ACUTE THERMAL AND CARDIORESPIRATORY RESPONSES TO TRANQUILIZATION AND ELECTRO‘ANESTHESIA IN SHEEP Thesis for the Degree of Ph. D. MICHIGAN STATE UNIVERSITY WENDELL FEY HOFMAN 1970 1.. IE RA R Y Michigan State University This is to certify that the thesis entitled Acute Thermal and Cardiorespiratory Responses to Tranquilization and Electro-anesthesia in Sheep presented by Wendel-l Fey Hofman has been accepted towards fulfillment of the requirements for Ph. D. degree in Physiology vi/B Wag Major professor Dana‘s //11 /?PO 0-169 (.5 BINDING BY? ;\l IIUAII & SIIIIS' BIIDK BINDERY IIIB: ABSTRACT ACUTE THERMAL AND CARDIORESPIRATORY RESPONSES TO TRANQUILIZATION AND ELECTRO-ANESTHESIA IN SHEEP BY wendell Fey Hofman Acute thermal and cardiorespiratory responses were examined in closely shorn adult sheep administered prOpio- promazine HCl (1.0 mg/kg) and electro-anesthesia (700 c.p.s. A.C., bitemporal electrodes) together, and independently during a 330 minute whole body exposure to three environmen- tal temperatures, 5°C., 25°C. and 35°C. Rectal (Tre) and 7 skin temperatures, oxygen consumption (V02), respiratory frequency (f), respiratory evaporative water loss (E), arterial blood pressure, heart rate, arterial pH, arterial carbon dioxide tension (Pacoz), bicarbonate concentration, and arterial hematocrits were measured. Values for alveolar ventilation (9A) and tidal volume (VT) were computed. At the 5°C. exposure, Tre's decreased in both the tranquilized (0.80C.) and tranquilized-electro-anesthetized sheep (1.6OC.) after 2 hours of their respective treatments. The depres- sion in Tre of these groups was associated with an inhibi— tion of shivering which was related to a decreased 90 , a 2 SUggested increase in net peripheral heat loss (ears and Wendell Fey Hofman face) and increased heat dissipation via E. Nevertheless, the sheep given electro-anesthesia alone showed no signifi- cant change in Tre' Little difference was recorded in Tre's for tranquilized and/or electro-anesthetized sheep from con— trol values at 25°C. However, an elevation in heat produc- tion (increased V02) was observed in the tranquilized and tranquilized-electro-anesthetized animals which overcame the increased net peripheral heat loss from vasoactive areas The elevation in Tre of the (i.e., ears and forelimbs). tranquilized (0.90C.), tranquilized—electro-anesthetized (1.50C.) and electro-anesthetized sheep (1.50C.) from con- trol measurements at the 35°C. exposure was attributed to a reduction in.E attendant todepression of f. At all ambient temperatures, PaCO was increased in tranquilized-electro- anesthetized sheep with smaller elevations observed when treatments were given separately. These elevations in PaC02 were related to decreases in arterial pH, f and 9A. Arterial blood pressure was decreased in animals administered prOpio- promazine alone and with electro-anesthesia. Heart rate was increased in prOportion to the fall in blood pressure. The animal administered electrical anesthesia alone exhibited an increase in blood pressure even though heart rate was in- creased only at the 35°C. exposure. Arterial hematocrits were increased in animals under electro—anesthesia but not in sheep given only propiopromazine. ACUTE THERMAL AND CARDIORESPIRATORY RESPONSES TO TRANQUILIZATION AND ELECTRO-ANESTHESIA IN SHEEP BY Wendell Fey Hofman A THESIS Submitted to Michigan State University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Department of Physiology 1970 ACKNOWLEDGMENTS I would like to express my sincere gratitude to Dr. G. D. Riegle, my major advisor, for his encouragement, guidance and help during my graduate program. I would also like to thank Dr. T. Adams and Dr. S. R. Heisey for their advice and assistance with this research effort. .My appreciation is also extended to Dr. J. E. Nellor and Dr. K. E. Moore for their suggestions and counsel. I would like to express my appreciation to the entire staff of the Endocrine Research Unit for their support and help and for providing facilities to conduct this study. I also wish to thank my wife, Karen, for her patience and sacrifices during my doctoral program. ***** ii TABLE OF CONTENTS INTRODUCTION . . . . . . . . . LITERATURE REVIEW' . . . Historical Review of Electro-Anesthesia Historical Review of Phenothiazine Tranquilizers . . . . Cardiorespiratory and Biothermal of Electro-Anesthesia . of Phenothiazine Tranquilizers METHODS Cardiovasculature . . Respiration . . . . . Temperature Regulation . CardioreSpiratory and Biothermal Cardiovasculature . . Respiration . . . . . Temperature Regulation AND MATERIALS . . . . Animals . . . . . . . . . Restraining Device . . . . Environmental Chamber . . Temperature Measurements . Oxygen Consumption . . . . Respiratory Evaporative Water Loss . . . Respiratory Frequency . . Blood Pressure and Heart Rate 0 0 Effects Arterial pH, Carbon Dioxide Tension and Bicarbonate Concentration Alveolar Ventilation and Electrical Anesthesia . . Experimental Procedures . Statistical Analyses . . . RESULTS Rectal Temperature . . . . Ear Skin Temperatures . . Face Skin Temperatures . . iii Tidal Volume . Page 11 12 14 15 15 16 18 18 .19 19 20 21 21 23 23 24 24 25 26 28 29 29 31 32 Page Forelimb Skin Temperatures . . . . . . . . . . . . 33 Trunk Temperatures . . . . . . . . . . . . . . . . 34 Oxygen Consumption . . . . . . . . . . . . . . . . 34 Respiratory Frequency . . . . . . . .... . . . . 35 Respiratory Evaporative Water Loss . . . . . . . . 37 Arterial pH, PC02 and HCO3 . . . . . . . . . . . . 38 Alveolar Ventilation and Tidal Volume . . . . . . 39 Arterial Blood Pressure and Heart Rate . . . . . . 40 Arterial Hematocrits . . . . . . . . . . . . . . . 42 Shivering . . . . . . . . . . . . . . . . . . . . 42 Electro-Anesthesia Observations . . . . . . . . . 43 DISCUSSION . . . . . . . . . . . . . . . 75 SUMMARY AND CONCLUSIONS . . . . . . . . . 92 REFERENCE LIST . . . . . . . . . . . . . . 96 APPENDIX A. FREQUENTLY USED SYMBOLS . . . . . . . . . . 104 105 B. STATISTICAL EQUATIONS . . . . . . . . iv LIST OF TABLES Page Effects of tranquilizer and electro— o anesthesia on rectal temperature at 5 C. . . . 44 Effects of tranquilizer and electro- o anesthesia on rectal temperature at 25 C. . . . 45 Effects of tranquilizer and electro- o anesthesia on rectal temperature at 35 C. . . . 46 Effects of tranquilizer and electro- anesthesia on ear skin temperature . . . . . . 47 Effects of tranquilizer and electro— anesthesia on face skin temperature . . . . . . 48 Effects of tranquilizer and electro- anesthesia on lower forelimb temperature . . . 49 Effects of tranquilizer and electro- anesthesia on mid-forelimb temperature . . . . 50 Effects of tranquilizer and electro- anesthesia on upper forelimb temperature . . . 51 Effects of tranquilizer and electro- anesthesia on trunk temperature . . . . . . . . 52 Effects of tranquilizer and electro- anesthesia on oxygen consumption . . . . . . . 53 Effects of electro-anesthesia on oxygen consumption . . . . . . . . . . . . . . . . . . 54 Effects of tranquilizer and electro- anesthesia on respiratory frequency . . . . . . 55 Effects of electro-anesthesia on respiratory frequency . . . . . . . . . . . . . 56 .Effects of tranquilizer and electro- anesthesia on respiratory evaporative . 57 O O O O O O O O O 0 water loss . . . . . . . Page Table 15. Effects of electro-anesthesia on respiratory evaporative water loss . . . . . . 58 16. Effects of tranquilizer and electro- anesthesia on arterial pH . . . . . . . . . . . 59 17. Effects of tranquilizer and electro- anesthesia on arterial PCO2 . . . . . . . . . . 60 18. Effects of tranquilizer and electro- anesthesia on arterial bicarbonate . . . . . . 61 19. Effects of tranquilizer and electro- anesthesia on alveolar ventilation . . . . . . 