Example of acute PH and Prematurity

These infants are also extremely sensitive to therapeutic interventions, including changes in ventilation, lung volume, oxygen exposure, and pharmacotherapies, all of which can further modulate PVR. Mechanical ventilation, oxygen toxicity, pain, inflammation, and infection may therefore precipitate or worsen pulmonary vascular constriction. Preterm neonates may present with acute PH in the setting of delayed pulmonary vascular transition or early pulmonary vascular disease, often related to antenatal or postnatal stressors such as placental dysfunction, severe maternal hypertensive disorders with associated fetal growth restriction, chorioamnionitis, or early-onset sepsis. The cardiovascular consequences may include right ventricular dilation and/or dysfunction, tricuspid regurgitation, interventricular dependence, and, in more severe cases, biventricular dysfunction. Given this heterogeneity, early and comprehensive echocardiographic assessment is essential to define the dominant physiology, guide phenotype-specific management, and titrate therapies such as inhaled pulmonary vasodilators, ventilation strategies, and cardiovascular support across these diverse clinical presentations.

This case involves an extremely preterm infant with a reactive pulmonary vascular phenotype in the context of inflammation and surgical stress. The infant demonstrates right-to-left shunting at both the patent foramen ovale (PFO) and the patent ductus arteriosus (PDA), despite sensitively adequate systemic blood pressure. The PDA is large and unrestrictive, providing an effective right-ventricular pop-off into the systemic circulation. While this mechanism protects the right ventricle, it occurs at the expense of a markedly reduced Qp:Qs, resulting in decreased left-atrial preload and promotion of right-to-left atrial shunting. These effects are further amplified by impaired right-ventricular compliance in the setting of positive-pressure mechanical ventilation, culminating in significant hypoxemia. Breaking this vicious cycle requires optimization of pulmonary vasodilation and cardiopulmonary coupling. Key strategies include supporting ventilation and oxygenation, maximizing lung recruitment while avoiding hyperinflation, ensuring adequate postoperative analgesia, and considering low-dose hydrocortisone to support both the pulmonary and systemic vasculature in the context of inflammation and stress. Although inhaled nitric oxide (iNO) is not formally approved in extremely preterm infants, its use in this case was associated with a rapid clinical improvement in oxygenation, consistent with a reversible pulmonary vascular component. The targeted neonatal echocardiography (TnECHO) images below demonstrate a large, unrestrictive right-to-left PDA, a right-to-left PFO, and preserved right and left ventricular systolic function, supporting the diagnosis of an acute pulmonary hypertension phenotype driven predominantly by elevated pre-capillary pulmonary vascular resistance.

Management strategies to consider in this phenotype:

1. Ensure appropriate ventilation, but avoid hypocapnia (cerebral vasoconstriction) 

   1. Surfactant for RDS or Meconium Aspiration Syndrome

   2. Appropriate pulmonary recruitment (being aware that increasing MAP can be problematic in terms of cardio-respiratory interactions; high MAP can increase RV afterload and decrease cardiac preload).

2. Sedation/Analgesia may be indicated to avoid reactive increase in PVR 

3. Oxygen should be administered to aim 90-95% saturation. Oxygen is a pulmonary vasodilator but also toxic when exposed in excess. 

   1. Due to right to left shunt, there is a threshold at which FiO2 increase has no impact and excessive O2 may cause lung injury by reactive oxygen species 

4. Despite optimization of status, still high PVR and hypoxic:

   1. iNO is one of the only agent studied in RCT for hypoxic respiratory failure (often with acute PH / PPHN) in the term and near-term newborns

   2. Wean if not working; Wean once phenotype changes/resolves (implies reassessments)

5. Increasing data that vasopressors like vasopressin and norepinephrine may improve the PVR/SVR ratio in acute PH

6. PGE may be considered once PDA becomes restrictive as a pop-off for the RV (if there is RV failure), see below. 

7. Hydrocortisone should be considered in certain situations

   1. We do not recommend necessarily to base on cortisol level - Challenge with cortisol is the aspect of relative adrenal insufficiency. What is the normal values of cortisol in the context of significant stress. We know that some of these babies may have adrenal ischemia, hemorrhage, immaturity or sepsis which may all overwhelm the adrenal function and response. I personally do not rely solely on cortisol values and often consider hydrocortisone in babies with significant hemodynamic derangements. 

   2. Appropriate response to stress essential for maintenance of hemodynamic stability. Glucocorticosteroids  adrenergic receptors in smooth muscles, inhibits NO synthase expression and ↓ reuptake of norepinephrine leading to an increase in vascular tone and support of myocardial function. Effective in increasing BP and decrease inotropic support. No study: improved clinical outcomes with steroids in newborn shock 

   3. Hydrocortisone normalizes PDE-5 activity in pulmonary artery smooth muscle cells from lambs with PPHN

TnECHO Imaging (selected clips)

Follow-up post-management

iNO 10 ppm

iNO 2 ppm