Toxicology, 62 (1990) 123--160 Elsevier Scientific Publishers Ireland Ltd.

Acute carbon monoxide poisoning: animal models: A review

David George Penney Departments

of

Physiology,

and Occupational and Environmental University, Detroit, MI 48201 (U.S.A.)

Health,

Wayne

State

(Received January 16th, 1990; accepted January 22nd, 1990)

Summary Animals have been used for well over a century in an attempt to understand the toxicology, physiology, and pathology of acute carbon monoxide poisoning. Whether the toxic effects of this gas result from primary hypoxia, as in hypoxic hypoxia to which it is frequently compared, or from direct tissue effects since it enters cells and binds to certain vital components, remains a point of controversy. Acute severe poisoning in man and animals affects primarily the cardiovascular and nervous systems, and frequently produces neurologic dysfunction. Morphologically, tissue damage is usually confined to the white matter. The root cause is at best poorly understood and major investigative efforts have been made toward its elucidation. Many studies with rats, cats and primates indicate a major role for CO-induced hypotension, which serves to compromise blood flow and exacerbate acidosis. The likely cellular mechanisms in this process are only now becoming apparent. This review critically examines the recent as well as a few older CO-animal studies. In scope, they fall into several broad categories: general cardiopulmonary effects, metabolic and tissue effects, general resistance (i.e. tolerance), effects on the central nervous system including blood flow, neurochemistry, morphology and behavior, and finally, experimental therapeutic approaches.

Key words: Carbon monoxide; Animal models; Cardiopulmonary effects; Metabolic effects; Resistance; Central nervous system; Neurologic sequelae;

1. Introduction Carbon monoxide binds to heme proteins, rendering them incapable of normal f u n c t i o n . P r o b a b l y as its m a j o r t o x i c e f f e c t , t h e o x y g e n c a r r y i n g c a p a c i t y o f h e m o g l o b i n is p r o g r e s s i v e l y r e d u c e d w i t h r i s i n g c a r b o x y h e m o g l o b i n ( C O H b ) s a t u ration. Unlike simple anemia, however, partial saturation of each hemoglobin

Address all correspondence to: David G. Penney, Ph.D., Associate Professor, Department of Physiology, Wayne State University School of Medicine, 540 E. Canfield, Detroit, MI 48201, U.S.A. 0300-483x/90/$03.50 © 1990 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland

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molecule with CO results in a tighter binding of the remaining oxygen, causing a left shift of the hemoglobin-oxygen association-dissociation curve. Hence, oxygen diffusion to tissue occurs at lower PO 2. Yet the magnitude of the Bohr effect is increased by elevated C O H b saturation [1], off-setting to some degree the tissue hypoxia otherwise produced as p H falls. As the result of impaired metabolism, ceils, tissues and organs are damaged, and if severe enough, it becomes incompatible with continued life of the organism. While damage may occur in almost every organ system, particular attention in this review is focused on the brain and to a lesser extent the heart, for three reasons; (1) their predominantly aerobic metabolism, (2) their inability to sustain substantial oxygen debt, and (3) their immediate and vital role in body function. The bulk of recent acute CO animal studies have been carried out with the rat and the cat. When large numbers of individuals are needed and the protocol simply requires determining time of death, as in studies of resistance (i.e. tolerance), the mouse has been used [2,3, and others]. Dogs have also been called upon [4], but the greater generosity of their cerebral blood supply relative to the cat has made the cat a much better model for studies of COs effect on brain function [5 - - 9 , and others]. This is also the case for the study of stroke and other conditions involving cerebral hypoxia/ischemia. The rat is less than ideal in this regard for the same reason as the dog, unless surgical measures are taken to place its brain at increased risk [10]. Monkeys have been used in a few CO studies [11], but the vastly increased cost all but prohibits their wider use. In developmental studies requiring fetal access [12], sheep remain a favorite. In addition to species, several other variables must be considered in any discussion of the toxicology/physiology/pathology of CO: CO dose level, duration of exposure, state of consciousness, and anesthetic agent, if present. Anesthetics, for instance, may depress metabolism and ventilation, hence decreasing tissue oxygen needs and rate of CO uptake. CO, even at high concentration, usually fails to produce pathology when exposure lasts 15 min or less [4]. These variables complicate comparisons between studies, and necessitate caution in drawing conclusions. Table I summarizes the CO concentrations, exposure durations, and conditions which have been used in studies with a number of species. The C O H b saturations given suggest that C O H b level is dependent upon a number of factors, including the method used to determine C O H b [37]. Controversy continues to rage as to whether CO exerts its toxic effect purely through limitation of tissue oxygen delivery by binding to hemoglobin, or whether it has a direct histotoxic effect, as by binding to the cytochromes, myoglobin, etc. While this issue is addressed in the present article, recent reviews should be consulted for a more thorough discussion [38,39]. Many studies [5,6,9,10,40] suggest that the hypotension resulting in relative ischemia (i.e. oligemia) plays an even larger role in tissue demise than does the direct effect of CO hypoxia. The following discussion summarizes much of the literature in which animal models have been used to increase our understanding of acute CO poisoning, and in particular, articles published during the past decade or two. Attention is focused on work with adult animals, although studies of the early developmental

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T ABLE I C A R B O X Y H E M O G L O B I N S A T U R A T I O N S A C H I E V E D IN S EV ER A L SPECIES BY E X P O S U R E TO D I F F E R E N T C O N C E N T R A T I O N S OF C A R B O N M O N O X I D E OVER VARIOUS P ER IO D S OF T I M E CO (ppm)

Duration (min)

Consc. (C)/ Unconsc. (U)

COHb (%)

Species

Reference

2500 97. ! 150 221 250 500 500 500 700 769 1000 1000 1000 1000 1000 1000 1000 1200 1500 2000 2500 3000 3000 3000 3700 4000 5000 5000 6000 8000 10 000 10 000 10 000 10 000 10 000 10 000 10 000 10 000 12 500 15 000 15 000 20 000 20 000 30 000 86 300 500

120 40 240 40 240 120 150 240 < 4 h 40 40 80 120 150 150 180 240 12 h 120 25 60 40 80 90 15 40 30 30 10 23.6 4 4 30 30 15 30 45 60 5 30 30 30 30 3.6 < 4 h < 4 h 120

C C C C C C U C C C C C C C U C C C C C C C C C C C U U C C C C U U U U U U C U U U U C C C C

69.5 9.5 15 20 23 35.4 35 43 37 50 45.7 48.5 40--45 52--56 55 56 63 48 55.7 75 65--72 63.5 81.2 55 83 76 26 35 87 71.3 72 81.5 55 45 50.2 65.5 63 64.9 93 63 60 72 70 79.2 7 26 25.3

Mouse rat rat rat rat rat rat rat rat rat rat rat rat rat rat rat rat rat rat rat rat rat rat rat rat rat rat rat rat rat rat rat rat rat rat rat rat rat rat rat rat rat rat rat guinea pig guinea pig guinea pig

3 13 14 13 14 15 16 14 17 13 18 18 19 20 16 21 14 22 23 24 25 18 18 10 24 22 26 27 24 28 22 18 26 27 27 27 27 27 24 26 27 26 27 28 17 17 15

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TABLE I (continued) CO (ppm)

Duration (min)

Consc. (C)/ Unconsc. (U)

COHb (070)

700 1000