HEAL - EEG - Neurophysiologic measures of Epo treatment for hypoxic-ischemic encephalopathy (HIE)

项目摘要 此应用程序的目标是利用NINDS资助的多中心、随机、 安慰剂对照的III期Hear(大剂量促红细胞生成素治疗窒息和脑病)临床试验 促红细胞生成素(EPO)与安慰剂对中/重度缺氧缺血新生儿的神经保护作用 脑病(HIE)患者同时接受亚低温治疗，以确定EPO对重要的 连续的视频脑电(CEEG)测量。建议进行的“康复-脑电”分项研究 父母治愈试验将检验中心假设，即接受EPO治疗的新生儿将有较低的 新生儿癫痫，cEEG背景异常和癫痫负担将与 安慰剂组和促红细胞生成素组在2年后出现发育障碍。我们将通过以下方式验证我们的假设 追求两个具体目标：1)确定接受促红细胞生成素治疗的新生儿癫痫负担是否较低 并评估较低的癫痫负担是否与较低的发病风险相关 不良神经发育结局和癫痫，2a)以确定是否接受EPO治疗的新生儿 改变了cEEG的背景，并评估cEEG预测儿童不良发育结局的能力 接受EPO治疗的新生儿与仅接受低温治疗的新生儿进行比较，以及2b)确定 在2年内预测神经发育结果是否有增量增加的准确性 将cEEG发作负荷和背景纳入临床检查和MRI损伤评分。CEEG从150开始 登记参加康复治疗的受试者将由两名在新生儿脑电方面有专长的神经生理学家进行分析 比较EPO组和安慰剂组的癫痫发作和背景模式，以及 检查六个特定时间点的cEEG背景模式与 2岁时使用贝利婴幼儿发育量表第3版的神经发育结果。 在成功完成拟议的研究后，我们预计我们的贡献将是一个详细的 促红细胞生成素对新生儿缺氧缺血性脑病发作负担的影响及脑电预测价值的研究 在使用和不使用促红细胞生成素的低体温新生儿中。这种方法是创新的，因为它利用了 这项前瞻性随机对照试验旨在以一种不能 完成纵向队列研究。Hear-EEG将是最大规模的仔细评估详细研究 CEEG在一种新型神经保护剂的多中心环境中进行测量。这项研究意义重大，因为 这将增加我们对EPO作用机制的理解，并为临床医生提供合理的 脑电图在新生儿缺氧缺血性脑病中的应用--通过确定癫痫发作的风险和时间以及预后 脑电地形图在低温术中及术后各时间点的应用。使用像cEEG这样的工具来预测 新生儿缺氧缺血性脑病早期神经发育结局对临床至关重要 决策和家长沟通。

Project Summary The objective of this application is to leverage the infrastructure of the NINDS-funded multicenter, randomized, placebo-controlled Phase III HEAL (High-Dose Erythropoietin for Asphyxia and Encephalopathy) clinical trial of erythropoietin (Epo) vs. placebo for neuroprotection in neonates with moderate/severe hypoxic-ischemic encephalopathy (HIE) who also receive therapeutic hypothermia to determine the effect of Epo on important continuous, video electroencephalogram (cEEG) measures. The proposed “HEAL-EEG” sub-study of the parent HEAL trial will test the central hypotheses that neonates who receive Epo will have a lower burden of neonatal seizures, and that cEEG background abnormalities and seizure burden will be associated with developmental disability at 2 years in both the placebo and Epo groups. We will test our hypotheses by pursuing two specific aims: 1) To determine whether neonates who receive Epo have a lower seizure burden than those who receive placebo and to assess whether lower seizure burden is associated with lower risk of adverse neurodevelopmental outcome and epilepsy, 2a) To determine whether neonates who receive Epo have altered cEEG background and to assess the ability of cEEG to predict adverse developmental outcome in neonates who receive Epo as compared to those who receive hypothermia alone, and 2b) To determine whether there is incremental added accuracy in predicting neurodevelopmental outcome at 2 years when adding cEEG seizure burden and background to clinical examination and MRI injury score. cEEG from 150 subjects enrolled in HEAL will be analyzed by two neurophysiologists with expertise in neonatal EEG for seizures and background patterns to compare seizure burden in Epo and placebo groups, as well as to examine the relationship between cEEG background pattern at six specified time points and neurodevelopmental outcome using Bayley Scales of Infant and Toddler Development, 3rd edition at 2 years. Upon successful completion of the proposed research, we expect our contribution to be a detailed understanding of how Epo affects seizure burden in neonates with HIE, as well as the predictive value of EEG in neonates undergoing hypothermia with and without Epo. The approach is innovative because it leverages the prospective randomized, controlled HEAL trial to evaluate critical cEEG measures in a way that cannot be accomplished in longitudinal cohort studies. HEAL-EEG will be the largest study to carefully evaluate detailed cEEG measures in a multicenter setting of a novel neuroprotective agent. The research is significant because it will add to our understanding of Epo’s mechanism of action, as well as inform clinicians in the rational utilization of cEEG in neonates with HIE by defining the risk and timing of seizures, as well as the prognostic utility of cEEG at various time points during and after hypothermia. Using tools like cEEG to predict neurodevelopmental outcome for neonates with HIE at the earliest possible time point is critical for clinical decision-making and parent communication.