TRIAL OF LATE SURFACTANT TO PREVENT BRONCHOPULMONARY

晚期表面活性剂预防支气管肺损伤的试验

• 批准号: 7950663
• 负责人: ERIC EICHENWALD
• 金额: $ 0.96万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7950663
• 关键词: Adrenal Cortex Hormones; Adverse effects; Age; Alveolus; Aspirate substance; Birth; Birth Weight; Bronchodilator Agents; Bronchopulmonary Dysplasia; Caffeine; Cessation of life; Chronic; Clinical Data; Clinical Research; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; Data; Deterioration; Diuretics; Dose; Enrollment; Environmental air flow; Extremely Low Birth Weight Infant; Frequencies; Functional disorder; Funding; Genetic; Grant; Incidence; Infant; Infasurf; Inflammation; Injury; Institution; Late Effects; Life; Lung; Lung diseases; Measurement; Mechanical Ventilators; Mechanical ventilation; Monitor; Morbidity - disease rate; Necrotizing Enterocolitis; Neonatal; Outcome; Patent Ductus Arteriosus; Pathogenesis; Periventricular Leukomalacia; Pharmaceutical Preparations; Pilot Projects; Placebo Control; Pregnancy; Premature Infant; Prevalence; Prevention approach; Procedures; Pulmonary Surfactant-Associated Protein B; Pulmonary Surfactants; Randomized Controlled Trials; Research; Research Personnel; Resources; Retinopathy of Prematurity; Safety; Sampling; Severities; Source; Surface Tension; Therapeutic; Toxic effect; United States; United States National Institutes of Health; Ventilator; Vitamin A; base; high risk; improved; inhaled nitric oxide; intraventricular hemorrhage; oxygen toxicity; pilot trial; postnatal; premature; prevent; respiratory; surfactant

