Introduction
Persistent pulmonary hypertension of the newborn (PPHN) is one of the most feared complications in neonatal medicine. It represents a failure of circulatory adaptation at birth, where the pulmonary arteries remain abnormally constricted, preventing the normal transition from intrauterine to extrauterine life. The result is hypoxemia that is difficult to correct and, in severe cases, life-threatening. Mortality rates remain high, and survivors may face long-term neurodevelopmental impairment.
The gold standard of therapy in high-income countries is inhaled nitric oxide (iNO), a selective pulmonary vasodilator. It has saved countless newborn lives but comes with serious limitations: it is expensive, technically demanding, and unavailable in many resource-limited settings. Worse still, about one-third of infants fail to respond to iNO at all. This reality has spurred the search for affordable alternatives that can be delivered in neonatal intensive care units (NICUs) without sophisticated infrastructure.
Two candidates stand out: sildenafil, a phosphodiesterase-5 inhibitor, and bosentan, an endothelin receptor antagonist. Both drugs are orally available and theoretically capable of reducing pulmonary arterial pressure. But which works better, and how quickly? The recent randomized controlled trial (RCT) from India directly compared them in neonates with PPHN. Its findings shed new light on how clinicians might rethink pharmacological strategies in the absence of iNO.
Understanding the Pathophysiology of PPHN
PPHN arises when pulmonary vascular resistance fails to fall after birth. Normally, the first breaths, oxygen exposure, and biochemical signals trigger relaxation of pulmonary arterioles. In PPHN, this mechanism breaks down, leading to sustained high pulmonary arterial pressure (PAP), right-to-left shunting across the foramen ovale or ductus arteriosus, and profound hypoxemia.
The etiology is varied. PPHN can accompany meconium aspiration syndrome, pneumonia, sepsis, or idiopathic cases without clear lung pathology. It is especially problematic in late preterm and term infants, though occasional preterm cases occur. Regardless of cause, the underlying theme is maladaptive vascular tone, compounded in some infants by structural remodeling of the pulmonary vasculature.
Therapeutic strategies target two goals: lowering pulmonary vascular resistance and maintaining systemic perfusion. Oxygen and mechanical ventilation form the baseline, but when these are insufficient, pharmacological vasodilation becomes essential. iNO provides a direct, rapid, selective route to pulmonary vasodilation. Without it, clinicians turn to systemic agents like sildenafil or bosentan, which act less selectively but remain feasible in settings without specialized equipment.
Sildenafil: The Well-Studied Workhorse
Sildenafil enhances nitric oxide signaling by inhibiting phosphodiesterase-5, the enzyme responsible for breaking down cyclic GMP. By preserving cGMP levels, sildenafil prolongs smooth muscle relaxation and dilates pulmonary vessels.
Evidence for its role in PPHN has accumulated over two decades. A 2017 Cochrane review concluded that sildenafil reduces mortality and improves oxygenation in neonates, particularly in countries where iNO is unavailable. It is inexpensive, orally administered, and relatively safe, though hypotension and gastrointestinal side effects occasionally occur.
The main limitation of sildenafil is that its onset of action is not instantaneous. Unlike iNO, which works within minutes, sildenafil requires enteral absorption and systemic circulation. Still, in many NICUs across Asia, Africa, and Latin America, sildenafil has become the de facto alternative therapy for PPHN, bridging the gap between ideal and feasible care.
Bosentan: The New Contender
Bosentan works on a different pathway. It antagonizes endothelin-1 receptors (both ETA and ETB), preventing one of the most powerful endogenous vasoconstrictors from exerting its effects. In theory, blocking endothelin signaling should reduce pulmonary arterial pressure and improve blood flow.
Its use in adults with pulmonary arterial hypertension (PAH) is well established. In neonates, however, the evidence is thin and mixed. Some retrospective studies and small RCTs suggested that bosentan could improve oxygenation and reduce pulmonary pressures, especially when combined with iNO. Yet, other trials failed to demonstrate clear benefits. The pharmacokinetics of bosentan in neonates are poorly understood, and absorption may be slow in the early postnatal period.
Nevertheless, the appeal is clear: an oral agent with a novel mechanism that bypasses the nitric oxide pathway. For infants who fail sildenafil or iNO, bosentan represents hope—at least in theory.
The Indian RCT: Design and Methods
The trial by Kallimath and colleagues was conducted at a tertiary care NICU in Pune, India, between July 2022 and January 202412887_2024_Article_5107. It enrolled 36 neonates with confirmed PPHN, defined as pulmonary arterial systolic pressure (PASP) > 35 mmHg and oxygen requirement above room air. Importantly, infants with major congenital heart disease or diaphragmatic hernia were excluded, ensuring a relatively homogeneous population.
The infants were randomized into two groups:
- Sildenafil group: received 2 mg/kg orally every 6 hours.
- Bosentan group: received 1 mg/kg orally every 12 hours.
The primary outcome was clear and clinically relevant: reduction of PASP by 25% within 48 hours of starting therapy. Secondary outcomes included changes in oxygen requirement (FiO₂), oxygen saturation (SpO₂), ventilation needs, hospital stay, and mortality. Functional echocardiography was used to measure PASP daily, providing objective hemodynamic data.
