Biomarkers of Brain Injury in Critically-Ill Children on Extracorporeal Membrane Oxygenation (ECMO)

体外膜氧合 (ECMO) 危重儿童脑损伤的生物标志物

• 批准号: 10331871
• 负责人: Melania Maria Bembea
• 金额: $ 63.7万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10331871
• 关键词: Acute; Adaptive Behaviors; Address; Adult; Astrocytes; Benchmarking; Biological Markers; Brain; Brain Injuries; Brain Ischemia; Brain hemorrhage; Brain-Derived Neurotrophic Factor; CCL2 gene; Caring; Cell Death; Cessation of life; Child; Childhood; Choline; Classification; Clinical; Clinical Chemistry; Clinical Research; Clinical Trials; Complement; Creatine; Critical Illness; Critically ill children; Data; Development; Diagnosis; Encephalitis; Exposure to; Extracorporeal Membrane Oxygenation; Failure; Feedback; Fright; Future; Glial Fibrillary Acidic Protein; Glutamates; Goals; Health; Heart Arrest; Heart failure; Hospitals; IL8 gene; Impairment; Inflammation; Inflammatory; Infrastructure; Injury; Inositol; Institutes; Intensive Care Units; Interleukin-1 beta; Interleukin-10; Interleukin-6; Intervention; Ischemia; Kynurenine; Life; Lipids; Longitudinal cohort; Measures; Metabolic; Methods; Monitor; N-acetylaspartate; Necrosis; Nervous System Trauma; Nested Case-Control Study; Neurologic; Neurological outcome; Neurons; Observational Study; Organ; Outcome; Pathology; Pathway interactions; Patients; Pediatric Hospitals; Performance; Phase; Plasma; Proteins; Public Health Schools; Recovery; Refractory; Research; Research Infrastructure; Resources; Respiratory Failure; Risk; Risk Factors; Sampling; Savings; Schools; Shock; Survivors; TNF gene; Techniques; Technology; Testing; Time; Training; Treatment Efficacy; alpha synuclein; base; blood-brain barrier disruption; brain magnetic resonance imaging; circulating biomarkers; cohort; cost; cytokine; disability; experience; high risk; imaging biomarker; improved; inflammatory marker; injury recovery; insight; interest; modifiable risk; mortality; mortality risk; neurogranin; neuroimaging; neuroinflammation; novel; pre-clinical; prospective; response; stem; survival outcome; telencephalin

PROJECT SUMMARY With advances in technology, the use of extracorporeal membrane oxygenation (ECMO) for severe refractory heart and lung failure has quadrupled in children and increased tenfold in adults in the last 15 years. ECMO is life-saving, but costly, resource-intensive, and high-risk. Up to 30% of pediatric ECMO patients develop neurologic injury. Mortality increases by 89% if injury occurs, and 10%-60% of survivors have clinically important neurologic disability that impairs normal development and school performance. We currently lack the ability to accurately stratify children at risk for death or disability, and to diagnose injury in subclinical phase, thus missing the window for potential neuroprotective interventions. The overall goal of this research is to develop and refine a brain injury multimarker panel for accurate neurologic monitoring at the bedside and early classification of mortality and disability outcomes that will allow real-time neuroprotective interventions, with the ultimate goal to improve neurodevelopmental outcomes of these critically ill children. We hypothesize that circulating markers of brain injury and inflammation can assist in diagnosing difficult-to-image neurologic injury; provide real-time feedback to neuroprotective or potentially deleterious interventions in the intensive care unit; identify patients at risk for long-term neurologic disability; and serve as entry criteria and benchmarks of therapeutic efficacy in future interventional clinical trials through a more refined approach than is currently possible. Based on preliminary data from single and two-center studies, we propose a multicenter prospective observational study (9 centers, 225 subjects) that will seek to determine the association between plasma and imaging markers of brain injury and inflammation during ECMO and short and long-term survival and neurologic outcomes of critically-ill children who require extracorporeal support. Using targeted and discovery approaches, we will address our overall goal in the following specific aims, with the support and well-established research infrastructure of the Johns Hopkins Bloomberg School of Public Health, Pediatric Neurocritical Care Research Group and the Kennedy Krieger Institute: (1) Determine if circulating levels of brain injury markers during ECMO and brain MRI abnormalities at 2 weeks after ECMO are associated with survival at 18 months after ECMO with a score ≥85 on the Vineland Adaptive Behavior Scales, third edition (VABS-III); (2) Determine whether the presence and degree of inflammation during ECMO and markers of neuroinflammation on brain MRS at 2 weeks after ECMO are associated with survival at 18 months after ECMO with a score ≥85 on VABS-III; (3) Determine whether metabolic and lipid neuroinflammatory pathways will distinguish between at-risk for, acute, and recovery phases of neurologic injury during ECMO.

项目概要 随着技术的进步，使用体外膜肺氧合（ECMO）治疗严重难治性患者 在过去 15 年里，儿童心力衰竭和肺衰竭的发病率增加了四倍，成人的发病率增加了十倍。 ECMO 是 可以挽救生命，但成本高昂、资源密集且风险高。高达 30% 的儿科 ECMO 患者出现了这种情况 神经损伤。如果发生伤害，死亡率会增加 89%，并且 10%-60% 的幸存者有临床重要意义 损害正常发育和学校表现的神经功能障碍。我们目前缺乏能力 准确地对有死亡或残疾风险的儿童进行分层，并在亚临床阶段诊断损伤，从而漏掉 潜在的神经保护干预措施的窗口。本研究的总体目标是开发和完善 脑损伤多标记物面板，用于床边准确的神经系统监测和早期分类 死亡率和残疾结果将允许实时神经保护干预，最终目标是 改善这些危重儿童的神经发育结果。我们假设循环标记物 脑损伤和炎症可以帮助诊断难以成像的神经损伤；提供实时 对重症监护病房的神经保护或可能有害的干预措施的反馈；识别患者 长期神经功能障碍的风险；并作为疗效的准入标准和基准 未来的介入临床试验将通过比目前更精细的方法进行。基于 根据单中心和两中心研究的初步数据，我们提出了一项多中心前瞻性观察研究 （9 个中心，225 名受试者）将寻求确定血浆和成像标记物之间的关联 ECMO 期间的脑损伤和炎症以及短期和长期生存以及神经系统结果 需要体外支持的危重儿童。使用有针对性的和发现的方法，我们将 在支持和完善的研究的支持下，实现以下具体目标的总体目标 约翰霍普金斯大学彭博公共卫生学院的基础设施，儿科神经重症监护研究 小组和肯尼迪克里格研究所：（1）确定 ECMO 期间脑损伤标志物的循环水平 ECMO 后 2 周的脑部 MRI 异常与 ECMO 后 18 个月的生存率相关 Vineland 适应行为量表第三版 (VABS-III) 得分≥85； (2) 判断是否 ECMO 期间炎症的存在和程度以及 2 周时脑 MRS 上的神经炎症标志物 ECMO 后与 ECMO 后 18 个月的生存相关，且 VABS-III 评分≥85； (3)确定 代谢和脂质神经炎症途径是否能够区分有风险、急性和恢复期 ECMO期间神经损伤的阶段。