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Xerox University Microfilms 300 North Zeeb Road Ann Arbor, Michigan 48106 75-3149 MUIR, D.V.M.» William Wallace, III, 1946- ARRHYTHMIAS— THEIR DETERMINANTS AND PREVENTION IN ASSOCIATION WITH THIOBARBITURATES AND HALOTHANE ANESTHESIA. The Ohio State University, Ph.D., 1974 Physiology

Xerox University MicrofilmsAnn , Arbor, Michigan 48106 (

THIS DISSERTATION HAS BEEN MICROFILMED EXACTLY AS RECEIVED. ' ARRHYTHMIAS - THEIR DETERMINANTS AND PREVENTION

j IN ASSOCIATION WITH THIOBARBITURATES AND HALOTHANE ANESTHESIA

DISSERTATION

Presented in Partial Fulfillment of the Requirements for ! the Degree Doctor of Philosophy in the Graduate School of The Ohio State University

William Wallace Muir III, B.S., D.V.M., M.S.

*****

The Ohio State University

1974

Reading Committee: Approved By Dr. Robert L. Hamlin Dr. Thomas E. Powers Dr. Roger A. Yeary Dr. Jean Hensel TCdvTser Department of Veterinary Physiology 5 Pharmacology acknowledgements

I am extremely grateful to Professor Robert L. llamlin for his untiring encouragement and support of this study. His constructive critisisms and interest in cardiac rhythm were of great help in the completion of this work. A special work of thanks to M s . Linda Werner for her skilled technical assistance throughout all phases of this study. Her organization and coordination of labora tory facilities were greatly appreciated. I thank Mr. Ron McClean for his aid in the arrange ment and completion of many of the figures. This thank you is extended to the entire photography area associated with the Ohio State University College of Veterinary Medicine. I am very grateful to the Department of Veterinary Physiology and Pharmacology for the financial support and especially to Drs. Jean Hensel and Thomas Powers for their analytical critisisms and suggestions. Sincere thanks are due Mrs. Ricki Bishop for the accuracy, high quality and speed with which she completed the typing of this text. I am indeed grateful to Mrs. Karen Rosenberry for her clinical support. Her assistance in the teaching and ii service areas of clinical veterinary anesthesia gave me added time to complete this work. Finally, I wish to acknowledge my wife Cheryl for her support and patience in the many hours spent studying and preparing this transcript. VITA

July 8, 1946 . . . Born, Bay City, Michigan

1968 ...... B.S., Michigan State University, East Lansing, Michigan

1968-1970...... Member of Open Heart Surgery Team Michigan State University, East Lansing, Michigan

1970-1974 ...... Teaching Associate, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio

1 9 7 1 ...... M.Sc., The Ohio State University, Columbus, Ohio

PUBLICATIONS Exploratory Measurements of Arterial Flow in Horses. Jon A. Rumberger, David R. Gross, William W. Muir, III, Gary L. Geiger, Robert M. Nerem and Robert L. Hamlin. October, 1972. J. Biomed. Eng.

Respiratory Fluctuations in Durations of Phases of Ven tricular Systole in the Dog. William M. Muir, D.V.M., M.Sc. and Robert L. Hamlin, D.V.M., Ph.D. May, 1973. J.A.V.M.R., 647-651. Right and Left Ventricular Systolic Intervals During Ventilation and Sinus Arrhythmia in the Dog: Genesis of Physiologic Spliting of the Second Heart Sound. Robert L. Hamlin, D.V.M., Ph.D., William W. Muir, III, D.V.M., M.Sc., David R. Gross, D.V.M., M.S., Frank S. Pipers, D.V.M., M.Sc., January, 1974, J.A.V.M.R., 6-13. FIELDS OF STUDY

Major - Veterinary Physiology and Pharmacology. Studies in Cardio-Pulmonary Physiology Robert L. Hamlin, D.V.M., Ph.D., Adviser

iv TABLE OF CONTENTS

Page

ACKNOWLEDGEMENTS i i VITA...... iv LIST OF TABLES...... vi LIST OF F I G U R E S ...... vii

INTRODUCTION...... • ...... 1 Chapter I. REVIEW OF LITERATURE ...... 5 Determinants of Arrhythmia Formation Thiobarbiturates and Arrhythmias Atropine and Arrhythmias Halothane and Arrhythmias Phenothiazines and Arrhythmias Experimental Models for Arrhythmia Production

