The stakes are high. PPHN affects roughly two to six infants per 1,000 live births worldwide and accounts for about 10 percent of neonatal intensive care deaths. In developing countries, reported mortality climbs to as high as 20 percent, a gap driven largely by inequities in access to the gold-standard therapies. Inhaled nitric oxide, which directly relaxes pulmonary vessels, and extracorporeal membrane oxygenation, which oxygenates blood outside the body, both require expensive infrastructure and specialist teams that many hospitals in low- and middle-income countries simply cannot provide. Even where nitric oxide is available, abruptly stopping it can trigger a dangerous rebound spike in lung pressures, and prolonged mechanical ventilation risks chronic lung injury.

Into this therapeutic vacuum steps sildenafil, a selective inhibitor of the enzyme phosphodiesterase type 5. By blocking the breakdown of cyclic guanosine monophosphate, or cGMP, sildenafil amplifies the nitric oxide signaling pathway that tells pulmonary arteries to dilate. The drug is cheap, stable, and can be given by mouth, making it an attractive option where inhaled therapies are out of reach. Previous trials and observational series, including work from Baquero and colleagues and more recent studies, have suggested that sildenafil can improve oxygenation in neonates with an acceptable safety profile, but the response varies with disease severity, underlying causes, and comorbidities such as sepsis or heart muscle dysfunction.

The Surabaya team mined electronic medical records for all neonates diagnosed with PPHN who received oral sildenafil between January 2024 and October 2025. To enter the paired before-and-after analysis, babies needed complete documented measurements of heart rate, respiratory rate, and peripheral oxygen saturation both before the first sildenafil dose and at the final assessment before the drug was stopped or the baby was discharged. Those who died, were transferred, or lacked complete records were excluded, a point that would later prove crucial for interpreting the results. The final cohort comprised 54 neonates, and because no commercial neonatal formulation of sildenafil exists, hospital staff crushed 20-milligram adult tablets and dispersed them in water immediately before each oral dose.

The demographic picture was strikingly consistent with known PPHN epidemiology. Every baby in the cohort began treatment within the first week of life, all within days zero to seven. Males outnumbered females 57.4 percent to 42.6 percent, and 87 percent were term infants, echoing the well-established pattern that PPHN preferentially strikes term or near-term babies whose circulations must make the dramatic transition from fetal to neonatal physiology. Nearly all weighed at least 2,500 grams at birth, and 98 percent never needed invasive mechanical ventilation, though a small number received continuous positive airway pressure. Comorbidity, however, was the rule rather than the exception, with metabolic or systemic disorders present in 74 percent, pulmonary diseases such as respiratory distress syndrome and meconium aspiration in 43 percent, sepsis in 26 percent, congenital heart defects in 20 percent, and birth asphyxia in nearly 15 percent.

The dosing patterns reveal the pragmatic reality of neonatal pharmacology in a tertiary Indonesian hospital. Nearly two-thirds of the infants, 63 percent, received doses above 0.5 milligrams per kilogram per dose, while the rest received less. The overwhelming majority, 96.3 percent, were dosed four times daily, reflecting the drug’s pharmacokinetic profile and the prevailing practice in neonatal PPHN. Treatment was typically brief: 70 percent of babies received sildenafil for a week or less, 28 percent for one to two weeks, and only a single infant for 15 days or more. The average duration was 6.4 days, with a range of 3 to 36 days, suggesting that most babies either stabilized quickly or had their therapy escalated or redirected. Dose selection and adjustment rested entirely on the clinical judgment of the attending neonatologists, since no standardized protocol governed the practice.

The headline clinical finding concerned breathing. The mean respiratory rate fell from 53.44 breaths per minute before treatment to 49.63 breaths per minute at the final documented assessment, a statistically significant decrease confirmed by the Wilcoxon signed-rank test with a p-value of 0.008. Heart rate, by contrast, remained essentially unchanged, edging from 137.28 to 136.87 beats per minute with no statistical significance, a stability that is pharmacologically reassuring in principle, since a falling heart rate in a critically ill neonate can signal either recovery or cardiovascular deterioration. Peripheral oxygen saturation rose numerically from 96.37 to 97.26 percent, but the change fell just short of significance at p equals 0.067, likely because many babies started near the ceiling of what pulse oximetry can register, a classic ceiling effect compounded by concurrent oxygen supplementation.

The authors are admirably candid about what these numbers cannot prove. Because every baby also received routine supportive care, most notably oxygen therapy, and because there was no comparator group receiving placebo or standard treatment alone, the observed improvements represent the combined effect of everything done in the unit, not the isolated action of sildenafil. The complete-case design compounds the problem: babies who died or were transferred had to be excluded from the paired analysis, and those infants were likely the sickest, meaning the favorable changes may be overestimated. Detailed information on oxygen delivery methods, concentrations, and timing was inconsistently recorded, so even the contribution of supportive therapy cannot be disentangled from the drug’s effect. The safety picture is similarly incomplete, as blood pressure changes and adverse events were not assessed under a standardized prospective monitoring protocol.

What the study does deliver is a rare, granular portrait of how sildenafil is actually prescribed in a real-world, resource-constrained environment, filling a gap left by most evidence, which comes from high-income countries and tightly controlled settings. It documents that Indonesian neonatologists are reaching for the higher end of the per-dose dosing range, favoring four-times-daily regimens, and generally achieving short treatment courses. It also confirms the expected epidemiology of PPHN in a tertiary referral population, with its heavy burden of comorbid disease shaping each baby’s trajectory. The pharmacological rationale remains sound: preserving cGMP should lower pulmonary vascular resistance and ease the work of breathing, and the significant respiratory rate reduction is consistent with that mechanism, even if causation cannot be claimed.

The research team concludes that prospective, controlled trials are now essential, ideally incorporating standardized sildenafil dosing protocols, comprehensive hemodynamic monitoring including blood pressure, and serial echocardiographic assessment of pulmonary pressures. Until such studies are done, oral sildenafil will continue to serve as an accessible lifeline in settings where inhaled nitric oxide is a luxury, and clinicians will weigh its growing but incomplete evidence base against the urgent needs of newborns whose lungs will not yet accept the air around them. For the 54 babies whose records told this story, the trajectory was, on balance, one of improvement, a cautiously hopeful signal from a drug that costs pennies but targets one of neonatal medicine’s most lethal failures of transition.

Subject of Research: Oral sildenafil use and clinical outcomes in neonates with persistent pulmonary hypertension of the newborn

Article Title: Utilization pattern of oral sildenafil and changes in clinical parameters among neonates with persistent pulmonary hypertension: A retrospective study in an Indonesian hospital

Article References: Yulistiani, Rohmaan, Y., Utomo, F. N., Nurhariansyah, R., Nusantara Ratri, D. M., Nilamsari, W. P., & Dewi, D. M. R. D. (2026). Utilization pattern of oral sildenafil and changes in clinical parameters among neonates with persistent pulmonary hypertension: A retrospective study in an Indonesian hospital. Pharmacia, 73, Article e205304. https://doi.org/10.3897/pharmacia.73.e205304

Image Credits: AI Generated

DOI: 10.3897/pharmacia.73.e205304

Keywords: persistent pulmonary hypertension of the newborn, sildenafil, neonatology, pulmonary vasodilator, oxygen saturation, retrospective study, Indonesia, neonatal intensive care, phosphodiesterase type 5 inhibitor, resource-limited settings, heart rate, respiratory rate