Case Report

Pathophysiology and Management of Hypoxic Spell :

What should We Do Next?

Fridyan Ratnasari
1906344525

Supervisor:
dr. Radityo Prakoso, SpJP(K)

Division of Pediatric Cardiology and Congenital Heart Disease

Departement of Cardiology and Vascular Medicine
Faculty of Medicine Universitas Indonesia
January 2021
 HALAMAN PERNYATAAN ORISINALITAS

Laporan kasus ini adalah hasil karya saya sendiri, dan semua sumber baik yang dikutip
maupun dirujuk telah saya nyatakan dengan benar.

Nama : Fridyan Ratnasari

NPM : 190344525
Tanda Tangan :

Tanggal : 4 Januari 2021

Abstract

Background : Hypoxic spells present as paroxysmal event with profound cyanosis that occur
because of right ventricular outflow obstruction (RVOT) obstruction with interventricular
shunt. The pathophysiology of hypoxic spell is the condition of low pulmonary blood flow
with increasing right to left through interventricular shunt which need lifesaving management.
The pathophysiology of hypoxic spell can be provoked by increasing amount of right to left
shunt. The approach in managing these conditions based on their pathophysiology.

Objective: To report the approach in managing cyanotic spell patients with RVOT obstruction
in National Cardiovascular Center Harapan Kita (NCCHK).

Case Illustration: Three patients, a 4-months old baby girl, a 8 months old baby boy, and a
5-months old baby boy were presented to the emergency unit with hypoxic spell. The concern
for these three patients is about immediate interventions in managing hypoxic spells in spite of
optimal medical therapy. The therapeutic approach had been performed including supportive,
pharmacological, and palliative interventional treatment. The different approach for these three
patients were all based on pathophysiology and patients’ condition for lifesaving management.

Summary: We reported a case of hypoxic spell patient with RVOT obstruction with shunt
which was confirmed by clinical finding, chest x-ray, electrocardiography, and
echocardiography. The intervention for lifesaving management in these three patients was
performed well. Patient’s outcome was improved and patient was hemodynamically stable.

Keywords : hypoxic spell, right ventricular outflow tract obstruction

Abstrak

Latar belakang : Spel hipoksia merupakan kejadian paroksismal yang ditandai biru yang
semakin biru akibat adanya obstruksi pada alur keluar ventrikel kiri disertai dengan pirau
interventricular. Patofisiologi spel hipoksia disebabkan adanya kondisi penurunan aliran darah
ke paru disertai peningkatan pirau kanan ke kiri pada level interventricular. Penanganan spel
hipoksia dilakukan berdasarkan patofisiologi kejadian spel.

Tujuan : Melaporkan pendekatan yang dilakukan dalam manajemen pasien spel hipoksia
dengan osbtruksi alur keluar ventrikel kanan di Rumah Sakit Pusat Jantung dan Pembuluh
Darah (RSJPD) Harapan Kita.

Ilustrasi kasus: Tiga pasien, bayi perempuan usia 4 bulan, bayi laki-laki usia 8 bulan, dan
bayi laki-laki usia 4 bulan, masuk melalui unit gawat darurat dengan presentasi biru, spel
hipoksia. Pengenalan dan penanganan cepat dan tepat dilakukan dengan medikamentosa yang
optimal dilanjutkan dengan intervensi segera. Manajemen spel hipoksia meliputi terapi suportif,
farmakologis, dan intervensi paliatif. Tindakan intervensi paliatif yang berbeda dilakukan pada
tiap pasien berdasarkan patofisologi dan kondisi masing-masing pasien sebagai upaya
penyelamatan hidup.

Simpulan: Dilaporkan serial kasus spel hipoksia pada pasien dengan obstruksi alur keluar
ventrikel kanan dengan pirau berdasarkan klinis, elektrokardiogram, rontgen paru,
ekokardiogafi. Selain medikamentosa optimal, intervensi yang dilakukan pada pasien
menghasilkan luaran yang signifikan dalam penanganan spel hipoksia.

Keywords : hypoxic spell, right ventricular outflow tract obstruction

Introduction

Cyanotic spells are a pediatric emergency requiring prompt recognition and treatment.
Cyanotic spells are paroxysmal hypoxic events in a child due to decreased pulmonary blood
flow and right to left shunting. The leading cause of morbidity and mortality in patients who
have uncorrected RVOT obstruction with intraventricular shunt are acute episodes of hypoxia
and cyanosis known as hypoxic, hyper-cyanotic, or “tet” spells. These spells are characterized
by a paroxysm of hyperpnea, irritability or agitation, and prolonged crying, leading to
worsening cyanosis. The underlying pathophysiology involves a shunting of deoxygenated
blood from the right to left ventricle through the VSD, which results from increased pulmonary
outflow tract obstruction, decreased systemic vascular resistance, and obstruction of the right
ventricular outflow tract.1 Hypoxia or "tet" spell may be triggered by potential precipitants
include crying (increased pulmonary resistance), defecation (reduced systemic resistance),
fever (reduced systemic resistance), awakening from naps, feeding, tachycardia (reduced
preload) and angiotensin ACE inhibitors (reduced afterload / systemic resistance). 1,2 During a
spell the reduced oxygen saturation cause cerebral irritability leading to further crying; this
increases pulmonary vascular resistance further exacerbating the problem. During spells, the
patient may develop abruptly worsening cyanosis and breathlessness if this condition left
untreated, it may cause death. 3

