INHALED NO FOR THE PREVENTION OF CHRONIC LUNG DISEASE

吸入 NO 预防慢性肺病

• 批准号: 6954850
• 负责人: John Patrick Kinsella
• 金额: $ 124.53万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-29 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6954850
• 关键词: antiinflammatory agents; chemoprevention; chronic disease /disorder; clinical research; clinical trials; cooperative study; disease /disorder proneness /risk; human subject; human therapy evaluation; hypoxia; lung disorder; nitric oxide; pathologic process; patient oriented research; premature infant human; pulmonary hypertension; respirators; respiratory oxygenation; respiratory therapy

Inhaled nitric oxide (iNO) therapy is a safe and effective treatment for term newborns with persistent pulmonary hypertension and hypoxemic respiratory failure. However, little is known about the potential role of iNO in the treatment of premature newborns with respiratory failure. Premature newborns are 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. 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. We recently conducted a masked, randomized, controlled pilot study of low- dose iNO in premature newborns with severe hypoxemic respiratory failure. Eighty patients from 12 centers were randomized to treatment with iNO (5 ppm) or placebo. Low-dose iNO caused acute improvement in oxygenation and reduced ventilator days. Moreover, important trends in CLD reduction were noted in this pilot trial, without an increased incidence of adverse events (e.g. intracranial hemorrhage). Based on the beneficial effects of iNO on gas exchange and lung inflammation, we hypothesize that early treatment with low-dose iNO may reduce the incidence of CLD in premature newborns with respiratory failure. To test this hypothesis, we have designed a multicenter, randomized, controlled, masked trial without crossover. Specific aims of this study are to determine if: l) iNO reduces CLD in premature newborns (gestational age<34 weeks and birth weight 500-1250 grams) with respiratory failure requiring mechanical ventilation in the first 48 hours of life; 2) early serum and tracheal aspirate markers of inflammation are reduced by iNO therapy and predict recovery without CLD; and 3) to assess the safety of iNO. We estimate the incidence of CLD to be 40% for this population. A 25% reduction in CLD disease occurred in our pilot trial. We estimate that a similar reduction in CLD could be achieved in less severely ill newborns. To permit an 80% chance of detecting a 25% reduction in CLD with iNO treatment (40% reduced to 30% with equivalent mortality), 400 patients will be randomized in each group (total n = 800). With 10 centers participating and enrolling a minimum of 30 patients per center per year, the study enrollment duration would be 2 years, 8 months. This study design also allows for insights into the role of inflammatory markers in prediction of CLD risk in the premature newborn.

吸入一氧化氮(INO)治疗足月儿持续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在治疗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。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。我们最近进行了一项掩蔽、随机、对照的试验性研究，对患有严重低氧性呼吸衰竭的早产儿使用低剂量iNO。来自12个中心的80名患者被随机分为iNO(5ppm)或安慰剂治疗。小剂量iNO可显著改善氧合，减少呼吸机使用天数。此外，在这项试点试验中，注意到了CLD减少的重要趋势，而没有增加不良事件(如颅内出血)的发生率。根据iNO对气体交换和肺部炎症的有益作用，我们假设早期使用小剂量iNO可以减少早产儿呼吸衰竭的CLD发生率。为了验证这一假设，我们设计了一项多中心、随机、对照、无交叉的掩蔽试验。本研究的具体目的是确定：L，iNO是否能降低早产儿(胎龄34周，出生体重500-1250克)的慢性阻塞性肺疾病(CLD)，并在出生后48小时内发生呼吸衰竭需要机械通气；2)iNO治疗可降低早期血清和气管吸出物炎症标志物，并预测无CLD时的康复；以及3)评估iNO的安全性。我们估计这一人群的CLD发病率为40%。在我们的试点试验中，CLD疾病减少了25%。我们估计，在病情较轻的新生儿中，CLD也可以实现类似的减少。为了有80%的机会检测到使用iNO治疗后慢性阻塞性肺疾病减少25%(在相同死亡率的情况下，40%减少到30%)，每组400名患者将被随机分配(总计n=800)。有10个中心参与，每个中心每年至少招募30名患者，研究登记持续时间为2年零8个月。这项研究设计还允许深入了解炎症标志物在预测早产儿CLD风险中的作用。