiovascular ↑ cardiac output ↑ myocardial contractility ↑ heart rate
Vasoconstriction
Renal ↓ proximal tubular Na+ reabsorption ↑ renal blood flow Variable effect on renal blood flow
↑ renal blood flow
GI ↑ splanchnic blood flow ↑ splanchnic blood flow Variable effect on splanchnic blood flow
Reproduced from Gardner, McDonagh & Walker, Oxford Specialist Handbook in Heart Failure, 2007, Oxford University Press with permission from Oxford University Press.

hypotension. As before, there is no evidence suggesting that these levosimendan appeared to exert a more profound hypotensive
agents improve outcomes in AHF. and tachycardic effect than dobutamine. Currently, levosimendan
is available for clinical use in some European countries, but not
Milrinone in North America.
IV milrinone has a half-​life of 2.5 hours. It is renally excreted,
so dose adjustment is required in renal impairment (see E
Table 46.4). The Outcomes of a Prospective Trial of Intravenous
Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-​ General considerations in patients
CHF) study randomized patients with AHF to IV milrinone or with acute heart failure
placebo, in addition to standard therapy [45]. This trial demon-
strated no improvements in mortality, length of hospital stay, or Pre-​existing pharmacotherapy
readmission rates. Of note, sustained hypotension and new atrial An important and early consideration in those patients admitted
arrhythmias were more frequent in the milrinone group. with ADCHF is whether or not to continue their current medica-
tion. This deserves careful consideration in the case of β-​blockers.
Enoximone
Data from the OPTIMIZE-​HF registry suggest that post-​discharge
Enoximone is approximately ten times less potent than milrinone. mortality rates were lower in patients whose β-​blocker was con-
Enoximone is currently available for clinical use in Europe, but tinued on admission [48]. Post hoc analyses of the Carvedilol Or
not in North America. Metoprolol European Trial (COMET) and Evaluation Study of
Congestive Heart Failure and Pulmonary Artery Catheterization
Calcium sensitizers Effectiveness (ESCAPE) trials produced similar results [49,  50].
Levosimendan Furthermore, initiation of a β-​blocker in ‘high-​risk’ patients in
Levosimendan is a Ca2+-​sensitizing agent that increases the sensi- the Carvedilol Prospective Randomized Cumulative Survival
tivity of the myocardial contractile apparatus to Ca2+, supposedly (COPERNICUS) trial, a proportion of whom were hospitalized at
without significantly affecting cAMP or intracellular Ca2+ concen- the time of randomization, was safe and the benefits of β-​blockade
trations. This leads to an increase in inotropy without increasing were apparent from as early as 14 days following initiation of treat-
O2 demand. It also has a vasodilator effect mediated by its ability ment [51]. A  randomized trial of β-​blocker continuation versus
to activate K+-​sensitive ATP channels in vascular smooth muscle withdrawal demonstrated that continuation of therapy does not
cells. The active metabolite of levosimendan has a half-​life of ap- adversely impact on outcomes and is associated with a higher
proximately 80 hours. Peak effect is noted by 30 minutes following rate of chronic prescription of β-​blocker therapy 3  months later
commencement of the infusion. Levosimendan reduces wedge [52]. A meta-​analysis reported that discontinuation of β-​blocker
pressure, increases cardiac output, and reduces pulmonary and therapy in patients admitted with AHF was associated with signifi-
systemic vascular resistance, with a modest reduction in MAP. cantly higher in-​hospital mortality, short-​term mortality, and the
The Levosimendan Infusion versus Dobutamine (LIDO) trial combined endpoint of short-​term rehospitalization or mortality
randomized patients with AHF to receive either levosimendan [53]. It is therefore recommended by both the ESC and American
or dobutamine, in addition to standard therapy [46]. Patients College of Cardiology/​AHA that patients’ existing medications be
receiving levosimendan were more likely to reach the primary carefully reviewed on admission and β-​blocker treatment withheld
endpoint of an increase of 30% or more in cardiac output and or stopped only if decompensation has occurred shortly after initi-
a decrease of 25% or more in PCWP (P  =  0.02). Mortality at ation or an increase in β-​blocker therapy (i.e. likely culprit under-
6 months was higher in the dobutamine group (P = 0.029). This lying the presentation) or the patient is shocked [1,  15]. RAAS
comparison was investigated in the larger Survival of Patients with antagonists should be continued, unless hypoperfusion or acute
Acute Heart Failure in Need of Intravenous Inotropic Support renal insufficiency preclude this. Any agent with negatively ino-
(SURVIVE) trial [47]. There was no difference in the primary tropic (non-​dihydropyridine Ca2+ channel antagonists) or fluid-​
outcome of all-​cause mortality between the groups. However, retaining properties (e.g. NSAIDs) should be stopped.
 Emerging pha r m ac ol o g i ca l ther a pi es for  acu te hea rt   fa i lure 627

Thromboprophylaxis
Emerging pharmacological therapies
Patients with AHF are at high risk of DVT and PE due to the pre-
ponderance to higher venous pressures and lower cardiac output. for acute heart failure
The occurrence of a VTE is associated with considerable morbidity Given the high morbidity and mortality associated with AHF
and mortality [54]. Based on data from RCTs, guidelines univer- and the lack of any pharmacological therapies which improve
sally support the use of thromboprophylaxis (e.g. LMWH) in all prognosis, efforts are ongoing to identify new disease-​modifying
appropriate hospitalized AHF patients, unless contraindicated treatments. The following are currently under investigation in
(most commonly due to the existing use of oral anticoagulants) [1, phase III trials, with a variety of other drugs at earlier stages of
15, 55, 56]. development.
Predischarge Omecamtiv mecarbil
All guidelines recommend that patients with LV systolic dys-
Omecamtiv mecarbil is a myosin-​activating agent which po-
function who stabilize with the above therapy should ideally
tentiates excitation–​contraction coupling and increases sys-
be commenced on a low-​dose ACE-​I, β-​blocker, and MRA, if
tolic ejection time, contractility, and stroke volume. In theory,
appropriate, once euvolaemic and prior to hospital discharge
it has no arrhythmogenic potential, given its lack of effect on
if tolerated [1,  15]. A  recently published trial investigated
phosphodiesterases, intracellular Ca2+ concentration, or myo-
whether the initiation of the first-​in-​class ARNI sacubitril/​
cardial O2 consumption. Phase II studies in stable heart failure
valsartan was safe and effective in patients hospitalized for
patients have confirmed its ability to increase stroke volume
AHF, given the benefits in reducing morbidity and mor-
[60]. The randomized, placebo-​controlled Acute Treatment
tality seen with ARNIs, compared to the gold standard ACE-​I
with Omecamtiv Mecarbil to Increase Contractility in Acute
enalapril, in patients with chronic ambulatory HFrEF [57, 58].
Heart Failure (ATOMIC-​AHF) study examined three doses
A total of 881 patients were randomized to sacubitril/​valsartan
of IV omecamtiv mecarbil, given as a 48-​hour infusion, in
(target dose 97/​103 mg twice daily) or enalapril (target dose
patients with AHF [61]. The primary endpoint of reduction
10 mg twice daily) in the Comparison of Sacubitril–​Valsartan
of dyspnoea within 48 hours was not reduced in any of the
versus Enalapril on Effect on NT-​proBNP in Patients Stabilized
three dose cohorts, compared to a pooled placebo group.
from an Acute Heart Failure Episode (PIONEER-​HF) trial
However, in a pre-​specified supplemental analysis, the highest
[58]. The reduction in NT-​proBNP levels was significantly
dose of omecamtiv mecarbil resulted in greater dyspnoea re-
greater in those randomized to sacubitril/​valsartan, compared
lief at 48 hours and through to 5  days. Furthermore, treat-
to enalapril, and this benefit was evident as early as 1 week
ment with omecamtiv mecarbil led to significant decreases
following randomization. Initiation of sacubitril/​ valsartan
in LV end-​ systolic volume and LV systolic ejection time.
was safe, with no significant difference in rates of worsening
Following on from similar positive findings in a phase II
renal function, hyperkalaemia, symptomatic hypotension, and
study with oral omecamtiv mecarbil in patients with chronic
angio-​oedema between the two groups. Similar findings re-
HFrEF, the oral formulation is currently being investigated in
garding the safety of initiation of sacubitril/​valsartan were re-
a phase III morbidity and mortality outcomes trial in chronic
ported in the Comparison of Pre-​and Post-​discharge Initiation
HFrEF and will include patients hospitalized at the time of
of Sacubitril/​Valsartan Therapy in HFrEF Patients After an
randomization—​the Global Approach to Lowering Adverse
Acute Decompensation Event (TRANSITION) study, in which
Cardiac outcomes Through Improving Contractility in Heart
patients with AHF (24% ACE-​I/​ARB-​naive) were randomized
Failure (GALACTIC-​HF) trial (ClinicalTrials.gov identifier:
to the initiation of open-​label sacubitril/​valsartan either pre-​
NCT02929329) [62].
or post-​discharge [59]. No difference in tolerability or safety
was observed between the two strategies (although there was
only a mean of 3-​day difference between initiation in the pre-​
Sodium–​glucose cotransporter 2 inhibitors
and post-​discharge groups). Furthermore, in the PIONEER-​ Sodium–​glucose cotransporter 2 (SGLT2) inhibitors are a class
HF trial, treatment with sacubitril/​valsartan reduced the risk of glucose-​lowering medication which reduce morbidity and
of a composite endpoint consisting of death, rehospitalization mortality in patients with type 2 diabetes and high cardiovas-
for heart failure, implantation of an LV device, and inclu- cular risk. A  meta-​analysis of a trio of RCTs—​Empagliflozin
sion on the list of patients eligible for heart transplantation Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus
[58]. Following on from the results of PIONEER-​ HF and Patients–​Removing Excess Glucose (EMPA-​REG OUTCOME)
TRANSITION, and considering the benefits observed in pa- [63], CANagliflozin cardioVascular Assessment Study (CANVAS)
tients with chronic ambulatory HFrEF, we believe that initi- Program [64], and Dapagliflozin Effect on Cardiovascular
ation of sacubitril/​valsartan in patients stabilized from an Events–​Thrombolysis in Myocardial Infarction 58 (DECLARE-​
admission with AHF is both safe and effective. TIMI58) [65]—​reported a significant 31% reduction in the risk
628 CHAPTER 46   Ac u te h eart failu re:  early pha r m ac ol o g i ca l  ther a p y

of heart failure hospitalization with SLGT2 inhibitors, compared more than trace oedema assessed on the third morning after
to placebo [66]. This benefit, along with a significant reduction hospital admission [72].
in cardiovascular death, was observed in both patients with and
those without a history of heart failure at baseline [66]. The clin- Intravenous iron
ical benefits observed with SGLT2 inhibitors are thought to be Patients with heart failure are frequently iron deficient, irre-
due to non-​atherothrombotic effects as a result of both a rapid spective of the presence of anaemia, and intravenous iron replace-
emergence of the benefit observed and a relatively modest effect ment has been shown to improve functional capacity, exercise
on atherothrombotic outcomes [67]. The mechanisms behind tolerance, and quality of life in patients with chronic ambulatory
these benefits are yet to be fully elucidated. However, it is thought HFrEF [73]. Meta-analyses of small randomized controlled trials
that they primarily result from osmotic diuresis secondary to in- have also reported a reduction in the risk of HF hospitalization
creased urinary Na+ and glucose loss, along with reno-​protective and mortality with intravenous iron replacement compared with
properties. Diuresis resulting from SGLT2 inhibition may reduce placebo [73, 74]. Iron deficiency is present in up to 80% of patients
the intravascular volume, thereby reducing cardiac pre-​and hospitalized with AHF and is an independent predictor of adverse
afterload and improving myocardial O2 supply and potentially outcomes. The Study to Compare Ferric Carboxymaltose With
cardiac systolic and diastolic function. This suggested pathway Placebo in Patients With Acute Heart Failure and Iron Deficiency
may explain the lower risk of heart failure hospitalization ob- (AFFIRM-AHF) trial randomized patients hospitalized with
served and it has been suggested that the risk of fatal cardiac ar- AHF to intravenous iron replacement with ferric carboxymaltose
rhythmias may also be reduced [67]. Improvements in cardiac or placebo. The primary endpoint of AFFIRM-HF was a com-
function (along with reduced venous pressures) may also con- posite of total (first and recurrent) HF hospitalizations and car-
tribute to improvements in renal blood flow and function. Two diovascular death; although neutral with regards to the primary
RCTs, the Dapagliflozin and Prevention of Adverse Outcomes endpoint, a pre-specified sensitivity analysis accounting for the
in Heart Failure trial (DAPA-HF) [68] and the Empagliflozin impact of the severe acute respiratory syndrome coronavirus 2
Outcome Trial in Patients with Chronic Heart Failure and a (SARS-CoV-2) pandemic reported a significant benefit with
Reduced Ejection Fraction (EMPEROR-Reduced) [69], have intravenous ferric carboxymaltose on cardiovascular death and
demonstrated the efficacy of SGLT2 inhibitors in reducing the risk HF hospitalization [75].
of cardiovascular death and heart failure hospitalization in pa-
tients with chronic HFrEF, regardless of diabetes status. Trials are
ongoing in patients with HFpEF and one of these trials includes
patients hospitalized at the time of randomization [Dapagliflozin Conclusion
Evaluation to Improve the LIVEs of Patients With PReserved Patients presenting with AHF represent a diverse spectrum of path-
Ejection Fraction Heart Failure (DELIVER)] (ClinicalTrials.gov ologies and severity. The choice of initial pharmacological therapy
identifier: NCT03619213). Given their diuretic effect and reno-​ is governed by the presence, or not, of CS. Many of the recom-
protective properties, as well as other potential cardiovascular mendations for AHF treatments are based on lower levels of evi-
benefits, any potential role in AHF is currently also under in- dence and can vary between guidelines (see E Table 46.1). To date,
vestigation [Effect of Sotagliflozin on Cardiovascular Events in no pharmacological therapy has been shown to improve prognosis
Patients With Type 2 Diabetes Post Worsening Heart Failure in AHF.
(SOLOIST-​WHF), ClinicalTrials.gov identifier:  NCT03521934;
Effects of Empagliflozin on Clinical Outcomes in Patients With
Acute Decompensated Heart Failure (EMPA-​ RESPONSE),
ClinicalTrials.gov identifier:  NCT03200860; Dapagliflozin and
Appendix: the evidence base
Effect on Cardiovascular Events in Acute Heart Failure (DAPA
ACT HF-TIMI 68), ClinicalTrials.gov identifier: NCT04363697].
Nitrates
Acetazolamide
Design: RCT of high-​dose isosorbide dinitrate (ISDN) and low-​
Acetazolamide is a carbonic anhydrase inhibitor which results
dose furosemide versus high-​ dose furosemide and low-​ dose
in inhibition of proximal tubular Na+ reabsorption. When ad-
ISDN in AHF.
ministered as monotherapy, it has very little natriuretic or di-
uretic effect. However, when used in combination with a loop Subjects: n  =  104; mean age  =  74  years; 52% males; mean
diuretic, small studies have reported increased natriuresis and LVEF = 42%.
diuresis, compared to loop diuretic therapy alone [70, 71]. Background therapy: 87% ACE-​I; 50% β-​blocker.
An RCT is currently recruiting around 500 patients to treat- Results: less requirement for mechanical ventilation (P = 0.0041)
ment with either IV loop diuretics alone or the addition of and fewer MI (P = 0.047) in high-​dose ISDN group.
acetazolamide for 3 consecutive days. The primary endpoint is
Reference: Cotter G, et al. [26]
treatment success defined as successful decongestion with no
 Ul a ri t i de 629

REVIVE-​II (Randomized Multicentre Evaluation

Nesiritide of Intravenous Levosimendan Efficacy Versus Placebo in the
Short-​Term Treatment of Decompensated Heart Failure)
VMAC (Vasodilation in the Management of Acute CHF)
Design: double-​blind RCT of levosimendan versus placebo.
Design: double-​ blind RCT of nesiritide versus nitroglycerin
versus placebo. Subjects: n  =  600; heart failure admission; LVEF ≤35%; mean
Subjects: n  =  489; inpatients with dyspnoea at rest; mean age = 63 years; 72% males.
age = 62 years; 69% males. Follow-​up: 6 months.
Results: at 24 hours:  no significant difference in perceived dys- Results: trend towards an increase in mortality at 90  days; re-
pnoea; greater reduction in PCWP with nesiritide (P = 0.04). duction in hospitalization by 2 days (P = 0.001); more reports of
Reference: Publication Committee for the VMAC Investigators [31] hypotension and AF.
ASCEND-​HF (Acute Study of Clinical Effectiveness Reference: American Heart Association Scientific Session, Dallas,
of Nesiritide in Decompensated Heart Failure) TX, November 2005.
Design: double-​blind RCT of nesiritide versus placebo in patients SURVIVE
hospitalised with AHF.
Design: double-​blind RCT of levosimendan versus dobutamine.
Subjects: n  =  7141; mean age  =  67  years; 66% males; 80% with
Subjects: n = 1327; AHF with LVEF ≤30%; mean age = 59 years;
LVEF <40%.
87% males.
Results: did not achieve pre-​specified reduction in dyspnoea at
Follow-​up: 180 days.
6 hours; no significant difference in rehospitalization/​death at
30 days; no significant difference in death at 30 days; no differ- Results: no significant difference in mortality at 180 days (P = 0.40).
ence in eGFR (P = 0.11). Reference: Mebazaa A, et al. [47]
Reference: O’Connor CM, et al. [32]

Serelaxin
Milrinone RELAX-​AHF (Recombinant Human Relaxin-​2 for the
OPTIME-​CHF Treatment of Acute Heart Failure)
Design: double-​blind RCT of IV milrinone versus placebo in pa- Design: double-​blind RCT of serelaxin versus placebo.
tients with an acute exacerbation of chronic heart failure. Subjects: n = 1161; within 16 hours of a heart failure admission;
Subjects: n = 951; mean age = 66 years; 93% NYHA class III/​IV; mean age = 72 years; 63% males.
mean LVEF = 23%. Follow-​up: 6 months.
Follow-​up: 60 days. Results: improvement on visual analogue scale (P  =  0.007), but
Results: no difference in length of hospital stay and in-​hospital not on the Likert scale for dyspnoea (both primary endpoints); no
or 60-​day mortality; more frequent hypotension (P <0.001) and change in cardiovascular death or heart failure rehospitalization
atrial arrhythmias (P = 0.004) with milrinone. (P  =  0.001) (secondary endpoint); reduction in mortality at
180  days [42 deaths with serelaxin, 65 with placebo; HR 0.63
Reference: Cuffe MS, et al. [45]
(0.42–​0.93); P = 0.019]. This was neither a primary or secondary
endpoint.
Reference: Teerlink JR, et al. [38]
Levosimendan
LIDO study (Levosimendan Infusion versus
Dobutamine Study) Ularitide
Design: double-​blind RCT of levosimendan versus placebo.
TRUE-​AHF (Trial of Ularitide’s Efficacy and Safety in Patients
Subjects: n  =  203; NYHA class  IV; LVEF ≤35%; mean with Acute Heart Failure)
age = 59 years; 87% males.
Design: double-​blind RCT of ularitide versus placebo in patients
Follow-​up: 6 months. hospitalized with AHF.
Results: 12% absolute (43% RRR) lower mortality with Subjects: n  =  2157; mean age  =  68  years; 66% males; 66% with
levosimendan, compared with dobutamine, at 6  months LVEF <40%.
(P = 0.029); 13% (90% RRR) more patients had haemodynamic
Results: no difference in cardiovascular death during 15-​month
improvement at 24 hours with levosimendan, compared with
follow-​up (P = 0.75).
dobutamine (P = 0.022).
Reference: Packer M, et al. [35]
Reference: Follath F, et al. [46]
630 CHAPTER 46   Ac u te h eart failu re:  early pha r m ac ol o g i ca l  ther a p y

Further reading
Ezekowitz JA. Novel pharmacologic therapies in development for acute Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the
decompensated heart failure. Curr Cardiol Rep 2013;15:329. diagnosis and treatment of acute and chronic heart failure. Eur Heart
Givertz MM, Teerlink JR, Albert NM, et al. Acute decompensated heart J 2016;37:2129–​200.
failure:  update on new and emerging evidence and directions for Stevenson LW. Clinical use of inotropic therapy for heart failure: looking
future research. J Card Fail 2013;19:371–​89. backward or forward? Part I: inotropic infusions during hospitalization.
Harjola VP, Mullens W, Banaszewski M, et al. Organ dysfunction, injury Circulation 2003;108:367–​72.
and failure in acute heart failure: from pathophysiology to diagnosis Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/​AHA Guideline for
and management. A  review on behalf of the Acute Heart Failure the Management of Heart Failure: A Report of the American College
Committee of the Heart Failure Association (HFA) of the European of Cardiology Foundation/​American Heart Association Task Force on
Society of Cardiology (ESC). Eur J Heart Fail 2017;19:821–​36. Practice Guidelines. J Am Coll Cardiol 2013;62:e147–​239.

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 CHAPTER 47

Low cardiac output states

and cardiogenic shock
Holger Thiele and Suzanne de Waha-​Thiele

Contents
Summary  633
Summary
Introduction  633 Low cardiac output and cardiogenic shock are associated with high mortality.
Definition  634 Among the multiple heterogenous reasons for low cardiac output and cardiogenic
Causes of cardiogenic shock  634 shock, acute coronary syndromes are the most frequent cause. Mortality is still ap-
Pathophysiology  634 proaching 50%. The extent of ischaemic myocardium has a profound impact on ini-
Risk factors and prognosticators  634 tial, in-​hospital, and post-​discharge management and prognosis of the cardiogenic
Treatment  636 shock patient. Careful risk assessment for each patient, based on clinical criteria, is
Revascularization  636 mandatory to decide appropriately regarding revascularization by primary percu-
Revascularization strategy  638 taneous coronary intervention or coronary artery bypass grafting, drug treatment
Transradial versus transfemoral
approach  639 using inotropes and vasopressors, mechanical circulatory support, additional in-
Adjunctive medical treatment  640 tensive care treatment, triage among alternative hospital care levels, and allocation
Antithrombotic drugs  640
Fluids and catecholamines  640
of clinical resources. This chapter will outline the underlying causes and diagnostic
Adjunctive monitoring and treatment  641 criteria, pathophysiology, and treatment of cardiogenic shock, focusing on acute
Haemodynamic management  641 coronary syndromes, including mechanical complications and shock from right
Glucose control  641 ventricular failure. There will be a major focus on potential therapeutic issues from
Renal replacement therapy  641
Liver function  642 an interventional cardiologist’s and also an intensive care physician’s perspective
Bleeding and haemoglobin targets  642 on the advances in new therapeutic arsenals, both percutaneous mechanical circu-
Mechanical ventilation  642 latory support and pharmacological support. Since studying the cardiogenic shock
Hypothermia  642
Percutaneous mechanical circulatory population in randomized trials remains challenging, this chapter will also touch
support  642 upon the specific challenges encountered in previous clinical trials and the impli-
Intra-​aortic balloon pump  642 cations for future perspectives in cardiogenic shock.
Percutaneous active mechanical circulatory
support devices  642
TandemHeart™  643
Impella® family  643
HeartMate PHP™  643
iVAC 2L®  643
Extracorporeal life support systems  643
Mechanical complications and right Introduction
ventricular dysfunction  644
The incidence of low cardiac output and predominantly CS in patients with AMI differs,
Ventricular septal defect  644
Free wall rupture  645 depending on the CS definitions, but it ranges from 4% to 15%, with some decline in the
Acute ischaemic mitral regurgitation  645 last years in some of the observational cohorts [1–​3]. Assuming a 5–​8% incidence of CS
Right ventricular failure  645
in all hospitalized AMIs, this translates into approximately 60 000–​70 000 cases per year
Personal perspective  646
in Europe [4, 5]. Numerous clinical complications are associated with the development of
References  646
AMI, but none is more potentially devastating for prognosis than CS.
The mortality of patients with AMI could be reduced from 30% to <5% for non-​CS
patients during the last decades. In the subgroup of patients with CS, improvements
were also substantive with reductions from formerly 80% to nowadays 40–​50% [1, 3,
6, 7]. Despite advances in treatment over the last decades, leading to a steady reduction
in mortality, CS remains the leading cause of death, with hospital mortality rates still
634 CHAPTER 47   L ow cardiac ou tpu t stat es a n d ca rdi o g en i c sho ck

approaching 50%. Some recent registries suggested an increase

in the CS setting despite an increase in invasive measures and Pathophysiology
revascularization rates which may be related to the higher age
The CS pathophysiology is complex, and its understanding has
and higher-​risk profile of patients [8, 9]. Other recent registries
emerged over the last decades [20–​23]. In general, the underlying
did not observe this increase in mortality and rather suggested
pathophysiology is a profound depression of myocardial con-
a further decline in mortality [3,  10]. Interestingly, public re-
tractility, resulting in a vicious spiral of reduced cardiac output,
porting negatively affects the number of patients with invasive
low blood pressure, further coronary ischaemia, and subsequent
angiography in CS. Therefore, CS patients should be excluded
reduction in contractility and cardiac output, leading to death
from public reporting [11,  12]. Major efforts are still needed
if not interrupted by adequate treatment. Previously, the classic
and also intensified research should be directed to improve the
paradigm predicted that compensatory systemic vasoconstric-
prognosis of CS.
tion would occur in response to cardiac functional depression
[24]. Nowadays, it is well known that CS is the result of acute
to subacute derangements in the entire circulatory system. Loss
Definition of LV function is the major cause, with subsequent systolic and
diastolic dysfunction, but other parts of the circulatory system
CS of every cause is a state of impaired end-​organ perfusion due
may also contribute to shock with inadequate compensation or
to reduced cardiac output. It is characterized by hypotension,
by contribution of additional defects. Extremity and vital organ
usually pulmonary congestion or elevated ventricular filling pres-
hypoperfusion is the hallmark of CS. Compensatory mechan-
sures, and impaired tissue and vital organ perfusion. In general,
isms by vasoconstriction lead to an intermittent improvement
CS can be clinically defined. However, in particular, in some clin-
in coronary and peripheral perfusion, at the cost of an increased
ical trials, additional haemodynamic parameters, such as assess-
afterload. However, vasoconstriction can often be reverted by sys-
ment of LV filling pressures or the cardiac index, were used to
temic inflammation, leading to subsequent pathologic vasodila-
define CS [13, 14]. Although not mandatory in clinical practice,
tation which occurs frequently with increasing shock duration.
objective haemodynamic parameters, such as reduced cardiac
Endothelial and inducible NO synthase (NOS) may play a major
index and elevated PCWP, are helpful for diagnosis confirm-
role, with the production of inadequate high NO levels and also
ation, enabling comparisons across CS cohorts and randomized
peroxynitrite which has cardiac toxicity and is negatively ino-
clinical trials, and are essential for defining RV function in CS.
tropic. Other inflammatory markers, such as interleukins and
Definitions applied in European guidelines and selected major
TNF-​α, might also contribute to this phenomenon [21].
randomized trials are shown in E Table 47.1.
Another important aspect is bleeding which might also con-
Most recently, efforts of the Society for Cardiovascular
tribute to increased mortality, as shown previously in trials with
Angiography and Interventions (SCAI) have been directed to-
predominantly stable haemodynamic conditions [22, 25]. In par-
wards a more uniform CS definition and a classification scheme
ticular in CS, bleeding may trigger transfusion, since it is gener-
similar to the INTERMACS heart failure classification [15]. Based
ally believed beneficial that raising Hb levels via transfusion will
on this new definition, there are five categories ranging from at-​
increase O2 delivery. However, blood transfusion itself increases
risk and pre-​shock to extreme CS labelled as A to E (see E Figure
the mortality risk. Alterations in erythrocyte NO biology in
47.1). This new classification system of different shock states will
stored blood may provide a partial explanation, leading to initial
also be helpful to make different trials of CS better comparable and
vasoconstriction, platelet aggregation, and ineffective O2 delivery.
may also trigger new randomized trials on the pre-​shock state.
In addition, bleeding itself, as well as transfusion, contributes to
inflammation [26, 27]. The mechanisms behind the associations
of bleeding and also transfusions with mortality are complex and
Causes of cardiogenic shock may relate to several factors [26]. This complexity expands the
AMI with subsequent LV dysfunction is the most common current concept of CS pathophysiology and its potential treat-
cause of CS complicating AMI. The median time after STEMI ment options to interrupt the vicious shock spiral, as shown in
for the occurrence of shock is in the range of 5–​6 hours [14]. E Figure 47.2.
Shock complicating NSTE-​ACS seems to occur at a later time
period, with a median of 76 and 94 hours, respectively [16, 17].
In general, a loss of >40% of functional myocardium is required Risk factors and prognosticators
to cause CS, as shown in autopsy studies [18]. However, mech-
Because of the serious consequences of CS, identification of pa-
anical complications, such as acquired VSD, FWR, and papillary
tient subgroups with ACS, including STEMI and NSTE-​ACS, at
muscle rupture or dysfunction, with subsequent ischaemic MR,
high risk of developing CS is important. In the fibrinolytic era,
also contribute to CS after AMI [19]. The incidence of CS causes
algorithms have been developed to predict the occurrence of in-​
has been described to be 78.5% for LV failure, 3.9% for VSD,
hospital CS among patients with different types of STEMI and
6.9% for ischaemic MR, 2.8% for RV failure, and 1.4% for cardiac
NSTE-​ACS. These algorithms were validated in subsequent trials,
tamponade [19].
 Ri sk factor s a n d  pro g no st i c ator s 635

Table 47.1  Definition of cardiogenic shock in clinical trials and guidelines

SHOCK [14] TRIUMPH [13] IABP-​SHOCK II [46] CULPRIT-​SHOCK [43] ESC Heart Failure
Guidelines [60]
1. (a) SBP <90 mmHg for ≥30 1. Patency of IRA 1. SBP <90 mmHg for 1. Planned early SBP <90 mmHg with
minutes, OR spontaneously or after PCI ≥30 minutes OR revascularization by PCI adequate volume and
(b) Support to maintain 2. Refractory CS >1 hour after catecholamines 2. Multivessel CAD defined clinical or laboratory signs
SBP ≥90 mmHg, AND PCI with SBP <100 mmHg to maintain SBP as >70% stenosis in at least of hypoperfusion
2. End-​organ hypoperfusion despite vasopressors >90 mmHg, AND two major vessels (≥2 mm Clinical hypoperfusion: cold
(urine output <30 mL/​hour (dopamine ≥7 micrograms/​ 2. Clinical pulmonary diameter) with identifiable extremities, oliguria, mental
or cool extremities, AND kg/​min or noradrenaline congestion, AND culprit lesion confusion, dizziness, narrow
heart rate >60 bpm) or adrenaline ≥0.15 3. Impaired end-​organ 3. (a) S BP <90 mmHg for >30 pulse pressure
3. Haemodynamic criteria*: micrograms/​kg/​min) perfusion with at least one minutes, OR Laboratory hypoperfusion:
(a) CI of <2.2 L/​min/​m2, 3. End-​organ hypoperfusion of the following criteria: (b) Catecholamines metabolic acidosis, elevated
AND 4. Clinical or haemodynamic (a) Altered mental status required to maintain lactate, elevated creatinine
(b) PCWP ≥15 mmHg criteria for elevated LV (b) C old/​clammy skin and SBP >90 mmHg
filling pressure extremities 4. Pulmonary congestion
5. LVEF <40% (c) U rine output <30 mL/​ 5. Impaired organ perfusion
hour with at least one of the
(d) Lactate >2.0 mmol/​L following criteria:
(a) Altered mental status
(b) C old/​clammy skin and
extremities
(c) U rine output <30 mL/​
hour
(d) Lactate >2.0 mmol/​L
bpm, beats per minute; CAD, coronary artery disease; CI, cardiac index; CS, cardiogenic shock; ESC, European Society of Cardiology; IRA, infarct-​related artery; LV, left ventricular; LVEF,
left ventricular ejection fraction; PCI, percutaneous coronary intervention; PCWP, pulmonary capillary wedge pressure; SBP, systolic blood pressure.
*
Not required in anterior infarction or if pulmonary congestion on chest X-​ray.

E Stage E: ‘Extremis’ CS. Patients experiencing cardiac arrest with

ongoing cardiopulmonary resuscitation (CPR) and/or ECMO
Extremis

Stage D: CS signals deteriorating or ‘doom’. Similar to

D
stage C, but getting worse and failing to respond to
Deteriorating initial interventions

Stage C: Classical CS. Manifest CS with hypoperfusion

C requiring intervention (inotropes, vasopressors, or MCS,
Classical cardiogenic shock excluding ECMO) beyond volume resuscitation to
restore perfusion

Stage B: Clinical evidence of relative hypotension

B or tachycardia without hypoperfusion, being at
Beginning cardiogenic shock ‘beginning’ of CS (pre-shock)

Stage A: Currently no signs/symptoms

A of CS, but being ‘at risk’ of its
At risk of cardiogenic shock development development

Figure 47.1  Cardiogenic shock pyramid according to SCAI definition. There are five categories of cardiogenic shock: stage A, at risk—​patients ‘at risk’ of CS
development, but not currently experiencing signs/​symptoms of CS; stage B: patients with clinical evidence of relative hypotension or tachycardia without
hypoperfusion, being at ‘beginning’ of CS; stage C: patients in the state of ‘classic’ CS; stage D: CS signals deteriorating or ‘doom’; stage E: patients in ‘extremis’
such as those experiencing cardiac arrest with ongoing CPR and/​or ECMO CPR.
Reproduced from Thiele H, Ohman EM, de Waha-​Thiele S, Zeymer U, Desch S. Management of cardiogenic shock complicating myocardial infarction: an update 2019. Eur Heart J
2019;40(32):2671–​2683. doi:10.1093/​eurheartj/​ehz363 with permission from Oxford University Press.
636 CHAPTER 47   L ow cardiac ou tpu t stat es a n d ca rdi o g en i c sho ck

Acute myocardial infarction

systolic diastolic
dysfunction
Ventilation LVEDP
Lung oedema
Inotropes/ SIRS Cardiac output
+ +
vasopressors Stroke volume

Mechanical
support: + Hypotension
eNOS Hypoxia
IABP/LVAD/ Peripheral perfusion
Bleeding/ iNOS
ECMO Coronary
transfusion
perfusion
Ischaemia
Reperfusion: +
PCI/CABG NO
Peroxynitrite Vasoconstriction
Fluid retention Progressive
Interleukins
left ventricular
TNF-α
dysfunction

SVR
Pro-inflammation
Catecholamine sensitivity Death
Contractility

Figure 47.2  Pathophysiological concept of the expanded shock spiral. Treatment options, such as (1) reperfusion by PCI or CABG, (2) mechanical support
by IABP or LVAD, (3) inotropes or vasopressors, and (4) ventilation to reverse the shock spiral, are shown on the left-​hand side in red. Potential drawbacks of
therapeutic interventions, including bleeding complications and influence on systemic inflammation, are shown. CABG, coronary artery bypass grafting; eNOS,
endothelial nitric oxide synthase; IABP, intra-​aortic balloon pump; iNOS, inducible nitric oxide synthase; LVAD, left ventricular assist device; LVEDP, left ventricular
end-​diastolic pressure; NO, nitric oxide; PCI, percutaneous coronary intervention; SIRS, systemic inflammatory response syndrome; SVR, systemic vascular
resistance; TNF, tumour necrosis factor.
Reproduced from Thiele H, Allam B, Chatellier G, Schuler G, Lafont A. Shock in acute myocardial infarction: the Cape Horn for trials?. Eur Heart J 2010;31(15):1828–​1835. doi:10.1093/​
eurheartj/​ehq220 with permission from Oxford University Press.

with a high concordance index, indicating that these algorithms (3 or 4 points), and high risk categories (5–​9 points) have a 30-​
are applicable to both populations [28, 29]. day mortality risk of 20–​30%, 40–​60%, and 70–​90%, respectively.
In the PCI era, several clinical and biological factors have been This score may also be a suitable tool to tailor more aggressive
used for prognosis assessment. Those factors have been summar- treatment strategies such as MCS. However, this requires further
ized in multiple scores in the following settings:  (1) pre-​shock; validation in randomized trials. There are also scores for predic-
(2) full CS; and (3) MCS with ECMO (see E Table 47.2). In clin- tion of outcome in patients with MCS, mainly ECMO (see E
ical practice, CS encompasses a spectrum ranging from stage B Table 47.2).
(beginning or pre-​shock) to overt, severe, or extremis shock In addition to the above described scores, initial haemo-
stages C–​E (see E Figure 47.1). Identifying the pre-​shock state is dynamic parameters are predictive of short-​term mortality. The
appealing as it may reduce mortality by preventing progression to strongest haemodynamic predictor is the cardiac power index
overt CS through initiating adequate management strategies. The which is derived from the product of the simultaneously meas-
best validated score in this setting is the recently introduced ORBI ured cardiac index (CI) and the MAP. Therefore, by coupling both
(Observatoire Régional Breton sur l’Infarctus) score to predict the pressure and flow domains of the cardiovascular system, this is a
development of CS [30]. Based on 11 routinely collected variables measure of cardiac pumping [32]. It is calculated by (CI × MAP
available in the catheterization laboratory, the ORBI score allows × 0.0022) and is expressed as W/​m2. Among CS patients under-
predicting independently the development of in-​hospital CS after going PCI, the time from symptom onset or FMC to PCI and the
primary PCI (low risk, 0–​7 points; low to intermediate risk, 8–​ post-​PCI TIMI flow grade are also independent predictors of
10 points; intermediate to high risk, 11–​12 points; high risk, >13 mortality [33, 34].
points).
Until recently, a limitation of all published scores in the setting
of classical CS was the lack of sufficient validation and also applic- Treatment
ability in clinical practice. Currently, there is only one CS score
with both internal and external validation derived from the IABP-​ Revascularization
SHOCK II trial (see E Table 47.2) [31]. Based on six variables—​ The SHOCK trial is one of the most important randomized
including biomarkers lactate, creatinine, and glucose—​with a trials in CS [14]. Based on this trial, early revascularization is
maximum of 9 points, this IABP-​SHOCK II score is divided into the most important treatment strategy in CS after AMI [14]. Of
three risk categories—​patients in low (0–​2 points), intermediate note, the trial failed to meet the primary endpoint of lowering
 T re atm e n t 637

Table 47.2  Risk classification and scores in cardiogenic shock

Study Year Components Development database (n) Validation database (n)

Scores to predict development of CS
Obling et al. [114] 2018 Age 2247 STEMI patients treated –​
Stroke by primary PCI from a bicentric
Symptom onset to intervention registry in Denmark
Anterior STEMI
Heart rate/​SBP ratio
Comatose status after resuscitation from cardiac arrest
ORBI risk score 2018 Age >70 years (2 points) 6838 patients without CS 2208 from RICO cohort
Auffret et al. [30] Prior stroke/​TIA (2 points) on admission and treated by
Cardiac arrest upon admission (3 points) primary PCI included in the
Anterior STEMI (1 point) ORBI
FMC-​to-​PCI delay >90 minutes (2 points)
Killip class (2 points)
Heart rate >90 bpm (3 points)
Combination of SBP <125 mmHg and pulse pressure
<45 mmHg (4 points)
Glycaemia >10 mmol/​l (3 points)
Culprit lesion left main (5 points)
Post-​PCI TIMI flow <3 (5 points)
Scores in overt CS
ALKK 2004 Left main disease 1333 from ALKK registry –​
Zeymer et al. [33] TIMI flow <3 after PCI
Older age
Three-​vessel disease
Longer time intervals between symptom onset and PCI
Sutton et al. [115] 2005 Previous MI 113 –​
Age >70 years
Failed reperfusion
ACC-​NCDR 2005 Age 483 from ACC-​NCDR –​
Klein et al. [116] Female gender
Creatinine >2.0 mg/​dL
Total occlusion of the LAD
No stent used
No GPI used
TRIUMPH trial 2009 SBP 396 from TRIUMPH trial 79 from SHOCK-​2 trial
Katz et al. [117] Creatinine clearance
Number of vasopressors
Noradrenaline dose
SHOCK trial 2010 Clinical score: 1217 from SHOCK trial and –​
Sleeper et al. [118] Age registry
Anoxic brain damage
End-​organ hypoperfusion
Shock on admission
Prior CABG
Non-​inferior infarction
Creatinine ≥1.9  mg/​dL
SBP
SHOCK trial 2010 Haemodynamic + clinical score: 872 from SHOCK trial and –​
Sleeper et al. [118] Stroke work registry
LVEF <28%
Age
Anoxic brain damage
End-​organ hypoperfusion
638 CHAPTER 47   L ow cardiac ou tpu t stat es a n d ca rdi o g en i c sho ck

Table 47.2  Continued

Study Year Components Development database (n) Validation database (n)

CARD-​SHOCK 2015 Prior CABG 219 multicentre European 384 from IABP-​SHOCK II trial
Harjola et al. [119] ACS aetiology registry
Confusion
Previous infarction
Lactate
LVEF
Age
SBP
IABP-​SHOCK II 2017 Age >73 years (1 point) IABP-​SHOCK II study (600) IABP-​SHOCK II
risk score History of stroke (2 points) Registry (188)
Pöss et al. [31] Glucose >191 mg/​dL (10.6 mmol/​L) (1 point) CardShock (137)
Creatinine >1.5 mg/​dL (>132.6 micromoles/​l) (1 point)
Lactate >5 mmol/​L (2 points)
TIMI flow <3 after PCI (2 points)
Scores for CS patients on VA-​ECMO
SAVE (ECMO) 2015 Cause of CS 3846 patients from 161 in Australian population
Schmidt et al. [120] Age Extracorporeal Life Support with VA-​ECMO
Weight Organization (ELSO) registry
Pre-​ECMO organ failures
Chronic renal failure
Pre-​ECMO cardiac arrest
Duration of intubation prior to ECMO
Peak inspiratory pressure
HCO3–​
Diastolic blood pressure
Pulse pressure
ENCOURAGE 2016 Age >60 138 derived from bicentric –​
Muller et al. [121] Female sex ECMO registry
Body mass index >25 kg/​m2
Glasgow Coma Scale score <6
Creatinine >150 micromoles/​L
Lactate <2, 2–​8, or >8 mmol/​L
Prothrombin activity <50%
PREDICT-​VA 2018 Lactate 205 VA-​ECMO patients from 244 patients recruited from
ECMO Score pH single-​centre registry an independent tertiary
Wengenmayer et al. HCO3–​ referral hospital
[122]
ACC-​NCDR, American College of Cardiology–​National Cardiovascular Data Registry; ACS, acute coronary syndrome; CABG, coronary artery bypass grafting; CS, cardiogenic shock;
ECMO, extracorporeal membrane oxygenation; FMC, first medical contact; GPI, glycoprotein IIb/​IIIa inhibitor; HCO3–​, bicarbonate; IABP, intra-​aortic balloon pump; LAD, left anterior
descending; MI, myocardial infarction; ORBI, Observatoire Régional Breton sur l’Infarctus; PCI, percutaneous coronary intervention; SBP, systolic blood pressure; STEMI, ST-​segment
elevation myocardial infarction; TIA, transient ischaemic attack; TIMI, Thrombolysis In Myocardial Infarction; VA-​ECMO, veno-​arterial extracorporeal membrane oxygenation.