In National Cardiovascular Center Harapan Kita, there were 258 cases of RVOT
obstruction with intraventricular shunt in 2018, accounting to 10,28% of congenital heart
disesase (CHD) patients. In unrepaired patients, the leading cause of morbidity and mortality
is acute episode of central cyanosis due to total occlusion of right ventricular outflow
intraventricular communication known as hypoxic spell. In 2018, 18,6% RVOT obstruction
with intraventricular shunt patients in National Cardiovascular Center Harapan Kita was
hospitalized due to hypoxic spell, with 22,9% spell patients need to underwent urgent
transcatheter and surgical intervention. 4
20 ___
The management in hypoxic spell included supportive, pharmacological, and palliative
interventional treatment. Acute treatment of spell includes oxygen, intravenous fluid
administration, beta blocker regiment, sedation and analgesia, and metabolic acidosis
correction. 5 After the acute treatment, the intervention can be performed transcatheter or
surgical based on patients profile and pathophysiology. Surgical repair of palliation is often
needed to relive cyanosis, however complete repair during infant period is not routinely
performed in critical setting. Transcatheter has its own benefit from surgical intervention.
Modified Blalock-Taussig shunt (BT Shunt) has been the treatment of choice to improve
pulmonary blood flow in infants. However, mortality and morbidity after BT shunt procedure
remain high. Furthermore, BT Shunt procedure proved to be challenging in infants with
hypoxic spells and low birth weight.
Objective
To report the different approach in managing cyanotic spell in patients with RVOT
obstruction with interventricular shunt caused by hypoxic spell in National Cardiovascular
Center Harapan Kita (NCCHK).

Case Illustration

Case 1

The first patient is a-4 months old baby girl presented to emergency room with
inconsolably crying with cyanotic since 3 hours before getting to the hospital. The baby had
initial saturation 52% in room-air. She was first child from 18 years old parents with history of
fever and cough during pregnancy. The history of herbs and drugs during pregnancy was
denied. The mother has no history of hypertension and diabetes. The baby was delivered
prematurely with body weight 1450 grams, in the second trimester. The baby was hospitalized
for 30 days in intensive care unit and referred to NCCHK.
From physical examination was found heart rate 167 beat per minute with saturation of
52% in room air. Her body weight was 3.2 kgs. From auscultation, it revealed normal and
regular S1 and normally splitting S2, continuous murmur grade 3/6 in upper left sternal border
heard. Electrocardiogram showed sinus rhythm, 150 beat per minutes, QRS axis +150 (right
axis deviation), PR interval 120 ms, QRS duration 80 ms, no ST-T changes. The chest x-ray
revealed cardiothoracic ratio 50% with normal aortic and pulmonal segments, downward apex,
oligemic, with no infiltrate.
Echocardiography showed right atrium (RA) isomerism, right hand topology,
pulmonary atresia with aorta arose from right ventricle (RV), all pulmonary veins goes to the
left sided atrium. Complete atrioventricular septal defect (CAVSD) with hypoplastic left
ventricle (LV) was observed, small tortuous L-R shunt patent ductus arteriosus (PDA) with
continuous flow, good RV contractility without atrioventricular (AV) valve regurgitation, left
aortic arch without sign of coarctation aorta, coronary sinus dilatation with bilateral superior
vena cava (SVC).

Fig. 1 Chest X-Ray

 Fig.2 Electrocardiogram

In emergency room, the patient was given oxygen with knee chest position, propranolol
was up titrated from 2 mg per 8 hours to 3 mg per 8 hours. The saturation increased from 52%
to 60% and the patient was transferred to intermediate ward. While in the ward, the medication
consisted of morphine drip 2 mcg/kg/min, propranolol 3x3 mg, and bicnat 1meq/kgbb. The
saturation fell to 12%, the patient was transferred to catheterization lab to performed PDA
stenting The PDA stenting was successfully done, the saturation increased to 90%. The patient
sent to the Intensive Care Unit post procedure for further evaluation.

Case 2

A-8 months old baby boy came to National Cardiovascular Center Harapan Kita came
to the emergency room with worsening blue appearance during crying. The patient had history
of repeated spell at home since six month of age. No prior history of repeated cough or fever.
During pregnancy no problem was found, he was born normally with spontaneous crying, no
history of blue appearance after birth. His birthweight was 3050 gr, the first child with no
history of familial congenital heart disease. There were no history of illness, hypertension, and
diabetes during pregnancy. He already took daily medication Propranolol 2 x 2,5 mg.

