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Journal of Criminal Law and Criminology Volume 54 Article 12 Issue 4 December

Winter 1963 Physiological Prinicples of Carbon Monoxide Poisoning Frank R. Dutra

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Recommended Citation Frank R. Dutra, Physiological Prinicples of Carbon Monoxide Poisoning, 54 J. Crim. L. Criminology & Police Sci. 513 (1963)

This Criminology is brought to you for free and open access by Northwestern University School of Law Scholarly Commons. It has been accepted for inclusion in Journal of Criminal Law and Criminology by an authorized editor of Northwestern University School of Law Scholarly Commons. POLICE SCIENCE

PHYSIOLOGICAL PRINCIPLES OF CARBON MONOXIDE POISONING

FRANK R. DUTRA

Frank R. Dutra, M.D., is Pathologist, Eden Hospital, Castro Valley, California, and Associate Clinical Professor of Pathology, University of California Medical School, San Francisco. Dr. Dutra is a Diplomate of the American Board of Pathology in Anatomical Pathology and Forensic Pathology, and was formerly Associate Professor of Forensic Pathology, University of Cincinnati Medical School, and Pathologist for the Coroner of Hamilton County, Ohio. Dr. Dutra has served as an Associate Editor of this Journal for a number of years and is the author of more than sixty publications on pa- thology and legal medicine.-EDITOR

"But the carbon monoxide, in displacing the air is as rapid as the flow from the alveoli into the that it had expelled from the , blood. The time required for the blood to reach remained chemically combined in the blood ... this state of equilibrium is essentially identical at so that death came through death of the mole- different of carbon monoxide in the cules of blood, or in other words by stopping when the rate and depth of their exercise of a physiological property es- are constant. sential to life". Claude Bernard (1813-1878) When a person inhales air containing carbon This statement, first printed a century ago, indi- monoxide, the quantity of this gas passing into cates the earliest understanding of the fact that the blood and combining with before the primary toxic effect of carbon monoxide de- equilibrium is established depends upon the partial pends upon the ability of the gas to combine with of carbon monoxide and oxygen and on hemoglobin and to interfere with the of the relative affinity of hemoglobin for each of the oxygen by hemoglobin throughout the body. All two gases. With the relative affinity of other results of carbon monoxide poisoning are hemoglobin for carbon monoxide and oxygen es- secondary to the reduction in the supply of oxygen tablished as 210:1, if the of carbon to the tissues during the period of intoxication. monoxide in the air is known, it is possible to The combination of hemoglobin and carbon predict by the formula of Sayers and Yant (2) the monoxide is entirely reversible, and neither the proportion of hemoglobin that will be combined hemoglobin nor the erythrocytes are damaged by with this gas when equilibrium is attained: an interlude of carbon monoxide transport. % Hb combined with CO ABSOREpT0N or CARBON MON0XIDE aCO X tCO During the early part of a period of exposure to (aCO X tCO) + (aOs X tO.) X 100 carbon monoxide, about half of the total quantity a = relative affinity of Hb for the gas of the gas which enters the passes across the t = percentage of the gas in the alveolar alveolar walls into the blood. It enters the erythro- air cytes and combines with hemoglobin to form Thus, a concentration of 0.05 percent (500 p.p.m.) , a compound structurally anal- of carbon monoxide in the pulmonary air (which ogous to oxyhemoglobin (1). contains approximately 15 percent of oxygen), As more and more of the hemoglobin combines would result in an equilibrium at which about 41 with carbon monoxide, the rate of retention of the percent of the hemoglobin would be in combination inhaled carbon monoxide diminishes considerably. with carbon monoxide: After a time, for any given sublethal concentration % Hb combined with CO of carbon monoxide in the atmosphere, the concen- tration of the gas in the blood will reach an 210 X 0.05 equilibrium with that of the atmosphere, so that (210 X 0.05) + (1 X 15) X 100 the flow of the gas from the blood into the alveolar - 41.2% FRANK R. DUTRA [Vol. 54

