Does inhaled nitric oxide treatment of pulmonary hypertension in extremely premature infants improve patient outcomes?

Single-center double-blinded randomized control trial (RCT). Infants born less than or equal to 29 weeks’ gestation who received positive pressure ventilation at 72 ± 24 postnatal hours were eligible. Screening echocardiograms were obtained at 72 ± 24 postnatal hours. PH was defined according to patent ductus arteriosus (PDA) gradient, tricuspid regurgitant peak velocity (TRV max ), or end-systolic interventricular septal positioning. Echocardiography exclusion criteria included flow associated PH from a large left to right PDA, severe left ventricular (LV) dysfunction (ejection fraction less than 40%) and/or presence of a complex cardiac defect. Patients were also excluded for prior iNO use, genetic conditions, major anomalies, or maternal COVID history. Enrolled infants were categorized with moderate or severe PH. Moderate PH was characterized by an estimated pulmonary arterial pressure (PAP) greater than half to less than systemic systolic blood pressure (sBP) or flat end-systolic interventricular septum. Severe PH was characterized by estimated PAP equal or greater to systemic sBP or end-systolic septal bowing into the LV. Patients were randomized to receive 20 ppm iNO or placebo. Randomization was stratified by gestational age and PH severity, irrespective of oxygen requirement. Intervention response was measured daily for 72 h, then every 24–48 h up to 14 days. Response was qualified by changes in PAP on echocardiogram and/or respiratory response through respiratory severity score (RSS), SpO 2 / FiO 2 ratio, or oxygenation index (OI). Interventions were weaned as PH resolved on echocardiogram or if patients were non-responders after 72 h of intervention. Non-responders were characterized by a lack of improvement in PAP on serial echocardiograms and/or less than 10% improvement from baseline RSS, SpO 2 / FiO 2 ratio, or OI. Intervention weaning occurred over 24 h and was suspended for 24 h for rebound PH or 10% absolute increase in supplemental oxygen. The primary outcome was death or BPD at 36 weeks postmenstrual age. BPD was defined as requiring oxygen after a room air challenge or needing positive pressure ventilation. Statistical analysis for categorical variables and continuous variables were performed by Chi-square test or a Student’s t test/non-parametric tests, respectively. Relative risk was determined for the primary outcome. In total, 683 infants were screened; 180 patients were enrolled. Of these patients, 148 infants were excluded due to evidence of PH from a large left to right PDA, complex cardiac defects, or had prior iNO use. In total, 32 patients were randomized: 16 in each intervention arm, stratified by gestational age and PH severity. All, but one, infants were invasively ventilated and received surfactant. Two infants were categorized as severe PH, while the remaining had moderate PH. There were no differences in maternal or neonatal characteristics. There was no difference in the primary outcome of death or BPD (68% iNO group vs 62% placebo, p = 0.99). Treatment response within 72 h of therapy did not differ (68% iNO group vs 93% placebo, p = 0.17) Treatment duration did not differ between groups (median iNO therapy 99 h vs. 75 h placebo, p = 0.54). There were no differences in Grade 3 or 4 IVH (12.5% iNO vs. 12.5% placebo, p = 0.99), methemoglobinemia ( p = 0.68), necrotizing enterocolitis ( p = 0.23), LV dysfunction ( p = 0.99), PDA requiring treatment ( p = 0.99), hyperbilirubinemia ( p = 0.99), or thrombocytopenia ( p = 0.6) between groups. In total, 51 excluded infants received iNO clinically before enrollment and were more likely to have: lower gestational age (25.2 weeks vs. study cohort 26.2 weeks, p = 0.04), less antenatal steroids (65% vs. study cohort 94%, p < 0.01), lower 5 min APGARs (25% vs. study cohort 6%, p = 0.02), >60% FiO 2 to maintain SpO 2 > 85% for hypoxemic respiratory failure (HRF) (100% vs. study cohort 6%, p < 0.01), severe PH (29% vs. study cohort 6%, p = 0.01), any IVH (88% vs. study cohort 50%, p < 0.01) and death (47% vs. study cohort 6%, p < 0.01). The study ended at mid-interval data analysis. The authors concluded that iNO treatment for early PH without HRF may be futile. Similar treatment duration and responses were seen between intervention groups.