INHALED NO IN PREVENTION OF CHRONIC LUNG DISEASE

呼吸道疾病，特别是慢性肺部疾病(CLD)，仍然是早产儿长期发病率和死亡率的主要原因。虽然肺表面活性物质替代治疗降低了急性呼吸道疾病的发病率和死亡率，但并未降低慢性阻塞性肺疾病的发生率。其他一些方法，包括产前促甲状腺激素释放激素联合皮质类固醇，产后类固醇应用，以及维生素E、利尿剂和支气管扩张剂的应用，并没有导致临床上重要的CLD减少。患有最严重的慢性阻塞性肺疾病的婴儿会继续发展出提示患有肺心病的肺动脉高压的结果。在患有严重慢性肺部疾病的早产儿中，有初步证据表明，低剂量吸入一氧化氮可以显着减轻疾病并降低死亡率。我们提出了一项多中心、对照和盲法试验，以调查这样一种假设，即对出生体重在500克到1250克之间的早产儿使用低剂量吸入一氧化氮，这些早产儿在10天大时继续需要机械通气，可以在月经后36周增加没有CLD的存活率。要证明没有CLD的存活率从50%增加到60%，需要726名随机婴儿具有80%的能力来检测这种差异，同时控制单边阿尔法为0.05，并允许对三分之一的结果数据进行一次中期分析。次要结果是呼吸机持续时间、需氧量和住院时间。此外，我们预计与吸入一氧化氮治疗相关的婴儿呼吸状况(呼吸支持、呼吸道阻力和顺应性)将得到改善。炎症和氧化应激的指标将分别通过测量气管吸出物和血浆样本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(包括脑室出血)以及早产儿其他疾病(坏死性小肠结肠炎、早产儿视网膜病变和感染)的发生率来评估这种疗法的安全性，并评估两岁后的神经发育结果。总之，这项临床试验将评估吸入一氧化氮改善早产儿一种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.