Journal of

Clinical Medicine

Review
Extracorporeal Membrane Oxygenation (VA-ECMO) in
Management of Cardiogenic Shock
Klaudia J. Koziol 1 , Ameesh Isath 2 , Shiavax Rao 3 , Vasiliki Gregory 3 , Suguru Ohira 4 , Sean Van Diepen 5 ,
Roberto Lorusso 6 and Chayakrit Krittanawong 7, *

1 School of Medicine, New York Medical College and Westchester Medical Center, Valhalla, NY 10595, USA
2 Department of Cardiology, Westchester Medical Center, Valhalla, NY 10595, USA
3 Department of Medicine, MedStar Union Memorial Hospital, Baltimore, MD 21218, USA
4 Division of Cardiothoracic Surgery, New York Medical College and Westchester Medical Center,
Valhalla, NY 10595, USA
5 Division of Cardiology and Critical Care, University of Alberta, Edmonton, AB T6G 2R3, Canada
6 Cardio-Thoracic Surgery Department, Heart & Vascular Centre, Maastricht University Medical Centre,
Cardiovascular Research Institute Maastricht, 6202 AZ Maastricht, The Netherlands
7 Cardiology Division, NYU Langone Health and NYU School of Medicine, New York, NY 10016, USA
* Correspondence: [email protected]

Abstract: Cardiogenic shock is a critical condition of low cardiac output resulting in insufficient
systemic perfusion and end-organ dysfunction. Though significant advances have been achieved
in reperfusion therapy and mechanical circulatory support, cardiogenic shock continues to be a
life-threatening condition associated with a high rate of complications and excessively high patient
mortality, reported to be between 35% and 50%. Extracorporeal membrane oxygenation can provide
full cardiopulmonary support, has been increasingly used in the last two decades, and can be used to
restore systemic end-organ hypoperfusion. However, a paucity of randomized controlled trials in
combination with high complication and mortality rates suggest the need for more research to better
define its efficacy, safety, and optimal patient selection. In this review, we provide an updated review
on VA-ECMO, with an emphasis on its application in cardiogenic shock, including indications and
contraindications, expected hemodynamic and echocardiographic findings, recommendations for
Citation: Koziol, K.J.; Isath, A.; Rao, weaning, complications, and outcomes. Furthermore, specific emphasis will be devoted to the two
S.; Gregory, V.; Ohira, S.; Van Diepen, published randomized controlled trials recently presented in this setting.
S.; Lorusso, R.; Krittanawong, C.
Extracorporeal Membrane
Keywords: extracorporeal membrane oxygenation (ECMO); venoarterial; cardiogenic shock (CS);
Oxygenation (VA-ECMO) in
mechanical circulatory support (MCS); left ventricle (LV)
Management of Cardiogenic Shock. J.
Clin. Med. 2023, 12, 5576. https://
doi.org/10.3390/jcm12175576

Academic Editor: Sasa Rajsic 1. Introduction

Received: 27 June 2023 Cardiogenic shock (CS) is a life-threatening condition in which a low cardiac output
Revised: 13 August 2023 results in insufficient end-organ perfusion and frequently requires hemodynamic sup-
Accepted: 17 August 2023 port [1,2]. Hemodynamic criteria typically used to define CS in clinical trials have included
Published: 26 August 2023 systolic blood pressure < 90 mmHg for 30 min prior to the initiation of inotropes and vaso-
pressors, cardiac index ≤ 2.2 L/min/m2 , and elevated pulmonary capillary wedge pressure
≥15 mmHg [1,3]. End-organ hypoperfusion, including tissue ischemia, altered mental
status, oliguria, elevated arterial lactic acid levels, and multiorgan failure, are fundamental
Copyright: © 2023 by the authors.
features of CS and can also aid in establishing the diagnosis [2]. CS can occur in the setting
Licensee MDPI, Basel, Switzerland.
of an acute cardiac event or due to decompensation of underlying chronic cardiomyopa-
This article is an open access article
thy [4]. The leading cause, accounting for approximately 80% of cases, is acute myocardial
distributed under the terms and
infarction (AMI), and patients presenting with ST-segment elevation myocardial infarction
conditions of the Creative Commons
are at greatest risk [5,6]. Other common causes include chronic heart failure, fulminant
Attribution (CC BY) license (https://
myocarditis, valvular heart disease, high-risk pulmonary embolism, and hemodynamically
creativecommons.org/licenses/by/
4.0/).
unstable arrhythmias, and the incidence of these etiologies is increasing [2,7]. CS accounts

J. Clin. Med. 2023, 12, 5576. https://doi.org/10.3390/jcm12175576 https://www.mdpi.com/journal/jcm

 J. Clin. Med. 2023, 12, 5576 2 of 19

for an estimated 100,000 hospital admissions annually, and despite significant advances
achieved in reperfusion therapy and mechanical circulatory support (MCS), CS remains
associated with a high rate of complications and excessively high patient morbidity and
mortality [4,8].
Extracorporeal membrane oxygenation has been increasingly used in the last two
decades and has been shown to be an effective tool in the management of CS [2,9,10].
Venoarterial (VA) ECMO provides rapid, robust biventricular circulatory support and
ventilatory support with impaired cardiac output [3,11]. It allows time for diagnostic and
definitive therapeutic interventions and potential organ recovery, often serving as a bridge
to recovery, bridge to further decision-making, or bridge-to-destination therapy [1,10,12].
Although the utilization and understanding of VA-ECMO is increasing and the Extracor-
poreal Life Support Organization (ELSO) has proposed several general recommendations,
the scarcity of data from controlled trials for management, in combination with high
complication and mortality rates, suggest ongoing challenges and continued room for
improvement [4,10]. In this article, we provide an updated, comprehensive review on
VA-ECMO and evaluate the current literature for its application in CS.

