Hasan Shabih U, Potenziano Jim, Konduri Girija G, Perez Jose A, Van Meurs Krisa P, Walker M Whit, Yoder Bradley A
Department of Pediatrics, Cumming School of Medicine, University of Calgary, Alberta Children's Hospital Research Institute, Calgary, Alberta, Canada.
Mallinckrodt Pharmaceuticals, Hampton, New Jersey.
JAMA Pediatr. 2017 Nov 1;171(11):1081-1089. doi: 10.1001/jamapediatrics.2017.2618.
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.
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.
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).
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.
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.
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.
clinicaltrials.gov Identifier: NCT00931632.
支气管肺发育不良（BPD）发生于约40%孕龄小于30周出生的婴儿中，且与不良的肺部和神经发育结局相关。
测试在出生后第5至14天需要正压呼吸支持的早产儿中给予吸入一氧化氮是否能提高无BPD存活几率。
设计、地点和参与者：这项意向性治疗研究是在美国和加拿大33个新生儿重症监护病房进行的一项随机临床试验。参与者包括451名孕龄小于30周、出生体重小于1250克、在出生后第5至14天接受机械通气或正压呼吸支持的新生儿。入组时间从2009年12月23日至2012年4月23日，神经发育结局研究于2014年4月4日完成。
安慰剂（氮气）或起始浓度为20 ppm的吸入一氧化氮在开始治疗后72至96小时降至10 ppm，然后在第10或11天降至5 ppm。婴儿持续使用5 ppm剂量直至治疗结束（24天）。
主要结局是在月经龄（PMA）36周时无BPD的存活几率。次要结局包括BPD严重程度、出生后使用皮质类固醇、呼吸支持、存活情况以及在PMA 18至24个月时的神经发育结局。
总共222名婴儿（52.3%为男性[n = 116]）接受安慰剂，229名婴儿（50.2%为男性[n = 115]）接受吸入一氧化氮。他们的平均（标准差）孕龄分别为25.6（1.5）周和25.6（1.4）周，平均（标准差）出生体重分别为750（164）克和724（160）克。在PMA 36周时，安慰剂组和吸入一氧化氮组无BPD的存活几率相似（31.5%[n = 70]对34.9%[n = 80]）（优势比，1.17；95%置信区间，0.79 - 1.73）。两组间重度BPD发生率（26.6%[207例中的55例]对
