Characterizing the Cerebrovascular Physiology of Circulatory Death During Withdrawal of Life Sustaining Therapies in Humans

MAIN STUDY

PURPOSE The goal of this project is to characterize the cerebrovascular physiology of circulatory death during withdrawal of life sustaining measures in humans.

JUSTIFICATION Death is defined as the permanent loss of brain function following absence of cerebral blood flow (CBF). Such physiology can result from two clinical scenarios: a) absent CBF in patients with a beating heart (neurological brain death) or b) after natural circulatory arrest. In the latter scenario, eventual cessation of innate cardiac output leads to absent CBF, brain tissue oxygenation and irreversible loss of brain function. Pertinent to solid organ transplantation, death must occur prior to consideration of organ donation. In the setting of circulatory death, withdrawal of life-sustaining measures (WLSM) is undertaken and organ donation commences after the declaration of death. This process is termed controlled donation after cardiac death (DCD). Due to the scarcity of available organ donation opportunities, the emergence of DCD has provided increased access to life-saving solid organ transplants for recipients. However, challenges remain with respect to successes of DCD graft organ function and optimal recipient outcomes. Principally, the timeliness from WLSM to circulatory death declaration is crucial to graft viability with prolonged periods associated with worse graft organ ischemia, function and adverse recipient outcomes. To this extent, the determination of the precise timing of death determination during DCD is imperative to inform timely diagnosis of death and optimize retrieval of high-quality grafts for solid organ transplant recipients.

The characterization of the cerebrovascular physiology of circulatory death in humans has knowledge gaps. Current guidelines define a pulse pressure < 5mmHg (systolic - diastolic blood pressure) using radial arterial line monitoring as the acceptable threshold for timing of circulatory death. Although pragmatic, this definition assumes that in vivo hemodynamic physiology generated by the heart (reflected by the arterial line) is simultaneously reflected in the cerebral circulation. It is well known that systemic hemodynamics do not necessarily correlate with cerebral hemodynamics during critical illness. Pathophysiologic sequelae (e.g. elevated intracranial pressure) in critically ill acutely brain injured patients who undergo WLSM suggest that cerebral perfusion may cease before systemic hemodynamics (detected by radial arterial line monitoring) deteriorate irreversibly. As such, it is plausible that cerebral perfusion ceases before a pulse pressure < 5mmHg is achieved thereby setting the conditions by which the physiologic requirement of circulatory death is present (absent CBF) but the clinical definition has not (pulse pressure < 5mmHg) been reached. Clinically, this scenario would expose viable graft organs to prolonged ischemia and negatively affect solid organ transplant recipient outcomes

HYPOTHESES AND AIMS