2. VA-ECMO
VA-ECMO, also commonly referred to as extracorporeal life support (ECLS), is a form
of cardiopulmonary bypass that uses a centrifugal flow pump, membrane oxygenator, as
well as venous inflow and arterial outflow cannulas [3,11]. Additional ports may also be
added to the ECMO machinery to be used for ultrafiltration and hemodialysis [13]. In
ECMO, deoxygenated blood drained from a central vein is passed through the membrane
oxygenator, which is responsible for helping normalizing the pCO2, pO2, and pH, and
is then pumped back into the systemic circulation via the centrifugal pump. Cardiac
J. Clin. Med. 2023, 12, 5576 support can be up to 6–7 L of blood per minute [2,14]. The pump can be set to3 either
of 19
partially or completely unload the heart by adjusting flow and left ventricular unloading
configurations [15] (Figure 1).

VAECMO
Figure1.1.VA
Figure ECMOcentral
centralconfiguration.
configuration.

ItCannulation
is important may occur
to note thatcentrally
VA-ECMO or can
peripherally [11,16]. Appropriate
also be accomplished selection
via a novel ambula-of
cannula size is critical to reduce the risk of vascular injury and avoid negative
tory approach. In ambulatory ECMO, cannulation in the groin is avoided and sufficient inflow and
high outflow pressures: 18–28 Fr venous and 15–19 Fr arterial cannulas are most
oxygen is provided to allow patients to stand, walk, and participate in active physiother- commonly
apy and thus help prevent deconditioning [21,22]. Although no studies have been com-
pleted to date to assess its safety and efficacy in patients with CS, there have been small
studies showing safety and feasibility in carefully selected patients, and several case re-
ports have shown success when used as a bridge to cardiac transplant [23,24]. Most of the
 J. Clin. Med. 2023, 12, 5576 3 of 19

used [2]. In central cannulation, the venous inflow cannula is placed directly into the right
atrium and arterial outflow directly into the ascending aorta, which allows for physiologi-
cal anterograde circulation [16,17]. However, given the invasive nature of the procedure,
central cannulation is performed in the operating room and most frequently occurs in
patients who are unable to be weaned off cardiopulmonary bypass after cardiotomy [11,16].
Peripheral cannulation is typically performed with a percutaneous approach or surgical
grafting of the peripheral vasculature [18]. In the femorofemoral configuration, the inflow
and outflow sites are the femoral vein and artery, respectively, therefore resulting in perfu-
sion in the retrograde direction [16]. Peripheral cannulation may also involve the arteries of
the upper extremity—the axillary, subclavian, or carotid arteries—allowing for anterograde
perfusion, improved cerebral perfusion, and increased patient mobility [11,16]. Addition-
ally, unlike with central cannulation, peripheral cannulation via the femoral approach
can be performed safely outside of the operating room, including in the catheterization
J. Clin. Med. 2023, 12, 5576 laboratory, at the bedside in the ED or ICU, or even remotely “in the field” during4 ofpatient
19
stabilization and transfer [10,19,20] (Figure 2).

Figure 2. VA ECMO peripheral configuration.

Figure 2. VA ECMO peripheral configuration.
It is important to note that VA-ECMO can also be accomplished via a novel ambulatory
3. Indications
approach. In and Contraindications
ambulatory of VA-ECMO
ECMO, cannulation in the groin is avoided and sufficient oxygen
isPatient
provided to allow patients to stand, walk, and
selection is an important, though clinicallyparticipate in active
challenging physiotherapy
component of VA-and
ECMO use that aims to identify patients with the highest chance of recovery or candidacy to
thus help prevent deconditioning [21,22]. Although no studies have been completed
for destination therapy [10,11,34]. ELSO has suggested guidelines for indications and con-
traindications; however, the decision to initiate VA-ECMO should be individualized
[4,34]. Comorbidities, patient-specific risk factors, weaning strategies, and overall prog-
nosis need to be considered, as patients with a low likelihood of recovery are unlikely to
benefit from the invasive method and may be best managed with a conservative approach
J. Clin. Med. 2023, 12, 5576 4 of 19

date to assess its safety and efficacy in patients with CS, there have been small studies
showing safety and feasibility in carefully selected patients, and several case reports have
shown success when used as a bridge to cardiac transplant [23,24]. Most of the current
understanding and experience with ambulatory ECMO has been in patients in respiratory
failure on venovenous (VV) ECMO awaiting lung transplant [21,25]. However, given that
ambulatory ECMO is associated with minimized deconditioning, improved rates of return
to independent functioning, decreased rates of delirium, and shorter ICU and hospital
lengths of stay, it may become more commonplace in the treatment of patients with CS in
the future [23,26].
Once ECMO is initiated, frequent monitoring of hemodynamics and assessment
of arterial and venous blood gases, as well as gas samples from the VA-ECMO circuit,
are essential to ensure that the cardiac output and oxygenation can promote myocardial
recovery and help restore renal, hepatic, and pulmonary function, acid–base balance,
coronary perfusion, and neurological status [4,10,27]. It is generally recommended that
the flow target be in the range of 4–6 L/min, mean arterial pressure (MAP) target above
60 mmHg, arterial oxygen saturation target above 90%, the venous saturation target above
60%, although there is currently limited literature and lack of standardized guidelines
regarding optimal titration and management [27–31]. Nonetheless, the utilization of VA-
ECMO for CS has been rapidly increasing over the last two decades in the ELSO registry.
With use in over 15,000 adult patients—an estimated increase of over 1000%—analysis of
these cases may provide sufficient data to propose specific standardized guidelines for
optimal patient management in the near future [11,32,33].