30-​day mortality with early revascularization, in comparison Recent registries have suggested a detrimental effect of
to initial medical stabilization. However, there was a signifi- revascularization delays on outcome [34,  41]. Therefore, efforts
cant mortality reduction at longer follow-​up after 6  months need to be directed towards immediate transfer to 24/​7 PCI ter-
and 1 and 6  years [14,  35]. Since the widespread use of early tiary care centres. There is a lack of evidence to support fibrin-
revascularization, multiple registries have confirmed the sig- olysis in CS. However, if an early invasive approach cannot be
nificant decrease in mortality from the previous 70–​80% to 40–​ completed in a timely fashion, fibrinolysis may be considered in
50% [2]‌. Therefore, the current Class 1B recommendation in CS associated with STEMI [23].
ESC and US guidelines seems to be more than justified (see E
Figure 47.3) ]36–​38]. Revascularization strategy
The apparent lack of benefit for the elderly in the SHOCK trial Approximately 70–​ 80% of patients with CS present with
was likely due to imbalances between the groups. Several sub- multivessel CAD with additional stenoses/​occlusions, in addition
sequent studies, including the SHOCK registry, have shown a to the IRA [5]‌. These patients have higher mortality, compared to
consistent benefit of revascularization in elderly patients, which patients with single-​vessel disease [42]. Current guidelines rec-
suggests that clinicians are capable of identifying those older pa- ommend early revascularization by PCI or CABG, depending on
tients who are appropriate for revascularization [39, 40]. the coronary anatomy and amenability to PCI [36–​38].
 T re atm e n t 639

Cardiogenic shock complicating infarction (STEMI or NSTEMI)

Emergency invasive angiography (IB)

Immediate echocardiography (IC)
Cause of Left ventricular dysfunction (~80%) Right ventricular dysfunction (~7%) Mechanical complication (~13%)
cardiogenic shock
VSD (~4%) MR (~7%) Free wall rupture (~2%)

Heart team
Catheterization
laboratory/OR

Surgical/interventional Mitral repair/ Surgery (1C)

closure (IC) replacement (IC) pericardiocentesis
Emergency PCI of culprit lesion (IB)
Emergency CABG (if not amenable to PCI) (IB) Emergency PCI of culprit lesion in case of interventional treatment
(IB)
No routine PCI of non-IRA lesions (III B) Simultaneous CABG in case of surgical treatment (IB)

Fluid challenge as first-line therapy if no sign of overt fluid overload (1C)

goal 65 mmHg, optimal
mean blood pressure

end-organ perfusion,
General measures:

lactate clearance

Invasive blood pressure monitoring (1C)

Pulmonary artery catheter (IIb/C)
Ventilatory support/O2 according to blood gases (1C)
Intravenous inotropes to increase cardiac output (IIb/C)
Vasopressors (noradrenaline preferable over dopamine) in presence of persistent hypotension (IIb/B)
Ultrafiltration in refractory congestion not responding to diuretics (IIb/C)

No routine IABP (III B) IABP (IIa/C)

circulatory support
Mechanical

Stabilization? No
Yes
Weaning Short-term percutaneous MCS in selected patients/refractory cardiogenic shock (IIb/C)

Yes Recovery cardiac function?

No
Weaning Severe neurological deficit?
Yes No Age, comorbidities?
Long-term surgical MCS

Bridge-to recovery Destination therapy Bridge-to transplant

Figure 47.3  Treatment algorithm for patients with CS complicating myocardial infarction. The class of recommendation and level of evidence according to
the most recent ESC guidelines are provided, if available [36, 37, 60]. Class I recommendations are depicted in green. Class IIa recommendations are depicted in
yellow. Class IIb recommendations are depicted in orange. Class III recommendations are depicted in red.
Reproduced from Thiele H, Ohman EM, de Waha-​Thiele S, Zeymer U, Desch S. Management of cardiogenic shock complicating myocardial infarction: an update 2019. Eur Heart J
2019;40(32):2671–​2683. doi:10.1093/​eurheartj/​ehz363 with permission from Oxford University Press.

Until recently, guidelines encouraged to perform multivessel revascularization should be limited to the culprit lesion, with
PCI of all critical stenoses, in addition to the culprit lesion possible staged revascularization of other lesions at a later time
(Class IIa C recommendation) in CS [37]. Recently, the random- point. Some specific angiographic scenarios, such as subtotal
ized, multicentre CULPRIT-​SHOCK trial showed a significant non-​culprit lesions with reduced TIMI flow or multiple possible
clinical benefit of a culprit-​lesion-​only strategy with a reduc- culprit lesions, may benefit from immediate multivessel PCI.
tion in the primary endpoint of 30-​day mortality or RRT (45.9% However, this should be considered on an individual basis.
culprit-​lesion-​only PCI versus 55.4% immediate multivessel PCI; There may also be a role for emergent CABG; however, there
relative risk 0.83; 95% CI 0.71–​0.96; P  =  0.01). This result was is little evidence to guide surgical versus PCI revascularization.
mainly driven by an absolute reduction in 30-​day mortality of Based on evidence from four observational reports, comparing
8.2% (43.3% versus 51.5%; relative risk 0.84; 95% CI 0.72–​0.98; PCI versus CABG, the type of revascularization did not influence
P = 0.03) [43]. Based on this trial, the ESC 2018 revascularization outcome in CS [45]. Despite these considerations and in contrast
guidelines now advise against routine immediate multivessel PCI to the SHOCK trial (37.5% underwent immediate CABG), CABG
(Class  III B recommendation) (see also E Figure 47.3) [36]. is nowadays rarely performed in CS, with rates of <5% in regis-
The 30-​day results of CULPRIT-​SHOCK could be confirmed tries and randomized trials [2, 46].
recently with a consistent reduction in the composite endpoint E Figure 47.4 presents the recommended revascularization
at 1-​year follow-​up for the culprit-​lesion-​only PCI with a pos- strategies according to the extent of coronary disease of the in-
sible staged revascularization strategy [44]. The difference in all-​ dividual patient.
cause mortality was slightly attenuated and, as expected, more
patients underwent additional revascularization after culprit-​ Transradial versus transfemoral approach
lesion-​only PCI. The CULPRIT-​SHOCK results were consistent In haemodynamically stable AMI patients, randomized data
across all predefined subgroups [43, 44]. Thus, in clinical practice, demonstrated superiority of transradial over transfemoral access
640 CHAPTER 47   L ow cardiac ou tpu t stat es a n d ca rdi o g en i c sho ck

Cardiogenic shock complicating infarction (STEMI or NSTEMI)

Emergency invasive angiography (IB)
Emergent setting
One-vessel disease Two-vessel disease Three-vessel disease
Amenable to PCI?
Yes No

Emergency PCI of culprit lesion (IB) Emergency PCI of culprit lesion (IB) Emergency PCI of culprit lesion (IB) Emergency CABG (IB)

In case of failed PCI of culprit lesion Emergency CABG (IIa C)

No routine immediate PCI of non-IRA No routine immediate PCI of non-IRA

lesions (III B) lesions (III B)

Non-emergent setting after stabilization

Staged PCI of non-culprit lesions Staged PCI of non-culprit lesions
based on ischaemia or symptoms based on ischaemia or symptoms

Figure 47.4  Treatment algorithm for the use of revascularization therapies depending on the coronary anatomy. Class I recommendations are depicted in
green. Class IIa recommendations are depicted in yellow. Class IIb recommendations are depicted in orange. Class III recommendations are depicted in red.

[47–​49]. In CS, the benefit of transradial access is uncertain and upstream therapy with the GPI abciximab did not show any clin-
has only been retrospectively investigated in registries and one ical benefit [51].
small subanalysis of the RIFLE-​STEACS trial [50]. Theoretically, In CS, the use of antithrombotic agents administered PO (e.g.
a reduction of all-​cause mortality driven by significant reduction clopidogrel, prasugrel, ticagrelor) in the acute phase may be
of bleeding could also translate into improved prognosis in CS limited or even impossible. Even if crushed drug administra-
patients. A  meta-​analysis analysing data on 8131 patients dem- tion via a gastric tube is performed, GI absorption of these drugs
onstrated that transradial access was associated with a reduction may be delayed and does not guarantee optimal platelet inhib-
in all-​cause mortality, as well as major adverse cardiac and cere- ition during PCI [52]. Accordingly, the use of IV antiplatelet
bral events at 30-​day follow-​up in CS patients. The mechanisms agents, such as acetylsalicylic acid [53], glycoprotein receptor
behind this potentially improved outcome following transradial blockers [54], or cangrelor [55], and IV anticoagulants like
access have not been fully elucidated yet. Most likely, bleeding-​ UFH, LMWH, or bivalirudin is desirable to achieve an effective
related haemodynamic instability and other adverse influences, antithrombotic strategy in the setting of PCI. An ongoing trial
such as blood transfusion-​related oxidative stress, may be espe- is currently testing the IV use of the P2Y12 inhibitor cangrelor
cially critical in CS patients. Further, due to a lower rate of ac- in this setting—​the Dual Antiplatelet Therapy for Shock pa-
cess site bleeding, patients undergoing transradial access could tients with Acute Myocardial Infarction (DAPT-​SHOCK-​AMI)
be more likely to receive aggressive antithrombotic therapy such trial (ClinicalTrials.gov identifier:  NCT03551964). At present,
as GPIs. In general, in patients with a palpable radial pulse, the the ESC STEMI guidelines should be followed with respect to
transradial access appears to be at least feasible. The radial ac- antithrombotic therapy in CS [37].
cess site may thus be used by experienced interventionalists in
Fluids and catecholamines
CS. However, the radial route poses many potentially time-​
consuming technical challenges and the catheterization team CS treatment includes initial stabilization with volume expansion
should be prepared for a quick crossover to transfemoral access to obtain optimal filling pressures, vasopressors, and inotropes,
in case of difficulties. Operators without extensive experience in plus additional therapy for multiorgan system dysfunction
transradial access are well advised to stick to a familiar (usually (see E Figure 47.3). Fluid administration is mainly based on
femoral) access or at least have a low threshold for crossover to a pathophysiological considerations and has not been studied in
femoral approach. adequate RCTs. The same applies to catecholamines, with patho-
physiological considerations being based on the observation that
stunned myocardium requires time until functional recovery after
Adjunctive medical treatment revascularization. This time should be bridged by inotropic and/​
Antithrombotic drugs or vasopressor support. The choice of catecholamine is mainly
No specific randomized trials on optimal antithrombotic treat- based on individual experience, institutional policy, and patho-
ment of patients with CS are available, with the exception of the physiological considerations. The mode of action of different
relatively small PRAGUE-​7 study (n  =  80 patients), in which inotropes and vasopressors has been summarized in the AHA
 A dj u n cti ve mon i tori n g a n d   t re atm e n t 641

scientific statement [23]. Despite the favourable haemodynamic in ESC guidelines. This reflects the uncertainty in this field due to
effects of all catecholamines, none has produced consistent im- the lack of EBM and the need for large randomized trials in CS.
provement in symptoms and many have shortened survival [56].
These findings may be related to the fact that these agents in-
crease myocardial O2 consumption and also the concentrations Adjunctive monitoring
of cAMP, producing an increase in intracellular Ca2+ that possibly
leads to myocardial cell death and/​or increases lethal arrhythmias and treatment
[57]. As a consequence, all catecholamines should be used in the Haemodynamic management
lowest possible doses and for the shortest period of time.
In addition to non-​invasive monitoring by echocardiography,
A number of trials have compared some of these drugs, par-
PACs are frequently used in heart failure to confirm the diagnosis
ticularly dopamine with noradrenaline, but the largest trial was
of CS, to ensure that filling pressures are adequate, and to guide
performed in patients with predominant septic shock. In this situ-
changes in therapy. The best use of this technique is to establish
ation, dopamine was not associated with an increase in mortality
the relationship of filling pressures to the cardiac index in the in-
in the overall shock population [58]. However, there was a higher
dividual patient and additional clinical assessment of responses.
incidence of arrhythmic events, compared to noradrenaline ad-
Haemodynamic data derived from PAC measurements, particu-
ministration. In this large (n  =  1679) multicentre, double-​blind,
larly cardiac power and stroke work index and also RV indices,
randomized trial, a total of 280 patients (17%) with CS were in-
have powerful short-​term prognostic value [32]. In addition, PAC
cluded [58]. In the pre-​specified subgroup with CS (only a minority
yields useful information on right atrial pressure, PAP, PCWP,
with CS complicating AMI), there was a mortality decrease in the
mixed venous oxygenation, SVR, PVR, and pulmonary artery
noradrenaline group. Based on the recent Study Comparing the
pulsatility index (PAPI) [67]. In recent years, there has been a de-
Efficacy and Tolerability of Epinephrine and Norepinephrine in
cline in PAC use, relating to controversy regarding the benefit,
Cardiogenic Shock (OptimaCC) trial suggesting fewer side effects
as shown in a meta-​analysis [68]. Individualized PAC use is now
and less refractory CS with noradrenaline, compared with adren-
recommended for the monitoring of haemodynamic variables or
aline [59], noradrenaline may be the vasoconstrictor of choice
to monitor treatment in patients with severe heart failure not re-
when blood pressure is low and tissue perfusion is insufficient
sponding to appropriate treatment [60]. Clinical assessment with
(Class IIb, LoE B in ESC guidelines) (see E Figure 47.3) [37, 60].
echocardiography is a reasonable alternative. Consensus docu-
The most recent ESC guidelines for the diagnosis and treat-
ments give recommendations on the use of haemodynamic moni-
ment of AHF and chronic heart failure were published in 2016
toring in circulatory shock and in CS [23, 69].
[60]. In these guidelines, treatment with inotropic drugs (e.g.
dobutamine) in patients with hypotension (SBP <85  mmHg)
and/​or hypoperfusion is classified as a Class IIb recommendation
Glucose control
(LoE C) [60]. Vasopressin has not been studied in the CS setting. Patients in CS, as well as other patients in intensive care medi-
Therefore, no recommendations based on evidence can be made. cine, often develop hyperglycaemia as a result of relative in-
The target MAP is also not well defined in CS. In analogy to septic sulin resistance and accelerated glucose production. It is also
shock, an MAP of >65 mmHg is probably not required and may well known that the glucose level at admission is a strong inde-
be associated with more side effects [61]. pendent predictor for mortality in patients with and without a
To overcome these problems inherited with catecholamines, previous diagnosis of diabetes mellitus. The Normoglycemia in
there has been increasing interest in pharmacological agents Intensive Care Evaluation–​ Survival Using Glucose Algorithm
acting on contractility without the drawbacks of catechol- Regulation (NICE-​SUGAR) trial showed a mortality increase in
amines. Among these, levosimendan is a Ca2+ sensitizer and a patients with intensive insulin treatment, presumably caused by a
K+–​ ATP channel opener, improving myocardial contractility. higher incidence of hypoglycaemia. Therefore, glycaemic control
It might be an ideal agent in CS, because, in comparison to to target a blood glucose concentration of between 144 mg/​dL
other inodilators, it improves myocardial contractility without and 180 mg/​dL (8–​10  mmol/​L), yet avoiding hypoglycaemia, is
increasing O2 requirements and induces peripheral and cor- recommended [70].
onary vasodilatation with a potential anti-​stunning and anti-​
ischaemic effect. However, current evidence for inodilators such Renal replacement therapy
as levosimendan and also phosphodiesterase inhibitors in CS is Urinary production, as well as renal function by serial creatinine
very limited. A very small trial of 32 CS patients suggested lower measurements, should be measured and RRT initiated in cases of
mortality with levosimendan, in comparison to enoximone [62]. acute renal failure with clinical signs of uraemia, otherwise un-
However, recent large-​scale trials involving >2200 patients in treatable volume overload, metabolic acidosis (pH <7.2), and/​or
sepsis or cardiac surgery—​no CS—​failed to show any benefit refractory hyperkalaemia (>6.0 mmol/​L). Based on these criteria,
with levosimendan on mortality or organ protection [63–​66]. RRT was necessary in 14% of patients in the CULPRIT-​SHOCK
Treatment with levosimendan or a phosphodiesterase inhibitor trial [43]. Earlier initiation of RRT had no effect on outcome in
is classified as Class IIb recommendation, with also Class C LoE ICU patients with AKI [71].
642 CHAPTER 47   L ow cardiac ou tpu t stat es a n d ca rdi o g en i c sho ck

Liver function Hypothermia
Elevated liver parameters often follow generally poor haemo- In most of the randomized hypothermia trials on out-​of-​hospital
dynamic status as a result of RV congestion. Liver function tests cardiac arrest, patients in CS were excluded. Nevertheless, tem-
are altered in >50% of CS patients [72]. Elevated transaminases perature management is generally applied and recommended for
can be interpreted as a direct sign of liver hypoperfusion, asso- patients with CS after resuscitation [77]. In the IABP-​SHOCK II
ciated with increased mortality [72]. Haemodynamics should be and CULPRIT-​SHOCK trials, >40% and 50% of patients, respect-
stabilized for optimal liver perfusion. ively, were resuscitated before randomization with subsequent in-
duced hypothermia, showing the relevance of this condition in CS
Bleeding and haemoglobin targets [43,  46]. In non-​resuscitated CS patients, experimental, animal,
Moderate/​severe bleeding is common in CS, ranging from 20% and early human data suggested beneficial effects of hypothermia
to 90%, depending on the definition used and also influenced by on haemodynamics and multiple other targets [78]. However,
concomitant use of MCS [5, 73]. Trials in non-​CS patients with the recent randomized Mild Hypothermia in Cardiogenic Shock
bleeding demonstrated that a restrictive transfusion regimen can Complicating Myocardial Infarction (SHOCK-​COOL) trial in
improve outcome. General accepted ICU strategies avoid correc- non-​resuscitated CS patients showed no benefit of hypothermia
tion of Hb levels of >7 g/​dL (>4.3 mmol/​L), unless there is a clin- versus standard treatment on the surrogate endpoint cardiac
ical bleeding problem [74]. power index. Moreover, there was possible harm of hypothermia,
as shown by impaired lactate clearance [79].
Mechanical ventilation
Mechanical ventilation is highlighted in more detail in E
Chapters 17 and 22. In brief, oxygenation and airway protection Percutaneous mechanical
are critical in the therapy of patients with AHF syndromes and/​ circulatory support
or CS; intubation and mechanical ventilation are commonly re-
quired. However, although PPV may improve oxygenation and A more detailed description of MCS is provided in E Chapter 28.
reduce work of breathing, it may also compromise venous return,
preload, and thus cardiac output (see E Figure 47.2). Studies in Intra-​aortic balloon pump
patients with ACPO have shown NIV to improve haemodynamics IABP is a mature technology after approximately five decades of
and reduce the intubation rate [75]. However, mortality remained use. Through diastolic inflation and rapid systolic deflation in the
unaffected. aorta, it improves the peak diastolic pressure and lowers the end-​
In patients with CS and low cardiac output state not re- systolic pressure without any effect on the MAP. Furthermore,
sponding to initial more conservative measures, including NIV, other haemodynamic effects on cardiac output are negligible [80].
endotracheal intubation and invasive mechanical ventilation In the large-​scale IABP-​SHOCK II trial, there was no difference
represent an important therapeutic option. The primary indica- in the primary study endpoint of 30-​day mortality between the
tion for this option is respiratory failure leading to hypoxaemia two treatment groups and these results were confirmed by a lack
(e.g. SpO2 <90%, PaO2 <6–​7 kPa), hypercapnia (respiratory rate of beneficial effects for any of the secondary study endpoints and
>30–​35/​minute), and acidosis (increased CO2 pressure in arterial mortality after 1 year [46, 81]. Just recently, the 6-​year data con-
blood—​PaCO2 >9–​10 kPa or pH <7.3 demonstrating that the pa- firmed no benefit of IABP on long-​term outcome [82]. Therefore,
tient cannot maintain a normal pH by spontaneous breathing) routine use of IABP cannot be recommended, based on current
[76]. Invasive mechanical ventilation can decrease the negative evidence, and should be limited to patients with mechanical com-
sequelae of difficult breathing at a time of severely impaired car- plications (see E Figure 47.3).
diac function. Physical exhaustion/​patient discomfort, dimin- The impact on clinical practice of the IABP-​SHOCK II results
ished consciousness, and the inability to maintain or protect the and the downgrading in guidelines has been shown in multiple
airway are other reasons to consider intubation and ventilation. registry trials, with a steady decline in IABP use and a subsequent
Non-​ invasive methods of positive pressure ventilation [non-​ increase in active MCS [83–​85].
invasive positive pressure ventilation (NIPPV)] in patients with
ACPO can avert tracheal intubation [75]. NIPPV induces a more Percutaneous active mechanical circulatory
rapid improvement in respiratory distress and metabolic dis- support devices
turbance than does standard O2 therapy. However, no mortality Active percutaneous MCS devices have been used in patients not
benefit was detected over O2 for either continuous or bilevel NIV responding to standard treatment, including catecholamines,
[76]. NIPPV in cooperative, fully conscious (not fatigued) pa- fluids, and IABP, and also as a first-​line treatment. Current experi-
tients with pulmonary oedema, with the aim to improve breath- ence and use are increasing, but evidence is still limited [73]. The
lessness and reduce hypercapnia and acidosis, has recently been current devices and mode of action of these MCS devices in CS
categorized as Class IIa, LoE B in the ESC heart failure guidelines have been summarized previously and also in E Chapter 28 [22].
[60]. NIPPV is considered contraindicated in cases of electrical E Figure 47.5 shows current percutaneous MCS devices and
instability and vomiting [76].
 Percu ta n eou s m echa n i ca l ci rcu l atory   supp ort 643

Right Left ventricular support

ventricular support

2.5
(a) Impella RP (b) TandemHeart (c) VA-ECMO (d) IABP (e) Impella 3.5
5.0
(f) TandemHeart (g) iVAC 2L
RA-PA

Flow: max. 4.0 L max. 4.0 L max. 7.0 L 2.5–5.0 L max. 4.0 L max. 2.8 L
Pump speed: 33.000 rpm max. 7.500 rpm max. 5000 rpm max. 51.000 rpm max. 7.500 rpm 40 ml/beat
Cannula size: 22 F 29 F 14–19 F arterial 12–14 F 12–19 F arterial 17 F
17–21 F venous 7–8 F 21 F venous
Insertion/ Femoral vein Internal jugular Femoral artery Femoral artery Femoral artery Femoral artery Femoral artery
Placement vein Femoral vein Femoral vein
for LA access
LV unloading – – – (+) +–++ ++ +
RV unloading + + ++ – – – –

Figure 47.5  Schematic drawings of current percutaneous mechanical support devices for cardiogenic shock, with technical features. On the left-​hand side are
devices for right ventricular support, and on the right-​hand side those for left ventricular support. (a) Impella® RP; (b) TandemHeart™ RA-​PA; (c) VA-​ECMO;
(d) IABP; (e) Impella®; (f) TandemHeart™; (g) iVAC 2L®. IABP, intra-​aortic balloon pump; RA-​PA, right atrium–​pulmonary artery; VA-​ECMO, veno-​arterial
extracorporeal membrane oxygenation.
Reproduced from Thiele H, Ohman EM, de Waha-​Thiele S, Zeymer U, Desch S. Management of cardiogenic shock complicating myocardial infarction: an update 2019. Eur Heart J.
2019;40(32):2671–​2683. doi:10.1093/​eurheartj/​ehz363 with permission from Oxford University Press.

provides an updated overview on technical features, including RV Impella®-​treated versus 237 otherwise treated CS patients could
and LV or biventricular support. confirm a lack of mortality benefit with the Impella® device (30-​
day mortality 48.5% versus 46.4%, respectively; P  =  0.64) [90].
TandemHeart™ Of note, severe or life-​threatening bleeding (8.5% versus 3.0%;
This device has been tested in two small randomized trials, with P  <0.01) and peripheral vascular complications (9.8% versus
improvement in haemodynamic parameters; however, it was also 3.8%; P = 0.01) were observed more frequently with the Impella®
associated with more complications. In addition, there was also device.
no observed trend in 30-​day mortality [86, 87]. A recent meta-​analysis of active MCS devices against control,
including the IMPRESS-​in-​severe-​SHOCK trial, showed no dif-
Impella® family
ference in overall mortality for 148 included randomized patients.
The 2.5 L Impella® version has been tested in a small RCT in 26 There were improvements in arterial lactate and MAP after de-
CS patients, in comparison to IABP, showing an improved car- vice insertion. On the other hand, there were no effects on other
diac index with the use of the Impella® device. In the IMPRESS-​ haemodynamic parameters and, more importantly, the haemo-
in-​severe-​SHOCK trial, 48 patients with CS complicating STEMI dynamic effects were counterbalanced by significantly more
and a need for mechanical ventilation underwent randomization bleeding complications [73]. Currently, there is another ongoing
to Impella® CP versus IABP [88]. This trial had 30-​day mortality Danish and German (DanGer) randomized trial on the newly
as a primary endpoint. However, this trial was based on a power introduced Impella® CP, in comparison to standard treatment,
calculation with non-​realistic mortality rates, and thus this trial with or without IABP, powered for a mortality endpoint [91].
is markedly underpowered. The patients included were not in
severe CS and mortality rates at 6-​month follow-​up were very HeartMate PHP™
similar to other much larger trials. It is thus not surprising that Currently, this device is not available on the market.
there was no difference in the primary endpoint of all-​cause mor-
tality after 30 days. However, the lack of benefit in any of the other iVAC 2L®
parameters, including lactate, is a concern with respect to the ef- Data on this device are limited to small case series and the clinical
ficacy of the device and the concept of MCS. Being largely under- impact of this device needs to be further investigated [92].
powered, IMPRESS-​in-​severe-​SHOCK can thus only be regarded
as a feasibility trial. Reasons for the failure of this concept can Extracorporeal life support systems
be found in the accompanying editorial for IMPRESS-​in-​severe-​ The integral features of ECMO are a blood pump, a heat exchanger,
SHOCK [89]. Recently, a matched-​pair mortality analysis of 237 and an oxygenator (see E Figure 47.4). Previous devices with
644 CHAPTER 47   L ow cardiac ou tpu t stat es a n d ca rdi o g en i c sho ck

predominant surgical insertion were inherited with substantial together, although MCS with LV or RV devices or ECMO is
complications such as lower extremity ischaemia (16.9%), com- theoretically appealing to interrupt the vicious spiral of is-
partment syndrome (10.3%), amputation (4.7%), stroke (5.9%), chaemia, hypotension, and myocardial dysfunction, allowing
major bleeding (40.8%), and significant infections (30.4%) [93]. for the recovery of ischaemic myocardium, extracorporeal sup-
Recent developments with miniaturized systems and percutan- port and contact with artificial surfaces might further promote
eous cannula insertion have led to a wider adoption by inter- inflammation. A second and potentially deleterious complica-
ventional cardiologists for the treatment of CS using VA-​ECMO. tion of these devices is severe bleeding. Currently, percutan-
A common issue related to peripheral insertion is an increase in eous MCS treatment should be restricted to use in refractory
afterload which may lead to inadequate LV unloading. Multiple CS and will rely on individual experience in dedicated centres
venting manoeuvres have been described to prevent LV volume for selected patients. Additional randomized trials are needed
overload such as combining VA-​ECMO with IABP, Impella®, for a more complete assessment of the role of different circula-
atrial septostomy, or others [94]. A recent meta-​analysis summar- tory supportive strategies in CS.
izing the evidence based on observational data suggests a mor- A scheme taking into account different haemodynamic and la-
tality decrease by venting [95]. boratory markers and possible reflections on futility and predom-
Advantages of VA-​ECMO are low costs, in comparison to other inant ventricular failure is shown in E Figure 47.6.
percutaneous devices, a high flow providing full circulatory sup-
port, even in resuscitation situations (stage E CS patients), the
ability to provide full oxygenation, and also combined RV and LV Mechanical complications and right
support (see E Figure 47.4).
Outcome data on VA-​ECMO in CS are scarce. A recent meta-​ ventricular dysfunction
analysis including only prospective and retrospective cohort A more detailed description of mechanical complications is pro-
studies revealed a significant mortality benefit with VA-​ECMO vided in E Chapter 40. This part focuses only on CS.
use [96]. In total, four registries of CS patients and ten registries
of cardiac arrest patients undergoing resuscitation were included Ventricular septal defect
[96]. In cardiac arrest, VA-​ECMO use [ECMO cardiopulmonary
VSD complicating AMI is a relatively rare event associated
resuscitation (eCPR)] was associated with an absolute increase in
with high mortality. The incidence of infarct-​ related VSD
30-​day survival of 13%, compared to the control (95% CI 6–​20%;
without reperfusion ranged from 1% to 2% [101, 102], with a
P <0.001; number needed to treat = 7.7). However, optimal pa-
decrease to 0.2% in the era of reperfusion [103]. Without sur-
tient selection for eCPR is still a matter of intense debate [97]. In
gical repair of post-​infarction VSD, 90% of patients die within
CS, VA-​ECMO resulted in a 33% higher 30-​day survival, com-
2 months [104].
pared to IABP (95% CI 14–​52%; P <0.001; number needed to
The current mortality rate of surgical post-​infarction VSD
treat = 3) [96]. In a small recent randomized trial (n = 42), VA-​
closure—​in a mixture of non-​CS and CS patients—​is as high
ECMO did not result in an improvement in LVEF, in comparison
as 50%, with a decrease in surgical mortality over time [105].
to the control. Mortality rates were also not different [98]. Recent
However, in two prospective registries including only VSD
data indicate that VA-​ECMO is increasingly used within a 9-​year
with CS, mortality rates were as high as 81–​100% [103, 106].
observational period. Despite this rapid increase, the 30-​ day
Current guidelines recommend immediate surgical VSD
in-​hospital mortality remained unchanged over time (59.0% in
closure, irrespective of the patient’s haemodynamic status, to
2007–​2012 versus 61.4% in 2013–​2015; P = 0.94) [99].
avoid further haemodynamic deterioration [37]. Nevertheless,
Ongoing trials include a randomized trial of ECMO in eCPR—​
a subgroup of patients with VSD exists, for whom surgery is
the Prague Out-​of-​Hospital Cardiac Arrest trial (Clinicaltrials.
futile, because mortality approaches 100%; this includes the
gov identifier:  NCT01511666). Furthermore, two randomized
very elderly and patients with poor RV function. As a result
trials are in the early phase of patient recruitment to assess VA-​
of the high mortality and suboptimal surgical results with a
ECMO for CS treatment—​the EURO-​SHOCK (Clinicaltrials.gov
post-​operative residual shunt found in up to 20% of treated
identifier: NCT03813134) and ECLS-​SHOCK (Clinicaltrials.gov
patients, the technique of percutaneous VSD device closure
identifier:  NCT03813134). Both trials are adequately powered
has been developed [107]. Such less invasive approach with
and use 30-​day mortality as the primary endpoint. Until more
a catheter-​based intervention may offer improved survival
data are available, thorough consideration must be used to iden-
or provide haemodynamic stabilization as a bridge to sur-
tify appropriate candidates for VA-​ ECMO support to avoid
gery. Furthermore, it might be used as an adjunctive therapy
unnecessary use, which might consume resources and expose pa-
for residual post-​surgical shunts. Currently, data are limited
tients to possible complications.
for post-​infarction VSD interventional closure. The largest
Based on all these results, percutaneous MCS cannot be re-
single-​centre experience in 29 patients reported a survival rate
commended as first-​line treatment in CS and are currently only
at 30  days of 35%, with much higher mortality in CS, as op-
considered in refractory CS with a Class  IIB, LoE C recom-
posed to non-​shock patients (88% versus 38%; P <0.001) [107].
mendation in ESC guidelines (see E Figure 47.3) [100]. Taken
Procedure-​related complications are frequent, which further
 Mechanica l c o m pl i cati on s a n d ri g ht ven tri cu l a r  dysf un c t i on 645

Impella RP TandemHeart ECLS 2.5

Impella 3.5 TandemHeart ECLS
RA-PA (ECMO) 5.0
(ECMO)
(1a) (1b) (1c) (1) (2) (3)

RV LV
dysfunction dysfunction
predominant predominant
Cardiogenic shock
severity
(a) Lactate ↑↑
(b) Vasopressor doses ↑↑
(c) Shock scores
(d) Haemodynamic parameters
No MCS considerations
(a) Age
(b) Futility
(c) Anoxic brain injury
(d) Comorbidities
Oxygenation
(e) Prolonged resuscitation

ECLS 2.5
(1) (ECMO) (2) Impella 3.5
5.0 (3) TandemHeart

Figure 47.6  Possible treatment algorithm for mechanical circulatory support selection, based on clinical parameters of cardiogenic shock severity and also on
factors which might oppose the use of mechanical circulatory support. Based on predominant right ventricular or left ventricular dysfunction and also on the
requirement for oxygenation, different mechanical circulatory support devices may be considered. Accordingly, schematic drawings of current percutaneous
mechanical support devices are provided and these devices should be considered, with preference of some devices over others, based on the underlying cause of
cardiogenic shock.

demonstrates the requirement for technical improvement. An Acute ischaemic mitral regurgitation

overview of potential technical improvements and outcomes
In acute ischaemic MR, only PMR needs immediate repair. Other
has been described [108]. Furthermore, a meta-​analysis of all
causes, such as LV global or regional remodelling or ischaemic
published reports with percutaneous VSD closure has recently
papillary muscle dysfunction, may resolve after revascularization
been published [109].
and recovery of LV function. Accordingly, only 46% of patients in
the SHOCK trial registry underwent mitral valve surgery [111].
Free wall rupture
In contrast to VSD repair, surgery of PMR does not involve nec-
Since many patients with FWR present with sudden, profound rotic myocardium in suture lines. Therefore, mortality associated
CS, often rapidly leading to PEA caused by pericardial tam- with this repair is lower [111]. The unpredictability of a rapid de-
ponade, there are limited treatment options. However, there terioration and death with PMR makes early surgery necessary,
might also be subacute presentations in cases of a covered rup- even though there may be an initial apparent haemodynamic sta-
ture. An immediate pericardiocentesis can confirm the diag- bilization with initial IABP therapy, which is recommended by
nosis, in addition to echocardiography which is the cornerstone guidelines as a bridge to surgery, although no randomized data
of the diagnostic work-​up. Pericardiocentesis relieves pericar- are available for this condition (see E Figure 47.3) [37]. The first
dial tamponade at least momentarily for an immediate surgical percutaneous approaches with the MitraClip system have also
repair, if available. In a less acute clinical course, this allows for been reported for the treatment of acute ischaemic MR in CS.
potentially lifesaving therapeutic interventions. In the SHOCK However, current evidence is limited to small patient series and
trial registry, 28 patients presented with pericardial rupture or case reports [112].
tamponade. The overall in-​hospital mortality for this specific
cohort, of which 75% underwent surgery, was as low as 39% Right ventricular failure
[110]. However, this was a selected patient group, with not all
The deleterious effect of acute RV dysfunction in patients suf-
having an overt clinical FWR.
fering from AMI with RV involvement are well known [67]. RV
646 CHAPTER 47   L ow cardiac ou tpu t stat es a n d ca rdi o g en i c sho ck

involvement may be asymptomatic or present as refractory CS. importantly PAPI [67]. Furthermore, PAC allows evaluating the
The typical triad is hypotension, distended jugular veins, and response to filling tests and treatment.
clear lungs. The three main elements forming the basis of the The specific therapeutic management of RV-​associated CS is
diagnosis are ECG, echocardiography, and RHC using PAC. based on the aetiological treatment of RV dysfunction, i.e. cor-
ST-​segment elevation in right precordial leads (V3R and V4R) onary reperfusion, usually with primary PCI of an occluded prox-
has high specificity for the diagnosis of RV involvement, and imal RCA, including acute marginal branches if needed. Effective
these should be done in all patients with STEMI, particularly if reperfusion usually leads to rapid haemodynamic improvement.
hypotensive. Restoring sinus rhythm in patients with complete AV block or AF
Echocardiography plays a major role in the diagnosis of RV in- is also essential, as the loss of atrial kicks may cause a severe drop in
volvement. RV dilatation, particularly in the presence of RV re- cardiac index in patients with acute severe RV involvement. If not
gional wall abnormalities, is highly suggestive. Echocardiographic restored after reperfusion, synchronized dual-​chamber pacing or
indices used to evaluate RV function include:  fractional short- cardioversion may be needed. The general principles of RV dys-
ening, tricuspid annular plane systolic excursion (TAPSE), pulsed function management have been reviewed elsewhere [113]. These
Doppler tissue imaging, and the Tei index. Other important echo- include: (1) optimal volume management with or without vaso-
cardiographic indices for the investigation include RV distension, pressor therapy; (2) optimization of heart rate; (3) enhanced RV
RV ejection fraction, right atrial size, pulmonary or tricuspid re- inotropy and improved cardiac index, usually with dobutamine;
gurgitation, estimations of pulmonary pressures, and evaluation and (4)  reduction of RV afterload and pulmonary resistance.
of the LV, interventricular septum, and pericardium. RHC yields Lastly, the use of MCS with dedicated RV support or VA-​ECMO
useful information on right atrial pressure, PAP, and PCWP and may be considered in certain patients with refractory CS (see E
allows calculation of the cardiac index, SVR, PVR, and most Figures 47.5 and 47.6) [67].

