Indomethacin and delayed umbilical cord clamp for preterm infant IVH

描述(申请人提供)：脑室出血(IVH)和脑室周围白质软化(PVL)是通常发生在早产儿的脑部病变，是公认的长期脑损伤和以后生活中相关残疾的主要因素。尽管IVH的流行率、长期后果以及巨大的医疗和社会成本，但IVH的机制和预防或治疗其发生的最佳策略尚不清楚，特别是对极早产儿。只有一种药物疗法，即在生命的前3天预防性使用吲哚美辛，已被证明可以预防或减轻早产儿IVH的严重程度，但其使用受到毒副作用和对长期结果有争议的影响的限制。一些小型研究和病例报告表明，延迟夹住脐带(DCC)也可以降低早产儿IVH的发生率，但到目前为止，这些试验在夹脐带的方案中混合了吲哚美辛治疗。因此，我们将对4个治疗组进行随机、盲法研究：1)对照组(不干预)；2)单纯DCC；3)单独预防性使用吲哚美辛；4)联合使用DCC/吲哚美辛，观察存活率、IVH或PVL的发生率和严重程度、神经发育结果和相关的机制效应。我们的具体目标是：1)比较吲哚美辛、DCC及其组合在影响28周胎龄婴儿IVH/PVL发生率和严重程度方面的有效性和安全性(主要结果是衡量4组中没有严重IVH或PVL的幸存者的比例)，以及长期神经认知功能；目的2)探讨预防性吲哚美辛、DCC及其组合对胎龄28周以下婴儿(血容量/循环状态、炎性应激、祖细胞)的机制影响；以及目的3)确定治疗组(总共400例)的临床结果与机制指标之间的关系。随着极端早产儿的稳步增加以及IVH与长期残疾的明确联系，有必要改善对这些患者的护理。这个多学科项目为研究不足的患者群体解决了一个重要的医学问题，目前的做法有明显的局限性。

DESCRIPTION (provided by applicant): Intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL) are brain lesions that commonly occur in preterm infants and are well-recognized major contributors to long-term brain injury and related disabilities later in life. Despite its prevalence, long term consequences, and enormous medical and social costs, mechanisms of IVH and optimal strategies to prevent or treat its occurrence are poorly defined, especially for extremely premature infants. Only one medical therapy, prophylactic indomethacin during the first 3 days of life, has been shown to prevent or decrease the severity of IVH in preterm infants, but its use is limited by toxic side effects and debatable effects on long-term outcomes. Several small studies and case reports suggest that delayed umbilical cord-clamping (DCC) may also decrease the incidence of IVH in premature infants, but thus far these trials have indomethacin treatment mixed within their cord clamping protocols. We will therefore conduct a randomized, blinded investigation of 4 treatment groups: 1) Control (no intervention); 2) DCC alone; 3) Prophylactic indomethacin alone; 4) Combination of DCC/indomethacin, with respect to survival, IVH or PVL incidence and severity, neurodevelopmental outcomes, and relevant mechanistic effects. Our Specific Aims are: Aim 1) Compare efficacy and safety of prophylactic indomethacin, DCC, and their combination, in affecting the incidence and severity of IVH/PVL in infants <28wks gestational age (primary outcome measure of 'fraction of survivors with no severe IVH or PVL' among the 4 groups), and longer term neurocognitive function; Aim 2) Investigate mechanistic effects of prophylactic indomethacin, DCC, and their combination in infants less than 28wks gestational age (blood volume/circulatory status, inflammatory stress, progenitor cells); and Aim 3) Determine relationships between clinical outcomes and mechanistic measurements among treatment groups (n=400 total cases). With the steady rise in extreme prematurity births and clear links of IVH to long-term disabilities there is a need to improve care for these patients. This multi-disciplinary project addresses an important medical problem for an understudied patient population, where the current practice has clear limitations.