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

Abstract

Background: Inhaled nitric oxide (iNO) is an effective therapy for pulmonary hypertension and hypoxic respiratory failure in term infants. Fourteen randomized controlled trials (n = 3430 infants) have been conducted on preterm infants at risk for chronic lung disease (CLD). The study results seem contradictory.

Design/methods: Individual-patient data meta-analysis included randomized controlled trials of preterm infants (<37 weeks' gestation). Outcomes were adjusted for trial differences and correlation between siblings.

Results: Data from 3298 infants in 12 trials (96%) were analyzed. 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.

Figures

FIGURE 1

Primary outcomes. All P > .05 (χ2 test for heterogeneity). RRs, CIs, and P values were derived from 1000 iterations of a log-binomial model using the multiple-outputation method.

FIGURE 2

Secondary outcomes. RRs, CIs, and P values were derived from 1000 iterations of a log-binomial model using the multiple-outputation method. a χ2 test for heterogeneity: P = .04; all other P > .05. IVH indicates intraventricular hemorrhage; ROP, retinopathy of prematurity.

FIGURE 3

Death or CLD according to subgroup. All P > .05 for subgroup-by-treatment interaction effects. Estimates were derived from 1000 iterations of a Poisson regression model with robust error variance using the multiple-outputation method. PDA indicates patent ductus arteriosus.

FIGURE 4

Severe neurologic events according to subgroup. All P > .05 for subgroup-by-treatment interaction effects. Estimates were derived from 1000 iterations of a Poisson regression model with robust error variance using the multiple-outputation method. PDA indicates patent ductus arteriosus.

FIGURE 5

Death or CLD according to dosage. Estimates were derived from 1000 iterations of a Poisson regression model with robust error variance using the multiple-outputation method.

FIGURE 6

Death or CLD according to trial. All P > .05 (χ2 test for heterogeneity). Estimates were derived from 1000 iterations of a log-binomial model using the multiple-outputation method.