Fig. 3 Chest X-Ray

 Fig. 4 Electrocardiogram

From physical examination, his saturation was 20%, body weight of 6 kilograms.
From auscultation first heart sound was normal with single-attenuated second heart sound, no
murmur was found. From the electrocardiography, we found sinus rhythm, rate 125 beat per
minutes, p wave axis +60, p wave normal, QRS axis 135 (normal axis-borderline to right axis
deviation), with an abrupt R wave and right ventricular hypertrophy (RVH). Chest X-ray
revealed cardiothoracic ratio of 60%, normal aorta and pulmonary segment, upright apex, and
decreased pulmonary vasculature. Echocardiography was found ventricular septal defect and
he was diagnosed as tetralogy of fallot with confluent pulmonary artery. Echocardiography
revealed patent foramen ovale bidirectional shunt, ventricular septal defect (VSD) subaortic
diameter 6-7 mm R-L shunt, overriding aorta < 50%, no patent ductus arteriosus, good left
ventricular function with ejection fraction 61%, TAPSE 1.27 cm, tight infundibular valvar-
sub valvar pulmonary stenosis, diameter of right ventricular outflow tract is 4.3-5 mm,
confluent pulmonary artery, right pulmonary artery diameter 4-5 mm, left pulmonary artery
diameter 5 mm, mild tricuspid regurgitation with tricuspid valve gradient 60 mmHg, all
mitral and aortic valve are normal, left aortic arch, and aortic diameter 0.93 cm (McGoon
ratio 1-1.1).

In emergency room, the patient, in hypoxic spell with saturation 20%, was given
oxygen with knee chest position. Fluid was administered 55 cc, repeated thrice intravenously,
propranolol 3x3 mg up titrated to 3x5 mg then up titrated to 3x8 mg, morphine 10 mcg/kg/hour.
The saturation increased from 20% to 55%. The baby was transferred to the Intermediate
Pediatric ward. In pediatric ward, the surgery conference was held for this patient. The team
agreed to perform right ventricular outflow tract stent (RVOT) stent for this patient. The patient
was sent to the catheterization laboratory for RVOT stenting. RVOT stenting was done with
no complication during and after procedure. Peripheral saturation was increased from 59% to
94%.

Case 3
A-5 months old baby boy presented to emergency room from outpatient clinic with
history of cyanotic while crying. History of repeated respiratory infection was denied. He had
difficulty of feeding and failure to thrive. The baby delivery followed by cyanotic and
spontaneous crying, with birth weight of 3200 grams. The mother has routine antenatal visit to
obstetric gynecologist and no history of fever, hypertension and diabetes. The history of
smoking and drinking were denied. The baby was the fourth children of four and other siblings
have no history of cardiac disease. The age of father and mother were 32 years old and 34 years
old.
The baby administered to emergency unit with saturation of 56% and weight 5.8 kgs.
From physical examination normal first heart sound (S1), normally splitting with no attenuated
second heart sound (S2) was found with ejection systolic murmur grade 3/6 in upper left sternal
border. Electrocardiogram showed sinus rhythm, 150 beat per minutes, QRS axis 135, p wave
axis +60, right atrial enlargement (RAE), PR interval 120 ms, QRSd 80 ms, no ST-T changes.

Fig. 5 Chest X-Ray

Fig. 6 Electrocardiogram

Chest X-ray showed cardiothoracic ratio of 65%, normal aorta, pulmonary arterial bay
segment, upright apex, and increased pulmonary vasculature. From his echocardiography, it
revealed restricted muscular ventricular septal defect (VSD) R-L shunt, pulmonary stenosis
(PS) valvar subvalvar severe pressure gradient (PG) 72 mmHg. Right pulmonary artery (RPA)
3,5 mm, left pulmonary artery (LPA) 5.5 mm, aortic arch was on the left. Z score tricuspid +
4.04, mitral Z score - 0.3. From the echocardiographic, we could conclude transposition of
great arteries-ventricular septal defect (TGA- VSD) muscular restrictive, pulmonic stenosis
(PS) valvar-subvalvar severe, patent foramen ovale (PFO).
 Due to his chief complaint of getting more cyanotic since crying and low saturation, he
was managed in emergency room with oxygen in knee chest position with propranolol 3x7,5
mg, intravenous fluid loading 50 cc and maintenance 600 cc/24 jam, morphine 20 mg/hour,
and bicnat 6 mEq. The patient was transferred to intermediate ward. In intermediate, his
saturation fell suddenly to 10-50% even adequate spell management was done adequately with
morphine continuous drip 20 mg/hour. The team managed to intubate and puncture venous
access. The surgical conference was held urgently which resulted in urgent Blallock-Tausig
shunt (BT-Shunt), atrial septectomy. This patient was undergone urgent BT-shunt with the no
complication along and after the procedure.

DISCUSSION

Right Ventricular Outflow Tract Obstruction with interventricular shunt (RVOTO)

Infants with severe RVOT obstruction with interventricular shunt have reduced
pulmonary blood flow. In cyanotic CHD, systemic venous vessels bypass pulmonary
circulatory system leading to right-to-left shunt in which higher resistance to right ventricular
outflow results in more cyanosis symptoms. Hyper-cyanotic spell. The common physiology is
one of a large unrestricted ventricular septal defect (VSD) resulting in equalization of pressures
in both ventricles. The downstream resistance determines the directionality of the shunt across
the VSD. 7

Fig 7. Blood flow during hyper-cyanotic spells

Systemic vascular resistance and the pulmonary outflow obstruction determine the
amount of net forward flow from the ventricles. A decrease of systemic vascular resistances
will favoured systemic blood flow, resulting in shunting of deoxygenated blood from the right
ventricle to the systemic circulation through the VSD precipitating the obstruction in right
ventricular, there is more right-to-left shunting across the VSD. It caused a steady decline
in resting oxygen saturation. After the newborn period into childhood, these patients can
present with hyper-cyanotic spells. 8

