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

项目总结 随着技术的进步，使用体外膜氧合(ECMO)治疗重症难治性 在过去的15年里，心肺衰竭在儿童中增加了四倍，在成年人中增加了十倍。ECMO IS 挽救生命，但代价高昂，资源密集型和高风险。高达30%的儿科ECMO患者发生 神经损伤。如果发生伤害，死亡率会增加89%，10%-60%的幸存者具有重要的临床意义 损害正常发育和学习成绩的神经功能障碍。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，从而遗漏 这是潜在的神经保护干预措施的窗口。这项研究的总体目标是开发和完善 脑损伤多标记物组合用于床边准确的神经学监测和早期分类 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。我们假设循环中的标志物 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 对重症监护病房中神经保护性或潜在有害干预的反馈；在 长期神经功能障碍的风险；并作为进入标准和治疗效果的基准 通过比目前可能的更精细的方法进行未来的介入临床试验。基于 来自单中心和双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)，将寻求确定血浆和脑出血成像标志物之间的关联 体外反搏中的脑损伤和炎症以及患者的短期和长期生存和神经学结果 需要体外支持的危重儿童。使用定向和发现方法，我们将 在支持和成熟的研究的支持下，在以下具体目标中解决我们的总体目标 约翰霍普金斯大学彭博公共卫生学院的基础设施，儿科神经危重护理研究 小组和肯尼迪·克里格研究所：(1)确定ECMO期间循环中脑损伤标志物的水平 ECMO后2周的脑MRI异常与ECMO后18个月的存活率有关 文兰适应行为量表第三版(VABS-III)上的≥85分；(2)确定 ECMO中炎症的存在和程度以及2周时脑MRS上的神经炎症标志物 体外反搏后与术后18个月的存活率有关，VABS-III评分为≥85；(3)确定 代谢和脂质神经炎症通路是否会区分高危、急性和恢复 体外反搏中神经损伤的分期。

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.