Case March 2025 - Pre-Post differences in a premature infant

Case by Gabriel Altit -  - Posted February 21st, 2025

A mother presented to the birthing center with profoundly decreased fetal movements over the past 24 hours. Upon evaluation, the fetal tracing demonstrated poor variability and severe bradycardia, with a heart rate of 75 bpm. Given these findings, the obstetrical team proceeded with an emergency cesarean section. A premature infant, born at 30 weeks' gestation, was delivered in the context of significant perinatal asphyxia. There was no history of antepartum hemorrhage, such as placental abruption or previa. The initial cord blood gas revealed a pH of 6.8, pCO₂ of 42 mmHg, bicarbonate of 6 mmol/L, and a base excess of -18, indicative of severe metabolic acidosis. The initial hemoglobin was 157 g/L.

The infant was intubated in the delivery room and required 12 minutes of chest compression, 2 dosages of intravenous epinephrine and one normal saline bolus. The baby was brought to the NICU and managed on high-frequency oscillatory ventilation (HFOV) with a mean airway pressure (MAP) of 12 cmH₂O and an FiO₂ of 100%. The patient received surfactant therapy. The chest radiograph was not typical for respiratory distress syndrome and demonstrated an oligemic pattern with good expansion. In the first few hours of life, the infant remained acidotic and developed hypoxic respiratory failure, prompting further evaluation. Blood cultures were obtained, and empirical antibiotic therapy was initiated. 

At the time of assessment, the systemic blood pressure via the umbilical arterial line was 29/10 mmHg, and the infant had been anuric since birth. A significant pre- and post-ductal saturation difference was noted, with pre-ductal oxygen saturation at 85% and post-ductal saturation at 65%. Neurologically, the infant was poorly responsive to stimulation, exhibiting significant hypotonia and encephalopathy, raising concerns for hypoxic-ischemic brain injury. The infant exhibited poor perfusion, generalized mottling, and a prolonged capillary refill time of approximately 4 seconds. Pulses were weak in both the upper and lower extremities. There was distant heart sounds on the high frequency ventilation but a Normal S1S2 were perceived with possibly the presence of a S3 (although heart rate was quite fast in the 160s). There was a systolic 1/6 murmur at the lower sternal border and a 1/6 diastolic murmur at the right upper sternal border. No radiation was noticed. The liver edge was palpable 2-3 cm below the costal margin. The abdomen was soft and non-distended.

Lactate levels were markedly elevated at 22 mmol/L. A repeat arterial blood gas, obtained from the umbilical arterial line, showed pH 6.7, pCO₂ 38 mmHg, HCO₃⁻ 5 mmol/L, BE -19, with a PaO₂ of 37 mmHg. Blood glucose was within the normal range at 4.8 mmol/L, and electrolyte levels were acceptable (Na 133 mmol/L, K 4.8 mmol/L, Ca 1.1 mmol/L). 

Pathophysiology

This is a case of left ventricular (LV) stunning. It is a functional single ventricular physiology, analogous to hypoplastic left heart syndrome. There is minimal LV motion (almost no contraction), leading to profoundly depressed LV output. In this scenario, the patent ductus arteriosus (PDA) remains widely open, with a right-to-left shunt, as the right ventricle (RV) is sustaining systemic circulation. This is a ductal dependent systemic circulation. In this particular patient, the PDA is wide open and unrestrictive. While there is some degree of RV dysfunction, the LV dysfunction is significantly more severe. This case is particularly striking due to the presence of profound pre- and post-ductal saturation differences. This is because the right to left shunt at the ductal level brings deoxygenated blood into the aorta - which is essential for maintaining systemic and coronary perfusion. The systemic circulation relies on retrograde flow from the pulmonary artery (PA) through the PDA into the aorta, ensuring blood supply to the body.  Coronary perfusion is dependent on this retrograde filling of the aorta. 

Notably, during systole, retrograde flow is observed in the pre-ductal descending aorta, meaning that the PDA is actively filling the pre-ductal aorta in a retrograde manner. This is evidenced by clear retrograde flow in the pre-ductal aorta, compensating for the severely reduced forward LV output. While most of the blood entering the aorta via the PDA is directed toward the descending aorta, the relative underfilling of the ascending aorta allows for some retrograde compensation, leading to pre-ductal desaturation—though typically not as severe as the post-ductal desaturation. This is an important observation because, in normal physiology, a patient with only an interatrial left-to-right shunt (PFO) should not have pre-ductal desaturation, unless ventilation-perfusion (V/Q) mismatch is present (or if there is another right to left shunt at the ventricular level). In this case, retrograde flow in the aortic arch further contributes to pre-ductal desaturation. 

We often observe retrograde flow in the aorta in the context of cerebral vasodilation due to asphyxia, seizures, or loss of cerebro-vascular autoregulation. Seizures, in particular, can lead to vasomotor instability, further exacerbated by the vasodilatory effects of antiseizure medications. Typically, retrograde flow related to cerebral vasodilation is seen in diastole, affecting the entire aorta. However, in our case presented here, retrograde flow occurs during systole, reinforcing the fact that systemic circulation is dependent on PA-to-aorta shunting via the PDA. As such, the retrograde flow observed here is not in diastole, but in systole, and likely predominantly secondary to the poor LV function and dramatically decreased LV output. 

Another crucial hemodynamic feature in this case is the completely left-to-right interatrial shunt at the PFO, driven by significantly elevated LV end-diastolic pressure (LVEDP). This results in higher left atrial (LA) pressure relative to right atrial (RA) pressure, leading to continuous LA-to-RA flow. Since LA pressure equalizes with LV pressure during diastole when the mitral valve is open, a failing LV that cannot effectively empty its preload exacerbates LA hypertension, reinforcing the left-to-right interatrial shunt. 