Personal perspective
Mortality of CS patients is still unacceptably high. The inci- optimal mechanical ventilation, and treatment of bleeding
dence of CS, however, is declining slightly, due to more rapid complications, among many others. Some of these open ques-
and efficient reperfusion by primary PCI. In cases where CS tions are being addressed by ongoing trials [4]‌.
has developed, there is crucial importance for a multidiscip- In general, RCTs in CS are difficult to perform and are often
linary team and a specialized centre in its management to more costly than trials in other clinical conditions, due to
improve the clinical outcome of these patients. If patients are the complexity of the studies. Therefore, many believe that
treated according to guidelines, with early reperfusion for all conducting a randomized study in this critically ill popula-
patients and an optimal intensive care treatment, the mortality tion is still not possible, due to difficulties of enrolling and
of CS may be further reduced. randomizing these critically ill patients. However, as infarc-
Currently, there are many unsettled issues such as optimal tions are frequent and CS is inherited with high mortality,
inotropic or vasopressor support, the role and potential treat- any intervention which reduces mortality is likely to have
ment options of concomitant inflammation, the selection major public health implications and should therefore be
thoroughly tested.
and timing of patients for MCS, including the type of device,

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 CHAPTER 48

Non-​pharmacological
therapy of acute heart
failure: when drugs alone
are not enough
Jeroen Dauw, Wilfried Mullens, Johan Vijgen,
and Pascal Vranckx

Contents
Summary  651 Summary
Introduction  651 Acute heart failure syndrome has been defined as new-​onset or a recurrence of
Background  652 worsening signs and symptoms of heart failure necessitating urgent or emergency
Non-​pharmacological therapy of acute management. The management of acute heart failure syndrome is challenging,
heart failure  654 given the heterogeneity of the patient population in terms of the clinical presen-
Pathway from stabilization to
intervention  654 tation, pathophysiology, prognosis, and therapeutic options. The management of
Mechanical ventilation and oxygen acute heart failure syndrome is a dynamic process, requiring ongoing simultan-
transport  654 eous diagnosis (monitoring) and treatment. Pharmacological agents remain the
Mechanical ventilation  655
Transfusion of red blood cells  656 mainstay of therapy for acute heart failure syndrome. However, at all times, during
Coronary revascularization and the early diagnostic, aetiologic, and therapeutic work-​up, non-​pharmacological
(percutaneous) aortic valve
intervention  657 therapy may be indicated and should be considered.
Temporary, short-​term mechanical The management of the complex cardiac patient with acute heart failure syn-
circulatory support  657 drome and/​or (potential) haemodynamic compromise has become a special di-
Fluid management beyond diuretics,
haemofiltration with or without mension for specialized myocardial intervention centres, providing 24 hours per
dialysis  658 day and 7 days per week state-​of-​the-​art facilities for (primary) percutaneous cor-
Sinus rhythm and arrhythmia devices in heart
failure  659
onary intervention and cardiac intensive care, including mechanical ventilation,
Direct current cardioversion  659 ultrafiltration, with or without dialysis, and short-​term percutaneous mechanical
Ablation therapy  659 circulatory support.
Pacing and cardiac resynchronization
therapy  659 Through the understanding of the underlying pathophysiology and approaches
Personal perspective  661 into the problems of acute heart failure syndrome, one should be better prepared
Further reading  661 to understand and treat its many facets.
References  661

Introduction
Acute heart failure syndrome (AHFS) is characterized by a deterioration in car-
diac function resulting from numerous underlying heart diseases and precipi-
tating factors, with congestion being the predominant clinical profile in most
patients with AHFS [1]‌. Only a smaller proportion of patients present with periph-
eral hypoperfusion or cardiogenic shock (CS), warranting inotropic agents and/​ or
652 CHAPTER 48   N on - p​ harmac ol o gical t h era p y of acu te hea rt fa i lu re

mechanical support. Both congestion and hypoperfusion can lead Compensated

to organ injury, impairment, and, if not treated properly, failure NYHA I II III
of target organs, which are associated with increased morbidity
and mortality [1]. Therefore, the prevention and correction of Rebuild the heart
organ dysfunction have evolved as therapeutic targets of interest
Episode of acute
in AHF. AHFS may be the first presentation of heart failure (‘de

Clinical status
decompensation
novo’ AHF); however, in most cases, it arises as worsening chronic Chronically
heart failure at different pathophysiological stages of the disease decompensated
(see E Figures 48.1 and 48.2). The syndrome is complex and en-
compasses multiple contributing diseases. The symptoms of heart
failure may be aggravated by non-​cardiovascular comorbidities,
such as obstructive lung disease, or coexisting end-​organ disease, Death

especially renal dysfunction. Hospitalizations

In severe cases, a reasonably accurate diagnosis of CS can be Acutely Time (years)
decompensated
made at the patient’s bedside. It is defined as hypotension (SBP
<90  mmHg) despite an adequate filling status with signs of Figure 48.2  Worsening chronic heart failure at different stages of the
hypoperfusion. Such a patient should immediately undergo a disease. Treatment of reversible causes of heart failure (‘rebuilding the heart’,
e.g. PCI, aortic or mitral revalving) may impact prognosis.
comprehensive assessment, including ECG to rule out ACS and
echocardiography. Invasive monitoring with an arterial line and
continuous ECG monitoring are guideline recommendations There will be a focus on physiological approaches addressing
(Class I, LoE C) [2]‌. However, there is no agreement on the op- the balance between O2 demand and delivery (see E Background,
timal method of haemodynamic monitoring in assessing and p. 652), on the manipulation of cardiopulmonary interactions to
treating patients in CS, including PAC. optimize ventricular function, and on specific concepts of the
Although the immediate goals of AHFS treatment are to re- pathophysiology related to preservation and/​or restoration of
lieve the patient’s symptoms and to stabilize the haemodynamic cardiac function, the importance of obstructive CAD and cardiac
condition, longer-​term management, including immediate post-​ valve disease, as well as renal function. Cross references, mainly to
discharge care, is also important to prevent (early) recurrence the ESC Textbook of Cardiovascular Medicine, to related chapters
and improve prognosis. Pharmacological agents traditionally in this textbook, and to ESC practice guidelines, will be provided.
have been the mainstay of therapy for AHFS; however, in each
phase of hospital evaluation and management, concomitant non-​
pharmacological therapy should be considered (see E Figure Background
48.3). The pathophysiology of AHFS and early pharmacological
therapy are extensively reviewed elsewhere (see E Chapters 45 The heart can be conceptually approached as a hydrodynamic
and 46) (see E Figure 48.1). input–​output system, a haemodynamic compression pump, a
The intent of this chapter is to provide a readable, concise muscular pump, or a pluricellular tissue pump. The heart acts in
clinical overview of the non-​ pharmacological treatment of close relationship to the lungs and circulation, with the ultimate
different AHFS which would cover the basis for clinical algo- goal to preserve adequate tissue oxygenation and function (see
rithms and provide the clinical use of evidence-​based treatment E McMurray, J. et al. Heart failure. In: Camm JA, Luscher TF,
guidelines. Maurer G, Serruys PW, editors. ESC Textbook of Cardiovascular
Medicine, third edition. Oxford University Press:  Oxford; 2018
Chapter 23.
ACS with
The primary physiological task of the cardiorespiratory system
Right heart
heart failure failure
is to deliver adequate O2 (DO2) to meet the metabolic demands of
Pulmonary the body (VO2). O2 delivery (DO2) is the amount of O2 delivered
oedema
to the peripheral tissue and is obtained by multiplying the arterial
O2 content (CaO2) by the cardiac output (CO), as shown in E
Hypertensive AHF Normotensive AHF
or vascular AHF or cardiac failure
Equation 1 below:
or de novo AHF or acutely decompensated
chronic heart failure
DO2 = C a O2 × CO
Hypotensive The O2 content of blood is the volume of O2 carried in each 100
AHF/cardiogenic
shock mL of blood. It is calculated as shown in E Equation 2 below:

Figure 48.1  Clinical classification of AHF. ACS, acute coronary syndrome; (O2carried by Hb) + (O2in solution) = (1.34 × Hb × SaO2 × 0.01)
AFH, acute heart failure. + (0.023 × PaO2 )
Adapted from Filippatos G et al. Heart Failure Rev 2007;12:87–​90.
 Bac kg roun d 653

Early, <24 hours

Time
NIV
Mechanical

Arrhythmia control: cardioversion/pacing

ventilation

PCI/CABG: planned, emergent

IABP

Renal replacement therapy

Temporary mechanical
circulatory support

Non-pharma
Pharma
In-hospital

AHF

Chronic heart failure

Predischarge

Bridging/destination
CRT ± ICD • Circulatory support

Exercise • Cardiac transplantation

Figure 48.3  Four phases for hospital evaluation and management are proposed: (1) the initial or early phase (i.e. ED); (2) the in-​hospital phase; (3) the
predischarge phase; and (4) the early post-​discharge phase. AHF, acute heart failure; CABG, coronary artery bypass grafting; CRT, cardiac resynchronization
treatment; IABP, intra-​aortic balloon pump; ICD, implantable cardioverter–​defibrillator; NIV, non-​invasive ventilation; PCI, percutaneous coronary intervention.
Source data from Gheorghiade M, Zannad F, Sopko G, Klein L, Pina IL, Konstam MA, et al. Acute heart failure syndromes: current state and framework for future research. Circulation
2005;112(25):3958–​68.

Where: SaO2 is the percentage saturation of Hb with O2; Hb is Hb 12-​lead ECG might indicate potential myocardial ischaemia
concentration in grams per 100 mL of blood; and PaO2 is partial and rhythm or conduction abnormalities warranting an early
pressure of O2 (0.0225 = mL of O2 dissolved per 100 mL of plasma invasive approach. Transthoracic 2D and Doppler echocardi-
per kPa, or 0.003 mL per mmHg). ography is a highly valuable, non-​invasive tool for assessment
The initial AHFS evaluation (e.g. in ED) should begin with of the cardiac anatomy and function [4]. In addition to its es-
a careful history and physical examination. Early triage and tablished critical roles in the early diagnostic, aetiologic, and
management may be guided by vital signs, physical find- therapeutic work-​up of AHFS, echocardiography plays an im-
ings, and urinary output (see E Box 48.1) [3]‌. A  standard portant clinical role in early ‘prognostication’ and triage to a
more oriented therapy [5,  6]. For details, see E McMurray,
J. et al. Heart failure. In:  Camm JA, Luscher TF, Maurer
Box 48.1  Adverse vital signs and clinical symptoms in acute
heart failure G, Serruys PW, editors. ESC Textbook of Cardiovascular
Medicine, third edition. Oxford University Press: Oxford; 2018,
◆ Vital signs: Chapter 23.
Heart rate >100 bpm
● A more definitive resuscitation strategy in advanced AHFS
SBP <90 mmHg or MAP <60 mmHg
● not responding to standard pharmacological therapy and/​
Proportional pulse pressure ≤0.25 (CI <2.2 L/​min/​m2)
● or in patients (at high risk of) developing circulatory failure
Tachypnoea >20 breaths/​minute (>30 breaths/​minute)
● may require invasive monitoring and goal-​oriented manipula-
Pulse O2 saturation <92%
●
tion of cardiac preload, afterload, and contractility to achieve
a balance between systemic O2 delivery and O2 demand (see
Clinical symptoms of tissue hypoperfusion/​hypoxia:
◆
E Figure 48.4). Endpoints used to confirm the achievement
Cool extremities
of such a balance include normalization of values for mixed
●

● Decreased capillary refill or mottling venous O2 saturation, arterial lactate concentration, base def-

● Decreased urine output (<1 mL/kg/​hour) icit, and pH [7]‌. Mixed venous O2 saturation, as shown in E

● Alteration in mental status Equation 3 below (also see E Figure 48.4), has been shown to
Proportional pulse pressure  =  (systolic blood pressure – diastolic blood be a surrogate for cardiac index as a target for haemodynamic
pressure)/systolic blood pressure.
therapy.
Orthopnoea:  cough may be the equivalent of orthopnoea, especially in
semi-recumbency.
CI, cardiac index in L/​min/​m2 (normal range: 2.6–​4.2); MAP, mean arterial
{ }
SVO2 = SaO2 − VO2 / CO × ( Hb × 13.9)
pressure; SBP, systolic blood pressure.
654 CHAPTER 48   N on - p​ harmac ol o gical t h era p y of acu te hea rt fa i lu re

Oxygen transport
Non-​pharmacological therapy
300 of acute heart failure
VO2
Pathway from stabilization to intervention
VO2 mL/min

200
Patient care in AHFS is a dynamic process, requiring ongoing
100
simultaneous diagnostic work-​up and treatment. Four phases for
Lactate
patient evaluation and management are proposed [11]:

0 Uptake supply dependency 1. The initial (early) phase of stabilization (i.e. ED).

2. The in-​hospital phase.
0 500 1000
DO2 mL/min 3. The predischarge phase.
4. The early ‘vulnerable’ post-​discharge phase (see E Figure 48.3).
Figure 48.4 O2 uptake supply dependency. Under normal conditions,
during exercise, if O2 demand is increased, the supply is increased also by The goal of early treatment (‘stabilization’) in the pre-​hospital
increasing minute ventilation and cardiac output. When O2 delivery starts setting or in the emergency room is to optimize the haemo-
to fall off (e.g. in a patient who has progressively worsening respiratory or dynamics and tissue oxygenation. Although not ‘evidence-​based’
cardiovascular function), this lower O2 delivery is initially compensated
for by making use of the physiological reserve. Blood is preferentially in the same way as treatments for chronic heart failure, the key
redistributed to the tissues that need them, and the amount of O2 drugs are O2, diuretics, and vasodilators (see E Chapter  46).
extracted (extraction ratio, O2 ER) increases. Eventually, reserve runs out and Opiates and inotropes are used more selectively, and MCS is re-
a critical point (‘kink’ on the diagram) is reached—​there is just not enough quired only rarely. Non-invasive ventilation (NIV) is used com-
O2 to match supply and anaerobic glycolysis takes place. This is known as monly in many centres. Escalation to endotracheal intubation
‘physiological dependence of VO2 on DO2’ and can be measured by an
increase in the arterial lactate concentration. The critical O2 ER is the point and an invasive approach may be needed in cases of decreased
where anaerobic glycolysis takes place. The critical DO2 in health is about level of consciousness (to protect the airway), persisting respira-
7–​10 mL/​kg/​minute. tory failure, circulatory failure, and life-​threatening refractory ar-
rhythmias (e.g. VT storm).
At all stages, myocardial ischaemia should be excluded and
treated, whenever possible, as this carries a worse prognosis [12].
In cases in which insertion of a PAC is impractical, venous O2 Patients with AHFS complicating ACS, requiring emergent PCI,
saturation (central venous O2 saturation, SVO2) can be meas- are at considerable risk of haemodynamic compromise or col-
ured in the central circulation [8]‌. Importantly, trends of haemo- lapse at the time of intervention. Management of the complex
dynamic measures in the right direction are as important as cardiac patient with (potential) haemodynamic compromise has
targeting pre-​specified numbers. In addition, while inotropic become a special dimension for specialized myocardial inter-
therapy is often used in such situations to improve haemo- vention centres (MICs), providing state-​of-​the-​art facilities for
dynamic measures, its use is eclipsed by a higher number of mor- (primary) PCI, including experienced senior operators, avail-
tality [9, 10]. able on a 24-​hour/​day and 7-​day/​week basis, and critical care
In the critically ill (cardiac) patient, the cardiocirculatory physicians experienced in all aspects of diagnosing and treating
system is mainly challenged by two different conditions—​first, a complex cardiac patients. If these facilities are not available on
drop in DO2 which can be induced by anaemia, hypoxia, hypo- site, upgrading and transfer to a specialized MIC should be
volaemia, low cardiac output, or any combination of these. initiated early.
Second, fever, pain, stress, and/​or respiratory failure, etc. may Other comorbidities, including arrhythmias, infections, pul-
further decrease SVO2 or ScVO2 by increasing whole body VO2. monary diseases, severe anaemia, and renal or hepatic dysfunc-
It is of pivotal importance that the physician dealing with this tion, must be addressed and corrected, when appropriate, on an
type of patient understands these basic principles. Three items ongoing basis during the hospital stay (see E Figure 48.3).
should be evaluated throughout the early stabilization period
(acronym: VIP): Mechanical ventilation and oxygen transport
1. The need for sedation and ventilatory support (Ventilation). AHFS is haemodynamically defined as pulmonary and/​ or
systemic congestion, due to elevated ventricular filling pres-
2. The need for inotropic/​vasopressor support—​does the patient
sures. AHFS can lead to a decrease in cardiac output and tissue
need a central venous access? (Infuse).
hypoperfusion, but this is not always the case. Lung dysfunction
3. The need for MCS (Pump). can be evaluated in terms of lung mechanics and gas diffusion
In the context of non-​pharmacological therapy of AHFS, the (see E Chapter 13). It is recommended to administer O2 as early
‘I’ may become ‘Intervention’, including electric cardioversion, as possible in hypoxaemic patients to achieve an arterial O2 sat-
revascularization, and percutaneous aortic revalving, e.g. ‘re- uration of ≥90% [2]‌. Caution is indicated in COPD patients, be-
building the heart’ (see E Figure 48.2). cause liberal O2 administration can cause hypoventilation with
 N on - pha r m ac ol o g i ca l ther a p y of acu te hea rt   fa i lure 655

hypercapnia. O2 should not be administered to non-​hypoxaemic 10–​14 cmH2O. EPAP and IPAP can be adjusted further, according
patients, as this might induce systemic vasoconstriction and re- to the effect on oxygenation and ventilation, respectively.
duce cardiac output [13]. NIV should not be used in patients with haemodynamic instability,
Following the formula to calculate DO2 (see E Equation limited cooperation, reduced levels of consciousness or unprotected
2), tissue O2 delivery could be increased just by administering airway. Refractory respiratory failure requires endotracheal intub-
supplemental O2 to increase the arterial O2 tension (PaO2), ation in these patients. The response to NIV should be assessed after
provided there is an adequate Hb concentration. Of note, spon- 60 minutes, and thereafter on a continuous basis. Signs of NIV failure
taneous ventilatory efforts require muscular activity, thereby are patient fatigue, progressive worsening of level of consciousness,
consuming O2 and producing CO2. The inspiratory effort in haemodynamic instability, and persistent tachypnoea (>35 breaths/​
acute respiratory failure is about 4–​6 times the normal value minute), acidosis, hypoxaemia, or hypercapnia [23].
[14]. This increases the VO2 significantly. As such, respiratory High flow nasal cannula (HFNC) can deliver high O2 flow rates
failure with increased work of breathing will stress the cardio- (40–​60 L/​minute) administered through the nostrils and is an al-
vascular response to increase the cardiac output to meet the ternative to NIV [23]. HFNC also provides a low level of PEEP
increased VO2. (<5 cmH2O) [24], which may be beneficial in AHFS. Yet, to date,
Mechanical ventilation will not only influence the arterial O2 there are insufficient data to support routine use in AHFS with
content, but by decreasing the work of breathing, it will also de- respiratory failure. HFNC could be reserved for cases where NIV
crease the VO2 of the respiratory system and reduce cardiac stress. is not well tolerated.
Furthermore, ventilation affects the circulation by altering the Endotracheal intubation and mechanical ventilation are only
preload and afterload conditions of the heart through changes in required in a minority of AHFS patients, as most will respond to
the intrathoracic pressure (ITP) and lung volume [15, 16]. NIV. Patients at risk for intubation are those with an extremely
high respiratory rate, severe hypoxaemia despite high-​dose O2
Mechanical ventilation administration, circulatory failure, patients requiring a stressful
In patients with severe cardiopulmonary distress, for whom the intervention (e.g. coronary angiography) or interhospital trans-
effort of breathing is intolerable or inefficient, mechanical venti- port, or patients not improving after 1 hour of NIV.
lation will artificially replace the action of the respiratory muscles In positive pressure ventilation (PPV), a PEEP will be set and
(see E Chapter 22). The objectives of mechanical ventilation are combined with an IPAP (pressure-​controlled ventilation) or a fixed
primarily to decrease the work of breathing and reverse hypox- tidal volume (volume-​controlled ventilation), a respiratory rate,
aemia or respiratory acidosis. One has to bear in mind that the and an FiO2 (see E Chapter 22). Some ventilation modes allow
mechanically assisted inspiration will result in increased ITP, and spontaneous breathing. In contrast, in NIV, only airway pressures
mechanically assisted expiration in decreased ITP, which is the and FiO2 are set, with the patient determining the respiratory rate.
opposite of normal ventilation. The need for mechanical venti- It is important to note that PPV (mechanical ventilation as
lation and artificial airways can be reduced by substituting with well as NIV) influences not only gas exchange, but also haemo-
NIV support, when appropriate. dynamics (see E Figure 48.5). As PPV raises ITPs, systemic
NIV (see E Chapter 21) is delivered through tight-​fitting face venous return (RV preload) is decreased, PVR (RV afterload) is
masks and can be either CPAP or bilevel positive airway pres- increased, pulmonary venous return (LV preload) is decreased,
sure (BiPAP). NIV maintains adequate gas exchange, reduces and LV wall tension (afterload) is decreased [25]. Overall, the
the work of breathing, and limits the need for endotracheal in- haemodynamic effects of PPV are beneficial in most AHFS and
tubation in patients with ARF due to acute pulmonary oedema might improve cardiac output, with the exception of RV failure.
and COPD [17–​21] (see E Chapter  21). Of note, in 2008, a Adequate PPV pressures can result in improved LV preload and
large RCT—​the Three Interventions in Cardiogenic Pulmonary afterload. Recruiting closed alveoli can also reduce the amount of
Oedema (3CPO) trial—​in AHFS patients with respiratory acid- hypoxia-​induced vasoconstricted pulmonary arterioles and can
osis failed to demonstrate a mortality benefit or reduction in reduce RV afterload. However, too high pressures will compress
the rate of endotracheal intubation with any type of NIV, when the vena cava and result in insufficient systemic venous return,
compared with standard O2 therapy [22]. However, a lot of pa- leading to reduced cardiac output. Moreover, high inspiratory
tients in this trial were not hypoxaemic and there was a high pressure and high PEEP can induce or worsen RV failure, by
crossover rate of nearly 20% of the patients, which could explain increasing RV afterload.
these results [23]. According to the current guidelines, NIV has A large variety of ventilator modes are nowadays available and
a Class  IIa, LoE C recommendation and should be considered there is still an ongoing debate about classification of these dif-
in AHFS patients with respiratory distress (respiratory rate >25 ferent modes (see E Chapter 22). The choice of ventilation mode
breaths/​minute, SpO2 <90%) [2]‌. depends on physician preference and experience, local expertise,
If there is only hypoxaemia, CPAP is the mode of choice. In level of consciousness of the patient, and the underlying cause of
cases of hypoxaemia and hypercapnia, BiPAP is preferred. CPAP respiratory failure. In all modes, an adequate PEEP should be set
is generally started with a pressure of 5  cmH2O, which is in- to prevent intermittent alveolar collapse, to provide adequate oxy-
creased in a stepwise manner to up to 10  cmH2O. In BiPAP, it genation by keeping recruited alveoli open, and to reduce LV pre-
is reasonable to start with an EPAP of 5 cmH2O and an IPAP of load and afterload without affecting venous return. A reasonable
656 CHAPTER 48   N on - p​ harmac ol o gical t h era p y of acu te hea rt fa i lu re

Pulmonary oedema

Persistent respiratory distress despite oxygen therapy

SpO2 <90%
Respiratory rate >25 breaths/minute
High work of breathing

Yes Severe respiratory distress or

contraindication for NIV
No
Yes No
Hypercapnia?

Start BiPAP? Start CPAP

HFNC
IPAP: 10–12 cm H2O Pressure: 5–10 cmH2O Flow rate >40 L/min
EPAP: 5cm H2O FiO2 with goal SpO2 ≥92%
FiO2 with goal SpO2 ≥92% FiO2 with goal SpO2 ≥92%
Minimal trigger
Titrate according to patient Titrate according to patient
response response

Improvement after 60 minutes

No Decreased work of breathing Yes
Decreased respiratory rate
SpO2 ≥92%

Intubation and mechanical Continue treatment until

ventilation stabilized

Figure 48.5  Non-​invasive ventilation implementation and settings. BiPAP, bilevel positive airway pressure; CPAP, continuous positive airway pressure; HFNC,
high-​flow nasal cannula.
Reproduced from Alviar CL, Miller PE, McAreavey D, et al. Positive Pressure Ventilation in the Cardiac Intensive Care Unit. J Am Coll Cardiol. 2018;72(13):1532–​1553. doi:10.1016/​
j.jacc.2018.06.074 with permission from Elsevier.

PEEP to start with is 5 cmH2O, which can be increased in a step- 30% in chronic heart failure and up to 50% in AHFS [29].
wise manner to 10 cmH2O in case of inadequate oxygenation. If Human tolerance of anaemia is dependent on the recruit-
blood pressure falls on increasing PEEP, either venous return is ment of physiological reserve, a major component of which is
obstructed or RV failure is induced by increased RV afterload. the ability to increase the cardiac output. Patients with heart
Tidal volumes can be fixed or dependent on a set IPAP, corres- failure lack normal physiological reserve to compensate for de-
ponding to either volume-​controlled or pressure-​controlled ven- creased Hb and may manifest a decreased aerobic capacity, in
tilation, respectively. In acute lung injury, the benefit of so-​called response to mild degrees of anaemia [30]. The clinical utility of
‘lung-​protective ventilation’ with low tidal volumes is well recog- blood transfusion in critically ill anaemic patients with CVD
nized [26,  27]. Some retrospective data suggest that this might remains controversial [31–​33], and also in post-​cardiac sur-
also be the case in AHFS [28], possibly by limiting ventilator- gery patients, there is conflicting evidence [34, 35]. There have
induced lung injury. Therefore, tidal volumes of 6–​8 mL/​kg are been no trials addressing blood transfusion in AHFS specif-
advised. IPAP (or Pplat in case of volume-​controlled ventilation) ically. Furthermore, it is unclear which Hb threshold should
should be kept at ≤30 cmH2O. be used to initiate transfusion and what the optimal Hb goal
should be. On balancing risks and benefits, transfusion should
Transfusion of red blood cells only be considered as an acute treatment for severe anaemia on
Anaemia is defined as a Hb concentration of <13 g/​dL in men an individualized basis. Correctable causes of anaemia should
and <12 g/​dL in women. Anaemia is very common among pa- be treated as per the standard of care, although often no definite
tients with heart failure, with a prevalence of approximately aetiology can be identified.
 N on - pha r m ac ol o g i ca l ther a p y of acu te hea rt   fa i lure 657

Iron deficiency (either serum ferritin <100 micrograms/​L or benefits into account (see E Chapter 57). In a minority of pa-
serum ferritin 100–​299 micrograms/​ L with transferrin satur- tients with AS presenting with haemodynamic instability or who
ation of <20%) is an emerging treatment target in heart failure are refractory to treatment, balloon aortic valvotomy may be con-
and current guidelines give a Class IIa, LoE B recommendation sidered as a bridge to definite therapy (Class IIb, LoE C recom-
for treating iron deficiency in symptomatic HFrEF patients [2]‌. mendation according to the ESC Guidelines on VHD) [45]. There
However, in AHFS, measures of iron deficiency are not always are some small studies suggesting urgent transcatheter aortic
reliable [36] and there is currently no evidence supporting early valve implantation as an alternative safe option in these patients
administration of IV iron in AHFS [37]. [46, 47], but further research is needed.

Coronary revascularization and (percutaneous) Temporary, short-​term mechanical

aortic valve intervention circulatory support
ACS is one of the most common precipitating factors in AHFS, In current everyday practice, vasopressors and inotropes are ad-
described in 15–​30% of cases [38, 39]. Moreover, about half of ministered in CS in an attempt to preserve blood pressure and
AHFS patients have underlying CAD [40, 41]. The presence of cardiac output. However, inotropes not only increase contract-
ischaemic and/​or stunned/​hibernating myocardium may have a ility, heart rate, and afterload, but also increase myocardial O2
profound impact on initial, in-​hospital, and post-​discharge man- demand in an already failing myocardium, potentially leading to
agement and prognosis [38, 42]. In the case of ACS, an early in- ischaemia-​driven myocardial necrosis and increased mortality
vasive strategy targeting revascularization is warranted [43, 44]. [9, 10]. In addition, despite increasing doses of vasopressors and
In all other patients, risk stratification and non-​invasive stress inotropes, some patients will suffer a further deteriorating con-
testing should be performed to screen for CAD or to reassess dition. Hence, the interest in percutaneous, short-​term MCS is
the current status of known CAD. Revascularization should be growing (see E Chapter 28).
performed according to guidelines and is discussed elsewhere Historically, Intra-aortic balloon pump (IABP) was the first and
(see E Chapter 43). Surgical procedures to eliminate or exclude most used form of MCS. However, in 2012, the IABP-​SHOCK II trial
areas of infarction (surgical ventricular restoration), to repair changed current practice, as IABP versus medical therapy in AMI
MR, or to support the failing myocardium will be discussed in complicated by CS did not improve 30-​day mortality. Since then,
E Chapter 49. routine use of IABP in CS has been abandoned (Class III, LoE B) [2]‌
Likewise, aortic valve disease may cause or aggravate AHFS. and other forms of MCS have gained attention (see E Figure 48.6).
Acute management of these patients, especially aortic stenosis, Both Venoarterial extracorporeal membrane oxygenation
can be particularly complex. In general, congestion should be (VA-ECMO) and the Impella® are currently the most widely
treated first and indication for aortic valve replacement should used MCS. VA-​ECMO has the advantage to provide full respira-
be evaluated after stabilization. Whether surgical aortic valve re- tory and biventricular circulatory support, but it comes at the
placement or transcatheter aortic valve implantation is indicated expense of countercurrent aortic flow increasing LV afterload,
should be discussed in the heart team, taking patient risks and LV myocardial O2 demand, and filling pressures [48]. As a

Positive pressure ventilation

Positive intrathoracic pressure

(ITP)

Improved Work of Gradient of Gradient between Abolition of negative

↓

arterial breathing systemic venous the LV and the swings in ITP

oxygenation return extrathoracic
arteries

RV preload LV afterload
↓

Intrathoracic blood volume

↓

Cardiac performance
↓

Figure 48.6  Haemodynamic effects of positive pressure ventilation.

