Inhaled nitric oxide for prevention of bronchopulmonary dysplasia in premature babies (EUNO): a randomised controlled trial.
BACKGROUND
In animal models, inhaled nitric oxide improved gas exchange and lung structural development, but its use in premature infants at risk of developing bronchopulmonary dysplasia remains controversial. We therefore tested the hypothesis that inhaled nitric oxide at a low concentration, started early and maintained for an extended period in babies with mild respiratory failure, might reduce the incidence of bronchopulmonary dysplasia.


METHODS
800 preterm infants with a gestational age at birth of between 24 weeks and 28 weeks plus 6 days (inclusive), weighing at least 500 g, requiring surfactant or continuous positive airway pressure for respiratory distress syndrome within 24 h of birth were randomly assigned in a one-to-one ratio to inhaled nitric oxide (5 parts per million) or placebo gas (nitrogen gas) for a minimum of 7 days and a maximum of 21 days in a double-blind study done at 36 centres in nine countries in the European Union. Care providers and investigators were masked to the computer-generated treatment assignment. The primary outcome was survival without development of bronchopulmonary dysplasia at postmenstrual age 36 weeks. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00551642.


RESULTS
399 infants were assigned to inhaled nitric oxide, and 401 to placebo. 395 and 400, respectively, were analysed. Treatment with inhaled nitric oxide and placebo did not result in significant differences in survival of infants without development of bronchopulmonary dysplasia (258 [65%] of 395 vs 262 [66%] of 400, respectively; relative risk 1.05, 95% CI 0.78-1.43); in survival at 36 weeks' postmenstrual age (343 [86%) of 399 vs 359 [90%] of 401, respectively; 0.74, 0.48-1.15); and in development of bronchopulmonary dysplasia (81 [24%] of 339 vs 96 [27%] of 358, respectively; 0.83, 0.58-1.17).


CONCLUSIONS
Early use of low-dose inhaled nitric oxide in very premature babies did not improve survival without bronchopulmonary dysplasia or brain injury, suggesting that such a preventive treatment strategy is unsuccessful.


BACKGROUND
INO Therapeutics.
Mercier
Jean-Christophe
JC
Assistance Publique-Hôpitaux de Paris, Université Paris-7 Denis Diderot, Hôpital Robert Debré, Paris, France. jean-christophe.mercier@rdb.aphp.fr
Hummler
Helmut
H
Durrmeyer
Xavier
X
Sanchez-Luna
Manuel
M
Carnielli
Virgilio
V
Field
David
D
Greenough
Anne
A
Van Overmeire
Bart
B
Jonsson
Baldvin
B
Hallman
Mikko
M
Baldassarre
James
J
D000280:Administration, Inhalation; D001997:Bronchopulmonary Dysplasia / Q000150:complications / Q000453:epidemiology* / Q000208:ethnology / Q000517:prevention & control*; D045422:Continuous Positive Airway Pressure; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005062:European Union / Q000706:statistics & numerical data; D005260:Female; D016166:Free Radical Scavengers / Q000008:administration & dosage*; D005865:Gestational Age; D006801:Humans; D002534:Hypoxia, Brain / Q000209:etiology / Q000517:prevention & control; D015994:Incidence; D007231:Infant, Newborn; D007234:Infant, Premature; D008297:Male; D009569:Nitric Oxide / Q000008:administration & dosage*; D016019:Survival Analysis; D016896:Treatment Outcome
D016166:Free Radical Scavengers; D009569:Nitric Oxide