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

开发血清、影像和临床生物标志物驱动模型以指导儿科心脏骤停后的临床管理

• 批准号: 9104845
• 负责人: ERICKA LINN FINK
• 金额: $ 56.31万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9104845
• 关键词: Adaptive Behaviors; Adult; Adverse effects; Asphyxia; Basal Ganglia; Bedside Testings; Behavioral; Biological Markers; Brain; Brain Injuries; Cardiolipins; Child; Child Care; Childhood; Classification; Clinical; Clinical Management; Complement; Critical Care; Data; Development; Diffusion Magnetic Resonance Imaging; Disease Outcome; Emotional; Etiology; Event; Failure; Family; Fingerprint; Funding; Glial Fibrillary Acidic Protein; Health; Heart Arrest; Hospitals; Image; Industry; Injury; Intervention; Knowledge; Laboratories; Link; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Mitochondria; Modality; Modeling; Monitor; Morbidity - disease rate; Multicenter Studies; N-acetylaspartate; Neuroglia; Neurologic; Neurologic Deficit; Neurological outcome; Neuron-Specific Enolase; Neuronal Injury; Neurons; Outcome; Outcome Measure; Parietal Lobe; Pathway interactions; Patient-Focused Outcomes; Patients; Pediatric Brain Injury; Pediatric Hospitals; Physical Examination; Population; Prospective Studies; Quality of life; Recovery; Rehabilitation therapy; Research; Research Personnel; Resuscitation; Risk; Sensitivity and Specificity; Serum; Severities; Severity of illness; Staging; Syndrome; Testing; Thalamic structure; Therapeutic; United States National Institutes of Health; Validation; Work; base; biomarker panel; biomarker-driven; clinical biomarkers; clinical care; design; hazard; imaging biomarker; improved; improved outcome; ineffective therapies; innovation; mortality; new therapeutic target; next generation; novel; novel therapeutics; outcome prediction; oxidation; patient stratification; prospective; public health relevance; rehabilitation strategy; research study; response; spectroscopic imaging; success; targeted treatment; tool; ubiquitin C-terminal hydrolase

 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.

 描述（由申请人提供）：心脏骤停 (CA) 儿童的死亡率为 50-90%，这主要是由于作为复苏后综合征一部分的神经功能衰竭，在准确分类结果方面存在严重的知识和工具差距。儿科 CA 后，体格检查和实验室测试无法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因治疗无效和表面上健康但后来发现患有神经系统疾病的患者不接受治疗而产生的不良影响。早期准确地识别神经损伤的最终严重程度将有助于及时对特定风险人群进行神经保护干预和/或更有针对性地测试新疗法。建议在经验支持下对脑损伤的血清和影像生物标志物进行建模和验证，并评估其与儿科 CA 后分类结果的临床变量的准确性。我们寻求利用 NIH 资助的儿科单中心随机对照试验的可靠初步数据。 CA 和我们的业绩记录我们的中心假设是，脑损伤的血清和影像生物标志物以及临床变量将在儿科 CA（Vineland 适应性行为量表评分 > 70）1 年后的早期分类中发挥重要作用。一项多中心前瞻性研究（8 个中心和 248 名受试者）中的儿科 CA。强有力的初步数据支持这一假设，并且将在以下 3 个具体目标中测试生物标志物的结果分类准确性：目标 1）神经元的血清生物标志物。 （神经元特异性烯醇化酶和泛素羧基末端水解酶-L1）和神经胶质损伤（S100b 和神经胶质纤维酸性蛋白）；目标 2）区域（枕顶叶皮质、基底神经节和丘脑）脑 MRI（T1/T2 和扩散-加权成像）和神经元损伤（N-乙酰-天冬氨酸）和能量衰竭的磁共振波谱生物标志物（乳酸）；目标 3 将模拟脑损伤的强血清和成像生物标志物与临床变量的组合，我们将在探索性目标中评估脑线粒体损伤的血清生物标志物与新治疗靶点（心磷脂和氧化心磷脂）的潜力。这项拟议的研究具有创新性，因为我们将前瞻性地开发和优化血清和成像生物标志物与临床变量的组合，以准确对儿科 CA 后的结果进行分类。这些拟议的目标利用了最近的试点成功，并应生成准确可靠的生物标志物模型。此外，随着即将开发出能够准确分类的血清生物标志物即时检测和生物标志物组，这些结果预计将对推进这些儿童的神经重症监护产生积极影响。对于信徒和研究人员来说，存在不利结果的风险，需要根据受伤的严重程度进行分层，监测对治疗的反应，并最终帮助他们康复和恢复。