Dose-dependent cerebral metabolic impairment in a swine model of carbon monoxide poisoning.

Carbon monoxide (CO) poisoning is a leading cause of environmental poisoning in the United States and can impair cellular metabolism through both hypoxia and direct mitochondrial toxicity, particularly via inhibition of cytochrome c oxidase (Complex IV, CIV). In this study, we performed a comprehensive assessment of the cerebral metabolic response to CO exposure in a swine model. Twenty-nine swine (∼10 kg) were assigned to three groups: Sham (n = 10), CO 1000 ppm (n = 8), and CO 2000 ppm (n = 11). Animals in the CO groups were exposed to CO for 120 min followed by 30 min of room air. Cerebral metabolism was assessed using invasive cerebral microdialysis and continuous non-invasive diffuse optical monitoring of cerebral blood flow, oxygenation, and CIV redox state. Following the exposure period, brain tissue was harvested for mitochondrial respiration analysis and western blotting. Severe CO exposure (2000 ppm) produced significant cerebral metabolic impairment, demonstrated by decreased oxidation of cytochrome-c-oxidase, reduced oxygen metabolism, and increased microdialysis markers of metabolic stress including lactate-to-pyruvate ratio and glycerol. In contrast, moderate CO exposure (1000 ppm) resulted in minimal metabolic changes despite elevated carboxyhemoglobin levels. Ex-vivo mitochondrial respirometry also demonstrated impaired mitochondrial respiration in CO-exposed animals. These findings demonstrate greater cerebral metabolic dysfunction with higher CO exposure and suggest that carboxyhemoglobin levels alone may not accurately reflect the degree of cerebral metabolic injury.