INHALED NO FOR THE PREVENTION OF CHRONIC LUNG DISEASE

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肺动脉高压和低氧性呼吸衰竭。然而，关于iNO在治疗患有呼吸衰竭的早产儿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，这些不良影响会导致慢性肺病（CLD）的发展。尽管使用外源性表面活性剂和类固醇治疗，CLD仍然是早产儿发病和死亡的主要原因。 早期临床观察表明，低剂量iNO可改善早产儿的氧合，减少对机械通气支持的需求。除了其对气体交换的影响之外，最近的实验室和临床观察表明，iNO还可以充当肺特异性抗炎治疗，并减少肺部炎症对早产儿急性和慢性肺损伤演变的贡献。我们最近进行了一项低剂量iNO治疗严重低氧性呼吸衰竭早产儿的盲法、随机、对照初步研究。来自12个中心的80名患者随机接受iNO（5 ppm）或安慰剂治疗。低剂量iNO引起氧合的急性改善和呼吸机天数的减少。此外，在该初步试验中观察到CLD减少的重要趋势，而不良事件（例如颅内出血）的发生率没有增加。基于iNO对气体交换和肺部炎症的有益作用，我们假设早期低剂量iNO治疗可能会降低早产儿呼吸衰竭CLD的发生率。为了验证这一假设，我们设计了一个多中心、随机、对照、无交叉的盲法试验。本研究的具体目的是确定：1）iNO是否减少在生命的前48小时内患有需要机械通气的呼吸衰竭的早产新生儿（胎龄<34周，出生体重500-1250克）的CLD; 2）炎症的早期血清和气管抽吸物标志物通过iNO治疗减少，并预测没有CLD的恢复;和3）评估iNO的安全性。我们估计CLD的发病率为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也可以达到类似的降低。为了允许80%的机会检测到iNO治疗的CLD降低25%（40%降低至30%，具有等同的死亡率），每组将随机分配400名患者（总共n = 800）。10家临床试验机构参与，每家临床试验机构每年至少入组30例患者，研究入组持续时间为2年8个月。这项研究设计还可以深入了解炎症标志物在预测早产儿CLD风险中的作用。

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.