62 20. Effects of tranquilizer and electro- anesthesia on tidal volume . . . . . . . . . . 63 21. Effects of tranquilizer and electro- anesthesia on blood pressure . . . . . . . . . 64 22. Effects of electro-anesthesia on blood pressure 0 O O I O O O I O 0 O O C O O O O 0 0 65 23. .Effects of tranquilizer and electro— anesthesia on heart rate . . . . . . . . . . . 66 24. Effects of electro-anesthesia on heart rate O O O O O O O O O O O O O O O O O 0 O 0 O 67 25. Effects of tranquilizer and electro- . 68 anesthesia on arterial hematocrit . . . . . vi INTRODUCTION The application of trans-cranial electrical currents of various voltages and frequencies for the production of general anesthesia has been designated as "electrical anes- thesia" or "electro-anesthesia." The impetus for research into electro-anesthesia is related to the advantages it affords over conventional chemical anesthetics. Electrical anesthesia has provided an efficacious technique for obtain- ing nearly instantaneous induction, reliable control and rapid recovery from anesthesia with few post-anesthetic complications. Nevertheless, like chemical anesthetics, electro-anesthesia is not without untoward physiological side effects. These include hyperthermia, hypertension tachycardia and muscle Spasms. In order to ameliorate some of these effects and also to reduce electrical current re- quirements, concurrent drug therapy has been used. In ruminants phenothiazine tranquilizers have been recommended as preanesthetic medications, but no studies have been undertaken to detach explicitly those physiolog- ical abberations associated with electro-anesthesia from those attributable to drug treatment. This study describes some thermoregulatory and cardiorespiratory responses of sheep, acutely exposed to a range of environmental temperatures, when electrical anesthesia and a phenothizaine tranquilizer were adminis- tered independently and in combination. LITERATURE REVIEW Homeotherms are animals which utilize many physio— logical systems to maintain their deep body temperature within narrow limits. Mechanisms of thermoregulation in homeotherms have been widely reviewed (Hardy, 1961: von Euler, 1961; Hammel, 1968). There have also been extensive reviews on both electro-anesthesia (Stephen, 1959; Smith g; 11., 1967; Herin, 1968) and substituted phenothiazine tranquilizers (Dundee, 1954: Dobbin gt g1,, 1956; Lear, 1966). However, a brief historical background of these treatments is presented below. Historical Review of Electro—Anesthesia The studies of French professor Leduc (1902, 1903) and those with his associate (Rouxeau (1903a, 1903b, 1903c) were the first extensive investigations into the use of electrical currents solely for the purpose of anesthesia. They produced sleep-like states in dogs and rabbits by means of interrupted direct current. The current was dispensed through electrodes positioned on the back of the head (cathode) and over the kidney (anode). A wheel interrupter was used to produce a frequency of 100 to 200 cycles per second with a pulse duration of l millisecond. A potential of 0 to 80 volts was supplied by large capacity storage batteries. Anesthesia was obtained with a frequency of 100 cycles per second and current intensities of 2 and 10 milli- amperes in the rabbit and dog, respectively. A sudden high amperage input followed by a transient decrease in current intensity was utilized to induce anesthesia. The success attained in animal experiments, encouraged Leduc to attempt electro—anesthesia on himself. The experience was described as a "nightmare state" duringwhich he noted a sensation of numbness, dimming of vision and loss of motor function. The studies of Leduc and Rouxeau resulted in a reproducible technique for electrical anesthesia and served as a stimulus for further investigations in the succeeding years. Robinovitch (1906), a student of Leduc's, success— fully obtained deep anesthesia in rabbits by use of an interrupted direct current similar to Leduc's. A few years later, Robinovitch (1914) wrote a chapter in Gwathmey's textbook Apesthesia relating a detailed description for the successful application of electro-anesthesia to humans. Even though Leduc maintained that electro-anesthesia could be produced only by pulsatile direct current, van Harreveld and Kok (1934) successfully obtained anesthesia using 60 cycle per second, sinusoidal wave alternating current (300 milliamperes) delivered to dogs via bitemporal electrodes. A few years later, van Harreveld and CO‘WOIKQIS (1942) compared the anesthetic prOperties of different cur— rent forms in the dog. The anesthetic potential of constant direct current was regarded as less than that of pulsed direct or alternating currents. Frostig and colleagues (1944) studied the effect of 60 cycle per second alternating current in dogs and humans. They described two types of electro-anesthesia in the dog: a narcotic type which resembled sleep, with slow deep breath- ing and bradycardia; a kinetic type characterized by general restlessness with accelerated respiratory and heart rates. Knutson (1954) induced electro-anesthesia in 25 dogs for periods as long as 3 hours with a sinusoidal wave alter— nating current of 700 to 1500 cycles per second (25 to 80 milliamperes) applied through bitemporal electrodes. Knutson and coaworkers (1956) administered the same current form to human subjects, but were unable to obtain successful anesthesia because of cardiovascular complications. Anan'ev and co-workers (1957) used a rectangular wave alternating current at a frequency of 100 cycles per second (pulse duration of l to 1.4 milliseconds) applied in combination with a direct current component. They reported a total average current (A.C. plus D.C.) of 7 to 10 milli- amperes was sufficient for general anesthesia in dogs, but higher current intensities facilitated muscle relaxation. The current was applied through electrodes positioned directly over the eye and on the mastoid region, over the occiput. .Smith_;§__l. (1961), using a modification of Anan'ev's technique, successfully induced anesthesia in 200 dogs, 6 monkeys, and l chimpanzee. Hardy and colleagues (1961) used 700 cycle per second alternating current to obtain anesthesia in dogs for periods as long as 8 hours. Histological examination of the brains of these animals revealed no gross microsc0pic injury. Herin (1964) was the first to use bitemporally positioned hypodermic needle electrodes to administer 700 cycle per second alternating current to dogs. Encephalographic pat- terns recorded from 20 animals immediately before and after electro-anesthesia were not noticeably different. Short (1965b) also employed subcutaneously placed hypodermic needles to deliver 700 cycle per second current (20-85 milli— amperes) to over 100 animals including cattle, horses, sheep and pigs. Basically, two types of anesthesia-producing current forms have develOped, 700 to 1500 cycle per second alternat- ing currents and 100 cycle per second pulsatile direct cur- rent. .Each appears to have selective advantages over the other. Alternating current allows the use of hypodermic needle electrodes with negligible tissue damage or burning and minimal electrode iontOphoresis. Advocates of direct current claim a more flexible current in meeting the anes- thetic requirements of the animal as well as a smoother induction phase. Basically, however, the anesthesia and concurrent side effects (hyperthermia, hypertension, somatic muscle hypertonicity) are qualitatively similar. Historical Review of Phenothiazine Trangyilizers According to a historical deve10pment of the pheno- thiazine tranquilizers by Lear (1966), the phenothiazine molecule was first synthesized by Bernthsen in 1883. A historical review by Jarvik (1967) relates that it was nearly 50 years later before phenothiazine was first used as an anthelmintic, urinary antiseptic and insecticide. In 1940, phenothiazine and some of its newly synthesized deriv- atives were tested for other pharmacological properties by French investigators (Lear, 1966). These investigators observed that substituted phenothiazines had potent antihistaminic prOperties and produced transient feelings of annihilation and lethargy. Laborit (1951) was the first to introduce promethazine as a potentiator of anesthesia. Dundee (1954) relates that in 1950 M. P. Charpentier syn- thesized chlorpromazine, a compound structurally resembling promethazine but with a more pronounced central depressant action. Laborit and co‘workers (1952) reported that chlor- promazine also facilitated aneSthesia and was capable of producing "artificial hibernation" without loss of con- sciousness. Courvoisier and colleagues (1953) conducted the first comprehensive investigations on chlorpromazine. They i ._ h _' ~— ‘h-‘JU- I “1v— . - ..;_ V ,_ ,. w _ (— ’h- . . .