High Dose Erythropoetin Neuroprotection Trial for Neonatal Cardiac Surgery

描述（由申请人提供）：最近在各种体外和动物模型（包括灵长类动物）中发现促红细胞生成素（EPO）在保护大脑抗缺氧方面发挥重要作用，在这些模型中可减少50-70%的神经元死亡。无论在缺氧损伤前、中、甚至几小时后给予促生成素，都会产生这些影响。因此，EPO有望成为临床神经保护剂；然而，到目前为止，还没有发表的关于使用促生成素的儿科患者的临床研究。我们使用近红外光谱（NIRS）测量脑氧血红蛋白饱和度，证明了新生儿心脏搭桥手术围手术期脑缺氧的显著发生率。据报道，在过去20年中，21%-69%的新生儿或婴幼儿接受心脏手术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、随机试验将大剂量EPO神经保护用于新生儿心脏手术伴低温体外循环，将检验EPO在这种情况下可以减少脑损伤并改善短期和长期神经发育结局的假设。该方案是一种新颖的，转化的，跨学科的方法，与NIH的使命相一致，即促进创造性的研究策略，这将潜在地改善重要患者群体的健康结果。新生儿心脏手术模型代表了EPO神经保护试验的理想临床环境，因为可预测的时间和脑低氧血症的发生，以及已知的后来异常神经发育结果的发生率。如果成功，这种方法可以在各种神经系统预后有风险的儿科临床环境中进行测试：老年患者的心脏手术、围产期窒息、心脏骤停、神经创伤和中风。我们将随机选取计划进行心脏手术的新生儿进行动脉转换手术、诺伍德I期姑息治疗或主动脉弓重建。每位患者将在术前、术中和术后接受近红外光谱监测，共96小时；同期术前、术后脑电图监测；以及手术前和手术后7天的脑部核磁共振检查。患者将随机接受EPO，每剂量1000单位/公斤IV或安慰剂，在手术前12-24小时、手术当天和手术后一天给予。患者还将在3-6个月时进行第三次脑部MRI检查；在1岁，3岁和5岁时做一个完整的神经发育评估。早期主要结局变量为MRI损伤严重程度评分；之后的主要结果是贝利婴儿发育量表得分。促红细胞生成素是一种药物，可以保护心脏和脑细胞免受新生儿心脏手术时可能发生的损伤。这项研究将表明，与未接受药物治疗的婴儿相比，接受促红细胞生成素治疗的婴儿发育迟缓是否更少。

DESCRIPTION (provided by applicant): 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 animal 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 clinical neuroprotectant 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 surgery in 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 a third brain MRI at 3-6 months; and a complete neurodevelopmental assessment at age 1, 3, and 5 years. The early primary outcome variable will be MRI severity of injury score; and later primary outcome will be Bayley Scales of Infant Development scores. Erythropoetin is a drug that protects heart and brain cells from damage that may occur when newborns have heart surgery. This study will show if babies that are given erythropoetin have fewer delays in development than babies that do not receive the drug.