A PROSPECTIVE, RANDOMIZED, PLACEBO-CONTROLLED HIGH-DOSE ERYTHROPOETIN NEUROPR

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 促红细胞生成素(EPO)最近被发现在各种体外和动物模型中发挥重要的脑保护作用，包括灵长类动物，在这些模型中，神经元死亡减少了50%-70%。无论EPO是在低氧侮辱之前、期间，甚至是在低氧侮辱后几个小时内注射，这些效应都会发生。因此，EPO作为一种临床神经保护剂很有希望；然而，到目前为止，还没有发表过在儿科患者中使用EPO发挥这一作用的临床研究。 我们使用近红外光谱分析(NIRS)来测量脑氧合血红蛋白饱和度，结果显示，在新生儿体外循环心脏手术围术期有明显的脑缺氧发生率。据报道，在过去20年中，在接受心脏手术的新生儿或婴幼儿中，有21%-69%的儿童存在长期神经发育障碍。这项前瞻性、安慰剂对照、双盲、随机、大剂量促红细胞生成素在低温体外循环新生儿心脏手术中的神经保护试验，将检验促红细胞生成素将在这种情况下减少脑损伤并改善短期和长期神经发育结果的假设。该方案是一种新颖的、翻译的、跨学科的方法，符合美国国立卫生研究院的使命，旨在促进创造性的研究战略，这将潜在地改善大量患者的健康结果。新生儿心脏手术模式代表了EPO神经保护试验的理想临床环境，因为可以预测脑低氧血症的发生时间和发生情况，以及后来神经发育异常结果的已知发生率。如果成功，这一方法可以在各种神经后果面临风险的儿科临床环境中进行测试：心脏手术、老年患者、围产期窒息、心脏骤停后以及神经创伤和中风。我们将对计划进行心脏手术的新生儿进行随机分组，包括动脉转换术、Norwood I期姑息手术或主动脉弓重建。每个患者在术前、术中和术后共接受96小时的NIRS监测；在同一时期进行术前和术后的脑电监测；在术前即刻和术后7天进行脑磁共振检查。患者将随机接受EPO，每剂静脉注射1000单位/公斤，或安慰剂，在手术前12-24小时、手术当天和手术后第二天给予。患者还将在3-6个月时进行第三次脑部核磁共振检查，并在1岁、3岁和5岁时进行完整的神经发育评估。早期的主要结果变量将是MRI损伤严重程度评分，稍后的主要结果将是贝利婴儿发育量表评分。

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. Erythropoetin (EPO) has recently been discovered to play an important role in protection of the brain against hypoxia, in a variety of in vitro and amimal models, up to and including primates, reducing neuronal death by 50-70% in these models. These effects occur whether EPO is given before, during, or even a few hours after the hypoxic insult. Thus EPO holds promise as a clinicalneuroprotectant agent; however to date there are no published clinical studies in pediatric patients using EPO in this role. We have demonstrated a significant incidence of cerebral hypoxia in the perioperative period for neonatal cardiac surgery with bypass, using near-infrared spectroscopy (NIRS) to measure brain oxyhemoglobin saturation. Long term neurodevelopmental impairment is reported in 21%-69% of children undergoing cardiac surgery as newborns or young infants in the past 20 years. This prospective, placebo-controlled, double blind, randomized trial of high dose EPO neuroprotection for neonatal cardiac surgery with hypothermic cardiopulmonary bypass, will test the hypothesis that EPO will reduce brain injury in this setting and improve short and long term neurodevelopmental outcomes. This protocol is a novel, translational, interdisciplinary approach consistent with the NIH mission to foster creative research strategies which will potentially improve health outcomes of a significant patient population. The neonatal cardiac surgery model represents the ideal clinical setting for an EPO neuroprotection trial because of the predictable timing and occurrence of cerebral hypoxemia, and the known incidence of later abnormal neurodevelopmental outcomes. If successful, this approach could be tested in a variety of pediatric clinical settings where neurological outcomes are at risk:cardiac surgeryin older patients, perinatal asphyxia, post cardiac arrest, and in neurological trauma and stroke. We will randomize newborns scheduled for cardiac surgery for the arterial switch operation, Norwood Stage I palliation, or aortic arch reconstruction. Each patient will undergo NIRS monitoring pre-, intra- and postoperatively for a total of 96 hours; pre- and postoperative EEg monitoring during the same period; and a brain MRI immediately prior to surgery, and 7 days after surgery. Patients will be randomized to receive EPO, 1000 units/kg per dose IV, or placebo, administered 12-24 hours before surgery, the day of surgery, and the day after surgery. patients will also have had a third brain MRI at 3-6 months; and a complete neurodevelopmental assessment at age 1,3, and 5 yars. The early primary outcome variable will be MRI severity of injury score, and later primary outcome will be Bayley Scales of Infant Development scores.