Hypoxic Spell

Hypoxic spell is cardinal manifestation of an increasing right-to-left shunt. Any process

that decreases systemic resistance or increases the pulmonic resistance will result in worsening
cyanosis. It mostly occur in children aged 2 months to 2 years old. It commonly happened early
in the morning when the intravascular volume is relatively low but can occur anytime of the
day. Hypoxic spells can be triggered by a variety of different stimuli or can occur
spontaneously with no apparent cause. 9 Normal activities such as crying, feeding, or defecation
can initiate a cyanotic spell. Anxiety, fever, dehydration, anemia, cardiac catheterization, and
supraventricular tachycardia are all known to precipitate these spells. During a cyanotic spell,
the ejection systolic murmur decreases in intensity and at times becomes inaudible. Prolonged
hypoxic spells that are not treated can lead to hypoxic neurological injury, seizures,
cerebrovascular accidents, and death. Seizure in hypoxic spell can be manifested as
spontaneous attack of cyanotic spells and loss of consciousness often occur in the morning
which can be induced by crying and pain. The child often lies to his abdomen and persist in
this condition for minutes. If the cyanosis become intense, the baby may loss his consciousness
with or without convulsion. During the attack the pupils are extremely small. 10

Congenital anomaly causes hypoxic spell other than TOF are pulmonary atresia with
VSD, double outlet right ventricle with pulmonary stenosis, tricuspid atresia with pulmonary
stenosis (PS), transposition of great vessels with PS, single ventricle physiology with PS or
pulmonary atresia, and transposition of great arteries with VSD. 11-13

Fig 8. Mechanism of Hypoxic Spell

Stimulation of mechanoreceptors in the right ventricle due to an increase in

catecholamine-induced cardiac contractility combined with a decrease in right ventricular size
may initiate the hypoxic spell by increasing right ventricular outflow obstruction. This also
triggers a reflex hyperventilation and systemic vasodilation without bradycardia. Woods et al.
have postulated that cyanotic spells are a result of right ventricular infundibular spasm leading
to right-to-left shunting with progressively worsening hypoxemia and metabolic acidosis. The
common physiology is one of a large unrestricted ventricular septal defect (VSD) resulting in
equalization of pressures in both ventricles. The downstream resistance determines the
directionality of the shunt across the VSD. Hypoxic spells are caused by spasm of the
infundibulum of the RV, a progressively increasing right to left shunting. 6,8

The cyanotic spells in patients with right ventricular outflow tract obstruction may
result from stimulation of right ventricular mechanoreceptors. Increase in infundibular
contractility, peripheral vasodilation, hyperventilation. Increase in infundibular activity results
in a decrease in pulmonary blood flow, clinically view as reduction in intensity of murmur
across the right ventricular outflow during spell. Increased contractility may result in
endogenous norepinephrine which support the use of beta blocker in spell management.
Peripheral vasodilation also plays a role in decreasing the intensity of murmur and blood flow
to the lungs because of the increasing shunt of the right ventricle blood to the aorta through
VSD and lessen the flow of blood to the lung. 11

a) Hyperventilation due to hyperpnoea increases the oxygen demand and cardiac output.
Hyperpnea increases the systemic venous return leading to right to left shunt as well as
oxygen consumption through increase work of breathing. Frequent occurrence of spells
in the morning hours after good night. The hyperpnoea will increase cardiac output and
decrease pulmonary blood flow resulting in further right to left shunt and greater arterial
hypoxemia. This vicious cycle resulting in spell with the proposed mechanism in this
picture. 3,7

Fig 9. Mechanism of Hyperpnea in Hypoxic Spell

b) Crying, defecation, supraventricular tachycardia, and feeding. For these activities,

there is increased contractility due to the catecholamines and decreased cavity size of
the right ventricle during crying, bowel movement (like Valsava maneuver or SVT due
to shortened diastole that can induce cyanotic spell.
 c) Hot weather, infections: peripheral vasodilation during summer or in infection
condition facilitates better emptying of right ventricle into aorta, which could reduce
the cavity size and may increase the susceptibility to cyanotic spells.
d) Cardiac catheterization: direct mechanical stimulation of the receptors by a cardiac
catheter may induce a cyanotic spell. Dehydration due to overnight fasting (which may
decrease the right ventricular size), or peripheral vasodilation induced by premeditation
may also be contributory. 8
e) Time of the day: the more frequent occurrence of spells during the morning hours may
relate to catecholamine secretion on awakening or to circadian variations in the
endogenous catecholamines secretions
f) Cyanotic spells in pulmonary atresia: the reflexes originating from the hypertrophied
ventricles in the patients with pulmonary atresia and ventricular septal defect can trigger
hyperventilation, vasodilation and the sequence of the spells. Blood flow to the lungs
through collaterals or patent ductus arteriosus would be reduced with peripheral dilation,
and hyperventilation would increase the metabolic demands. Similar considerations
may apply to other cyanotic heart diseases where spell occurs.
g) The effects of beta-blockers and morphine: Beta-blockers are useful in the treatment
and prevention of cyanotic spells because they decrease myocardial contractility. The
use of beta-blockers in vasovagal syncope may decrease contractility which is
important in preventing mechanoreceptor stimulation and hence the spells. Morphine
is very effective in the treatment of cyanotic spells, but its mechanism of action is not
clear. It may be relevant that endogenous opioids inhibit the sympathetic system, and
more recently have been implicated in pathogenesis of vasodepressor syncope.
h) Age of the patients: The cyanotic spells generally start from 2 months of age and
mysteriously disappear after about 2 yr. Although entirely speculative, it may be related
to growth of ventricular cavity and infundibulum such that it results in decreased
susceptibility of receptors to stimulation. 3

