Inhaled nitric oxide in premature neonates with severe hypoxaemic respiratory failure: a randomised controlled trial

Lancet. 1999 Sep 25;354(9184):1061-5. doi: 10.1016/s0140-6736(99)03558-8.


Background: Inhaled nitric oxide improves oxygenation and lessens the need for extracorporeal-membrane oxygenation in full-term neonates with hypoxaemic respiratory failure and persistent pulmonary hypertension, but potential adverse effects are intracranial haemorrhage and chronic lung disease. We investigated whether low-dose inhaled nitric oxide would improve survival in premature neonates with unresponsive severe hypoxaemic respiratory failure, and would not increase the frequency or severity of intracranial haemorrhage or chronic lung disease.

Methods: We did a double-blind, randomised controlled trial in 12 perinatal centres that provide tertiary care. 80 premature neonates (gestational age < or = 34 weeks) with severe hypoxaemic respiratory failure were randomly assigned inhaled nitric oxide (n=48) or no nitric oxide (n=32, controls). Our primary outcome was survival to discharge. Analysis was by intention to treat. We studied also the rate and severity of intracranial haemorrhage, pulmonary haemorrhage, duration of ventilation, and chronic lung disease at 36 weeks' postconceptional age.

Findings: The two groups did not differ for baseline characteristics or severity of disease. Inhaled nitric oxide improved oxygenation after 60 min (p=0.03). Survival at discharge was 52% in the inhaled-nitric-oxide group and 47% in controls (p=0.65). Causes of death were mainly related to extreme prematurity and were similar in the two groups. The two groups did not differ for adverse events or outcomes (intracranial haemorrhage grade 2-4, 28% inhaled nitric oxide and 33% control; pulmonary haemorrhage 13% and 9%; chronic lung disease 60% and 80%).

Interpretation: Low-dose inhaled nitric oxide improved oxygenation but did not improve survival in severely hypoxaemic premature neonates. Low-dose nitric oxide in the most critically ill premature neonates does not increase the risk of intracranial haemorrhage, and may decrease risk of chronic lung injury.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Administration, Inhalation
  • Bronchodilator Agents / administration & dosage
  • Bronchodilator Agents / adverse effects
  • Bronchodilator Agents / therapeutic use*
  • Cerebral Hemorrhage / chemically induced
  • Double-Blind Method
  • Female
  • Gestational Age
  • Humans
  • Hypoxia / drug therapy*
  • Infant, Newborn
  • Infant, Premature*
  • Lung Diseases / prevention & control
  • Male
  • Nitric Oxide / administration & dosage
  • Nitric Oxide / adverse effects
  • Nitric Oxide / therapeutic use*
  • Respiratory Distress Syndrome, Newborn / classification
  • Respiratory Distress Syndrome, Newborn / drug therapy*
  • Respiratory Distress Syndrome, Newborn / mortality
  • Severity of Illness Index
  • Treatment Outcome


  • Bronchodilator Agents
  • Nitric Oxide