PATHOPHYSIOLOGY OF CARBON MONOXIDE POISONING ? Carbon monoxide (CO) diffuses rapidly across the pulmonary capillary membrane and binds to the iron moiety of heme (and other porphyrins) with approximately 240 times the affinity of oxygen (show figure 1). The degree of carboxyhemoglobinemia (COHb) is a function of the relative amounts of CO and oxygen in the environment, duration of exposure, and minute ventilation. (See "Oxygen delivery and consumption"). Nonsmokers may have up to 3 percent carboxyhemoglobin at baseline; smokers may have levels of 10 to 15 percent [1]. Severe chronic obstructive pulmonary disease can cause a modest but significant elevation in carboxyhemoglobin levels, even among patients without exposure to tobacco smoke. The mechanism and clinical significance of this finding is unclear [14].
Once CO binds to the heme moiety of hemoglobin, an allosteric change occurs that greatly diminishes the ability of the other three oxygen binding sites to off-load oxygen to peripheral tissues. This results in a deformation and leftward shift of the oxyhemoglobin dissociation curve, and compounds the impairment in tissue oxygen delivery (show figure 2).
CO also interferes with peripheral oxygen utilization. Approximately 10 to 15 percent of CO is extravascular and bound to molecules such as myoglobin, cytochromes, and NADPH reductase, resulting in impairment of oxidative phosphorylation at the mitochondrial level [6,15]. The half-life of CO bound to these molecules is longer than that of COHb. The importance of these nonhemoglobin-mediated effects has been best documented in the heart, where mitochondrial dysfunction due to CO can produce myocardial stunning despite adequate oxygen delivery [16].
CO also interferes with peripheral oxygen utilization by inactivating cytochrome oxidase in a manner similar to, but clinically less important than, cyanide. CO and cyanide poisoning can occur simultaneously in patients following smoke inhalation, and their combined effects on oxygen transport and utilization appear to be synergistic [17,18]. (See "Smoke inhalation", section on Cyanide).
The effects of CO on oxygen delivery and utilization, however, cannot account for the delayed neurologic sequelae (DNS) that may occur after CO poisoning. The mechanism of DNS is incompletely understood, but it probably involves lipid peroxidation by toxic oxygen species generated by xanthine oxidase. Xanthine oxidase is produced in situ from xanthine dehydrogenase via enzymes released by white blood cells that adhere to damaged endothelial cells [19-23]. During recovery from CO exposure, events analogous to ischemia-reperfusion injury and exposure to hyperoxia may exacerbate the initial oxidative damage [2,24].