Development of quantitative optical tools to continuously monitor cerebral autoregulation, blood flow, oxygenation and inflammation during pediatric extracorporeal life support
Study ID: STU-2020-0594
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 support. use of eCMo is expanding rapidly and it has supported over [Greater Than]71,000 children worldwide. advances in eCMo have allowed more children to survive 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 final common pathway of neurological injury during eCMo is excessive or insufficient cerebral perfusion, leading to hemorrhage or ischemia, yet perfusion is not monitored and thus cannot be optimized. The underlying disease and eCMo may (1) disrupt cerebral autoregulatory mechanisms and (2) cause neuroinflammation, which may also disrupt autoregulatory mechanisms. Disrupted cerebral autoregulation predisposes the brain to hemorrhagic or ischemic injury via excessive or inadequate perfusion. Current clinical tools do not predict neurological injury, greatly inhibiting the development of neuroprotective protocols. Specifically, there is no monitor to continuously assess the adequacy of cerebral perfusion, 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 goal of this proposal is to test the hypothesis that continuous point-of-care optical neuromonitoring can predict injury acquired during eCMo. a pilot study led by the Pi has demonstrated the feasibility of using advanced non-invasive optical monitors to assess cerebral autoregulation, and oxygen perfusion. a very recent case study has shown highly disrupted autoregulation indices prior to a stroke during eCMo. This proposal will utilize diffuse optics to longitudinally monitor cerebral autoregulation and inflammation throughout eCMo in a large pediatric population. in aim 1, we will demonstrate that alterations in optical metrics of cerebral autoregulation during eCMo precede clinical and CT/MRi recognition of neurological injury, further using diffuse optical measurements to improve interpretation of standard-of-care cerebral oximetry. in aim 2, we will demonstrate that optical metrics predict the temporal course of neuroinflammation, as evidenced by blood biomarkers. in both aims, optical metrics averaged over the entire course of eCMo will be assessed for ability to predict injury on post-eCMo MRi. if successful, the work of this interdisciplinary team of physical scientists, clinicians, and neuroscientists will establish the value of specific continuous quantitative optical monitoring metrics to prospectively identify periods of disrupted autoregulation and neuroinflammation, leading to 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.
- Cancer Related
- Healthy Volunteers
- UT Southwestern Principal Investigator
- LAKSHMI RAMAN
Worldwide, [Greater Than]71,000 children have been supported by extracorporeal Membrane oxygenation (eCMo, long-term cardiopulmonary bypass). although advances in eCMo have allowed more children to survive critical illness, neurological injury reduces survival by 50-60% and leads to significant acute and long-term neurologic morbidity. over 50% of neonatal and pediatric eCMo patients acquire ischemic or hemorrhagic neurological injury during eCMo. We found that eCMo disrupts cerebral autoregulation (Ca),1 the processes that permit the brain to maintain appropriate cerebral perfusion during changes in cerebral perfusion and blood pressures, and that neuroinflammation is associated with disrupted Ca.4 excessive or insufficient cerebral perfusion is the final common pathway of intra-eCMo ischemic and hemorrhagic injury, yet perfusion is not monitored. Blood pressures are monitored, yet disrupted Ca changes the range of blood pressures which provide adequate cerebral perfusion. understanding of injury mechanisms and potential interventions is limited by a critical gap in knowledge due to inadequate methods to non-invasively and continuously monitor cerebral perfusion, Ca, and neuroinflammation during eCMo. our long-term goal is to develop neuromonitoring tools to support neuroprotective eCMo management and ultimately minimize mortality and neurological morbidity. our first-of-its-kind pilot study utilized non-invasive optical monitoring (oM) during eCMo to measure microvascular blood flow in the brain and derive a Ca metric, DCSx. This revealed that Ca was both impaired and variable with time. impaired Ca may shift or narrow the safe range of blood pressures and lead to either inadequate or excessive cerebral blood flow. in our ongoing pilot study, we observed elevated DCSx values prior to stroke during eCMo. in addition, our parallel pilot study found a strong correlation between neuroinflammatory biomarkers in the blood and acquired neurological injury. Point-of-care oM metrics of neuroinflammation have been applied to e.g., arthritis, but have not been translated into neurological injury. in this study, we will use state-of-the-art oM (diffuse optical and correlation spectroscopies) to assess Ca, and neuroinflammation for the first 24 hours of eCMo, and for 6 hr/day for up to 1 week following initiation, in combination with standard-of-care monitors in a large pediatric population. our central hypothesis is that periods of inadequate or excessive cerebral perfusion associated with disrupted Ca and neuroinflammation precede neurological injury. This application's overall objective is to demonstrate that continuous oM predicts eCMo-associated neurological injury. if successful, this work will establish the utility of oM to prospectively identify periods of disrupted hemodynamics leading to injury. Continuous oM monitoring will enable a paradigm shift in eCMo management away from protocols based on systemic vital signs to neuroprotective protocols that can prevent or mitigate acquired neurological injury.[?]