The blood of a resting human being who is obtained by multiplying the square meters of exposed to a low, constant concentration of carbon body surface by 3; the body surface area can be monoxide will reach half the final saturation in obtained by conversion charts from height and approximately 47 minutes, and will be maximally or may be calculated by the DuBois saturated for this atmospheric concentration at method.) approximately 5 hours after the start of the ex- A nomogram developed from human experi- posure (3). Experiments indicate that when the mental data by Forbes, Sargent, and Roughton (1) concentration exceeds 0.07 percent (700 p.p.m.) of graphically depicts the rate of absorption of carbon carbon monoxide in the atmosphere the rate of monoxide from air containing various concen- rise of blood concentration toward saturation may trations of the gas, and this permits easy estimation be somewhat more rapid (4). Equilibrium will be of the concentration of carbon monoxide in the reached more rapidly in the blood of small mam- blood at any time during a period of exposure when mals which have a high rate of respiratory exchange the atmospheric concentration of carbon monoxide per unit of body weight (5). is known (Fig. 1). The rate of absorption is greatly increased by physical activity, the resting rate being approxi- COMBINING WITH HEMOGLOBIN mately doubled during moderate exercise such as walking, and tripled during heavy exercise (4). Each molecule of hemoglobin can combine with Even though the final equilibrium is the same, from one to four molecules of either oxygen or regardless of the rate with which it is achieved, carbon monoxide. However, hemoglobin has a the person who is engaged in some physical activity much greater affinity for carbon monoxide than is more likely to suffer injury from carbon mon- for oxygen, accounting for the harmful effects of oxide than is one exposed to the same atmosphere carbon monoxide when the ratio of carbon mon- at rest. The reasons for this are that the former will oxide to air is relatively low. In 1929, Sendroy, attain maximal saturation more rapidly, thereby Liu, and Van Slyke (7) observed a constant re- suffering a longer period of oxygen deficiency to lationship between the affinity of human hemo- his tissues, and that the oxygen requirement of his for carbon monoxide and for oxygen, this tissues is greater because of his activity. relationship being 210:1. In none of their de- An equation that has proved to be of practical terminations was the variation from the average value for calculating the rate of absorption of greater than -2.5 per cent. A number of samples carbon monoxide has been presented by Pace, of ox blood were also examined, and a relationship Consolazio, White, and Behnke (6). Its validity of 179:1 was constant with bloods from 10 different is said to be high until the concentration in the oxen. blood has reached one-third of the predicted The differential affinity of hemoglobin for two equilibrium for the concentration under consider- gases is the ratio between the partial pressures of ation; as the concentration in the blood increases the gases that will saturate the hemoglobin to the beyond this, the rate of uptake of carbon monoxide same degree with each. This ratio can be ascer- diminishes considerably so that the formula is not tained empirically by mixing the two gases (each at a known partial ) with a of applicable. Assuming that the blood contains no hemoglobin, after which the concentrations of carbon monoxide when the exposure begins, the oxyhemoglobin and carboxyhemoglobin are de- calculation is as follows: termined. % Hb combined with CO aCO HbCO X p0 Relative affinity of hemoglobin: -C = HbO X pC0 % CO in Air X Minute Volume X Exposure Time a2 HbO2XpCO 46.5 X Blood Volume As an examr-le, consider that after a mixture of X 10,000 oxygen at a of 28 mm. Hg and (The minute volume is the volume of respiration carbon monoxide at a partial pressure of 0.133 in liters per minute, corrected to S.T.P.; ex- mm. Hg attains equilibrium with a solution of posure time is the duration of exposure in human hemoglobin, exactly 50 percent of the minutes; blood volume is expressed in liters, and hemoglobin is combined with oxygen and 50 for the purposes of this calculation it may be percent with carbon monoxide. Then, applying 19631 CARBON MONOXIDE POISONING

~;~7 C~Jj~4 ~jI 0, *1 1 ~) 410 II ..... do-?561

3?-8 % I'M

",0 24.6%

A *1 24.6 Co~bb 2E •aluo*t ttc . C..... t-M 14.0%

Minuts of i IonsureA icordinoto Scales fio~n Relow 2o 250 ------6-==------'Rest Pdlse 70 Lt. Act. Pulse 80 2O0 2------Lt Work Pulse 110

