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)是一种形式的体外循环 为危重儿童和成人提供数周的救命支持，这些儿童和成年人的病情仍在恶化，尽管 传统疗法。ECMO的使用正在迅速扩大，它已经支持了全球7.1万名儿童。 ECMO的进步使更多的儿童能够在一种本来是致命的疾病中存活下来，尽管是神经疾病 损伤会使存活率降低50%-60%，并导致严重的长期神经系统疾病。只有一半的ECMO 幸存者的神经行为结果正常。潜在的疾病和ECMO可能都会破坏 大脑自动调节机制，并引起神经炎症，这也可能扰乱自动调节。 大脑自我调节功能紊乱使大脑易于通过过量的或 血液灌注量不足，但在ECMO期间不进行监测。目前的临床工具不能预测神经学 损伤，极大地抑制了神经保护方案的发展。具体地说，没有监视器可以 持续评估大脑自动调节状态，迫使临床医生依赖不完善的系统 可能不会反映即将发生的神经损伤风险的代用品。 这项研究的长期目标是为危重病人开发连续的无创床边监护仪。 病人。该建议的主要目标是：(1)检验连续的医疗护理点光学 监测脑自我调节可预测ECMO后48小时内的神经损伤 证明光学测量的大脑自我调节指数与神经炎性有关 整个ECMO系列血样中的生物标记物。由人民解放军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 和儿童ECMO患者的脑血流灌注。我们正在进行的试点研究显示 自我调节指数与ECMO术后发现的神经损伤相关。这项建议将利用 弥散光学纵向监测整个ECMO中的脑自动调节和炎症 儿童人口(0-18岁，n=125)。在目标1中，我们将演示光学度量的变化 ECMO中的脑自我调节可预测ECMO内CT发现的神经损伤。在目标2中，我们将 证明大脑自动调节的光学测量测量了神经炎症的时间进程， 实验室血液分析中的生物标记物证明了这一点。 如果成功，这个由物理学家、临床医生和神经科学家组成的跨学科团队的工作将 建立脑自动调节连续定量光学监测对前瞻性研究的价值 确定体外反搏期间损伤的高危时段。这些结果将使发展专注于大脑的 体外循环方案(例如，血压滴定)，以降低神经损伤率和 ECMO患者的相关死亡率和发病率。

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.