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: 9925298
• 负责人: ERICKA LINN FINK
• 金额: $ 51.04万
• 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 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9925298
• 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; Heterogeneity; Hospitals; Industry; Injury; Intervention; Knowledge; Laboratories; Length of Stay; Link; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Mitochondria; Modality; Modeling; Monitor; Morbidity - disease rate; Multicenter Studies; N-acetylaspartate; Nervous System Trauma; Neuroglia; Neurologic; Neurologic Deficit; Neurological outcome; Neuron-Specific Enolase; Neuronal Injury; Neurons; Outcome; Outcome Measure; Oxides; Parietal Lobe; Patient-Focused Outcomes; Patients; Pediatric Brain Injury; Pediatric Hospitals; Physical Examination; Population; Prospective Studies; Quality of life; Recovery; Rehabilitation therapy; Research; Research Design; Research Personnel; Resuscitation; Risk; Sensitivity and Specificity; Serum; Severities; Severity of illness; Syndrome; Testing; Thalamic structure; Therapeutic; Time; United States National Institutes of Health; Validation; Work; base; biomarker panel; biomarker-driven; care outcomes; clinical biomarkers; clinical care; hazard; imaging biomarker; improved; improved outcome; ineffective therapies; innovation; mortality; multimodality; new therapeutic target; next generation; novel; novel therapeutics; out-of-hospital cardiac arrest; outcome prediction; oxidation; patient stratification; prognostic; prospective; public health relevance; rehabilitation strategy; research study; response; spectroscopic imaging; success; targeted treatment; tool; treatment response; 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 allow 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 favorable 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%，主要是由于复苏后综合征中的神经功能衰竭所致。儿科 CA 后准确分类结果的知识和工具存在严重差距。体格检查和实验室检测不足以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而产生不良反应的风险，以及对表面上健康但后来发现患有神经缺陷的患者不进行治疗的风险。及早准确地识别神经损伤的最终严重程度将有助于及时采取神经保护干预措施和/或更针对特定风险人群进行更有针对性的新疗法测试。我们的长期目标是改善 CA 幸存儿童的神经系统结果。在这里，我们建议在经验支持下对脑损伤的血清和成像生物标志物进行建模和验证，并评估其与临床变量一起对儿科 CA 后的结果进行分类的准确性。我们寻求利用 NIH 资助的儿科 CA 单中心随机对照试验的可靠初步数据以及我们在儿科脑损伤生物标志物研究方面的跟踪记录。我们的中心假设是，在一项多中心前瞻性研究中，脑损伤的血清和影像生物标志物以及临床变量将极大地帮助儿科 CA 后早期对有利结果进行分类（Vineland 适应性行为量表评分 > 70）。 （8 个中心和 248 个科目）。强有力的初步数据支持这一假设，生物标志物将在以下 3 个具体目标中测试结果分类的准确性： 目标 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）和神经胶质损伤（S100b 和神经胶质细胞）的血清生物标志物纤维酸性蛋白）；目标 2) 区域（枕顶皮质、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（乳酸）的 MR 波谱生物标志物； Aim 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。我们将评估脑线粒体损伤的血清生物标志物，以探索性的方式寻找新的治疗靶点（心磷脂和氧化心磷脂）。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，应该生成准确可靠的生物标志物模型，显着改善 CA 后儿童的复苏后临床护理。此外，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，即将开发出血清生物标志物护理测试和生物标志物组合，为需要按严重程度分层的临床医生和研究人员准确分类不良结果的风险的伤害，监测对治疗的反应，并最终协助他们的康复和恢复。

项目成果

Multistakeholder Qualitative Research Methods to Impact Culture of Care Practices in the ICU.

影响 ICU 护理实践文化的多利益相关者定性研究方法。

• DOI: 10.1097/pcc.0000000000001564
• 发表时间: 2018
• 期刊: Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies
• 作者: Olson,LenoraM;Chrisman,MaddieJ;Houtrow,AmyJ;Fink,ErickaL
• 通讯作者: Fink,ErickaL

Association of Blood-Based Brain Injury Biomarker Concentrations With Outcomes After Pediatric Cardiac Arrest.

• DOI: 10.1001/jamanetworkopen.2022.30518
• 发表时间: 2022-09-01
• 期刊: JAMA NETWORK OPEN
• 影响因子: 13.8
• 作者: Fink, Ericka L.;Kochanek, Patrick M.;Panigrahy, Ashok;Beers, Sue R.;Berger, Rachel P.;Bayir, Hulya;Pineda, Jose;Newth, Christopher;Topjian, Alexis A.;Press, Craig A.;Maddux, Aline B.;Willyerd, Frederick;Hunt, Elizabeth A.;Siems, Ashley;Chung, Melissa G.;Smith, Lincoln;Wenger, Jesse;Doughty, Lesley;Diddle, J. Wesley;Patregnani, Jason;Piantino, Juan;Walson, Karen Hallermeier;Balakrishnan, Binod;Meyer, Michael T.;Friess, Stuart;Maloney, David;Rubin, Pamela;Haller, Tamara L.;Treble-Barna, Amery;Wang, Chunyan;Clark, Robert R. S. B.;Fabio, Anthony
• 通讯作者: Fabio, Anthony

The Post-PICU Growth Curve.

• DOI: 10.1097/pcc.0000000000002997
• 发表时间: 2022-08-01
• 期刊: Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

Assessment of Brain Magnetic Resonance and Spectroscopy Imaging Findings and Outcomes After Pediatric Cardiac Arrest.

• DOI: 10.1001/jamanetworkopen.2023.20713
• 发表时间: 2023-06-01
• 期刊: JAMA network open
• 影响因子: 13.8

Use of Magnetic Resonance Imaging in Neuroprognostication After Pediatric Cardiac Arrest: Survey of Current Practices.

• DOI: 10.1016/j.pediatrneurol.2022.06.011
• 发表时间: 2022-09
• 期刊: Pediatric neurology
• 影响因子: 3.8
• 作者: Piantino JA;Ruzas CM;Press CA;Subramanian S;Balakrishnan B;Panigrahy A;Pettersson D;Maloney JA;Vossough A;Topjian A;Kirschen MP;Doughty L;Chung MG;Maloney D;Haller T;Fabio A;Fink EL;POCCA Investigators
• 通讯作者: POCCA Investigators