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

Objectives. To assess the dose-related effects of inhaled nitric oxide (I-NO) as a specific adjunct to early conventional therapy for term i nfants with persistent pulmonary hypertension (PPHN), with regard to n eonatal outcome, oxygenation, and safety. Methods. Randomized, placebo -controlled, double-masked, dose-response, clinical trial at 25 tertia ry centers from April 1994 to June 1996. The primary endpoint was the PPHN Major Sequelae Index ([MSI], including the incidence of death, ex tracorporeal membrane oxygenation (ECMO), neurologic injury, or bronch opulmonary dysplasia [BPD]). Patients required a fraction of inspired oxygen [FIO2] of 1.0, a mean airway pressure >10 cm H2O on a conventio nal ventilator, and echocardiographic evidence of PPHN. Exogenous surf actant, concomitant high-frequency ventilation, and lung hypoplasia we re 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 = 15 5 (320 planned). Results. The baseline oxygenation index (OI) was 24 /- 9 at 25 +/- 17 hours old (mean +/- SD). Efficacy results were simil ar among NO doses. By 30 minutes (no ventilator changes) the PaO2 for only the NO groups increased significantly from 64 +/- 39 to 109 +/- 7 8 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 E CMO rate was 34% for control and 22% for the NO doses (P = .12). Eleva ted methemoglobin (>7%) and nitrogen dioxide (NO,) (>3 ppm) were obser ved only in the 80 ppm NO group, otherwise no adverse events could be attributed to I-NO, including BPD. Conclusion. For term infants with P PHN, early I-NO as the sole adjunct to conventional management produce d an acute and sustained improvement in oxygenation for 24 hours witho ut short-term side effects (5 and 20 ppm doses), and the suggestion th at ECMO use may be reduced.