3. Indications and Contraindications of VA-ECMO

Patient selection is an important, though clinically challenging component of VA-
ECMO use that aims to identify patients with the highest chance of recovery or candidacy
for destination therapy [10,11,34]. ELSO has suggested guidelines for indications and con-
traindications; however, the decision to initiate VA-ECMO should be individualized [4,34].
Comorbidities, patient-specific risk factors, weaning strategies, and overall prognosis
need to be considered, as patients with a low likelihood of recovery are unlikely to ben-
efit from the invasive method and may be best managed with a conservative approach
(Table 1) [1,4,10].
Indications for VA-ECMO include CS refractory to conventional medical and device-
based therapy, most commonly in the setting of acute coronary syndrome, acute on chronic
decompensated heart failure, fulminant myocarditis, and unsuccessful cardiopulmonary
bypass weaning following cardiotomy [10,11,31]. Less commonly seen, but increasing in
incidence is the use in CS due to pulmonary hypertension with subsequent cor pulmonale
and due to PE with hemodynamic compromise [4]. VA-ECMO can also be used in cardiac
arrest through extracorporeal cardiopulmonary resuscitation (ECPR), as well as in cases
where temporary mechanical support is needed as a bridge prior to left ventricular assist
device (LVAD) placement or cardiac transplant [2,4]. It has been reported that VA-ECMO
can be an effective treatment for ventricular septal rupture and severe primary graft dys-
function after cardiac transplantation [35–38]. In addition, there have been case reports
describing the use of VA-ECMO in the management of COVID-19-associated acute my-
ocardial injury complicated by cardiogenic shock, though additional studies are needed in
order to accurately assess its safety and in this subset of patients [39,40]. Lastly, the use of
VA-ECMO in patients with sepsis remains controversial, though it may be appropriate in
carefully selected patients with refractory septic shock [41].
J. Clin. Med. 2023, 12, 5576 5 of 19

Table 1. Common indications, contraindications, and considerations for patient selection in VA-ECMO.

Patient Selection
Patient-Specific Risk Factors, Potential Benefit, Patient Prognosis, Comorbidities, and Weaning Approaches Need to Be
Considered in Each Individual Patient Prior to VA-ECMO Initiation
Indications Contraindications
Cardiogenic Shock Refractory to Conventional Medical and Patients with an Overall Poor Prognosis and at High Risk of
Device-Based Therapy Morbidity and Mortality
Absolute
• Cardiac disease that is unlikely to recover
• Poor life expectancy, typically less than one year
• Preexisting conditions that have an expected mortality rate
greater than 95%
• Acute or chronic decompensated HF • Preexisting conditions that are incompatible with ECMO
• Fulminant myocarditis weaning and recovery
• Unsuccessful post-cardiotomy cardiopulmonary • Neurological injury
bypass weaning • Disseminated malignancy
• Pulmonary hypertension with subsequent cor pulmonale • Irreversible multiorgan failure
• PE with hemodynamic compromise
• Unwitnessed or prolonged cardiac arrest
• Cardiac arrest • Incompatible patient goals of care, including
• Ventricular septal rupture and severe primary graft DNR/DNI orders
dysfunction after cardiac transplantation • Significant aortic insufficiency
• COVID-19-associated acute myocardial injury • Contraindication to anticoagulation
• Additional cases where temporary mechanical support is
needed to bridge to LVAD or cardiac transplant Relative
• Advanced age
• Cognitive impairment
• Medical comorbidities
• Poor compliance
• Inadequate social support

Overall, ECMO should not be used as therapy in patients with cardiac disease that is
unlikely to recover, as well as in patients with a poor life expectancy, typically less than one
year, and in patients with preexisting conditions that have a very high mortality rate and
that are incompatible with ECMO weaning and recovery, most notably severe neurological
injury, disseminated malignancy, and irreversible multiorgan failure [2,17]. Additional
absolute contraindications include unwitnessed or prolonged cardiac arrest as well as
incompatible patient goals of care, such as “do not resuscitate” (DNR) orders [1,2]. VA-
ECMO should also be avoided in patients with severe aortic insufficiency, as the increase in
afterload puts the patients at risk of further hemodynamic compromise [10]. It may also be
contraindicated in patients who cannot be anticoagulated, as therapeutic anticoagulation
is currently standard practice with VA-ECMO [2,10]. Furthermore, for the femorofemoral
approach specifically, the presence of a vena cava filter and severe aortoiliac disease are
additional contraindications. Advanced age, cognitive impairment, medical comorbidities,
poor compliance, and inadequate social support are additional relative contraindications
that need to be considered [31,42]. Although age alone is not a contraindication to VA-
ECMO, studies have consistently reported that advanced age is an independent predictor
of in-hospital mortality [42,43]. To aid physicians in selecting appropriate patients and
identifying those at risk of poor outcomes, several clinical indices—including the Survival
After VA-ECMO (SAVE) score and the new simplified cardiac ECMO score—have been
proposed to assess the likelihood of in-hospital mortality and predict recovery and hospital
discharge [11,44,45]. Although the scores may prove to be beneficial, because they have
been validated in people who have been put on VA-ECMO, their drawback is that they
come with an inherent selection bias. In all cases, the risk factors, potential benefit, patient
prognosis, comorbidities, and weaning approaches need to be considered in each individual
patient prior to VA-ECMO initiation [4,17].
J. Clin. Med. 2023, 12, 5576 6 of 19

