Effect of early low-dose hydrocortisone on survival without bronchopulmonary dysplasia in extremely preterm infants (PREMILOC): a double-blind, placebo-controlled, multicentre, randomised trial
Effect of early low-dose hydrocortisone on survival without bronchopulmonary dysplasia in extremely preterm infants (PREMILOC): a double-blind, placebo-controlled, multicentre, randomised trial
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DOI：
10.1016/s0140-6736(16)00202-6
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发表时间：
2016-04-30
期刊：
影响因子：
168.9
通讯作者：
Alberti, Corinne
中科院分区：
文献类型：
--
作者：
Baud, Olivier;Maury, Laure;Alberti, Corinne
背景 支气管肺发育不良是极度早产的主要并发症，治疗选择很少。产后类固醇的使用存在争议，但低剂量氢化可的松可能会防止炎症对发育中的肺部产生有害影响。在这项研究中，我们旨在评估低剂量氢化可的松是否可以提高极早产儿的生存率，而不会出现支气管肺发育不良。 方法 在这项在 21 个法国三级护理新生儿重症监护室 (NICU) 进行的双盲、安慰剂对照、随机试验中，我们通过安全研究网站将极早产儿（出生在与 NICU 同一地点的产科病房出生）随机分配（1:1）：妊娠不足 28 周，在产后 10 天内接受静脉注射低剂量氢化可的松或安慰剂。随机分配到氢化可的松组的婴儿每天接受 1 mg/kg 氢化可的松半琥珀酸酯，分为每天两次剂量，持续 7 天，然后每天接受一剂 0.5 mg/kg，持续 3 天。随机分组按胎龄分层，所有婴儿在出生后 24 小时内入组。研究人员、家长和患者对治疗分配情况不知情。主要结局是经后 36 周时无支气管肺发育不良的生存率。我们使用基于治疗意图的序贯分析设计，以避免在确定疗效或无效后延长试验时间。该试验在 ClinicalTrials.gov 注册，编号为 NCT00623740。结果在 2008 年 5 月 25 日至 2014 年 1 月 31 日期间对 1072 名新生儿进行了筛查，其中 523 名被随机分配（256 名氢化可的松，267 名安慰剂）。在父母撤回对每组中一名儿童的同意后，255 名服用氢化可的松的婴儿和 266 名服用安慰剂的婴儿被纳入分析。在接受氢化可的松治疗的 255 名婴儿中，有 153 名（60%）存活，没有出现支气管肺发育不良，而接受安慰剂治疗的 266 名婴儿中有 136 名（51%）存活（根据胎龄组和中期分析调整的比值比 [OR] 1.48，95% CI 1.02-2.16，p=0.04）。需要接受治疗才能获得无支气管肺发育不良生存的患者人数为 12 名（95% CI 6-200）。整个研究人群的脓毒症发生率没有显着差异，但亚组分析显示，仅在胎龄 24-25 周出生并接受氢化可的松治疗的婴儿中，脓毒症发生率较高（83 名婴儿中的 30 名 [40%] vs 90 名婴儿中的 21 名 [23%]；子危险比 1.87，95% CI 1.09-3.21，p=0.02）。其他潜在的不良事件，特别是胃肠道穿孔，在各组之间没有显着差异。 解释 在极早产儿中，预防性使用低剂量氢化可的松可显着提高经后 36 周时无支气管肺发育不良的生存率。这一基于生理学原理的策略可能会显着改善大多数早产儿的管理。
Background Bronchopulmonary dysplasia, a major complication of extreme prematurity, has few treatment options. Postnatal steroid use is controversial, but low-dose hydrocortisone might prevent the harmful effects of inflammation on the developing lung. In this study, we aimed to assess whether low-dose hydrocortisone improved survival without bronchopulmonary dysplasia in extremely preterm infants.Methods In this double-blind, placebo-controlled, randomised trial done at 21 French tertiary-care neonatal intensive care units (NICUs), we randomly assigned (1: 1), via a secure study website, extremely preterm infants inborn (born in a maternity ward at the same site as the NICU) at less than 28 weeks of gestation to receive either intravenous low-dose hydrocortisone or placebo during the first 10 postnatal days. Infants randomly assigned to the hydrocortisone group received 1 mg/kg of hydrocortisone hemisuccinate per day divided into two doses per day for 7 days, followed by one dose of 0.5 mg/kg per day for 3 days. Randomisation was stratified by gestational age and all infants were enrolled by 24 h after birth. Study investigators, parents, and patients were masked to treatment allocation. The primary outcome was survival without bronchopulmonary dysplasia at 36 weeks of postmenstrual age. We used a sequential analytical design, based on intention to treat, to avoid prolonging the trial after either efficacy or futility had been established. This trial is registered with ClinicalTrials.gov, number NCT00623740.Findings 1072 neonates were screened between May 25, 2008, and Jan 31, 2014, of which 523 were randomly assigned (256 hydrocortisone, 267 placebo). 255 infants on hydrocortisone and 266 on placebo were included in analyses after parents withdrew consent for one child in each group. Of the 255 infants assigned to hydrocortisone, 153 (60%) survived without bronchopulmonary dysplasia, compared with 136 (51%) of 266 infants assigned to placebo (odds ratio [OR] adjusted for gestational age group and interim analyses 1.48, 95% CI 1.02-2.16, p=0.04). The number of patients needed to treat to gain one bronchopulmonary dysplasia-free survival was 12 (95% CI 6-200). Sepsis rate was not significantly different in the study population as a whole, but subgroup analyses showed a higher rate only in infants born at 24-25 weeks gestational age who were treated with hydrocortisone (30 [40%] of 83 vs 21 [23%] of 90 infants; sub-hazard ratio 1.87, 95% CI 1.09-3.21, p=0.02). Other potential adverse events, including notably gastrointestinal perforation, did not differ significantly between groups.Interpretation In extremely preterm infants, the rate of survival without bronchopulmonary dysplasia at 36 weeks of postmenstrual age was significantly increased by prophylactic low-dose hydrocortisone. This strategy, based on a physiological rationale, could lead to substantial improvements in the management of the most premature neonates.