IMPROVED OXYGENATION IN A RANDOMIZED TRIAL OF INHALED NITRIC-OXIDE FOR PERSISTENT PULMONARY-HYPERTENSION OF THE NEWBORN

Objective. To determine the effect of inhaled nitric oxide (NO) on cli nical outcome in newborns with persistent pulmonary hypertension (PPHN ). Design. A prospective, randomized trial of patients referred to a l evel 3 nursery in a single large center. Clinicians were not masked to group assignment. Crossover of patients from control to NO treatment was not permitted. Methods. We randomized 49 mechanically ventilated n ewborns, transferred to our center with clinical and echocardiographic evidence of severe PPHN (arterial oxygen tension [PaO2] <100; fractio nal inspired oxygen = 1) to treatment with or without NO. Patients wit h gestational age <34 weeks or with congenital heart disease or diaphr agmatic hernia were excluded. High-frequency oscillatory ventilation w as used but not allowed concomitantly with NO. Primary outcome variabl es were oxygenation, mortality, and use of extracorporeal membrane oxy genation (ECMO). Results. Meconium aspiration syndrome and isolated PP HN were the most common diagnoses (32/49) and were distributed equally between groups. The median age at the time of entry into the study wa s similar between groups, 25 hours for control patients and 18 hours f or NO patients. Median baseline oxygenation index (OI) was similar in 23 control (OI = 29) and 26 NO (OI = 30) patients. Mortality (8%), use of ECMO (33%), median days on mechanical ventilation (9 days), and du ration of supplemental oxygen (13 days) were not different between tre atment groups. PaO2, oxygen saturation, and OI improved in the NO grou p compared with baseline and to control patients at 15 minutes. The me dian percent change in OI (-31%) in the NO group was significantly dif ferent from baseline and from the control group. The difference in oxy genation between treatment groups was still apparent 12 hours after ba seline. Before cannulation for ECMO, oxygenation was better in the NO group compared with control patients. Among patients who were placed o n ECMO, the median time from baseline to ECMO cannulation was 2.4 hour s (range, 1 to 12 hours) among control patients and 3.3 hours (range, 2 to 68 hours) for those randomized to receive NO. There was a tendenc y to observe fewer adverse neurologic events (seizure and intracranial hemorrhage) in the NO group (4/26 vs 8/23). One child with alveolar c apillary dysplasia confirmed by postmortem examination could not be we aned from 80 parts per million of NO and transiently developed methemo globinemia (peak methemoglobin level = 17%). No other side effects wer e observed. Conclusions. Although mortality and ECMO use were similar for both treatment groups using this study size and design, sustained improvement in oxygenation with NO and better oxygenation at initiatio n of ECMO may have important clinical benefits. We speculate that modi fication of treatment to include specific lung expansion strategies wi th NO treatment and recognition that early improvement of oxygenation may be sustained with NO may lead to reduced use of ECMO in NO treated patients compared with controls.