4. Hemodynamic Findings
Cardiogenic shock is the most severe form of LV failure, in which systolic or diastolic
dysfunction leads to diminished cardiac output (CO), most often due to a decrease in
contractility and a subsequent severe reduction in LVEF [11,46–48]. Reduced CO, low
cardiac index, typically below 2.2 L/min/m2 , and a profound fall in blood pressure lead to
low systemic and coronary perfusion, triggering reflex-mediated increases in heart rate and
systemic vascular resistance (SVR) [11,49]. In the classic paradigm of cardiogenic shock, the
compensatory sympathetic stimulation contributes to worsening cardiac dysfunction, as the
increase in heart rate and contractility increases myocardial oxygen demand, and systemic
vasoconstriction and increase in SVR lead to an increase in the functional circulating blood
volume, up to 50% of total blood volume, elevating the biventricular afterload and LV
end diastolic pressure [46,50]. Volume overload is further exacerbated by an augmented
preload, due to renal salt and fluid retention through activation of the renin–angiotensin–
aldosterone system [50]. Ultimately, the resulting hypotension, tachycardia, and decreased
coronary perfusion in the setting of increased myocardial oxygen demand exacerbate
myocardial ischemia and dysfunction, further deteriorate myocardial contractility, and
lead to a vicious cycle of declining CO, SV, and BP and increasing LV volume, resulting in
progressive end-organ hypoperfusion, and if not resolved, eventual death [46,49,50].
The hemodynamic effects of a mixed shock state also need to be considered, as
approximately 20% of patients admitted to the cardiac intensive care unit have this form
of shock [51]. Typically, the mixed state is a combination of cardiogenic and distributive
shock, which may occur in the setting of systemic inflammation or sepsis, and results in
pathological vasodilation in the setting of reduced cardiac output. Acute cardiac injury
can trigger capillary leakage and the release of inflammatory mediators, which can lead to
systemic vasodilation, decreased SVR, and exacerbate hypotension [5]. It is estimated that
almost a fifth of patients presenting with an AMI have a vasodilatory shock component due
to myonecrosis induced inflammatory changes [5]. The resulting tissue underperfusion
leads to the formation of lactic acid, additionally contributing to cardiac dysfunction [11,47].
Nonetheless, despite certain differences in the hemodynamics, in both cases of cardiogenic
and mixed shock, low cardiac output and decreased coronary perfusion lead to progressive
cardiac dysfunction, and if uncorrected, end in death.
The specific hemodynamic effects of VA-ECMO on the heart and cardiovascular sys-
tem in CS are still being analyzed. It is known that VA-ECMO reduces central venous
pressure while increasing MAP and the arteriovenous pressure gradient, thereby increasing
systemic perfusion [2]. One theory suggests that VA-ECMO reduces right ventricular
(RV) preload, RV blood flow into the pulmonary artery, and peripheral venous congestion,
which results in a decrease in LV end diastolic volume and pressure and promotes hemo-
dynamic stabilization [2,6,11,52]. However, another proposes that VA-ECMO increases
cardiac afterload, which subsequently results in a rise in LVEDP, left atrial pressure, and
pulmonary capillary wedge pressure, contributing to worsening of LV function and pul-
monary edema [4,6,14,53]. It has been estimated that up to 30% of patients placed on
VA-ECMO will exhibit pulmonary edema [17,53–55]. Furthermore, especially in patients
with no native cardiac ejection or those with severe LV dysfunction placed on high flow
rates, the significant increase in afterload may result in insufficient opening of the aortic
valve (AV), LV blood accumulation, and LV distention, further contributing to worsening
of pulmonary edema [11,18,52]. Additionally, the increased afterload and LV distention in
the setting of elevated LV filling pressures decreases the transcoronary perfusion gradient,
leading to impaired myocardial perfusion and worsening dysfunction [11].
The major disadvantage with peripheral VA-ECMO is that it lacks complete LV “un-
loading” capabilities—it does not lessen the work of the LV—therefore, optimization of
preload, afterload, and contractility may be needed to maintain forward flow through the
LV and prevent pulmonary edema and decreased LV function [6,17,18]. When medical
therapy with diuretics and inotropes are insufficient, mechanical means, or LV “venting”
strategies, are often used [3,18].
J. Clin. Med. 2023, 12, 5576 7 of 19

