Pulmonary hypertension and acute hypoxic respiratory failure in preterm neonates

Pulmonary hypertension (PH) in preterm infants is a complex and heterogeneous condition that significantly contributes to hypoxic respiratory failure (HRF), bronchopulmonary dysplasia (BPD), and mortality. Unlike term infants, PH in preterm neonates arises from multiple overlapping pathophysiological mechanisms and distinct hemodynamic phenotypes. These diverse phenotypes complicate diagnosis and limit the effectiveness of uniform treatment approaches. Despite increasing recognition of this heterogeneity, current literature and clinical guidelines provide limited clarity on the optimal diagnosis and management of HRF with PH in preterm infants. In particular, the role of inhaled nitric oxide (iNO) remains highly controversial in this population. Although advances in targeted neonatal echocardiography and functional hemodynamic assessment have enhanced our ability to characterize cardiovascular physiology at the bedside, the integration of these tools into standardized management strategies remains inconsistent. As a result, clinical decision-making in preterm infants with PH is often variable and not clearly guided by evidence-based frameworks. This narrative review provides a comprehensive, physiology-based overview of the diagnosis and management strategies for acute PH and HRF in preterm infants, with a focus on the controversies surrounding iNO use and the role of inotropic and vasoactive agents in optimizing hemodynamics. While iNO may improve oxygenation in selected cases, randomized trials have not demonstrated reductions in mortality or BPD in preterm infants, and concerns persist regarding an increased risk of severe intraventricular hemorrhage. Accordingly, management should be guided by the underlying physiological phenotype, integrating clinical assessment, serial functional echocardiographic evaluations, and targeted therapeutic strategies to optimize outcomes in this vulnerable population.