The cyanosis may be due to an increased right-to-left shunt at the ventricular level.
Three mechanism involved: (1) decreased in systemic resistance mechanism begin with
peripheral vasodilatation induced by the hot atmosphere. Decreasing systemic resistance
permits an increase in the right to left shunt. (2) an increased pulmonary arterial resistance due
to anoxia can be masked in diminished pulmonary blood flow. This mechanism is believed as
the sequel of spell which induced by the pharyngeal obstruction, (3) an infundibular obstruction
or spasm of infundibular in RV will result in the increase in the amount of blood shunted from
the right ventricle to the aorta by increasing the resistance to the flow of blood from right
ventricle to the pulmonary artery. 4

Overall the pathophysiology of spells occurs due to an acute imbalance between

systemic and pulmonary blood flow resulting from a vicious spiral of changes in inotropy
secondary to endogenous catecholamine release, increased systemic oxygen consumption,
reduced systemic vascular resistance, and reduced RV preload due to increased heart rate. 3,6
The acute management consist of relieving pain and anxiety to reduce heart rate and systemic
oxygen consumption, increase systemic vascular resistance, and increase pulmonary blood
flow spells are provoked, or worsened, by crying the infant should be picked up and comforted
as soon as an episode begins, ideally while being held in a position of flexed knees and hips
that kinks or compresses the femoral arteries and increases peripheral systemic vascular
resistance. The first actions should be to place the child in the knee-chest position and
administer oxygen by face mask. If no improvement is seen within a few minutes, oxygen
should be administered and intravenous access obtained. Spells can occur in patients with a
dynamic sub-pulmonary obstruction. Patients may not present with cyanosis at all if pulmonary
obstruction is minimal. The physiology can be relatively well balanced but may resemble a
large ventricular septal defect if the pulmonary blood flow is high.

The VSD is almost always large and nonrestrictive and is situated in the subaortic
region. Rarely, additional muscular VSDs may co-exist. The PS is variable both with regard to
the location and severity of obstruction. The narrowing may be at infundibular, valvar, supra-
valvar or branch pulmonary artery level or at multiple levels. The magnitude of narrowing may
be very mild without any arterial desaturation, or it may be very severe causing severe cyanosis.
The RV hypertrophy is typically severe in degree. The degree of over-riding of the aorta over
the ventricular septum (dextroposition) varies from one patient to the next. The Ao descends
on the right side in nearly 25% of cases. Atrial septal defects (ASDs) may be present in 15%
of the cases and when TOF is seen with ASD, it is called pentology of Fallot. 1,3

Hyper-cyanotic spells may be seen in TOF patients and may be described as anoxic
spells, hypoxic spells, paroxysmal hyperpnea, blue spells, tetralogy spells, paroxysmal
hypoxemic spells and hyper-cyanotic episodes. 3 The spells most usually occur between one
and 12 months of age, with a higher frequency in two- to three-month-old babies. The spells
are most common in the morning after awakening from sleep. Defecation, crying and feeding
commonly precede these episodes. The spells are exhibited by elevated rate and depth of
respiration and increased cyanosis, with progression to limpness and syncope. However, they
usually recover. Rarely, the spells end up in convulsions, cerebrovascular accidents, or even
death. The cause of the spell syndrome is unknown, but several theories have been postulated,
and most possible mechanisms are right ventricular outflow tract spasm precipitated by an
acute increase in catecholamines and any stimulus producing hyperpnea.

Management of Hypoxic Spell

In many centers, a move toward earlier corrective surgery has obviated the need for
medical management in this condition. However, in some circumstances, a limited period of
medical management may still be appropriate and, in the instance of an acute hypoxic spells,
medical management can be lifesaving. Depending on the nature of their outflow tract
obstruction, infants with RVOT obstruction may develop symptoms related to either too little
or too much pulmonary blood flow. Those who develop heart failure usually derive some
benefit from pharmacotherapy. 3,8

Tet spells require a rapid and aggressive approach including positioning (knee-chest)
to increase systemic vascular resistance, oxygen therapy to cause pulmonary vasodilation and
a systemic vasoconstriction, intravenous fluid bolus to improve the right ventricle filling and
pulmonary flow; morphine, intravenous beta blockers to help improve the right ventricle
outflow obstruction by relaxing the muscle, and intravenous phenylephrine to increase
systemic afterload

The acute management of spell begins with nicest position, giving supplemental oxygen
and an intravenous fluid bolus. 8,11 Place child in comforted position, knee-chest position, the
baby supine or on the parent’s shoulder with the knee to chest position is beneficial. This kinks
the femoral arteries, increases peripheral vascular resistance, and decreases the right-to-left
intracardiac shunt. This helps to increase systemic vascular resistance, thereby reducing the
right-to-left shunt and resulting in more blood flow through the lungs. The actions should be
to place the child in the knee-chest position while administering oxygen by face mask. If the
child is extremely restless. Initial administration of oxygen, which may decrease the hypoxemia
sufficiently to prevent arterial vasodilation.