‘t H-‘-_’ ‘. _.- l .V —- 7—“- ‘ reported that chlorpromazine had a definite depressant action upon the central and autonomic nervous systems, enhanced effects of barbiturates and narcotics, depressed the hypothalamic thermoregulatory centers and the medullary chemoreceptor trigger zone and demonstrated some antifibril— latory and antishock potential. Currently, chlorpromazine and numerous closely related derivatives are employed clin- ically in human and veterinary medicine as preanesthetics, tranquilizers and antiemetics. Cardiorespiratory and Biothermal Effects of Electro-Anesthesia Cardiovasculature Most cardiovascular abberations during electro- anesthesia have occurred during initial current application. Ivy and Barry (1932) observed that a rapid, high amperage induction produced transient bradycardia and hypotension. This was attributed to stimulation of the medullary cardio- inhibitory center. Subsequent current reduction resulted in tachycardia and an elevation in blood pressure which was ascribed to stimulation of the vasoconstrictor center. Vagotomy or atr0pine, together with rapid induction, dimin- ish the bradycardia and hypotension concurrent with the rapid induction technique (Frostig §t_§1,, 1944). Neverthe- less, several other investigators using a sudden induction procedure have-reported only hypertension and tachycardia (Knutson, 1954; Hardy §§_§l,, 1961: Herin, 1963a; Photiades _£__1,, 1963; Price and Dornette, 1963). Herin (1969) found that heart rate may be depressed during induction if the time-course of current application is too rapid. The hyper— tension associated with "crash" induction has been prevented by adenergic blocking agents (Cameron and McIntyre, 1963). Hardy §£_§1, (1961) attributed the hypertension to general stimulation of the sympathetic nervous system, since it was not observed in sympathectomized dogs. In contrast, studies utilizing a gradual induction technique have shown that blood pressure may either increase or decrease during induc- tion (Anan'ev §E_§1,, 1961; Smith, 1964). When anesthetizing currents are adjusted to mainte- nance levels, cardiac and blood pressure responses are variable. Increased systemic arterial blood pressure, bradycardia, and decreased cardiac output have been reported in electro-anesthetized dogs (Elkin and Vasko, 1966), but tachycardia and hypertension have been a more common observa- tion (Knutson, 1954; Knutson et al,, 1956: Hardy et_§1,, 1961; Price and Dornett, 1963). Herin (1968) studied electro-anesthesia in dogs produced by various current wave forms and found an increase in pulse rate and blood pressure with all current forms tested. Massion and Downs (1969) examined peripheral hemo- dynamics in an isolated forelimb preparation which was perfused with blood from a dog under electro-anesthesia. The vasoconstriction observed in the isolated limb was 10 attributed to catecholamine liberation in the intact anes- thetized animal. In contrast, cross circulation studies with rabbits showed elevated arterial blood pressure only t al., in the animals under electro-anesthesia (Volpitto 1962). Nevertheless, elevated plasma catecholamimes have been reported and postulated to be a contributing factor to the hypertension observed in electro—anesthetized dogs (Hardy §§_§1,, 1961). Wood and c04workers (1964) found hypertension was abated with the placement of electrodes in certain locations (e.g., roof of the mouth and vertex of skull). The cardiovascular responses were probably dampened in that all dogs were premedicated with pentobarbital. Some cardiac arrhythmias have also been associated with electro- l., 1944; Knutson, 1954; Hardy gt_ 1. anesthesia (Frostig gt. t al., 1962). 1961; Volpitto In dogs under electro-anesthesia Frostig and col- leagues (1944) found that red blood cell counts were in- creased apparently due to Splenic contraction. The studies of Martin (1966) showed that the hematocrit increased as current intensity increased. The hematocrit of splenecto- mized dogs did not increase under 700 cycle per second anesthesia (Powers and Wood, 1964). Herin (1968) showed an elevated hematocrit in dogs only with certain wave forms. 11 W Ventilatory responses to electro—anesthesia have not been extensively studied although changes in respiratory frequency have been used to gauge the rapidity of current application during induction and to evaluate anesthetic depth (Wulfsohn and McBride, 1966; Smith, 1963; Ramo Rao, 1966). Some investigators have reported increases in respi- ratory frequency during electro-anesthesia (Geddes, 1964: Himes, 1965), whereas Smith and co-workers (1964) reported a decrease in respiratory frequency, a small decrease in respiratory minute volume, and a doubling of tidal volume from preanesthetic measurements. In addition, arterial hemoglobin saturation remained above 9T% and arterial PCO2 rose significantly. On the other hand, a small decrease in arterial PCOZ' with a slightly depressed respiratory fre- quency, was reported in dogs anesthetized with 700 cycle per second sine wave current (Herin, 1968). In squirrel monkeys, arterial PCO2 increased and P02 decreased under electrical anesthesia (Larson and Sances, 1968). Data reported by Shaikh and colleagues (1968) sug— gested hyperthermic polypnea was inhibited during electro- anesthesia in sheep premedicated with a substituted pheno- thiazine tranquilizer (prOpiopromazine). A marked metabolic acidosis has been reported in dogs under electrical anesthesia even though PC02 was reduced due to mild hyperventilation by a mechanical respi— rator (Hardy e£_§l,, 1961). Similarly, Herin (1968) found 12 a mild acidosis, a decreased arterial PCO2 and decreased arterial bicarbonate concentration in electro-anesthetized dogs with unassisted respiration. Nevertheless, Cutherbert— son e£_§l, (1965), showed that central (carbon dioxide) and peripherally medicated central (cyanide) respiratory reflexes in dogs were unaffected by electrical anesthesia. Temperature Regulation An elevation in the deep body temperature of dogs during electro—anesthesia has been reported by numerous investigators (Anan'ev et a1,, 1957; Smith §t_g1,, 1961; Geddes, 1964: Herin, 1964: McIntyre and Voloshin, 1964: Cuthbertson §£_§l,, 1965). The hyperthermia has been pos- tulated to result from a temporary derangement of the hypo- thalamic temperature regulating center and increased somatic muscle activity during electro-anesthesia (Smith _tflgl., 1961; Herin, 1969). In order to reduce current—induced muscle spasms, Herin (1964) administered a muscle relaxant (gallamine) to intubated dogs. However, 8 of 10 animals still had elevated colonic temperatures of 2 to 3°C. at the conclusion of electro—anesthesia. Gowing (1964), observed that intubated