0 30- 0 600 Hd Work ------. Pulse355

FIGUREn 1 the 20 minute line are 20 minutes. The equilibrium values which each curve approaches and which would Nomogram for estimating human rate of absorption at infinite time are indicated after the final blood concentration of carbon monoxide be reached and symbol "t = 0". from various atmospheric concentrations of the gas With this nomogram it is possible to determine the and at different rates of ventilation. This was con- increase in carboxyhemoglobin that will occur over a structed from experimental data in the ranges repre- given period of time when an average normal adult is sented by solid lines, the dotted lines being extrap- exposed to any air concentration of carbon monoxide olations. The upper and lower quadrants give the between 0.01 per cent and 2.0 per cent at sea level and relationships of four variables: (1) absorption of at any ventilation rate between 6 and 30 liters per carbon monoxide, (2) concentration of carbon monoxide minute. in atmosphere, (3) period of exposure, and (4) rate of Example: What would be the concentration of ventilation in liters per minute. carboxyhemoglobin in the blood of a previously To use, first determine the approximate rate of unexposed man whose ventilation rate is 25 liters per ventilation and fix this point upon the vertical (ordi- minute after 85 minutes' exposure to air containing nate) scale of ventilation; then draw a horizontal line 0.05 per cent carbon monoxide? First, draw a horizontal .to the right intercepting the time curves (marked 10, line from 25 liters on the lower left hand scale to a 20, 30, etc.). The points of interception define the time point half way between the 80 and 90 minute lines. scale for the rate of ventilation under consideration, and a vertical line raised from the point of intersection Then raise another line vertically to the 0.05 per cent of these two lines to the curve which reflects the air curve in the upper half of the figure, and thence hori- concentration of CO in the upper quadrant will give zontally to the left to the ACOHb scale. The answer is on the ordinate scale the increase in the per cent of 28.5 per cent carboxyhemoglobin. (This nomogram is carboxyhemoglobin resulting from this degree of reproduced with permission of the authors, Forbes, exposure over this period of time. The curved lines in Sargent, and Roughton, (1), and the Editor of the the lower quadrant indicate time, i.e., all points on American Journal of .)

the formula: human hemoglobin for carbon monoxide and oxygen are correctly expressed as 210:1 appears aCO 50 X 28 to have been proved by the recent work of Sji- aO2 50 X 0.133 strand (8); this constant is an essential part of his aCO 210 theory for determining the concentration of carbon monoxide in the blood by analyzing samples of a0 2 1 alveolar air, and the success of the method attests Thus, the relative affinity of human hemoglobin to the constancy and validity of this ratio. for carbon monoxide and oxygen is 210:1. The most reasonable explanation for the differ- The fact that the relative degrees of affinity of ence in the affinity of hemoglobin for the two FRANK R. DUTRA [Vol. 54 gases is that while oxygen and carbon monoxide slowest when the victim inhaled only air, and was both combine rapidly with hemoglobin, the time most rapid with the of the mixture of required for the dissociation of carboxyhemoglobin and oxygen. At first, the gas is lost is much greater than for oxyhemoglobin (9, 10, rapidly but the rate diminishes progressively until 11, 12). toward the end of the excretory period elimination Carbon monoxide combines rapidly with hemo- proceeds very slowly. The curves of are globin and will displace oxygen from oxyhemo- of the exponential type: the log of any percentage globin until equilibrium is reached. Under experi- (S') of carboxyhemoglobin after a lapse of time mental conditions with carbon monoxide at a (t) from the termination of exposure is equal to partial pressure of 75 mm. Hg, the gas combines the log of the initial saturation (S), plus a constant with hemoglobin from an adult sheep over the (b log e), multiplied by the time (t): following periods of time (13): log S' = log S + (b log e) t Average Time for Half Reaction The constant (b) is a negative number and was Hemoglobin in Erythrocyte Hemoglobin in Solution determined from experimental curves of elimi- 0.15 second 0.06 second nation made under varying respiratory con- are The difference in rate of reaction depends on the ditions, and the following average values greater accessibility of the molecules of hemoglobin given: in the solution as compared with those in the Patient b erythrocytes. Air -0.00178 In the circulating blood, carbon monoxide com- Pure Oxygen -0.00693 COz in Pure Oxygen -0.01169 bines with hemoglobin in proportion to its partial pressure, while the concentration of the gas which The value for log e is 0.4343. Sample calculation remains dissolved in the plasma depends upon its to determine the proportion of carboxyhemo- olubility and partial pressure. The same rules globin that would be present 100 minutes after apply to oxygen; thus, blood leaving the lungs start of therapy with mixture of oxygen and during exposure to carbon monoxide carries an carbon dioxide, when the initial hemoglobin almost normal concentration of oxygen dissolved saturation with carbon monoxide was 35 per in the plasma, but because of the greater affinity cent: bf hemoglobin for carbon monoxide disproportion- log S' = log S + (b log e) t ately less oxygen is carried by the hemoglobin. log S'= log 35 + (-0.01169 X 0.4343) X 100 Blood entering the arterial has an almost log S' = 1.544 + (-0.0050770) X 100 log S'= 1.544 - 0.50770 normal partial pressure of dissolved plasma oxygen, log S' = 1.0363 but as that gas diffuses into the tissues, the absence Saturation after 100 minutes treatment = 10.87% reserves of oxygen in the erythrocytes of the usual The data from the experiments of Sayers and becomes apparent. Yant (2) were expanded and presented in curves EXCRETION OF CARBON MONOXIDE to illustrate the varying rates of carbon monoxide elimination, depending upon whether the subject The only route for excretion of carbon monoxide was breathing air, oxygen, or carbogen. These in is the , whence it is eliminated demonstrate that the increase of the oxygen tension moved from the the expired air. When a patient is of the alveolar air enhances the elimination of contaminated atmosphere, elimination of the gas carbon monoxide from the blood. The additional begins at once. The rate of elimination depends effect of carbon dioxide results from stimulation of upon the composition of the atmosphere being the respiratory centers yielding increased pulmo- breathed. nary ventilation, and on lowering the pH of the Yant (2) studied the elimination of Sayers and blood causing the- equilibrium of the equation carbon monoxide by human subjects during the Hb + CO - HbCO to shift to the left. inhalation of air, of oxygen, and of a mixture of 8 to 10 percent carbon dioxide with pure oxygen.' EFFECT OF CARBON MONOXmE ON DISSOCIATION As was anticipated on the basis of the work of OF OXYHEMOGLOBIN Henderson and Haggard (14), elimination was If certain pecularities of carbon monoxide intoxi- IThis mixture is known as "carbogen." cation are to be understood, it is essential to CARBON MONOXIDE POISONING

