Development of Serum, Imaging, and Clinical Biomarker Driven Models to Direct Clinical Management after Pediatric Cardiac Arrest

 描述(由申请人提供)：心脏骤停(CA)的儿童死亡率为50%-90%，主要是由于神经衰竭作为复苏后综合征的一部分。在对儿童CA术后结果进行准确分类方面，在知识和工具方面存在严重的差距。体检和实验室检测不能充分评估神经损伤的严重程度和结果。错误分类的危险包括无效治疗和不对表面上很好的患者进行治疗的不良影响，这些患者后来被发现有神经缺陷。及早准确地确定神经损伤的最终严重程度将需要及时的神经保护干预和/或在特定危险人群中对新疗法进行更有针对性的测试。我们的长期目标是改善CA存活儿的神经预后。在这里，我们建议用经验支持来模拟和验证脑损伤的血清和影像生物标记物，并结合临床变量评估它们在儿童CA术后预后分类中的准确性。我们寻求利用NIH资助的儿童CA单中心随机对照试验的强劲初步数据和我们在儿童脑损伤生物标记物研究方面的记录。我们的中心假设是，在一项多中心前瞻性研究(8个中心和248名受试者)中，脑损伤的血清和成像生物标记物，以及临床变量，将在儿科CA(Vineland适应行为量表评分和GT；70)后一年的儿科CA(Vineland Adapter Behavior Scales Score&GT；70)后对早期有利结果的分类起关键作用。强有力的初步数据支持这一假说，将在以下3个特定目标测试生物标记物的结果分类准确性：目的1)神经元(神经元特异性烯醇化酶和泛素羧基末端水解酶-L1)和胶质损伤(S100B和胶质纤维酸性蛋白)的血清生物标志物；目的2)区域(枕顶皮质、基底节和丘脑)脑MRI(T1/T2和扩散加权成像)和磁共振波谱生物标志物(N-乙酰-天冬氨酸)和能量衰竭(乳酸)；以及目标3将建模脑损伤的强血清和成像生物标志物与临床变量的组合。我们将评估脑线粒体损伤的血清生物标记物，以及寻找新的治疗靶点(心磷脂和氧化心磷脂)的可能性。这项拟议的研究是创新的，因为我们将前瞻性地开发和优化一组具有临床变量的血清和成像生物标记物的组合，以准确地对儿童CA术后的结果进行分类。这些拟议的目标利用了最近的试验成功，并应产生准确和可靠的生物标记物模型，显著改善CA后儿童复苏后的临床护理。此外，这些结果预计将对推进这些儿童的神经危重护理产生积极影响，即将开发出一种血清生物标记点测试和生物标记物小组，将准确地对不良结局的风险进行分类，临床医生和研究人员需要根据损伤的严重程度进行分层，监测治疗反应，最终帮助他们康复和康复。

 DESCRIPTION (provided by applicant): Children with cardiac arrest (CA) have mortality rates of 50-90%, largely due to neurological failure as part of the post-resuscitation syndrome. There is a critical gap of knowledge and tools to accurately classify outcome after pediatric CA. Physical examination and laboratory testing inadequately assess the severity of neurologic injury and outcome. Hazards of misclassification include risking adverse effects from ineffective therapies and non-treatment of ostensibly well patients who later are found to have neurologic deficits. Early and accurate identification of the eventual severity of neurologic injury would allw for timely neuroprotective interventions and/or more targeted testing of new therapies in specific risk populations. Our long term objective is to improve the neurological outcome of children surviving CA. Here we propose to model and validate serum and imaging biomarkers of brain injury with empirical support, and to assess their accuracy together with clinical variables in classifying outcome after pediatric CA. We seek to capitalize on robust preliminary data from an NIH-funded single center RCT in pediatric CA and our track record in biomarker research in pediatric brain injury. Our central hypothesis is that serum and imaging biomarkers of brain injury, together with clinical variables, will critically aid in the early classification of favorale outcome after pediatric CA (Vineland Adaptive Behavior Scales score > 70) 1 year after pediatric CA in a multicenter prospective study (8 centers and 248 subjects). Strong preliminary data supports this hypothesis, and biomarkers will be tested for outcome classification accuracy in the following 3 specific aims: Aim 1) Serum biomarkers of neuronal (neuron specific enolase and ubiquitin carboxy-terminal hydrolase-L1) and glial injury (S100b and glial fibrillary acidic protein); Aim 2) Regional (occipital-parietal cortex, basal ganglia, and thalamus) brain MRI (T1/T2 and diffusion-weighted imaging) and MR spectroscopy biomarkers of neuronal injury (N-acetyl-aspartate) and energy failure (lactate); and Aim 3 will model the combination of strong serum and imaging biomarkers of brain injury with clinical variables. We will assess serum biomarkers of brain mitochondrial injury with potential for novel therapeutic targets (cardiolipin and oxidized cardiolipin) in an exploratory aim. This proposed research is innovative, because we will prospectively develop and optimize a combined panel of serum and imaging biomarkers with clinical variables to accurately classify outcome after pediatric CA. These proposed aims leverage recent pilot successes and should generate accurate and reliable models of biomarkers that markedly improve post-resuscitation clinical care in children after CA. Furthermore, these results are expected to have a positive impact in advancing neurocritical care for these children, with forthcoming development of a serum biomarker point of care test and biomarker panels that will accurately classify risk of unfavorable outcome for clinicians and researchers needing to stratify by severity of injury, to monitor response to therapy, and ultimately to assist in their rehabilitation and recovery.