According to the ELSO, of the 12,734 adult patients who received VA-ECMO between
2010 and 2019, 3399 patients required mechanical unloading, 82.9% with the intra-aortic
balloon pump (IABP) and 17.1% with transvalvular percutaneous ventricular assist de-
vice (pVAD), such as the Impella [56]. The IABP, a percutaneous device placed into the
descending aorta, can be an effective tool for LV unloading due to its ability to improve
the myocardial oxygen supply-to-demand ratio. It increases the coronary and myocardial
perfusion while decreasing the left ventricular afterload during systole and thus reduces the
myocardial work [57,58]. The most recent systematic meta-analysis by Zeng et al. examin-
ing nine manuscripts and over 2500 patients found a significant in-hospital survival benefit
in CS patients on VA-ECMO in combination with IABP compared with VA-ECMO alone,
with comparable rates of adverse bleeding and infection [59]. The pVAD, a catheter-based
miniaturized ventricular assist device that is placed across the aortic valve and into the LV,
works to unload the ventricle by maintaining a systemic circulation via actively pumping
blood from the LV into the ascending aorta [60,61]. Fiorelli et al. conducted a meta-analysis
examining outcomes in VA-ECMO in combination with the Impella (ECPELLA) vs. VA-
ECMO alone in 972 CS patient across five studies. They found that LV unloading with
ECPELLA was associated with lower mortality rates—56.1% compared to 63.7% in the
control [54,57,58,62].
Less commonly utilized means of unloading the LV include atrial septostomy, left
atrial or pulmonary artery VA-ECMO, and an LV direct surgical vent [3,18,62]. Surgical
or percutaneous balloon atrial septostomy creates a left-to-right shunt, which provides an
immediate reduction in preload and afterload and decreases ventricular workload [63].
A multicenter registry of 223 patients who underwent atrial septostomy for VA-ECMO
unloading showed that septostomy was associated with significant complications, includ-
ing arrhythmia and tamponade, and had an overall hospital mortality rate of 46% [64].
Although there are no randomized or systematic trials examining efficacy and mortality
of LA and pulmonary artery VA-ECMO, small, single-center cases have reported they
are effective methods for LV unloading and can be utilized for successful weaning from
VA-ECMO [65–67]. Partial ECMO flow is an additional venting strategy to prevent LV
distention, while allowing ejection from the LV [68–70].
Although multiple studies have reported lower mortality and higher rates of weaning
in adult patients with CS treated with VA-ECMO in combination with LV mechanical
unloading, there are currently no randomized trials comparing the various venting strate-
gies [71,72]. Early detection of LV distention and intervention is important. Diagnostic
modalities to evaluate for LV distention include X-ray, arterial line wave form, pulmonary
artery catheter, and monitoring of clinical symptoms, including bloody secretions.
A further hemodynamic concern is the development of “north–south syndrome,”
also known as “harlequin syndrome,” which has been reported to occur in up to 8.8%
of patients on VA-ECMO [73,74]. This rare phenomenon occurs in patients with femoral
artery cannulation, where well-oxygenated blood from the VA-ECMO circuit is returned
in a retrograde fashion up the aorta and mixes with poorly oxygenated blood from the
native circulation, often in patients with pulmonary compromise in which gas exchange
is severely impaired [74,75]. As the cardiac function improves or supplemental left-sided
mechanical support devices for ventricular unloading are introduced, the outflow from the
native LV can overcome the retrograde flow from the circuit and lead to selective hypoxia,
with poorly oxygenated blood, often below 90% saturation, perfusing the brain, coronary
arteries, and upper extremities [10]. In this condition, switching to central cannulation or
peripheral cannulation from the upper extremities is an option. Though there are currently
no standardized criteria to diagnose harlequin syndrome, detection of an arterial oxygen
saturation gradient higher than 15% between right and left radial arteries is suggestive of
the syndrome, and opting to switch from femoral cannulation to central or upper extremity
cannulation may be beneficial [76].
The hemodynamic benefits of VA-ECMO are irrespective of intrinsic LV function and
have an advantage over IABP and Impella devices alone by functioning regardless of RV
J. Clin. Med. 2023, 12, 5576 8 of 19

function due to bypassing the pulmonary circuit for oxygenation [14]. Thus, unlike IABP
or Impella support alone, VA-ECMO may be used in refractory biventricular failure [2].
Ultimately, despite recognized benefits of the use of VA-ECMO in patients with cardiogenic
shock, the hemodynamic responses of this group of patients are variable and complex, and
critical gaps remain in our understanding.

5. Echocardiographic Findings
Echocardiography plays an important role in VA-ECMO management. Although no
specific guidelines currently exist, assessment with the imaging modality provides anatom-
ical and diagnostic information that can aid in patient selection, facilitates safe cannulation
and weaning, and serves as a standardized tool to monitor patients and evaluate for com-
plications [52,77]. Comprehensive echocardiographic evaluation, either by transthoracic
echocardiography [78] or transesophageal echocardiography [78], should be completed in
all VA-ECMO candidates, though the assessment may need to be omitted in patients with
hemodynamic instability in urgent need of MCS cannulation [53]. Echocardiography is
able to establish baseline anatomy, including LV size and wall thickness, and objective mea-
surements of systolic and diastolic function, including LVEF, which can serve as a reference
in assessing myocardial recovery. Furthermore, TTE/TEE provides a thorough assessment
of valvular morphology and competence and can recognize underlying structural defects
or the presence of mechanical valves [52,53]. Insufficiency of the aortic and mitral valves
especially need to be identified and quantified, as initiation of VA-ECMO may worsen the
degree of preexisting regurgitation due to the significant increase in afterload [52]. Lastly,
an echocardiograph may be able to determine the precise etiology of CS or identify any
potential contraindications to VA-ECMO initiation [53].
Once it is determined that VA-ECMO is indicated, cannulation can be performed
under fluoroscopy, TTE, or TEE guidance to allow for direct visualization of the guidewire,
ensure appropriate cannula placement, and promptly identify complications during in-
sertion and positioning, including life-threatening pericardial effusion, aortic dissection,
and stroke or other embolic event [52,53]. These modalities may not be available during
ECPR due to ongoing CPR, which makes cannulation more challenging. After VA-ECMO is
initiated, serial evaluations with daily TEE are the most reliable method to ensure sufficient
emptying of the ventricles and monitor left ventricular function, distension, and degree
of unloading [17,52]. With increasing VA-ECMO flow rates, the aortic pressure increases,
which leads to increased LV volume and distension. On TEE, this is characterized by a
dilated and impaired LV, significant mitral regurgitation during systole and diastole, and in
severe cases, failure of aortic valve (AV) opening [14,52,53]. A closed AV increases the risk
of thrombus formation due to blood stasis, which on TEE is depicted as an intracavitary
spontaneous echo contrast [53]. Intracardiac thrombi account for approximately 5% of all
VA ECMO complications and may be intracavitary, most often found in the left-sided heart
chambers, or along the aortic root in cases where the LV is not vented or has significantly
diminished LV ejection [10,18,79]. Though they have potential to embolize and increase the
risk of cerebral, renal, and mesenteric ischemia, which can significantly contribute to in-
creased mortality, echocardiography has been reported to be an effective tool in prevention
and diagnosis [53,80]. Monitoring with TEE can also aid in detecting ECMO dysfunction
and complications, including cannula displacement, cardiac tamponade, vascular obstruc-
tion, or cannula-associated thrombi, including a PE [77]. Lastly, echocardiography can
facilitate clinical decision-making regarding circulatory support weaning, as it is able to
track LV function from baseline through various VA-ECMO flow rates, and thus helps in
assessing cardiac recovery [77]. Improvement in LVEF, absence of LV dilation, increased
AV opening, and left ventricular outflow tract velocity time integral—a measure of car-
diac systolic function and cardiac output—above 10 cm on TEE are all indicators of LVEF
improvement [52,81].
J. Clin. Med. 2023, 12, 5576 9 of 19