appreciate that carbon monoxide in the blood In an effort to obtain information concerning the enhances the combination of oxygen with hemo- mechanism whereby the presence of carbon mon- globin (15, 16). Thus, when some of the hemoglobin oxide in the blood diminishes the ease of dissoci- is combined with carbon monoxide, the concen- ation of oxyhemoglobin, an investigation has been tration of oxygen in the tissues must fall to lower made by Drabkin et al. (18) into the nature of the than usual levels before oxygen will dissociate intimate relationship that exists between carbon from oxyhemoglobin and move into the tissues. monoxide and hemoglobin. After dogs had been A person whose blood oxyhemoglobin is diminished exposed to an atmosphere containing carbon because of the presence of carbon monoxide will monoxide until the animals' hemoglobin was 75 have more severe symptoms than one whose percent saturated with the gas, the animals oxyhemoglobin is diminished to an identical degree collapsed with evidence of cardiac and respiratory as a result of . failure; in those that survived, extensive necrotic In an example cited by Stadie and Martin (16), changes were later found in the brain and heart. a contrast has been made between an individual In another group of dogs, the concentration of who had only 40 percent of his total hemoglobin carbon monoxide in the blood was brought to 75 available for combination with oxygen due to percent of saturation by partial replacement trans- carbon monoxide poisoning, and another individual fusion with washed erythrocytes that had been whose hemoglobin was diminished to 40 percent of completely saturated with carbon monoxide. In the normal amount because of pernicious anemia. the latter animals, there were no signs of deficiency In both cases, the maximum amount of oxygen of oxygen; they were later killed, and autopsies available to the tissues was 8 ml. 02 per 100 ml. of revealed no evidence of myocardial or cerebral blood, and the tissues oi both patients required damage. In addition, the rate of carbon monoxide about 4 ml. 02 per 100 ml. of blood, or approxi- elimination was reported to be twice as rapid as mately one-half the maximum amount of oxygen from dogs which had inhaled the gas. On the basis that might be available. In the patient with of the dissociation curve of oxyhemoglobin in the pernicious anemia, the required quantity of oxygen presence of 75 percent saturation with carbon would dissociate from the hemoglobin at a partial monoxide, the dogs that had inhaled the carbon pressure in the blood greater than 28 mm. of monoxide actually had available for the tissues oxygen, but the oxygen tension in the blood of the not 25 percent of the normal amount of oxygen, individual with carbon monoxide poisoning must but only 11 percent. On the other hand, the dogs drop to 12 mm. before half of the oxygen would that were transfused with erythrocytes saturated be dissociated from the hemoglobin. Because of with carbon monoxide had available to their tissues this increase in the affinity of hemoglobin for 25 percent of the amount of oxygen normally oxygen in the presence of carbon monoxide, pro- carried by the blood in the absence of carbon found deficiency of oxygen in the tissues can result monoxide. These observations indicated that there during carbon monoxide poisoning even though was no change in the ability of oxygen to dissociate the amount of oxygen actually present in the from the oxyhemoglobin in the erythrocytes which blood is two or three times that necessary to were substantially free of carboxyhemoglobin. maintain function. Drabkin (19) then postulated that the left shift The contrast of the effects of carbon monoxide of the dissociation curve of oxyhemoglobin in poisoning with those of methemoglobinemia serves carbon monoxide poisoning is due to the simul- to emphasize the clinical importance of the altered taneous combination of oxygen and carbon mon- dissociation curve of oxyhemoglobin in the presence oxide with the hemoglobin molecules. He illustrates of carboxyhemoglobin (17). Human beings who this with a hypothetical patient who has 25 percent have concentrations of equivalent of the hemoglobin present as carboxyhemoglobin. to 30 percent of their total circulating hemoglobin Functional impairment is greater than from the are cyanotic but have no other apparent symptoms; simple loss of one quarter of the blood's capacity on the other hand, when 30 percent of the hemo- to carry oxygen. Assuming that none of the globin has been converted to carboxyhemoglobin, molecules of hemoglobin escaped combination with such symptoms as headache, weakness, nausea, carbon monoxide, the blood then would contain and a considerable feeling of discomfort are in- "100 percent of partially poisoned molecules of the variably present. species, Hb4(0 2)a(CO)." According to Drabkin's FRANK R. DUTRA [Vol. 54 hypothesis, further saturation of the blood with carrying capacity of the hemoglobin so that de- carbon monoxide produces "progressive molecular pletion into the tissues of the small amount of poisoning, consonant with the existence of inter- oxygen dissolved in the plasma leaves little oxygen mediate molecular species of the type Hb 4 (0 2)3 reserve in the erythrocytes. Thus, the supply of

