High Dose Erythropoetin Neuroprotection Trial for Neonatal Cardiac Surgery

描述（由申请人提供）：最近已经发现，在多种体外和动物模型中，包括灵长类动物，红细胞生成素（EPO）在保护脑免受缺氧中起重要作用，在这些模型中减少了50-70%的神经元死亡。无论EPO是在缺氧损伤之前、期间还是甚至在缺氧损伤之后几小时给予，这些作用都会发生。因此，EPO有望成为临床神经保护剂;然而，迄今为止，还没有在儿科患者中使用EPO发挥这一作用的已发表临床研究。我们已经证明了一个显着的发病率脑缺氧的围手术期新生儿心脏手术与旁路，使用近红外光谱（NIRS）测量脑氧合血红蛋白饱和度。 在过去的20年中，有21%-69%的新生儿或幼儿接受心脏手术的儿童报告了长期神经发育障碍。这项前瞻性的、安慰剂对照的、双盲的、随机的试验，研究了高剂量EPO对低温体外循环新生儿心脏手术的神经保护作用，将检验EPO将减少这种情况下的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，符合NIH的使命，即培养创造性的研究策略，这将有可能改善重要患者人群的健康结局。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，因为脑低氧血症的可预测时间和发生率，以及已知的后期异常神经发育结局的发生率。如果成功，这种方法可以在各种儿科临床环境中进行测试，其中神经系统的结果是有风险的：老年患者的心脏手术，围产期窒息，心脏骤停后，神经创伤和中风。我们将随机安排接受心脏手术的新生儿进行动脉调转术、诺伍德I期姑息术或主动脉弓重建术。每例患者将在术前、术中和术后接受NIRS监测，共96小时;在同一时间段内进行术前和术后EEG监测;术前即刻和术后7天进行脑部MRI。患者将随机接受EPO，1000单位/kg/剂IV或安慰剂，在手术前12-24小时、手术当天和手术后第二天给药。患者还将在3-6个月时进行第三次脑部MRI;并在1岁，3岁和5岁时进行完整的神经发育评估。早期主要结局变量将是MRI损伤严重程度评分;后期主要结局将是贝利婴儿发育量表评分。 红霉素是一种保护心脏和脑细胞免受新生儿心脏手术损伤的药物。这项研究将表明，如果婴儿给予红细胞生成素有较少的延迟发展比婴儿没有收到的药物。

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.