1. Intravenous fluid boluses (5 to 10 mL/kg initially) would increase right ventricular

preload and improve the intravascular volume. Excessive fluid administration should
be avoided in light of the complications of pulmonary and cerebral edema, and the
dilutional effects on the hypoxic patient’s compensatory polycythemia.
2. Morphine can be given intravenously or intramuscularly at a dose of 0.05–0.1 mg/kg.
Its use ad a strong tranquilizer and analgesic agents, will blunt the central hyperpnea
drive, alleviates pain and discomfort, decreases release of endogenous catecholamines,
and reduces the heart rate, and decrease infundibular tone.
3. If the hyper-cyanotic spells persist, alpha-adrenergic agonists, can be administered as a
bolus of 10–20 mcg/kg followed by 2–5 mcg/kg/min can be used. It is known to
increase systemic vascular resistance and increase arterial oxygen saturation which in
turn decreases the right-to-left shunt resulting in improved oxygen saturation.
Phenylephrine infusions should be used if prolonged resuscitation is necessary.
Intravenous administration of phenylephrine (boluses of 0.005 to 0.001 mg/kg) or
norepinephrine (0.05 to 1.0 mg/kg/min) may be required.
4. If this fails, treatment with a β-blocking agent such as Propranolol, 0.1 mg/kg slow IV
push. It can be repeated in 15 minutes. It will reduce tachycardia, increase systemic
resistance, decrease myocardial contractility and oxygen consumption, and reduce the
dynamic right ventricular outflow obstruction.
5. Correcting the metabolic acidosis 1-2 meq/kg IV that is potentiating the hyperpnea
cycle in the setting of prolonged hyper cyanosis. Prolonged periods of paroxysmal
hyperpnea have been terminated successfully with the administration of intravenous
sodium bicarbonate.
6. If the infant continues to be hypoxia despite all these measures, emergency intervention
is indicated. Either non surgical or surgical intervention could relieve the right
ventricular outflow obstruction. However, even if the hypoxic spell resolves,
intervention should be considered urgent. 8,10
Pharmacological Therapy

a) Phenylephrine stimulates α1-adrenergic receptors and has relatively little effect on

other adrenergic receptors. It causes vasoconstriction and increased systemic vascular
resistance with a risk in lowering the heart rate. It has been used acutely during hypoxic
spell episodes to increase systemic resistance, reduce the right-to-left shunt, increase
pulmonary blood flow, and thereby improve systemic oxygenation.
b) β-Blockers can be classified as first generation, nonselective for β1 and β2 blockade
(e.g., propranolol); second generation with relative selectivity for β1 receptors (e.g.,
metoprolol and atenolol); and third-generation drugs (selective or nonselective; e.g.,
carvedilol, and nebivolol). The most commonly used β-blockers in infants are
propranolol and esmolol. Propranolol is available for oral or intravenous administration,
but if intravenous β-blocker therapy is necessary, the short-acting β-adrenergic blocker,
esmolol is preferred because of the risk of hypotension and bradycardia from the
intravenous administration of propranolol. Propanolol used in an attempt to reduce the
frequency and severity of hypoxic spell in infants some infants especially with critical
pulmonary stenosis. Other choice of drug like metoprolol may cause greater CNS
effects (dizziness, depression, sleep disturbances) and also inflexibility in the dosage
form to permit weight-based. Carvedilol is a third-generation β-adrenergic receptor
blocker that blocks β1-, β2-, and α1-adrenergic receptors.
c) Morphine 0.1 to 0.2 mg/kg IV, intramuscularly, or subcutaneously is frequently
recommended for sedating awake patient with hyper-cyanotic spells to increase the
period of right ventricular filling by decreasing the heart rate and promote relaxation of
the infundibular spasm. However, morphine often causes both arterial and venodilation,
resulting in paradoxical exacerbation of cyanosis. It is commonly known that morphine
depresses respiratory center, increasing the risk of repetitive apneas.
d) Midazolam has the shortest action in relation to other benzodiazepines. It is water-
soluble hypnotic-sedative drug with immediately increased systemic arterial saturation,
probably by decreasing sympathetic tone, augmenting pulmonary blood flow.
cardiorespiratory stability make it useful in cardiac patients. Sedation is an important
step in the management of patients with cyanotic spells. Intranasal midazolam offers
an alternative use as an initial method of calming the child that was effective in a patient
with a severe cyanotic spell because of tetralogy of Fallot in the emergency department.
Intranasal route has been frequently used in children undergoing dental procedures,
laceration repairs, and for the rapid sedation of patients in which intravenous (IV)
access was not possible and for the emergency treatment of seizures. The elimination
half-life of intranasal midazolam at a dose of 0.2 mg/kg is similar to that when the drug
is given intravenously. 12
e) Fentanyl is an alternative strategy, combining a painless and effective route of
administration with the use of opioid less likely to cause hemodynamic instability and
a decrease in systemic vascular resistance. It can be administered 2 mcg/kg intranasal
using mucosal atomization device. The route of administration is needless which avoid
children from being distress and hyperpnea. Fentanyl has been shown to be as effective
 as IV morphine and had a similar side effect profile. Onset of action is 2 to 5 minutes,
lasting at least 60 minutes. Pediatric dosing is safe and most effective when given range
of 1-3 mcg/kg. A case report in fentanyl successfully has been used to abort a blue “tet
spell” in an infant with the cyanotic CHD. 13