6. Complications
VA-ECMO is a promising form of MCS in patients with CS; however, utilization, must
be carefully weighed against potential complications, many of which can significantly
increase the risk of morbidity and mortality [4,10].
Because therapeutic anticoagulation is standard practice with VA-ECMO, bleeding is
the most commonly reported adverse event, reportedly occurring in 30–79% of patients
with VA-ECMO use [4,29,82–84]. Bleeding is frequently reported at cannulation sites; how-
ever, VA-ECMO may also lead to systemic hemorrhage, most commonly in the upper and
lower gastrointestinal tract, thorax, and pericardium [2,10]. The ECMO circuit can also con-
tribute to hemolysis and thrombocytopenia, increases the risk of disseminated intravascular
coagulation and heparin-induced thrombocytopenia, and given the disproportionately
high shear stress it causes within the cardiovascular system, can result in acquired von
Willebrand factor deficiency. An increased number of units transfused is associated with a
higher mortality rate [10].
Risk of hemorrhagic complications must be balanced with risk of thrombosis, as
thrombotic complications are also regularly encountered, occurring in up to 22% of pa-
tients [4,29,83,85–87]. A prothrombotic inflammatory environment can result from blood
exposure to the VA-ECMO artificial surfaces as well as intraventricular or aortic root
blood stagnation, and may result in both thromboembolic events in the patient and VA-
ECMO pump malfunction [11]. There is currently no clear consensus on anticoagulation
strategy and management differs significantly between patients, though current ELSO
guidelines for anticoagulation during ECMO recommend an initial heparin infusion rate
of 7.5–20.0 units/kg/h [88,89]. Furthermore, the conventional recommendation, based
largely on expert opinion, is regular monitoring of coagulation studies and using un-
fractionated heparin to target an activated clotting time of 180 to 220 s, a partial throm-
boplastin time (aPPT) target in the 60–80 range, and anti-Xa level in the 0.3–0.7 IU/mL
range [2,4,10,11,89–91]. Although anticoagulation has been thought to be standard prac-
tice, a recent report demonstrated the safety and efficacy of VA-ECMO support without
anticoagulation. Patients receiving no anticoagulation had comparable mortality rates and
lower overall complication rates—including bleeding—compared to their anticoagulated
counterparts [68,92]. Overall, preventing bleeding and thrombosis is challenging as it
requires finding the optimal balance between anticoagulation and hemostasis. Thoughtful
review of patient medications and medical history, meticulous surgical or cannulation
technique, close monitoring of patient clinical presentation, medication, and lab work,
as well as an interdisciplinary approach, including an expert in hemostasis, can aid in
preventing hemorrhagic or coagulant complications [68,93,94].
Limb ischemia is also a known complication of VA-ECMO, and its associated mortality
rate is reported to be as high as 60% [10,11,34]. Percutaneous or surgical placement of
a distal perfusion cannula is performed to provide antegrade femoral blood flow to the
cannulated leg and lower the risk of ischemic limb injury, though it is still reported to
occur in 13–35% of patients with peripheral VA-ECMO [4,11,17,29]. Some centers advocate
aggressive placement of a distal perfusion catheter, while other centers use a selective
approach with careful monitoring of limb ischemia by using either a somatic oximetry
sensor or near-infrared spectroscopy (NIRS) [54,95–99]. It is also important to keep in mind
that limb ischemia can occur as a result of severe cardiogenic shock, vasoconstriction, or
hypothermia. To rule out acute limb ischemia, physical examination, Doppler pulse check,
and ultrasound are paramount. Furthermore, the frequency of compartment syndrome
and need for fasciotomy and lower extremity amputation, respectively, is reported to be
7.3–14.5% and 2.3–9.3% [2]. Prevention of vascular complications related to VA-ECMO is
crucial, as these adverse events are significantly associated with survival [98].
Acute kidney injury (AKI) is another frequently encountered complication. The
incidence is estimated to be between 43–85% and typically occurs within 48 h of VA-ECMO
cannulation [34,100,101]. The pathophysiology of ECMO-associated AKI is complex and
multifactorial, though the hemodynamic changes that occur with vasopressors and inotrope
J. Clin. Med. 2023, 12, 5576 10 of 19

use, as well as with ECMO cannulation, and the subsequent changes in renal blood flow
resulting in ischemia and reperfusion, are thought to play a major role [100–102]. It has been
suggested that severity of kidney dysfunction at ECMO initiation is a strong predictor of
long-term survival, as single-center studies have shown that patients with AKI who require
renal replacement therapy had an 80% mortality rate compared with a mortality rate of
20% in non-AKI patients [11,84,100,102]. However, it is important to note that because
AKI and subsequent renal failure is often one of the early signs of multiorgan failure and
death, it is unclear whether AKI and renal failure directly increase the risk of mortality
or whether they simply correspond to the severity of the critical illness [34,54,101,103].
Continuous renal replacement therapy (CRRT) can be undertaken through an integrated
approach within the VA-ECMO circuit or via a parallel system with separate VA-ECMO
and CRRT circuits [54,101,103]. However, although studies have reported that CRRT is
safe and feasible in patients with VA-ECMO, data regarding renal recovery and overall
outcomes continue to be limited [101].
Other common complications of VA-ECMO include infections, most commonly ac-
cessed site, bloodstream, and lower respiratory and urinary tract infections, which are
reported to occur in up to 20% of patients and can be prevented by utilizing strict aseptic
technique. Additionally, patients can experience neurological complications, such as acute
ischemic stroke, intracerebral hemorrhage, seizure, and anoxic brain injury; These can be
mitigated with an improved understanding of potential neurological complications that
can be expected with VA-ECMO that can lead to morbidity and mortality, as well as with
regular and multimodal monitoring, in order to arrive at an early diagnosis and initiate
timely treatment [10,68,104–106].

