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性肺动脉高压和低氧性呼吸衰竭的方法。然而，对于iNO在治疗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引起的肺损伤、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。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，一氧化氮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。我们最近进行了一项蒙面、随机、对照的试验研究，研究了低剂量iNO对患有严重低氧性呼吸衰竭的早产新生儿的影响。来自12个中心的80名患者被随机分配到iNO （5ppm）或安慰剂治疗组。低剂量一氧化氮引起急性氧合改善和呼吸机天数减少。此外，在该试点试验中注意到CLD减少的重要趋势，没有增加不良事件（如颅内出血）的发生率。基于一氧化氮对气体交换和肺部炎症的有益作用，我们假设早期使用低剂量一氧化氮可以降低呼吸衰竭早产儿CLD的发生率。为了验证这一假设，我们设计了一项无交叉的多中心、随机、对照、掩盖试验。本研究的具体目的是确定：1)在出生后48小时内出现呼吸衰竭需要机械通气的早产儿（胎龄<34周，出生体重500-1250克），iNO是否能降低CLD；2) iNO治疗可降低早期血清和气管吸入物炎症标志物，预测无CLD的恢复；3)评价iNO的安全性。我们估计该人群中CLD的发生率为40%。在我们的试点试验中，CLD发病率降低了25%。我们估计，在病情较轻的新生儿中，可以实现类似的CLD减少。为了使接受iNO治疗的CLD降低25%的几率达到80%（降低40%至30%，死亡率相当），每组随机抽取400例患者（总n = 800）。10个中心参与，每个中心每年至少入组30例患者，研究入组时间为2年8个月。该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。

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.