dogs, premedicated with gallamine and an anesthetic dose of a barbiturate, did not become hyperthermic under electro-anesthesia if respiratory rate was artificially increased above the spontaneous rate. Cuthbertson _§__l. (1965) associated the hyperthermia of electro-anesthesia to room temperature. Since elevations in deep body temperature 13 to 43.50C. were observed in intubated dogs in I'hot" weather but not at "cool“ ambient temperatures, or when animals were paralyzed with succinyl choline. Intubation alone, result- ing in limited respiratory evaporative cooling, has been suggested as a contributing factor to the hyperthermia associated with electrical anesthesia (Smith, 1964). Changes in deep body temperature have also been reported during electro-anesthesia in animals other than the dog. In sheep and cows pretreated with a phenothiazine tran— quilizer (prOpiOpromazine) Short (1964) found increases in deep body temperature of less than 10F. in cows and 2 to 30F. in sheep. Shiakh and associates (1968) examined some thermo- regulatory changes during electro-anesthesia in sheep acutely exposed to a range of ambient temperatures. They reported significant increases in colonic temperatures of animals exposed to environmental temperatures of 18 to 23°C. and 27 to 29°C. The hyperthermia was attributed to inhibi- tion of panting and increased somatic muscle tone. Their animals were also pretreated with prOpiOpromazine prior to anesthesia. There have been only a few studies on the effects of electro-anesthesia on peripheral skin temperatures. Cuth- bertson and colleagues (1965), reported increases in paw skin temperatures of some animals, whereas others exhibited no change during electro—anesthesia. On the other hand, Wood §E_§l, (1964) found reduced peripheral skin temperatures 14 in dogs given an anesthetic dose of pentobarbital and treated with anesthetizing currents. Oxygen consumption (V02) measurements as an index to whole body metabolic rate or as an indirect assessment of the heat production attendant to increased somatic muscle tone during electro-anesthesia have received little atten- tion. McIntyre and Voloshin (1964) reported increases in V62 of 20 to 100%.in electro-anesthetized dogs over that for dogs under thiOpentone anesthesia. .Estimates of respiratory evaporative water loss as a measure of heat loss during electro-anesthesia are totally lacking: the effects of electro-anesthesia on whole body temperature regulation are also unclear. No experiments have been conducted at controlled ambient temperatures with coincident evaluation of the biothermal (thermoregulatory) effects of concurrent drug therapy. Cardiorespiratory and Biothermal Effects of Phenothiazine Tranquilizers Chlorpromazine is generally considered the prototype phenothiazine tranquilizer and therefore has been more exten- sively studied than related substituted phenothiazines. It is tacitly assumed that the basic pharmacology of chlorproma- zine is qualitatively similar to that of prOpiOpromazine. 15 Cardiovasculature Chlorpromazine has been reported to act directly on the heart and vasculature and indirectly through the central and autonomic nervous systems (Jarvik, 1967). In dogs, chlorpromazine-induced hypotension has been associated with a depression of centrally mediated pressor reflexes, as well as, a direct vasodilator action on peripheral vessels (Moyer .;E._l., 1954). Courvoisier and CO‘WOIkerS (1953) found that chlorpromazine inhibited epinephrine-induced vasoconstric- tion in proportion to the dosage given. Chlorpromazine has also been reported to have a negative inotrOpic effect on cardiac muscle (Finkelstein et_§1,, 1954: Courvoisier t al,, 1953) and to decrease cardiac irritability (Melville, 1954). Respiration Studies on the respiratory reSponses to substituted phenothiazine administration are sparse and frequently con— flicting. In dogs, anesthetized with pentobarbital Kissel and Yelnosky (1968) found no effect of chlorpromazine (0.2 to 4.0 mg/kg) on C0 -stimulated reSpiration. Others have 2 reported a therapeutic dose of chlorpromazine to have a respiratory stimulant action (LabOrit, 1950; Reckless, 1954). Rabbits anesthetized with urethane exhibited a 20 to 40% increase in respiratory minute volume following 0.05-2 mg/kg chlorpromazine medication (Courvoisier t al., 1953). On the other hand, Lear (1959) found triflupromazine (20 mg) given intravenously to humans produced a 23% decrease in 16 tidal volume. Similarly, Dobkins and co-workers (1956) reported that chlorpromazine (0.3-2 mg/kg) depressed both tidal volume and minute volume. Higgins gt a1, (1964) noted that panting appeared to be less pronounced in prOpiOpromazine treated dogs (2.2 mg/kg) during heat stress (37.80C.) than in untreated animals. Similarly, Shiakh and colleagues (1968) observed a reduction in respiratory frequency following propiopromazine (1.1 mg/kg) treatment in sheep during exposure to various ambient temper— atures. The initiation of panting in chlorpromazine treated (3 mg/kg) pigs was slower than non-treated animals during whole body heat eXposure (Juszkiewicz and Jones, 1961). Temperature Regulation Many studies have examined the biothermal conse- quences of substituted phenothiazine treatment in animals. The hypothermic-producing capacity of these compounds is well documented (Courvoisier §£_gl,, 1953; Dundee t al., 1953: Ripstein §£_gl,,.l954; Higgins _EH_L., 1964). During whole body cold eXposure, peripheral vasodilation has been implicated as one avenue of increased heat loss in chlor- promazine treated animals (Decourt 23.21:: 1953; Giaja, 1953; Kollias and Bullard, 1964). Courvoisier _£__l, (1953) postulated that a de- pressed metabolic rate (e.g., V02) during tranquilizer medication contributed to whole body cooling. However, others suggested that metabolic depression was a secondary 17 effect of hypothermia (Giaja and Markovic-Giaja, 1954). The results of Kollias and Bullard (1964) in rats, suggested a direct relationship between V02 depression and the dosage of chlorpromazine given. At an ambient temperature of 230C., the administration of a very high dose of chlorpromazine (25 mg/kg) decreased V02 coincident with an increased tem— perature and blood flow in the tail; shivering and piloerec- tion were also diminished. With a lower dose of chlorproma- zine (6.25 mg/kg), the rate of cooling was approximately half that of the higher level. In addition, shivering was not inhibited nor V02 depressed with low-dose treatment. Chlorpromazine has been reported to facilitate muscle relax— ation by a selective depression of the gamma efferent system, which may diminish shivering thermogenesis during cold exposure (Henatsch and Ingrar, 1956). At ambient temperatures above the thermoneutral zone, the biothermal responses to phenothiazine compounds are equivocal. Decourt §£_g1.(1953) reported a relative hypo- thermia in numerous different homeotherms given chlorprom- azine at environmental temperatures greater than their internal body temperature. Although chlorpromazine has been demonstrated to increase survival rate in pigs exposed to ambient temperatures of 40°C. (Juszkiewicz and Jones, 1961) others have reported that chlorpromazine-treated animals become hyperthermic and survival rate is decreased (Binet and Decaud, 1954: Kollias and Bullard, 1964). METHODS AND MATERIALS Thermoregulatory and cardiorespiratory effects of propiOpromazine and electrical anesthesia administered simultaneously and independently were evaluated in a series of experiments conducted during the interim of April 1, to November 22, 1969. For this study, care was taken to use a well-defined experimental subject, tested under controlled environmental exposure conditions. Animals. Three non-pregnant, 2 year old purebred Dorset ewes (59 to 65 kg. body weight) were used in this study. Five months prior to the start of the experiments, the left com- mon carotid artery of each animal was surgically exterior- ized and sutured within a skin tube (Bone _E__l., 1963). To insure uniform insulatory prOperties of wool, the sheep were closely shorn (less than 0.3 cm. of fleece remained) at weekly intervals. The animals were housed in individual pens (4 x 8 feet) in a building maintained at a temperature Of 170C. to 30°C. Each animal was fed a balanced ration of approximately 1500 kcal/day with water provided ag_libitgm. The animals were subjected to a training regime in a re— straining device prior to the start of the trials (Figure l). 