7. Weaning
VA-ECMO serves as a window during which the decision to proceed with durable
LVAD or cardiac transplantation is performed or reversible causes of cardiac failure can
be treated [31]. Weaning from support is considered once there are signs of myocardial
recovery: the initial condition requiring VA-ECMO has resolved or improved, and va-
soactive medications are significantly reduced or no longer needed [2,53]. The weaning
process and evaluation of improvement in cardiac function can be supported with serial
echocardiography, both TTE and hemodynamic TEE, and invasive hemodynamic monitor-
ing [10,52,107,108]. Nonetheless, determining the optimal weaning strategy is challenging,
as there are currently no randomized clinical trials and physicians heavily rely on expert
opinion and their own clinical decision-making in order to balance the risks of prema-
ture weaning, including cardiac compromise from high-dose inotropes, hemodynamic
instability, or need for emergent recannulation, with the risks of delayed weaning, most
notably prolonging exposure to VA-ECMO and its associated complications and high risk
of morbidity and mortality [52,107,109]. The most recent guidelines, proposed in 2022 by
the American Heart Association (AHA), recommend daily assessment of cardiac function,
with the goal of withdrawing VA-ECMO as soon as patients show improvement in the
underlying cause of their CS, are intravascularly euvolemic, and are hemodynamically
stable with minimal intravenous support. A stepwise decrease in support flow is recom-
mended, typically a reduction in increments of 0.5 to 1 L/min until the level of 1.5 to
2.0 L/min, at which point decannulation can occur. The standard frequency of the stepwise
flow reduction is every 2 to 4 h; however, weaning may occur more rapidly, every 5 to
15 min, in a small subset of patients, including patients with CS due to AMI following
revascularization and LVEF recovery and patients with CS due to valvular lesions that have
been corrected [78].
Several other weaning algorithms have been proposed, though the basis of each
strategy includes weaning trials, in which the performance of the ventricles and patient
hemodynamic response is assessed throughout an incremental decrease in support in
order to determine whether VA-ECMO can safely be terminated [2,107]. There are several
considerations that need to be addressed prior to the initiation of the weaning process.
J. Clin. Med. 2023, 12, 5576 11 of 19

Initially, the prospective recovery of the underlying cause of CS needs to be evaluated. Next,
clinical, hemodynamic, and echocardiographic data should be consistent with myocardial
recovery significant enough to ensure sufficient end-organ perfusion and meet the metabolic
demands of the body [10]. Any metabolic disturbances or end-organ dysfunction should be
recovered or supported by other means [10,54]. Furthermore, pulmonary function should
not be severely impaired; pulmonary oxygenation with a PaO2 /FiO2 greater than 200 on
0.21 FiO2 is recommended, and transition to VV-ECMO should be considered in patients
with PaO2 /FiO2 less than 100 [52,54,109]. Lastly, the patient should have recovered a
pulsatile arterial waveform for at least 24 h and be hemodynamically stable [109,110]. The
baseline mean arterial pressure (MAP) should be greater than 60 mmHg in the absence
of or with low doses of catecholamines and vasopressors, though data suggest that better
outcomes are linked with lower levels of pharmacological hemodynamic support at time
of weaning [10,110]. It is common to use another form of temporary MCS when VA-ECMO
weaning is attempted, for example, percutaneous devices such as IABP or the Impella, and
many patients are weaned from VA-ECMO with these devices still in place.
Once these criteria are met and patients are deemed ready for weaning, an algo-
rithmic approach is recommended for incrementally decreasing the bedside VA-ECMO
blood flow rate, exposing the patient to an increased RV preload and decreased LV after-
load [15]. In patients with CS, VA-ECMO flow support is typically run at approximately
3 to 4 L/min, although higher rates may be necessary [11]. With weaning, the flow rate
is gradually decreased to a fraction of its baseline value, and then to a minimum of 1 to
1.5 L/min [11,17,53]. Throughout this process, cardiac function is assessed using hemody-
namic and echocardiographic data to determine whether the degree of myocardial recovery
will allow for complete removal of VA-ECMO. LVEF above 30%, maintenance of mean
arterial pressure, and left ventricular ejection above the ECMO flow rate are all indicative
of tolerating VA-ECMO weaning [17]. In these patients, a complete wean is scheduled in
an operating room to allow for controlled decannulation or expedited recannulation and
MCS initiation if removal of VA-ECMO is not tolerated [10].
The precise criteria to define successful weaning have not been established, though
VA-ECMO device removal with no further necessity for MCS in the following 30 days
for refractory CS is generally accepted [109]. Successful weaning from VA-ECMO is
multifaceted and difficult to predict [109,111]. The reported rates of successful weaning
in the literature range from 31% to 76% [2,112]. For patients who cannot be weaned off
ECMO, LVAD, cardiac transplantation, or end-of-life care need to be considered [10,17].

