Leveraging biomarkers of traumatic brain injury in adults to assess pediatric neurocritical illness

项目摘要 在美国，每年约有230，000 - 480，000名儿童入住儿科重症监护室（PICU）。 美国的在这些儿童中，16%患有神经危重症。神经危急状况的范围从 创伤性脑损伤（TBI）、中风、癫痫发作和癫痫持续状态，至心脏起搏后缺氧性脑损伤 逮捕了虽然PICU的总死亡率从20世纪80年代的11%显著下降到2000年的1.3%-5%， 当代，患有神经危重症的儿童死亡率高达12%，其中最高死亡率为 心脏骤停（24%）。脑损伤和神经系统衰竭是65%的近端死因 在PICU的所有死亡病例中，14%的儿童在PICU住院期间发生脑损伤。所有PICU 神经危重症儿童的神经功能状态下降率也较高（7.3%）， 与一般PICU人群（4.8%）相比，出院时间vs基线。因此，现代神经批评 护理的重点是监测神经功能状态，并防止加重 初始损伤和恶化的长期结果（例如，低血压、低血糖、体温过高、缺氧， 颅内高压或癫痫发作）。我们目前缺乏有效的工具来及时评估的严重性， 初始脑损伤，用于监测继发性神经损伤，并用于风险分层和结局 在危重患儿的PICU过程中早期进行分类。无法充分分类和选择研究 参与者的有针对性的干预措施是一个很好的描述在重症监护研究的问题。这个项目的总体目标是 一项提案是设计一种用于儿科神经危重症的即时血浆脑损伤生物标志物面板， 使用已在成人人群中验证的生物标志物，30分钟得出结果。我们假设 脑损伤生物标志物的即时检测将允许及时识别将受益于治疗的患者。 大多数来自神经保护干预，需要快速启动以获得最佳疗效，然后可以用于 监测大脑对这种干预的反应。由于生物标志物的独特组合可能具有上级优势， 对于每种情况，我们将使用已经存在的良好表型的PICU队列和血浆储存库， Meso Scale为成人TBI开发的由14种脑损伤生物标志物组成的综合护理点小组 诊断（MSD，Rockville，MD）。我们将在以下具体目标中实现我们的总体目标：（1）确定 一种新的平台检测PICU儿童血浆脑损伤生物标志物的灵敏度 临床神经损伤;和（2）确定脑损伤生物标志物的循环水平 在PICU住院期间预测A）出院前死亡率，B）住院时神经功能障碍 放电，和C）与神经影像学异常相关。如果损伤的敏感性和预测值 结果得到证实，为成人TBI开发的即时护理设备将在未来进行前瞻性测试 儿科临床研究。

PROJECT SUMMARY Approximately 230,000-480,000 children are admitted to Pediatric Intensive Care Units (PICU) annually in the United States. Of these children, 16% present with neurocritical illness. Neurocritical conditions range from traumatic brain injury (TBI), stroke, seizures and status epilepticus, to hypoxic brain injury following cardiac arrest. While overall PICU mortality has declined significantly from 11% in the 1980s to 1.3%-5% in the contemporary era, mortality in children with neurocritical illness is as high as 12%, with highest mortality following cardiac arrest (24%). Brain injury and neurological system failure represent the proximal cause of death for 65% of all deaths in the PICU, with 14% of children acquiring brain injuries during their PICU stay. Among all PICU survivors, children with neurocritical illness also have higher rates of decline in neurofunctional status (7.3%) at the time of discharge vs baseline, compared to the general PICU population (4.8%). Thus, modern neurocritical care focuses on monitoring neurologic functional status and preventing secondary injuries that exacerbate the initial injury and worsen long-term outcomes (e.g., hypotension, hypoglycemia, hyperthermia, hypoxia, intracranial hypertension, or seizures). We currently lack valid tools for timely evaluation of the severity of the initial brain injury, for monitoring of secondary neurologic injury, and for risk stratification and outcome classification early in the PICU course of critically ill children. Inability to adequately classify and select study participants for targeted interventions is a well described problem in critical care studies. The overall goal of this proposal is to design a point-of-care plasma brain injury biomarker panel for pediatric neurocritical illness with a 30 minute time-to-results, using biomarkers that have been validated in adult populations. We hypothesize that point-of-care testing of brain injury biomarkers will allow for timely identification of patients who would benefit the most from neuroprotective interventions needing rapid initiation for optimal efficacy, and could then be used to monitor cerebral response to such interventions. As unique combinations of biomarkers are likely to be superior for each condition, we will use an already existing well phenotyped PICU cohort and plasma repository, and a comprehensive point-of-care panel of 14 brain injury biomarkers developed for adult TBI by Meso Scale Diagnostics (MSD, Rockville, MD). We will address our overall goal in the following specific aims: (1) Determine the sensitivity of a novel platform for detection of plasma brain injury biomarkers in children admitted to the PICU with clinical neurologic injury; and (2) Determine the extent to which circulating levels of brain injury biomarkers during PICU admission predict A) mortality before hospital discharge, B) neurologic disability at hospital discharge, and C) association with abnormalities on neuroimaging. If sensitivity of injury and predictive value for outcomes are confirmed, the point-of-care device developed for adult TBI will be tested prospectively in future pediatric bedside studies.