The overall goal for the project is to test assumptions about brain function and physiology at the onset of cerebral ischemia in humans. Knowledge about the physiology of acute brain ischemia to date has been generated almost exclusively from animal models and cell culture experiments. Recent frustrations in establishing efficacy in thrombolytic and neuroprotective stroke protocols in humans has raised questions as to whether our understanding of the ischemic cascade in animals can be extrapolated directly to the prevention of human stroke. In humans, clinical stroke occurs outside the laboratory and we can hope to identify the earliest physiologic and clinical manifestations of ischemia only as quickly as the patient can reach a neurologist or an MRI scanner after symptoms of a stroke begin. The protocol in this project presents a new approach to our gap in knowledge of the earliest manifestations of human cerebral ischemia. We will study the hyperacute phase of ischemia in two clinical settings that lend themselves as """"""""natural experiments:"""""""" first, in patients with inoperable carotid cavernous aneurysms or head and neck tumors encasing the carotid who require """"""""test occlusions"""""""" of the ICA to assess their tolerance to carotid occlusion should the treatment plan require permanent ICA sacrifice; second, in cardiac failure patients with implantable left ventricular assist devices who are tested routinely at our institution for their ability to tolerate reduction in cardiac output by temporarily reducing the action of their mechanical pumps as a test of native heart function. By monitoring higher cerebral function in these two groups of patients during intentional, reversible cerebral hypoperfusion and simultaneously measuring quantitative cerebral blood flow, alterations in circle of Willis collaterals, and brain tissue oxygenation, we have an opportunity to develop a human model of ischemia that can begin to address how closely the human brain's early response to ischemia matches what we know of the early physiologic responses to ischemia in animals. Our study of patients undergoing test occlusions of the ICA also bears on the clinical entity of hemodynamic stroke from carotid artery disease, and our study of global hypoperfusion in the heart failure patients bears directly on cerebral ischemia from cardiac arrest.
Specific aim 1 is to establish the time course of the onset and persistence of the clinical manifestations of early ischemia under known hemodynamic conditions.
Specific aims 2 and 3 are to determine what hemodynamic and physiologic factors produce neurologic dysfunction during cerebral hypoperfusion, and Specific aim 4 is to use the behavioral and physiologic data from the cerebral hypoperfusion testing to predict risk for subsequent hemodynamic ischemia in those patients in whom permanent carotid artery occlusion is required.
| Marshall, Randolph S; Lazar, Ronald M; Young, William L et al. (2002) Clinical utility of quantitative cerebral blood flow measurements during internal carotid artery test occlusions. Neurosurgery 50:996-1004; discussion 1004-5 |
| Marshall, R S; Lazar, R M; Pile-Spellman, J et al. (2001) Recovery of brain function during induced cerebral hypoperfusion. Brain 124:1208-17 |