658 CHAPTER 48   N on - p​ harmac ol o gical t h era p y of acu te hea rt fa i lu re

consequence, VA-​ECMO often requires some form of additional As large prospective data on MCS and mortality are lacking,
LV unloading (see E Chapter 28). MCS must be tailored to each patient, in order to optimize the
The Impella® has a more favourable haemodynamic profile as benefits and minimize risks. MCS can be used as a bridge to re-
it not only increases forward flow, but also decreases LV myo- covery, a bridge to a VAD, or a bridge to heart transplant and
cardial O2 demand and filling pressures. Percutaneous models should only be considered as a temporary measure in a larger
of Impella® can provide flow of up to 2.5 (Impella® 2.5) and 4 L/​ treatment plan (see E Figure 48.7). Awaiting the results of
minute (Impella® CP), implying this form of MCS cannot fully ongoing randomized trials, current guidelines state that short-​
replace cardiac output and minimal residual cardiac function is term MCS may be considered in refractory CS, depending on
necessary. This should be taken into account when deciding on patient age, comorbidities, and neurological function (Class IIb,
the type of MCS in a specific patient. In case higher flows, add- LoE C).
itional extracorporeal gas exchange, or RV support are required,
VA-​ECMO remains the MCS of choice [49]. Of note, an RV
Impella® was developed very recently. Fluid management beyond diuretics,
The potential benefit of Impella® and its adoption in clinical haemofiltration with or without dialysis
practice have been derived mainly from registries and animal Adequate and thorough decongestion should be the main goal
studies in CS complicating MI suggesting reduced mortality and in AHFS, as congestion impairs organ function [1]‌and increases
infarct size if inserted prior to PCI. To date, only two small ran- mortality if still present at discharge [53]. Loop diuretics are
domized, but underpowered, trials have failed to show a mortality the cornerstone of current decongestive therapy for fluid over-
benefit of Impella®, compared to IABP [50, 51]. load and are often combined with vasodilators. A detailed prag-
Whether MCS should be inserted in the early phase of shock to matic approach with regard to the use of diuretics, with early
prevent further deterioration or used as bailout in cases of refrac- assessment of diuretic efficacy and adaptations of dosing and/​
tory shock is still a topic of ongoing debate. Some data suggest a or agents, has been proposed recently by the European Heart
potential benefit of early initiation of Impella® in AMI with CS Failure Association [54]. However, diuretic efficacy decreases
[52], but in other forms of CS (e.g. myocarditis), there is no evi- as heart failure progresses. Moreover, loop diuretics increase
dence on the timing of initiation. neurohormonal activation by blocking Na+ reabsorption in the

(a) IABP (b) Impella® (c) TandemHeart™ (d) ECMO

Figure 48.7  Current mechanical support devices. (A) The intra-​aortic balloon pump (IABP) is a counterpulsatory balloon system, inserted via the femoral
artery and placed in the descending thoracic aorta. By inflating the aortic balloon during diastole, diastolic blood pressure and coronary perfusion increase. In
systole, rapid deflation reduces afterload through a vacuum effect. (B) The Impella® is a single catheter-​based axial flow pump system. The pump is inserted via
the femoral or axial artery across the aortic valve, expelling aspirated blood from the left ventricle into the ascending aorta with an adjustable pump speed.
(C) The TandemHeart™ offers a form of extracorporeal support requiring transseptal puncture. Via femoral vein access, the inflow catheter is introduced over
the interatrial septum in the left atrium. An extracorporeal centrifugal pump aspirates blood from the left atrium and provides a continuous flow into the
abdominal aorta or femoral artery via a femoral cannula. (D) Veno-​arterial extracorporeal membrane oxygenation (ECMO) is a centrifugal pump system offering
full cardiorespiratory support. Deoxygenated blood is aspired from the right atrium via a femoral vein-​inserted cannula. The blood then passes through a
membrane oxygenator, providing adequate gas exchange, and is reinfused into a femoral artery cannula with the ability to provide high flow rates.
Reproduced from Werdan K, Gielen S, Ebelt H, Hochman JS. Mechanical circulatory support in cardiogenic shock. Eur Heart J 2014;35(3):156–​167. doi:10.1093/​eurheartj/​eht248 with
permission from Oxford University Press.
 N on - pha r m ac ol o g i ca l ther a p y of acu te hea rt   fa i lure 659

macula densa and produce hypotonic urine, leading to a greater Direct current cardioversion
loss of water than Na+. These factors might contribute to a de- When a rapid ventricular response in AF does not respond
creased diuretic treatment effect. promptly to pharmacological therapy or in cases of severe haemo-
Ultrafiltration is an attractive alternative to diuretic therapy. dynamic compromise and intractable myocardial ischaemia, im-
In ultrafiltration, blood is forced under high pressure against a mediate direct current cardioversion (biphasic, synchronous, and
semi-​permeable membrane, filtering out an adjustable amount of high-​energy 200–​360 J) is recommended (Class I, LoE C) [2]‌. In
plasma. Newer ultrafiltration devices only require peripheral vas- patients who relapse after a successful cardioversion, it can be
cular access, are easy to handle, and can be used outside the in- useful to repeat the procedure, following the administration of
tensive care setting. Three main advantages of ultrafiltration over appropriate antiarrhythmic medication.
diuretics can be noted [55]. First, fast removal of fluid is possible,
which is interesting because plasma refill time from oedema is Ablation therapy
highest at the beginning of decongestive therapy. Second, there is When, in selected patients, the rapid ventricular response is re-
no increase in neurohormonal activation. Third, isotonic fluid is fractory to pharmacological therapy and/​or cardioversion, ab-
removed, leading to a higher magnitude of Na+ clearance, com- lation of the AV junction by catheter radiofrequency energy,
pared to diuretics. with subsequent pacemaker implantation, may be considered to
Despite the possible advantages of ultrafiltration, to date, trials improve cardiac performance (Class IIb, LoE B) [2]‌. The choice
have failed to show benefits of ultrafiltration over diuretic therapy between a single-​or dual-​chamber pacemaker depends on the
[56–​58]. One small randomized study compared ultrafiltration probability of restoring a sinus rhythm, but in cases of reduced
with continuation of diuretic therapy versus diuretic therapy LVEF, resynchronization will be preferred. When in the chronic,
alone in 56 AHFS patients and found a significant reduction in 1-​ predischarge phase, curative AF ablation seems to be a better
year heart failure hospitalization in favour of ultrafiltration [59]. therapeutic option [64,  65]. Furthermore, the recent Catheter
However, ultrafiltration was not superior, compared to stepped Ablation versus Standard Conventional Therapy in Patients with
pharmacological diuretic therapy, in preventing worsening renal Left Ventricular Dysfunction and Atrial Fibrillation (CASTLE-​
function or achieving effective decongestion in patients with CRS AF) trial showed that AF ablation can reduce mortality in patients
in the CARRESS-​HF trial [56]. As such, there is currently in- with an LVEF of ≤35% [66] (see E Chapter 53).
sufficient evidence to support routine use of ultrafiltration. ESC
guidelines state that ultrafiltration may be considered for patients Pacing and cardiac resynchronization therapy
with refractory congestion who failed to respond to diuretic-​ In cases of atropine-​or isoproterenol-​ resistant bradycardia,
based strategies (Class IIb, LoE B)  [2]‌. transvenous pacing may be used as an interim measure. In
In certain cases, especially in cases of metabolic disturbances general, pacemaker implantation is indicated according to the
and severe renal dysfunction, ultrafiltration will not suffice and guidelines. However, in heart failure patients, CRT should be
RRT will be necessary. The following criteria may indicate the considered as well. The purpose of resynchronization is to pro-
need for initiation of RRT in patients with refractory volume vide electromechanical coordination and improved ventricular
overload:  oliguria unresponsive to fluid resuscitation measures, synchrony in symptomatic patients who have severe systolic
severe hyperkalaemia (K+ >6.5  mmol/​L), severe acidaemia (pH dysfunction and clinically significant intraventricular conduc-
7.2), serum urea level >25 mmol/​L (150 mg/​dL), and serum cre- tion defects, particularly left bundle branch block (LBBB). With
atinine >300 mmol/​L (>3.4 mg/​dL) [2]‌. CRT, the pacemaker leads are placed to stimulate both ventricles,
resulting in improved electromechanical coordination and ven-
Sinus rhythm and arrhythmia devices tricular synchrony.
in heart failure A large body of evidence has emerged in the last decades that
Electrical and conduction abnormalities may frequently precipi- underscores the harmful effects of long-​term RV pacing-​induced
tate or aggravate AHFS and should be treated aggressively [60]. AF LV dyssynchrony [67–​69]. In patients with LVEF ≤50% and an
and heart failure often coexist [61]. The prevalence of AF increases AV block, CRT, compared to conventional RV pacing, reduces
with the severity of heart failure and worsens its course by loss of LV remodelling and heart failure hospitalization [70]. In add-
atrial contraction, poor rate control, and irregular rhythm [62]. ition, CRT reduces mortality and heart failure hospitalization in
Some component of (reversible) tachycardia-​induced myopathy patients with LVEF ≤35% and QRS ≥130 ms, irrespective of the
is seen in up to 50% of patients with LV dysfunction and AF [63]. pacing indication, especially when LBBB is present [2]‌. In these
Furthermore, the detrimental effects of AF on heart failure also patients, CRT results in reversed remodelling, with a reduced
may derive from the negative inotropic effects of antiarrhythmic heart size and decreased ventricular volumes, an improved EF,
drugs. Over the last decade, the non-​pharmacological armament- and a decreased MR [71]. For guideline recommendations, see
arium for heart failure patients has expanded. E Table 48.1.
660 CHAPTER 48   N on - p​ harmac ol o gical t h era p y of acu te hea rt fa i lu re

Table 48.1  Guideline recommendations

Recommendation Class Level Guideline

O2 therapy is recommended in patients with AHF and SpO2 <90% or PaO2 <60 mmHg (8.0 kPa) to correct hypoxaemia I C HF
Non-​invasive PPV (CPAP, BiPAP) should be considered in patients with respiratory distress (respiratory rate >25 breaths/​ IIa C HF
minute, SpO2 <90%) and started as soon as possible in order to decrease respiratory distress and reduce the rate of
mechanical endotracheal intubation
Non-​invasive PPV can reduce blood pressure and should be used with caution in hypotensive patients. Blood pressure
should be monitored regularly when this treatment is used
Intubation is recommended if respiratory failure, leading to hypoxaemia [PaO2 <60 mmHg (8.0 kPa)], hypercapnia I C HF
[PaCO2 >50 mmHg (6.65 kPa)], and acidosis (pH <7.35), cannot be managed non-​invasively
In patients with CS complicating ACS, immediate coronary angiography is recommended (within 2 hours from hospital I C HF
admission) with an intent to perform coronary revascularization
Balloon aortic valvotomy may be considered as a bridge to SAVR or TAVI in haemodynamically unstable patients or in IIb C VHD
patients with symptomatic severe AS who require urgent major non-​cardiac surgery
IABP is not routinely recommended in CS III B HF, STEMI
Short-​term mechanical circulatory support may be considered in refractory CS, depending on patient age, comorbidities, IIb C HF, STEMI
and neurological function
Ultrafiltration may be considered in patients with refractory congestion who failed to respond to diuretic-​based strategies IIb B HF, STEMI
Renal replacement therapy should be considered in patients with refractory volume overload and acute kidney injury IIa C HF
Urgent electrical cardioversion is recommended if AF is thought to be contributing to the patient’s haemodynamic I C HF
compromise in order to improve patient clinical condition
In AF, AV node catheter ablation may be considered to control heart rate and relieve symptoms in patients unresponsive IIb B HF
or intolerant to intensive pharmacological rate and rhythm control therapy, accepting that these patients will become
pacemaker-​dependent
AF ablation may be considered in order to restore sinus rhythm to improve symptoms in patients with persisting IIb B HF
symptoms and/​or signs of HF, despite OMT and adequate control of ventricular rate, to improve clinical/​symptomatic
status
CRT is recommended for symptomatic patients with HF in sinus rhythm with a QRS duration of ≥150 ms and LBBB QRS I A HF
morphology and with LVEF ≤35% despite OMT in order to improve symptoms and reduce morbidity and mortality
CRT should be considered for symptomatic patients with HF in sinus rhythm with a QRS duration of ≥150 ms and non-​ IIa B HF
LBBB QRS morphology and with LVEF ≤35% despite OMT in order to improve symptoms and reduce morbidity and
mortality
CRT is recommended for symptomatic patients with HF in sinus rhythm with a QRS duration of 130–​149 ms and LBBB I B HF
QRS morphology and with LVEF ≤35% despite OMT in order to improve symptoms and reduce morbidity and mortality
CRT may be considered for symptomatic patients with HF in sinus rhythm with a QRS duration of 130–​149 ms and non-​ IIb B HF
LBBB QRS morphology and with LVEF ≤35% despite OMT in order to improve symptoms and reduce morbidity and
mortality
CRT should be considered for patients with LVEF ≤35% in NYHA Class III–​IVd despite OMT in order to improve IIa B HF
symptoms and reduce morbidity and mortality, if they are in AF and have a QRS duration of ≥130 ms, provided a
strategy to ensure biventricular capture is in place or the patient is expected to return to sinus rhythm
In patients with HFrEF who require pacing and who have high-​degree AV block, CRT, rather than RV pacing, is I A HF
recommended
In patients with HFrEF who require pacing and who do not have high-​degree AV block, pacing modes that avoid IIa C HF
inducing or exacerbating ventricular dyssynchrony should be considered
ACS, acute coronary syndrome; AF, atrial fibrillation; AHF, acute heart failure; AS, aortic stenosis; AV, atrioventricular; BiPAP, bilevel positive airway pressure; CPAP, continuous positive
airway pressure; CRT, cardiac resynchronization therapy; CS, cardiogenic shock; HF, heart failure; HFrEF, heart failure with reduced left ventricular ejection fraction; IABP, intra-​aortic
balloon pump; LBBB, left bundle branch block; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; OMT, optimal medical treatment; PPV, positive pressure
ventilation; RV, right ventricular; SAVR, surgical aortic valve replacement; STEMI, ST-​segment elevation myocardial infarction; TAVI, transcatheter aortic valve implantation.
HF: 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure [2]‌; STEMI: 2017 ESC Guidelines for the management of acute myocardial infarction in
patients presenting with ST-​segment elevation [43]; VHD: 2017 ESC/​EACTS Guidelines for the management of valvular heart disease [45].
Reproduced from Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart
failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of
the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016;37(27):2129–​200; Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-​Ducci C, Bueno H, et al. 2017 ESC Guidelines
for the management of acute myocardial infarction in patients presenting with ST-​segment elevation: The Task Force for the management of acute myocardial infarction in patients
presenting with ST-​segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2018;39(2):119–​77; Baumgartner H, Falk V, Bax JJ, De Bonis M, Hamm C, Holm PJ, et al.
2017 ESC/​EACTS Guidelines for the management of valvular heart disease. Eur Heart J 2017;38(36):2739–​91 with permission from Oxford University Press.
 RE F E RE N C E S 661

Personal perspective
Improving post-​discharge outcomes for patients with AHFS is a introduced and are being further investigated. In the near
fundamental goal of therapy. A variety of non-​pharmacological future, this might change the early management of AHFS
approaches complement drug therapy for AHFS. NIV is now with CS. Finally, the role of ultrafiltration in decongestion
an established, very useful tool to avoid the need for mechan- is still a topic of debate. However, while awaiting more evi-
ical ventilation in a large proportion of patients. In addition, dence, diuretics remain the cornerstone of decongestion.
newer forms of temporary mechanical support have been

Further reading
Gheorghiade M, Abraham WT, Albert NM, et  al.; OPTIMIZE-​HF Thiele H, Jobs A, Ouweneel DM, et  al. Percutaneous short-​termactive
Investigators and Coordinators. Systolic blood pressure at admission, mechanical support devices in cardiogenic shock: a systematic review
clinical characteristics, and outcomes in patients hospitalized with and collaborative meta-​analysis of randomized trials. Eur Heart J
acute heart failure. JAMA 2006;296:2217–​26. 2017;38:3523–​31.

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 CHAPTER 49

Heart failure surgery

and transplantation
Felix Schoenrath, Jan Klages, and
Volkmar Falk

Contents
Summary  664
Summary
Heart failure coronary artery bypass The number of patients with end-stage ischaemic heart disease or valvular heart
grafting and left ventricular disease that present with concomitant heart failure is steadily increasing. Despite
aneurysmectomy  664
Indications and guideline
an increased operative risk in patients with poor left ventricular function, coronary
recommendations  664 artery bypass surgery and surgical valve repair or replacement can not only pro-
Technical aspects of CABG conduct  665 vide symptomatic relief but also a prognostic benefit. The decision-making process
Heart failure and valvular heart disease  666 should be guided by a specialized heart failure team with a thorough understanding
Aortic regurgitation  666
Aortic stenosis  667 of the risks and benefits of all available medical, percutaneous, and surgical treat-
Choice of intervention in aortic stenosis  667 ment options. End-stage heart failure patients may benefit from heart transplant-
Mitral regurgitation  668 ation or left ventricular assist device (LVAD) therapy. A careful preoperative
Acute mitral regurgitation  668
Chronic primary mitral regurgitation  668 evaluation is key for the optimal timing and success of surgery. The postoperative
Chronic secondary mitral management after LVAD implantation is often challenging and requires a deep
regurgitation  668
Mitral stenosis  669 understanding of the technology and typical device-associated complications. The
Surgical approach  669 postoperative care after heart transplantation requires a principal understanding of
Concomitant tricuspid regurgitation  670 immunosuppressive therapy and its potential side effects.
Prosthetic valve thrombosis  670
Bioprosthetic valve failure  670
Mechanical circulatory support  670
Indications and guideline
recommendations  670
Prognosis and INTERMACS level  670
MCS implantation  671
Weaning  673 Heart failure coronary artery bypass grafting and
Heart transplantation  673
Indications and guideline
left ventricular aneurysmectomy
recommendations  673
Technical aspects of heart
Indications and guideline recommendations
transplantation  673 AHF patients with ACS are classified as high-​risk patients and should be considered for
Post-​operative care after heart
transplantation  674 revascularization with CABG or PCI before being considered for MCS or HTx [1–​2].
Immunosuppression and infectious ACS includes the continuum of UA (20%), NSTEMI (30–​40%), and STEMI (10–​20%)
control  675 [3, 4].
References  675
Patients with CS whose anatomy is not suitable for PCI should undergo emergency
CABG revascularization with no delay (I B), including patients without full restoration
of platelet function after DAPT administration. For all other (more stable) patients, inter-
ruption of 3–​7 days with regard to the specific half-​life of the used P2Y12 inhibitor and
continuation of aspirin treatment are recommended [3]‌. The SHOCK trial demonstrated
that in patients with CS, emergency revascularization with PCI or CABG improved long-​
term survival when compared with initial intensive medical therapy [1, 5].
For further reading, see E Chapter 38.
Heart failure c oronary artery bypas s g r a fti n g a n d l eft ven tri cu l a r  a n eu rysm e c to m y 665

According to current ESC/​European Association of Cardio-​ A meta-​analysis of 21 studies with 16 191 patients comparing
Thoracic Surgery (EACTS) guidelines, in patients with chronic different methods of revascularization (CABG or PCI) against
heart failure and systolic LV dysfunction (EF ≤35%), CABG each other or medical treatment in patients with CAD and
should be performed as the first revascularization strategy choice LVEF ≤40% showed a significant mortality reduction with both
in patients with multivessel disease and acceptable surgical risk CABG and PCI, compared to medical treatment. Between the
(I B). For patients with one-​or two-​vessel disease, PCI should two revascularization strategies, CABG still showed a survival
only be considered as an alternative to CABG when complete benefit, compared to PCI. Taken together with the overall lower
revascularization can be achieved (IIa C). In patients with three-​ rates of recurrent MI and repeated target vessel revascularization,
vessel disease, PCI should only be considered based on evaluation these data indicate that surgical revascularization in patients
by the heart team of the patient’s coronary anatomy, the expected with HFrEF should be regarded as the preferred strategy [10].
completeness of revascularization, diabetes status, and comorbid- In a cohort of 1738 propensity-​matched patients with reduced
ities (IIa C)  [1]‌. LVEF and diabetes, PCI, was associated with a higher risk for
Randomized clinical trial data comparing CABG MACCEs in cohorts with LVEF 35–​49% and <35%. PCI was asso-
revascularization in heart failure patients with medical therapy ciated with an increased risk of death and repeat revascularizations
are available from the STICH trial. One analysis from this trial in both the LVEF 35–​49% and LVEF <35% cohorts and an in-
showed that CABG can be performed with acceptable  30-​day creased rate of MI in the LVEF <35% cohort. Diabetic, patients
mortality rates (5.1%) in patients with LV dysfunction (LVEF treated with CABG exhibited better long-​term survival over PCI,
≤35%) [6]‌. Extended follow-​up in the STICH Extension Study without a higher risk of stroke [11].
(STICHES) supports a significant survival benefit of CABG com- Untreated myocardial infarction can lead to the develop-
bined with medical therapy versus medical therapy alone in a 10-​ ment of left ventricular aneurysm. Progressive dilatation may
year observation period [7]. Ischaemic heart disease remains a lead to progression of heart failure. The standard technique
high-​risk and lethal condition, as indicated by an observed overall for left ventricular aneurysmectomy has been developed by
mortality of 62.5% (with a median follow-​up of 9.8 years) in the Dor (endoventricular circular patch plasty) and modified by
medical arm despite guideline-​ directed therapy [7]. The rate Jatene [12, 13] with the goal to reduce the volume of the left
of death from any cause over 10 years was lower by 16% (an 8-​ ventricle by excluding the aneurysm (surgical reverse remod-
percentage point absolute difference in the 10-​year Kaplan–​Meier elling). Following left ventricular aneurysmectomy, both left
rates) among patients who underwent CABG, in addition to re- ventricular end-diastolic and end-systolic volume acutely de-
ceiving medical therapy [7]. Overall, CABG was associated with crease and ejection fraction and left ventricular stroke work
an incremental median survival benefit of nearly 18 months and index increase. Concomittant mitral valve repair or replace-
prevention of one death due to a cardiovascular cause for every ment are sometimes needed for reconstruction of posterior
11 patients treated [7]. Among the patients randomly assigned wall aneurysms. Revascularization can be performed simultan-
to undergo CABG, 91% of patients in the STICH trial received eously if indicated [14]. The resection of large apical or anterior
a LIMA graft [7], which might have contributed to the excellent wall aneurysms in symptomatic patients has shown the best
long-​term results. results with both symptomatic and prognostic improvements.
Observational data comparing the effectiveness of CABG Patients with severe diastolic dysfunction and small ventricles
versus PCI with everolimus-​ eluting stent (EES) in 2126 are not good candidates for aneurysmectomy. TOE and TTE
propensity-​matched patients with severe LV systolic dysfunc- as well as CMR are performed to assess myocardial anatomy
tion (LVEF <35%) showed a benefit for CABG over PCI with and the extent of scar tissue, and to detect regional wall mo-
EES in patients with three vessel disease and when PCI re- tion abnormalities. Surgical planning can be supported by
sulted in incomplete revascularization after a median follow-​ multi-​slice computerized tomography (MSCT). MSCT-guided
up of 2.9  years. PCI was also associated with a higher risk of aneurysmectomy has shown excellent mid-​term results [15].
MI (in those with incomplete revascularization) and repeat Current guidelines recommend LV aneurysmectomy in
revascularization; however, CABG was associated with a higher combination with CABG (IIa C) or in centres with expertise
risk of stroke [8]‌. Another study comparing CABG versus PCI as a standalone procedure (IIb C) but emphasize that a post-​
with DES on long-​term mortality in 911 patients with signifi- operative LV-​ESV index of <70 mL/​m2 should be predictably
cant CAD and severe LV dysfunction showed that the risk of all-​ achieved [1]‌.
cause death, cardiac-​cause death, and repeat revascularization
was significantly lower in the CABG group, compared to the Technical aspects of CABG conduct
PCI group, despite the fact that CAD was more severe in pa- E Figure 49.1. provides an overview of guideline recommenda-
tients who underwent CABG than in those who underwent tions for coronary bypass surgery. The peri-​and post-​operative
PCI. No significant differences were found in the risk of MI and treatment after major cardiac surgery is addressed in depth in
stroke between the two groups [9]. the current EACTS guideline regarding perioperative care [16].
666 CHAPTER 49   Heart failu re su rgery and  tr a n spl a n tati on

Figure 49.1  Schematic illustration of current guideline recommendations for the performance of coronary bypass surgery. BIMA, bilateral internal mammary
artery; LAD, left anterior descending; LIMA, left internal mammary artery.

Important key aspects concerning the perioperative management

after CABG surgery are that β-​blockers should be used with cau- Heart failure and valvular
tion in patients with an LVEF <35% (to prevent the periopera- heart disease
tive risk of hypotension and subsequent ischaemia). ACE-​Is or
ARBs should be stopped preoperatively, since the risk of peri- Aortic regurgitation
operative hypotension and vasodilatory shock is increased. Target Acute aortic regurgitation (AR) should be considered in all pa-
LDL levels for patients undergoing CABG surgery is <70 mg/​dL tients presenting with acute pulmonary oedema or CS. The most
(<1.8  mmol/​L). Cefazolin or cefuroxime are recommended as common aetiologies for acute AR are IE and dissection of the as-
perioperative antibiotic prophylaxis, starting 1 hour before sur- cending aorta [17,  18]. These conditions are discussed in more
gical incision with an optimal duration of 24 hours and not ex- detail in E Chapters 57 and 59, respectively.
ceeding 48 hours. Rhythm control should be preferred over rate In acute severe AR, the large regurgitant volume leads to an
control after surgery in patients with post-​operative AF. acute increase in LV end-​diastolic pressure (LVEDP) due to
See E Chapter 38 for further details. limited distensibility of the unprepared LV and pericardium.
 Hea rt fa i lu re a n d va lvu l a r hea rt   di se ase 667

Eventually, this results in an extensive increase in left atrial for low-​flow, low-​gradient AS without flow reserve, the calcium
pressure (LAP) and ultimately in pulmonary oedema. Urgent, score of the aortic valve may be determined by MSCT to verify
or even emergent, surgery is indicated in these circumstances the severity of AS. MSCT may concomitantly be used to evaluate
[17–​19]. aortic root anatomy and access sites to plan the appropriate
Paravalvular regurgitation (PVR) after transcatheter aortic mode of intervention (TAVI or surgical AVR) [19, 29]. Recently,
valve implantation (TAVI) is another infrequent cause for acute it has been proposed that patients with HFrEF and moderate AS
AR. Due to the usually comparatively uncompliant, hypertro- may benefit from AVR. At this time, clinical trials are addressing
phied LV, even moderate PVR may lead to considerable acute this question [30].
haemodynamic compromise [20]. Balloon post-​ dilatation,
transcatheter valve-​in-​valve placement or transcatheter device Choice of intervention in aortic stenosis
closure may be attempted to close the leak [21–​23]. Surgical AVR Specific trials to address the therapy of choice (TAVI or sur-
is another option after failing TAVR and can be safely performed gical AVR) in the heart failure population are lacking. Current
in experienced centers. guidelines recommend that aortic valve interventions should
Current guidelines recommend surgery for chronic AR in only be performed in heart valve centres with on-​site depart-
asymptomatic patients showing signs of LV impairment. Despite ments of cardiology and cardiac surgery, including structured
these recommendations some patients present late with symp- collaboration in the arrangement of a heart team. Balloon
toms of heart failure due to long-​lasting AR. In these patients, sur- aortic valvuloplasty may be considered as a bridge to transfer
gery is recommended, irrespective of LV function, if the operative to a heart valve centre in unstable patients. The heart team
risk is not prohibitive [19]. In cases with a very high operative should take into account patient-​and procedure-​specific char-
risk and a suitable aortic root anatomy, TAVI may be considered acteristics to define whether SAVR or TAVI is the most appro-
an alternative to surgery [24–​26]. In exceptional circumstances, priate mode of intervention for severe AS. While details can
safe anchoring of a TAVI prosthesis by pre-​stenting of the aortic be found in the guidelines on valviular heart disease, in gen-
root may be achieved in cases with an unfavourable anatomy [27]. eral, TAVI is recommended in elderly patients (>75  years of
Aortic valve repair is an excellent alternative to valve replace- age) with increased surgical risk (STS/EuroSCORE II ≥4%) and
ment in patients with a suitable anatomy. AV repair should there- favourable anatomy for transfemoral access, while concomi-
fore be discussed in a heart team and patients be transferred to a tant CAD with an indication for surgical revascularization and
heart valve centre with special expertise in aortic valve repair [19]. severe primary mitral or tricuspid valve disease or aneurysm
of the ascending aorta favour SAVR [19]‌. Since publication of
Aortic stenosis these guidelines, several trials have compared SAVR to TAVI
Acute decompensation with heart failure, angina, or syncope may in a low-​risk patient population [31–​35]. The two largest ran-
be the first symptom of undiagnosed aortic stenosis (AS), but domized multicentre trials, each including >1000 patients with
even if the condition is known and managed by watchful waiting, a mean age of >73 years, showed non-​inferiority with respect
life-​threatening deterioration may occur [28]. to the primary endpoints (a composite of death, stroke, or
Transthoracic Doppler echocardiography is the preferred diag- rehospitalization at 2 years or a composite of death or disabling
nostic tool to confirm the diagnosis and to grade the severity of stroke, respectively) at 2-​year follow-​up [32, 35]. Considering
AS. The details of a stepwise approach can be found in a recent the lack of long-​term outcome data in this patient population,
position paper from the EACVI [29] and the current ESC/​EACTS a general recommendation for TAVI in low-​risk patients seems
Guidelines for the management of valvular heart disease (VHD) not yet appropriate. The same holds true for younger patients
[19]. Having excluded a reversible high-​ flow status, a mean who differ in regard to valve anatomy, with bicuspid valves
transvalvular gradient >40  mmHg reliably defines severe high-​ being much more common. Bicuspid valves are less amenable
gradient AS and should prompt urgent intervention in the setting to TAVI and were, in general, excluded in clinical trials [19].
of AHF. Because of very poor spontaneous prognosis, there is vir- In younger patients, mechanical valves should be considered
tually no lower EF limit for intervention in this setting [19]. an option due to their unlimited durability and haemodynamic
The diagnosis and management of AS with a mean transvalvular properties [36].
gradient below 40 mmHg are more challenging. Primarily, aortic Over the past years, interest in minimal-​access aortic valve re-
valve area (AVA) is determined, with an AVA >1  cm2 virtually placement (MAAVR) has steadily grown and different techniques
excluding severe AS as the primary cause of heart failure. In such as mini-​ sternotomy or right anterolateral thoracotomy
the setting of reduced LVEF (<50%), dobutamine stress echo- (RALT) have been developed (see E Figure 49.2) [37–​42]. While
cardiography (DSE) is recommended to distinguish truly se- no large-​scale randomized trials comparing MAAVR to conven-
vere low-​flow, low-​gradient AS from pseudo-​severe AS, which tional SAVR have been conducted, smaller trials and retrospective
is defined by an increase to an AVA >1 cm2 without significant studies have confirmed that MAAVR is a safe strategy [37–​40, 43–​
increase in transvalvular pressure gradients under flow normal- 50]. In our institutional experience, MAAVR is feasible in most
ization. In CS, DSE may not be feasible and a different diagnostic patients requiring SAVR. Preoperative MSCT is required to plan
approach should be taken. Analogous to the recommendations and to evaluate the most appropriate access route.
668 CHAPTER 49   Heart failu re su rgery and  tr a n spl a n tati on

(a) (b)

Figure 49.2  Minimally invasive aortic valve replacement via right anterolateral thoracotomy (RALT). (A) Insertion of cardiopulmonary bypass cannulae via the
femoral artery and vein by a 2-​to 3-​cm longitudinal incision above the left inguinal crease. (B) Intraoperative view of the 5-​to 6-​cm transverse incision over the
right second intercostal space and a heavily calcified bicuspid aortic valve.

Mitral regurgitation wall motion abnormalities resulting in tethering of one or

both of the mitral valve leaflets. The best treatment options in
Mitral valve regurgitation (MR) is classified as primary or sec-
these circumstances remain unclear, as MR may improve after
ondary, distinguishing between organic (primary) MR, which
revascularization.
results from abnormalities of the mitral valve apparatus, and
Acute severe MR due to primary degenerative or myxomatous
functional (secondary) MR, which is due to LV disease of is-
valve disease is usually the result of chordal rupture and flail leaflet.
chaemic (CAD) or non-ischaemic (cardiomyopathy) origin and
Urgent surgery is indicated in patients presenting with symptoms
subsequent remodelling [19].
of heart failure, with mitral valve repair being the preferred tech-
nique when the results are expected to be durable. In patients with
Acute mitral regurgitation
very high or prohibitive operative risk, as judged by the heart team,
Acute MR may be the consequence of a multitude of aetiologically percutaneous edge-​to-​edge mitral valve repair may be considered if
different disease states, including, but not limited to, infective endo- valve anatomy fulfils the criteria of eligibility [19, 63].
carditis (IE), myocardial ischaemia, and myxomatous or rheumatic
heart disease. Similarly to acute AR, volume overload in acute MR Chronic primary mitral regurgitation
leads to a marked decrease in cardiac output and a markedly raised Surgical mitral valve repair is indicated in chronic primary MR
LVEDP, often resulting in CS and pulmonary oedema. in asymptomatic patients with signs of LV remodelling, AF, or
Valvular regurgitation in IE may occur as a result of mitral pulmonary hypertension (PH). The development of even mild
chordal rupture, leaflet rupture (flail leaflet), leaflet perforation, symptoms by the time of surgery is an indicator of an ongoing
or interference of the vegetation mass with leaflet closure. MR remodelling process and associated with impaired long-term out-
resulting in CS or causing symptoms of heart failure is an indi- comes despite optimal repair [19, 64].
cation for emergent or urgent surgery, respectively [17]‌(see E Symptoms of heart failure may be the first sign of previously
Chapter  57. Both valve repair and replacement are reasonable undiagnosed severe primary MR. In these patients, timely sur-
options in IE of the mitral valve, depending on the extent of gery is indicated if LVEF is above 30% and mitral repair should be
valvular destruction and perivalvular affection [51–​53]. the preferred technique [19]. In patients with severe LV dysfunc-
Acute myocardial infarction (AMI) may lead to papillary tion (LVEF <30% and/​or LVESD >55 mm), surgery may still be
muscle rupture (PMR), resulting in acute MR, usually within 2–​ a reasonable therapeutic option, depending on the operative risk,
7 days after onset of ischaemia. The rupture may be complete or comorbidities, and the likelihood of successful repair [19].
involve one or more of the papillary muscle heads and most often Percutaneous edge-​to-​edge mitral valve repair may be con-
involves the posteromedial papillary muscle due to its single-​ sidered in symptomatic patients if the heart team has judged the
vessel blood supply (see E Chapter  40). According to current operative risk as very high or prohibitive and has been shown to
guidelines, emergent surgery is indicated, although it carries high improve symptoms and induce reverse remodelling of the LV in
operative mortality [54]. Valve replacement is often required, but selected patients [63]. However, compared to surgical repair, the
surgical repair may be a reasonable alternative in experienced rate of residual MR is higher [65].
hands [55–​58]. For patients with a prohibitive risk for surgery,
percutaneous edge-​to-​edge mitral valve repair has been reported Chronic secondary mitral regurgitation
with reasonable results [59–​62]. In secondary MR, formerly also termed as functional MR, the valve
Severe secondary MR after AMI may present as a result of leaflets and the subvalvular apparatus are structurally unaffected.
papillary muscle dysfunction or displacement due to regional Regurgitant flow across the mitral valve results from a coaptation
 Hea rt fa i lu re a n d va lvu l a r hea rt   di se ase 669

deficit due to remodelling of the mitral valve annulus, LV, and MR, mitral valve repair using an undersized ring to restore leaflet
LA, leading to annular dilatation, displacement of the papillary coaptation can be performed with acceptable perioperative risk
muscles, and tethering of the mitral leaflets [66]. The presentation and good long-​term results. Preoperative predictors of recurrent
of secondary MR as a result of myocardial ischaemia is frequently secondary MR after an isolated undersized annuloplasty include
dynamic in its nature, due to inducible regional wall motion abnor- markers of mitral valve deformation, local and global LV remod-
malities and changes in ventricular pre-​and afterload under ex- elling (LVEDD >65 mm, posterior mitral leaflet angle >45°, sys-
ercise. This may result in recurrent symptoms of heart failure and tolic tenting area >2.5 cm2, coaptation distance >10 mm, distal/​
pulmonary oedema. apical anterior leaflet tethering, end-​systolic interpapillary muscle
In contrast to primary MR, convincing evidence that correc- distance >20  mm, and systolic sphericity index >0.7), basal an-
tion of secondary MR improves survival has been lacking until eurysms, and dyskinesia [74–​78]. In patients at high likelihood
now, resulting in a lower level of evidence in treatment recom- of MR recurrence, valve replacement should be considered [19].
mendations and highlighting the importance of the heart team in
decision-​making  [19]. Mitral stenosis
It is generally accepted that surgery of the mitral valve for se- Acute mitral stenosis (MS) is a very rare, but severe, complication
vere secondary MR is indicated in patients with LVEF >30% of IE and warrants urgent or emergent surgery, depending on the
undergoing CABG for CAD. In symptomatic patients who pre- severity of symptoms [17].
sent with severely reduced LVEF (<30%), but showing evidence Chronic rheumatic MS has greatly decreased in industrial-
of myocardial viability, concomitant revascularization and MV ized countries, but the incidence of calcific mitral valve disease is
surgery should be considered [19, 67]. increasing in the elderly population [19].
If a patient remains symptomatic in spite of optimal medical treat- Mitral valve intervention is indicated in all symptomatic pa-
ment (OMT) and revascularization is not indicated, recommenda- tients with significant MS [mitral valve area (MVA) <1.5  cm2],
tions depend on LV function and surgical risk. In case of LVEF >30% with percutaneous mitral commissurotomy (PMC) being the
and low surgical risk, surgery may be considered. If LVEF is above intervention of choice in suitable patients, while surgical therapy,
30%, but surgical risk is high, percutaneous edge-​to-​edge repair may usually valve replacement, is reserved for patients with a contra-
be considered if mitral valve anatomy is suitable [19]. In chronic indication or unfavourable anatomical features for a PMC (LA
HFrEF (LVEF <30%), mitral valve surgery or a percutaneous edge-​to-​ thrombus, moderate or severe MR, severe or bi-​commissural cal-
edge procedure may be considered by the heart team after thorough cification, absence of commissural fusion, severe disease of other
evaluation of other treatment options, including durable MCS or HTx valves, or CAD requiring surgery) [19].
(see respective sections of this chapter). Two recently published pro-
spective randomized controlled trials showed conflicting results after Surgical approach
edge-​to-​edge repair in patients with secondary MR and severely im- In recent years, different less invasive techniques have been de-
paired left ventricular function [68, 69]. This led to the (not undis- veloped, of which the right lateral mini-thoracotomy (see E
puted) concept of disproportionate MR, which was used to in part Figure  49.3) has been widely adopted for mitral repair and re-
explain the finding that especially patients with a disproportionately placement [79,  80]. According to a consensus statement from
larger effective regurgitation orifice area (EROA) and a less dilated the International Society of Minimally Invasive Cardiothoracic
ventricle seemed to benefit from edge-​to-​edge repair [70]. If the LVEF Surgery (ISMICS) published in 2010, minimally invasive sur-
is <15%, a valve intervention is generally no longer advised [19, 71]. gery may be an alternative to conventional mitral valve surgery,
There is limited evidence to guide the decision of whether to with comparable short-​and long-​term mortality and morbidity.
repair or replace the valve in secondary MR [72, 73]. In patients Compared to conventional surgery, minimally invasive surgery re-
without echocardiographic risk factors for residual or recurrent sults in reduced sternal complications, transfusions, post-​operative

(a) (b) (c)

Figure 49.3  Video-assisted minimally invasive mitral valve surgery via right lateral mini-thoracotomy. (A) Setup: incision at fourth intercostal space with a
soft tissue retractor, a transthoracic clamp, an endoscope, and an arm for the atrial roof retractor; insertion of peripheral cardiopulmonary bypass cannulae via
the femoral artery and vein. (B) Intraoperative view of a mitral valve with posterior leaflet prolapse (black arrow) and flail due to a ruptured cord (white arrow).
(C) Corresponding intraoperative TOE demonstrating prolapse of the P2-​segment of the mitral valve.
670 CHAPTER 49   Heart failu re su rgery and  tr a n spl a n tati on

