Case by Gabriel Altit and Sariya Sahussarungsi (Fellow in NH-TNE at McGill University) - Posted February 21st, 2025

A pregnant mother presented with concerns about decreased fetal movement at 37 weeks of gestation. Her past medical and surgical history was unremarkable. Obstetrically, she had previously delivered multiple term infants, all via spontaneous vaginal delivery. Her current pregnancy was complicated by gestational diabetes mellitus requiring insulin therapy. Serial ultrasounds had shown a normal fetal morphology at 20 weeks with an estimated fetal weight (EFW) at the 50th percentile. However, at 21 weeks, an echocardiogram revealed myocardial hypertrophy. A follow-up ultrasound at 26 weeks confirmed stable ventricular hypertrophy.  The patient presented to a peripheral Hospital with concerns about decreased fetal movements, which she initially mentioned noticing the day prior. However, upon discussion, there was progressively decreased fetal movement in the past 2 weeks before delivery. There was also a drop in fetal growth on last ultrasound 3 weeks prior to presentation (EFW at 20th percentile). Fetal monitoring revealed sustained fetal bradycardia, prompting an urgent decision for an emergency cesarean section. A male infant was delivered at 37 weeks’ gestation with a birth weight of 3000 grams. The baby was born in critical condition, with Apgar scores of 0, 2, 2, and 4 at one, five, and ten minutes, respectively. He was initially pulseless with no spontaneous respiratory effort. Positive pressure ventilation was initiated, followed by intubation and chest compressions. After five minutes, his heart rate improved to a range of 60-100 bpm. He initially requiring a maximum FiO₂ of 100%, which was subsequently weaned to 50%. He was then transferred by a transport team for therapeutic hypothermia due to moderate to severe encephalopathy (Sarnat stage 2-3). Initial blood gas analysis at 30 minutes showed severe metabolic and respiratory acidosis with a pH of 6.86 and a pCO₂ of 74.4. Repeat testing at one hour showed partial improvement (pH 7.10, pCO₂ 29, base deficit -21, lactate 19). Persistent hypoglycemia required three boluses of D10W, and a total fluid intake of 100 ml/kg/day was initiated. Neurologically, he appeared lethargic with a weak suck, absent gag reflex, incomplete Moro response, strong distal flexion, mild axial hypotonia, and hypertonic limbs. Continuous aEEG monitoring revealed seizures, prompting treatment with phenobarbital (20-10-10 mg/kg). Seizures were refractory. Coagulation studies showed significant abnormalities (INR 6.25, PT 56, PTT 78), necessitating a transfusion of fresh frozen plasma (10 ml/kg). At 24 hours of life, the infant developed profound hypotension, thought to be secondary to cumulative effects of multiple antiseizure medications. Dopamine was initiated for its vasoconstrictive properties, but despite this, his blood pressure remained low (42/22, MAP 31). He was subsequently escalated to norepinephrine at 0.02 mcg/kg/min. A repeat arterial blood gas showed persistent metabolic acidosis (pH 7.24, pCO₂ 23, base deficit -16.5, lactate 17), while on minimal setting intubated. However, the patient was on FiO2 of 100% due to pre- and post-ductal saturation in the 75-80% range. Given his hemodynamic instability and history of myocardial hypertrophy, a targeted neonatal echocardiography (TnECHO) consult was requested for further evaluation and guidance on management. At the time of the evaluation the amplitude integrated electroencephalogram was showing a pattern of isoelectric very low voltages. There were still occasional bursts of seizures on the full montage EEG.

Pathophysiology:

Functional pulmonary (valvular) atresia (or stenosis if there is some forward flow) occurs when the right ventricular (RV) function is severely compromised, leading to an extremely low right ventricular output (RVO). As a result, pulmonary blood flow becomes entirely dependent on a left-to-right shunt at the ductal level. When the RV faces significant afterload, particularly in the setting of markedly elevated pulmonary vascular resistance (PVR), it may initially compensate by increasing contractility. The PVR can be high in a newborn when there is, for example, a context of acute pulmonary hypertension (commonly termed "persistent pulmonary hypertension of the newborn"), and a failure to relax the PVR in the post-natal setting. If the RV afterload remains critically high, the RV fails. This is especially true when the ductus arteriosus progressively constricts and the RV is forced to eject exclusively into a severely constricted pulmonary circulation. Indeed, then the afterload burden on the RV escalates further. In this scenario, the RV loses its ability to effectively "pop off" into the systemic circulation, leading to increasing strain and, ultimately, RV failure.