The diagram above summarizes the hemodynamic parameters, including estimated chamber pressures derived from the targeted neonatal echocardiography images shown below, and the clinical data (systemic blood pressure, PDA gradient, and RV-RA gradient assessed via tricuspid regurgitation jet). Additionally, I have included saturation values, illustrating where blood mixing occurs and explaining the mechanisms behind the observed pre- and post-ductal saturation differences. 

As mentioned, pre-ductal desaturation in this case is likely secondary to the retrograde flow in the aortic arch, carrying deoxygenated blood from the PA (via the PDA) into the pre-ductal aorta. However, other potential contributors to the pre-ductal territorial desaturation include: V/Q mismatch due to pulmonary disease, as well as V/Q mismatch in the setting of pulmonary venous congestion. Indeed, high LVEDP can lead to high LA pressure which can impeded pulmonary venous drainage and eventually cause pulmonary edema.

Management for Severe LV/Biventricular Dysfunction with PDA-Dependent Systemic Circulation

The management of this case revolves around optimizing systemic and pulmonary perfusion while addressing the underlying biventricular dysfunction. The key goals include:

1. Supporting right ventricular (RV) and left ventricular (LV) function

2. Ensuring adequate systemic perfusion

3. Maintaining pulmonary blood flow

4. Preventing further hemodynamic deterioration

Supporting Right and Left Ventricular Function: Given that RV function is sustaining systemic circulation through the right-to-left PDA shunt, while LV function remains profoundly depressed, targeted support is essential:

• • Epinephrine or Dobutamine are first-line choices to enhance contractility and provide mild chronotropic effects, improving cardiac output and systemic perfusion.

  • Milrinone may lead to profound hypotension and the risk for renal accumulation. These patients often have acute kidney injury and SiADH, which puts them at risk of accumulating milrinone, leading to profound hypotension. Milrinone does not act quickly. This patient requires inotropic support that will act rapidly to restore LV contractility and sustain RV output (which in this case is both providing pulmonary and systemic output). 

  • Vasopressor Therapy may increase systemic vascular resistance and worsen the LV dysfunction.

  • Pulmonary Vasodilation and Its Impact on Systemic Circulation: Inhaled nitric oxide (iNO) or other pulmonary vasodilators may effectively reduce pulmonary vascular resistance (PVR); however, this often occurs at the expense of increased systemic vascular resistance (SVR). This rise in SVR is a compensatory response to the low systemic blood flow, as the body auto-regulates by vasoconstricting to maintain arterial pressure. Since pressure is a function of flow × resistance, a drop in flow triggers an increase in resistance to compensate. A reduction in PVR may inadvertently shift ductal shunting toward the pulmonary circulation, further diverting flow away from the systemic circulation. Knowing that this is a ductal-dependent systemic circulation physiology, one should try to promote systemic flow. Indeed, adequate systemic blood flow through the ductus must be preserved, as systemic perfusion remains heavily dependent on right-to-left shunting through the PDA. Thus, pulmonary vasodilators should be avoided in the acute phase, at least until LV function improves. Once the LV recovers and can generate sufficient cardiac output, the patient may be in a state of elevated PVR (since these patients often experienced a distrubed post-natal transition, which may have affected the natural PVR drop). At which point, pulmonary vasodilation may be considered to facilitate forward RV output. However, in the immediate phase of this physiology, initiating iNO or other pulmonary vasodilators could be detrimental, as it may worsen systemic perfusion by increasing pulmonary steal. 

  • Avoiding excessive fluid repletion. Unless there is a history of blood loss or third-spacing, these patients may not tolerate excessive fluid repletion. Because of the acute kidney injury and often concomittant SiADH, they may actually be in fluid overload. Also, equally important, attempting over-diuresis or excessive fluid restriction could compromise systemic blood flow, particularly in the setting of low LV preload due to reduced pulmonary venous return. Careful volume management is required.

  • Maintaining Pulmonary Blood Flow: Since systemic circulation is PDA-dependent, prostaglandin E1 (PGE1) should be considered if the ductus becomes restrictive or closes. However, if the ductus is wide open, PGE1 may be on standby as the medication may lead to significant vasodilation and hypotension, dropping diastolic pressure and impacting coronary perfusion. If initated, the risk of PGE1-induced systemic vasodilation must be monitored closely, as it can lead to a drop in diastolic pressure and compromise coronary and systemic perfusion. In these situation, an increasing dose of an agent like epinephrine or introducing a small dose of a vasopressor may need to be considered.

  • A stepwise approach should be taken, with close monitoring of systemic blood pressure, PDA flow patterns, and cardiac output.

  • Consider ECMO if medical therapy fails: Veno-arterial (VA) ECMO may be considered if biventricular dysfunction is profound and systemic perfusion is critically low, and if the medical therapy has failed to rescue the phenotype. This is particularly true in situations where the RV is failing, leading to poor RV and LV output (since the RV drives both the pulmonary and systemic flow).  

The management of severe LV/biventricular dysfunction with PDA-dependent systemic circulation requires a careful balance of inotropic support, and PDA maintenance. The risk of PDA closure must be anticipated and aggressively managed, as systemic perfusion relies on continued right-to-left shunting. If medical therapy fails, ECMO may be required as a bridge to recovery. However, every intervention must be guided by ongoing hemodynamic assessment (TnECHO, blood gases, saturation trends, and clinical examination) to ensure optimal management tailored to the patient’s evolving physiology. Therapeutic decisions should be made in a multi-disciplinary fashion and with ongoing discussions with the family.

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