The pathogenesis of carbon monoxide anoxia

Abstract

This survey was prompted by the belief that the toxic effects of carbon monoxide were not due entirely to its combination with the circulating haemoglobin. An attempt has been made to convey that belief in a critical description of the clinical and pathological manifestations combined with a study of the after- effects, chronic exposure and acclimatizationIt was next necessary to review the gaseous combinations of the circulating haemoglobin and the influences affecting these combinations and dissociations. It can safely be assumed that all the effects of carbon monoxide anoxia are due primarilly to its initial combination with the circulating haemoglobin; for any extra - circulatory combinations which may take place are dependent upon the circulation of haemoglobin for the transportation of carbon monoxide.It seems that the total quantity of carbon monoxide inhaled and combined with the circulating haemoglobin is excreted by the lungs and can be recovered in the expired air. From this it is concluded that carbon monoxide is not metabolized in any way by the body. It was further observed that GO -70% of the total was recovered within the first hour, and the remainder took several hours to be released, even when the process of elimination was speeded up by the inhalation of oxygen. Such a decrease in the rate of elimination would be expected if carbon monoxide diffused from the circulating haemoglobin to combine with substances in the tissues. Subsequently, as the carbon monoxide saturation of the circulating haemoglobin decreased the extra -circulatory combination would dissociate and the carbon monoxide would be attracted back into the circulation and carried to the lungs for "excretion."A number of extra -circulatory substances which could combine with carbon monoxide in this way has been described. The "pseudo- haemoglobin" of Barkan has a far greater affinity for carbon monoxide than blood haemoglobin has, and evidence is presented showing that it probably does combine with carbon monoxide in the living animal.Other possibilities include muscle haemoglobin, cytochrome oxidase and the Pasteur enzyme. The fullest possible knowledge of these substances has been given before attempting to show any relevant actions they may possess. They all combine with carbon monoxide in vitro and the combination is by competition with oxygen for saturation of the haem molecule with which they are constituted. Their affinities for carbon monoxide and oxygen differ but muscle hae_qoglobin and the "Pasteur enzyme" have a greater affinity for carbon monoxide than for oxygen, while the affinity of cytochrome oxidase for these gases is reversed. These affinities refer to in vitro experiments where the gases <.re a, ailable in gaseous form but in the living animal the gases are made available by their combination with the circulating haemoglobin. For instance, if cytochrome oxidase were exposed to an atmosphere containing about 0.1% of carbon monoxide, no combination would take place and the activity of the oxidase would be uninhibited; but if a human subject were exposed to such a concentration his blood in time would reach about 70% saturation and the cytochrome oxidase of his tissues would be subjected to an even greater relative concentration of carbon monoxide than the blood saturation would suggest.No originality is claimed in postulating t.at muscle haemoglobin and cytochrome oxidase ._'_re affected in carbon monoxide ano_Lia. Combination with muscle haemoglobin has been accepted although its true sign - ificnce has never been fully appreciated. This has been discussed not only in its quantitative relation to extra- circulatory combination but also its qualitative relation to function in ,:,cute anoxia and acclimatization. Some authors have recognised the possibility of inhibition of cytochrome oxidase but because of its greater affinity for oxygen in vitro the possibility was discarded. There is no evidence of a previously recorded attempt to associate inhibition of the Pasteur enzyme with the carbon monoxide problem and it is felt that the present attempt has been warranted.A short survey of the properties of carbonic anhydrase has been given. In virtue of it being a zinc protein and not a haerain protein, its inhibition by carbon monoxide is subject to somewhat different conditions. There is no competition between oxygen and carbon monoxide, but the partial pressure necessary to cause inhibition is probably never great enough in the living animal subjected to carbon monoxide anoxia. Nevertheless, further experimental work is indicated before this possibility can be finally rejected.