8. ECMO Outcomes in Cardiogenic Shock

Based on retrospective and observational studies, morbidity and mortality remain
exceptionally high in patients requiring VA-ECMO, and outcomes are largely dependent on
the underlying indication, patient comorbidities, severity of organ dysfunction at initiation,
and complications or adverse events during MCS [20,109]. The reported overall survival to
hospital discharge has been reported to be between 29% and 63.1% [11,83,84,113–115]. A
systematic review of 24 studies and nearly 2000 patients found the survival rate at discharge
to be 30.8% [116]. It should be noted that between 20% and 65% of patients successfully
weaned from VA-ECMO support do not ultimately survive to hospital discharge, mainly
due to concomitant neurological injuries and multisystem organ failure, and the overall
in-hospital mortality rate in patients requiring VA-ECMO for CS is estimated to be as high
as 60% [8,11,109,112,114,117]. The one-year survival rate following successful VA-ECMO
treatment was reported to be 73.7% in patients with ischemic heart disease and 75% in their
non-ischemic heart disease counterparts [12]. Various predictors of in-hospital mortality
have been described, and several variables have been linked with an increased risk of
patient mortality [34]. Advanced age, diabetes, obesity, poor LVEF, renal insufficiency,
elevated lactate, metabolic acidosis, elevated CK-MB at admission, greater use of inotropes
and vasopressors, and ECMO insertion outside the operating room have all been linked
with poorer outcomes [20,68,114,118,119].
J. Clin. Med. 2023, 12, 5576 12 of 19

To date, there have been two randomized controlled trials (RCT) examining VA-
ECMO use in patients in CS: the Extracorporeal Membrane Oxygenation in the Therapy
of Cardiogenic Shock (ECMO-CS trial) and the Venoarterial Extracorporeal Membrane
Oxygenation or Standard Care in Patients with Cardiogenic Shock Complicating Acute
Myocardial Infarction (EURO SHOCK trial).
The ECMO-CS trial examined the effectiveness of VA-ECMO in patients with rapidly
deteriorating or severe cardiogenic shock. Specifically, the study compared outcomes in
patients randomly assigned to immediately start VA-ECMO with those who were assigned
to start with conservative management (CM) with delayed VA-ECMO initiation in the
case of hemodynamic worsening. Of the patients in the CM group, 39% were ultimately
started on VA-ECMO, an average of 1.9 days following randomization. The incidence of
adverse events (61.3% in VA-ECMO; 61.0% in CM), as well as all-cause mortality at 30 days
(50.0% in VA-ECMO, 47.5% in CM), was similar between the two groups, suggesting that
immediate initiation of VA-ECMO in rapidly progressing or severe cardiogenic shock did
not improve outcomes [120].
The EUROSHOCK trial was a prospective, multicenter RCT that examined outcomes
of VA-ECMO vs. standard therapy in 35 patients with CS 30 min following percutaneous
coronary intervention, of which 17 were randomized to the VA-ECMO group and 18 to
standard therapy. The all-cause mortality at 30 days was 43.8% in the VA-ECMO group
compared with 61.1% in the control, and at one year 51.8% and 81.5%, respectively. The
rate of adverse events was found to be significantly higher in the VA-ECMO group: 21.4%
of patients experienced vascular complications and 35.7% had bleeding complications,
compared with 0% and 5.6% in the standard therapy group. Although the survival out-
comes suggest a benefit in using VA-ECMO, given the limited sample size and risk of
complications, definitive recommendations cannot be made based on this trial [121].
It is also important to note that the addition of VA-ECMO to CPR for cardiac arrest is
reported to significantly improve patient outcomes [122,123]. Although RCTs are lacking,
especially in the setting of CS, observational studies report an overall in hospital and out of
hospital survival rate between 15% and 50% with ECPR compared with 10–20% in conven-
tional CPR [122,124,125]. Chen et al. reported 34.1% overall survival to hospital discharge
in patients with cardiac arrest undergoing ECPR [122,126]. Favorable neurological out-
comes have also been reported with ECPR [125]. In an RCT by Belohlavek et al. examining
256 participants, it was found that 31.5% of patients receiving ECPR survived to 180 days
with good neurologic outcomes compared with 22.0% in the standard CPR group [127].
Shin et al. reported a higher 2-year survival with minimal functional deficits in ECPR
compared to traditional CPR in a study of 321 patients [122,128]. Lastly, a recent study by
Tonna et al. examining over 1075 patients from over 200 centers identified six variables
associated with in-hospital mortality—age, time of day, presenting rhythm, history of renal
insufficiency, patient type, and cardiac arrest duration—and developed the RESCUE-IHCA
score for bedside mortality prediction, which may be useful in identifying good candidates
for VA-ECMO and ECPR [129].
In sum, despite the significant risk of mortality and potentially fatal complications,
VA-ECMO offers a substantial chance of survival for patients in cardiogenic shock with
an otherwise particularly poor prognosis [118]. Many questions remain regarding best
utilization practices, though experts have traditionally agreed that prompt recognition of
clinical deterioration and initiation of VA-ECMO in appropriate candidates allows for the
greatest chance of survival and positive outcomes [54,130].

9. Conclusions
VA-ECMO provides rapid, complete biventricular circulatory support in addition
to simultaneous gas exchange to allow time for diagnostic and therapeutic interventions
and potential organ recovery, often serving as a bridge to recovery, bridge to further
decision-making, or bridge to cardiac transplantation, and offers a chance of survival for
patients in cardiogenic shock refractory to conventional medical and device-based therapy
J. Clin. Med. 2023, 12, 5576 13 of 19

with an otherwise poor prognosis. Despite recognized benefits of the use of VA-ECMO,
utilization must be carefully weighed against potential complications and patient selection
is an important component of VA-ECMO use that aids in optimizing patient outcomes,
while avoiding medical futility. Outcomes following VA-ECMO are largely dependent
on the underlying indication, patient comorbidities, severity of organ dysfunction at
initiation, and complications or adverse events during MCS. Significant advances have
been achieved in our understanding of VA-ECMO; however, rigorous investigation with
prospective, randomized controlled trials are needed in order to establish standardized
evidence-based guidelines for optimal management of patients with cardiogenic shock
requiring VA-ECMO.

Author Contributions: Conceptualization, K.J.K. and A.I.; writing—original draft preparation, K.J.K.;
writing—review and editing, A.I., S.O., S.V.D. and R.L.; visualization, A.I., S.R. and V.G.; supervision,
A.I., C.K., R.L., S.V.D. and S.O. All authors have read and agreed to the published version of
the manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.

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