INHALED NITRIC OXIDE FOR PREVENTION OF CHRONIC LUNG DISEASE IN PREMATURE INFANTS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。吸入一氧化氮（iNO）治疗是一种安全有效的治疗足月新生儿持续性肺动脉高压和低氧性呼吸衰竭的方法。然而，对iNO在早产新生儿呼吸衰竭中的潜在作用知之甚少。早产新生儿特别容易受到呼吸机诱导的肺损伤、氧中毒和肺部炎症的不良影响，这些不良影响有助于慢性肺病（CLD）的发展。尽管外源性表面活性剂和类固醇治疗，CLD仍然是早产新生儿发病和死亡的主要原因。此外，越来越多的证据表明类固醇治疗会导致长期不良的神经发育和心肺后遗症。早期临床观察表明，低剂量iNO可改善早产儿的氧合，减少对机械呼吸机支持的需求。除了对气体交换的影响外，最近的实验室和临床观察表明，iNO还可能作为肺部特异性抗炎治疗，减少肺部炎症对早产儿急性和慢性肺损伤演变的贡献。为了开始解决低剂量一氧化氮（5ppm）在早产儿中的潜在作用，我们首先在极早产羔羊（妊娠115天，足月78%）中进行了一系列动物实验，然后在患有严重低氧性呼吸衰竭的早产儿中进行了低剂量一氧化氮的初步研究。我们的实验室实验表明：1)内源性NO在妊娠早期调节胎儿肺血管张力，过渡性过早肺循环扩张响应于iNO；2) iNO改善了严重呼吸窘迫综合征（RDS）早产儿的气体交换，使肺血管阻力持续降低，但不增加肺血管泄漏；3) iNO降低机械通气RDS早产儿羔羊肺中性粒细胞积累。这些实验室实验和其他实验为早产儿低剂量iNO的临床试验提供了依据。为了验证iNO可以改善早产新生儿的氧合而不增加出血并发症的假设，我们最近在患有严重低氧血症性呼吸衰竭的早产新生儿中进行了一项低剂量iNO的蒙面、随机、对照试验研究。我们认为，iNO在早产儿中的初步试验必须只包括病情最严重的患者，以产生判断安全性和有效性的数据。本研究旨在确定iNO对存活至出院（主要结局指标）和不良事件（次要结局指标：脑出血、脑室周围白质软化、肺出血、慢性肺病）的影响。在研究停止时，80名患者被随机分配到12个中心的两个胎龄层中，其中48名iNO患者和32名对照患者。在研究停止时（因为我们不太可能在建议的样本量上达到假设的死亡率差异），我们发现iNO治疗组和对照组的出院生存率没有差异（52%的iNO对47%的对照组）。然而，与之前的病例报告相比，我们发现两组之间的不良结局没有差异（ICH 2-4级= 28% iNO vs 33%对照组），脑室周围白质软化= 8% iNO vs 13%对照组，妊娠36周慢性肺病= 60% iNO vs 80%对照组)。基于这些实验室和临床观察，我们假设早期使用低剂量iNO治疗可能会降低呼吸衰竭早产儿慢性肺部疾病的发病率。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Inhaled nitric oxide (iNO) therapy is a safe and effective treatment for term newborns with persistent pulmonary hypertension of the newborn and hypoxemic respiratory failure. However, little is known about the potential role of iNO in premature newborns with respiratory failure. The premature newborn is particularly susceptible to the adverse effects of ventilator-induced lung injury, oxygen toxicity, and lung inflammation which contribute to the development of chronic lung disease (CLD). Despite treatment with exogenous surfactant and steroids, CLD remains a major cause of morbidity and mortality in premature newborns. Moreover, there is increasing evidence that steroid treatment causes long term adverse neurodevelopmental and cardiopulmonary sequelae. Early clinical observations suggest that low-dose iNO improves oxygenation and decreases the need for mechanical ventilator support in the premature infant. In addition to its effects on gas exchange, recent laboratory and clinical observations suggest that iNO may also act as a lung-specific anti-inflammatory treatment and reduce the contribution of lung inflammation to the evolution of acute and chronic lung injury in premature infants. To begin to address the potential role of low-dose iNO (5 ppm) in premature subjects, we first performed a series of animal experiments in extremely premature lambs (115days gestation, 78% of term), then conducted a pilot study of low-dose iNO in premature newborns with severe hypoxemic respiratory failure. Our laboratory experiments demonstrated that: 1) endogenous NO modulates fetal pulmonary vascular tone early in gestation and the transitional premature pulmonary circulation dilates in response to iNO; 2) iNO improves gas exchange and causes sustained reductions in pulmonary vascular resistance in the premature lamb with severe respiratory distress syndrome (RDS), without increasing lung vascular leak; and 3) iNO decreases lung neutrophil accumulation in the mechanically ventilated premature lamb with RDS. These laboratory experiments and others provided the rationale for clinical trials of low-dose iNO in premature newborns. To test the hypothesis that iNO would improve oxygenation in premature newborns without increasing bleeding complications, we recently conducted a masked, randomized, controlled pilot study of low-dose iNO in premature newborns with severe hypoxemic respiratory failure. We felt that the initial trials of iNO in premature newborns must include only the most severely ill patients to generate data from which to judge safety and efficacy. This study was designed to determine the impact of iNO on survival to discharge (primary outcome measure) and adverse events (secondary outcome measures: ICH, periventricular leukomalacia, pulmonary hemorrhage, chronic lung disease). Eighty patients were randomized within two gestational age strata in 12 centers with 48 iNO patients and 32 control patients at the time the study was stopped. At the time the study was stopped (because we were unlikely with the proposed sample size to achieve the mortality differences hypothesized), we found no difference in survival to discharge between iNO treated and control groups (52% iNO vs. 47% control). However, in contrast to previous case reports of iNO treated babies, we found no difference in adverse outcomes between groups (ICH grade 2-4 = 28% iNO vs. 33% control), periventricular leukomalacia = 8% iNO vs. 13% control, chronic lung disease at 36 weeks gestation = 60% iNO vs. 80% control). Based on these laboratory and clinical observations, we hypothesize that early treatment with low-dose iNO may reduce the incidence of chronic lung disease in premature newborns with respiratory failure.