THE CARDIOVASCULAR AND RESPIRATORY RESPONSES OF DOGS TO LETHAL CONCENTRATIONS OF CARBON MONOXIDE DISSERTATION Pi Q Pi resented in Partial Fulfillment of the Requirements for the egree Doctor of Philosophy in the Graduate School of the Ohio State University BY Kenneth Rae Coburn, B. S. The Ohio State University i960 Approved by AdvisorA r ^ T ri Department of Physiology ACKNOWLEDGMENTS I wish, to express my sincere appreciation for the guidance, enthusiasm and invaluable aid of Doctors Fred A0 Hitchcock, Earl T. Carter and Joseph F„ Tomashefski without whose assistance this study could never have been carried out. I am grateful to all those of the Cardiopulmonary Laboratory of the Ohio State Tuberculosis Hospital for the aid and assistance which they offered. CONTENTS Introduction ........................................................................ 1 Survey of the Literature A. Early History of CO Poisoning............................................ 4 B. Absorption and Excretion of C O...................................................... 5 C. Oxygen, Carbon Monoxide and Hemoglobin........ 8 D. Blood and Circulatory Changes in CO Poisoning...............................15 a. Blood Changes . 15 b. Blood Vessels and CO ................................................16 c. Behaviour of the Heart ...................................................16 E. Effect of CO on Respiration .............. 18 F. Recent Integrated Studies.............................................................................. 19 Methods and Procedures A. Anesthesia and Surgical Preparation...........................................................21 B. Respiration Measurements . 22 C. Experimental Protocol........................... 25 D. Blood Analysis.........................................................................................................27 E. Statistical Analysis ................................ 30 Results A. Ventilatory Response ..........................................................................32 B. Blood Changes.........................................................................................................32 C. Cardiovascular Changes .................................... 33 Discussion................................................................................................. 35 iii Summary and Conclusions . ...........................................................................................43 F ig u r e s ................................................... - ................................44-69 T a b le s ................................................... 70-75 Bibliography .............................................................. 76-81 Autobiography ..............................82 iv LIST OF FIGURES Page 1. Equilibrium Concentrations of CO with Respect to T im e ........................................... 44 2. The Haldane Shift ............................ 45 3. Representative Data Taken from Swann and Brucer . 46 4. Schematic Diagram of Experimental Set-Up....................... 47 5. Terminal Yentilogram................................................................................. 48 6-26 Individual Data Plots of Experimental Animals.... 49-69 v LIST OF TABLES Page 1. Cardiovascular Responses to CO ...........................................70 2. Blood Gases ...........................................................................................71-73 3. Blood Changes ............................................ 74 4. Ventilatory Response................................................... 75 vi INTRODUCTION One of the first of the insidious and deadly by-products of civilization appears to have been carbon monoxide, CO. As soon as man became civilized enough to carry fire into a restricted environ­ ment the hazards of CO poisoning became constant companions of man. While thousands of years were to pass before the mechanism of CO poisoning was discovered and described, it has been associated since the earliest times with the presence of fire. For thousands of years the only common source, of CO was from the incomplete combustion of vegetable fuels, but with the advent of the fifteenth century the increasing use of coal as a fuel led to a tremendous increase in the incidence of CO poisoning. With each development of more effective means of power production the problems grew until, with the invention of the internal combustion engine, it became one of the major problems not only of industry but of common usage. In our present industrial age with natural gas heating, myriads of gasoline engines, jet propulsion and the widely diversified manufacturing processes required for the maintenance of our current standards, we find that CO intoxication has become one of the most widely distributed and frequently en­ countered types of poisoning. Carbon monoxide, CO, has a specific gravity of 0.9671 ( air = 1 ) and a density of 1. 2504 grams per liter ( STPD ) with a molecular weight of 28.01. 1 It is colorless in all concentrations and is odorless in concentrations up to about 80 per cent. In higher concentration it has a distinct garlic- like odor. It melts at -207° Centigrade and boils at -192° Centigrade. The following list which was compiled from the Bureau of Mines^ shows the approximate proportion of CO in gases to which relatively large proportions of the population of the United States may at one time or another be exposed. Type and Source CO by volume per cent Blast furnace stack gas 28. 0 Bessemer furnace gas 25.0 Producer gas from coke 25.0 TNT blast gas 60.0 Fuel gas 30.0 Gas range using natural gas 0.2 Room heater using natural gas 0. 5 Automobile exhaust gas 7.0 Natural gas water heater 1. 0 Arc furnace melting aluminum 3 2, 2 The toxicity of CO is due to the fact that it becomes bound strongly to the hemoglobin of the circulating blood and in this manner interferes not only with the normal transport of O£ from the lungs to the tissues but with the reciprocal function of the bLood in respiration, i.e., that of transporting CO2 from the various tissues of the body to the lungs for excretion. In this it would seem that CO poisoning is merely another form of anemic hypoxia and that in describing the physiological relationships of one, such as hypochromic anemia, one would in essence be describing the relationships in ail. This is not strictly true inasmuch 2 as CO has a discrete action on the blood vessels of the body which must be taken into the overall picture if a concise knowledge of the mechanisms by which it acts is to be obtained. In addition, CO is known to combine with cytochrome oxidase in such a way as to inhibit the action of this enzyme. However, the affinity of cytochrome oxidase for CO is 1, 000 times Less than its affinity for O^ and it .is questionable whether this mechanism has a role in CO poisoning. ® In view of the fact that the rational treatment of CO poisoning depends upon a dear knowledge of all the pathophysiological mechanisms involved in the entity of CO intoxication, it was decided that a rather comprehensive investigation of the cardiopulmonary responses of mammals to lethal concentrations of CO be undertaken in an attempt to clarify the relationship between the ventilation effects and the cardiovascular response to CO. Of particular interest were certain time relationships existing between the respiratory center and the vasomotor center throughout the exposure to a lethal concentration of CO. Is the ultimate cause of death in the intoxicated animal due prim arily to respiratory failure or is this merely a manisfestation of a more subtle process. 4 SURVEY OF THE LITERATURE A. Early History of CO Poisoning The first case of CO poisoning probably occurred when one of the first humans to use fire in a cave rolled a rock into the opening of his cave to seal it for the night. By early historical times the effect, if not the cause, of CO poisoning was known. Sayers and Davenport, ^ from whom the unnumbered references to follow are cited, report that Lewin ^ lists numerous incidents of CO poisoning which were described in the early Greek and Roman literature. One of the first was reported by Livius during the Second Pumic War, about 200 B„C0, who wrote the commanders of the allies and other Roman citizens were seized suddenly and fastened in the public baths for guarding, where the glowing fire and heat took their breath away and they perished in a horrible manner. ^ CO used as a means of self-destruction was first reported by PLutarch who wrote that Catalus kilLed him self by closing him self in a bath with the vapor from many glowing coals. It would appear then that the lethal effect of enclosed fire was well known and documented by the ancients. The nature of its action was, however, to remain obscure for many years. Cassius attributed the ill effects not to fire but to the dry heat it produced. As late as the eighteenth century CO intoxication was still being superstitiously attributed to the work of the devil. However, in 1648 Bacomis de Verulamio noted the fact that the gas was odorless and he referred to this gas as vapor carbonum. Previous to Verulamio the rather vague term fumus had been applied to the causative agent in CO poisoning. Van Helmont, in 1667, was the first investigator to use the term carbon gas, while Boerhaave found that all red-hot organic matter released fumes which were lethal 4 to animals. Pure CO was first prepared in 1796 by F. de Lassone who reduced zinc oxide with pure carbon. Lavosier knew that CO could be burned to produce