As RV output declines, forward flow across the pulmonary valve diminishes, reducing pulmonary artery (PA) perfusion. When the RV can no longer generate sufficient output to sustain flow through the pulmonary valve, the pulmonary circulation becomes entirely dependent on ductal shunting from the aorta. At this stage, the contribution of the RV output to the pulmonary artery flow dimishes dramatically. Since pressure is a function of flow and resistance, even though PVR remains extremely high, the near absence of forward flow results in a profound drop in PA pressure. Eventually, PA pressure falls below aortic pressure, favoring the left-to-right ductal shunt—an unexpected hemodynamic pattern, as clinicians often expect to face a right-to-left shunting at the ductal level in the context of acute pulmonary hypertension or PPHN. The left to right ductus arteriosus signifies that there will not be any pre- to post-ductal saturation differences clinically. 

In the majority of cases of PPHN/acute PH, the RV remains functional and forcefully ejects against elevated resistance, generating suprasystemic PA pressures and a right-to-left ductal shunt. As such, there is often supra-systemic pulmonary arterial pressure (hence the term coined: acute pulmonary hypertension) and  supra-systemic PVR. In contrast, in functional pulmonary valve stenosis or atresia with severe RV failure, PA pressure becomes infrasystemic due to the absence of effective RV output. Yet, despite the low PA pressure, PVR remains high, often suprasystemic, due to severe pulmonary vasoconstriction. As such, there is infras-systemic pulmonary arterial pressure and, typically, supra-systemic PVR. This phenomenon is particularly exacerbated by ongoing seizures, which can impair pulmonary vasoreactivity and induce pulmonary vasospasm. As RV failure progresses, RV output further declines, and the pulmonary valve opening time shortens significantly. In extreme cases, only brief spurts of red blood cells are ejected into the PA before the pulmonary valve rapidly shuts—if any forward flow exists at all. When there is no forward flow across the pulmonary valve—meaning no effective ejection from the RV through the RV outflow tract into the main pulmonary artery—the pulmonary valve remains closed. This hemodynamic state is referred to as "functional pulmonary atresia." 

Rising RV end-diastolic pressure (RVEDP) leads to a significant increase in right atrial (RA) pressure, promoting a right-to-left shunt at the atrial level. This shunt introduces deoxygenated systemic venous blood directly into the left atrium (LA), where it mixes with pulmonary venous return. If the lungs efficiently oxygenate any blood that reaches them—provided there is no underlying pulmonary pathology or ventilation-perfusion mismatch— the limited pulmonary blood flow comes back to the left atrium appropriately oxygenated. The high PVR limits pulmonary blood flow, thereby reducing venous return to the LA. As a result, LA pressure drops, further exacerbating the right-to-left interatrial shunt. The volume of shunted blood depends on the size of the interatrial communication and the RA-LA pressure gradient.

The systemic consequences of RV failure are profound. Inferior and superior vena cava (IVC, SVC) dilation occurs due to venous congestion, and hepatomegaly is common from hepatic congestion. However, if the RA decompresses effectively via a large atrial shunt, RA pressure may quasi-normalize, potentially mitigating liver congestion. A failing RV can also have a significant impact on LV function. With severely reduced RV output, pulmonary blood flow is diminished, leading to decreased pulmonary venous return and, consequently, low LV preload. As a result, the LA and LV become underfilled (and the LA often appears small), which directly contributes to a reduction in LV output and systemic perfusion. Additionally, the failing RV is often dilated, leading to interventricular septal shift. This septal bowing or "pancaking" of the LV further compromises LV filling and contractility due to mechanical constraints within the shared pericardial space. As a result, both ventricles become functionally impaired, with the failing RV exacerbating LV dysfunction through a combination of low preload, altered ventricular geometry, and impaired compliance. 

