GLUTAMATE EXCITOTOXICITY - A MECHANISM OF NEUROLOGIC INJURY ASSOCIATED WITH HYPOTHERMIC CIRCULATORY ARREST

Glutamate, the major central nervous system neurotransmitter, may have potent neurotoxic activity under conditions of metabolic stress. By r eceptor autoradiography, we have demonstrated that brain regions most vulnerable to injury during prolonged hypothermic circulatory arrest h ave the highest density of glutamate receptors. To test the hypothesis that such injury could be mediated by glutamate excitotoxicity, we us ed dizocilpine (MK-801), a selective N-methyl-D-aspartate-glutamate re ceptor antagonist in a canine survival model of hypothermic circulator y arrest. Eighteen male dogs (20 to 25 kg) were supported by closed-ch est cardiopulmonary bypass, subjected to 2 hours of hypothermic circul atory arrest at 18 degrees C, and rewarmed on cardiopulmonary bypass. All were mechanically ventilated and monitored for 20 hours before ext ubation and survived for 3 days. Group A dogs (n = 9) received a prear rest intravenous bolus of dizocilpine (0.75 mg/kg) followed by continu ous infusion (75 mu g/kg per hour), resulting in electroencephalograph ic silence. Dizocilpine was weaned before extubation, Group B dogs rec eived vehicle only. According to a species-specific behavior scale tha t yielded a neurologic deficit score ranging from 0 (normal) to 500 (b rain dead), all animals were neurologically assessed every 12 hours. A fter the dogs were killed at 72 hours, brains were examined by recepto r autoradiography and histologically for patterns of selective neurona l necrosis; they were scored blindly from 0 (normal) to 100 (severe in jury). Group A dogs had better neurologic function than group B (neuro logic deficit score 21 +/- 15 versus 192 +/- 40, p < 0.001) and had le ss neuronal injury (7.3 +/- 3 versus 48.3 +/- 9, p < 0.0001). Densitom etric receptor autoradiography revealed preservation of neuronal N-met hyl-D-aspartate-glutamate receptor expression in group A only. These r esults represent the first direct evidence of a role for glutamate exc itotoxicity in the development of hypothermic circulatory arrest-induc ed brain injury and suggest that selective glutamate receptor antagoni sts may have a neuroprotective capacity in prolonged periods of hypoth ermic circulatory arrest.