(CO), Hb 4(02)2(CO) 2, and Hb4 (0 2)(CO)3, in be- oxygen to important organs may be greatly im- tween completely oxygenated Hb 4(0 2) 4 and com- paired, resulting in irreversible damage, even pletely poisoned Hb 4(CO)a." The greater the though the and depth are not saturation of the molecules with carbon monoxide, altered during the episode of poisoning. the more firm become the bonds between the J.S. Haldane (5) demonstrated that the physio- hemoglobin and the remaining oxygen molecules. logical effects of carbon monoxide could be miti- In other words, the partial pressure of oxygen in gated considerably by increasing the partial pres- the plasma must fall to a lower level before hemo- sure of oxygen in the blood. For example, a mouse globin wi give up oxygen when carbon monoxide exposed to air contaminated with 0.022 percent is also attached to the hemoglobin molecule than of carbon monoxide died in 2 hours and 25 minutes, when only molecules of oxygen are bound to it. but in an atmosphere comprised of 97 percent On the other hand, the possibility that the oxygen, 2.84 percent nitrogen, and 0.25 percent explanation of Drabkin represents an over-simplifi- carbon dioxide, about 0.08 percent of carbon cation is suggested by the report of Allen, Guthe, monoxide was required to "distinctly affect a and Wyman (20) which supports the concept that mouse, and very much more to produce death." the four oxygen-combining centers of a molecule In discussing the results of these experiments, of hemoglobin are all inherently identical. Their Haldane wrote (5), "In the case of pure oxygen work indicates that the curve of dissociation of the tension of oxygen is nearly five times as great oxygen from each combining-center is the same, as in air, so that to produce equal saturation of and is unaffected by the presence or absence of the haemoglobin of the corpuscles with carbonic oxygen in combination with any of the other three. oxide (carbon monoxide) in oxygen and in air, the tension of carbonic oxide would presumably require EFFEcTS oF OXYGEN DEFICIENCY to be five times as great in the oxygen as in the air. Hence on the hypothesis on which the investi- Oxygen deficiency of the arterial blood in carbon gation started one might expect that carbonic monoxide poisoning is, in one respect, even more oxide would turn out to be about five times as pure than that in hypoxemia from decrease of poisonous in air as in oxygen--that is to say, that atmospheric oxygen as at high altitudes. In the five times as high a percentage of carbonic oxide latter, the diminished partial pressure of oxygen in would be required in oxygen to produce the effect the plasma of the arteries results in hyperpnea of a given percentage in air. which becomes complicated by respiratory alka- "Now the experiments.. . clearly showed that losis. carbonic oxide is much more than five times as Differences in deaths from carbon monoxide poisonous in air as in oxygen. In the latter gas the poinsoning and from hypoxemia due to diminished poisonous action is reduced to about a tenth or oxygen pressure in the atmosphere have been less. Evidently then some other factor has to be described by Haldane and Priestley (21). When taken into account besides the relative tensions of death results purely from insufficiency of oxygen, oxygen and carbonic oxide." the immediate cause is failure of the respiratory In order to account for this discrepancy between centers. This is in part predisposed by hyperpnea the original hypothesis and the subsequent experi- associated with diminishing partial pressure of mental data, "the hypothesis suggested itself that oxygen in the plasma. On the other hand, in the higher the oxygen tension the less dependent carbon monoxide poisoning the partial pressure of an animal is on its red corpuscles as oxygen oxygen in the circulating plasma is normal as the carriers, since the oxygen supply simply dissolved blood reaches the bodies, so that in the blood becomes considerable when the oxygen hyperpnea does not occur. However, the carbon tension is high." monoxide present has greatly reduced the oxygen- Accordingly, Haldane contrived an experiment 2 The organs that initiate reflex hyperpnea when to assess this possibility. He found that mice in a there is a fall in the oxygen tension of their afferent blood. chamber containing only oxygen at a pressure of 19631 CARBON MONOXIDE POISONING two would suffer but slight distress oxidases, and thereby probably results in functional as carbon monoxide was added up to a pressure of disturbance. It is possible that the