Inhaled nitric oxide in preterm infants: an individual-patient data meta-analysis of randomized trials.

BACKGROUND: Inhaled nitric oxide (iNO) is an effective therapy for pulmonary hypertension and hypoxic respiratory failure in term infants. Thirteen randomized controlled trials (n 3430 infants) have been conducted on preterm infants at risk for chronic lung disease (CLD). The results of these studies seem contradictory. DESIGN/METHODS: Individual-patient data meta-analysis included randomized controlled trials of preterm infants (37 weeks’ gestation). Dichotomous outcomes were analyzed by using log-binomial regression models that adjusted for trial differences and correlation between siblings from multiple births. RESULTS: 3298 Infants from 11 trials (96% data). There was no statistically significant effect of iNO on death or CLD (59% vs 61%: relative risk [RR]: 0.96 [95% confidence interval (CI): 0.92–1.01]; P .11) or severe neurologic events on imaging (25% vs 23%: RR: 1.12 [95% CI: 0.98 –1.28]; P.09). There were no statistically significant differences in iNO effect according to any of the patient-level characteristics tested. In trials that used a starting iNO dose of 5 vs 5 ppm there was evidence of improved outcome (interaction P .02); however, these differences were not observed at other levels of exposure to iNO. This result was driven primarily by 1 trial, which also differed according to overall dose, duration, timing, and indication for treatment; a significant reduction in death or CLD (RR: 0.85 [95% CI: 0.74–0.98]) was found. CONCLUSIONS: Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended. The use of a higher starting dose might be associated with improved outcome, but because there were differences in the designs of these trials, it requires further examination.