Assessing the impact of cerebral injury after cardiac surgery: Will determining the mechanism reduce this injury?

Background. Central nervous system dysfunction continues to produce signifi cant morbidity and associated mortality in patients undergoing cardiac surg ery. Using a closed-chest canine cardiopulmonary bypass model, dogs underwe nt 2 h of hypothermic circulatory arrest (HCA) at 18 degrees C, followed by resuscitation and recovery for 3 days. Animals were assessed functionally by a species-specific behavioral scale, histologically for patterns of sele ctive neuronal necrosis, biochemically by analysis of microdialysis effluen t, and by receptor autoradiography for N-methyl-D-aspartate (NMDA) glutamat e receptor subtype expression. Results. Using a selective NMDA (glutamate) receptor antagonist (MK801) and an AMPA antagonist (NBQX), glutamate excitotoxicity in the development of HCA-induced brain injury was documented and validated. A microdialysis tech nique was employed to evaluate the role of nitric oxide (NO) in neuronal ce ll death. Arginine plus oxygen is converted to NO plus citrulline (CIT) by the action of NO synthase (nNOS). CIT recovery in the cerebrospinal fluid a nd from canine cortical homogenates increased during HCA and reperfusion. T hese studies demonstrated that neurotoxicity after HCA involves a significa nt and early induction of nNOS expression, and neuronal processes leading t o widespread augmentation of NO production in the brain. To further investigate the production of excitatory amino acids in the brai n, we hypothesized the following scenario: HCA--> up arrow glutamate, up ar row aspartate, up arrow glycine--> up arrow intracenular ca(2+)--> up arrow NO + CIT. Using the same animal preparation, we demonstrated that HCA caus ed increased intracerebral glutamate and aspartate that persists up to 20 h post-HCA. HCA also resulted in CIT (NO) production, causing a continued an d delayed neurologic injury. Confirmatory evidence of the role of NO was de monstrated by a further experiment using a specific nNOS inhibitor, 7-nitro indazole. Animals underwent 2 h of HCA, and then were evaluated both physio logically and for NO production. 7-Nitroindazole reduced CIT (NO) productio n by 58.4 +/- 28.3%. In addition, dogs treated with this drug had superior neurologic function compared with untreated HCA controls. Conclusions. These experiments have documented the role of glutamate excito toxicity in neurologic injury and have implicated NO as a significant neuro toxin causing necrosis and apoptosis. Continued research into the pathophys iologic mechanisms involved in cerebral injury will eventually yield a safe and reliable neuroprotectant strategy. Specific interventional agents will include glutamate receptor antagonists and specific neuronal NO synthase i nhibitors. (C) 1999 by The Society of Thoracic Surgeons.