extreme mus- one atmosphere of the latter gas. Thus, the intro- cular weakness which accompanies significant ab- duction of enough carbon monoxide to saturate sorption of carbon monoxide is, in part, the result the hemoglobin completely, had little deleterious of the carboxymyoglobin in the skeletal muscles. effect because the oxygen dissolved in the plasma The presence of carboxymyoglobin is indicated was able to meet the resting metabolic requirement, at the postmortem examination of persons who although Haldane recognized that the amount of have died during exposure to carbon monoxide by oxygen that could dissolve in the plasma at this the bright red appearance of the skeletal muscles. pressure would not support great physical activity. Some years later J. B. S. Haldane (22) per- TissuE OXYGEN REQuIREmENTS formed a similar experiment with rats as subjects The rate at which any tissue utilizes oxygen in and found that when the animals were under a order to maintain the life of its cells may be con- pressure of three atmospheres of oxygen and one sidered as the "survival oxygen requirement" of of carbon monoxide, their activities were essentially that tissue. This survival requirement differs normal, but that the addition of a second atmos- greatly in different kinds of tissue, and even with phere of carbon monoxide caused hyperventilation different cells within the same tissue. For example, and, within a few minutes, convulsions and death. the requirement for nerve cells of the cerebral Such effects were not observed when the experi- cortex is considerably greater than that for the ment was repeated using nitrogen in place of nerve cells of the various nuclei of the medulla carbon monoxide. The elder Haldane (5) had oblongata. concluded on the basis of his experiment that Recognition of the differences in the survival carbon monoxide is not toxic except for its capacity oxygen requirements of different tissues and cells to diminish the oxygen-carrying capacity of the is the key to an understanding of some of the hemoglobin, but the experiment of J. B. S. Haldane peculiarities of the pathology of carbon monoxide indicated that at higher pressures of carbon mon- poisoning. The cells that have the greatest require- oxide the gas does affect the metabolic activities ment are the first to die during the development of the body. J. B. S. Haldane believed this effect of carbon monoxide poisoning, while other tissues of carbon monoxide to be the result of its combi- adjacent to them may be affected little or not at nation with one or more enzymes that are con- all during the poisoning episode. cemed with intracellular oxidation-reduction re- In this connection it is also proper to indicate actions, and that this effect is fundamentally that organs receiving less than optimal blood similar to the effects of carbon monoxide on yeasts, supply are more susceptible during carbon mon- germinating seeds, and on (moths) that he -oxide poisoning. Thus, the heart in which severe used in other studies. sclerosis of the coronary arteries exists is much more likely to sustain anoxic damage than one in COB INATION OF CARBON MONOXIDE WEFH which the vessels are widely patent. Not all of the carbon monoxide that is absorbed DURATION oF DEFICIENCY OF OXYGEN remains within the blood. Myoglobin has a much A considerable clinical difference will exist be- greater affinity for oxygen than does hemoglobin, tween two patients each of whom has 40 percent so that oxygen passes with great facility from the of his hemoglobin combined with carbon monoxide, blood to combine with the myoglobin. The affinity and who are similar in all respects except that one of myoglobin for carbon monoxide is also high. has attained this degree of saturation by exposure Therefore, in the presence of carboxyhemoglobin to a relatively high atmospheric concentration of in the blood, carbon monoxide will be transferred carbon monoxide for a short time, while the other to the myoglobin of the skeletal muscles and heart was exposed to a relatively low concentration for a and will remain there until the carbon monoxide number of hours. Assuming that the first person is eliminated from the blood (23). This combination had been exposed to air containing 0.5 percent of carbon monoxide with myoglobin does not result carbon monoxide for 20 minutes, he would tend to in direct damage to the muscle but does tend to respond quickly to treatment with carbogen, and disrupt the flow of oxygen to the intracellular virtually complete recovery would probably occur FRANK R. DUTRA [Vol. 54

