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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 吸入一氧化氮(INO)治疗足月新生儿持续性肺动脉高压和低氧性呼吸衰竭是一种安全有效的治疗方法。然而，对iNO在早产儿呼吸衰竭中的潜在作用知之甚少。早产儿特别容易受到呼吸机引起的肺损伤、氧中毒和肺部炎症的不良影响，这些都会导致慢性肺部疾病(CLD)的发展。尽管使用外源性表面活性物质和类固醇治疗，CLD仍然是早产儿发病率和死亡率的主要原因。此外，越来越多的证据表明，类固醇治疗会导致长期的不良神经发育和心肺后遗症。早期的临床观察表明，小剂量的iNO改善了早产儿的氧合，减少了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还可能作为一种肺特异性抗炎治疗，减少肺炎症在早产儿急、慢性肺损伤演变中的作用。 为了开始探讨低剂量iNO(5ppm)在早产儿中的潜在作用，我们首先在极早产儿(妊娠115天，足月的78%)上进行了一系列动物实验，然后在患有严重缺氧性呼吸衰竭的早产儿中进行了小剂量iNO的初步研究。 我们的实验室实验证明：1)内源性NO调节妊娠早期胎儿的肺血管张力，过渡性早产肺循环对iNO的反应是扩张；2)iNO改善严重呼吸窘迫综合征(RDS)早产羔羊的气体交换，导致肺血管阻力持续降低，而不增加肺血管渗漏；3)iNO减少机械通气早产羔羊RDS的肺中性粒细胞聚集。这些实验室实验和其他实验为低剂量iNO在早产儿中的临床试验提供了理论基础。 为了验证iNO可以在不增加出血并发症的情况下改善早产儿氧合的假设，我们最近进行了一项掩蔽、随机、对照的试验性研究，对患有严重缺氧性呼吸衰竭的早产儿使用小剂量iNO。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，以产生数据来判断安全性和有效性。这项研究旨在确定iNO对存活到出院(主要结果指标)和不良事件(次要结果指标：ICH、脑室周围白质软化、肺出血、慢性肺部疾病)的影响。在研究停止时，80名患者在12个中心的两个胎龄范围内被随机分为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下实现假设的死亡率差异)，我们发现iNO治疗组和对照组之间的存活率和出院时间没有差异(52%iNO对47%对照)。然而，与以前关于接受iNO治疗的婴儿的病例报告相比，我们发现两组之间的不良结局没有差异(ICH分级2-4=28%iNO与对照组33%)，脑室周围白质软化=8%iNO与对照组13%，36周慢性肺部疾病=60%iNO与80%对照组。 基于这些实验室和临床观察，我们假设早期使用小剂量iNO治疗可以降低早产儿呼吸衰竭的慢性肺部疾病的发生率。

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 (115 days 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.