AF, duration of ventilation, and ICU and hospital length of stay. of post-​operative AF. It is also highlighted that direct oral anticoagu-
stay at the cost [81]. Excellent long-term and durable repair rates lants (DOAC) should be avoided after mechanical valve replace-
have been reported [82, 83]. ment. Furthermore, cefazolin or cefuroxime are recommended as
perioperative antibiotic prophylaxis, starting 1 hour before sur-
Concomitant tricuspid regurgitation gical incision, with an optimal duration of 24 hours, and not ex-
Secondary TR is a common sequela of left-​sided heart disease. ceeding 48 hours.
Concomitant tricuspid repair to left-​sided valve surgery does
not increase the operative risk. In contrast, reoperation for per-
sisting severe TR carries a high risk of mortality and morbidity. Mechanical circulatory support
Therefore, tricuspid surgery is indicated in patients undergoing
left-​sided valve surgery with severe secondary TR. If tricuspid an- Indications and guideline recommendations
nular dilatation exists (≥40 mm or >21 mm/​m2) or recent signs of In patients with acute or chronic heart failure refractory to med-
right heart failure are documented, surgery should be considered ical therapy, short-​and long-​term MCS therapy may be considered
in the presence of only mild to moderate TR. Surgery may even [71]. Short-​ term assistance with percutaneous and extracor-
be considered in patients without tricuspid annular dilatation but poreal, non-​durable life support systems is recommended for
with mild to moderate TR. Whenever achievable, valve repair is ‘bridge to decision’ (BTD) or ‘bridge to recovery’ (BTR). This rec-
preferred [19]. ommendation applies to AHF patients with HFrEF, CS, and pro-
found haemodynamic compromise (IIa B) for resuscitation and
Prosthetic valve thrombosis as a stabilizing measure for diagnostic or therapeutic procedures
Acute valve thrombosis is rare but should be suspected in any (angiography and revascularization) [71, 93,  94]. For critically
patient with any type of prosthetic valve presenting with recent ill patients (AHF/​CS, resuscitated cardiac arrest), a BTD recom-
signs of heart failure or thromboembolism and should be treated mendation is made to prevent death, achieve haemodynamic
as a life-​threatening emergency as rapid deterioration may occur stability and end-​organ perfusion and allow for more time to as-
[84–​86]. The diagnosis should be confirmed by echocardiography sess the prognosis and to discuss the therapeutic options (see E
(TOE if TTE is inconclusive), cine-​fluoroscopy, or CT [87]. Chapters 23 and 39 for further details).
In critically ill patients without serious comorbidities, ob- For durable, long-​term MCS therapy, candidates with end-​
structive valve thrombosis is an indication for urgent or emergent stage chronic heart failure of ischaemic or non-​ischaemic origin
valve replacement, depending on the clinical status. If surgery is are either considered for ‘bridge to transplantation’ (BTT), ‘bridge
not available in a timely manner or the surgical risk is very high, to transplantation candidacy’ (BTC), ‘destination therapy’ (DT),
fibrinolysis should be considered [19]. or very rarely bridge to recovery (BTR) [95]. BTT describes the
MCS strategy to support high risk transplant eligible patients
Bioprosthetic valve failure while waiting until a donor organ becomes available (IIa C) [71].
Bioprosthetic valve failure is usually a process of slow onset and BTC involves application of MCS to patients with one or more
may present with primarily stenotic, regurgitant, or combined relative contraindications to transplantation that are deemed po-
lesions. Acute valvular regurgitation, causing symptoms of heart tentially reversible or treatable (PH, cancer, obesity, tobacco use,
failure, may arise due to tearing of calcified cusps or IE. While etc.) [96]. DT describes the need for permanent MCS, without the
left-​sided prosthetic valve endocarditis causing symptoms of heart option of transplantation. It has been traditionally applied in non-​
failure or leading to CS is always an indication for urgent or emer- transplant eligible patients with refractory end-​stage heart failure
gent redo surgical valve replacement [17], transcatheter-​based to prolong life (IIa B) [95]. LVAD for DT currently represents
interventions have been introduced for degenerative bioprosthetic approximately 46% of all LVAD implantations, with increasing
valve failure or failure after annuloplasty in recent years [88–​91]. support durations and similar implantation numbers to HTx per-
To date, randomized prospective trials comparing redo sur- formed in the US [95].
gical valve replacement to catheter-​based valve-​in-​valve (ViV) In everyday clinical practice, these classifications lack direct
or valve-​in-​ring (ViR) interventions are lacking. A recent meta-​ applicability due to the variability in patient prognosis and treat-
analysis of retrospective data showed increased transvalvular ment course over time. In Europe, only 10% of patients with an
gradients in the ViV-​TAVI cohort and raised concerns regarding initial BTT indication for MCS with an LVAD are transplanted
higher mortality in this group of patients [92]. Therefore, ViV or within the first year and hence ‘prolonged LVAD therapy, despite
ViR interventions may be reasonable alternatives in patients at eligibility for transplantation, has become a clinical reality’ [97].
increased surgical risk, with the heart team discussing the best
therapeutic strategy for each individual patient [19].
Prognosis and INTERMACS level
Perioperative medical treatment after major cardiac surgery is The indication for LVAD can be considered when:  LVEF <25%
addressed in current EACTS guidelines [16]. and NYHA classes III–​ IV despite guideline-​ directed medical
Regarding valve surgery, one key aspect is the probable su- treatment (GDMT), including CRT if indicated, with either high
periority of rhythm control over rate control in patients with predicted 1-​year mortality [>20%, as calculated by currently used
 M echa n i ca l ci rcu l atory   supp ort 671

scoring systems, e.g. Seattle Heart Failure Model (SHFM), or me- advanced age, female gender, presence of right heart failure (as a
dium/​high risk on the Heart Failure Survival Score (HFSS)] or sign of long-​standing, and therefore biventricular, heart failure),
dependence on continuous parenteral inotropic support [93]. and the need for concomitant cardiac surgery [95, 99].
The current practice and pre-​implantation profiles of VAD Independent of the respective INTERMACS profile, a main
recipients from 2013 and 2017 were reflected in the third concern is whether univentricular left support is sufficient.
International Society for Heart and Lung Transplantation To date, there are three viable options in terms of mid-​to
Mechanically Assisted Circulatory Support (IMACS) re- long-​term RV/​biventricular support, which include implant-
port:  INTERMACS profile 1, critical CS in 17%; INTERMACS ation of a total artificial heart (TAH), extracorporeal displace-
profile 2, ‘sliding on (IV) inotropes’ in 33%; INTERMACS profile ment pumps, and biventricular continuous-​f low assist devices
3, stable but (IV) inotrope-​dependent in 34%; INTERMACS pro- (BiVAD). These options might be needed if standard medical
file 4, resting symptoms and ‘frequent flyer’ in 13%; INTERMACS therapy (inotropic support, reduction of PVR) and respiratory
profile 5, exertion-​ intolerant and ‘housebound’ in 2%; therapy fail to sufficiently support a failing right ventricle.
INTERMACS profile 6, exertion-​limited and ‘walking wounded’ Continuous-​flow VADs are currently not approved for RV
in 1%; and INTERMACS profile 7, advanced NYHA class III in support, but clinical evidence of their use is growing (see E
1% of registered patients [98]. This represents the worldwide clin- Figure 49.4) [98, 100].
ical practice in contrast to the current guideline recommenda- The IMACS report provided the contemporary implant-
tions that recommend for LVAD therapy only for INTERMACS ation rates based on device type, which were: LVAD, in 92.9%;
profiles 3–​5 and only for selected cases in INTERMACS profiles 2 RVAD, in 0.17%; BiVAD, in 5%; and TAH, 1.9% of registered
and 6–​7. Clear preference for short-​term MCS should be given in patients [98].
acute CS (INTERMACS profile 1).
Factors for early mortality after MCS implantation include MCS implantation
renal dysfunction, liver dysfunction and elevated lactate levels (as Careful perioperative management and LVAD implantation
signs of impaired acute or chronic secondary end-​organ damage), techniques have been directly associated with better patient

Aorta
Pulmonary artery

Left ventricle

Right ventricle

RVAD pump
LVAD pump

Figure 49.4  Left ventricular assist device (LVAD) and a biventricular assist device (BiVAD) [101, 102].
Reproduced from Patangi SO, George A, Pauli H, et al. Management issues during HeartWare left ventricular assist device implantation and the role of transesophageal
echocardiography. Ann Card Anaesth 2013;16(4):259–​267. doi:10.4103/​0971-​9784.119173 with permission from Wolters Kluwer and Ventricular assist device (VAD). Accessed on
09.04.2019, M https://​www.mayoclinic.org/​tests-​procedures/​ventricular-​assist-​device/​about/​pac-​20384529. Used with permission of Mayo Foundation for Medical Education and
Research, all rights reserved.
672 CHAPTER 49   Heart failu re su rgery and  tr a n spl a n tati on

(a) (b)

Figure 49.5  (A) Median sternotomy procedure for LVAD implantation. (B) Implantation of the LVAD pump using a lateral thoracotomy approach [104, 108].
Reproduced from McGee E Jr, Danter M, Strueber M, et al. Evaluation of a lateral thoracotomy implant approach for a centrifugal-​flow left ventricular assist device: The LATERAL
clinical trial. J Heart Lung Transplant 2019;38(4):344–​351. doi:10.1016/​j.healun.2019.02.002 with permission from Elsevier.

outcomes. Full median sternotomy and aortic anastomoses have new, less invasive off-​pump implantation techniques. The lateral
long been the standard approach for implantation of LVADs. thoracotomy approach uses two smaller incisions to implant the
However, less invasive non-​ sternotomy approaches are be- pump, leaving the sternum intact, which allows for early post-​
coming more popular. As pump size is decreasing allowing for operative ambulation and improved patient outcomes (see E
intra-​pericardial placement, it has been possible to introduce Figures 49.5 and 49.6) [103].

(a) (b)

(c) (d)

Figure 49.6  LVAD insertion configurations. (A) OG to ascending aorta. (B) OG to axillary artery. (C) OG to descending aorta. (D) OG to supracoeliac aorta.
LVAD, left ventricular assist device; OG, outflow graft [109].
Based on Makdisi G, Wang IW. Minimally invasive is the future of left ventricular assist device implantation. J Thorac Dis 2015;7(9):E283–​E288. doi:10.3978/​j.issn.2072-​1439.2015.08.30.
 Hea rt tr a n spl a n tat i on 673

Table 49.1  Advantages and disadvantages of minimally invasive the number of patients with refractory chronic heart failure
HVAD™ implantation [110] is steadily increasing, a stagnant number of organ dona-
tions has led to longer waiting times (median ~6–​7  months;
Advantages Disadvantages
Eurotransplant), and resulted in a waiting list mortality of 20%
Less trauma Technical hurdles [112]. This illustrates the dilemma demonstrates that heart
Less bleeding Reduced visual access
Less right heart failure Challenging estimation of length of transplantation is not an option for the vast majority of patients
Better outcome the outflow graft that are in a critical state and would potentially benefit. These
Reduced complications Concomitant procedures benefits include an increased survival and an improved quality
Fewer inflow cannula malpositions Missing comparative studies of life [71]. The survival rates are steadily improving, with a
Shorter ECC time Fairly new
current mean survival of 11.1 years [113, 114].
Shorter OR time
Shorter ICU time Current ESC guideline indications for heart transplantation
Shorter respirator time include end-​stage heart failure with severe symptoms and poor
Shorter length of hospital stays prognosis (mortality >20% within currently used heart failure
Economic benefits scores, e.g. HFSS, SHFM) [96], with no alternative conventional
Less adhesions
Facilitates cardiac transplantation treatment option. Absolute and relative contraindications include
Better survival active infection [human immunodeficiency virus (HIV) and
hepatitis C are no longer a strict contraindication since medical
Source data from Deniz E, Chatterjee A, Feldmann C, Hanke J, Dogan G, Berliner D,
Shrestha M, Haverich A, Schmitto J. How to do it: tips and tricks of minimal-​invasive treatment has dramatically improved over the past years [96]],
HVAD® implantation—​the lateral approach. J Thorac Dis 2018;10(15), S1829–​S1833. severe peripheral arterial or cerebrovascular disease, irreversible
PH, cancer with tumour recurrence, irreversible renal dysfunc-
Recently, the LATERAL study, a multicentre, prospective, study tion (creatinine clearance <30 mL/​min), BMI >35 kg/​m2, alcohol
in a BTT population with advanced heart failure demonstrated and drug abuse, and any other serious comorbidity with poor
that the lateral thoracotomy approach was safe and effective com- prognosis [71, 96]. Note irreversible PH and creatinine clearance
pared to the historical control [104] (see E Table 49.1). <30 mL/​min are both a contraindication for HTx alone.
Various devices have been implanted off-​ pump via thora- Various studies exploring recipient and donor factors that de-
cotomy and mini-​sternotomy to date, including the HeartWare™ termine the outcome after heart transplantation have shown that
HVAD™, CentriMag™ BiVAD system, and HeartMate 3™ LVAD donor criteria [age, hypertension, diabetes mellitus, LV dysfunc-
[105, 106] (see E Chapter 50). tion (EF <50%, LV hypertrophy)] are independent risk factors for
Though the non-​invasive off-​pump lateral thoracotomy approach long-​term mortality [115]. With optimal management allocation
offers advantages, it is not feasible when concomitant valve repair of marginal organs can be used with good outcomes and poten-
or replacement procedures are needed. [107]. Placement of the tially extend the donor pool [116–​118].
LVAD in the pleural space could complicate future operations and Long ischaemia times are associated with a higher risk of mor-
create adhesions to the lung, phrenic nerve, and diaphragm [105]. tality [119]. Ex vivo perfusion with organ care systems could po-
For further reading, see E Chapter 50. tentially overcome this issue within the near future [120].
More than 50% of all transplant recipients are bridged to HTx
Weaning with MCS. Currently used continuous-​flow implantable LVADs in
BTT patients have increased survival for patients on the waiting
In about 5% of patients, LV function recovers after prolonged LVAD
list to transplant and there has been no impaired survival after
support. In these patients, after careful assessment (including spe-
transplantation [121]. Even temporary circulatory support is in-
cific pump stop exams), weaning and explantation of the LVAD
creasingly applied to patients in CS awaiting, or considered for,
may be considered. Various explantation techniques for LVADs
transplantation [113].
are currently available, including mechanical plugs (INNOVO
Solutions GmbH, Germany) and custom made titanium plugs Technical aspects of heart transplantation
(Fittkau GmbH, Germany), which allow for both an off-​pump ex-
Orthotopic bi-​ caval transplantation represents the currently
plantation, but also for a fast redo-​implantation in case of recur-
used standard method for HTx worldwide. The originally used
rent LV failure, since the sewing ring remains preserved [111].
method of bi-​atrial transplantation was replaced by the bi-​caval
method, in which the recipient’s right atrium is fully excised and
the recipient’s vena cava is anastomosed to the donor vena cava
Heart transplantation [113], resulting in a lower incidence of atrial arrhythmias and
tricuspid valve insufficiencies. Heterotopic HTx was used in the
Indications and guideline recommendations 1970s and 1980s as biological biventricular support but is no
HTx is still the gold standard of heart failure therapy for the longer used today because of inferior long-​term survival (see E
treatment of patients in end-​stage chronic heart failure. While Figure 49.7) [113].
674 CHAPTER 49   Heart failu re su rgery and  tr a n spl a n tati on

(a) (b)

Figure 49.7  Recipient heart after cardiectomy. The left atrium is resected by the conventional technique. The posterior aspect of the right atrium is resected,
leaving a trapezoidal connection to the left atrium and both venae cavae (A). Carrying-​out of our preferred bi-​caval technique for orthotopic cardiac
transplantation (B) [126].
Reproduced from Tsilimingas NB. Modification of bicaval anastomosis: an alternative technique for orthotopic cardiac transplantation. Ann Thorac Surg 2003;75(4):1333–​1334.
doi:10.1016/​s0003-​4975(02)04550-​2 with permission from Elsevier.

Post-​operative care after heart transplantation Again, medical therapy or, if needed, mechanical support of the
donor organ is a viable treatment option.
During the initial post-​operative phase after HTx, the unique situ-
Furthermore, increased PVR as a result of PH or as a relative
ation of a transplanted organ with reduced compensatory mech-
increase (if donor RV function is impaired) has to be addressed
anisms due to ischaemia, reperfusion injury, and denervation
during this initial period. Treatment options include use of ino-
(with chronotropic and inotropic insufficiency) has to be taken
tropic support, inhaled NO, sildenafil, prostacyclin analogues, ad-
into account. Therefore, careful adjustment of preload, afterload,
justment of respirator settings, or as ultima ratio MCS.
and cardiac contractility is of utmost importance, together with
Arrhythmias, such as bradycardia and supraventricular ar-
a stable heart rhythm, to achieve optimal cardiac performance
rhythmias, are typically the most frequent rhythm disturbances
and adequate organ perfusion (displayed by decreasing lactate
occurring after HTx, associated with denervation or secondary
levels and SVO2 >65%). Continuous monitoring with a Swan–
sinus node damage (ischaemia-​triggered) or that might be in-
Ganz catheter (in selected cases, continuous TOE or direct LAP
duced by (positive inotropic) medication or due to electrolyte
measurement), together with central venous and arterial lines, is
shifts, therefore requiring prompt attention and in-​depth evalu-
strongly recommended [114]. Inotropic support and inodilators
ation. Furthermore, they could be due to acute rejection or peri-
(to decrease pulmonary resistance and support the untrained
cardial effusion and an echocardiographic examination should be
right ventricle) may be neccessary during the first days [114]. If
performed immediately [123]. Without parasympathetic influ-
patient haemodynamics remain unstable through these manage-
ence (due to denervation), heart rates are approximately 100 bpm;
ment options, temporary MCS may be needed to avoid end-​organ
heart rates <90 bpm should be considered as relative bradycardia.
dysfunction [122].
Within the first 6 months after transplantation, the risk of acute
Primary graft dysfunction, defined as uni-​or biventricular
rejection is at its peak, prompting centres to perform routine sur-
failure (not including PH, volume overload, and acute rejec-
veillance heart biopsies [113]. These are still the gold standard,
tion) occurring within the first 24 hours after transplantation, is a
with non-​invasive methods such as TTE, strain echocardiog-
major concern during the initial post-​operative phase. Although
raphy, cell-​free DNA (cfDNA), and gene profiling [124,  125]
the aetiology is not completely understood, relevant contributors
increasingly being used and replacing protocol biopsies in
are donor organ injury during brain death, reperfusion injury,
many centres. Furthermore, cardiac allograft vasculopathy, the
and potential pre-​existing heart disease of the donor organ [122].
leading cause of long-​term mortality after HTx, with a complex
 RE F E RE N C E S 675

pathogenesis (immunological and non-​ immunological factors or complete weaning during the first year), all with their own
are contributing), could be seen during the initial post-​operative inherited side effect profiles such as infection, malignancy,
phase (since ischaemia and reperfusion damage are important nephrotoxicity, hypertension, hyperglycaemia, and various
triggers) manifesting as diffuse, pan-​arterial thickening of cor- drug–​drug interactions (via cytochrome P450) [113, 114] (see
onary arteries. This stands in contrast to a potentially pre-existing E Chapter 73). Protocols exist to avoid or reduce side effects
CAD of the donor organ. Both pathologies can be complicated by within months after transplantation throughout implemen-
denervation, since angina symptoms are often missing after HTx. tation of mammalian target of rapamycin (mTOR) inhibitors
(everolimus, sirolimus), but they are not routinely used in the
Immunosuppression and infectious control acute post-​operative setting, since impaired wound healing is
The use of immunosuppression can be subdivided into induc- one of the major side effects and their immunosuppressive po-
tion therapy, rejection treatment, and maintenance therapy (see tential is not as high as the potential of calcineurin inhibitors
E Chapter 73). As many as 50% of HTx programmes currently [132] (see E Chapter 73).
employ a strategy of induction therapy during the early post-​ Generally speaking, nosocomial infections play a significant
operative or even in the intraoperative phase [127], especially in role within the first month after transplantation, while within the
sensitized patients (patients with increased immunological risk). first year, atypical pathogens [Gram-​ negative bacteria and vir-
Sensitized patients with cytotoxic donor-​specific antibodies are uses (herpesviridae), as well as Candida and Aspergillus species]
at highest risk of fatal rejection [128]. Furthermore, induction are frequent triggers. However, with increasing durations post-​
therapy is more frequently given in paediatric transplant patients transplantation and a concomitant reduction in immunosuppres-
than in adults, most commonly antithymocyte globulin (ATG), sants, typical pathogens play a rather predominant part [133]. To
with less use of interleukin-​2 receptor antagonist (IL-​2RA) in- avoid opportunistic infections, ganciclovir (IV) or valganciclovir
duction [129]. These agents may reduce the risk of early rejection (PO) are given to prevent cytomegalovirus activation (see E
and could furthermore be used to delay calcineurin inhibitor ini- Chapter 73). Furthermore, prophylaxis against Pneumocystis jirovecii
tiation (and therefore avoid side effects, mainly acute renal in- pneumonia (sulfamethoxazole/​trimethoprim) and mucocutaneous
jury), but they have also been associated with an increased risk of candidiasis (e.g. locally applied amphotericin B) are given during the
infection [130]. first 3–​6 months after transplantation. In patients without severe in-
Early allograft rejection has been associated with a sig- fection prior to transplantation, perioperative antibiotic prophylaxis
nificant increase in mortality rates at 30  days and 1  year post-​ against skin flora is usually used. A  more sophisticated protocol,
transplantation [130]. It can present itself as uni-​or biventricular often consisting of broad-​spectrum penicillin or carbapenem, to-
dysfunction and usually stems from an acute cellular rejection, gether with daptomycin or vancomycin, is used in patients with
less often from antibody-​mediated rejection (AMR) [113]. The preoperative severe VAD or cardiac implantable electronic device
recommended treatment protocols for cellular rejection in- infection if the primary pathogen is unknown.
clude repeated ATG and IL-​2RA therapy, as well as steroid pulse In current practice, advanced care regimens in patients with
treatment, combined with increased baseline immunosuppres- severe heart failure should include surgical treatment options
sive therapy. Furthermore, rituximab, eculizumab, bortezomib, due to their proven long-​term benefits. Decisions for these pa-
plasmapheresis, immunoglobulin substitution, photopheresis, or tients should be made by an interdisciplinary heart failure team.
combinations thereof are potential options for severe humoral re- Heart failure team decisions have been practised in the field of
jection [128, 131]. HTx for decades and have been promoted by competent moni-
Modern immunosuppression consists of maintenance therapy toring authorities. The heart team approach is recommended in
with calcineurin inhibitor (predominantly tacrolimus), an anti- the settings of endocarditis, CAD, or valve disease. Especially due
metabolite (mycophenolate mofetil or mycophenolic acid have to increasing and necessary sub-​specializations in cardiac surgery
almost completely replaced azathioprine), and steroids (usu- and cardiology, such team approaches are essential for achieving
ally a high dose is used initially, with attempts of reduction optimal results for the patient.

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 CHAPTER 50

Implanted cardiac
support devices
Andrew C Morley-​Smith, André R Simon, and
John Pepper

Contents
Summary  680 Summary
Introduction  680 Mechanical circulatory support forms a crucial and expanding element of ad-
Desirable features for an implantable vanced heart failure management. Short-​term assistance is delivered in emer-
ventricular assist device  681 gency situations or where the underlying condition is likely to quickly worsen,
Devices used in clinical practice  682 and these approaches are discussed in E Chapter 28. Here this chapter focuses
Choosing candidates for left ventricular on implantable devices intended for the medium and long term. The first half of
assist device therapy  682
the chapter is aimed directly at practical clinical management, while the second
Prevention and management of
complications  684
half considers the evidence base for contemporary practice. The chapter concludes
Device infection  684 by considering new paradigms for implantable cardiac support. Most frequently,
Erythrocyte destruction  684 these devices support left ventricular function (left ventricular assist devices), and
Thrombosis and thromboembolism  684 this comprises the majority of our discussion.
Coagulopathy and bleeding tendency  685
Stroke  685
Chronic right ventricular failure  685
Emergency management of the long-​term
ventricular assist device patient  685
Arrhythmia  686
Bleeding  686
Pump suction events  686 Introduction
Pump stoppage  686
Evolution and evidence base  686 Therapy for advanced heart failure has been transformed in recent decades, but there
Early devices  686 remains a cohort of patients for whom the most advanced medical device and cellular
Continuous flow and widespread adoption of therapies are insufficient to augment myocardial function and ameliorate the worsening
destination therapy  686
Newest implantable ventricular assist devices
heart failure syndrome. For these patients, cardiac transplantation delivers the best long-​
in practice  687 term outcome, but cardiac support devices are increasingly important. Short-​term as-
Myocardial recovery  688 sistance is delivered in emergency situations or where the underlying condition is likely
Other implantable support systems  688 to recover in days to weeks, and these approaches are discussed in E Chapter 28. Here
Isolated right ventricular assist devices  688
Total artificial heart  688 we focus on implantable devices intended for the medium and long term, typically in
Personal perspective  688 patients whose underlying heart function is expected to decline further or remain poor
Further reading  688 over months to years.
References  689 The first VADs were developed in the 1980s as a continuum for post-​cardiotomy
patients unable to wean from CBP [1]‌and evolved through the 1990s as untethered
implantable devices used to sustain life until an organ became available for cardiac trans-
plantation. Their use in this bridge to transplantation setting allows improvements in
cardiac output and blood pressure to reconstitute patients’ end-​organ dysfunction suffi-
ciently to undergo transplantation safely.
The technology and clinical application have continued to evolve rapidly, reducing the
high morbidity associated with early devices and now including patients whose age and
comorbidities would previously have been contraindications to VAD therapy. The bur-
geoning use of VADs as an independent long-​term treatment (DT) has greatly improved
therapy for patients with advanced heart failure. However, it remains expensive and is
 Desirable f eatu res for  a n i m pl a n ta b l e ven tri cu l a r as si st   dev i c e 681

associated with significant morbidity, and consequently funding a ‘pocket’ in the thorax and/​or abdomen. This pump accelerates
for such programmes remains controversial in resource-​limited blood to an outflow cannula which is grafted onto a major vessel
health economies [2]‌. (e.g. the aorta). The pump is connected to external batteries and
The first half of the chapter is directed at practical clinical man- a control unit via a percutaneous driveline, which usually exits
agement, while the second half considers the evidence base for through the anterior abdominal wall.
contemporary practice. We conclude by considering new para- There are several features that the pump design needs to attain:
digms for implantable cardiac support. Most frequently, these ◆ The pump should be capable of immediately and consistently
devices support LV function (LVADs), and this comprises the generating blood flow and pressure to sustain organ function.
majority of our discussion. ◆ The device should be quick and straightforward to implant in
even the sickest patient.
◆ Long-​term use requires that the device is reliable and durable,
Desirable features for an implantable with a low risk of pump failure.
ventricular assist device ◆ Aside from pump failure, the device should minimize peri-
operative or long-​ term complications, particularly stroke,
Clinicians and engineers together invest significant efforts in coagulopathy/​bleeding, thromboembolism, and infection.
designing the ideal implantable VAD. The essential features are ◆ The pump requires power, and this should be delivered to the
shown in Figure 50.1. Blood is drawn from the heart (usually patient in a manner that minimizes the risk of infection from
from the LV) through an inflow cannula to a pump sited within percutaneous connections.

HeartMate battery HeartMate battery

worn externally worn externally
in holster in holster

Aorta

Heart

Power lead Power lead

Percutaneous
lead exiting
body
HeartMate II
LVAD or
‘heart pump’

HeartMate II LVAS
system controller

Figure 50.1  Key features of a contemporary implantable VAD.

Reprinted with the permission of Thoratec Corporation.
682 CHAPTER 50   Im pl anted cardiac su pp ort devi ces

◆ An important consideration is that the device is easy to remove maintained continuous flow and led to new innovations in pump
or replace in the event of myocardial recovery or requirement for design and are already the mainstay of practice in many European
pump replacement. centres. The main devices in each generation are summarized
◆ Juxtaposed to the need for a superlative technology (and without in E Table 50.1. The detailed history and clinical evidence are
compromising it) is the desire for the device to be inexpensive to reviewed later.
manufacture, purchase, and maintain.

Choosing candidates for left

Devices used in clinical practice ventricular assist device therapy
The evolution of VADs has been one of steady incremental im- Choosing the right patients for LVAD therapy is a complex pro-
provements, punctuated by sudden disruptive changes that clas- cess, best undertaken by a multidisciplinary team. Three key con-
sify devices into ‘generations’ of technology. The first-​generation siderations come into play.
devices were large with pulsatile flow and displacement pumps First, there should be a predetermined clinical strategy,
that entered into practice in the 1980s. By contrast, the second-​ intending for the LVAD to be either a BTT or as DT. However, in
generation devices are rotary pumps generating continuous flow. reality, some patients require urgent implantation that precludes
These entered into practice in the first years of the twenty-​first cen- a full transplant assessment, and in others, there may be rela-
tury and, over the past 10 years, have superseded first-​generation tive contraindications to transplantation (such as secondary PH
technology. More recently, the third-​ generation devices have or renal impairment) that are likely to improve with circulatory

Table 50.1  Implantable VADs and their essential characteristics

Device Key facts

Volume displacement Thoratec HeartMate >5000 implants worldwide. Evolved from pneumatic to vented electric to XVE designs, reducing
I-​VE-​XVE the calibre of the driveline. Contains two porcine valves. Unique titanium microsphere lining
means anticoagulation not required. Largely superseded by continuous-​flow pumps
Thoratec IVAD LVAD or RVAD. Based on its paracorporeal predecessor (PVAD). Pneumatic driver. Polyurethane
surface requires anticoagulation
Novacor LVAS >1600 implants, with support for up to 6 years and low risk of device failure. Porcine valves and
polyurethane pump sac
Rotary—​axial flow Thoratec HeartMate II Most implanted device worldwide (>14 000 patients), with strongest clinical evidence base
to date. Impeller sits on ruby bearing with long durability. Recent increase in rates of pump
thrombosis. FDA-​approved for BTT and DT
Jarvik 2000 First device using intraventricular pump placement, avoiding the need for pump pocket and
minimizing infection risk. Impeller sits in titanium housing and is the only moving part, using
ceramic bearings with long durability. Novel post-​auricular power connector
ReliantHeart HeartAssist 5 Impeller supported by two mechanical pivot bearings. Flow rate can be measured directly and
monitored remotely. Continued focus on high rates of thrombus formation
Berlin Heart InCOR Rotor suspended magnetically to avoid wear. All blood-​contacting surfaces are heparin-​coated
to improve biocompatibility. High rate of stroke initially, reduced after modifications to inflow
cannula
Rotary—​centrifugal flow WorldHeart Levacor Active and passive magnetic bearing suspends centrifugal impeller. Polished titanium surfaces to
reduce thrombus risk. Target INR 3.0–​3.5 and requires triple antiplatelet therapy
Terumo DuraHeart Largest and heaviest of the rotary pumps, but large clearance gaps from axial magnetic bearings
may reduce blood trauma
HeartWare HVAD* Intra-​pericardial placement, with short inflow unit housed within pump itself. Impeller is only
moving part and is stabilized by electromagnetic and hydrodynamic forces. No mechanical
bearings. Easy to replace and explant. Possibility for less invasive ± off-​pump implant. FDA approval
for BTT and DT
Thoratec HeartMate 3* Similar design to HVAD, with short inflow unit, apical pump placement and electromagnetic rotor
levitation. FDA approval for BTT and DT
Rotary—​mixed atrial and CircuLite Synergy Partial support for INTERMACS profiles 4 and above. Left atrium to right subclavian artery.
centrifugal flows Off-​pump mini-​thoracotomy for insertion. Implants ceased after problems with device thrombosis
and inflow cannula fracture
*
Contemporary first-​line devices.
LVAS, left ventricular assist system.
 Ch o osing ca n di dates for  l eft ven tri cu l a r as si st devi c e   t h e r a p y 683

support [3, 4]. LVAD implants in these patients allow a ‘bridge to borderline cases, pulmonary vasodilators (e.g. inhaled NO),
candidacy’, with a view to future reassessment; some transition combined with inotropes, may augment the native RV func-
to BTT, while others remain transplant-​ineligible and become tion sufficiently for the perioperative phase.
DT patients. Intended DT represents an increasing proportion Aortic valve disease: LVAD therapy creates a large pressure gra-
◆
of VAD implants worldwide [5]‌, and long-​term outcomes may dient from the aorta to the LV (see E Chapter 57) transmitted
be nearing those of cardiac transplantation [6]. Contemporary across the aortic valve. This can lead to aortic insufficiency
guidelines recognize both indications; the chronic heart failure (AI), which decreases the efficacy of support and longevity of
guideline from the ESC [7] recommends BTT at level IIa/​C and the device (see E Figure 50.2). All LVAD patients are at risk of
DT at level IIa/​B. acquired AI (and up to 50% will have moderate to severe AI at
Second, the severity of the patient’s heart failure must be suffi- 18 months [11, 12]), but implantation with existing AI is self-​
ciently poor to warrant the risks of implantation and ongoing sup- defeating. In these cases, the valve should be treated at the time
port. Severity can be quantified using INTERMACS profiles [8]‌ of LVAD implantation (e.g. using central aortic valve closure
that subcategorize NYHA classes III and IV (see E Table 50.2). [13] or an aortic bioprosthesis). A  pre-​existing mechanical
Historically, LVADs were used as a last option, often as an emer- aortic valve usually warrants exchange to a bioprosthetic alter-
gency and typically in patients with critical CS (INTERMACS native. AI occurring de novo after implant and recurrent AI are
profiles 1 and 2). However, trial and registry data have shown that more difficult to treat. Options include an open or transcatheter
better outcomes can be achieved by anticipating deterioration and valve replacement [14] or cardiac transplantation.
offering implant earlier in disease progression to patients with better ◆ Other valve disease: tricuspid valve incompetence may warrant
retained end-​organ function [5, 9]. Thus, the group of patients con- concomitant repair. MR is often functional and improves with
sidered for LVAD therapy has steadily expanded to include patients LV volume unloading. Valve prostheses in the mitral position
in INTERMACS profiles 3 and 4. Further expansion to profiles 5 carry a theoretical risk of thromboembolism and, for biologic
and above will rely on either a marked reduction of associated risks prostheses, deterioration of the leaflets. There are little data
or the demonstration of a major clinical benefit to justify it. available, but an existing mitral valve prosthesis is usually con-
Third, assessment of heart failure complications and comorbid- sidered a relative contraindication to LVAD therapy.
ities will identify some patients with contraindications that make ◆ Disease aetiology: patients with restrictive or hypertrophic car-
LVAD therapy unacceptably risky or unfeasible. These include: diomyopathy can be challenging, as the disease typically involves
◆ Biventricular and isolated right heart failure:  increasing both ventricles, and thick ventricular walls leave a small LV
the cardiac output with an LVAD requires the RV to show a cavity and make LVAD implantation challenging. These patients
matched increase in output to sustain LV preload and to handle have higher rates of RV failure post-​operatively.
the increased venous return, and pre-​existing RV failure is as- ◆ Anaesthetic and surgical factors such as severity of lung, renal, or
sociated with high mortality after LVAD implantation. Features hepatic disease, BMI (both obesity and poor nutrition will accrue
associated with subsequent right-​sided failure are the require- additional risk), age, any previous abdominal surgery if creating
ment for preoperative invasive ventilation, severe tricuspid an abdominal pocket, and the number of previous sternotomies.
insufficiency, high CVP, or tachycardia of >100 bpm [10]. Psychosocial factors:  VAD therapy requires a high degree of
◆

If present, the options are to plan for concurrent LVAD and patient autonomy, combined with adherence to agreed man-
right ventricular assist device (RVAD) implantation (either as agement plans. If physical, emotional, or social factors could im-
a long-​term BiVAD system or as an implantable LVAD with pede this, then it may not be appropriate to recommend VAD
a short-​ term RVAD), TAH, or cardiac transplantation. In implantation.