The study was modest in size but rigorously designed, representing one of the few head-to-head comparisons of these two agents in neonates.
Results: The Verdict Favors Sildenafil
At baseline, the two groups were well matched in maternal and neonatal characteristics. Both had mean PASP around 46 mmHg, and oxygen requirements were similar.
The differences emerged quickly after treatment began:
- Time to achieve a 25% reduction in PASP: median 36 hours for sildenafil vs. 96 hours for bosentan (p = 0.008).
- Treatment failure rate: 16.6% in sildenafil group vs. 66.6% in bosentan group (p = 0.002).
- Need for additional vasodilators: 16.6% in sildenafil group vs. 61.1% in bosentan group (p = 0.006).
- Oxygen requirement: decreased significantly more at 24 hours with sildenafil (p = 0.021).
In terms of safety, both drugs were generally well tolerated. Only one infant in each group developed hypotension, and there was a single death in the sildenafil group due to multisystem inflammatory syndrome rather than direct drug toxicity.
Taken together, the findings strongly suggest that sildenafil provides faster and more reliable hemodynamic improvement in neonates with PPHN compared to bosentan.
Discussion: Why the Difference?
Why did sildenafil outperform bosentan so clearly in this trial? Several factors may explain it.
First, pharmacokinetics: sildenafil is absorbed and acts relatively quickly, while bosentan’s absorption is slower, particularly in neonates with immature gut function. In a condition like PPHN, where every hour counts, onset of action is critical.
Second, pathophysiology: the nitric oxide–cGMP pathway may be more directly relevant to PPHN than the endothelin pathway, at least in the acute phase. Endothelin may contribute to chronic vascular remodeling, but acute pulmonary vasoconstriction appears to respond better to cGMP modulation.
Third, dose and schedule: sildenafil was given every 6 hours, maintaining steady plasma levels. Bosentan, in contrast, was dosed every 12 hours, potentially leading to fluctuating efficacy. The neonatal pharmacodynamics of bosentan remain poorly studied, making it difficult to optimize dosing.
Finally, clinical context: this study was performed in a resource-limited setting without iNO. In such environments, clinicians need rapid, reliable improvement. Bosentan’s potential benefits may be more nuanced or delayed, rendering it less useful as a first-line monotherapy.
Clinical Implications
The implications of this trial are both practical and philosophical.
On the practical side, the message is clear: in NICUs without access to iNO, sildenafil should remain the first-choice oral vasodilator for PPHN. It is inexpensive, effective, and supported by a growing body of evidence. Bosentan, while intriguing, appears slower, less consistent, and in greater need of further study.
On the philosophical side, the trial reminds us that neonatal pharmacology is not simply a matter of repurposing adult drugs. Mechanisms that succeed in adult pulmonary arterial hypertension may not translate directly to the fragile physiology of newborns. Neonatal circulation, absorption, and metabolism are unique, and so must be our therapeutic approaches.
Moreover, this study underscores the value of locally generated evidence. While global guidelines often emphasize iNO, they may not reflect the realities of resource-limited countries. Trials like this provide context-specific data that can guide clinicians working under constraints.
Strengths and Limitations of the Study
The trial had several strengths: randomized design, objective echocardiographic outcomes, and relevance to real-world practice in low- and middle-income countries. It directly addressed a critical evidence gap.
However, limitations must be acknowledged. The sample size was small, raising the risk of type II error for secondary outcomes. The open-label design introduced potential bias, as blinding was not feasible due to different dosing schedules. Finally, long-term outcomes—such as neurodevelopmental status—were not assessed. These limitations do not diminish the importance of the findings but highlight the need for larger multicenter trials.
Conclusion
Persistent pulmonary hypertension of the newborn remains a formidable challenge, especially in resource-limited settings where iNO is unavailable. The recent RCT from India provides compelling evidence that oral sildenafil achieves faster and more consistent improvement in pulmonary pressures than bosentan.
Both drugs were well tolerated, but bosentan required additional vasodilator support far more often, limiting its value as monotherapy. While bosentan’s role in neonatal care is not yet settled, sildenafil remains the pragmatic, evidence-backed choice for clinicians seeking to improve outcomes in infants struggling with this life-threatening condition.
Future research should continue to explore bosentan, perhaps in combination therapy or in carefully selected subgroups. For now, however, the verdict is clear: when seconds matter, sildenafil delivers.
FAQ
1. Why is sildenafil preferred over bosentan in PPHN?
Sildenafil works faster and more reliably, reducing pulmonary arterial pressures within 36 hours, whereas bosentan may take up to 96 hours. In critically ill neonates, this time difference can be decisive.
2. Is bosentan unsafe for newborns?
No. In the trial, bosentan was well tolerated, with no major safety concerns. The problem is not safety but efficacy—bosentan acted more slowly and required additional vasodilators in most infants.
3. Could bosentan still have a role in PPHN management?
Possibly. Bosentan may be useful as an adjunctive therapy, in cases where sildenafil alone is insufficient, or in chronic pulmonary hypertension beyond the neonatal period. More research is needed to clarify its role.
