This subproject aims to determine the patterns of ionic flux, excitatory amino acid (EAA) release, and local tissue metabolism following focal and diffuse brain injury. We have used intracerebral microdialysis to measure changes in cortical extracellular fluid (ECF), for up to four days after severe head injury. This pilot data has shown a seven-fold sustained increase in glutamate and aspartate, persisting twenty-four hours or more in contused brain. This EAA release may perpetuate ionic flux in the periphery of contused tissue, thus inducing astrocyte swelling and worsening cytotoxic edema. Trauma models show increases in ECF potassium (from 4 to 30-fold) in the first minutes following impact. A concomitant inward sodium flux should also therefore occur. We have demonstrated a 5 to 15 mmol increase in ECF sodium, and a concomitant decrease in ECF potassium, 4-6 hours after severe injury. These dynamic events may represent restoration of ionic homeostasis across membranes. Previous studies have shown that ion pumping may be achieved by anaerobic glycolysis, primarily causing increased ECF lactate. The early post-traumatic reductions in cerebral blood flow (CBF) which we have demonstrated may result in insufficient delivery of energy substrates to cerebral tissue. This may cause acidosis and further increases in lactate. High ICP and low CPP may exacerbate this an cause EAA release. The severity and duration of ionic disturbance in ECF, may determine the amount of astrocyte swelling, and thus lead to raised ICP. Our pilot studies show that ECF sodium initially rises and potassium falls, when ICP is stable or declining. During uncontrolled increases in CIP, potassium efflux occurs. Potassium efflux is buffered by astrocyte swelling. We will use brain water mapping by magnetic resonance imaging, to test the relationships between ionic flux, raised ICP, edema, and energy metabolite status. We will test glutamate release inhibitors and NMDA antagonist drugs, and temperature changes upon these events.
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