Development of quantitative optical tools to continuously monitor cerebral autoregulation, blood flow, oxygenation and inflammation during pediatric extracorporeal life support

体外膜氧合（ECMO）是一种心肺转流术， 为重症儿童和成人提供数周的救生支持，尽管他们的病情最大限度地恶化， 传统疗法。ECMO的使用正在迅速扩大，它已经支持了全球超过71，000名儿童。 ECMO的进步使更多的儿童能够在其他致命疾病中存活下来， 损伤使存活率降低50-60%，并导致显著的长期神经系统发病率。只有一半的ECMO 幸存者的神经行为正常基础疾病和体外膜肺氧合都可能破坏 脑自动调节机制，并引起神经炎症，这也可能破坏自动调节。 脑自动调节紊乱使脑易于出血或缺血性损伤， 灌注不足，但在ECMO期间没有监测。目前的临床工具不能预测神经系统 损伤，极大地抑制了神经保护方案的发展。具体来说，没有监视器 持续评估大脑自动调节的状态，迫使临床医生依赖不完善的系统性 可能无法反映即将发生的神经损伤风险的替代物。 这项研究的长期目标是为重症患者开发连续无创床边监护仪 患者该提议的主要目标是（1）测试连续即时护理光学成像的假设， 监测脑自动调节可以预测ECMO最初48小时后的神经损伤，（2） 表明脑自动调节的光学测量指数与神经炎性相关， 在整个ECMO过程中连续血液样本中的生物标志物。由Pl领导的一项试点研究表明， 使用先进的无创光学监测器评估脑自动调节的可行性 和小儿ECMO患者的脑灌注。我们正在进行的试点研究显示， 自动调节指数与ECMO成像后发现的神经损伤相关。该提案将利用 弥散光学纵向监测整个ECMO中的脑自动调节和炎症， 儿科人群（0-18岁，n=125）。在目标1中，我们将证明， ECMO期间的脑自动调节可预测ECMO内CT发现的神经损伤。在目标2中，我们 表明脑自动调节的光学度量测量神经炎症的时间过程， 如基于实验室的血液分析中的生物标志物所证明的。 如果成功的话，这个由物理科学家、临床医生和神经科学家组成的跨学科团队的工作将 建立脑自动调节的连续定量光学监测的价值， 确定ECMO期间损伤的高风险期。这些结果将使开发以大脑为中心的 心肺旁路方案（例如，血压滴定），以降低神经损伤的发生率， 相关的死亡率和发病率。

Extracorporeal Membrane Oxygenation (ECMO) is a form of cardiopulmonary bypass which provides days to weeks of life-saving support to critically ill children and adults whose illness is progressing despite maximal conventional therapies. Use of ECMO is expanding rapidly and it has supported >71,000 children worldwide. Advances in ECMO have allowed more children to survive an otherwise fatal illness, however neurological injury reduces survival by 50-60% and leads to significant long-term neurologic morbidity. Only half of ECMO survivors have normal neurobehavioral outcomes. The underlying disease and ECMO may both disrupt cerebral autoregulatory mechanisms and cause neuroinflammation, which may also disrupt autoregulation. Disrupted cerebral autoregulation predisposes the brain to hemorrhagic or ischemic injury via excessive or inadequate perfusion, yet it is not monitored during ECMO. Current clinical tools do not predict neurological injury, greatly inhibiting the development of neuroprotective protocols. Specifically, there is no monitor to continuously assess the state of cerebral autoregulation, forcing clinicians to rely on imperfect systemic surrogates that may not reflect risks of impending neurological injury. The long-term goal of this research is to develop continuous non-invasive bedside monitors for critically ill patients. The primary goals of this proposal are to (1) test the hypothesis that continuous point-of-care optical monitoring of cerebral autoregulation can predict neurologic injury after the first 48 hours of ECMO and (2) demonstrate that optically measured indices of cerebral autoregulation are associated with neuroinflammatory biomarkers in serial blood samples throughout ECMO. A pilot study led by the Pl has demonstrated the feasibility of using advanced non-invasive optical monitors to assess cerebral autoregulation and cerebral perfusion in pediatric ECMO patients. Our ongoing pilot study has shown disrupted autoregulation indices correlate with neurological injury found on post-ECMO imaging. This proposal will utilize diffuse optics to longitudinally monitor cerebral autoregulation and inflammation throughout ECMO in a large pediatric population (0-18 y.o., n=125). In Aim 1, we will demonstrate that alterations in optical metrics of cerebral autoregulation during ECMO predict neurological injury found on intra-ECMO CT. In Aim 2, we will demonstrate that optical metrics of cerebral autoregulation measure the temporal course of neuroinflammation, as evidenced by biomarkers in lab-based blood assays. If successful, the work of this interdisciplinary team of physical scientists, clinicians, and neuroscientists will establish the value of continuous quantitative optical monitoring of cerebral autoregulation to prospectively identify periods of high risk of injury during ECMO. These results will enable the development of brain-focused cardio-pulmonary bypass protocols (e.g., blood pressure titration) to reduce the rate of neurologic injury and associated mortality and morbidity in ECMO patients.