Normal: Hb binds oxygen and delivers it to peripheral tissue with low PO 2. Hemoglobin (Hb) and mitochondrial effects of CO. In addition to Hb, CO binds to other heme-containing proteins, including myoglobin in heart and skeletal muscle, mitochondrial cytochrome c oxidase (COX complex IV), and others ( Figure 1). This suggests that the toxic effects of CO result from the global impact of CO inhibition on oxygen delivery as well as on the binding to cellular heme-containing proteins. In canine studies, the toxicity of CO gas administered by inhalation is greater than transfusion of a similar concentration of CO-exposed erythrocytes ( 16). Neither the clinical severity nor the clinical improvement of CO-poisoned patients directly correlates with the blood COHb level or COHb clearance ( 14, 15). CO binding to Hb also stabilizes the relaxed, high-affinity quaternary state of Hb (known as R-state), increasing the affinity for oxygen of other sites within the Hb tetramer, and further reducing oxygen release and delivery. CO competes with oxygen for binding to Hb and, by displacement of oxygen, reduces oxygen carrying capacity. Hb has a 250-fold greater affinity for CO than for oxygen ( 13). In these patients, it is difficult to attribute CO poisoning alone as a cause of death, regardless of COHb level, due to concomitant severe burn and inhalational injuries.ĬO binds with high affinity to many ferrous heme-containing proteins. In a group of burn victims, three-quarters had carboxyhemoglobin (COHb) levels high enough to cause death or harm ( 9). In over 25,000 residential fire-related injuries treated in emergency departments in 2001, more than 50% had a diagnosis of anoxia, suggesting CO poisoning from smoke inhalation ( 8). Inhalational injury occurs in greater than two-thirds of fire-related deaths ( 7). There are approximately 15,000 intentional CO poisonings annually, accounting for over two-thirds of reported deaths ( 4– 6). Recent studies show declining numbers of CO death, most recently found to be 1,319 in 2014, from estimates of 2,700 in the mid-2000s ( 1– 4). The best available estimates of the yearly incidence of carbon monoxide (CO) poisoning in the United States, based on emergency department visits, are 50,000 (16.0 cases per 100,000 population). New methods to directly target the toxic effect of CO, such as CO scavenging agents, are currently under development. There has been some early success in therapies targeting the downstream inflammatory and oxidative effects of CO poisoning. Although hyperbaric oxygen significantly reduces the permanent neurological and affective effects of CO poisoning, a portion of survivors still have substantial morbidity. Conventional therapy is limited to normobaric and hyperbaric oxygen, with no available antidotal therapy. Management of these patients requires the identification of accompanying drug ingestions, especially in the setting of intentional poisoning, fire-related toxic gas exposures, and inhalational injuries. Imaging studies reveal cerebral white matter hyperintensities, with delayed posthypoxic leukoencephalopathy or diffuse brain atrophy. Long-term neurocognitive deficits occur in 15–40% of patients, whereas approximately one-third of moderate to severely poisoned patients exhibit cardiac dysfunction, including arrhythmia, left ventricular systolic dysfunction, and myocardial infarction. The neurologic deficits do not necessarily correlate with blood CO levels but likely result from the pleiotropic effects of CO on cellular mitochondrial respiration, cellular energy utilization, inflammation, and free radical generation, especially in the brain and heart. A significant number of patients who survive CO poisoning suffer from long-term neurological and affective sequelae. The clinical presentation runs a spectrum, ranging from headache and dizziness to coma and death, with a mortality rate ranging from 1 to 3%. Carbon monoxide (CO) poisoning affects 50,000 people a year in the United States.
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