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

项目摘要 随着技术的进步，使用体外膜肺氧合（ECMO）治疗严重难治性肺损伤， 在过去的15年里，儿童的心脏和肺衰竭增加了四倍，成人增加了十倍。ECMO是 拯救生命，但成本高，资源密集，风险高。多达30%的儿科ECMO患者会出现 神经损伤如果发生损伤，死亡率增加89%，10%-60%的幸存者具有临床重要的 损害正常发育和学校表现的神经系统残疾。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， 潜在的神经保护干预的窗口。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旁准确的神经病学监测和早期分类 死亡率和残疾结果，这将允许实时神经保护干预，最终目标是 改善这些重症儿童的神经发育结果。我们假设循环中的 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 对重症监护室中的神经保护或潜在有害干预的反馈; 长期神经功能障碍的风险;并作为治疗有效性的入选标准和基准， 未来的干预性临床试验，通过更精细的方法比目前可能的。基于 根据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），将寻求确定血浆和成像标记物之间的关联， ECMO期间的脑损伤和炎症以及ECMO的短期和长期生存率和神经学结局 需要体外支持的危重儿童。使用目标和发现方法，我们将 在以下具体目标中实现我们的总体目标，并得到支持和完善的研究 约翰霍普金斯彭博公共卫生学院儿科神经重症监护研究基础设施 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MRI异常与ECMO后18个月的生存率相关， 在Vineland适应行为量表第三版（VABS-III）上得分≥85;（2）确定 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VABS-III评分≥85的患者与ECMO后18个月的生存率相关;（3）确定 代谢和脂质神经炎性通路是否将区分处于危险中、急性和恢复 ECMO期间的神经损伤阶段。

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.