Table 50.2  Judging the severity of disease and the urgency of intervention using INTERMACS profiles

Patient profile Clinical characteristics Urgency of intervention

1 Critical CS despite escalating support Within a few hours
2 Progressive decline with inotrope dependence Within a few days
3 Clinically stable, with mild to moderate inotrope dependence Elective implantation over the next few weeks
4 Recurrent, not refractory, advanced heart failure that can be stabilized with intervention Elective implantation over weeks to months
5 Exertion-​intolerant but comfortable at rest and able to perform activities of daily living Variable: depends on nutrition, organ function,
with slight difficulty and activity
6 Exertion limited: able to perform mild activity, but fatigue results within a few minutes of Variable: depends on nutrition, organ function,
any meaningful physical exertion and activity
7 Advanced NYHA functional class III At this time, MCS is not indicated
684 CHAPTER 50   Im pl anted cardiac su pp ort devi ces

(a) (b)

Figure 50.2  Echocardiogram showing continuous regurgitation across the aortic valve. (A) Two-​dimensional image of the aortic valve with an eccentric
regurgitant jet. (B) Colour M-​mode study of the left ventricular outflow tract, confirming continuous regurgitation throughout the cardiac cycle.
Courtesy of Shelley Rahman Haley at Harefield Hospital.

debridement or device explant. This is a complex clinical scen-

Prevention and management ario, balancing the high risk of continued infection versus the
of complications need for continued haemodynamic support and risk of surgery.
If medical therapy achieves the resolution of infection, then
A key driver behind the evolution of VAD technology has been chronic suppressive antimicrobial therapy may be indicated.
the persistently high rates of complications, with consequent pa- If an explant is required, the usual routes would be either ur-
tient morbidity, increased costs, and reluctance to expand the se- gent cardiac transplantation or short-​term support, followed by
lection criteria for implantation. transplantation or reimplantation of a long-​term VAD. All of
these strategies carry high risk.
Device infection
An implanted VAD is an inevitable focus for microbial coloniza-
Erythrocyte destruction
tion due to its composition from non-​biological materials, per- Circulating markers of haemolysis include free Hb, haptoglobin,
cutaneous driveline, and immunosuppression associated with bilirubin, and LDH, and these are ubiquitously elevated to varying
severe heart failure (see E Chapter  70). There are two distinct extents. In most cases, the degree of chronic haemolysis is clin-
clinical syndromes: infection of blood-​contacting elements of the ically inconsequential, though a sudden increase in haemolysis
device circuit, akin to IE, and infection of the external surfaces of can herald pump dysfunction, typically pump thrombus, causing
the device, including the pocket and driveline. There are various an increase in flow turbulence [16]. In this situation, laboratory
general strategies that reduce the risk of a serious infection and markers of haemolysis show an upward trend, often accompanied
aid its management [15]: by dark yellow urine and/​or jaundice. Typically, these findings are
indicative of early pump thrombosis.
◆ At initial implantation, there must be assiduous attention to the
sterility of the personnel and equipment. In the septic patient,
a short-​term VAD may be preferred initially, while the patient
Thrombosis and thromboembolism
is stabilized and the infection treated, before moving to a long-​ Platelets exposed to shear stress and non-​biological materials
term VAD later. show increased adhesion to pump surfaces and reduced resist-
◆ Patients and their families are trained in driveline site care, ance to aggregation. The formation of a thrombus within the
including dressing and recognition of signs of infection. This pump can cause impeller obstruction and pump stoppage or can
is regularly monitored by the VAD team, either remotely (e.g. cause thromboembolism. Complete pump stoppage can be im-
emailed photographs) or in clinic. mediately fatal in patients whose circulation relies entirely on the
◆ Routine checks of inflammatory markers and microbiology VAD, though, in other patients, their residual LV function will
swabs of the driveline site allow monitoring of the microbial en- maintain enough organ perfusion to survive to emergency sur-
vironment and facilitate early targeted antimicrobial therapy, if gery. The most feared embolic phenomenon is a stroke, discussed
necessary. Consider fungal, as well as bacterial, colonization. in E Stroke, p. 685.
If a driveline site infection is suspected, blood cultures and fur-
◆ Prevention of thrombosis is paramount. Engineering strategies
ther swabs should be performed to identify new pathogens, and include minimizing shear stress within the pump, maximizing bio-
early targeted antimicrobial therapy should be initiated. compatibility of all blood-​contacting surfaces, avoidance of blood
◆ More serious infection includes pump pocket, intravascular, or stasis and heating in the pump structures, and use of washing
severe driveline site infection. All cases require prolonged IV to direct other flows of blood to high-​risk areas. Preventative
antibiotic therapy, alongside early consideration for surgical medical therapies are systemic anticoagulation (normally with
 Emergency management of the l on g - ter m ven tri cu l a r as si st devic e pat i e n t 685

warfarin) and antiplatelet therapy, and assiduous care to ensure immediately fatal. Haemorrhage is related to both coagulopathy
therapeutic levels are maintained. and angiodysplasia of cerebral vessels.
The diagnosis of pump thrombosis is challenging. Any of the fol- The prevention of stroke lies in maintaining precise levels of
lowing can be suggestive: a history of recent non-​compliance with anticoagulation. Clinical management in either setting is usually
anticoagulation or previous pump thrombosis; subtherapeutic conservative. In embolic stroke, anticoagulation is continued and
INR; upward trends in pump power consumption and calculated additional antiplatelet drugs could be considered, though there is
flow; blood haemolysis markers increased (discussed earlier); a danger of secondary haemorrhage in the acute phase. In haem-
haemoglobinuria; signs of end-​organ hypoperfusion; and ele- orrhagic stroke, the key decision is regarding anticoagulation;
vated ventricular filling pressures and reduced cardiac output on discontinuation or reduction could improve the neurological
cardiac catheterization [17]. Echocardiography can provide in- prognosis but could precipitate pump failure. A  craniotomy for
direct evidence such as LV chamber dilatation or an increase in haematoma evacuation may be appropriate in some cases but is
the aortic valve opening frequency. risky with ongoing anticoagulation. Specialist rehabilitation is es-
There is no consensus management strategy, though any po- sential in patients who survive the acute phase, with particular
tential benefit is balanced against the risk of thromboembolism consideration to new neurological deficits that impede the ability
and bleeding and, in particular, ICH. Initial medical treatment to look after the VAD. (See also E Chapter 65.)
with IV heparin may be followed by tirofiban and consideration
of fibrinolytics in some cases [18]. Treatment efficacy may be im- Chronic right ventricular failure
proved by therapy being targeted by catheter delivery. Patients Many LVAD patients with initially preserved RV function will de-
who are refractory to medical therapy, or with circulatory shock velop a degree of chronic RV failure. This typically presents with
due to pump stoppage, should undergo urgent surgery to replace evidence of high right atrial pressure (such as oedema, hepatic con-
the pump or receive cardiac transplantation. gestion, renal venous congestion and failure, and ascites) and re-
duced RV output (causing reduced LV preload, reduced LVAD flow,
Coagulopathy and bleeding tendency and functional impairment), but it is difficult to assess and diag-
At least two-​thirds of patients will require red cell transfusion in nose. Management is with diuretics in the first instance. Ischaemia
the perioperative period, and bleeding remains a problem with should be identified and treated. If RV failure continues to progress,
ongoing support (see also E Chapter 68). Coagulopathy is multi- cardiac transplantation should be the first-​line treatment, if avail-
factorial, with the required anticoagulation, underlying heart able, before end-​organ function deteriorates too far. Other options
failure, liver congestion, poor bone marrow perfusion, and con- are implantation of a temporary [24] or long-​term RVAD, or TAH.
sumptive coagulopathy all involved, but particularly important is
the syndrome of acquired vWF deficiency [19]. vWF is essential in
initiating and controlling coagulation and platelet activation, ad-
hesion, and aggregation in response to damage to the vessel wall
Emergency management of the
[20]. Shear stress leads to a loss of large vWF multimers [21]. This long-​term ventricular assist device
occurs almost immediately after LVAD implant and is quickly re- patient
versible on explant [22, 23]. Furthermore, a continuous VAD flow
causes an increased tendency to vessel fragility, angiodysplasia, VAD patients can present as emergencies in hospitals without
and the formation of arteriovenous malformations (AVMs), par- specialist VAD teams. Close liaison with the patient’s implanting
ticularly in the GI tract. VAD centre is essential, and patients requiring inpatient care
The management of bleeding is reactionary. At the present should be transferred there as soon as possible.
time, there is no reliable way to quantify the degree of vWF defi- The principles of management are the same as for any patient
ciency in the clinical setting, and there is no reliable way to antici- with AHF, though there are some specific practical points to
pate GI bleeding. The priorities are to maintain haemodynamic remember:
stability and to stop the bleeding. Anticoagulation may need to 1. Continuous-​flow VAD patients do not have a palpable pulse
be discontinued or reversed in some situations, though, of course, and do not have Korotkoff sounds for blood pressure meas-
this will increase the risk of device thrombosis. An important side urements. Bedside assessment of circulatory function relies
effect of repeated red cell transfusion is the accumulation of anti- on indirect measures of perfusion, such as conscious level,
bodies to human leucocyte antigens which can create barriers to peripheral warmth, and capillary refill time, but bear in mind
subsequent cardiac transplantation. that these can be confounded by systemic sepsis. Non-​invasive
‘mean’ blood pressure can be measured using a peripheral cuff
Stroke and a US Doppler probe.
Stroke in VAD patients can be either ischaemic due to thrombo- 2. Pump alarms and fluctuations in pump power consumption
embolism or haemorrhagic due to primary intracranial bleeding. can indicate pump dysfunction but acutely will not help to
It can range from small perioperative microemboli, which differentiate between a primary pump problem (e.g. pump
may be largely inconsequential, to catastrophic ICH which is thrombosis) and a systemic circulatory problem (e.g. bleeding
686 CHAPTER 50   Im pl anted cardiac su pp ort devi ces

and hypovolaemia). The priority is to treat the patient’s clinical alarms, unstable haemodynamics, ventricular arrhythmia, or syn-
presentation. cope. Subsequently, the periods of very low VAD flow can trigger
3. The VAD controller displays a flow reading in litres per minute, pump thrombosis. The most frequent precipitant is a reduction
but this should never be reassurance that the cardiac output is in LV inflow, e.g. due to hypovolaemia (e.g. bleeding), decreased
adequate. The flow reading is usually an estimate, calculated SVR (e.g. sepsis), or RV failure. Treatment is with fluid resuscita-
from in vitro laboratory data from the pump’s power consump- tion and then directed at the underlying cause.
tion and impeller rotation speed, and many causes of acute
pump dysfunction invalidate the assumptions on which this Pump stoppage
calculation is based. A patient with circulatory arrest can show The main causes of pump stoppage are loss of power, pump
a normal calculated flow. thrombosis obstructing the impeller, and mechanical failure.
4. The problem might be non-​cardiac. For example, in a VAD pa- Auscultation over the pump (usually at the cardiac apex) will
tient with reduced conscious level, there must be a high index normally reveal a characteristic whirring noise of the rotating im-
of suspicion for intracranial bleeding, warranting a neuro- peller. The presence of this sound does not necessarily indicate a
logical assessment and CT of the brain. normal pump function, but its absence suggests pump stoppage.
The priority is to check all external power connections; the drive-
5. ALS management algorithms apply (see E Chapter 9). There line exits the anterior abdominal wall and should connect to the
is a risk of dislodging the inflow cannula with chest compres- controller, which is, in turn, connected to two batteries. A charged
sions, but if a clinical assessment suggests the pump is not spare battery from the patient’s emergency bag can be substituted.
working and the patient has circulatory arrest, then the patient If the pump is stopped and the patient remains in CS, then follow
requires CPR. If defibrillation is required, the best position for the standard algorithms (e.g. inotropic therapy, balloon pump, re-
the pads is anterior–​posterior, as this avoids placement over the spiratory support), and discuss with the implanting VAD centre.
pump unit.
6. In all cases, the implanting VAD centre should be contacted
early to discuss further management. Evolution and evidence base
Important and quickly treatable causes of acute circulatory col-
lapse are arrhythmia, bleeding, pump suction events, and pump Early devices
stoppage. First-​generation pumps were large, pulsatile displacement pumps
such as the Thoratec HeartMate® I-​VE-​XVE series. Perioperative
Arrhythmia mortality was around 15–​20% and the duration of support rarely
The response of VAD patients to ventricular arrhythmia is variable exceeded 6 months, with 60–​70% of patients surviving until de-
and dependent on how successfully the RV maintains LV filling. vice explantation [26–​28]. These devices were groundbreaking
Some patients can sustain ventricular arrhythmia for several hours in their time, but their clear haemodynamic benefits were offset
and others suffer a loss of cardiac output immediately at onset [25]. by high morbidity, in particular, from the extensive surgical dis-
The temptation in a situation where an ECG shows VF is to imme- section due to their hefty size, high rates of infection due to the
diately cardiovert the patient, but if the patient is conscious, this high-​calibre driveline and pump pocket haematomas, and limited
should clearly be delayed and performed under sedation. In the durability necessitating reoperation [29].
presence of an ICD, anti-​tachycardia pacing may be appropriate Nonetheless, expanding patient numbers with an insufficient
for VT. Acute triggers for the arrhythmia, such as pump suction supply of donor organs led to work to reduce device-​related mor-
events, ACS, and newly deteriorating RV failure, should be diag- bidity and to develop strategies for long-​ term device therapy.
nosed and treated. Antiarrhythmic therapy can be useful, and in As such, in 2001, the prospective Randomized Evaluation of
the long term, an ICD may be required. (See also E Chapter 54.) Mechanical Assistance for the Treatment of Congestive Heart
Failure (REMATCH) trial confirmed a potential role for LVADs
Bleeding as longer-​term therapy for end-​stage heart failure in patients un-
This is discussed in the previous section. Acute priorities are fluid suitable for transplantation, with 1-​year survival of 52% with the
resuscitation, addressing the source of bleeding, and deciding HeartMate® XVE versus 25% with standard therapy (P  =  0.002)
how to manage anticoagulation. In some cases, it may be appro- [30]. However, morbidity remained significant, including markedly
priate to discontinue or reverse anticoagulation, but this may re- increased rates of bleeding, neurological dysfunction, and sepsis in
sult in pump thrombosis and should never be done without the the LVAD group and a high rate of suspected LVAD malfunction.
agreement of the implanting VAD centre.
Continuous flow and widespread adoption
Pump suction events of destination therapy
The VAD creates a negative pressure within the LV that draws Throughout the 1990s, the number of patients undergoing implant
blood to the pump, and if this negative pressure exceeds the as BTT was increasing, and work was under way to supersede the
LVEDP, then LV collapse can occur. This can manifest with pump displacement pump in favour of an axial rotary impeller design
 Evolu ti on a n d evi de n c e   base 687

that created a continuous flow of blood to the aorta. These second-​ with the contemporary standard for DT, the HeartMate® II, and
generation devices were led by the HeartMate® II and brought the ultimately made the case for HVAD in DT. This prospective trial
benefits of a smaller size, an easier implant, and a greater dur- randomized 297 patients with HVAD versus 148 with HeartMate®
ability. After the initial problems with high thrombosis rates were II and found non-​inferiority of HVAD for the composite pri-
overcome by alterations to the pump design, the HeartMate® II was mary outcome of 2-​year survival free from disabling stroke with
established as a tool for BTT by Miller and colleagues [31] in 2007. ongoing VAD therapy, elective transplantation, or device explant
They studied the HeartMate® II in an intervention-​only prospective for recovery [36]. There was a significantly higher rate of non-​
study considering a primary outcome of cardiac transplantation, disabling stroke (Rankin score <4) in the HVAD arm (29.7%
myocardial recovery, or ongoing support with transplant eligibility versus 12.1%) and a higher rate of device failure, predominantly
at 6 months. A total of 133 patients were recruited, and the me- due to pump thrombosis, in the HeartMate® II arm. This was im-
dian duration of support was 126 days (IQR 1–​600 days). Seventy-​ portant following contemporary concerns about HeartMate® II
five per cent (n  =  100) reached the primary outcome, and 19% pump thrombosis and made a case for movement towards HVAD
(n = 25) died. Stroke occurred in 8% (n = 11) but accounted for but was tempered by the potential for stroke complications.
42% of deaths, and bleeding and local infection were frequent AEs There was a subgroup analysis suggesting stroke predominated
(2.09 and 1.13 events/​patient year, respectively). Subsequently, the in patients with higher MAP, and a subsequent extension of the
HeartMate® II was evaluated, in comparison with its predecessor ENDURANCE study supported the idea that better blood pres-
the pulsatile HeartMate® I device, as a tool for DT. Slaughter and sure control protected against this complication [37].
colleagues studied 200 patients randomized 2:1, with a primary The concepts of centrifugal impeller and magnetic levita-
composite endpoint of survival at 2 years free of disabling stroke tion were adopted by Thoratec (now subsumed into Abbott)
or reoperation to replace the device [32]. HeartMate® II was su- for the HeartMate® 3, in part as response to the unwanted focus
perior (46% versus 11%, HR 0.38, 95% CI 0.27–​0.54; P <0.001), on HeartMate® II and pump thrombosis. An initial single arm
though there were stubbornly high rates of disabling stroke that study in Europe enrolled 50 patients who were all treated with
did not differ between the study groups, and overall 44% of pa- the HeartMate® 3 (82% in INTERMACS levels 2 and 3 and 54/​
tients implanted with the HeartMate® II still suffered death or dis- 46% with BTT/​DT indication), with 44 patients (88%) continuing
abling stroke within 2  years. Nonetheless, these studies laid the LVAD support at 6  months and two having undergone trans-
path for its widespread take up for BTT and (where funded) DT plantation at 50 and 132  days post-​implant [38]. In this study,
indications, and for the abandonment of first-​generation tech- six patients (12%) suffered from stroke and 19 (38%) from sig-
nology, such that continuous-​flow devices are now first choice in nificant bleeding, though there were no episodes of pump mal-
most situations. For several years, the HeartMate® II was the most function, including thrombosis. Notably, in addition to 12%
frequently implanted LVAD worldwide, though there were con- of patients adjudicated as stroke (with Rankin score >3), there
cerns raised in 2014 about an abrupt increase in rates of device were another four patients (8%) with other neurological dys-
thrombosis. Approaches to medical therapy (e.g. increased aspirin function, including TIA, which was likely to be device-​related.
dose) and surgical technique (e.g. focus on position of the inflow Subsequently, the Multicenter Study of MagLev Technology in
within the LV) helped to alleviate this, but nonetheless persistent Patients Undergoing Mechanical Circulatory Support Therapy
concerns accelerated the uptake of newer technologies. with HeartMate 3 (MOMENTUM-​3) study randomized 294 pa-
tients 1:1 to HeartMate® II or HeartMate® 3 in 69 centres in the
Newest implantable ventricular assist devices US [39]. The composite primary outcome measured at 6 months
in practice comprised survival free of disabling stroke or survival free of
The newest devices have evolved from axial to centrifugal im- reoperation to replace or remove the device. This was met by 86%
peller design. The HeartWare™ HVAD was the first of these third-​ of HeartMate® 3 recipients and 77% of HeartMate® II recipients,
generation pumps and was revolutionary for its intra-​pericardial meeting the thresholds for non-​inferiority (absolute difference
placement and its combined use of hydrodynamic and electro- 9.4%, 95% CI −2.1) and superiority (HR 0.55, 95% CI 0.32–​0.95;
magnetic forces to stabilize and rotate the impeller, obviating the P = 0.04). However, the primary endpoint success was powered by
need for any mechanical bearings [33]. An initial evaluation [34], a large difference in need for reoperation, mainly due to suspected
reported in 2011, studied NYHA class IV transplant candidates or confirmed pump thrombosis (one patient for HeartMate® 3
and showed 84%/​79% actual survival at 1 year/​2 years, respect- versus 11 patients for HeartMate® II) (HR 0.08, 95% CI 0.01–​0.60;
ively, with a rate of bleeding (20%) lower than with previous de- P = 0.002), and actually more disabling strokes occurred in the
vices, reflecting the lesser magnitude of surgery, but with a similar HeartMate® 3 group, though this was statistically comparable
incidence of stroke (12%). The subsequent ADVANCE trial com- (six patients versus four patients) (HR 1.31, 95% CI 0.37–​4.64;
pared 140 HVAD implants to 499 contemporaneous implants P = 0.59). Furthermore, there was again separation in analysis of
for BTT as controls [35]. The composite survival outcome was stroke from TIAs, so the overall rate of cerebrovascular compli-
achieved in 92% of HVAD patients versus 90% of controls, dem- cations may be higher. Nonetheless, the device has earned FDA
onstrating the non-​inferiority of HVAD, compared to contem- approval as BTT and DT and many centres are implanting it first
porary therapy (P <0.001; 15% non-​inferiority margin). Finally, line. A useful study would be a comparison of the HeartMate® 3
the ENDURANCE study looked at HVAD for DT, in comparison with its direct centrifugal competitor the HVAD.
688 CHAPTER 50   Im pl anted cardiac su pp ort devi ces

Myocardial recovery protective pulmonary capillary bed gives high susceptibility to in-

fection. Existing devices are being studied for potential isolated
In some patients, heart function improves, such that cessation of
RV use, and this might have a role in post-​cardiotomy and adult
mechanical support is possible. Among the first trials of LVAD
congenital heart disease populations.
therapy for myocardial recovery was the demonstration of a clear
and sustained improvement in the first 15 patients to complete
Total artificial heart
the Harefield protocol, which allies LVAD haemodynamic sup-
port with a staged uptitration of heart failure drugs, followed by The primary indication for TAH implantation is severe
the initiation of the β2-​adrenergic receptor agonist clenbuterol biventricular failure where a standard LVAD is inadequate
[40]. Of these 15 patients with non-​ischaemic cardiomyopathy and BiVAD therapy is challenging. Some centres such as ours
(which excluded acute myocarditis), 11 (73%) showed sustained have shown a role for TAH in the treatment of cardiac malig-
improvement in myocardial function and underwent device ex- nancy where total or subtotal cardiac resection is required. The
plant, and all but one showed sustained improvement throughout SynCardia TAH is the only such device in clinical use and com-
4 years of follow-​up [41]. However, subsequent studies elsewhere prises parallel volume displacement, pneumatically powered
have not reliably reproduced these outcomes, finding recovery pumps, and four valve prostheses. At implantation, the native
in around 5–​10% of patients [38, 39]. Outside clinical trials, the ventricles and valves are explanted.
rate is lower again (1–​2% in INTERMACS Registry data [5]‌). This The initial TAH trial started in 1993 and ultimately implanted 81
is an area of ongoing research, and new approaches include the patients with biventricular failure (and some compassionate-​use
combination of LVAD support with targeted cell or gene therapy. subjects were excluded from primary analysis) [40]. There was im-
proved BTT survival in patients receiving TAH (79%), compared
with both a mixed, non-​matched control group (46%) and against
contemporary BiVAD data (around 60%). Key complications were
Other implantable support systems bleeding and infection (mediastinal and driveline). Device failure
was rare. Notably 5-​year survival after transplantation was im-
Isolated right ventricular assist devices proved in the TAH group, reflecting better preoperative optimiza-
The use of isolated RVADs is normally confined to short-​term use tion, though mean time to transplantation in bridged patients was
only. This is due to various factors:  (1) in post-​cardiotomy RV 79 days, which is markedly shorter than the waiting time in many
failure, function will usually recover over days to weeks, making countries, including the UK. Subsequent INTERMACS registry
implantation of a long-​term device unnecessary; (2) there is dif- data show a small survival benefit of TAH versus BiVAD therapy
ficulty balancing between high RVAD flows that can lead to an at 1 year in the BTT population [42], though the device is yet to
overload of the native LV function and low RVAD flows that find widespread uptake, and urgent cardiac transplantation re-
increase the risk of VAD thrombosis; and (3)  the absence of a mains the preferred strategy for patients with biventricular failure.

Personal perspective
Implantable cardiac support devices are an essential tool for further technological innovation will deliver fewer AEs and
managing patients with the most advanced heart failure. They reduction in treatment cost, enabling proponents to make a
have clear roles in BTT and DT for patients with the most se- stronger cost-​effectiveness argument. With these steps, we can
vere disease. However, the continued high cost and high treat- establish a coherent evidence base for long-​term VAD therapy
ment morbidity associated with the use of implantable support as an alternative to cardiac transplantation and expand VAD
devices restrict the number of patients for whom VAD therapy programmes to include patients with less severe disease. This,
is available and appropriate, and it remains unclear whether combined with novel approaches, such as cellular or gene ther-
DT and cardiac transplantation offer true equivalence in long-​ apies, to augment myocardial function, will bring step change
term outcomes in the transplant-​eligible population. Data in the management of this poorly served group of heart failure
from the growing DT population will help address this, and patients.

Further reading
Aaronson KD, Slaughter MS, Miller LW, et  al.; HeartWare Ventricular Bartoli CR, Ailawadi G, Kern JA. Diagnosis, nonsurgical management,
Assist Device (HVAD) Bridge to Transplant ADVANCE Trial and prevention of LVAD thrombosis. J Card Surg 2014;29:83–​94.
Investigators. Use of an intrapericardial, continuous-​flow, centrifugal Kirklin JK, Pagani FD, Kormos RL, et  al. Eighth annual INTERMACS
pump in patients awaiting heart transplantation. Circulation report: Special focus on framing the impact of adverse events. J Heart
2012;125:3191–​200. Lung Transplant 2017;36:1080–​6.
 RE F E RE N C E S 689

Miller LW, Pagani FD, Russell SD, et  al.; HeartMate II Clinical Starling RC, Moazami N, Silvestry SC, et al. Unexpected abrupt increase in
Investigators. Use of a continuous-​flow device in patients awaiting left ventricular assist device thrombosis. N Engl J Med 2014;370:33–​40.
heart transplantation. N Engl J Med 2007;357:885–​96. Stewart GC, Givertz MM. Mechanical circulatory support for advanced
Nienaber JJ, Kusne S, Riaz T, et al.; Mayo Cardiovascular Infections Study heart failure:  patients and technology in evolution. Circulation
Group. Clinical manifestations and management of left ventricular 2012;125:1304–​15.
assist device-​associated infections. Clin Infect Dis 2013;57:1438–​48. Suarez J, Patel CB, Felker GM, Becker R, Hernandez AF, Rogers JG.
Pedrotty DM, Rame JE, Margulies KB. Management of ventricular Mechanisms of bleeding and approach to patients with axial-​flow left
arrhythmias in patients with ventricular assist devices. Curr Opin ventricular assist devices. Circ Heart Fail 2011;4:779–​84.
Cardiol 2013;28:360–​8. Westaby S. Cardiac transplant or rotary blood pump:  contemporary
Slaughter MS, Rogers JG, Milano CA, et al.; HeartMate II Investigators. evidence. J Thorac Cardiovasc Surg 2013;145:24–​31.
Advanced heart failure treated with continuous-​flow left ventricular
assist device. N Engl J Med 2009;361:2241–​51.

References
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powered implantable ventricular assist system. Artif Organs 1985;9:36. Study Group. Clinical manifestations and management of left
2. Clarke A, Pulikottil-​Jacob R, Connock M, et  al. Cost-​effectiveness ventricular assist device-​ associated infections. Clin Infect Dis
of left ventricular assist devices (LVADs) for patients with advanced 2013;57:1438–​48.
heart failure: analysis of the British NHS bridge to transplant (BTT) 16. Cowger JA, Romano MA, Shah P, et  al. Hemolysis:  a harbinger of
program. Int J Cardiol 2014;171:338–​45. adverse outcome after left ventricular assist device implant. J Heart
3. Myers TJ. Temporary ventricular assist devices in the intensive care Lung Transplant 2014;33:35–​43.
unit as a bridge to decision. AACN Adv Crit Care 2012;23:55–​68. 17. Bartoli CR, Ailawadi G, Kern JA. Diagnosis, nonsurgical management,
4. Kutty RS, Parameshwar J, Lewis C, et al. Use of centrifugal left ven- and prevention of LVAD thrombosis. J Card Surg 2014;29:83–​94.
tricular assist device as a bridge to candidacy in severe heart failure 18. Schlendorf K, Patel CB, Gehrig T, et  al. Thrombolytic therapy for
with secondary pulmonary hypertension. Eur J Cardiothorac Surg refractory hemolysis related to thrombosis of continuous flow ven-
2013;43:1237–​42. tricular assist devices. J Card Fail 2014;20:91–​7.
5. Kirklin JK, Naftel DC, Kormos RL, et al. Fifth INTERMACS annual 19. Suarez J, Patel CB, Felker GM, Becker R, Hernandez AF, Rogers JG.
report: risk factor analysis from more than 6,000 mechanical circula- Mechanisms of bleeding and approach to patients with axial-​flow left
tory support patients. J Heart Lung Transplant 2013;32:141–​56. ventricular assist devices. Circ Heart Fail 2011;4:779–​84.
6. Westaby S. Cardiac transplant or rotary blood pump: contemporary 20. Sadler JE, Budde U, Eikenboom JC, et  al.; Working Party on von
evidence. J Thorac Cardiovasc Surg 2013;145:24–​31. Willebrand Disease Classification. Update on the pathophysiology and
7. Ponikowski P, Voors AA, Anker SD, et al.; ESC Scientific Document classification of von Willebrand disease: a report of the Subcommittee
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acute and chronic heart failure:  The Task Force for the diagnosis 21. Tsai HM. Shear stress and von Willebrand factor in health and dis-
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Society of Cardiology (ESC). Developed with the special contribu- 22. Heilmann C, Geisen U, Beyersdorf F, et al. Acquired von Willebrand
tion of the Heart Failure Association (HFA) of the ESC. Eur Heart J syndrome in patients with ventricular assist device or total artificial
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9. Lietz K, Long JW, Kfoury AG, et al. Outcomes of left ventricular assist tients. Eur J Cardiothorac Surg 2011;40:1328–​33.
device implantation as destination therapy in the post-​REMATCH 24. Aissaoui N, Morshuis M, Schoenbrodt M, et al. Temporary right ven-
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tricular failure in the modern, continuous flow left ventricular assist 2013;146:186–​91.
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11. Cowger J, Pagani FD, Haft JW, Romano MA, Aaronson KD, Kolias arrhythmias in patients with ventricular assist devices. Curr Opin
TJ. The development of aortic insufficiency in left ventricular assist Cardiol 2013;28:360–​8.
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12. Aggarwal A, Raghuvir R, Eryazici P, et  al. The development of Left ventricular assist system. Multicenter clinical evaluation of
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supported patients. Ann Thorac Surg 2013;95:493–​8. tients awaiting heart transplantation. J Thorac Cardiovasc Surg
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14. Parikh KS, Mehrotra AK, Russo MJ, et al. Percutaneous transcatheter Cardiovasc Surg 1994;107:472–​80.
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29. Frazier OH, Rose EA, Macmanus Q, et al. Multicenter clinical evalu- Investigators. Use of an intrapericardial, continuous-​flow, centri-
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34. Strueber M, O’Driscoll G, Jansz P, Khaghani A, Levy WC, 41. Schmitto JD, Hanke JS, Rojas SV, Avsar M, Haverich A. First implant-
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 CHAPTER 51

Donor organ management
Arne P Neyrinck, Patrick Ferdinande, Dirk Van
Raemdonck, and Marc Van de Velde

Contents
Summary  691 Summary
Types of donors  691 Organ transplantation is the standard treatment modality for end-​stage organ dis-
Pathophysiology of brain death  692 ease in selected cases. Two types of potential organ donors can be identified: the
Autonomic dysregulation  692 brain-​dead ‘heart-​beating donors’, referred to as donation after brain death (DBD),
Neuroendocrine changes  694
Management of the brain-​dead donor  694 and the warm ischaemic ‘non-​heart-​beating donors’, referred to as donation after
Haemodynamic management  695 circulatory death (DCD).
Hormonal resuscitation  695 Brain death induces several physiological changes in the DBD donor. An auto-
Thyroid hormone  695
Vasopressin  696
nomic storm is characterized by massive catecholamine release, followed by
Desmopressin  696 autonomic depletion during a vasoplegic phase. This is associated with several hor-
Terlipressin  696 monal changes (suppression of vasopressin, the hypothalamic–​pituitary–​adrenal
Steroids  696
Coagulopathy  696 axis, and the hypothalamic–​pituitary–​thyroid axis) and an inflammatory response.
Pulmonary management  696 These physiological changes form the basis of organ donor management, including
Renal management  697 cardiovascular stabilization and hormonal therapy (including vasopressin and
Hepatic management  697
Donor management protocols  697 analogues, thyroid hormone, and cortisol). Donor management is the continu-
Management of the DCD donor  698 ation of critical care, with a shift towards individual organ stabilization. An aggres-
Agonal phase and comfort therapy  698 sive approach to maximize organ yield is recommended; however, many treatment
Prediction and determination of death  698 strategies need further investigation in large randomized trials.
Future perspectives: ex situ organ DCD donors have now evolved as a valid alternative to increase the potential
management  699
donor pool and challenge the clinician with new questions. Optimal donor com-
Conclusion  699 fort therapy and end-​of-​life care are important to minimize the agonal phase.
Personal perspective  700 A strict approach towards the determination of death, based on cardiorespiratory
Further reading  700 criteria, is a prerequisite.
References 700 Novel strategies have been developed, using ex situ organ perfusion as a tool, to
evaluate and recondition donor organs. They might become more important in the
future to further optimize organ quality.

Types of donors
Solid organ transplantation is the standard treatment modality for patients suffering
from end-​stage organ failure in selected cases. This lifesaving treatment is, however, still
hampered by an organ shortage, increasing the disparity between organ supply and de-
mand and leading to longer waiting times for listed patients, with a substantial risk of
patients dying prior to transplantation. Optimization of donor management is therefore
of utmost importance in order to maximize the utilization of selected organs.
Organ donors are classically divided into two major categories. The first category
comprises donors who die because of brain death, the so-​called ‘heart-​beating donors
692 CHAPTER 51   D on or organ management

(HBD)’, now referred to as ‘donors after brain death (DBD)’. In changes. These phases are accompanied by significant changes in
DBD donors, the organs are perfused until the moment of preser- haemodynamic parameters and lead to cardiovascular instability
vation, with rapid cooling using flush perfusion. and eventually will result in sustained inflammatory injury.
The second category includes donors who are declared dead,
based on circulatory criteria, the so-​called ‘non-​heart-​beating
Autonomic dysregulation
donors (NHBD)’, currently referred to as ‘donors after circu-
latory death (DCD)’. According to the Maastricht classification The autonomous nervous system plays an important role in the
[1]‌, four types of DCD donors were identified. Category I (dead haemodynamic changes following brain death. In 1902, Cushing
on arrival) and category II (unsuccessful resuscitation) comprise described the triad of arterial hypertension, bradycardia, and re-
uncontrolled DCD donors. Category III (awaiting cardiac arrest) spiratory irregularities (referred to as the Cushing reflex or re-
and category IV (cardiac arrest in brain-​dead donor) include sponse), following dog experiments with elevated ICP.
controlled DCD donors. In contrast to DBD donors, organs from Acute brain death, based on a sudden increase in ICP, leads
DCD donors suffer from warm ischaemia between circulatory ar- to an initial intense vagal activity, explaining the short period
rest and the start of organ cooling/​preservation. of bradycardia [6]‌. This period of bradycardia is transient and
The ultimate goal in transplantation is to reduce ischaemia–​ has not always been observed in different brain-​dead models
reperfusion injury which is, in fact, the end-​result of a series of [7]. The next period is characterized by an intense sympathetic
hits, beginning in the donor (due to brain death in HBD or warm activity, reflected by a period of severe tachycardia and hyper-
ischaemia in NHBD), continuing during preservation, and cul- tension. Eventually, this sympathetic discharge disappears and
minating upon reperfusion inside the recipient after transplant- results in a period of cardiovascular collapse with pronounced
ation. Donor management will focus on the aspects that can be hypotension.
modulated inside the donor before preservation. The hyperdynamic response is related to the release of the vaso-
active catecholamines adrenaline and noradrenaline into the cir-
culation [8–​11]. Graf et al. and Rosner et al. [9, 10] demonstrated
a temporal relationship between an acute elevation in ICP or fluid
Pathophysiology of brain death percussion brain injury with circulating catecholamine levels.
Brain death results from damage to the brainstem, with an irre- This rise in catecholamines was related to the haemodynamic
versible loss of its function [2]‌. The brain requires a constant cere- changes. The decline in catecholamine levels was slightly slower
bral blood flow (CBF), due to its high metabolic demands, and than that in arterial blood pressure after the initial storm. Van
uses a process of autoregulation where the CBF remains constant Loon et al. [11] gradually increased the ICP in a dog model, using
within a wide range of cerebral perfusion pressure (CPP). The an epidural balloon catheter. The catecholamine burst in their
CPP is the driving pressure gradient for cerebral perfusion and model reached a maximum when the CPP became negative, indi-
is defined as the difference between the mean arterial pressure cating that ischaemia in certain areas of the brain was the pri-
(MAP) and the intracerebral pressure (ICP) [3]: mary factor responsible for the secretion of the catecholamines.
The hyperdynamic state was observed only after the descending
CPP = MAP − ICP
ischaemia in the brainstem reached the area of the nucleus
The intracranial cavity has only a small reserve for accom- ambiguus in the medulla oblongata, causing functional vagotomy
modating additional volume, due to the enclosure within the whereby only sympathetic activation remained [12]. Slower in-
non-​expandable skull. Under normal circumstances, an increase creases in ICP resulted in lesser increases in catecholamine con-
in intracranial volume may be accommodated by only a small centration (200-​fold), compared to a rapid ICP increase. This
increase in ICP. Normal ICP ranges from 5 to 15  mmHg in an was also reflected in less myocardial ischaemic damage during a
adult [4]‌. However, in pathological conditions, such as an acute gradual ICP increase [13].
and massive increase in intracranial volume due to bleeding, the The origin of circulating catecholamines is attributed to dis-
volume reserve becomes exhausted and the volume will result charge at sympathetic nerve endings and to their release from
in a substantial elevation in ICP. In addition, the autoregulatory the adrenal medulla. In clinical studies, the rise in noradrenaline
mechanism will also be impaired, resulting in a CBF that is closely levels seems to be more important [14], probably because of con-
coupled to changes in CPP. The end-​result will be a drop in the tinued release from noradrenergic nerve terminals and limited
CBF and the development of brain ischaemia [3]. release in time from the adrenal medulla.
In addition to the development of brain ischaemia, localized pres- Chiari et  al. [15] described a biphasic hyperdynamic response
sure gradients may result in brain herniation, a shifting of the brain after brain death induction in a porcine model with an inflated sub-
contents outside their normal compartments. Uncontrolled hernia- dural balloon catheter. The first response occurred 1 minute after
tion may rapidly lead to irreversible brain injury or brain death [5]‌. brain death, the second 120 minutes later, and was accompanied
The induction of brain death results in a sequence of phe- with similar responses in catecholamine levels. Mertes et al. [16]
nomena that may contribute to the development of donor graft observed a second peak in noradrenaline levels only in interstitial
injury inside the donor. These phenomena are classically divided myocardial tissue. Also, Bittner et al. [7]‌observed a secondary peak
into a phase of autonomic dysregulation and neuroendocrine in serum adrenaline 360 minutes after the onset of brain death. It
 Pathophysi ol o g y of b ra i n   de at h 693

urges for a careful interpretation of different data observed in dif- pulmonary circulation and an increase in pulmonary artery pres-
ferent models but may also reflect the large range of responses that sure (PAP). An elevated hydrostatic pressure in the pulmonary
can be observed in experimental and clinical settings. capillaries induces the development of pulmonary oedema.
Following the hyperdynamic state, a hypodynamic state with Pulmonary venous constriction, occurring with a raised ICP and
pronounced systemic hypotension is documented following sympathetic stimulation, can further contribute to the increased
brain death. The exact origin of this hypotensive phase is prob- pulmonary capillary pressure [34].
ably multi-​factorial. This systemic vasoconstriction also activates endothelial cells
First, direct cardiac injury, following the catecholamine storm, which may then produce endothelin-​1, a potent vasoconstrictor
has been described as an important contributor to haemodynamic that further aggravates the pathological changes.
instability. Increased levels of noradrenaline in the myocardial Despite this straightforward mechanism, we know that patients
interstitium [17] result in a reduction in Ca2+ ATPase activity with neurogenic pulmonary oedema have a protein-​rich oedema
that leads to myocyte calcium overload and cell death. The struc- fluid, suggesting an altered capillary permeability, in addition to
tural damage is characterized by myocytolysis, contraction band the hydrostatic pressures [35].
necrosis, subendocardial haemorrhage, oedema formation, and West et al. [36] described the concept of capillary stress failure.
interstitial mononuclear cell infiltration [13, 18]. When transmural pulmonary capillary pressures rise, the wall
Others [19,  20] demonstrated that the catecholamine storm stress (circumferential tension) becomes extremely high and
produces coronary artery spasm, with insufficient blood flow for might approach the breaking stress of the ECM of the alveolar–​
adequate myocardial perfusion in relation to the increase in myo- capillary membrane. This stress failure might further disrupt the
cardial O2 demand, due to vasoconstriction and tachycardia. Also, endothelial or epithelial cell wall and lead to high-​permeability
production of O2-​derived free radicals due to cardiac ischaemia pulmonary oedema.
and reperfusion may directly injure the myocardium [21]. Bittner et al. [31], however, only observed a slight increase in
β-​adrenergic receptors in myocardial tissue are desensitized, PAP. They observed a significant decrease in the PVR and pul-
following brain death, which directly leads to ventricular dys- monary vascular impedance, following brain death in dogs, to-
function [22]. Also, specific β-​receptor polymorphisms are asso- gether with a marked increase in the pulmonary blood flow. This
ciated with cardiac dysfunction after brain death [23]. was attributed to an increased distensibility of the larger pul-
Second, changes in loading conditions may be important de- monary vessels. The increased pulmonary blood flow led to the
terminants of the cardiovascular collapse. The initial period of development of congestion and pulmonary oedema.
intense autonomic activity is followed by a loss of sympathetic Another explanation might be the fact that the capillary pres-
tone and a massive reduction in systemic vascular resistance sure, and more specifically the transmural pressure, is respon-
(SVR) due to profound vasodilatation. The ensuing reduction in sible, which is not reflected in the measurement of the PAP at its
afterload, coronary perfusion pressure, and preload reduces the large proximal segments, as was done in our study.
contractile state of the myocardium by the Frank–​Starling mech- Besides the ‘blast injury theory’, it is also possible that direct
anism, the Anrep effect, and the garden hose effect [24–​26]. α-​adrenergic stimulation might alter the pulmonary capillary
The cardiac injury is reflected in changes in the echocardio- permeability. This was first recognized in experiments where ani-
graphic systolic function [27], the occurrence of ECG abnor- mals developed neurogenic pulmonary oedema, despite normal
malities [26,  28] (ST-​segment depression or elevation, inverted pulmonary artery and capillary wedge pressures [37, 38].
T-​waves, atrial arrhythmias, ventricular arrhythmias, prolonged α-​adrenergic blockade could prevent the development of oe-
QT interval, short QT interval, conduction abnormalities, Q dema, indicating a direct role of noradrenaline in increasing
waves), and altered heart rate variability [29, 30]. permeability [39]. Another mediator neuropeptide Y, which is
The RV seems to be more vulnerable than the LV, following the co-​located in large dense vesicles in sympathetic nerve endings, is
events during the autonomic catecholamine storm. The RV might also secreted in large quantities. It was recently shown that neuro-
exert more hydraulic power in relation to a decreased pulmonary peptide Y is released from nerve endings, in response to brain
vascular resistance (PVR) [31]. However, following brain death, death, directly into the lungs and might alter endothelial perme-
the response to an increased PVR is abolished to sustain the pul- ability, rather than acting as a systemic vasoconstrictor [40].
monary vascular blood flow [32]. The pathophysiology of neurogenic pulmonary oedema there-
Brain death also leads to a significant level of pulmonary graft fore offers an explanation for the development of donor lung in-
injury, a process that is often referred to as neurogenic pulmonary jury in the brain-​dead organ donor and that there is a continuum
oedema. between hydrostatic and permeability oedema. The haemo-
The ‘blast injury theory’ describes a haemodynamic mechanism dynamic response to brainstem injury and neurogenic pulmonary
responsible for the development of pulmonary oedema [33]. The oedema can be prevented by α-​adrenergic blockade, spinal cord
autonomic storm, as described previously, results in massive sys- transection, splanchnectomy, and spinal anaesthesia, but not by
temic α-​adrenergic activation through the release of catechol- adrenalectomy or β-​blockade [41]. This indicates that a direct re-
amines. The resulting systemic vasoconstriction increases the lease of noradrenaline from the nerve endings is the mediator, ra-
SVR, leading to a decrease in LV output and an increase in left ther than a systemic release. The haemodynamic changes following
atrial pressure (LAP). This is followed by a shift of blood into the autonomic dysregulation are summarized in E Figure 51.1.
694 CHAPTER 51   D on or organ management