18 l9 Restraining Device During the environmental chamber exposure the sheep were confined in a restraining device (22 x 42 x 56 inches) constructed of slotted angle steel (RS, Figure l). The animals were supported by 2 plastic—coated canvas slings (SL, Figure 1) attached by ropes to a pulley system. During all trials, the animals were suspended so that their feet were just elevated off the floor of the restraining device in order to simulate the conditions of those trials where electro-anesthesia was used. Environmental Chamber All trials were conducted in an environmental cham- ber (3.5 x 5.5 x 7 feet) with an effective controlled temper- ature range of 50C. to 500C. :_1OC. A thermistor temperature controller (Yellowsprings Instrument Co., Model 71) regulated the pumping of either a heated or cooled liquid through two convective heat exchangers which were located in front of fans inside the chamber (Figure 1). Relative humidity of the chamber was controlled by a humidity controller (Hydrodynamic Inc., Model 15-3205) which regulated the cycling of chamber air through a humidifier (Kenmore, Model No. 758-72912) or dehumidifier (ColdSpot, Model No. 106-637140). Major temperature differences within the chamber were minimized by an 8 inch oscillating fan. 20 Two sliding plexiglass windows (26 x 36 inches) on both sides of the chamber allowed access to the animals during the experiments. Temperature Measurements Rectal and 7 skin temperature measurements were obtained using c0pper-constantan thermocouples (36 s.w.g.) referenced to an ice bath and calibrated daily to the near- est 0.l°C. against a National Bureau of Standards thermom- eter. An automatic stepping relay allowed temperatures to be sequentially monitored on one channel of an adjustable range, adjustable zero strip chart recorder (Mosley, Model 7100B). Rectal temperature (Tre) was measured with a ther— mocouple fixed within a semi-rigid polethylene catheter and inserted 10 cm. into the lower colon. Skin temperatures were measured as follows: a. Ear temperature (Te) was monitored from a thermo- couple taped to the dorsal side and approximate center of each ear. The mean skin temperature of the two ears was used in statistical analysis. b. Face skin temperature (Tf) was measured from a ther- mocouple taped to the dorsal midline, approximately 5 cm. anterior to the eyes. Forelimb skin temperatures were measured at 3 sites on the lateral surface of the right leg. The ther- mocouples were secured by a 1 cm.2 piece of nylon 21 screening attached to an elastic band which encir- cled the extremity. Lower forelimb skin temperature (T11) was measured immediately distal to the pastern joint and mid-forelimb skin temperature (Tml) was measured midway between the pastern and knee joints. Upper forelimb skin temperature (Tul) was monitored from approximately 5 cm. proximal to the knee joint. d. Trunk skin temperature (Tt) was measured with a thermocouple taped to the animal's left side, approximately 10 cm. lateral to the spinal column and 10 cm. posterior to the scapula. Oxygen Consumption Oxygen consumption (V02) was obtained by an Open circuit technique. Air was drawn at a rate of 50 l/min through a cylindrical hood (15 inches diameter, 24 inches long), placed over the head of the animal (HD, Figure 1). V02 (STPD) was determined using an oxygen analyzer (Oxford Instrument Co.) which compared the partial pressure of oxygen in expired air with that of chamber air. Respiratory-Evaporative Water Loss VRespiratory evaporative water loss (E) was estimated with a relative humidity transducer (Hydrodynamics, Model NO. 15-7012) by comparing the relative humidity of air entering and leaving the hood. A vacuum pump withdrew air 22 samples at the rate of 2.5 1/min. from the air flow system serving the oxygen analyzer: a reference air sample was drawn from within the chamber at an equal rate. Electrical potentials of 0 to 5.4 volts output (corresponding to 0 to 100% relative humidity) were metered on an adjustable range, adjustable zero strip chart recorder (Mosley, Model No. 7100B). Water evaporation was computed by: s (rho - rhi) v (1) II QHOH expressed as: QHOH = water loss (gm./m1n) S = grams of water in one liter of saturated air a ir (gm/1) rhO = relative humidity of chamber air (%) rh. = relative humidity of sample air (%) 1 V = air flow (l/min.). Heat of vaporization was calculated from the formula described by Kleiber (1961): A = (QHOH) (Kl - KZTre) (2) expressed as: heat of vaporization (kcal./min) A: QHOH = water loss (gm./m1n) K1 = 0.5959 latent heat of vaporization at 00C. (kcal/gm.H20) 23 K = 0.56 x 10"3 correction constant for temper- ature (kcal/gm.H20 OC.) '3 II re rectal temperature in oC. Respiratory Frequency Respiratory rate was measured with a mercury-in- rubber strain gauge matched to a plethysmograph (Parks Electronics, Model No. 270) and monitored on one channel of a strip chart recorder (Mosley, Model No. 7100B). The strain gauge was attached to an elastic band which encircled the abdominal area offering maximal respiratory movement. Blood Pressure and Heart Rate Arterial blood pressure was measured by a catheter (.034 inch i.d.) inserted into the carotid 100p (via 20 g. needle) and connected to a 4-way manifold valve, which served as a junction to a pressure transducer (Statham, Model No. P23A), an infusion pump (Harvard Apparatus Co., Model No. 1100) that flushed the catheter with heparinized saline (2 cc/hr.) and a blood sampling site. The blood pressure tracing was recorded with suitable amplification (Grass Preamplifier, Model No. SPIK) on one channel of an adjustable range, adjustable zero strip chart recorder (Mosley, Model No. 7100B). Heart rate was obtained from the pressure pulse trace. 24 Arterial pH, Carbon Dioxide Tension and Bicarbonate Concentration Arterial blood samples were collected anaerobically from the carotid 100p catheter via the manifold st0pc0ck. The samples were drawn into 5 cc. syringes (dead space filled with Na heparin; 1000 units/cc) immediately sealed with mercury-filled syringe caps and stored in ice water until the end of the experiment (4 hours). Arterial pH, PCO2 and HCOE concentration were determined by the Astrup technique using the nomogram (Radiometer, Code No. 984-200) deve10ped by Siggaard-Andersen (1962). Anaerobic pH mea- surements were made using a miCro-electrode chain attached to a Radiometer pH meter (Radiometer Co., Model 27). .Equi- libration of blood samples at known PCOZ'S was accomplished using a Radiometer microtonometer (Radiometer C0. Model AMT-1). The micro-electrode chain and microtonometer were thermostatted to the animal's rectal temperature. Alveolar Ventilation and Tidal Volume Alveolar ventilation (VA) Was computed (Rahn and Fenn, 1955) by assuming alveolar carbon dioxide tension (PACOZ) equal to arterial carbon dioxide tension (Pacoz), as: T o 2 V =0.760 -—r—e~ (3) A 273 Paco 25 where: VA = alveolar ventilation (l BTPS/min) Tre = rectal temperature (9K) V02 = oxygen consumption (ml STPD/min) P = arterial carbon dioxide tension (mm.Hg.) aC02 