Cerebral edema, hyperemia and elevated intracranial pressure (ICP) frequently occur after stroke, traumatic brain injury, cardiac arrest, hepatic encephalopathy, etc., requiring precise clinical management of ICP control. Maintenance of cerebral perfusion pressure (CPP) >60 to 70 mmHg to ensure adequate brain perfusion is recommended based on cerebral blood flow (CBF) autoregulation curves obtained by decreasing arterial pressure which may not apply to a reduction in CPP by increasing ICP. In fact, when CBF autoregulation is described by increasing ICP as opposed to decreasing arterial pressure, the lower limit of CBF autoregulation decreases by 50% which we hypothesize is due to a transition from capillary (CAP) to thoroughfare channel (TFC) flow and a pathologic """"""""apparent"""""""" maintained CBF at a lower CPP. We will study CBF autoregulation in two groups of rats of 20 rats each by either increasing ICP by """"""""mock"""""""" cerebrospinal fluid (CSF) infusion or lowering arterial blood pressure by phlebotomy. A third group of 20 rats will be studied as time controls without alterations in CPP throughout. Two-photon laser scan microscopy (2PLSCM) will be used to measure red blood cell (RBC) flow velocities in CAP and TFC characterized by RBC flow velocities <1.0 mm/sec and >1.0 mm/sec, respectively, all in the same proximity, with [cortical CBF by a laser Doppler single fiber probe, tissue PO2 by a flexible catheter microelectrode, and flexible temperature probes and continuous monitoring.] The specific aims are to: 1) Show that a reduction in the lower limit of CBF autoregulation by increasing ICP coincides with a transition from CAP to TFC flow by frequency histogram analysis of RBC flow velocities, an increase in jugular venous PO2 and decrease in brain tissue PO2 and a widening of the """"""""PO2 gap"""""""" suggesting shunt flow;2) Determine whether changes in cerebral arteriolar (<100 5m diam) dilation and increased internal carotid artery pressure at constant aortic pressure differ at the lower limit of CBF autoregulation by increased ICP compared to lowering arterial pressure;and 3) Show that fluorescein-dextran extravasation from microvessels indicating increased blood brain barrier permeability are associated with a transition from CAP to TFC flow at the lower limit of CBF autoregulation by raising ICP. These studies may provide insight into the pathogenesis of hyperemia, cerebral edema and increased ICP and the rationale for the application of the """"""""Lund concept"""""""" in ICP management with CPP at 60 mmHg, anti-stress pharmacotherapy, blood brain barrier protection and osmotherapy.
Cerebral blood flow (CBF) through the brain is maintained even in the face of a decrease in arterial blood pressure. However, the point at which CBF begins to fall, i.e. the critical threshold, is lower if the cerebral perfusion pressure (CPP) is reduced by increasing the pressure in the brain compared to that obtained when reduced by lowering arterial pressure. We hypothesize that the lower critical CBF threshold obtained when increasing the pressure in the brain is due to a pathologic CBF that is not perfusing brain tissue but rather going around capillaries in the brain. The proposed research tests this hypothesis by studying the pathway of red blood cells through capillaries as compared to what's known as thoroughfare channels or """"""""shunts"""""""" through the brain using a microscope that allows visualization of capillaries in the living rat.
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