within an hour or so. The second person may be poisoning result only from deficiency in the supply assumed to have been exposed to the concen- of oxygen to the tissues. tration of 0.05 percent carbon monoxide for 6 to 3. The presence of carbon monoxide in the blood 8 hours; carbogen therapy would also lead to appears to increase the strength of the chemical prompt elimination of carbon monoxide, but it is bonds between hemoglobin and oxygen, so that unlikely that this would be accompanied by quick whatever oxygen the hemoglobin may still be recovery of consciousness, while damage which had transporting is given up to the tissues only when occurred in the brain, heart, and other organs there has been unusual depletion of the tissue during the period of oxygen deficiency might be oxygen reserves. permanent. 4. Brief periods of oxygen deficiency can be When the absorption of carbon monoxide occurs relatively harmless, but deficiency of corresponding quickly, and resuscitative efforts are prompt, the intensity for several hours can cause extensive and blood vessels are injured only slightly or not at all, perhaps fatal injuries. and transudation of edema fluid and extravasation 5. Cells that require the largest amounts of of erythrocytes are minimal or absent. When the oxygen for survival are the first to die during period of is prolonged, the cells lining the poisoning. blood vessels may be damaged greatly, and 6. Diminution of the supply of blood to an organ vascular dilatation throughout the body is usually is more likely to be harmful when the blood con- marked. Fluid escapes from the damaged vessels, tains carbon monoxide than when it is free of this resulting in the development of hemoconcentration gas. and a tendency toward stagnation of the blood An understanding of these physiological princi- flow, thus further diminishing the supply of oxygen ples of carbon monoxide poisoning is necessary if to the tissues. The injured vessels also permit one is to comprehend the symptoms and injuries diapedesis of cellular elements, and perivascular that are produced during poisoning. Alleviation hemorrhages are common. of symptoms and prevention of tissue damage are It is possible for an oxygen debt to exist in the the aims of rational therapy. The disease is tissues for a relatively short period without anoxia, and the treatment is oxygen. damage. However, if oxygen is not supplied REFERENCES promptly, irreversible degenerative phenomena 1. FoRBEs, W. H., SARGENT, F., and ROUGHTON, become established in the central nervous system, F. J. W. The rate of carbon monoxide uptake by heart, kidney, and other organs. Such lesions are normal men. Am. J. PirysioL. 143: 594-608, 1945. well known as residua of carbon monoxide poison- 2. SAYERS, R. R., and YANT, IV. P. The elimination of carbon monoxide from blood, by treatment ing (24). Although elimination of carbon monoxide with air, with oxygen, and with a mixture of from the blood occurs rapidly with the inhalation carbon dioxide and oxygen. Pu. HEALTH REP. 38: 2053-2074, 1923. of carbogen, the coma may linger for days or even 3. KnLic, ESTHER M. Carbon monoxide anoxemia. weeks as a result of the damage to the central PmsioL. REv. 20: 313-344, 1940. nervous system caused by oxygen deficiency during 4. HENDERSON, Y., HAGGARD, H. W., TEAGUE, M. C., PRiScE, A. L., and WuNDERmcH, R. M. Physio- the episode of poisoning. logical effects of automobile exhaust gas and standards of ventilation for brief exposures. SU-MMARY J. INDUST. HYG. 3: 79-92; 137-146, 1921-1922. 5. HAL.DANE, J. The action of carbonic oxide on man. The signs and symptoms of carbon monoxide J. PmisioL. 18: 430-462, 1895. 6. PACE, N., CONSOLAZmO, W. V., WHrTE, W. A., JR., poisoning are manifold, but the physiological and BEHN E, A. R. Formulation of the principal principles can be stated in a few brief paragraphs: factors affecting the rate of uptake of carbon 1. Carbon monoxide and oxygen each combine monoxide by man. Am. J. PHYsIOL. 147: 352- 359, 1946. in the same manner with hemoglobin. However, 7. SENDROz, J., JR., Liu, S. H., and VAN SL=xa, hemoglobin has a much greater affinity for carbon D. D. The gasometric estimation of the relative monoxide than for oxygen so that relatively little affinity constant for carbon monoxide and oxy- gen in whole blood at 38'. Am. J. PnvsIOL. 90. carbon monoxide in the air can displace much of 511-512, 1929. the oxygen from the blood. 8. SJ6STRAND, T. A method for the determination of the total haemoglobin content of the body. 2. Carbon monoxide has no significant intrinsic ACTA Paysior. SCANDrNAV. 16: 211-231, 1948. toxicity for tissues. Injuries sustained during 9. RouGa-roN, F. J. W. The kinetics of haemoglobin. 19631 CARBON MONOXIDE POISONING

