Oral sildenafil in infants with persistent pulmonary hypertension of the newborn: a pilot randomized blinded study. Inhaled nitric oxide for the early treatment of persistent pulmonary hypertension of the term newborn: a randomized, double-masked, placebo-controlled, dose-response, multicenter study. The I-NO/PPHN Study Group.
Persistent pulmonary hypertension (PPHN) occurs in as many as 6.8 of 1000 live births. Mortality is approximately 10% to 20% with high-frequency ventilation, surfactant, inhaled nitric oxide, and extracorporeal membrane oxygenation but is much higher when these therapies are not available. Sildenafil is a phosphodiesterase inhibitor type 5 that selectively reduces pulmonary vascular resistance.
                Our goal was to evaluate the feasibility of using oral sildenafil and its effect on oxygenation in PPHN.
                This study was a proof-of-concept, randomized, masked study in infants >35.5 weeks' gestation and <3 days old with severe PPHN and oxygenation index (OI) >25 admitted to the NICU (Hospital Niño Jesús, Barranquilla, Colombia). The sildenafil solution was prepared from a 50-mg tablet. The first dose (1 mg/kg) or placebo was given by orogastric tube <30 minutes after randomization and every 6 hours. Preductal saturation and blood pressure were monitored continuously. OI was calculated every 6 hours. The main outcome variable was the effect of oral sildenafil on oxygenation. Sildenafil or placebo was discontinued when OI was <20 or if there was no significant change in OI after 36 hours.
                Six infants with an OI of >25 received placebo, and 7 received oral sildenafil at a median age of 25 hours. All infants were severely ill, on fraction of inspired oxygen 1.0, and with similar ventilatory parameters. Intragastric sildenafil and placebo were well tolerated. In the treatment group, OI improved in all infants within 6 to 30 hours, all showed a steady improvement in pulse oxygen saturation over time, and none had noticeable effect on blood pressure; 6 of 7 survived. In the placebo group, 1 of 6 infants survived.
                Oral sildenafil was administered easily and tolerated as well as placebo and improved OI in infants with severe PPHN, which suggests that oral sildenafil may be effective in the treatment of PPHN and underscores the need for a large, controlled trial. To assess the dose-related effects of inhaled nitric oxide (I-NO) as a specific adjunct to early conventional therapy for term infants with persistent pulmonary hypertension (PPHN), with regard to neonatal outcome, oxygenation, and safety.
                Randomized, placebo-controlled, double-masked, dose-response, clinical trial at 25 tertiary centers from April 1994 to June 1996. The primary endpoint was the PPHN Major Sequelae Index ([MSI], including the incidence of death, extracorporeal membrane oxygenation (ECMO), neurologic injury, or bronchopulmonary dysplasia [BPD]). Patients required a fraction of inspired oxygen [FIO2] of 1.0, a mean airway pressure >/=10 cm H2O on a conventional ventilator, and echocardiographic evidence of PPHN. Exogenous surfactant, concomitant high-frequency ventilation, and lung hypoplasia were exclusion factors. Control (0 ppm) or nitric oxide (NO) (5, 20, or 80 ppm) treatments were administered until success or failure criteria were met. Due to slowing recruitment, the trial was stopped at N = 155 (320 planned).
                The baseline oxygenation index (OI) was 24 +/- 9 at 25 +/- 17 hours old (mean +/- SD). Efficacy results were similar among NO doses. By 30 minutes (no ventilator changes) the PaO2 for only the NO groups increased significantly from 64 +/- 39 to 109 +/- 78 Torr (pooled) and systemic arterial pressure remained unchanged. The baseline adjusted time-weighted OI was also significantly reduced in the NO groups (-5 +/- 8) for the first 24 hours of treatment. The MSI rate was 59% for the control and 50% for the NO doses (P = .36). The ECMO rate was 34% for control and 22% for the NO doses (P = .12). Elevated methemoglobin (>7%) and nitrogen dioxide (NO2) (>3 ppm) were observed only in the 80 ppm NO group, otherwise no adverse events could be attributed to I-NO, including BPD.
                For term infants with PPHN, early I-NO as the sole adjunct to conventional management produced an acute and sustained improvement in oxygenation for 24 hours without short-term side effects (5 and 20 ppm doses), and the suggestion that ECMO use may be reduced.
Sildenafil in the treatment of PPHN has significant potential especially in resource limited settings. However, a large scale randomised trial comparing sildenafil with the currently used vasodilator, inhaled nitric oxide, is needed to assess efficacy and safety.