Intervention in RVOT Obstruction with Shunt

The initial palliative procedure to provide a more stable source of pulmonary blood
flow is often required prior to undergoing a more definitive palliation or repair. A surgical
shunt, most commonly the modified Blalock-Taussig shunt (BT Shunt), has been a widely used
initial palliative surgical procedure but it has been associated with high morbidity and mortality.
Risk factor for corrective surgery included low body weight, prematuruty, young age
(neonates), unfavorable pulmonary artery, abnormal coronary anatomy, and critical
preoperative condition. The alternative interventions are considered as palliative modality
which are less invasive are patent ductus arteriosus (PDA) stenting and RVOT stenting. 14

1. Non-Surgical Intervention

a) PDA stenting

Patent ductus arteriosus (PDA) stenting was described as an alternative to BT Shunt

placement to provide pulmonary blood flow. Patent ductus arteriosus stenting has the
advantages of being less invasive to dilate the arteriosus duct in duct dependent circulation
especially in children < 3 months old. This intervention could be as an alternative to median
sternotomy or lateral thoracotomy in neonatal period, potentially avoiding exposure to
cardiopulmonary bypass, and potentially allowing for more symmetric growth of the
pulmonary arteries. PDA stenting is successfully performed, it is an acceptable alternative to
surgical shunt placement and may, in fact, provide several advantages. The studies reviewed
herein demonstrate that PDA stent is associated with lower mortality and less morbidity than
surgical shunt. Indications for PDA stenting are :

• To maintain the PDA as the sole source of pulmonary blood flow in cyanotic heart
disease until the time of definitive surgery: conduit repair in TOF-PA and lesions with
similar physiology, and bidirectional Glenn shunt in hearts with single-ventricle
physiology.
• To augment the pulmonary blood flow in PAIVS and critical PS with moderate RV
hypoplasia following interventions to abolish RVOT obstruction. Elective PDA
stenting at the time of valvotomy in selected patients avoids the need for unplanned
PDA stenting or BT shunt following RVOT interventions.
• Severe Ebstein anomaly with functional pulmonary atresia: avoids prolonged PGE1
infusion during the transitional postnatal physiology.
• Simple TGA with involuted left ventricle to prepare the left ventricle for the arterial
switch operation as alternative to PA banding and BT shunt.
 Further, PDA stent palliation has been shown to result in similar or improved growth
of the pulmonary arteries, decreased duration of mechanical ventilation, decreased ICU length
of stay, and in some cases hospital length of stay, decreased diuretic burden, and lower rates of
acute complications. Potential disadvantages of PDA stenting include procedural
complications unique to this procedure (primarily vascular access related), concerns regarding
stent longevity with higher number of reinterventions.

b) RVOT stenting

RVOT stenting is now known as an effective and safe technique in the initial palliation
of selected patients with RVOT obstruction by dilating RVOT with stent. 15 This procedure has
been recently considered as a good alternative for BT shunt with acceptable early and long-
term outcome in high risk neonates and allowing PA growth until the child reaches optimal
codition for definite repair. Indications for this procedure are patients with severe RVOT
obstruction which cause cyanosis in children less than one year old, low body weight (less than
4 kg), small pulmonal annulus, (Nakata index <100 mm2/m2, pulmonal valve z-score < -5), and
complex anatomy or comorbidity included unroofed coronary sinus, chronic lung disease,
AVSD/Fallot who require early intervention are either prostaglandin dependent or severely
cyanosed and have tenuous antegrade pulmonary blood flow that is a consequence of the poor
anatomy of the right ventricular outflow tract (RVOT; infundibular or valvar stenosis) and/or
pulmonary arterial tree (hypoplastic vessels and multiple aortopulmonary collateral arteries
[MAPCAs]). RVOT stent was beneficial in creating right ventricular to pulmonary artery
continuity with an adequate size continuity and antegrade flow through central pulmonary
arteries could promote a uniform increase in vessel size and even angiogenesis of distal
microvessel.

