EVALUATION OF NONINVASIVE CEREBRAL PERFUSION AND OXYGENATION DIAGNOSTICS TO DETECT NEUROLOGIC INJURY IN A NONHUMAN PRIMATE MODEL OF SEVERE TRAUMATIC HEMORRHAGE

Background: Hemorrhagic shock (HS) and traumatic brain injury (TBI) are the leading causes of mortality among military and civilian populations. Although less frequently reported, brain injury can occur as a result of prolonged hypotension even in the absence of a direct mechanical injury. Our group has recently observed severe neurologic deficit in a non-human primate model of polytrauma and severe HS despite the absence of a TBI and recovery of systemic hemodynamics with resuscitation. Of these animals, 100% were considered 'survivors' to 6 hours post-injury; however, brain death was observed in 75% of the animals upon attempted recovery from anesthesia. Therefore, it is likely that a resuscitation strategy based solely on systolic or mean blood pressure (SBP or MAP, respectively) is ignoring critical derangements in blood flow to the brain. The underlying mechanisms, acceptable thresholds for malperfusion, and effective therapeutic resuscitation strategies to optimize neurologic outcomes in TBI and non-TBI remain poorly defined. The lack of effective clinical therapies is attributed to shortcomings with regard to effective methods to monitor brain physiology following injury. Maintenance of tissue oxygen is recognized as a main objective in critical care medicine. Ischemia and hypoxia contribute to brain damage; therefore, the ability to assess brain tissue oxygenation and detect cerebral hypoxia is vital in resuscitative efforts aimed at preserving neurocognitive function.Objectives: The objectives of the proposed research are to:(1) Characterize cerebral perfusion and oxygenation using currently available non-invasive and field deployable methods (i.e., transcranial Doppler [TCD] ultrasound and near-infrared [NIRS]-based cerebral oximetry) and invasive monitoring of cerebral oxygenation, intracranial pressure, and brain temperature (i.e., Licox®/Camino®).(2) Determine correlations between available prehospital diagnostic measures of cerebral perfusion and oxygen delivery to non-invasive and invasive systemic diagnostic markers (e.g., SBP and MAP).(3) Determine correlations between prehospital, non-invasive and invasive diagnostics to terminal endpoint neurologic outcomes (e.g., neurolcognitive function, advanced brain histology, serum/CSF markers).Hypothesis: Current prehospital diagnostics to guide resuscitation that are based on systemic hemodynamics (i.e., SBP) do not equate to adequate cerebral perfusion and oxygen delivery to ensure cerebral protection in the context of severe polytraumatic hemorrhage and resuscitation.Specific Aim: To determine the relationship between systemic and cerebral hemodynamics and oxygenation and identify parameters that can be used as potential targets for intervention to promote cerebral protection in the setting of severe hemorrhagic shock and polytraumatic injury and resuscitaiton.Study Design: Anesthetized Rhesus Macaques (8-12 kg) will be instrumented with invasive and non-invasive monitors for systemic hemodynamics and oxygenation, as well as, cerebral perfusion and oxygenation. Animals will undergo soft tissue injury, musculoskeletal injury, HS (MAP 20-24 mmHg) until cardiovascular decompensation then resuscitated with whole blood and 0.9% saline to recover SBP and MAP. Comprehensive monitoring of cerebral perfusion and oxygenation, as well as functional neurologic outcomes and terminal endpoint assessments of brain injury, will be performed and compared to standard-of-care monitoring outcomes.Impact: The proposed study is aligned with the following solicited focus areas:Focus Area 1: Understand the clinical implications of prolonged field care (PFC) and prolonged damage control resuscitation (pDCR). Improving the understanding of physiologic parameters requiring monitoring and intervention in order to reduce morbidity and mortality during acute treatment phase of TBI. Characterization and mitigation of pathophysiology of prolonged hypotension or hypotensive resuscitation. Identify and characterize PFC challenges to providing organ support and critical care interventions.Focus Area 2: Develop next-generation resuscitation and stabilization methods for PFC and pDCR. Point-of-injury/point-of-need/prehospital capabilities to monitor and/or stabilize acute TBI casualties. The goal is to enable earlier detection of life-threatening conditions, improve decision-making timelines, and/or mitigate progression of brain injury in pDCR and/or remote operating environment scenarios.Specifically, the research will provide a comprehensive assessment of cerebral perfusion and oxygenation using field deployable technologies in parallel with current standard of care monitoring methods. This study will provide valuable insight into the physiologic markers required for monitoring and identifying targets for resuscitation to improve brain protection and meaningful survival outcomes.