Tidal volume (VT) was estimated by assuming a dead space (VD) of 150 m1 (Hales and Webster, 1966), according to the formula: V = VA + VDf (4) T f where: VT = tidal volume (ml BTPS) VA = alveolar ventilation (ml BTPS/min) VD = dead space (m1 BTPS) f = respiratory frequency (breaths/min). Electrical Anesthesia A commercially available unit (Electronic Medical Instrument.Co., Model No. lOO-A) connected to an external oscillator (Hewlett Packard, Model No. 200AB) was used to produce electro-anesthesia. Bitemporal electrodes (18 gauge, 1.5 inch syringe needles) were inserted through the skin approximately 0.5 inches posterior to the base of the horns, immediately below the parietal crest, behind the coronoid process and deep enough ventrally to be in form contact with the skull. A local anesthetic (2% Lidocaine) was applied 26 to the electrode placement area prior to needle insertion. The electrodes were secured in place with adhesive tape. Electro-anesthesia was induced by presetting the oscillator at 700 cycles/second and gradually increasing the milli- amperage from 0 to between 20 to 30 milliamperes. Generally, 2 to 5 minutes were required before satisfactory anesthetic depth was reached which was evaluated by the strength of a nociceptor reflex initiated by pinching or pricking the distal forelimb. The level of anesthesia was maintained by occasional adjustment of the current strength and frequency. Experimental Procedures A total of 60 trials were conducted at three ambient temperatures, 5°C., 25°C., and 350C. Chamber relative humid- ity was controlled at 40% i_5% for trials at 25°C. and 35°C. The limited cooling capacity of the chamber prevented main— tenance of this humidity at the 50C. experiments. Relative humidity for the 50C. tests was maintained at 20% i 5%. All tests lasted for 330 minutes or until Tre reached 41.80C. Preliminary trials indicated that an approximate thermal "steady state" was achieved after a 90 minute chamber expo— sure at each ambient temperature. At each exposure temperature, the animal was sub- jected to one of the following four eXperimental treatments: 3° £2£££21_9£ untreated trials: The animals were given a 1.5 cc intramuscular saline injection at 90 minutes. 27 b. Tranquilization trials (TQ): Animals were given pr0piopromazine HCl (1.0 mg/kg) intramuscularly at 90 minutes. c. Tranquilization/Electro-Anesthesia trials (EA/TO): Animals were given pr0pi0promazine HCl (1.0 mg/kg) intramuscularly at 90 minutes followed by electro- anesthesia from 100 to 210 minutes. d. .Electro-Anesthesia trials (EA): Animals received only electro-anesthesia from 100 to 210 minutes° Tests on any sheep were separated by a minimum of 72 hours; no animal was in the same treatment group or at the same eXposure temperature for two consecutive tests. Replicate trials were conducted at each exposure temperature and treatment, with the exception of the electro-anesthesia group (without prior tranquilization). Only one of the three experimental animals could be successfully anesthe- tized without tranquilization which limited this group to a program of duplicate trials on only one sheep at each ambient temperature. Measurements of rectal temperature, 7 skin tempera- tures, blood pressure, heart rate, respiratory frequency and 602 were recorded at 10 minute intervals for the first and last 60 minutes of each trial and at 5 minute intervals during the intervening time period. Respiratory evaporative water loss was measured at 10 minute intervals throughout 28 the trial. Arterial blood samples were taken at 90, 150, 210, 240 and 300 minutes during each trial. Statistical Analyses Means, standard error of the means and statistical comparisons by Analysis of Variance with Student's t test (Appendix B) were computed on an Olivetti—Underwood Programma 101 computer. The T0 and EA/TQ treatment groups were statis- tically compared with the control group and with each other at corresponding time intervals. A within group statistical comparison was computed for the EA treatment group. Means for different time inter- vals or periods were compared to pretreatment (90 minute) means. Means that showed a probability of error of less than 5% (p<:0.05) were considered statistically different for all temperature, V V P A, T, aCOz’ hematocrit values. All other parameters (V02, f, E, blood pH, HCO§ and arterial pressure and heart rate) whose measurement error was greater than the above, were considered statistically different if the probability of error was less than T% (p<10.01). RESULTS Rectal and skin temperatures in any experimental group were not different when animals entered the chamber indicating the animals were housed at sufficiently uniform ambient temperatures to achieve similar initial "thermal states" for all trials (Tables 1-9). Additionally, all measured parameters reported for the tranquilized (T0) and electro-anesthetized-tranquilized (EA/TO) treatment groups during the “pretreatment" period (i.e., 90 minutes or 60 to 90 minutes) were not different from corresponding measure- ments for the control animals under the same exposure condi- tions. The electro-anesthesia (EA) treatment group was not statistically compared with control, T0 or EA/TQ groups at any time interval during the test period due to the unrepre- sentative composition and limited sample number comprising this group. Rectal Temperatures Mean rectal temperatures (Tre) for all groups are presented in Tables 1-3, and are plotted as a function of time in Figures 2-4. At 5°C. ambient temperature, Tre of the tranquilized animals was reduced from that of the con- trol group one hour after propiOpromazine medication. Deep 29 30 body temperature in this group did not show any additional alteration for the duration of the experiment. In the EA/TQ group, Tre was less than the control animals at the end of anesthesia (210 minutes) and throughout the "recovery" period. Although mean Tre of the EA/TQ group appeared to be lower than that of the TO sheep, the difference was not sig- nificant. The EA treatment group showed no difference in mean Tre at any time interval from the pretreatment (90 minute) Tre‘ At the 250C. eXposure temperature, mean Tre of the TO animals was lower than that of the control group at 210 minutes but not different from their own pretreatment Tre at this time interval. Mean Tre in the EA/TQ group was not different from corresponding control measurements during or after anesthesia. The T0 and EA/TQ animals at the 350C. ambient tem- perature both exhibited a significant elevation in mean Tre over that of the control animals at 150, 210 and 240 minutes. The Tre of the T0 group continued to rise for 170 minutes after drug medication. The EA/TQ animals showed an even more rapid rate of rise in Tre than did the T0 group. At the end of electro-anesthesia, Tre of the EA/TQ animals was greater than that of the TO group. ,Moreover, Tre of the EA/TQ animals continued to rise after the end of anesthesia forcing the termination of one trial at 260 minutes and two additional trials at 290 minutes. Although the EA treatment 31 group also exhibited a mean increase in Tre of 1.50C. during anesthesia, it was not statistically different from the mean "pretreatment" (90 minute) Tre' Ear Skin Temperatures Mean ear skin temperatures (Te) for each exposure temperature and experimental group are presented in Table 4. Mean Te for the TO group during the 50C. exposure ranged from 1.6 to 4.80C. higher than control group Te' However, Te's of the T0 group were different from the control animals only at one hour post-tranquilization. The EA/TQ animals Te's were 4.6 to 7.6OC. higher than untreated animals with statistical differences noted at both time intervals during the "recovery" period (240 and 300 minutes). The Te's for the EA/TQ group were not significantly higher than the TO group. Mean Te for the EA treatment group (Ta = 50C.) was not different from pretreatment measurements. At the 250C. exposure temperature, mean Te's of the TO and EA/TQ treatment groups were elevated over that of control animals at all post-treatment time intervals. The EA/TQ group had a higher mean Te than TQ animals at time intervals of 150, 240 and 300 minutes. The EA treatment group (Ta==250C.) also had an increased Te from pretreatment values during electro-anesthesia, but not during the “recov- ery" period. 