PATHOPHYSIOLOGY OF CEREBRAL INJURY AND FUTURE MANAGEMENT

Central nervous system dysfunction continues to represent significant morbidity and associated mortality in patients undergoing cardiac surg ery. Neurological dysfunction is most exaggerated in patients undergoi ng hypothermic circulatory arrest (HCA). Although surgical techniques, anesthetic management, and postoperative care have significantly impr oved over the past two decades, the incidence of stroke and other neur ocognitive deficits remains problematic. Understanding the mechanisms of cell death associated with HCA may provide information that is germ ane to all types of cerebral injury involved In cardiac surgery. Using a closed-chest cardiopulmonary bypass model, dogs underwent 2 hours o f circulatory arrest at 18 degrees C followed by resuscitation and rec overy for 3 days. Animals were assessed functionally by a species-spec ific behavioral scale, histologically for patterns of selective neuron al necrosis and receptor autoradiography for NMDA glutamate receptor s ubtype expression. Using a selective NMDA (-glutamate) receptor antago nist (MK801), an AMPA-antagonist (NBQX) and a nonspecific neuroprotect ant (GM(1)-ganglioside), the role of glutamate excitotoxicity in the d evelopment of HCA-induced brain injury was documented and validated. U sing a similar canine preparation, a microdialysis technique was used to evaluate the role of nitric oxide in neuronal death. Arginine plus oxygen is converted to nitric oxide plus citrulline by the action of n itric oxide synthase. Simultaneous infusion of artificial cerebrospina l fluid containing L-[C-14] arginine or L-[C-14] arginine and L-NAME ( a nitric oxide synthase inhibitor) was performed in contralateral hemi spheres. Citrulline recovery in the cerebrospinal fluid, citrulline pr oduction in vitro from canine cortical homogenates, and nitric oxide m etabolites in the serum were all significantly increased during HCA an d reperfusion. These studies demonstrated that neurotoxicity following HCA involves a significant and early induction of neuronal NOS expres sion and neuronal processes leading to widespread augmented NO product ion in the brain. Continued research into the pathophysiologic mechani sms involved in cerebral injury will undoubtedly yield a safe and reli abl e neuroprotectant strategy.