INHALED NO IN PREVENTION OF CHRONIC LUNG DISEASE

呼吸系统疾病，特别是慢性肺病（CLD），仍然是早产儿长期发病和死亡的主要原因。 虽然表面活性剂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给药，均未导致CLD发生具有临床意义的降低。 患有最严重CLD的婴儿继续发展提示肺动脉高压伴肺心病的结果。 在患有严重慢性肺病的早产儿中有初步证据表明，低剂量吸入一氧化氮可显著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，以研究以下假设：对出生体重在500克至1250克之间的早产儿给予低剂量吸入性一氧化氮，并在10天龄时继续需要机械通气，将增加经后36周无CLD的存活率。 要证明没有CLD的存活率从50%增加到60%，需要726名随机婴儿有80%的把握度来检测这种差异，同时控制单侧α = 0.05，并允许在三分之一的结果数据中进行一次中期分析。 次要结局是通气持续时间、需氧量和住院时间。此外，我们预期吸入一氧化氮治疗会改善婴儿呼吸状态（呼吸支持、气道阻力和顺应性）。炎症和氧化应激的指标将分别通过测量气管抽吸物和血浆样品中的特异性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（包括脑室内出血）测量的毒性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）的发生率来评价该治疗的安全性，并评估2岁内的神经发育结局。 总之，本临床试验将评估吸入一氧化氮改善早产儿重大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.