Hormonal and Systemic

metabolic derangement hypoperfusion

Brain death
Endothelial
Inflammation
activation

(Direct) Cardiac Systemic

Autonomic storm
injury hypoperfusion
α ↑ Pulmonary
capillary permeability
↑ Pulmonary
vasoconstriction

↑ Systemic vascular ↓ Left ventricular ↑ Left atrial ↑ Pulmonary

resistance output pressure capillary pressure

↑ Venous ↑ Lung blood

return volume

Autonomic depletion

↓ Preload
↓ Systemic vascular Load-dependent Systemic
resistance cardiac dysfunction hypoperfusion
↓ Afterload

Inflammation

Figure 51.1  Pathophysiological changes following brain death.

Neuroendocrine changes illness syndrome [6]‌. Also, reduced peripheral conversion of T4

to T3 has been postulated [46]. Reduced levels of T3 are related
After brain death, the levels of anterior and posterior pituitary
to a progressive loss of cardiac contractility, with haemodynamic
hormones are severely disturbed. The pituitary gland is a combin-
instability and the onset of anaerobic metabolism.
ation of two embryologically and functionally distinct portions.
Changes in the hypothalamic–​pituitary–​adrenal axis in brain-​
The anterior pituitary receives its blood supply from the hypo-
dead subjects have revealed conflicting results with regard to cor-
thalamus and produces adrenocorticotrophic hormone (ACTH)
tisol secretion, described as normal, low, or high. Reduced levels
and thyroid-​stimulating hormone (TSH). The posterior pituitary
of cortisol may be responsible for reduced cardiac performance
is responsible for the production of ADH or vasopressin.
[43, 44, 47–​50].
A rapid depletion of ADH occurs soon after brain death. The
Finally, insulin levels are reduced by half within 3 hours, indu-
physiological effects of vasopressin are mediated through three
cing systemic hyperglycaemia, decreasing intracellular glucose
receptor subtypes: V1 mediating the vasopressor effect; V2 medi-
concentrations, and producing an energy deficit in the donor [25].
ating the antidiuretic effect in the kidney; and V3 stimulating
In conclusion, these neuroendocrine changes will result in
ACTH release in the anterior pituitary. Loss of ADH secretion re-
hypovolaemia, vasodilation, energy deficit, cardiovascular in-
sults in diabetes insipidus, with hypovolaemia, hyperosmolarity,
stability, systemic hypoperfusion, and conversion to anaerobic
and hypernatraemia. Excessive fluid losses will contribute to se-
metabolism (see E Figure 51.1).
vere hypovolaemia, hypoperfusion, and metabolic acidosis [8,
25, 42].
Changes in the hypothalamic–​pituitary–​thyroid axis result in
a state referred to as the non-​thyroidal illness syndrome. This Management of the brain-​dead donor
has been documented with reductions in levels of circulating The fundamental principles of DCD organ donor management
free triiodothyronine (T3), normal levels of free thyroxine (T4), are merely a continuation of pre-​existing intensive care manage-
and variable levels of TSH [43–​45]. Low levels of T4 have also ment, but with a shift of paradigm, usually from creating a milieu
been described and may reflect a profound state of non-​thyroidal for brain recovery to optimal conditioning of donor organs. It is
 M a nag em en t of the b r a i n - de a d   d on or 695

of critical importance that the number of transplantable organs 800–​1200 dyn·s·cm-5; and insulin 1 U/​hour minimum, titrated to
from the small donor pool is maximized. If target physiological maintain blood sugar at 120–​180 mg/​dL.
variables are not achieved for one organ, it is still important to In a large retrospective analysis by the United Network for
aim to meet optimal criteria for other organs. Organ Sharing (UNOS) [51], the number of organs transplanted
from three-​drug HR donors (methylprednisolone, T3/​T4, ar-
Haemodynamic management ginine vasopressin) was 22.5% higher than that from non-​HR
The most challenging aspect of donor management is the treat- donors for all organs. A  second analysis in the heart recipients
ment of the large cardiovascular changes associated with the pro- indicated a significantly higher 1-​month survival of three-​drug
cess of brain death. The initial phase of autonomic storm is often HR hearts [66].
very short and not witnessed by the clinician. Clinical management Also, for kidneys, but not for livers, the implementation of a
is therefore often not possible; however, experimental studies sug- three-​drug HR therapy was associated with a reduced risk of 1-​
gest a benefit if this catecholamine response can be counteracted. year graft loss.
Loss of sympathetic tone at the vascular and cardiac levels must To date, the use of single or combined hormonal therapy re-
be offset by exogenous administration of catecholamines with mains controversial, given the lack of large randomized pro-
α-​agonist and β1-​agonist effects (preferably dopamine and nor- spective trials and the differences in protocols applied in each
adrenaline). Several studies recommended avoiding α-​adrenergic study [67].
drugs (noradrenaline >0.05 micrograms/​kg/​min) and limiting
Thyroid hormone
the use of dopamine to a maximum dose of 10 micrograms/​kg/​
min [51–​54]. This resulted in increased cardiac primary graft dys- The original animal experiments, performed by Novitzky et al.,
function [55] (especially RV failure) and increased mortality in indicated a 50% decline in plasma levels of free T3 and free T4,
recipients [56, 57]. Donor catecholamines were also reported to with no significant change in TSH level [42]. In observational
decrease pulmonary gas exchange [58] and to result in uncoup- human studies, a reduction in free plasma T3 has been con-
ling of the β-​receptors from adenylyl cyclase [59]. Other studies sistently documented, with variable changes in TSH and T4
related the use of donor catecholamines to improved organ func- levels [44, 68–​73]. Reversed T3 has been normal or increased,
tion [60, 61] and an anti-​inflammatory effect [62–​64]. consistent with a status of ‘sick euthyroid syndrome’. Human
The transplant community has slowly moved away from the studies regarding the benefit in using thyroid hormone as part
statement that the use of dopamine and noradrenaline is largely of donor management remain conflicting; however, its use is
deleterious, and they are a cornerstone in the restoration of recommended in the aggressive management protocol [53].
vasoplegia and loading conditions which cannot be achieved Macdonald et al. tried to critically review the clinical benefit of
by fluid administration alone [5]‌. Other interventions (see E thyroid hormone therapy and observed some interesting find-
Hormonal resuscitation, p. 695), in combination with vasopres- ings [74]. The focus on most studies was the impact of thyroid
sors, are now considered standard of care. hormone on the haemodynamic response, donor heart func-
A recent randomized trial indicated that the 3-​year survival, tion, and organ utilization. Thyroid hormone was administered
following heart transplant (HTx), was significantly increased preferably to haemodynamically unstable donors on large doses
when donors were treated with low-​dose dopamine (4 micro- of vasoactive drugs, with the aim to stabilize the hypodynamic
grams/​kg/​min)  [65]. status and to temper the use of vasopressors and inotropics [75–​
Arterial hypertension (blood pressure >160/​ 90  mmHg) is 78]. An important bias is that the administration of thyroid hor-
best treated with short-​acting β-​blockers (e.g. esmolol 100–​500 mone was often in combination with other hormones. Studies
micrograms) or a bolus of nicardipine 1 mg (followed by a con- reported haemodynamic stabilization and reduced vasoactive re-
tinuous infusion), as the haemodynamic storm is very transient. quirements, an improved number of organs procured per donor,
Monitoring serum lactate levels every 2–​4 hours and titrating the and an improved post-​transplant outcome [43, 51, 66, 79]. The
haemodynamic support to a mixed venous saturation of >60% are rare RCTs have not demonstrated any beneficial effect of thyroid
recommended. If the haemodynamic targets are not met, despite hormone [69, 80–​85]. The benefit of thyroid hormone adminis-
increasing doses of catecholamines, or the LVEF remains ≤40% on tration may be limited to a subset of brain-​dead donors (haemo-
2D echocardiography, a pulmonary artery catheter is indicated. dynamically unstable, high doses of inotropics and vasopressors,
echocardiographic abnormalities), and possibly in combination
Hormonal resuscitation with other hormones.
Theoretically, T4 administration would be less effective than
A consensus report in 2002, endorsed by the American Society of
T3, if the mechanism of deficiency is based on non-​thyroidal
Transplantation and the American Society of Transplant Surgeons,
illness syndrome. However, both drugs have been administered,
recommended a hormonal resuscitation (HR) protocol as a
and T4 seems to be effective in large IV doses. The different doses
standard donor management guideline [53]. The recommended
reported are: a bolus administration of T3 of 0.2–​0.6 micrograms
HR protocol consists of the following: methylprednisolone bolus
or a continuous infusion of T3 of 2–​4 micrograms/​hour [42, 75–​
of 15 mg/​kg; T3 bolus of 4 micrograms, then continuous infu-
77, 82]; a bolus administration of T4 of 100 micrograms/​day; or a
sion of 3 micrograms/​hour; arginine vasopressin bolus of 1 U, and
bolus administration of T4 of 20 micrograms, followed by a con-
then continuous infusion at 0.5–​4 U/​hour, titrated to an SVR of
tinuous infusion of 10 micrograms/​kg/​min [86, 87].
696 CHAPTER 51   D on or organ management

Vasopressin response is multi-​factorial. Mediators might be released directly

Depletion of ADH or vasopressin occurs in almost 80% of brain-​ from the damaged brain; the metabolism is switched to an anaer-
dead organ donors. In experimental studies [8]‌, vasopressin se- obic state; flow-​induced shear stress from endothelial cells might
cretion rapidly ceases. The clinical rationale behind the use of upregulate the response, and specific neuropeptides might be
vasopressin is based on a combined effect on its V1 and V2 re- released. Systemic hypoperfusion could lead to cytokine release
ceptors, resulting in restoration of vascular tone and treatment of from the gut [108].
diabetes insipidus. Initial clinical benefit of haemodynamic sta- In addition, decreased cortisol levels promote this inflam-
bilization was observed in the long-​term management of brain-​ matory and immunological activation and are now considered
dead patients [88]. Subsequently, in haemodynamically unstable standard of care in donor management. Methylprednisolone is
donors, administration of low-​dose vasopressin (0.04–​0.1 U/​min) usually given at a dose of 15 mg/​kg [5]‌and is associated with
significantly increased blood pressure and reduced catecholamine improved oxygenation, reduced extravascular lung water [109],
administration, indicating a defect in the baroreflex-​mediated se- and increased lung yield. Also, for the liver [110], heart [111],
cretion [89]. In the first randomized trial, low-​dose vasopressin and kidney [112], there is a clear reduction in inflammatory me-
(300 mU/​kg/​min) improved haemodynamic variables and de- diators. However, the effects of steroid administration on a var-
creased vasopressor use [90]. Venkateswaran et  al. successfully iety of inflammatory cytokine levels were not significant [113];
used vasopressin to wean their donors from noradrenaline, before methylprednisolone is associated with increased organ retrieval
starting their study protocol with T3 and methylprednisolone ad- and should be given as soon as possible [114]. Alternatively,
ministration [85]. The use of vasopressin was related to an overall hydrocortisone can be used (3 × 100 mg/​24 hours) [115].
increase in organ yield [91] and was independently associated
with lung procurement with better preservation of lung function.
Coagulopathy
As with the other hormone strategies, most studies have included Coagulopathy is a common disorder in traumatic brain in-
a triple-​hormone therapy, which makes it difficult to dissect the jury and occurs in 10–​90% of these patients [116]. Current evi-
contribution of vasopressin alone [51, 53, 92]. However, the use dence suggests that it is a dynamic process involving a state of
of vasopressin is becoming more important and should be con- hypercoagulability, followed by a bleeding diathesis. The most
sidered to treat haemodynamic instability. We recommend a dose commonly accepted hypothesis of the pathogenesis implies an
of 2–​4 U/​hour. alteration in local and systemic coagulation and fibrinolytic path-
ways, secondary to the release of tissue factor, disseminated intra-
Desmopressin vascular coagulation, platelet dysfunction, activation of protein
Desmopressin, or DDAVP (1-​deamino-​8-​d-​arginine-​vasopressin), C, and release of tissue thromboplastin from necrotic brain tissue
acts via V2 receptors and can be used to treat diabetes insipidus. [117–​120]. Brain-​dead lungs have a high incidence of pulmonary
Its use does not compromise renal graft function in recipients [93], arterial thrombosis [121]. Overall, 35% of donors had gross or
and it has even been demonstrated retrospectively that the use of microscopic evidence of either pulmonary arterial thrombosis or
donor DDAVP improved renal allograft survival [94]. pulmonary infarction, or both. Therefore, it is recommended to
maintain standard thromboprophylaxis and to treat coagulation
Terlipressin disorders when there is clinically significant bleeding.
Terlipressin is a synthetic analogue of vasopressin, characterized
by a greater selectivity for the V1 receptor than vasopressin [95].
The vasopressor (V1) to antidiuretic (V2) ratio of vasopressin and
Pulmonary management
terlipressin is 1 and 2.2, respectively. Terlipressin has been used Early respiratory management protocols used a non-​protective
sporadically to manage catecholamine-​ refractory hypotension ventilation strategy, based on tidal volumes of 10–​15 mL/​kg of
in solid organ donors (bolus of 0.25–​1 mg at 4-​hourly intervals) body weight [122]. This was also adopted by UNOS, using tidal
[96, 97]. volumes of 10–​12 mL/​kg of body weight, with a PEEP of 5 cmH2O.
Studies were performed to specifically introduce rigorous proto-
Steroids cols. These strategies were still based on large tidal volumes
There has been growing focus on the systemic inflammatory but included additional measures to optimize organ recovery.
response to brain death (see E Figure 51.1). Increased levels Recruitment strategies used high levels of PEEP (15 cmH2O) and
of inflammatory mediators have been identified in serum and inspiratory pressures of 25 cmH2O, bronchoscopy, 30° head ele-
specific organs. Important pro-​inflammatory cytokines include vation, and endotracheal cuff pressures of 25  cmH2O (to limit
TNF-​α, IL-​1β, IFN-​γ, IL-​8, and IL-​6, and NF-​κB is activated aspiration) [123, 124]. It was demonstrated that ventilation with
[41, 98–​103]. Also, the innate immune system by complement higher tidal volumes was an independent risk factor contributing
activation [104,  105] and activation of Toll-​like receptors is to the development of ALI [125]. Mascia et al. [126] were the first
involved [106]. to study prospectively the implementation of a protective venti-
Endothelial activation, reflected in the expression of the ad- lation strategy, based on tidal volumes of 6–​8 mL/​kg of predicted
hesion molecules ICAM-​1, VCAM-​1, E-​selectin, and P-​selectin, body weight, a PEEP of 8–​10 cmH2O, in combination with CPAP
has been observed [99,  107]. The origin of this inflammatory during the apnoea test, and recruitment manoeuvres (doubling
 D on or m a nag em en t  proto c ol s 697

ventilation with low tidal volumes for ten breaths) after ventilator has been related to poor liver outcomes and increased 1-​year
disconnection. This strategy increased the number of transplant- mortality after cardiac transplantation [140]. It is recommended
able organs and is in accordance with the current standard of to treat diabetes insipidus with a vasopressin infusion at 2.4 U/​
care for patients suffering from ARDS [127]. Recently, different hour or intermittent DDAVP 1–​4 mg IV, then 1–​2 mg every 6
strategies were implemented in a general protocol, including low hours, to obtain a urine output of ≤3 mL/​kg/​hour, in addition to
tidal volumes (8 mL/​kg), PEEP (8–​10 cmH2O), recruitment man- correction of hypovolaemia and ‘free water deficit’.
oeuvres (PEEP of 15–​18 cmH2O), fluid restriction (targeted CVP
of 6–​8 mmHg and extravascular lung water of <10 mL/​kg), use Hepatic management
of diuretics, if necessary, and addition of methylprednisolone Uncorrected donor hypernatraemia is considered as a risk factor for
(15 mg/​kg of body weight) and T4 if patients were on inotropes. early graft loss, following liver transplantation, with a cut-​off value
This improved lung utilization without jeopardizing the accept- of 155 mEq/​L [139, 141]. It is likely that increased hepatocellular
ance rate for kidney grafts [128]. Thyroid hormone alone, or in osmolality is the primary cause of hepatocyte death. More recent
combination with corticosteroids, had no effect on donor lung studies could not confirm these effects with even higher thresh-
function or organ yield [109]. The Beta-​agonists for Oxygenation olds (160–​170 mEq/​L), nor an impact of the difference between
in Lung Donors (BOLD) study was developed as a random- donor hypernatraemia and recipient hyponatraemia [142,  143].
ized, placebo-​controlled trial to evaluate the effect of nebulized Ischaemic preconditioning and pharmacological preconditioning
albuterol on donor oxygenation but failed to demonstrate any with sevoflurane and remifentanil seem to be promising to reduce
differences [129]. ischaemia–​reperfusion injury in the future [144–​148].

Renal management
Renal grafts are very sensitive to the autonomic storm during Donor management protocols
brain death and may undergo accelerated chronic rejection and
delayed graft function [130–​132]. Many organ procurement organizations have implemented crit-
For the kidney, vasoparesis management with low-​dose dopa- ical care endpoints as donor management goals, in an effort to
mine (4 micrograms/​kg/​min) has regained interest, since this re- increase organs transplanted per donor after neurological deter-
duced the need for post-​transplant dialysis (probably based on mination of death. The most important physiological endpoints
ischaemic tolerance and with a larger effect during ischaemic are summarized in E Table 51.1.
intervals exceeding 18 hours) [133], whereas the administration Analyses with historical control groups have revealed that, by
of noradrenaline was associated with an increased risk of pro- simply working towards specific targets on a protocolized basis,
longed delayed graft function [131]. this might increase the organ yield per donor. Historically, imple-
Fluid administration is necessary to support both loading con- mentation of the San Antonio Lung Transplant (SALT) protocol
ditions and kidney function. The target for urine output is 0.5–​3
mL/​kg/​hour. The use of hydroxyethyl starches in volumes >1500
mL is considered a risk factor for prolonged delayed graft function Table 51.1  Physiological targets to optimize organ donor management
[131]. However, the use of low-​molecular weight hydroxyethyl
starch was better than high-​molecular weight hydroxyethyl starch Parameter Target
for donor resuscitation [134]. It is generally assumed that rela- Heart rate 60–​120 bpm
tively high filling pressures (CVP of 10–​15 mmHg) correlate with Arterial pressure Systolic pressure >100 mmHg
better early graft function [135–​137]. Despite the concerns that Mean pressure 60–​100 mmHg
fluid restriction may have on the donor kidney and its later post-​
CVP 4–​10 mmHg
transplant dysfunction, these guidelines have now been switched
to slightly lower filling pressures (CVP of 6–​10 mmHg), in order EF >50%
to be more protective of the pulmonary function. Studies have Pulmonary capillary wedge pressure 6–​10 mmHg
indicated that these lower filling pressures are not deleterious to- Cardiac index 2.4 L/​min/​m2
wards kidney procurement (no kidney graft loss and no delayed SVR 800–​1200 dyn·s·cm−5
graft function) [92, 128, 138].
PaO2/​FiO2 >300 mmHg
The development of diabetes insipidus is a common problem
Urine output 0.5–​3 mL/​kg/​hour
encountered in brain-​ dead organ donors. Diabetes insipidus
is defined as urine output >4 mL/​kg/​hour, rising serum Na+ of ABG pH 7.35–​7.45
>150 mmol/​L and/​or serum osmolality of >300 mOsmol/​L, and pCO2 35–​45 mmHg
decreasing urinary osmolality of <200 mOsmol/​L [54]. Both Serum Na+ 135–​150 mmol/​L
hypo-​and hypernatraemia in the donor increase the risk of 1-​year Glucose 6–​10 mmol/​L
mortality in the liver transplant receptor [139]. Dysnatraemia in
Haemoglobin 7–​10 g/​dL
the organ donor is often a sign of poor donor management and
698 CHAPTER 51   D on or organ management

(a specific lung donor management protocol) [123] increased the therapy leading to circulatory arrest can be planned in advance,
number of lung donors and transplant procedures. Salim et  al. and therefore the length of the warm ischaemic interval is known
[149] also found an increased number of organs harvested per more precisely. Nowadays, the majority of DCD donors are cat-
potential donor and less cardiovascular collapse when a protocol egory III DCD. Potential controlled DCD donors are patients
for aggressive donor management was introduced [150]. Similar suffering from severe, irreversible brain damage but who do not
results in prospective randomized studies showed that a strictly-​ fulfil the criteria of brain death. The decision is made that life-​
per-​protocol approach, in combination with hormone therapy, sustaining therapy (disconnection of cardiovascular support and
increased the number of transplantable donor lungs [109]. When mechanical ventilation) will be withdrawn prior to, and com-
donor management goals are met, significantly more donors had pletely independent of, the option of organ donation. Imminent
four or more organs transplanted [151]. death is anticipated, and these patients become a donor after ces-
The clinical component of a strictly-​per-​protocol aggressive sation of circulation, respecting the ‘dead donor rule’. Ideally, this
donor management is based on:  (1) early identification of po- takes place in the operating room.
tential donors; (2)  intensive care admission and management
by a dedicated team; and (3)  early and aggressive resuscitation Agonal phase and comfort therapy
[152, 153]. The implementation of dedicated teams of intensivists After withdrawal of life-​sustaining therapy in controlled DCD, a
or the transfer of potential donors to specialized hospitals might variable period of progressive hypoxia and hypotension develops
even further increase the number of transplantable organs until the onset of circulatory arrest and determination of death,
[154, 155]. defined as the agonal phase [163,  164]. The importance of this
An interesting concept is the relationship between the time of agonal phase is dual. First, concerns have been raised about the
diagnosis of brain death and the moment of retrieval. It is not potential physical and psychological suffering imposed on the
always necessary to proceed to rapid procurement, once the diag- donor and how to provide optimal comfort therapy. Second, pro-
nosis of brain death has been made. If donors are adequately longed cardiopulmonary instability during this phase may result
managed [156], there might be an optimal ‘window of oppor- in an unsuccessful organ procurement, because of additional graft
tunity’ during which the organs can be retrieved. This concept injury jeopardizing the outcome of the recipient.
is referred to as ‘relax and repair’, rather than ‘rush and retrieve’. One critical aspect of the agonal phase is the administration of
Prolonging, however not unlimited, the interval before retrieval comfort therapy. As this applies to palliative care, the principle of
offers the opportunity for donor teams to actively manage the or- double effect supports the administration of treatments, with the
gans and might also trigger intrinsic repair mechanisms in the intent to support patient comfort and alleviate suffering, even if
organs to restore the detrimental effects following the insult of there is a risk of hastening death. Overall, data indicate that time
brain death. In a large retrospective analysis, longer duration of to death after withdrawal of life-​sustaining therapy to allow organ
brain death decreased the risk for delayed graft function and 1-​ donation is mostly limited to 60 minutes. Occasionally, longer
and 3-​year graft failure [157], with a potential cut-​off point at 470 intervals of up to 3 days have been reported [165]. Therefore, re-
minutes [158]. It was also shown that, for each individual organ, latives should be informed about this possibility, and protocols
there was no decrease in procurement with increasing time after should consider these cases. There are currently no useful guide-
brain death [159]. Heart recipients with donor hearts retrieved lines to assist the method of withdrawal of therapy. After with-
after long periods from brain injury had significantly improved drawal of care, bispectral index (BIS) values were consistent with
rejection-​free survival [160]. In contrast, one study reported lighter planes of anaesthesia, and this may warrant the use of hyp-
that delays of >13 hours between donor brain death and cross-​ notic or anaesthetic drugs [166]. The fear of hastening death is
clamping were associated with a higher risk of mortality in car- not supported, and no relation could be demonstrated between
diac recipients [161]. the quantities of sedatives, analgesics, and time to death [167–​
There is also a need for large clinical trials in donor man- 170]. Historically, the impact of the withdrawal phase (hypoxic
agement, focusing on specific donor interventions, including arrest, sudden cardiac arrest, exsanguination) is limited to 60–​90
long-​term outcomes. These studies might include strategies for minutes. The profound haemodynamic instability, rather than the
ischaemic and pharmacological preconditioning [162]. total duration of the withdrawal phase, might be more important
and has a negative impact on kidney graft function and liver out-
come [171]. Other studies revealed an immediate effect on kidney
Management of the DCD donor graft survival [172], and the impact of longer periods of instability
might become more important in the case of liver transplantation
To expand the donor pool, the number of organ transplantations [173]. In DCD lung donation, hypoxic pulmonary arrest was
from DCD donors rapidly increased over the last decade. DCD more detrimental [174].
donation takes place after the declaration of death, based on car-
diorespiratory criteria, in contrast to DBD donation.
Uncontrolled DCD occurs when a person dies unexpectedly. Prediction and determination of death
The length of the warm ischaemic period is often not known. In Predicting the time to donor asystole would enable resources to be
controlled DCD, the moment of withdrawal of life-​sustaining directed to procurements more likely to be successful and would
 C on c lusi on 699

optimize the quality of DCD grafts. The University of Wisconsin biochemical performance of the graft prior to transplantation and
[175] has developed an algorithm to assess the potential controlled may provide a tool to select ‘transplantable’ grafts to improve their
DCD. This score is computed, based on the patient’s age, BMI, function, to reduce ischaemia–​reperfusion injury, and possibly to
O2 saturation, method of intubation, level of spontaneous respir- safely increase the preservation time [191–​194].
ation, and requirement for vasopressors, all of which indicate the Machine perfusion of kidneys has historically gained the lar-
likelihood of death within 1 hour of extubation. Other protocols gest interest. Several clinical studies [195–​197], but not all [198],
have been developed, and some have been validated [165, 167, have shown it to reduce the rate of delayed graft function and to
168, 176–​178]. Most prediction models are tailored with respect improve graft survival after hypothermic machine perfusion. It is
to pulmonary and circulatory support. However, controlled DCD now believed to be the preferred method for preserving kidneys
donors also suffer from some degree of brain damage (but do not at higher risk (expanded criteria, older donors, DCD donors)
fulfil the criteria of brain death). Rabinstein et al. [179–​180] de- [191, 199–​ 202]. Clinical hypothermic machine perfusion of
veloped a DCD-​N score, based on mainly neurological criteria. the liver has still limited experience [203,  204]. Normothermic
Extubation of the patients might also hasten death, although evi- machine perfusion of the heart has also been started clinically,
dence is circumstantial. with only preliminary data reported so far. Normothermic lung
DCD donors are declared dead, using circulatory–​respiratory perfusion—​referred to as ex vivo lung perfusion (EVLP)—​has
criteria. In a non-​transplant setting, this is a straightforward cri- been increasingly reported in successful clinical transplantations
terion in the absence of resuscitation attempts. Potential contro- of questionable lungs and lungs from DCD donors [205–​212].
versies emerge when a potential DCD organ donor is identified International trials have been launched recently to study EVLP as
and the decision for withdrawal of life-​sustaining therapies is an alternative to cold static preservation.
made [181–​183]. Identification of the precise moment of death Currently, many different perfusion conditions have been
is necessary in order to comply with the ‘dead donor rule’. The described, with a large difference within and between organs.
determination of circulatory arrest is based on indirect meas- Various ranges of temperature have been used, from hypothermic
ures, but invasive arterial monitoring is required in a DCD set- (4°C) to normothermic perfusion (37°C). Solutions used as per-
ting [184, 185]. Autoresuscitation has not been reported in DCD fusate also differ between low K+ crystalloid solutions to blood-​
donation within 2 minutes, and all DCD protocols require a strict based solutions (full blood or packed RBCs) mixed with colloids
interval of ‘no touch’ of at least 5 minutes [186,  187]. This ‘no and albumin [190].
touch’ interval is to guarantee that the status of the dying patients The unique opportunity of ex situ machine perfusion is that
is permanent (meaning that the cessation of the circulation will it creates a ‘window’ between procurement and transplantation,
not be restored, neither spontaneously nor as a result of resuscita- during which the functional performance and viability of the
tion efforts), rather than be irreversible [188, 189]. graft under optimal conditions can be evaluated. In the near fu-
ture, this technique may also offer a tool for ex situ repair and
immunomodulation of organs and improvement of their quality
Future perspectives: ex situ prior to transplantation.

organ management
Static or cold storage with conventional preservation solutions Conclusion
has been the standard preservation strategy for solid organs for
decades. In the last decade, however, old techniques, dating from Donor management should be considered as a continuation of
the early days of transplantation, have re-​emerged whereby or- critical care, with a shift in focus towards individual organ func-
gans are continuously and dynamically perfused, instead of being tions. Considering the lack of transplantable donor organs, it is of
statically cold-​stored during their preservation. These techniques utmost importance to identify potential donors and to make all
of machine perfusion have now been put forward as the next step efforts to support them towards a successful organ procurement.
in donor organ management where a shift from ‘in situ’ to ‘ex situ’ During the last decades, we have learnt a lot about the patho-
organ conditioning has opened new perspectives [190]. physiological changes underlying brain death that are responsible
This technology has been substantially refined, and new port- for the detrimental effects on donor organs. Despite this growing
able machines have been developed and introduced in the clinical knowledge, our clinical practice is still lagging behind. Many ex-
arena to facilitate ‘ex situ’ machine perfusion of solid organs. The perimental treatment strategies were developed, based on physio-
technique consists of creating a flow through the organ, generated logical goals; however, their clinical translation and validation are
by a pump in a circuit, to recirculate a preservative solution at still limited. There is a need for large RCTs to elucidate some of
various temperatures through the vasculature. This allows better the controversial issues regarding treatment options. Institutions
intravascular distribution of preservation solutions, the delivery and organizations are launching many protocols which seem
of O2 and nutrients to the parenchyma, and the removal of toxic promising in increasing the quantity and quality of suitable donor
metabolites. In addition to improved preservation, machine per- organs, and aggressive donor management seems to be a corner-
fusion may allow real-​time monitoring of the functional and stone in the near future. Challenges include implementation and
further standardization of these guidelines and the development
700 CHAPTER 51   D on or organ management

of superior protocols focusing on all organs inside one donor, ra- practice in many countries. Finally, in the near future, donor
ther than the individual organs alone. In the continuous search to management will probably be extended towards a phase of ex situ
further increase the potential pool of donor organs, organs from treatment, with the potential to recondition grafts and further im-
circulatory arrested DCD donors have now become standard prove the quality of organs.

Personal perspective
Donor management has changed dramatically since the early Increasing interest in the use of new potential donor pools,
years and has now evolved into a true scientific specialty. including donation after circulatory death, and the use of non-​
Increasing studies and randomized trials have provided new standard, extended donors will further challenge the scientific
evidence into the pathophysiological processes and treat- community. This continuum in critical care is of utmost im-
ment options, including the use of clinical algorithms. Injury portance to improve the recipient’s outcome and to maximize
to donor organs should be considered as a first hit in a series the number of available organs.
of harmful events that will contribute to reperfusion injury.

Further reading
Benck U, Hoeger S, Brinkkoetter PT, et al. Effects of donor pre-​treatment Schnuelle P, Gottmann U, Hoeger S, et al. Effects of donor pretreatment
with dopamine on survival after heart transplantation. J Am Coll with dopamine on graft function after kidney transplantation:  a
Cardiol 2011;58:1768–​77. randomized controlled trial. JAMA 2009;302:1067–​75.
Macdonald PS, Aneman A, Bhonagiri D, et al. A systematic review and Smith M. Physiologic changes during brain stem death—​ lessons for
meta-​analysis of clinical trials of thyroid hormone administration to management of the organ donor. J Heart Lung Transplant 2004;23:S217–​22.
brain dead potential organ donors. Crit Care Med 2012;40:1635–​44. Szabo G. Physiologic changes after brain death. J Heart Lung Transplant
Mascia L, Pasero D, Slutsky AS, et al. Effect of a lung protective strategy for 2004;23:S223–​6.
organ donors on eligibility and availability of lungs for transplantation: a Van Raemdonck D, Neyrinck A, Rega F, Devos T, Pirenne J. Machine
randomized controlled trial. JAMA 2010;304:2620–​7. perfusion in organ transplantation:  a tool for ex-​vivo graft conditioning
McKeown DW, Bonser RS, Kellum JA. Management of the heartbeating with mesenchymal stem cells? Curr Opin Organ Transplant 2013;18:24–​33.
brain-​dead organ donor. Br J Anaesth 2011;108(suppl 1):i96–​107. Zaroff JG. Consensus Conference Report:  maximizing use of organs
Neyrinck A, Van Raemdonck D, Monbaliu D. Donation after circulatory recovered from the cadaver donor: cardiac recommendations March
death: current status. Curr Opin Anaesthesiol 2013;26:382–​90. 28–​29, 2001. Circulation 2002;106:836–​41.

