Inhaled Nitric Oxide in preterm infants: a systematic review and individual patient data meta-analysis

BACKGROUND: Preterm infants requiring assisted ventilation are at significant risk of both pulmonary and cerebral injury. Inhaled Nitric Oxide, an effective therapy for pulmonary hypertension and hypoxic respiratory failure in the full term infant, has also been studied in preterm infants. The most recent Cochrane review of preterm infants includes 11 studies and 3,370 participants. The results show a statistically significant reduction in the combined outcome of death or chronic lung disease (CLD) in two studies with routine use of iNO in intubated preterm infants. However, uncertainty remains as a larger study (Kinsella 2006) showed no significant benefit for iNO for this combined outcome. Also, trials that included very ill infants do not demonstrate significant benefit. One trial of iNO treatment at a later postnatal age reported a decrease in the incidence of CLD. The aim of this individual patient meta-analysis is to confirm or refute these potentially conflicting results and to determine the extent to which patient or treatment characteristics may explain the results and/or may predict benefit from inhaled Nitric Oxide in preterm infants. METHODS/DESIGN: The Meta-Analysis of Preterm Patients on inhaled Nitric Oxide (MAPPiNO) Collaboration will perform an individual patient data meta-analysis to answer these important clinical questions. Studies will be included if preterm infants receiving assisted ventilation are randomized to receive inhaled Nitric Oxide or to a control group. The individual patient data provided by the Collaborators will be analyzed on an intention-to-treat basis where possible. Binary outcomes will be analyzed using log-binomial regression models and continuous outcomes will be analyzed using linear fixed effects models. Adjustments for trial differences will be made by including the trial variable in the model specification. DISCUSSION: Thirteen (13) trials, with a total of 3567 infants are eligible for inclusion in the MAPPiNO systematic review. To date 11 trials (n = 3298, 92% of available patients) have agreed to participate. Funding was successfully granted from Ikaria Inc as an unrestricted grant. A collaborative group was formed in 2006 with data collection commencing in 2007. It is anticipated that data analysis will commence in late 2009 with results being publicly available in 2010

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. 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 (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