Inhaled nitric oxide for respiratory failure in preterm infants

Cochrane Database Syst Rev. 2006 Jan 25:(1):CD000509. doi: 10.1002/14651858.CD000509.pub2.


Background: Inhaled nitric oxide has been proven effective in term infants with hypoxic respiratory failure. The pathophysiology of respiratory failure, and the potential risks, differ substantially in preterm infants. Analysis of the efficacy and toxicities of inhaled nitric oxide in infants born before 35 weeks is therefore necessary.

Objectives: To determine whether, in preterm newborn infants (< 35 weeks gestation) who have hypoxic respiratory failure, treatment with inhaled nitric oxide improves oxygenation within 2 hours and reduces the rates of death, bronchopulmonary dysplasia, intraventricular haemorrhage, or neurodevelopmental disability

Search strategy: Standard methods of the Cochrane Neonatal Review Group were used. We searched MEDLINE, EMBASE, Healthstar and the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), using the following keywords: nitric oxide, clinical trial, newborn, and covering years from 1985 to 2005. In addition, we searched the abstracts of the Pediatric Academic Societies.

Selection criteria: Randomised and quasi randomised studies in preterm infants with hypoxic respiratory failure. Administration of inhaled nitric oxide compared to control with or without placebo. Clinically relevant outcomes that were analysed included death, bronchopulmonary dysplasia (defined as oxygen dependence at 36 weeks postconceptional age), intraventricular haemorrhage, long term neurodevelopmental outcome and short term effects on oxygenation.

Data collection and analysis: Standard methods of the Cochrane Neonatal Review Group were used. Two investigators extracted, assessed and coded separately all data for each study. Any disagreement was resolved by discussion.

Main results: Seven randomised controlled trials of inhaled nitric oxide therapy in preterm infants were found. One study consisted of infants determined to have a high risk of developing bronchopulmonary dysplasia (Subhedar 1997). One study studied routine use of inhaled NO in all ventilated preterm infants (Schreiber 2003). The remaining studies consisted of infants with high predicted mortality based on poor oxygenation (Kinsella 1999; Hascoet 2005; INNOVO 2005; Van Meurs 2005; Mercier 1999). No significant effect of inhaled nitric oxide on mortality or bronchopulmonary dysplasia was demonstrated. There was no evidence of effect on the risk of intraventricular haemorrhage. There may be short term improvements in oxygenation. Two studies (Schreiber 2003; INNOVO 2005) have so far presented data on long term neurodevelopmental outcome, one of which demonstrated improved outcome at two years corrected age.

Authors' conclusions: The currently published evidence from randomised trials does not support the use of inhaled nitric oxide in preterm infants with hypoxic respiratory failure. Further studies may need to be performed to evaluate the potential benefit of routine use of this therapy in infants with milder forms of respiratory failure, and these trials will need to be designed to evaluate not only neonatal survival, and the occurrence of neonatal morbidities, but should be powered to evaluate neurodevelopmental outcome at a minimum of two years of age.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Administration, Inhalation
  • Bronchopulmonary Dysplasia / mortality
  • Bronchopulmonary Dysplasia / prevention & control
  • Cerebral Hemorrhage / epidemiology
  • Humans
  • Incidence
  • Infant, Newborn
  • Infant, Premature
  • Infant, Premature, Diseases / therapy*
  • Nitric Oxide / administration & dosage*
  • Randomized Controlled Trials as Topic
  • Respiratory Insufficiency / therapy*
  • Vasodilator Agents / administration & dosage*


  • Vasodilator Agents
  • Nitric Oxide