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

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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.