Inhaled Nitric Oxide Treatment of Early Pulmonary Hypertension to Reduce the Risk of Death or Bronchopulmonary Dysplasia in Infants Born Extremely Preterm: A Masked Randomized Controlled Trial

Objective: To determine whether inhaled nitric oxide (iNO) treatment of early pulmonary hypertension (PH) would decrease the risk of death or bronchopulmonary dysplasia (BPD) among infants born extremely preterm.

Study design: This was a single-center, masked, randomized controlled trial involving infants born at ≤29 weeks' gestation and requiring positive pressure ventilation. Exclusion criteria included infants of COVID-19 positive mothers, large patent ductus arteriosus with left to right shunting, left ventricle dysfunction (ejection fraction <40%), significant congenital anomalies/genetic disorders, or iNO treatment by clinicians prior to the study echocardiogram. Initial echocardiogram was performed at 72 ± 24 hours of life to randomize infants with early PH into 2 study arms (iNO vs placebo). Serial echocardiograms were performed every 24-48 hours, up to 14 days of life. Treatment was weaned until PH resolved (responders) or if no improvement was documented ≥72-hours (nonresponders). Primary outcome was death or BPD at 36-weeks postmenstrual age.

Results: From July 2019 to October 2023, 683 eligible infants were admitted. We excluded 88 infants; 413 mothers declined consent or were not approached. iNO treatment was clinically started for 51 infants due to hypoxic respiratory failure. Screening echocardiograms were completed for 180 infants; of these, 32 infants with early PH were randomized to iNO or placebo groups. After a planned interim analysis, termination of the trial was recommended by the Data Safety Monitoring Committee because of futility.

Conclusion: iNO treatment does not reduce the risk of BPD or death among extremely preterm infants with echocardiographic evidence of early pulmonary hypertension without hypoxic respiratory failure.