INHALED NO IN PREVENTION OF CHRONIC LUNG DISEASE

呼吸系统疾病，特别是慢性肺病，仍然是早产儿长期发病和死亡的一个主要原因。虽然表面活性剂替代降低了急性呼吸道疾病的发病率和死亡率，但它并没有降低CLD的发病率。许多其他方法，包括产前促甲状腺激素释放激素联合皮质类固醇，产后类固醇给药，以及维生素E、利尿剂和支气管扩张剂的给药，都没有导致临床上重要的CLD降低。婴儿最严重的CLD继续发展的结果提示肺动脉高压与肺心病。有初步证据表明，低剂量吸入一氧化氮可显著减轻重症慢性肺病早产儿的病情，降低死亡率。我们提出了一项多中心、对照和盲法试验，以研究低剂量吸入一氧化氮对出生体重在500至1250克之间、在10天龄时继续需要机械通气的早产儿是否会增加经后36周无CLD的生存率。要证明无CLD的存活率从50%增加到60%，需要726名随机婴儿有80%的能力来检测这种差异，同时控制单侧α值0.05，并允许在三分之一的结果数据中进行一次中期分析。次要结局为通气时间、需氧量和住院时间。此外，我们预计吸入一氧化氮治疗将改善婴儿呼吸状态（通气支持、气道阻力和依从性）。炎症和氧化应激的指标将分别通过测量气管抽吸液和血浆样品中的特定细胞因子和蛋白质修饰来评估。我们还将通过评估临床出血的毒性来评估该疗法的安全性，包括脑室内出血以及其他早产儿发病率（坏死性小肠结肠炎、早产儿视网膜病变和感染），并评估两岁前的神经发育结局。总之，本临床试验将评估吸入一氧化氮改善早产儿主要疾病的有效性和安全性。

Respiratory morbidity, particularly chronic lung disease (CLD), remains a major cause of long-term morbidity and mortality for preterm infants. Although surfactant replacement has decreased acute respiratory morbidity and mortality, it has not reduced the incidence of CLD. A number of other approaches, including antenatal thyrotropin releasing hormone in conjunction with corticosteroids, postnatal steroid administration, as well as administration of Vitamin E, diuretics, and bronchodilators, have not resulted in clinically important decreases in CLD. Infants with the most severe CLD go on to develop findings suggestive of pulmonary hypertension with cor pulmonale. There is preliminary evidence in the preterm infant with severe chronic lung disease that low-dose inhaled nitric oxide may significantly attenuate the disease and decrease mortality. We propose a multi-center, controlled and blinded trial to investigate the hypothesis that low-dose inhaled nitric oxide administered to preterm infants between 500 and 1250 grams birth weight who continue to require mechanical ventilation at 10 days of age will increase survival without CLD at 36 weeks post menstrual age. Demonstrating an increase from 50 percent to 60 percent survival without CLD requires 726 randomized infants to have 80 percent power to detect this difference while controlling for a one-sided alpha of 0.05 and allowing for one interim analysis at one-third of outcome data available. Secondary outcomes are duration of ventilation, oxygen requirement and duration of hospitalization. We expect, in addition, that there will be improvement in infant respiratory status (ventilatory support, airway resistance and compliance) associated with inhaled nitric oxide treatment. Indicators of inflammation and oxidant stress will be assessed by measurements of specific cytokines and protein modifications in tracheal aspirate and plasma samples, respectively. We also will evaluate safety of this therapy by assessing toxicity as measured by clinical bleeding, including intraventricular hemorrhage as well as the incidence of other morbidities of the preterm infant (necrotizing enterocolitis, retinopathy of prematurity and infection) and assess neurodevelopmental outcome through two years of age. In summary, this clinical trial will assess the efficacy and safety of inhaled nitric oxide for amelioration of a major disease of premature infants.