Coexisting neonatal comorbidities may not have had time to resolve, for example,
prematurity, low weight, infection, neurological injury, and other conditions requiring
noncardiac surgery. 15 These comorbidities increase the risk of, or may delay, primary cardiac
repair. RVOT stenting resulted in relief of cyanosis, improve pulmonary artery growth, and
resolution of noncardiac comorbidities. The outcome of outcome RVOT stenting and BT shunt
in 4 studies showed no significant difference in improvement rate of arterial O2 saturation (OR
= 1.419, 95% CI: 0.645-3.123, P= 0.384) and death rate (RR=0.341, 95% CI: 0.057-2.024, P=
0.236). In conclusion, stenting of the right ventricular outflow tract in symptomatic high-
risk neonates is a feasible option that can be considered as an attractive alternative to
early surgical repair or palliative surgical measures. 16

2. Surgical Intervention

a) Blalock Taussig Shunts

BT-shunts was aimed to be a palliative surgery to increase pulmonary blood flow in a
controlled manner to alleviate cyanosis and improve exercise tolerance in patients. Besides that,
it also aimed to maintain adequate preload to prevent hemodilution, maintain afterload such as
systemic vascular resistance and hence the diastolic pressure to maintain coronary perfusion
pressure. 17
As initial corrective procedures are increasingly performed during infancy, palliative
shunts are not commonly done. Nevertheless, certain subsets of patients require initial
palliative surgery when cardiac disorders are not pliant for corrective surgery. The indications
for BT-shunts include those conditions who need to increase blood flow to the lungs in
conditions such as tricuspid atresia or other univentricular conditions where Glenn or Fontan
shunts can only be performed after the decline in pulmonary vascular resistance, pulmonary
atresia, TOF, neonatal Ebsteins with functional pulmonary artery. It could also be done in
condition where complete repair is not possible such as anatomical-aberrant coronary anatomy
left anterior descending coronary artery crosses the RVOT or physiological-prematurity,
intracerebral bleed, or other contraindications to cross pulmonary bypass. Other indications of
BT-shunts include hypoplastic left heart syndrome or to encourage growth of pulmonary
arteries in pulmonary atresia, ventricular septal defects with aortopulmonary collaterals, or
inadequate pulmonary arteries. 18

Fig 10 . Comparison of duct stenting intervention to BT-shunt based on complications,

mortality, and re-intervention.

A meta-analysis demonstrates duct stenting to have a lower risk of medium-term

mortality with shorter hospital and ICU length of stay compared to BT shunt. Duct stenting
however has no early survival benefit and has an increased risk of unplanned re-interventions.
Both methods provided no difference in postoperative oxygen saturation and pulmonary artery
growth. An adequately powered expertise based randomized trial is warranted to confirm these
findings with greater confidence. 19

However, often in infants requiring palliative surgery for RVOT obstruction with shunt
also have other comorbidities that could increase risk factors for higher mortality and
reintervention. Those comorbidities include prematurity, low weight, severe cyanosis,
pulmonary atresia rather than stenosis, and noncardiac comorbidities. Complications in BT-
shunts include pulmonary artery stenosis and pulmonary over circulation. In some centers,
RVOT stenting has emerged as the main bridging procedure. 20
 In this serial case, we observed three patients with different origin of cyanotic
congenital heart disease who admitted to emergency room with the same clinical presentation,
hypoxic spell. The patients have the same pathophysiology of RVOT obstruction with shunt.
From case 1 and 2, we learned that the management of spell in acute setting was adequately
done with administration of fluid intravenously, oxygenation, putting the baby in knee-chest
position and up titrated propranolol along the hospital stay. Meanwhile, the case 3 was
optimally managed with oxygenation, knee-chest position, adequate intravenous fluid,
intravenous morphine, and additional bicnat for metabolic acidosis. The patient gradually
showed improvement of general symptoms temporarily. However, hypoxic spell persisted
despite knee-chest position, oxygen supplement, normal saline intravenous infusion, morphine
and oral beta blocker and so that the intervention need to be performed.

As mentioned above, the pathophysiology of hypoxic spells should be thought of as an

acute imbalance between systemic and pulmonary blood flow. In these 3 cases, the cases
require intensive medical therapy. Each of patients has different profile, based on their age and
the history of medications. In this case, only case-2 who had taken beta-receptor antagonists
(oral propranolol) as daily medication. The therapy based on literature was given to each of the
patients, but not every patient got the optimal therapy. In practice, the availability of
medications like morphine, was not always readily available in every unit in hospital. Due to
this condition, the outcome of the patients can’t be analyzed in the same condition. In these
three patients, none of them were recorded given diazepam as the sedative agent during hypoxic
spell. There is no study had reported about the use of sedative agent like diazepam. The respond
to therapy was also different based on the patients condition. For patient case number 1, the
intervention was taken by PDA stenting due to duct dependent circulation with patent ductus
arteriosus and small pulmonary size. The intervention for case number 2 was performed by
RVOT stent due to its severe RVOT obstruction found from tight infundibular pulmonary
stenosis, his low body weight for surgical intervention. The case was treated by BT-shunt
procedure due to his small pulmonary artery with no patent ductus arteriosus. All of these
intervention were performed as palliative intervention procedure which was proposed as a
bridging intervention for definitive repair. The intervention need to be performed as soon as
possible when the medical therapy could not optimally control hypoxia spell condition which
was found in these three cases. Three of the patients had better outcome after the intervention
taken.

Conclusion

Hypoxic spells continue to be an important clinical presentation to immediately recognize

and treat in several cyanotic congenital heart diseases. Accurate diagnosis and appropriate
management may prevent the consequences of hypoxia leading to improved outcome and
avoiding morbidity or even death.
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