carbon monoxide

carbon monoxide is a gas which is best known to us as a product of incomplete combustion. As such, mankind must have been aware of its deadly effect since the discovery and use of fire, and increasingly so as the development of the industrial revolution led to more use of combustion as a source of energy. The important producers of carbon monoxide are industrial processes, heating equipment, accidental fire, cigarettes, and the internal combustion engine. Blast furnace gas contains 25% carbon monoxide, and coal gas, which was used as a fuel in Europe up until North Sea (natural) gas became plentiful, contains 16%. Carbon monoxide poisoning is the most common cause of fatal gassing and is the cause of death in about 90% of fire victims. Domestic gas supplies still lead to carbon monoxide poisoning, but now due to leakage of products of combustion from a damaged flue or poorly maintained equipment, rather than the fuel itself, since natural gas is carbon monoxide free. In the mining industry carbon monoxide contaminates the atmosphere during and after fires or explosions. The ‘afterdamp’ occurring in such situations is a mixture of carbon dioxide and carbon monoxide.

Carbon monoxide is a colourless, odourless gas which is tasteless and non-irritant. It is somewhat less dense than air and, although it is a product of imperfect combustion, it is inflammable. The gas was first identified by Joseph Priestley in the eighteenth century, but it was Claude Bernard in 1870 who discovered the affinity between carbon monoxide and haemoglobin which accounts for its deadliness: carboxyhaemoglobin is formed and oxygen transport from the lungs to the tissues disrupted. In 1895 J. S. Haldane demonstrated that the formation of carboxyhaemoglobin is an equilibrium reaction which depends upon the relative partial pressures of carbon monoxide and oxygen in inspired gas. Haldane's interest was stimulated by the problems caused by carbon monoxide in British coal mines. By breathing carbon monoxide gas which was passed through a bottle containing a mouse, he was able to determine that man was very much more resistant to the gas. Small animals such as mice and canaries, who are more vulnerable than man due to their high metabolic rate, were used in mines to give an indication of carbon monoxide contamination. Canaries responded to the gas by falling off their perches before workers noticed any ill effects, and this normally gave ample warning. Occasionally, however, in low concentrations of the order of 0.05% carbon monoxide, the bird adapted to the gas and the workers could collapse while the bird remained well.

Carbon monoxide, like oxygen, has an affinity for iron-containing molecules, but it is about 210 times more effective in binding to iron-containing haemoglobin than oxygen is. Since air contains 21% oxygen this means that only 0.1% carbon monoxide in the air will eventually lead to 50% of the haemoglobin being combined to form carboxyhaemoglobin. Once carboxyhaemoglobin is formed, and after exposure ceases, it takes 4–5 hours for its level in the blood to fall, exponentially, by 50%. The ill effect of the gas can therefore be cumulative, and a person can be poisoned by intermittent exposure during the day.

Because carboxyhaemoglobin does not carry oxygen, a level of 50% means that the oxygen carrying capacity of the blood is reduced by 50% and there is a corresponding reduction in the ability to perform maximum exercise. The body compensates for the blood's reduction in oxygen carrying capacity by increasing cardiac output, and in the early stages of carbon monoxide poisoning the heart beats faster and more strongly. Unfortunately, haemoglobin is not the only molecule affected. Muscle myoglobin also binds carbon monoxide, 60 times more effectively than it binds oxygen. This results in a reduction of heart muscle contractility and a failure of the body's compensatory mechanisms, leading to profound tissue hypoxia, which can be fatal. The presence of carboxyhaemoglobin also diminishes the oxygen held by the normal haemoglobin, which further compounds the hypoxic effect. As tissue oxygen level falls, carbon monoxide is able to bind to other iron-containing molecules: notably cytochrome P450, an important drug-metabolizing enzyme, and cytochrome A₃, an enzyme in the terminal respiratory chain which can also be poisoned by cyanide.

The scientific history of carbon monoxide is not one of uniform gloom, however. The intense affinity of carbon monoxide for haemoglobin has allowed low concentrations to be used as a marker for measurement of the speed of blood through the lungs and the surface area of the lung available for the transfer of oxygen. This latter remains as one of the standard lung function tests. In 1951 Sjöstrand discovered that Haldane's poison gas is a normal product of the body's metabolism. The enzyme haem oxygenase breaks down the haem from senescent red blood cells, and this reaction produces carbon monoxide and bile salts. The bile salts are excreted by the liver and the carbon monoxide released gives the blood a normal carboxyhaemoglobin level of 0.2–1.0%. This endogenous carbon monoxide was thought to be just a waste product, but more recent work by Verma has demonstrated that a type of haem oxygenase is located in specific areas in the brain, and suggested that the carbon monoxide produced acts as a neurotransmitter. The carbon monoxide activates the enzyme guanylyl cyclase, as does nitric oxide, regulating the intracellular levels of the second messenger cyclic GMP, which in turn regulates cellular activity. Other workers have demonstrated the haem oxygenase enzyme system in blood vessel walls and demonstrated that the carbon monoxide released causes vasodilation, as does nitric oxide. So far, endogenous carbon monoxide release has been suggested to have a role in the sense of smell, memory, cerebellar function (and hence the body's balance and co-ordination), control of blood hormone levels from the hypothalamus, and control of smooth muscle tone and vasodilatation.

The symptoms of carbon monoxide poisoning depend on the concentration breathed. The victim may pass out without warning, but often the onset of poisoning is slow. Headache, with or without nausea, is common, and this may relate to carbon monoxide's vasodilating effect. Drowsiness and lethargy then occur, along with breathlessness on exertion. At any stage there may be chest pain; this is angina due to cardiac hypoxia. At the stage of lethargy and drowsiness, cerebral function is affected and the person may not be able to think well enough to make an escape effort. Coma follows, and death. Treatment is by removal to an uncontaminated atmosphere and the administration of 100% oxygen. Hyperbaric oxygen speeds up recovery, and there is increasing evidence that it reduces long-term neurological problems.

Endogenous carbon monoxide function is undoubtedly disrupted during poisoning, but at our present state of knowledge it is difficult to say how this contributes to the toxic action of exogenous carbon monoxide. It may well be that our picture of the mechanisms of carbon monoxide poisoning will change as the function of endogenous carbon monoxide becomes clearer. Patients with carbon monoxide poisoning may have very poor balance and yet have good cerebral function. Short-term memory may also be severely disrupted. It is tempting to link these two features with the functions suggested for endogenous carbon monoxide. No doubt time will tell if there is a relationship.

John A. S. Ross

Bibliography

World Health Organisation (1979). Environmental health criteria 13: carbon monoxide. WHO, Geneva.
Dawson, T. M. and and Snyder, S. H. (1994). Gases as biological messengers: nitric oxide and carbon monoxide in the brain. (Review article.) Journal of Neuroscience, 14(9), 5147–59.