EXCITOTOXIC DAMAGE IN NEUROTRAUMA - FACT OR FICTION

Secondary brain injury is a well-demonstrated contributor to the morbi dity and mortality of severe head injury. At least ten new compounds w hich antagonize the effects of glutamate in the brain are currently un dergoing clinical evaluation as putative protectants against this seco ndary injury. None have yet shown clear benefit in humans. It is accep ted that excitatory amino acids, glutamate in particular, have 'neurot oxic' effects on the brain, especially when present in excessive amoun ts. Whether or not this excitatory amino acid toxicity represents the major pathway for secondary damage is disputed. In the laboratory, ove r 300 studies have now demonstrated the ability of glutamate antagonis t drugs of various types to prevent ischemic and post-traumatic acute brain damage. The magnitude and consistency of protection afforded by this group of compounds exceeds that which has ever been shown with an y other mechanisms. Laboratory studies using in vitro neuronal models have implicated glutamate as a promoter of ionic flux and calcium entr y across the cell membrane, which may then initiate astrocytic swellin g and neuronal necrosis. In vivo animal models of brain trauma and isc hemia have demonstrated glutamate release and potassium efflux into th e extracellular fluid (ECF). Outcome in these models is improved, as a ssessed by both histopathology and behavioral studies, when glutamate antagonists are used. Additionally, presynaptic glutamate blockade in animal models such as middle cerebral artery (MCA) occlusion and subdu ral hematoma, creates reduction in lesion size which is paralleled by reduced glutamate production. In bridging the gap between the laborato ry and the patient care setting, human microdialysis studies have show n massive release of excitatory amino acids into the ECF after severe head injury. Early studies with N-methyl-D-aspartate (NMDA) antagonist s in head injured humans have demonstrated a reduction of intracranial pressure and an improvement in cerebral perfusion. Future studies are needed to examine further the value of protection from excitatory ami no acid induced injury.