SOURCES

Carbon monoxide (CO) poisoning is the most common form of intoxication in humans in the United States. The molecule is produced by the incomplete combustion (oxidation) of carbon-containing compounds. Possible sources of carbon monoxide include propane-powered engines (e.g., forklifts and chain saws), catalytic radiant heaters, portable generators, kerosene heaters, gas log fireplaces, natural gas appliances, hibachi cookers, automobile exhaust, fires and subsequent smoke inhalation, and paint strippers and spray paints (Box 35-1). An improperly vented natural gas heater can make the air within a small room unsafe to breathe within a matter of minutes. However, several cases of carbon monoxide poisoning have occurred outdoors in association with the use of faulty equipment.

Gasoline internal combustion engine exhaust contains from 3% to 7% carbon monoxide. New emission standards for new cars in the United States require limitation of carbon monoxide emission to 0.5%. Numerous cases of intoxication of dogs and cats have been reported when they have been inadvertently left in enclosed garages in the wintertime while owners warmed up their cars. Another potent source of carbon monoxide is the smoke of cigarettes, cigars, and pipes, which can contain levels up to 4%. Likewise, diesel engines emit notable levels of CO in their exhaust. In the last decade nonvehicular sources of carbon monoxide exposure, preponderantly from faulty heating and cooking devices, have accounted for a growing number of poisonings. Fire continues to be an important source of exposure. Carbon monoxide is the leading cause of death in fire victims.

TOXIC DOSE

Lethal concentrations of carbon monoxide can be achieved within 10 minutes from a car running in the confines of a closed garage. An ambient CO concentration of 100 ppm (0.01%) produces no clinical signs during an 8-hour exposure. Dogs can tolerate 200 ppm (0.02% CO concentrations) for 90 days with no clinical signs. However, CO concentrations more than 1000 ppm (0.1%) cause unconsciousness, respiratory failure, and death if exposure is continued for 1 hour. Chronic poisoning in the sense of accumulation of carbon monoxide with repeated exposure does not occur. Nevertheless, repeated anoxia from carbon monoxide causes central nervous system (CNS) damage. Carbon monoxide exposure is particularly deleterious to pregnant animals because of fetuses’ greater sensitivity to the harmful effects of the gas. Final carboxyhemoglobin levels in the fetus may exceed levels found in the mother. The exaggerated leftward shift of fetal carboxyhemoglobin makes tissue hypoxia more severe because less oxygen is available to fetal tissue. Also, it is estimated that fetal elimination of carbon monoxide takes 3.5 times as long as maternal elimination of the poison. Although the teratogenicity of carbon monoxide is controversial, the risk of fetal injury caused by carbon monoxide is significant.

TOXICOKINETICS AND MECHANISM OF TOXICITY

In its pure form, carbon monoxide is undetectable. It is colorless, odorless, and nonirritating, and it disperses readily in room air and does not stratify (Box 35-2). Carbon monoxide combines with hemoglobin to form carboxyhemoglobin. This molecule is incapable of carrying oxygen (O₂), and tissue hypoxia results. Hemoglobin has an affinity for carbon monoxide that is 240 times greater than that of O₂. In addition, the presence of carbon monoxide increases the stability of the hemoglobin-O₂ bond. Thus the fixation of carbon monoxide on any one of the four oxygen-binding sites of hemoglobin increases the oxygen affinity at the remaining sites. As a result, carbon monoxide reduces the availability of oxygen to tissue in two ways: first, by its direct combination with hemoglobin, which thereby reduces the amount of hemoglobin able to carry oxygen, and second, by preventing the release or unloading of oxygen bound to hemoglobin at peripheral body tissues. This increased affinity for oxygen, known as the Haldane effect, causes the leftward shift of the oxygen hemoglobin dissociation curve. The carboxyhemoglobin molecule is relatively nontoxic. The toxicity of carbon monoxide lies in its capacity to reduce both the oxygen-carrying capacity of hemoglobin and the oxygen-unloading function of the molecule. The net effect of these two processes is decreased availability of oxygen to cells of the body.

In addition to the strong affinity of carbon monoxide for hemoglobin, carbon monoxide has a significant affinity for all iron or copper-containing sites and competes with oxygen at these active sites. In particular, muscle myoglobin has a selective affinity for carbon monoxide that is 40 times greater than that for oxygen and, like hemoglobin, displays a leftward oxygen dissociation shift when carbon monoxide is present. This binding with myoglobin is further enhanced by hypoxic conditions. Interference with cellular respiration at the mitochondrial level by carbon monoxide also has been demonstrated. Carbon monoxide binds with cytochrome oxidase in conditions of hypoxia and causes the release of mitochondrial-based free radicals. These molecules attract leukocytes that release proteases that activate a cascade of events that damage endothelium, destroy brain microvasculature, and result in lipid peroxidation of brain membranes.

Carbon monoxide toxicity cannot be explained based solely on a carboxyhemoglobin-mediated hypoxia. Clinical effects, tissue destruction, and subsequent neurological deficits cannot be predicted by only the extent of binding between carbon monoxide and hemoglobin. Dogs breathing 13% carbon monoxide die within 1 hour with carboxyhemoglobin levels of 54% to 90%. However, blood transfusions from the dying dogs into healthy dogs produced no deleterious effects. This observation suggests that the carbon monoxide itself is responsible at least partially for its pathological effects. In poisoned animals, 10% to 15% of total body carbon monoxide is found to be extravascular. The delivery of carbon monoxide itself intracellularly, its binding to heme proteins and other molecules other than hemoglobin, the migration and attachment of leukocytes to damaged endothelium and their destructive release of proteases, free radicals, and degradative enzymes all contribute to the toxicity of carbon monoxide in addition to its hypoxic effects.