Coronary perfusion:

One of the most critical repercussions of severe RV dysfunction is impaired coronary perfusion. Coronary circulation is diastolic-dependent, with perfusion occurring when aortic diastolic pressure exceeds RA pressure, allowing coronary blood to perfusion the myocardium and drain into the RA via the coronary sinus. When diastolic aortic pressure is low and RA pressure is high, the trans-coronary pressure gradient drops, severely compromising myocardial perfusion. This is particularly detrimental in the setting of increased myocardial oxygen demand from inotropic and vasopressor support. In this case, there was hepatomegaly, dilated subhepatic veins with retrograde flow and a dilated RA, suggesting markedly elevated RA pressure. The presence of a right-to-left interatrial shunt indicates that RA pressure is high enough to drive systemic venous blood into the left atrium. However, the shunt is unlikely to be fully decompressing the RA, leaving persistently elevated RA pressure that further impacts overall coronary sinus drainge. One critical consequence of this is impaired coronary perfusion. Coronary sinus pressure is likely elevated due to high RA pressure, which reduces the trans-coronary pressure gradient, making it more difficult for coronary blood flow to adequately perfuse the myocardium (dilated coronary arteries are often seen because of this). This is further exacerbated by low systemic diastolic pressure, which diminishes the driving force for coronary circulation. Additionally, severe RV dilation increases transmural pressure, further restricting subendocardial coronary flow. This is compounded by the cardiac hypertrophy, likely a result of maternal diabetes, which increases myocardial oxygen demand. The hypertrophied myocardium, combined with a high endogenous adrenergic load from stress and exposure to cardiovascular medications for the management, significantly raises metabolic demand, worsening the supply-demand mismatch. Ultimately, this constellation of factors—impaired coronary perfusion, increased myocardial oxygen demand, and restricted oxygenation due to compromised pulmonary circulation—creates the perfect storm for myocardial ischemia and dysfunction. The result is a vicious cycle in which worsening myocardial ischemia further reduces cardiac function, exacerbating hemodynamic instability and perpetuating the cycle of RV failure, poor LV output, and systemic hypoperfusion.

In this infant, additional metabolic stressors, including persistent neonatal hypoglycemia, likely compounded myocardial dysfunction. Hypoglycemia—potentially related to maternal diabetes as well as increased metabolic demands from seizures—limits the substrate availability for anaerobic energy production in the myocardium. Furthermore, autonomic dysregulation from seizures and perinatal asphyxia, combined with exposure to multiple antiseizure medications known to affect vascular tone, likely contributed to hemodynamic instability. Finally, left ventricular (LV) preload was significantly reduced due to low pulmonary blood flow, further impairing systemic cardiac output. Given these complex interactions, therapeutic interventions must be carefully tailored. Strategies should aim to optimize RV support, maintain adequate coronary perfusion, and ensure sufficient pulmonary blood flow, all while minimizing the deleterious effects of excessive inotropic and vasopressor stimulation.

Management considerations

In cases of severe RV dysfunction with elevated afterload and compromised pulmonary blood flow, the choice of inotropic and vasodilatory support must be carefully tailored to optimize both RV and LV function while preserving coronary and systemic perfusion.

For this patient, the decision was made to initiate dobutamine as the primary inotropic agent to support the failing RV. Given the already high lactate (epinephrine can increase lactate) and relative bradycardia (HR ~100 bpm), dobutamine was chosen to enhance RV contractility while also providing a modest increase in chronotropy to improve RV output (27 mL/kg/min) and LV output (88 mL/kg/min). Additionally, dobutamine may have a mild pulmonary vasodilatory effect, which could help promote forward flow into the pulmonary artery. Epinephrine would have also been a potential therapeutic choice, as it support inotropy. Dopamine was stopped because it tends to increase PVR. 

To further reduce RV afterload and rescue RV function, inhaled nitric oxide (iNO) was initiated to lower PVR, facilitating more efficient RV ejection into the pulmonary circulation. Reducing PVR in this context is critical to preventing complete RV failure and maintaining some degree of forward flow across the pulmonary valve.

Vasopressin was also introduced, with two key objectives:

1. Optimize the PVR/SVR ratio, thereby helping to balance systemic and pulmonary vascular resistances.

2. Increase diastolic systemic pressure, improving coronary perfusion by enhancing the trans-coronary pressure gradient. This is particularly important in the setting of elevated RA pressure, which can impair coronary flow.

Additional Considerations

• Hydrocortisone stress-dose supplementation was considered due to the risk of relative adrenal insufficiency, given the perinatal asphyxia and potential adrenal hypoxia. Adrenal dysfunction can contribute to refractory hypotension and poor vascular tone, making corticosteroid support an important adjunct in select cases.

