Abstract/Project Summary Impairment of microcirculatory blood flow has been implicated as a pivotal pathophysiologic event in acutely critically ill patients. As the brain is particularly sensitive to insufficient perfusion, cognitive impairment, particularly in the elderly, can prolong the recovery period and significantly impact the ability to live independently. Resuscitation or perfusion management in critically ill patients is primarily guided by macrocirculatory assessment (i.e., arterial blood pressure (ABP)) with little consideration of the microcirculation, as microcirculatory parameters are technically difficult to assess. Such practice operates under the assumption that resuscitation aimed at correcting macro-hemodynamic variables is also effective in correcting microcirculatory perfusion and oxygen delivery to the brain tissue, a relationship termed hemodynamic coherence. However, recent studies in pathophysiologic states (e.g., sepsis, shock) strongly suggest that microvascular perfusion is not restored despite the optimization of macrocirculatory parameters. Thus, there is an urgent need to learn what governs cerebral microcirculatory flow, dissect conditions that compromise hemodynamic coherence and define effective microcirculation resuscitation targets. Further, while research tools exist, there is no commonly accepted technique which can measure microcirculation through the intact skull. Therefore, it is essential to identify more accessible microcirculatory beds (e.g., sublingual, retinal) which may serve as surrogates for cerebral microcirculatory flow. Characterizing surrogate microcirculations as flow-biomarkers is a critical step towards practical clinical implementation of microcirculatory targets for resuscitation. Our long-term goal is to develop effective strategies to enhance microcirculatory perfusion and effective oxygen delivery to the brain under critical clinical conditions that require resuscitation. The primary goals of this proposal are to a) investigate the role of the microcirculation in cerebral hemodynamic coherence in the gyrencephalic brain and b) characterize effective cerebral microcirculation proxies that can be developed as non-invasive surrogate biomarkers for bedside clinical management. We will manipulate cardiovascular physiology reflecting common intraoperative scenarios (i.e., hemorrhagic hypotension) and hypothesize that current resuscitation strategies, in particular the use of high concentrations of vasopressors, do not restore microvascular function but lead to long- lasting cerebral microvascular constriction and result in brain injury. In Aim 1 we will assess cerebral hemodynamic coherence and oxygen delivery during induced hemorrhagic hypotension and resuscitation using multimodal microvascular imaging techniques. In Aim 2 we will determine the relationship between a) sublingual and b) retinal and cerebral microcirculatory dynamics and investigate their potential as surrogate biomarkers for bedside cerebral microcirculation perfusion management. Successful completion of this project will delineate resuscitation strategies that maintain microcirculatory perfusion and characterize surrogate microcirculations that can be monitored non-invasively and thereby help minimize brain injury.

Narrative Impairment of cerebral microcirculatory blood flow in critically ill patients has been implicated as a pivotal pathophysiologic event associated with cognitive impairment and secondary brain injury, especially in elderly patients. The proposed work will a) clarify the critical interplay between micro- and macro-circulatory perfusion during clinically relevant scenarios and inform development of resuscitation strategies that maintain and enhance microcirculatory perfusion, and b) determine the relationship between sublingual, retinal and cerebral microcirculatory dynamics and their utilization as surrogate biomarkers for bedside perfusion management and thereby minimize secondary brain injury.