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Pathophysiology of cerebral injury and future management
W A Baumgartner1, M Redmond, M Brock
1Division of Cardiac Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
Insights
Hypothermic circulatory arrest (HCA) during cardiac surgery causes brain injury via glutamate excitotoxicity and nitric oxide (NO) production. Targeting these pathways may lead to neuroprotective strategies for patients.
Area of Science:
- Neuroscience
- Cardiovascular Surgery
- Cellular Biology
Background:
- Central nervous system dysfunction is a major complication of cardiac surgery, particularly with hypothermic circulatory arrest (HCA).
- Despite surgical advances, stroke and neurocognitive deficits post-cardiac surgery remain significant challenges.
- Understanding HCA-induced brain injury mechanisms is crucial for developing neuroprotective treatments.
Purpose of the Study:
- To investigate the roles of glutamate excitotoxicity and nitric oxide (NO) in HCA-induced brain injury.
- To evaluate the efficacy of neuroprotective agents targeting these pathways.
- To elucidate the pathophysiological mechanisms of cerebral injury during HCA.
Main Methods:
- Utilized a canine closed-chest cardiopulmonary bypass model with 2 hours of HCA at 18°C.
- Assessed neurological function using behavioral scales and histological analysis.
- Examined NMDA glutamate receptor expression and evaluated neuroprotection with MK801, NBQX, and GM1-ganglioside.
- Employed microdialysis to measure nitric oxide synthase (NOS) activity and NO production via L-arginine and L-NAME infusion.
Main Results:
- Glutamate excitotoxicity plays a significant role in HCA-induced brain injury, as evidenced by the protective effects of NMDA and AMPA antagonists.
- Increased nitric oxide (NO) production, indicated by elevated citrulline and NO metabolites, was observed during HCA and reperfusion.
- Early induction of neuronal NOS expression and augmented NO production were confirmed as key contributors to HCA neurotoxicity.
Conclusions:
- HCA-induced neurotoxicity involves both glutamate excitotoxicity and excessive nitric oxide production.
- Targeting NMDA receptors and nitric oxide pathways shows promise for neuroprotection in cardiac surgery patients.
- Further research into these mechanisms is essential for developing effective neuroprotective strategies.
Abstract:
Central nervous system dysfunction continues to represent significant morbidity and associated mortality in patients undergoing cardiac surgery. Neurological dysfunction is most exaggerated in patients undergoing hypothermic circulatory arrest (HCA). Although surgical techniques, anesthetic management, and postoperative care have significantly improved over the past two decades, the incidence of stroke and other neurocognitive deficits remains problematic. Understanding the mechanisms of cell death associated with HCA may provide information that is germane to all types of cerebral injury involved in cardiac surgery. Using a closed-chest cardiopulmonary bypass model, dogs underwent 2 hours of circulatory arrest 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 selective neuronal necrosis and receptor autoradiography for NMDA glutamate receptor subtype expression. Using a selective NMDA (-glutamate) receptor antagonist (MK801), an AMPA-antagonist (NBQX) and a nonspecific neuroprotectant (GM1-ganglioside), the role of glutamate excitotoxicity in the development of HCA-induced brain injury was documented and validated. Using 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 nitric oxide synthase. Simultaneous infusion of artificial cerebrospinal fluid containing L-[14C] arginine or L-[14C] arginine and L-NAME (a nitric oxide synthase inhibitor) was performed in contralateral hemispheres. Citrulline recovery in the cerebrospinal fluid, citrulline production in vitro from canine cortical homogenates, and nitric oxide metabolites in the serum were all significantly increased during HCA and reperfusion. These studies demonstrated that neurotoxicity following HCA involves a significant and early induction of neuronal NOS expression and neuronal processes leading to widespread augmented NO production in the brain. Continued research into the pathophysiologic mechanisms involved in cerebral injury will undoubtedly yield a safe and reliable neuroprotectant strategy.