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Original Investigation
September 25, 2017

Effect of Inhaled Nitric Oxide on Survival Without Bronchopulmonary Dysplasia in Preterm InfantsA Randomized Clinical Trial

Author Affiliations
  • 1Department of Pediatrics, Cumming School of Medicine, University of Calgary, Alberta Children’s Hospital Research Institute, Calgary, Alberta, Canada
  • 2Mallinckrodt Pharmaceuticals, Hampton, New Jersey
  • 3Department of Pediatrics, Medical College of Wisconsin, Milwaukee
  • 4Department of Neonatology, Winnie Palmer Hospital, Pediatrix Medical Group, Orlando, Florida
  • 5Department of Pediatrics, Stanford University School of Medicine, Palo Alto, California
  • 6Lucile Packard Children’s Hospital Stanford, Palo Alto, California
  • 7Division of Neonatology, Department of Pediatrics, University of South Carolina School of Medicine, Greenville
  • 8Department of Pediatrics, University of Utah School of Medicine, Salt Lake City
JAMA Pediatr. Published online September 25, 2017. doi:10.1001/jamapediatrics.2017.2618
Key Points

Question  Does inhaled nitric oxide initiated on postnatal days 5 to 14 and continued for 24 days improve survival without bronchopulmonary dysplasia in preterm infants younger than 30 weeks’ gestation?

Findings  In this randomized clinical trial of 451 infants, no differences were observed in mortality, incidence of bronchopulmonary dysplasia, or respiratory or neurodevelopmental outcomes between the placebo and inhaled nitric oxide groups at 36 weeks’ postmenstrual age, 1 year, or 18 to 24 months’ postmenstrual age.

Meaning  This study provides evidence that inhaled nitric oxide administration does not improve survival without bronchopulmonary dysplasia or neurodevelopmental outcomes in very preterm infants.

Abstract

Importance  Bronchopulmonary dysplasia (BPD) occurs in approximately 40% of infants born at younger than 30 weeks’ gestation and is associated with adverse pulmonary and neurodevelopmental outcomes.

Objective  To test whether administration of inhaled nitric oxide to preterm infants requiring positive pressure respiratory support on postnatal days 5 to 14 improves the rate of survival without BPD.

Design, Setting, and Participants  This intent-to-treat study was a randomized clinical trial performed at 33 US and Canadian neonatal intensive care units. Participants included 451 neonates younger than 30 weeks’ gestation with birth weight less than 1250 g receiving mechanical ventilation or positive pressure respiratory support on postnatal days 5 to 14. Enrollment spanned from December 23, 2009, to April 23, 2012, and neurodevelopmental outcome studies were completed by April 4, 2014.

Interventions  Placebo (nitrogen) or inhaled nitric oxide initiated at 20 ppm was decreased to 10 ppm between 72 and 96 hours after starting treatment and then to 5 ppm on day 10 or 11. Infants remained on the 5-ppm dose until completion of therapy (24 days).

Main Outcomes and Measures  The primary outcome was the rate of survival without BPD at 36 weeks’ postmenstrual age (PMA). Secondary outcomes included BPD severity, postnatal corticosteroid use, respiratory support, survival, and neurodevelopmental outcomes at 18 to 24 months’ PMA.

Results  In total, 222 infants (52.3% male [n = 116]) received placebo, and 229 infants (50.2% male [n = 115]) received inhaled nitric oxide. Their mean (SD) gestation was 25.6 (1.5) vs 25.6 (1.4) weeks, and their mean (SD) birth weight was 750 (164) vs 724 (160) g. Survival without BPD at 36 weeks’ PMA was similar between the placebo and inhaled nitric oxide groups (31.5% [n = 70] vs 34.9% [n = 80]) (odds ratio, 1.17; 95% CI, 0.79-1.73). Rates for severe BPD (26.6% [55 of 207] vs 20.5% [43 of 210]) and postnatal corticosteroid use for BPD (41.0% [91 of 222] vs 41.5% [95 of 229]) and the mean (SD) days of positive pressure respiratory support (55 [40] vs 54 [42]), oxygen therapy (88 [41] vs 91 [59]), and hospitalization (105 [37] vs 108 [54]) were equivalent between the 2 groups. No differences in the incidence of common morbidities were observed. Respiratory outcomes on discharge to home, at 1 year, and at age 18 to 24 months’ PMA and neurodevelopmental assessments at 18 to 24 months’ PMA did not differ between groups.

Conclusions and Relevance  Inhaled nitric oxide, initiated at 20 ppm on postnatal days 5 to 14 to high-risk preterm infants and continued for 24 days, appears to be safe but did not improve survival without BPD at 36 weeks’ PMA or respiratory and neurodevelopmental outcomes at 18 to 24 months’ PMA.

Trial Registration  clinicaltrials.gov Identifier: NCT00931632

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