• Prostaglandin E1 (PGE1) was another key consideration in this case. In settings of diminished pulmonary blood flow with a small, restrictive left-to-right PDA, reopening the ductus with PGE could augment pulmonary blood flow, increase pulmonary venous return, and raise LA pressure, thereby reducing the right-to-left interatrial shunt and promoting LV preload. However, in this specific context, PGE1 must be considered while still being aware of the potential risks:

  • PGE-mediated vasodilation could further lower diastolic systemic pressure, leading to coronary steal, worsening myocardial perfusion.

  • A large unrestrictive left-to-right ductal shunt could create a significant diastolic runoff, exacerbating low systemic perfusion and coronary perfusion in diastole. This is particularly true when iNO is on board. 

  • It is important to Doppler the Right and Left Pulmonary arteries in order to evaluate if there is appreciatable velocities and stroke distance in the branch pulmonary arteries. If so, the PDA is able to feed the main pulmonary artery that feeds the branch PA and as such, one may consider going stepwise depending on the clinical scenarios. In the situation where systemic diastolic blood pressure is adequate or acceptable, one may consider intiate PGE from the onset. 

  • However, as mentioned, prostaglandin E1 (PGE) therapy can be beneficial by maintaining ductal patency to provide pulmonary blood flow. This, in turn, increases left atrial pressure through pulmonary venous return, reducing the right-to-left atrial shunt. PGE may also provide some pulmonary vascular dilatation effect. 

Given these concerns, the approach to PGE1 administration required extreme caution. A stepwise approach was favored, with vigilant monitoring and frequent repeat TnECHO assessments to evaluate the evolving hemodynamic state. If initial strategies to reduce RV afterload, optimize diastolic pressure, and improve cardiac contractility failed, then a trial of PGE1 would be strongly considered under close surveillance to assess its effects on systemic and coronary perfusion.

In some cases, paradoxically, once RV function begins to recover and output through the RV outflow tract (RVOT) increases, the ductal shunt may develop a bidirectional or even right-to-left component, leading to differential oxygen saturations. Initially, these infants often present with profound cyanosis and no pre- and post-ductal saturation differences. A significant volume of desaturated blood enters the systemic circulation at the atrial level, depending on the size of the foramen ovale and RV end-diastolic pressure. Hepatomegaly is often prominent due to systemic venous congestion.

If medical therapy fails, extracorporeal membrane oxygenation (ECMO) remains a potential life-saving intervention for these particularly challenging cases. The choice between veno-venous (VV) ECMO and veno-arterial (VA) ECMO depends on the degree of biventricular dysfunction and the overall hemodynamic state of the patient.

• VV ECMO can provide adequate pulmonary blood flow and oxygenation, helping to reduce pulmonary vascular resistance (PVR) through the vasodilatory effects of improved oxygen delivery. This would, in turn, restore preload to the left atrium (LA) and left ventricle (LV), improve LV-RV interaction, and enhance LV output, ultimately optimizing systemic oxygenation and perfusion.

• VA ECMO may be necessary if there is severe biventricular dysfunction, where LV output (LVO) is significantly depressed, and the circulation requires full cardiac support. In these cases, VA ECMO ensures adequate systemic perfusion while also bypassing the failing heart.

However, the decision to initiate ECMO must be carefully weighed against long-term prognosis and the goals and values of the family. The complexity of this physiology, the potential for prolonged cardiac dysfunction, and the uncertainty regarding long-term neurodevelopmental outcomes require open, transparent discussions with the family to align treatment strategies with their expectations and wishes. If the patient is undergoing therapeutic hypothermia (TH) at the time of ECMO consideration, the effects of cooling on PVR must also be taken into account. TH can exacerbate pulmonary vasoconstriction, potentially worsening RV dysfunction. The risks and benefits of continuing or actively rewarming the patient should be carefully deliberated with the family, taking into consideration the overall clinical trajectory. Ultimately, these situations require highly individualized, patient-centered management, as there is currently no clear consensus or robust trial data guiding the optimal approach in this rare and complex physiology. The decision-making process must integrate multidisciplinary expertise, ongoing reassessment of the patient's response to interventions, and thoughtful, family-centered discussions to ensure the best possible outcome.

Targeted Neonatal Echocardiography Views

Selected Clips

Doppler in the pulmonary vein. This confirms that there is pulmonary blood flow coming back to the LA and it is not a case of total anomalous pulmonary venous return. Further, it confirms that there is blood flow arriving within the pulmonary vascular bed and returning via the pulmonary veins. This flow depends on the ductus arteriosus. At this point, we are not in a situation where there is no flow in the pulmonary vasculature. However, there is likely insufficient flow.