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

项目摘要 本申请的目的是利用NINDS资助的多中心、随机、 安慰剂对照的III期HEAL（高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）与安慰剂对中度/重度缺氧缺血新生儿的神经保护作用 新生儿缺氧缺血性脑病（HIE），谁也接受治疗性低温，以确定Epo对重要的 连续视频脑电图（cEEG）测量。拟议的“HEAL-EEG”子研究 母HEAL试验将测试中心假设，即接受Epo的新生儿将有较低的负担， 新生儿癫痫发作，cEEG背景异常和癫痫发作负担将与 安慰剂组和Epo组2年时的发育障碍。我们将测试我们的假设， 追求两个具体目标：1）确定接受Epo的新生儿是否具有较低的癫痫发作负担 与接受安慰剂的患者相比，并评估癫痫发作负担较低是否与 不良神经发育结果和癫痫，2a）为了确定接受Epo治疗的新生儿 改变了cEEG背景，并评估cEEG预测儿童不良发育结局的能力， 接受Epo的新生儿与仅接受低温的新生儿相比，以及2b）为了确定 在2年时预测神经发育结果的准确性是否增加， 在临床检查和MRI损伤评分中增加cEEG癫痫发作负荷和背景。cEEG从150 入组HEAL的受试者将由两名具有新生儿EEG专业知识的神经生理学家进行分析， 癫痫发作和背景模式，以比较Epo组和安慰剂组的癫痫发作负担，以及 检查6个指定时间点的cEEG背景模式与 使用Bayley婴幼儿发育量表（第3版）评估2年时的神经发育结局。 在成功完成拟议的研究后，我们希望我们的贡献是一个详细的 了解Epo如何影响新生儿HIE的癫痫负荷，以及EEG的预测价值 在有和没有促红细胞生成素的情况下进行低温的新生儿中。这种方法是创新的，因为它利用了 前瞻性随机对照HEAL试验，以评估关键的cEEG指标， 在纵向队列研究中完成。HEAL-EEG将是最大的研究，仔细评估详细的 一种新型神经保护剂的多中心cEEG测量。这项研究意义重大，因为 它将增加我们对促红细胞生成素作用机制的理解，并为临床医生提供合理的信息， 通过确定癫痫发作的风险和时间以及预后， 在低温期间和之后的不同时间点的cEEG的效用。使用cEEG等工具来预测 在尽可能早的时间点对HIE新生儿的神经发育结果进行临床评估是至关重要的。 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.