A narrative review of sildenafil dosing and monitoring by indication in neonatal pulmonary hypertension

Abstract

Pulmonary hypertension in the neonate is a leading contributor to hypoxemic respiratory failure and carries substantial mortality across diverse etiologies, including persistent pulmonary hypertension of the newborn (PPHN), bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH), and the early postoperative course after surgery for congenital heart disease. Congenital diaphragmatic hernia, which frequently involves complex, multifactorial physiology, is considered outside the scope of this review. Inhaled nitric oxide remains the established first-line selective pulmonary vasodilator but is unavailable, ineffective, or impractical in a substantial proportion of clinical scenarios, particularly in resource-limited neonatal units. Sildenafil, an orally and intravenously bioavailable phosphodiesterase type 5 (PDE5) inhibitor, has become the most widely used adjunctive or alternative pulmonary vasodilator in the neonatal intensive care unit, despite remaining off-label for this indication. This narrative review consolidates contemporary, neonatal-specific evidence on the use of sildenafil in newborns and young infants. It focuses on developmental pharmacokinetics, evidence-based oral and intravenous dosing regimens for the principal indications, a structured framework for hemodynamic and echocardiographic monitoring, an indication-stratified clinical algorithm, and the safety profile relevant to this age group. The review also addresses the practical implications of the United States Food and Drug Administration warning derived from the STARTS-2 trial for the neonatal population, summarises the differing positions of international regulators, and outlines persistent knowledge gaps. Although the available evidence supports sildenafil as a clinically useful adjunct to or substitute for inhaled nitric oxide in neonates, particularly in resource-limited settings where iNO is unavailable and only with careful hemodynamic monitoring, individualized dosing, structured monitoring, and explicit weaning protocols remain essential to its safe and effective use. What this review adds It consolidates contemporary neonatal-specific evidence on sildenafil and provides a single, indication-stratified resource for clinicians caring for newborns with pulmonary hypertension. It presents a practical, evidence-based dosing table by route and indication, together with a structured monitoring framework that can be adopted at the unit level. It clarifies the relevance and the limits of the 2012 FDA warning for the neonatal population, supporting continued judicious use of sildenafil at conventional doses for established neonatal indications. It consolidates contemporary neonatal-specific evidence on sildenafil and provides a single, indication-stratified resource for clinicians caring for newborns with pulmonary hypertension. It presents a practical, evidence-based dosing table by route and indication, together with a structured monitoring framework that can be adopted at the unit level. It clarifies the relevance and the limits of the 2012 FDA warning for the neonatal population, supporting continued judicious use of sildenafil at conventional doses for established neonatal indications. It provides a structured, bedside monitoring framework and an explicit, organ-system-based account of safety—including the graded management of sildenafil-associated hypotension and the limits of current long-term data—to support safe and standardised use.