CO toxicity


Carbon monoxide (CO) is best known for its toxic and sometimes lethal effects. Many lives have been and continue to be lost by accidental or voluntary CO intoxication, even though CO is not particularly toxic when compared with equimolar doses of nitric oxide (NO) or cyanide (CN). The reason why CO is a leading agent so lethal to humans is due to its ready availability in large amounts from the incomplete oxidation of carbon based fuels. Moreover, its presence is not noticed since it is colorless, odorless and tasteless.

With increasing doses and time of exposure, symptoms of acute CO poisoning progress from mild headache to coma and death. The severity of CO poisoning may be estimated on the basis of available exposure data and COHb levels measured in a patient’s blood. In general, symptoms such as headache, shortness of breath and dizziness arise at COHb levels of 10-30%; weakness, nausea, tachycardia and tachypnea at 30-50%; and seizures, coma, cardiovascular toxicity, respiratory failure and death at COHb levels greater than 50%.  Neurological symptoms, such as reduced memory, disorientation and cognitive dysfunction, have been reported to occur with a delay of 1-3 weeks in victims of CO poisoning. However, the relationship of the “delayed” symptoms to the CO poisoning is often not clear.  In a recent study, no permanent neuropsychological abnormalities were found in patients without risk factors for neuropsychological sequelae after moderate to severe CO poisoning.

Epidemiological studies suggest that long term exposure to low doses of CO may cause neurological damage resulting in changes in memory, sleep, vision, sense of smell and direction or balance problems.  Such adverse effects are not seen in smokers with average COHb levels above 5% and peak levels of up to 18%. The question whether exposure to low CO doses has acute, adverse effects has been addressed in many experimental studies with human volunteers. Subtle effects of CO on visual sensitivity and several behavioral parameters such as tracking, vigilance or continuous performance tasks have been reported to occur in healthy volunteers at COHb levels below 5%. However, many of these findings were not reproducible. A double-blind study found no significant effects on tracking at COHb levels up to 16.6%.

Diseases may increase the susceptibility to CO. In patients with angina pectoris, the time of onset of exercise induced chest pain was shortened at COHb levels of 2.9 to 5.9%, suggesting that CO does not dilate coronary arteries under these conditions. However, smokers have less severe myocardial infarctions than nonsmokers, possibly because of the protective effect of CO against ischemia/reperfusion injury. The developing fetus is at an elevated risk due to the fact that fetal hemoglobin (HbF) binds CO more strongly than adult hemoglobin (HbA). Prolonged exposure of pregnant animals to CO has adverse effects on the fetus. Chronic exposure of pregnant women to low CO doses may increase the incidence of low birth weight. However, accidental exposure of pregnant women resulting in transient COHb levels of up to 18% had no adverse effect on fetal development.

It is generally assumed that CO toxicity is the result of impaired O2 transport and delivery. However, moderate levels of CO mediated hypoxia are compensated by increased blood flow, hemoglobin levels, and O2 consumption. In the brain, vasodilation maintains O2 delivery at COHb levels up to 30%, as demonstrated in sheep, goats and humans. Consumption of O2 begins to decline as COHb approaches levels of 30 to 50%. In addition to cytochrome c oxidase, a variety of other intracellular CO targets are likely to be affected. Conceivably, systemic CO effects on guanylyl cyclase, ion channels, and other yet to be identified targets cause adverse effects at COHb levels above 20% and contribute to the debilitating and lethal effects of CO at higher COHB levels.

Not surprisingly, CO toxicity is the most frequently raised concern against CO therapy. Indeed, CO toxicity is likely to limit CO inhalation therapy. However, the selective delivery of therapeutic CO doses to diseased tissues by CORMs is not expected to significantly raise CO levels in other tissues. Like increased CO production in diseases, CO delivery to selected target tissue results only in slight increases of COPHb levels. The clinical development of CORMs benefits from previous work on CO effects in humans. The safety of different CORM treatment modalities can be readily assessed by measurement of COHb levels. Based on preliminary data ALFAMA believes that CORM therapy will not be limited by CO toxicity. However, besides CO toxicity ALFAMAneeds to ensure the safety of the CORMs as well as of the molecules that are generated after the release of CO.