32 No differences in Te were found in T0 animals at 350C. Ta from control animals whereas, the EA/TQ group demonstrated a higher Te than control animals only at 300 minutes. .Even though mean Te of the EA group increased progressively during anesthesia and the "recovery" period, it was not significantly different from pretreatment measurements. Face Skin Temperatures Mean face skin temperatures (T for each treatment f) group and exposure temperature are presented according to time intervals in Table 5. At the 50C. Ta’ mean Tf of the T0 group was higher than that of control animals during the first and second hour post-medication, but not at subsequent time periods. The EA/TQ animals exhibited an increased Tf from both control and the T0 group, during and following electro-anesthesia. The EA group (without prior pr0p10pro- mazine treatment) had a higher Tf than pretreatment (90 minute) values only at the end of anesthesia (210 minutes). At ambient eXposure temperatures of 250C. and 35°C., both the T0 and EA/TQ animals had Tf only slightly higher than control animals. The Tf of the EA group was not mea— sured at the 25 and 350C. ambient temperatures. 33 Forelimb Skin Temperatures Mean forelimb skin temperatures (T11, Tml’ Tul) for each environmental temperature and treatment group are in reference to test time intervals in Tables 6—8. At the Ta of 5°C., mean T11, Tml and Tul for both TO and EA/TQ treat- ment groups were not different from corresponding control values. The EA treatment group exhibited a significantly lower Tul than the pretreatment (90 minute) mean during and after anesthesia whereas T11 and Tml were not different from pretreatment values. At the 250C. ambient temperature the T0 animals had a higher Tll than control animals at all time intervals following tranquilizer medication. Nevertheless, Tm1 and Tul were higher than control means only at 300 minutes. Similarly, the EA/TQ animals had higher Tll than the control group during anesthesia and the first half hour of the "recovery" period. However, Tml was elevated over control measurements only at the termination of anesthesia (210 minutes) ant Tul only at 300 minutes. The EA treatment group (Ta==250C.) demonstrated an increasein the T11 and Tm1 over pretreatment means at the end of anesthesia. The Tul was not different from pretreatment values during electro- anesthesia or the "recovery" period. The T0 animals at the 35°C. exposure temperature had a higher mean T and Tml than control animals at time inter- ll vals of 240 and 300 minutes, whereas Tul was significantly 34 greater only at 300 minutes. At this same exposure temper- ature, the EA/TQ treatment group exhibited an elevated Tll at the end of anesthesia (210 minutes) and a higher Tml than control animals during anestheSia and the "recovery" period. Mean Tul of the EA/TQ group was greater than control animals at 210, 240 and 300 minutes. However, Tables 6, 7 and 8 indicate that mean increases in forelimb skin temperatures for the EA/TQ group were not different from the T0 animals. Forelimb skin temperatures for the EA group (Ta =350C.) were not different from pretreatment means. Trunk Temperatures Mean trunk skin temperatures (Tt)’ at appropriate time intervals are reported for all treatment groups in Table 9. Mean Tt for T0 and EA/TQ treatment animals were not different from control animals or each other at any time interval or eXposure temperature. .Similarly, mean T of the t EA group was not significantly different at any time inter- val or exposure temperature from pretreatment (90 minute) me ans . Oxygen Consumption Mean oxygen consumption values (V02) for designated time periods are reported for each exposure temperature and treatment group in Tables 10 and 11. At the 5°C. ambient temperature, V02 for the To group was not different from 35 control animals during the first and second hour of medica- tion but was higher during the third hour. The EA/TQ group also exhibited a lower V02 during anesthesia than both con- trol and TO groups. Similarly, the EA group showed a reduc- tion in V02 during anesthesia from pretreatment measurements. At the 250C. environmental temperature, V02 for the TO animals was higher than that of control animals. The EA/TQ animals also exhibited an elevated V02 over control animals during the second 55 minutes of anesthesia and dur- ing the "recovery" period. The EA group (Ta==25°C.) in- creased VOZ during anesthesia and the "recovery“ period from pretreatment values. At 35°C. Ta, both the TO and EA/TQ groups had a lower V02 than control animals during the first hour of their respective treatments but not during the second hour. Also, both groups exhibited a significantly greater V02 than control animals during the "recovery" period. Oxygen con- sumption for the EA group was higher during anesthesia and the "recovery period than pretreatment values. RespiratoryfFrequency Respiratory frequency (f) means for different time periods, treatment groups and ambient temperatures are pre- sented in Tables 12 and 13. Although the T0 group exhibited no difference in f from control animals at the 50C. Ta’ the EA/TQ group had a lower f during anesthesia than either 36 control or T0 animals during the same time intervals. However, during the "recovery" period, f for EA/TQ and TO groups were not different from one another or control animals. The EA treatment animal (Ta: 50C.) demonstrated no significant change in f during anesthesia or the "recovery" period. At the 250C. exposure temperature, f for both TO and EA/TQ animals was lower than control animals for the duration of the eXperiment. However, f for the EA group was not dif- ferent from pretreatment values at any time interval. Changes in f for control, TQ and EA/TQ animals at the 350C. exposure temperature are plotted as a function of time in Figure 5. The f of T0 group was lower than that of control animals during both the first and second hour post- pr0p10promazine medication. The EA/TQ group exhibited a lower f than both control and TO animals during the electro- anesthesia period. However, neither the T0 nor EA/TQ groups had reSpiratory frequencies significantly different from control animals during the "recovery" period. Even though the EA animals had a higher f during anesthesia than the pretreatment period, respiratory rate more than doubled following the conclusion of anesthesia. 37 Respiratory Evpporative Water Loss Mean respiratory evaporative water loss (E) values at each environmental temperature for each treatment group at designated time intervals are reported in Tables 14 and 15. At 50C. both the TO and EA/TQ groups had a greater E than control animals at all time periods subsequent to their respective treatments. On the other hand, the EA group exhibited no difference in E during anesthesia from pre— treatment measurements. Although the E of the TO group was not different from control animals at the 250C. environmental temperature, the EA/TQ group had a reduced E during the first 55 minutes of anesthesia and an increased E during the "recovery" period compared to the control group. In contrast, the EA animal exhibited an increased E during anesthesia but not during the "recovery" period. At 350C. Ta’ E for the TO animal was reduced during the first hour of medication but not at subsequent time periods. The EA/TQ group had a lower E during anesthesia than both control and TO animals at corresponding time periods. However, during the "recovery" period E was not Significantly different from either control or T0 animals. In contrast, E for the EA group was increased during anes— thesia compared to the pretreatment period. 