title: 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.
  
  
  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.
authors.affiliation: National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia. laskie@ctc.usyd.edu.au
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Askie
authors.forename: Roberta A
authors.initials: RA
authors.lastname: Ballard
authors.forename: Gary R
authors.initials: GR
authors.lastname: Cutter
authors.forename: Carlo
authors.initials: C
authors.lastname: Dani
authors.forename: Diana
authors.initials: D
authors.lastname: Elbourne
authors.forename: David
authors.initials: D
authors.lastname: Field
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Hascoet
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Hibbs
authors.forename: John P
authors.initials: JP
authors.lastname: Kinsella
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Mercier
authors.forename: Wade
authors.initials: W
authors.lastname: Rich
authors.forename: Michael D
authors.initials: MD
authors.lastname: Schreiber
authors.forename: Pimol Srisuparp
authors.initials: PS
authors.lastname: Wongsiridej
authors.forename: Nim V
authors.initials: NV
authors.lastname: Subhedar
authors.forename: Krisa P
authors.initials: KP
authors.lastname: Van Meurs
authors.forename: Merryn
authors.initials: M
authors.lastname: Voysey
authors.forename: Keith
authors.initials: K
authors.lastname: Barrington
authors.forename: Richard A
authors.initials: RA
authors.lastname: Ehrenkranz
authors.forename: Neil N
authors.initials: NN
authors.lastname: Finer
mesh_terms: D000280:Administration, Inhalation; D001993:Bronchodilator Agents / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D055370:Lung Injury / Q000209:etiology / Q000517:prevention & control; D009569:Nitric Oxide / Q000008:administration & dosage*; D016032:Randomized Controlled Trials as Topic; D012127:Respiratory Distress Syndrome, Newborn / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D012306:Risk; D016896:Treatment Outcome
chemical_list: D001993:Bronchodilator Agents; D009569:Nitric Oxide