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 CHAPTER 52

Palliative care in the

intensive cardiovascular
care unit
Jayne Wood

Contents
Summary  706 Summary
Introduction  706 Specialist palliative care services originally focused on improving the quality of
Symptom control  707 life for patients with a diagnosis of cancer in the terminal phase of their illness.
Decision-​making  709 However, organizations such as the World Health Organization, supported by na-
Intensive cardiac care unit tional strategies such as the UK’s End of Life Care Strategy in 2008, promote the
environment  711 early integration of specialist palliative care into the management of patients with
Supporting staff  712 incurable disease, irrespective of the diagnosis.
Education and training  712 The primary goal of the intensive cardiac care unit is to help patients survive
Conclusion  713 acute threats to their lives. However, the suddenness and severity of illness, par-
Personal perspective  713 ticularly when associated with an underlying cardiological diagnosis, often mean
Further reading  714 that the provision of optimal specialist palliative care is challenging.
References  714 This chapter addresses key issues relating to the provision of specialist pallia-
tive care in the challenging and complex environment of the intensive cardiac care
unit, including symptom control, end-​of-​life care, decision-​making, and commu-
nication. The benefits of multidisciplinary working for effective quality improve-
ment in patient care and best support for patients, families/​carers, and staff are
also addressed. The importance of interdisciplinary working is highlighted, and by
embedding the principles of holistic care into daily practice, the intensive cardiac
care unit can ensure that patients and their families/​carers receive the support they
need in a timely manner from individuals who are well supported in what is often
considered to be one of the most challenging medical environments.

Introduction
The WHO (2002) [1]‌has defined palliative care as:
‘  . . .  an approach that improves the quality of life of patients and their families facing the
problem associated with life-​threatening illness, through the prevention and relief of suffering
by means of early identification and impeccable assessment and treatment of pain and other
problems, physical, psychosocial and spiritual . . . ’
Historically, the provision of palliative care has focused on improving the quality of
life for patients in the terminal phase of their illness. However, the WHO [1]‌and na-
tional strategies, such as the End of Life Care Strategy (EOLCS) (UK, 2008) [2], advise
that palliative care should be ‘applicable from early in the course of illness in conjunction
 Sym p tom   c on t rol 707

Disease-modifying therapy (curative,

life-prolonging, or palliative in intent)

Bereavement
care

PALLIATIVE CARE

Presentation/diagnosis Illness Death

Figure 52.1  Model of palliative care from the WHO.

Source data from National Cancer Control Programmes. Policies and Managerial Guidelines, 2nd edn. Geneva: WHO, 2002.

with other therapies which aim to prolong life’. E Figure 52.1 [1] active anti-​cancer treatment and the quality of life experienced by
illustrates this model. the patient and family.
Palliative care relies upon a multidisciplinary approach, Guidelines, such as the EOLCS (2008), have advocated the in-
with input from doctors, pharmacists, nurses, chaplains, social volvement of SPC in patients with a diagnosis of non-​malignant
workers, psychologists, and other allied health professionals, to disease [2]‌. Death from heart disease continues to be one of the
formulate a holistic management plan essential in providing op- leading causes of death. Data published by the Office for National
timal care for patients and their families/​carers. Palliative care in Statistics on deaths registered in England and Wales in 2014 re-
the ICCU is no different, often finding itself in the position of vealed that deaths from circulatory disease (accounting for 27% of
supporting symptom control, working to maximize the quality all deaths), including deaths from heart disease and stroke, con-
of life for the patient, and supporting staff through facilitation of tinue to be second only to those from cancer (29% of all deaths
decision-​making and education. registered) [3] and are often preceded by a period of deterioration
This chapter addresses key issues relating to the provision of associated with complex symptoms.
optimal palliative care in the challenging and complex environ- Two major studies have investigated symptoms in ter-
ment of the ICCU, including symptom control, EoLC, decision-​ minal heart disease—​the Study to Understand Prognoses and
making, education, and training and communication. The benefits Preferences for Outcomes and Risks of Treatment (SUPPORT)
of multidisciplinary working for effective quality improvement in [4]‌and the Regional Study of Care for the Dying (RSCD) [5].
patient care and best support for patients, families/​carers, and The RSCD, a population-​ based retrospective survey [6]‌of
staff are also addressed. a random sample of people dying in 20 English health districts
There is a paucity of literature available on the subject of pal- during 1990, included 675 patients dying from heart disease (of
liative care in the acute intensive cardiological setting. However, all causes), of which 600 had a non-​sudden death (where the re-
literature relating to the setting of the general ICU is often transfer- spondents gave no history of previous illness). Those known to
able to the ICCU and hence is cited in this chapter where relevant. the deceased receiving mail at the deceased’s address were inter-
The ICCU arguably presents some of the most challenging eth- viewed. Findings revealed a wide range of distressing symptoms,
ical dilemmas encountered in medicine. An intervention simply often experienced for >6 months (see E Box 52.1).
being available should not automatically mean that it is to be pro- These findings were consistent with those of SUPPORT, which
ceeded with. Rather it should be carefully considered, weighing included 263 patients with heart failure in the last 3 days of life,
up the risk versus benefit ratio, in both the short and long term. and found that 65% reported breathlessness and 42% reported se-
This chapter does not focus specifically on the ethical dilemmas vere pain [4]‌.
encountered in the ICCU, but on issues such as consent, with- The aetiology of pain in a patient with terminal heart disease is
drawal of treatment, and the impact that these have on decision-​ often unknown, but management usually follows the principles
making, and the quest to ensuring that patients receive the best of the WHO analgesic ladder (see E Figure 52.2) [7]‌. This was
care with minimal harm is considered throughout the chapter.

Box 52.1  Key results from the Regional Study of Care

for the Dying
Symptom control
Most commonly reported symptoms (% of patients):
The involvement of specialist palliative care (SPC) services in Pain (50%)
◆
patients with a diagnosis of cancer has long been recognized as Shortness of breath (43%)
◆
critical for the delivery of effective care. Access to SPC should
Low mood (59%)
◆
not be confined to the last days and weeks of life, but available
Anxiety (45%)
◆
throughout the cancer journey to optimize both the delivery of
708 CHAPTER 52   Palliative care in t h e int en si ve ca rdi ovas cu l a r ca re u n i t

Freedom from
cancer pain
_____________________

Pain persisting Step 3: Opioid for

Moderate to severe
or increasing pain (‘strong opioid’)
+/- non-opioid
+/- co-analgesic

________________________

Pain persisting Step 2: Opioid for mild to moderate pain

(‘weak’ opioid)
or increasing + non-opioid
+/- co-analgesic

_______________________

Step 1: Non-opioid
Pain +/- co-analgesic
________________

Figure 52.2  The WHO ‘analgesic ladder’ [7]‌.

Source data from The WHO Analgesic Ladder. Guidelines for symptom control: Department of Palliative Medicine, The Royal Marsden NHS Foundation Trust, 2016: p. 10.

designed as a framework for the management of chronic pain and introduced only once the symptom is deemed refractory to such
promotes five main principles, with regard to the use of analgesic interventions. Despite a poor understanding of the mechanism of
agents: action, evidence supports using opioids first line for the palliation
of breathlessness [8]‌. Benzodiazepines are frequently employed
1. ‘By mouth’: drugs should be given PO (where possible).
for their hypnotic, sedative, anxiolytic, and muscle relaxant prop-
2. ‘By the clock’: drugs should be given regularly. erties. There is a lack of evidence available to support their use
3. ‘By the ladder’: drugs should be given in a stepwise manner. first line, but since many patients with breathlessness feel anxious,
4. ‘For the individual’: opioid drugs should be individually titrated. it appears rational to support its use as second-​line therapy.
Major depression (DSM-​IV criteria) is present in 36.5% of pa-
5. ‘Attention to detail’: drugs should be regularly reviewed.
tients with chronic heart failure [9]‌and is more common in pa-
Co-​analgesics, otherwise known as adjuvant analgesics, are tients with severe illness and severe functional impairment such
agents primarily developed for non-​analgesic purposes that have as those admitted to the ICCU. Drugs typically used to manage
been found to relieve pain of certain types, including neuro- anxiety and depression can be associated with cardiotoxicity and
pathic, bone, and liver capsule pain or abdominal colic. Examples thus should be avoided in patients with heart disease. The high
of such drugs include tricyclic antidepressants and antiepileptic prevalence of mood-​related disorders in patients with chronic
drugs, including pregabalin and gabapentin. These are frequently heart failure, for example, highlights the importance of not only
used in conjunction with opioid analgesics. Particular attention to good holistic assessment, but also the involvement of psychiatric
the side effect profile of drugs is necessary when prescribing for and psychological services to optimize the quality of life.
patients with heart disease who often have associated comorbid- When patients are unable to self-​report their symptoms, such
ities. These will often challenge the use of drugs which ordinarily as in the ICCU, health care professionals, especially the nursing
would be considered first line and safe. An example of this might staff, become their proxy reporters. The accuracy of this rests in
be impaired renal function limiting, or even precluding, the use the ability to detect and interpret what are often non-​verbal signs
of neuropathic agents such as pregabalin and gabapentin; avoid- of distress.
ance of tricyclic antidepressants, effective neuropathic agents, due Puntillo et  al. [10] interviewed 22 nurses who had cared for
to associated cardiotoxicity; and avoidance of cyclizine, an anti- 19 critically ill patients, of whom 44% died during their hospi-
emetic often used first line in many circumstances, due to the risk talization, in two ICUs (a 24-​bed medical–​surgical ICU and a
of precipitating an arrhythmia. 16-​bed cardiac ICU) at a tertiary medical centre in western US.
Breathlessness may arise as an interaction between physio- The study objective was to explore how ICU nurses assess and
logical, psychological, social, and environmental factors and re- treat distressing symptoms in patients at high risk of dying. The
quires a holistic approach. Although objective measures may hint interviews revealed three themes:  signs of symptoms; treatment
at an underlying pathology, they do not reliably indicate the sub- of symptoms; and distinguishing between symptoms and signs.
jective experience. While the primary focus of managing breath- Nurses were found to use a combination of physiological markers
lessness should be on the identification of any reversibility in the (such as blood pressure and heart rate) and behavioural cues (such
underlying cause, palliation of the sensation of breathlessness as facial expression, tone of muscles, and presence of tears) to help
may occur during this stage of management, despite often being identify symptoms in this population. One might argue that the
 Deci sion -m a k i n g 709

latter requires a level of intuition and experience on the part of the

assessing health care professional. Signs and symptoms were often Decision-​making
not distinguished from each other, and although biophysiological
SUPPORT was a landmark study consisting of a 2-​year pro-
signs were routinely documented in clinical assessments, other
spective observational phase I  multisite study, followed by a 2-​
symptoms were not. The interviews also revealed that nursing staff
year controlled clinical trial carried out across five hospitals in the
frequently adopted a holistic approach, using non-​pharmacological
US [4]‌. It was designed to improve end-​of-​life decision-​making
measures, to achieve symptom control, including the use of touch
and reduce the frequency of a prolonged, symptomatic death for
and music, but often did not document this. Key components to
those patients seriously ill in hospital. In total, just under 1000
providing good holistic palliative care to the patient on the ICCU
patients were included, with an overall 6-​month mortality rate of
in the last few hours and days of life are no different to those re-
47%. The results of the study revealed many concerns around care
quired for patients dying in a non-​ICCU setting:
at the end of life associated with:
◆ Open and transparent communication with patients (where
◆ Communication.
possible) and their family/​carers.
◆ The use of aggressive treatment.
Regular and frequent assessments of symptoms, needs, and com-
◆
◆ The lack of knowledge relating to end-​of-​life preferences.
fort measures.
◆ The lack of DNACPR orders.
◆ Review of medications/​ interventions in light of treatment
burden and benefit, given underlying diagnoses. ◆ Long stays on the ICU.
◆ Compassionate care of patients and their family/​carer at all times. ◆ Poor pain management.

◆ Thorough documentation of the care plan and all communica- All attempts should be made to respect the principles of patient
tions that have taken place. autonomy, but due to the illnesses that have brought a patient to
the ICCU and the interventions that have thus far been necessary,
When the multidisciplinary team reaches the decision that a
patients often lack capacity and clinical decision-​making occurs
patient appears to be in the last hours/​days of life, a personal-
in their absence. For those patients who do not identify someone
ized EoLC plan should be formulated to address the following
close to support decision-​ making, an independent advocate
three areas:
might be sought, particularly when there is disagreement in the
1. Communication:  all health care professionals involved in physicians’ positions. In the UK, the Mental Capacity Act (2007)
the management of the patient should be made aware of the introduced Independent Mental Capacity Advocates (IMCAs)
changing goals of treatment, to include the primary treating to support decision-​making in such circumstances. Decision-​
physician managing the patient before the ICCU admission, making in the ICCU, however, often involves those closest to the
the patient (where possible), and the family/​carer to explain patient, such as family members and carers, sometimes referred
the current plan of care. Documentation of communications to as ‘surrogate’ or ‘substitute’ decision-​makers. Good practice is
should be complete and include the wishes of the patient re- to involve those closest in decision-​making (with patient consent)
lating to the preferred place of care and death, if identified. and may refer to advance care planning decisions made by the
Achievement of these preferences is not always possible, due patient, but in the ICCU, involvement of those closest may be the
to the rapid deterioration frequently encountered and the only way to find out what the patient’s preferences might have
ongoing requirement for interventions confined to the ICU to been, had they retained capacity. This is critical if the overall care
maintain symptom control. As above, the patient (where pos- provided in the ICCU is to be as optimal as possible, in terms of
sible) and the family/​carer should be kept updated to address informing choices, patients’ preferences, and the overall quality of
any questions or concerns about any aspect of care and do-​not-​ palliative care and EoLC.
attempt-​cardiopulmonary-​resuscitation (DNACPR) issues. Heyland et al. [12] conducted a prospective, multicentre cohort
2. Symptom control:  the management of symptoms encoun- study across six Canadian university-​affiliated ICUs investigating
tered at the end of life should follow the local guidelines and, substitute decision-​makers’ experiences in the ICU and to ascer-
where possible, involve the support from SPC. Regular assess- tain overall satisfaction with decision-​making. The study con-
ments and documentation of care needs should include mouth sisted of a validated self-​administered questionnaire, assessing 21
care, pain, breathlessness, agitation, constipation, nausea and key aspects of communication and decision-​making, to substitute
vomiting, access to hydration (PO or SC, as appropriate), and decision-​makers of patients who had been ventilated on the ICU
provision of psychological, social, and spiritual care. for >48 hours. A total of 789 surveys were returned (of which 258
were returned from substitute decision-​makers of eligible non-​
3. Care after death: when a patient dies, continued compassionate
surviving critically ill patients), which amounted to a 70.3% re-
care of the patient and family is paramount, as evidence indi-
turn rate. The key findings of the study were that while they were
cates that the final elements of care impact not only at the time,
satisfied overall with their experience of decision-​making, substi-
but also on the subsequent bereavement experience [11]. It is
tute decision-​makers were:
imperative that health care professionals known to the patient
in the primary sector are informed of the patient’s death as a ◆ Most satisfied with the frequency of communication with
matter of urgency nurses and least satisfied with that from physicians.
710 CHAPTER 52   Palliative care in t h e int en si ve ca rdi ovas cu l a r ca re u n i t

◆ The majority (81.2%) preferred some form of a shared decision-​ 4. What are the implications of making a mistake when
making process (14.8% preferred to leave all decisions to the prognosticating?
physicians, and 21.8% preferred to make the final decision 5. How do physicians vary in their views regarding predictions at
themselves).
the end of life?
◆ Mostly satisfied with decision-​making if they:
Were completely satisfied with the level of health care re-
●
The results showed that the frequency of prognostication varied
ceived by the patient. among specialties. Pulmonologist critical care physicians were
shown to address the question ‘How long do I have to live’ more
Felt that the information they had received had been complete.
●
frequently than the general internist, but less commonly than a
Felt supported through the decision-​making process.
●
typical haematologist oncologist. The results clearly showed that
These findings are consistent with other studies where the physicians try to avoid prognostication. A total of 89.9% believed
themes of shared decision-​making with family members and the that one should avoid being too specific when communicating
importance of facilitating family consensus and ensuring that the with patients; 43.7% said that they usually wait to be asked by
right amount of information is given at the right time, by the right a patient before offering a prediction; and 56.8% of respondents
person, and in the right way have been iterated [13]. reported that they had received inadequate training in prognosti-
Crucially, the delivery of good EoLC begins with an acknow- cation. The study also identified that the longer the internist had
ledgement that the patient is dying (i.e. last hours to days of life) and been in practice, the more likely they would be to wait to be asked
that further medical intervention would be futile. Medical futility for information.
may be classified in a number of ways, but essentially all methods The balance between burdening a patient with unwanted in-
agree that the probability of achieving an intended goal is exceed- formation and providing an open and honest communication is a
ingly unlikely. Patients admitted to the ICCU often have multiple fine one, but clinicians must be mindful of ‘opening the door’ for
comorbidities requiring dual prognostication, and this, combined patients and families/​carers, allowing time and creating an atmos-
with the rapid advancements in life-​sustaining technology, makes phere where they feel comfortable, in order for them to request
decisions relating to futility difficult. The usual cues that indicate a the information they need.
patient is entering the dying phase, such as a reduction in the ability The study reported that 91.7% of internists were ‘reluctant to
to tolerate oral medications and diet, increasing sleepiness, and im- make predictions about a patient’s illness when the clinical situ-
mobility, are often absent in the ICCU patient. In such settings, the ation was uncertain’. Physicians may feel that ‘getting it wrong’
dying phase is more commonly recognized by monitoring, for ex- will only serve to reduce the confidence that patients and their
ample, blood pressure readings and changes in the heart rhythm. families/​carers, and even their colleagues, have in them.
The alarms that are activated from these machines can become an Uncertainty in the ICCU can be compounded by the number
unwelcome source of distraction for the family. of health care professionals involved in one patient’s care. Patients
Prognostication empowers patients with their families/​carers admitted to the ICCU will often have built a close relationship
to make informed decisions regarding ongoing care and allows with their primary treating physician and may well have shared
an opportunity to express preferences for EoLC. Early prognos- information, either implicitly or explicitly, regarding preferences
tication is important for physicians to define appropriate levels for EoLC. Following admission, the care will often, if not always,
of medical intervention and to ensure timely introduction of pal- be led by the ICCU team who, without closely working with the
liative care. Tools, such as the Simplified Acute Physiology Score primary treating physicians, will not be privy to that information.
(SAPS) [14] and Acute Physiology and Chronic Health Evaluation The frequent shift patterns worked on the ICCU adds to the chal-
(APACHE) [15], are examples of tools used in the ICU that can lenge in maintaining communication relating to care and man-
help to delineate predicted morbidity and mortality and support aging the end of life phase well. Formal regular multidisciplinary
prognostication. However, even with such tools, a level of uncer- meetings are therefore crucial to enable all professionals to be ac-
tainty will exist which may, sometimes to the detriment, interrupt tively engaged in such important decision-​making exercises and,
the willingness of physicians to prognosticate and share such in- if not able to be physically present, to be informed through other
formation. The most effective model of prognostication is likely to communication channels.
be when a tool is accompanied by clinical judgement arising from While physicians may be reluctant to share prognostications
a multidisciplinary team discussion, including the patient, where with patients and their families/​carers for fear of provoking un-
possible, and the family/​carer. necessary anxiety, evidence suggests that patients and their fam-
Christakis et al. [16] carried out a survey of American internists ilies/​carers often feel quite differently. Evans et al. [17] conducted
to explore their attitudes and practice regarding prognostication. face-​to-​face interviews with 179 surrogate decision-​makers for
A  total of 1311 internists were mailed, and 697 responded. The 142 critically ill patients at high risk of death in four ICUs at the
survey addressed five related questions pertinent to the end of life: University of California, San Francisco Medical Center, including
1. How common is prognostication in medical practice? a cardiac ICU. The primary objective of the study was to under-
2. Do physicians believe they were adequately trained to make stand surrogate decision-​makers’ views on whether a physician
prognoses? should discuss prognosis in the face of uncertainty. The results
found that 87% of surrogates wanted physicians to discuss an
3. How do physicians feel about making prognoses?
 I n ten si ve ca rdiac ca re u n i t env i ron m e n t 711

uncertain prognosis. Five reasons for this were identified—​

a 3. Questioning: utilize a combination of open and closed questions,
belief that: with a preference to the former, where possible and appropriate.
1. Uncertainty is unavoidable. 4. Effective listening: encourage the patient and their family/​carer
2. Physicians are considered the only source for prognostic to engage in the consultation, and always wait for them to stop
information. speaking before you begin your next sentence.
3. Discussing prognostic uncertainty leaves room for realistic hope. 5. Responding:  appropriate responses may include questions, a
combination of empathic and factual responses, as well as si-
4. Sharing of uncertain prognostic information increases a
lence. Provide a summary of the meeting, being sure to pri-
surrogate’s trust in the physician.
oritize concerns raised. A management plan should be clearly
5. It signals a need to prepare for possible bereavement. explained, and a time given when a follow-​up to the meeting
Perhaps a critical finding of this study is that it identifies the will occur. This is particularly important following the delivery
importance of not only what is shared, but also how the informa- of end of life information when patients and their families/​
tion is shared. Patients and their families/​carers appreciate com- carers will need time to digest information and an opportunity
plete honesty and disclosure of information. to have further questions answered.
Communication is one of the most important factors associ- While there is little doubt that good communication at the end
ated with quality of care and patient safety, especially in the ICU. of life is vital for the experience and satisfaction of patients and
Despite this, research shows that many ICU patients and families/​ their families/​carers, there is also evidence to indicate that it can
carers report dissatisfaction with communication [18]. also have a positive effect on the subsequent bereavement experi-
Satisfaction with care is critically linked not only with timely ence for families/​carers [11,  22]. Communicating early, effect-
decision-​ making, but also with good communication among ively, frequently, and consistently with patients and their families/​
health care professionals, patients, and their families/​carers. In carers is of paramount importance.
the ICCU, where the environment is busy and clinical conditions Much of the discussion above might imply a scenario with
often change rapidly, this is not an insignificant challenge. An in- warning that a patient is entering the dying phase. However,
creased length of stay for patients often shows a decrease in good even in the face of a rapid change in condition, with little or no
communication [19]. Additionally, the patient with a diagnosis warning, these principles can still be applied. A more important
of a life-​limiting illness is likely to be in distress from physical, goal now might be to focus on the communication with, and sup-
psychological, and/​or spiritual causes which, with the associated port for, the family, rather than achieving goals such as the pre-
distress of their family/​carer, can pose a barrier to effective com- ferred place of care and death. Facilitation of such discussions
munication and affect the ability for all to engage in dialogue. In and the ability to provide optimal care in such circumstances are
such situations, there is an increased need for the health care pro- greatly enhanced by the presence of an active integrated multidis-
fessional to be observant for non-​verbal, as well as verbal, cues to ciplinary approach, including those with SPC expertise.
optimize the environment of the consultation and to ensure sup-
port is available, both during the consultation and following it.
Buckman [20] describes five key issues to consider in the struc-
ture of any consultation. They are particularly useful to bear in Intensive cardiac care
mind when communicating information about the end of life, unit environment
when it is perhaps never more crucial to remember that how
During the last half century, technological innovations in the ICU
something is said is as important as how it is said [21]:
setting have been vast. This has led to a change in the remit of the
1. Prepare for listening: collect as much information as possible ICU, with an increasing number of admissions of patients with
before the meeting from key members of the multidiscip- complex needs related to medical and surgical scenarios, rather
linary team. Comprehensive discussions with these mem- than trauma or infectious diseases. New generations of ICUs are
bers will provide a cohesive, collaborative approach to care. being designed to promote healing in a humanistic manner to
Identify key members of the patient’s family/​carers to attend meet the holistic needs of patients and their families/​carers [23].
the meeting who can then be responsible for the transfer of in- However, the environment continues to be a curative one and a
formation to the wider family network. The most appropriate place ‘for therapeutic trial of treatment’ [24] where the goals of
or convenient time to hold the meeting should also take into care are ultimately to support and treat reversible causes of critical
consideration the content to be discussed. At the beginning illness. Research suggests that 70–​95% of deaths that occur in the
of the consultation, ensure proper introductions of all those ICU follow the withdrawal of treatment [25]. Dying in an envir-
present. onment such as the ICU is complex and challenging, as a result of
2. Physical context:  the environment should be comfortable and its ever changing and dynamic nature and the fluctuating status
private and take into consideration the physical constraints of the of patients whose physical, psychological, and clinical signs of
patient and the environment of the ICCU. Ensuring that the pa- dying are suppressed by sedation, ventilation, and other interven-
tient is comfortable will help to reduce any restrictions that phys- tions. Regardless of the highly technical working environment,
ical symptoms might impose on the freedom of conversation. ICU staff share much in common with palliative care staff when
712 CHAPTER 52   Palliative care in t h e int en si ve ca rdi ovas cu l a r ca re u n i t

dealing with a dying patient. They are mindful of the importance teams and resources available. Many palliative care teams continue
of good EoLC and are often actively engaged in the achievement to be small, often consisting only of one or two members. A will-
of a natural and dignified death [26]. ingness to change local patterns of practice, in order to accommo-
Troug et al. [24] advise of the importance of integrating SPC into date all stakeholders, is necessary, and an overall willingness for
the ICU environment. Byock [27] agrees, stressing that although crit- commitment, collaboration, and openness to change will be key to
ical care and palliative care may appear to be opposites, they share strengthen the internal capability for palliative care delivery [33].
underlying themes. Both focus on the most vulnerable patients in the
health care system, and each discipline’s primary goal—​extending
life for the critical care patient, and comfort and quality of life for Supporting staff
the palliative care patient—​represents an important secondary goal
EoLC has been described as challenging, complex, and emo-
for the other. Collaboration between SPC and critical care can lead
tionally demanding, but if the staff have the necessary know-
to the provision of optimal EoLC, with improvements in symptom
ledge, skills, and attitudes, it can be one of the most important
control and patient and family satisfaction, as well as lower rates of
and rewarding areas of care [2, 32]. Providing EoLC in the high-​
in-​hospital deaths and shorter lengths of stay in hospital [28]. Penrod
pressured environment of the ICCU, where staff are exposed
et al. [29] point out that the inclusion of SPC is now recognized as a
to repeated stressful events, may increase the risk of emotional
marker of quality in the ICU setting, with guidelines recommending
burnout or post-​traumatic stress [34]. To prevent this, a sup-
early application of palliative care principles for symptom control to
portive and nurturing environment is vital. Pattison [31] agrees,
run in parallel with curative and restorative treatment [30].
stressing that the practical and emotional support needed by the
Despite there being considerable evidence that patients with
ICU staff must not be underestimated and can be provided by
heart disease may have significant palliative care needs, referral
mentorship and clinical supervision, as well as staff counselling.
rates remain low [28]. Initiatives to improve EoLC in the ICCU face
Consideration needs to be given to the workload and skill mix to
several important barriers. The rushed, often apparently chaotic,
enable this to take place. This support should extend to doctors
ICCU environment, with its focus on technology and its invariable
and all members of the multidisciplinary team, because the emo-
noises and buzzing alarms, is not conducive to EoLC discussions
tional implications of dealing with EoLC affect all [35].
with patients and families/​carers. More complex barriers include
Spinello [36] suggests that proper critical care training and
inflated expectations for critical care therapies, sometimes shared
management rests on three pillars:  evidence-​based patient care;
by clinicians, patients, and their families/​carers, a preoccupation
proficient procedural skills; and compassionate end of life man-
with an unattainable level of prognostic certainty, and fragmenta-
agement. Spinello points out that the last continues to be the
tion of the health care team into separate ‘silos’ of disciplines and
weakest, proposing reasons such as a reluctance to talk about
specialties. Withdrawal of treatment discussions do not always
death, a lack of training in EoLC, and even a concern for the legal
allow sufficient time for staff to have adequate EoLC planning
issues that might arise following a death.
[31], and there is often a sense of failure when patients deteriorate
Reflective practice or ‘debrief ’ sessions after a patient’s death
which pervades health care professionals’ feelings about care and
can help the ICCU staff to examine beliefs about death. This sup-
may contribute to subsequent burnout [32]. Ultimately, this can
port can improve communication between providers, patients,
lead to health care professionals’ avoidance of further engagement
and families/​carers and is therapeutic for staff, creating an envir-
in EoLC discussions. These barriers work to delay the attention to
onment that is seen to support dying, as well as curing.
palliative care needs for patients and families/​carers, resulting in
Further strategies for facilitating support can include morbidity
an inequity of care. Lack of SPC may also deny ICCU staff the sup-
and mortality meetings and Schwartz centre rounds. The latter, de-
port they need to deal effectively with EoLC issues.
veloped in the US and now being used in acute trusts across the UK,
Various strategies to improve SPC in the ICU have been docu-
provide a forum for staff from a range of disciplines to meet once
mented. One initiative established in the US is a web-​based re-
a month (or every other month) to explore together some of the
source [33], providing information and expertise to facilitate
challenging psychosocial and emotional issues that arise in caring
the principles of palliative care and the achievement of the best
for patients. These, if well managed, can be educative, as well as
possible EoLC in the ICU. Nelson et al. describes two models for
therapeutic, and can help to resolve certain issues or questions that
palliative care integration—​first, the ‘consultative’ model, which
remain unanswered relating to care and provide an opportunity to
focuses on increasing the involvement and effectiveness of pallia-
reflect and learn for the future on issues such as EoLC or the timing
tive care consultants in the care of ICU patients and their families/​
of decision-​making. It is important that these meetings are well fa-
carers, and focusing on those patients identified with the highest
cilitated, and they work best when there is a representation from
risk of poor outcomes; and second, the ‘integrative’ model, which
all those involved in care—​senior and junior team members alike.
seeks to embed palliative care principles and interventions into
daily practice by the ICU team for all patients. The models are not
mutually exclusive, and many institutions will adopt an overall ap-
proach from both models when planning an ICU–​palliative care
Education and training
initiative. There are advantages and disadvantages to both models, To manage the end of life effectively, whether it is preceded by much
and success or failure depends upon the commitment of both warning or not, relies on ongoing education and training to health
 Per s ona l  pe r spe c t i v e 713

have demonstrated patient-​centred care to be associated with

Box 52.2  Examples of educational support offered by SPC
better clinical outcomes [39].
◆ Regular participation in multidisciplinary staff meetings to The patient-​centred model ensures that:
enhance teamwork, share concerns, and encourage a culture 1.
Patients and families/​
carers are kept informed about,
to support palliative care in the ICCU environment
and actively involved in, medical decision-​
making and
Helping to develop and implement a system for the formal
◆
self-​management.
evaluation of the ICCU palliative care quality
2. Patient care is coordinated and integrated across groups of
Promoting an expanded role for palliative care specialists in
◆
health care providers.
ICCU clinical care and staff education
Planning an active role in interdisciplinary team meetings to
◆ 3. Health care delivery systems provide for the physical comfort
identify potential obstacles to ICU palliative care improve- and emotional support of patients and family members.
ment and strategies to overcome them 4. Health care providers have a clear understanding of patients’
Encouraging collaborative working to ensure joint learning
◆ concepts of illness and their cultural beliefs.
for ICCU and palliative care staff
5. Health care providers understand and apply the principles of
Collaboration between ICCU and palliative care staff for patient
◆
disease prevention and behavioural change, appropriate for di-
and family discussions relating to complex ethical decisions verse populations.
Patients and their families/​carers are expressing a desire for a
care professionals in the ICCU to effectively deal with even the most larger role in health care decision-​making and are asking pro-
suddenly occurring situations. This might take the form of informal viders to do a better job of responding to patient and family
and/​or formal teaching and ideally should be regular, face-​to-​face, needs. In spite of these concerns, families/​carers often feel unin-
and supported by SPC (see E Box 52.2). Critically, training pro- formed and disenfranchised from clinical decision-​making and
grammes for both intensivists and cardiologists, who are often in the the day-​to-​day care of loved ones in the ICU.
position of leading on care, should incorporate sufficient training to The patient-​centred care model, with respect to palliative care
enable them to perform well in such circumstances and at the very and EoLC, aims to create an environment that supports dying,
least acknowledge the benefits that SPC has to offer. as well as curing, to improve communication among providers,
patients, and families/​carers and to provide the small things that
often make a big difference at the end of life.
How best to provide palliative care to patients in each in-
Conclusion dividual ICCU will have to take into account the availability
The primary goal of the ICCU is to help patients survive acute of resources, the attitudes of stakeholders, the organizational
threats to their lives [37], but the suddenness and severity of structure of the ICCU, and the patterns of local practice
illness often mean that this is not possible. Important discussions throughout the rest of the hospital. Essential steps to improve
relating to the goals of treatment and patient’s wishes are not al- SPC on the ICU, however, as described by Nelson et al. [33],
ways possible with the patients themselves, and studies of fam- focus on the promotion of interdisciplinary working, the as-
ilies/​carers of patients who died in the ICU suggest that the care sessment of the needs and available resources, and the en-
and support offered is often at odds with the family’s perceptions gagement of the ICU team. Embedding these principles into
of what the patient might need or prefer. daily practice and introducing SPC as early as possible should
It has been strongly recommended that health care delivery begin to ensure that patients admitted to the ICCU, and their
systems become patient-​ centred, rather than clinician-​or families/​carers, receive the support they need in a timely
disease-​centred, to ensure that treatment recommendations and manner from individuals who are well supported in what is
decision-​making take into consideration the patient’s preferences often considered to be one of the most challenging medical
and beliefs [38]. This is supported by the fact that several studies environments.

Personal perspective
Historically, SPC services have focused on improving the early integration of SPC into the management of patients
quality of life for patients with a diagnosis of cancer in the ter- with an incurable disease, irrespective of the diagnosis. It is
minal phase of their illness. However, strategies now promote becoming increasingly commonplace therefore to find SPC
714 CHAPTER 52   Palliative care in t h e int en si ve ca rdi ovas cu l a r ca re u n i t

services integrated with teams, providing support to those with ensure that it is, in fact, appropriate to transpose from one to
a diagnosis of an incurable, non-​malignant disease. Despite the other. Advance care planning and formulation of personal-
often posing quite different challenges to those with a diag- ized care plans are critical to ensuring that the delivery of SPC
nosis of cancer, much of the treatments and models of working in the ICCU environment is patient-​centred, which sits at the
used derive from this group. This needs to be evaluated to heart of best practice.

Further reading
Addington-​ Hall JM, McCarthy M. Regional study of care of the [No authors listed]. A controlled trial to improve care for seriously
dying: methods and sample characteristic. Palliative Med 1995;9:27–​35. ill hospitalized patients. The study to understand prognoses and
Center to Advance Palliative Care. Integrating palliative care practices preferences for outcomes and risks of treatments (SUPPORT). The
in the ICU. 2020. Available from:  M https://​www.capc.org/​toolkits/​ SUPPORT Principal Investigators. JAMA 1995;274:1591–​8.
integrating-​palliative-​care-​practices-​in-​the-​icu/​. Pattison N. End of life in critical care: an emphasis on care. Nurs Crit Care
Evans LR, Boyd EA, Malvar G, et  al. Surrogate decision-​ makers’ 2011;16:113–​15.
perspectives on discussing prognosis in the face of uncertainty. Am J Seymour JE. Critical Moments: Death and Dying in Intensive Care. Open
Respir Crit Care Med 2009;179:48–​53. University Press: Buckingham; 2001.
Nelson JE, Campbell M, Cortez TB, et al. Organizing an ICU palliative Spinello IM. End-​of-​life care in ICU: a practical guide. J Intensive Care
care initiative:  a technical assistance monograph from the IPAL-​ICU Med 2011;26:295–​303.
Project. 2010. Available from: M M http://​ipal.capc.org/​downloads/​ipal-​
icu-​organizing-​an-​icu-​palliative-​care-​initiative.pdf.

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 SECTION VIII

Arrhythmias

53 Atrial fibrillation and supraventricular arrhythmias  719

Demosthenes G Katritsis and A John Camm
54 Ventricular tachyarrhythmias  740
Paolo Della Bella, Dagmara Dilling, and Francesca Baratto
55 Pacemakers and ICDs: troubleshooting  755
Neasa Starr and Haran Burri
 CHAPTER 53

Atrial fibrillation
and supraventricular
arrhythmias
Demosthenes G Katritsis and A John Camm

Contents
Summary  719 Summary
Supraventricular tachycardias  719 This chapter deals with the acute management of supraventricular tachycardias, i.e.
Introduction  719
Epidemiology  719
atrial arrhythmias, including atrial fibrillation, atrioventricular nodal re-​entry, and
Clinical presentation  720 atrioventricular re-​entry due to accessory pathway(s). Epidemiology data, clin-
Physical examination  720 ical presentation, and 12-​lead electrocardiogram morphologies that can provide
Differential diagnosis  721
Narrow QRS (<120 ms) tachycardia  721 diagnostic clues for differential diagnosis between supraventricular tachycardias
Wide QRS (>120 ms) tachycardia  721 and ventricular arrhythmias are discussed, and specific appropriate therapy is
Acute therapy in the absence of an presented.
established diagnosis  723
Acute therapy of tachycardias with an
established diagnosis  724
Sinus tachycardias  724
Focal atrial tachycardia  724
Multifocal atrial tachycardia  724
Atrial flutter  724
Atrioventricular nodal re-​entrant
tachycardia  727
Supraventricular tachycardias
Non-​re-​entrant junctional
tachycardias  727
Introduction
Atrioventricular re-​entrant Traditionally, the term supraventricular tachycardia (SVT) has been used to describe
tachycardia  728
Atrial fibrillation  729 all kinds of tachycardias, apart from ventricular tachycardias and AF, and has there