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Bronchopulmonary dysplasia (BPD) of prematurity has emerged as the most common, lethal and expensive neonatal pulmonary disorder in the United States. The pathogenesis of BPD is multi-factorial, has a genetic contribution, and involves injury and inflammation associated with oxygen toxicity and mechanical ventilation in an underdeveloped, immature lung. The estimated prevalence is 30,000 cases/year. Current therapeutic approaches to the prevention and treatment of lung disease in premature infants, including antenatal corticosteroid treatment, replacement surfactant at birth, postnatal administration of corticosteroids, vitamin A, diuretics, caffeine, and bronchodilators have not significantly impacted the overall occurrence of BPD. Recent clinical trials of inhaled nitric oxide (iNO) indicate a beneficial impact on the incidence and severity of BPD as well as short- and long-term safety including 2-year neurodevelopmental outcome. Extremely low birth weight infants (ELBW, defined as \ul <\ulnone 1000 g and \ul <\ulnone 30 wk gestation for the purposes of this study) who continue to require mechanical ventilation at 7 d of age have the highest incidence and severity of BPD, which is associated with chronic pulmonary disease and abnormal neurodevelopmental outcome. In recent studies we found that this group of infants has frequent respiratory deteriorations that are associated with dysfunctional pulmonary surfactant and decreased content of surfactant proteins (SP) B and C, which are critical for normal surfactant function to maintain patency of alveoli and terminal airways. Based on these observations, we have performed pilot studies of late administration of SP-B-containing commercial surfactant (Infasurf\plain\f3\fs18 ). Our preliminary data confirm that the majority of infants still requiring ventilation after 7 d of age have abnormal surface tension measurements and that late doses of surfactant are well tolerated and transiently improve respiratory status. Episodes of surfactant dysfunction also occur among infants receiving iNO. Moreover, surfactant dysfunction in iNO-treated infants is associated with adverse outcome. In this pilot study, we plan to study the addition of late surfactant administration to infants at high risk for BPD who are receiving iNO therapy. HYPOTHESIS We hypothesize that late booster doses of surfactant, in addition to iNO, administered to ELBW infants who continue to require mechanical ventilation between 7 and 14 days of age will significantly decrease the frequency of episodes of surfactant dysfunction in these infants. We further hypothesize that there will be no adverse effects of surfactant treatment on short-term outcomes including death or BPD at 36 weeks postmenstrual age. This pilot trial is being performed to assess the safety and efficacy of late, booster doses of surfactant combined with iNO in ELBW infants at high risk for BPD. This trial is the pilot for a multicenter, randomized controlled trial to assess the effect of late doses of surfactant on the occurrence and severity of BPD in ventilated ELBW infants receiving inhaled Nitric Oxide. Aim 1. Assess the effect of late doses of surfactant in infants receiving inhaled nitric oxide on frequency of dysfunctional surfactant episodes in ventilated ELBW infants. We will conduct a multi-center placebo-controlled pilot trial of late surfactant treatment in addition to iNO in infants at high risk of BPD. We will enroll 60 infants between 500-1000 g birth weight who are intubated requiring mechanical ventilator support between 7 and 14 d of age. Infants will be treated with either surfactant (Infasurf\plain\f3\fs18 ) or a sham procedure; study drug treatment will be repeated at intervals up to the fourth week of life if ventilator support is still required. Tracheal aspirate (TA) samples will be collected around each dose of surfactant and iNO dose change for isolation and analysis of surfactant. The trial will have sufficient statistical power to detect a decrease in frequency of episodes of surfactant dysfunction from 50% to 20% in infants receiving combined therapy. In addition, data will be obtained related to the duration of efficacy of administered surfactant in infants >1 week of age. Aim 2. Assess effects of late surfactant treatment on the respiratory status of ventilated ELBW infants\b0 . We will collect clinical data to investigate effects of surfactant treatment on both short-term respiratory support need, as assessed by the Respiratory Severity Score (RSS), and pulmonary status at 36 weeks' PMA (survival without BPD). We also will monitor for evidence of toxicity as indicated by any of the known complications of surfactant administration as well as by the occurrence and severity of other common morbidities of preterm infants, including intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL), patent ductus arteriosus (PDA), necrotizing enterocolitis (NEC) and retinopathy of prematurity (ROP). We expect that combined iNO-surfactant therapy will be safe. We will determine the relationship between surfactant function (Aim 1) and both short-term respiratory status and 36-week outcome.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 在美国，早产儿支气管肺发育不良（BPD）已成为最常见、最致命和最昂贵的新生儿肺部疾病。BPD的发病机制是多因素的，具有遗传贡献，并且涉及与氧毒性和未发育成熟的肺中的机械通气相关的损伤和炎症。 估计流行率为30 000例/年。目前预防和治疗早产儿肺部疾病的治疗方法，包括产前皮质类固醇治疗、出生时表面活性物质替代、出生后皮质类固醇、维生素A、利尿剂、咖啡因和支气管扩张剂给药，对BPD的总体发生率没有显著影响。 最近的吸入性一氧化氮（iNO）临床试验表明，对BPD的发病率和严重程度以及短期和长期安全性（包括2年神经发育结局）具有有益影响。 极低出生体重儿（ELBW，定义为妊娠期1000 g和30 wk）在7 d龄时继续需要机械通气的婴儿BPD的发生率和严重程度最高，与慢性肺部疾病和异常神经发育结果相关。 在最近的研究中，我们发现这组婴儿经常出现呼吸恶化，这与肺表面活性物质功能障碍和表面活性蛋白（SP）B和C含量降低有关，这对维持肺泡和末端气道通畅的正常表面活性物质功能至关重要。基于这些观察结果，我们对含SP-B的市售表面活性剂（Infasurf\plain\f3\fs18）的晚期给药进行了初步研究。我们的初步数据证实，大多数婴儿仍然需要通气后7天的年龄有异常的表面张力测量和后期剂量的表面活性剂耐受性良好，并短暂改善呼吸状态。在接受iNO的婴儿中也会发生表面活性剂功能障碍。 此外，iNO治疗婴儿的表面活性物质功能障碍与不良结局相关。 在这项初步研究中，我们计划研究在接受iNO治疗的BPD高危婴儿中增加晚期表面活性剂给药。 假设 我们假设，在7 - 14天龄之间继续需要机械通气的ELBW婴儿中，除了iNO外，晚期加强剂量的表面活性剂将显著降低这些婴儿表面活性剂功能障碍发作的频率。我们进一步假设，表面活性剂治疗对短期结局（包括死亡或经后36周的BPD）没有不良影响。 正在进行这项初步试验，以评估晚期加强剂量的表面活性剂联合iNO治疗BPD高危ELBW婴儿的安全性和疗效。本试验是一项多中心、随机对照试验的试点，旨在评估接受吸入一氧化氮的通气ELBW婴儿中晚期剂量表面活性剂对BPD发生率和严重程度的影响。 目标1.评估接受吸入一氧化氮的婴儿中晚期剂量的表面活性物质对通气ELBW婴儿中功能障碍性表面活性物质发作频率的影响。 我们将在BPD高危婴儿中进行一项多中心安慰剂对照的试验，在iNO的基础上进行晚期表面活性剂治疗。 我们将招募60名出生体重在500-1000 g之间的婴儿，他们在7 - 14 d之间需要机械呼吸机支持进行插管。婴儿将接受表面活性剂（Infasurf\plain\f3\fs18）或假手术治疗;如果仍然需要呼吸机支持，将在出生后第4周内每隔一段时间重复研究药物治疗。在每次表面活性剂和iNO剂量变化前后采集气管抽吸物（TA）样本，用于分离和分析表面活性剂。 该试验将有足够的统计功效检测接受联合治疗的婴儿中表面活性物质功能障碍发作频率从50%降低至20%。 此外，将获得与在>1周龄的婴儿中施用的表面活性剂的功效持续时间相关的数据。 目标2.评估晚期表面活性物质治疗对通气ELBW婴儿呼吸状态的影响\b0。 我们将收集临床数据，以研究表面活性剂治疗对短期呼吸支持需求（通过呼吸严重程度评分（RSS）评估）和36周PMA时的肺状态（无BPD生存期）的影响。我们还将监测毒性证据，如表面活性剂给药的任何已知并发症以及早产儿其他常见疾病的发生率和严重程度，包括脑室内出血（IVH）和脑室周围白质软化症（PVL）、动脉导管未闭（PDA）、坏死性小肠结肠炎（NEC）和早产儿视网膜病变（ROP）。 我们预期iNO-表面活性剂联合治疗是安全的。 我们将确定表面活性物质功能（目标1）与短期呼吸状态和36周结局之间的关系。