IV. General methods and theoretical basis for 16. STADIE, W. C., and MAuAn, K. A. The elimination the reactions with carbon monoxide. PRoc. of carbon monoxide from the blood. A theoretical Roy. Soc. LONDON, Series B 115: 451-464, 1934. and experimental study. 3. CLri. INvEsTiGATiON 10. ROUGHTON, F. J. W. The kinetics of haemoglobin. 2. 77-91, 1925-26. V. The combination of carbon monoxide with 17. BODANSY, 0., and GTmANN, H. Treatment of reduced haemoglobin. PRoc. Roy. Soc. LONDON, methemoglobinemia. J. PRARMACOL. & ExPER. Series B 115: 464-473, 1934. TaERAP. 90: 46-56, 1947. 11. ROUGHTON, F. J. W. The kinetics of haemoglobin. 18. DRABKf, D. L., LEwVEY, F. H., BELLET, S., and VI. Competition of carbon monoxide and oxygen EmucH, W. H. The effect of replacement of for haemoglobin. PRoc. Roy. Soc. LoNDoN, normal blood by erythrocytes saturated with Series B 115: 473-495, 1934. carbon monoxide. Am. J. M. Sc. 205: 755-756, 12. ROUGHTON, F. J. W. The kinetics of the reaction 1943. CO + 02Hb 02 + COHb in human blood at 19. DRABIN, D. L. of the hemin chromo- body . AM J. PHYSIOL. 143: 609- . Pmsion. REv. 31: 345-431, 1951. 620, 1945. 20. ALL;EN, D. W., GUTEm K. F., and WymA, 3., 13. ROUGHTON, F. J. W., LEGGE, J. W., and NIcOLSON, JR. Further studies on the oxygen equilibrium P. The kinetics of haemoglobin in solution and of hemoglobin. J. BIor. CuEm 187: 393-410, in the red blood corpuscle; in HAEMOGLOBIN, 1950. ed. by ROuGHTON, F. J. W., and KENDREw, 21. HALDAmq, J. S., and PRIESTLIEY, 3. G. RESPIRATION. J. C. London: Butterworths Scientific Publica- New Haven: Yale University Press, 1935. tions, 1949. (pp. 67-82). 22. HAKDANE, 3. B. S. Carbon monoxide as a tissue 14. HENDERSON, Y. and HAGGARD, H. W. The elimina- poison. Biocsm-. J. 21: 1068-1075, 1927. tion of carbon monoxide from the blood after a 23. DEDuvE, CHEjsTIm. The simultaneous spectro- dangerous degree of asphyxiation, and a therapy photometric determination of haemoglobin and for accelerating the elimination. J. PmuAvACO.. myoglobin in extracts of human muscle; in HAEMOGLOIN, Edited by F. 3. W. ROUGHTON EXPER. THERM,. 16: 11-20, 1920-21. and J. C. KENDRw. London: Butterworths 15. DOUGLAS, C. G., HAIuAE, J. S., and HALDAN, Scientific Publications, 1949. (p. 125). J. B. S. The laws of combination of haemoglobin 24. DUTRA, F. R. Cerebral residua of acute carbon with carbon monoxide and oxygen. J. PHYSIoL. monoxide poisoning. Am. 3. Cixg. PATH. 22:" 44: 275-304, 1912. 925-935, 1952.