38 Arterial pH, FCC, and Eco; Mean arterial pH, PCO2 and HCOS determinations for each treatment group and exposure conditions are reported in Tables 16, 17 and 18, respectively. At the 50C. exposure, the TO treatment group exhibited no significant change in arterial pH, PCO2 or HCOE from control animals even though arterial PC02 of the TO animals increased progressively following pr0pi0promazine treatment. An increased arterial PCO2 and decreased pH was found in EA/TQ animals during and after anesthesia compared to the control animals. However, HCOE concentration in the EA/TQ group did not vary from the control group. The EA group exhibited a rise in pH only during the "recovery" period (300 minutes) whereas (Ta==50C.) PaC02 and HCOE were not different from pretreatment values at any time interval. During whole body exposure to the 250C. ambient temperature, the TO animals showed no difference in arterial pH. Pco2 and HCOS concentration from control animals. How— ever, the EA/TQ group at this exposure temperature exhibited an increase arterial PCO2 with no difference in arterial pH from control animals during anesthesia. By the end of the . ' t 1 "recovery" period, Paco2 values were approaching con ro measurements. Arterial HCOE concentration in the EA/TQ animals varied little from control measurements. Dur1ng ._ o anesthesia and the "recovery" period the EA group (Ta—'25 C.) ' ' om had no significant change 1n arterial PCOZ or pH fr 39 pretreatment values. Arterial bicarbonate concentration during and after anesthesia in the EA animal was not dif- ferent from pretreatment determinations. The T0 animal at the 350C. exposure, showed no difference in arterial pH, PCO2 or HCOE concentration from control animals. A significant increase in arterial Pco2 and decrease in arterial pH from control measurements was found in the EA/TQ treatment group (Ta==350C.) at the end of 55 minutes of anesthesia. However, arterial pH and PC02 was not different from control animals at the termination of anesthesia or during the "recovery" period. Also, arterial bicarbonate concentration in the EA/TQ animal was not differ- ent from control animals at any sampling interval. The EA animal at 35°C. Ta demonstrated no statistical difference in PaCO , HCOS concentration or pH during and after anesthesia 2 from pretreatment determinations. Alveolar Ventilation and Tidal Volume Mean values for alveolar ventilation (VA) and tidal volume (VT) are presented according to time intervals in Tables 19 and 20, respectively, for each treatment group and exposure temperature. At the 50C. Ta, the TO animals exhib- ited no mean differences in either VA or VT from control animals. However, during anesthesia the EA/TQ animals demonstrated a reduced VA from both the control and TO group. The EA animals exhibited no difference in VA or VT during anesthesia from pretreatment measurements. 40 The T0 animals at the 25°C. Ta' showed a significant increase in VT (210 and 300 minutes), whereas VA was not significantly different from control animals at any time interval. However, the EA/TQ and EA groups showed no change in either VA or VT from respective control measurements. At the 35°C. Ta, V for the TO and.EA/TQ group was A not different from control animals even thoughvT was in- creased in the TO animals at 150 minutes and during anes- thesia in the EA/TQ group. The EA animals showed no differ- ence in either VT or VA during anesthesia or the “recovery" period from pretreatment measurements. Arterial Blood Pressure and Heart Rate Mean arterial blood pressure and heart rate responses for each eXposure condition and treatment group are presented in Tables 21-24. With the Ta at 5°C., the TO group had a lower mean arterial blood pressure and higher heart rate than control animals following pr0pi0promazine medication. The EA/TQ animal also had a lower blood pressure than con— trol animals at all time periods, and lower blood pressure than the TO group during the second 55 minutes of anesthesia. Heart rate in the EA/TQ animal was higher than control animals during the second 55 minutes of anesthesia and higher than both control and TO groups during the "recovery“ period. In contrast, the EA animal has a higher arterial blood pressure during anesthesia than pretreatment values at 41 °c., 35°C.). all environmental temperatures (i.e., 5°C., 25 During the “recovery" period, blood pressure in the EA animal was higher than pretreatment measurements only at the 5°C. exposure. Heart rate-was accelerated over pretreatment means in the EA animals only during anesthesia at the 35°C. environmental temperature and during the "recovery“ period at the 5 and 350C. ambient temperatures. At the Ta of 25°C., both the TO and EA/TQ groups had a lower blood pressure than control animals during the time periods of 115-160 minutes and 165-210 minutes. Heart rate in the TO group was increased over control animals at all time periods following medication, whereas heart rate in the EA/TQ group was increased over control and T0 animals during the second 55 minutes of anesthesia and during the "recovery" period. With the 350C. environmental temperature, mean arterial blood pressure in the TO group was lower than control animals only during the first hour of medication. However, heart rate for the above group was faster than control animals at all time periods following treatment. Although blood pressure of the EA/TQ group was not different from either control or T0 animals at any time period, heart rate of this group was more rapid than control animals dur— ing the second 55 minutes of anesthesia, and faster than both control and TO groups during the "recovery" period. 42 Arterial Hematocrits Mean values for arterial hematocrits are recorded in Table 25, for each treatment group and exposure temperature at the time intervals corresponding to arterial blood sampling. The T0 group had no change in hematocrit from control animals at any exposure temperature. The EA/TQ animals showed a significant increase in hematocrit over control and TO animals at the 50C. Ta‘ Arterial hematocrit of the EA/TQ group was also higher than control animals at the 35°C. exposure. The hematocrits of the EA animal were not statistically different from the pretreatment determina- tions at any of the exposure temperatures. Shivering. At the cold exposure temperature (i.e., 50C.) pro- piopromazine treatment inhibited observable shivering for approximately 25 minutes after medication, whereas, shiver- ing in the EA/TQ animal was abated for an average of 50 minutes after treatment. The EA animal also showed no visible signs of shivering for an average of 25 minutes after initial current application. 43 Electroegpesthesia Observations The animals administered pr0p10promazine 10 minutes prior to electro-anesthesia (EA/TO group) generally showed a 20 mm” Hg increase in blood pressure during initial current application. This was followed by a gradual fall and stabi— lization in blood pressure once the current was adjusted to "maintenance" levels. When the anesthesia was terminated, no appreciable change was detected in mean arterial blood pressure. The EA animal required from 5 to 10 more milli- amperes of current to produce an anesthesia similar to that of the groups which received tranquilizer premedication. 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