Early Prediction of Spontaneous Patent Ductus Arteriosus (PDA) Closure and PDA-Associated Outcomes

项目概要/摘要 动脉导管未闭（PDA）在早产儿中非常常见，与死亡率和有害的长期生存有关。 长期结果包括慢性肺病和神经发育迟缓。虽然，药理学和/或 介入治疗关闭动脉导管未闭可能有利于一些婴儿， 患有PDA的婴儿可能不会改善重要的结果。如果不进行治疗，大多数PDA在44- 月经后30周（PMA）。因此，动脉导管未闭的治疗越来越有争议， 机构和个人提供者之间的关系。相关的和仍然没有答案的临床问题不是是否 治疗所有患有PDA的早产儿，但治疗谁和何时治疗。治疗的益处可能大于益处， 由于所有形式的故意PDA闭合都有潜在的不良影响，特别是对于早产儿， 动脉导管未闭自发闭合。不幸的是，临床医生目前无法预测在第一个月， 持续性PDA的风险最高，以及临床风险因素、超声测量和 血清生物标志物可能是预测PDA相关损害的最佳方法。美国儿科学会在他们的PDA中 临床指导报告承认早期识别PDA高危婴儿是一项关键研究 为未来PDA治疗有效性试验提供信息的目标。本应用程序的目标是使用 未接受治疗的PDA婴儿的前瞻性队列，以预测自发性导管闭合时间并确定 出生后第一个月内存在的临床风险因素、超声心动图测量和生物标志物， 与长期损害有关。临床、血清和尿液生物标志物（BNP、NTpBNP、NGAL、H-FABP），以及 将检查在出生后前4周的每一周连续收集的超声心动图变量。 除了心肌变形成像（MDI）和组织多普勒成像（TDI），创新的 超声心动图方法，将有助于定量评价心肌性能。所有具体目标将 收集并检查出生后第一个月内患有PDA的早产儿的数据。目标1将估计 PDA自发闭合的概率，并使用超声心动图预测导管闭合的时间， 生物标志物和临床预测物。目标2将详细说明哪些超声心动图预测因子和生物标志物 与36周PMA时的死亡率和呼吸系统疾病严重程度相关。目标3将确定 超声心动图预测因子和生物标志物与22- 26个月的神经发育相关。所有车型将在 在另一组婴儿中得到验证。该项目将显著促进临床结果， 通过减少不必要的和有害的过度治疗的婴儿与早期动脉导管未闭的高概率管理 自发性PDA闭合，并将允许开展以结局为中心的试验，以检查 PDA闭合术在那些最有可能受益的“高危”婴儿中的有效性。

Project Summary/Abstract Patent ductus arteriosus (PDA), very common in preterm infants, is associated with mortality and harmful long- term outcomes including chronic lung disease and neurodevelopmental delay. Although, pharmacologic and/or interventional treatments to close PDA likely benefit some infants, widespread routine treatment of all preterm infants with PDA may not improve important outcomes. Left untreated, most PDAs close spontaneously by 44- weeks postmenstrual age (PMA). Thus, PDA treatment is increasingly controversial and varies markedly between institutions and individual providers. The relevant and still unanswered clinical question is not whether to treat all preterm infants with PDA, but whom to treat and when. Treatment detriments may outweigh benefits, since all forms of deliberate PDA closure have potential adverse effects, especially in infants destined for early, spontaneous PDA closure. Unfortunately, clinicians cannot currently predict in the first month which infants are at highest risk for persistent PDA, and which combination of clinical risk factors, echo measurements, and serum biomarkers may best predict PDA-associated harm. The American Academy of Pediatrics in their PDA Clinical Guidance Report acknowledged early identification of infants at high-risk from PDA as a key research goal for informing future PDA-treatment effectiveness-trials. The objective in this application is to use a prospective cohort of untreated infants with PDA to predict spontaneous ductal closure timing and to identify clinical risk factors, echo measurements, and biomarkers that are present in the first postnatal month and associated with long-term impairment. Clinical, serum and urine biomarkers (BNP, NTpBNP, NGAL, H-FABP), and echocardiographic variables sequentially collected during each of the first 4 postnatal weeks will be examined. In addition myocardial deformation imaging (MDI) and tissue Doppler imaging (TDI), innovative echocardiographic methods, will facilitate the quantitative evaluation of myocardial performance. All Specific Aims will collect and examine data from preterm infants with PDA within the first postnatal month. Aim 1 will estimate the probability of spontaneous PDA closure and predict the timing of ductal closure using echocardiographic, biomarker, and clinical predictors. Aim 2 will specify which echocardiographic predictors and biomarkers are associated with mortality and severity of respiratory illness at 36-weeks PMA. Aim 3 will identify which echocardiographic predictors and biomarkers are associated with 22- to 26-month neurodevelopment. All models will be validated in a separate cohort of infants. This project will significantly contribute to clinical outcomes and management of PDA by reducing unnecessary and harmful overtreatment of infants with a high probability of early spontaneous PDA closure, and will permit the development of outcomes-focused trials to examine the effectiveness of PDA closure in those “high-risk” infants most likely to receive benefit.