II. MATERIALS AND METHODS...... 65 III. RESULTS...... 78 IV. DISCUSSION ...... 126 V. SUMMARY...... 145

BIBLIOGRAPHY...... 158

v LIST OP TABLES

Table Page 1. Techniques Used in the Production of Cardiac Arrhythmias...... 56

2. Mean Heart Alterations After the Initial Pressure Peak Due to the Administration of Epinephrine Intravenously ...... 110 3. Minimum Maximum and Mean Dose of Epinephrine (ugm) Needed to Produce a Dysrrythmia ...... Ill

4. Effect of Alterations in Mean Arterial Blood Pressure on the Dosage of Epinephrine Needed to Produce Multifocal Ventricular Tachycardia (MVT) After Admini stration of Surital and Halo th a n e ...... 118 5. Effect of Acetylpromazine (0.5 mg/lb) on Cardiac Mean Blood Pressure and Heart Rate in Unanesthetized D o g s ...... 124

6. Mean and Standard Error Values for Venous Blood Gas Samples in Groups 1 through 9 ...... 125

7. Mean Arterial Pressure Alterations After the Initial Pressure Peak Due to the Administration of Epinephrine Intravenously...... 140

vi LIST OF FIGURES

Figure Page X. Diagramatic Representation of the Phases of the Action Potential in Automatic and Non-automatic Cardiac Tissues...... 7 2. Diagramatic Representation of the Effects of Halothane on Canine Cardiac Fibers...... 38 3. Basic Structure of the Phenothiazine Molecule and Several of its Derivatives. . . 44

4. Diagramatic Representation of the Effects of Phenothiazines on Canine Cardiac Fibers...... 49

5. Classification of Arrhythmias Associated with the Administration of Epinephrine and Anesthesia...... 76

6. Control Electrocardiagram and Response to Varying Doses of Epinephrine in the Dog...... 82

7. Relationship Between Heart Rate and Blood Pressure in the Unanes thetized Dog Given 20 ugm of Epinephrine...... 84 8. Effects of Epinephrine on the Relationship Between Heart Rate and Blood Pressure in Halothane Anesthetized Dogs Given Acetyl- promazine...... 91 9. Effects of Definitive Doses of Epinephrine on Cardiac Rhythm in Unanesthetized Do g s ...... 93

vii LIST OF FI CURES-Continue cl Figure Page

10. Effects of Definitive Doses of Epinephrine on Cardiac Rhythm in Dogs as Influenced by Surital...... 95 11. Effects of Definitive Doses of Epinephrine on Cardiac Rhythm in Dogs as Influenced by Halothane...... 97

12. Effects of Definitive Doses of Epinephrine on Cardiac Rhythm in Dogs as Influenced by Surital and Halothane...... 99 13. Effects of Definitive Doses of Epinephrine on Cardiac Rhythm in Dogs as Influenced by Surital, Halothane and Atropine ...... 101

14. Effects of Definitive Doses of Epinephrine on Cardiac Rhythm in Dogs as Influenced by Acepromazine, Surital and Halothane...... 103 15. Effects of Definitive Doses of Epinephrine on Cardiac Rhythm in Dogs as Influenced by Surital, Halothane and Acepromazine...... 105

16. Three Dimensional Representation of Anesthetic Regimen vs. Dose of Epinephrine vs. Arrhythmia F o r m e d ...... 107 17. Specific Arrhythmias Associated With Various Anesthetic Regimens and Dosages of Epinephrine...... 109 18. Effect of the Pressor Agent Phenylephrine upon Cardiac Rhythm in the Presence of Halothane...... 113 19. Effects of Inflow Occlusion Upon Arterial Blood Pressure and Cardiac Rhythm ...... 114

viii LIST OF FIGURES-Continued

Figure Page

20. Effect of Nitroglycerin Upon Arterial Blood Pressure and Cardiac Rhythm...... 116 21. Effect of Two-stage Ligation of the Left Coronary Artery Upon Cardiac RhythmV...... 120 22. Effect of Acetylpromazine Upon Arrhythmias Initiated by Two-stage Ligation of the Left Coronary Artery ...... 123 23. Diagramatic Response of 1-Ieart Rate (HR) and Blood Pressure (BP) . to Epinephrine in the Presence of Varying Anesthetic Regimens ...... 138

24. Changes in Heart Rate vs. Mean Arterial Blood Pressure for Several of the Groups Studied. C-Control, S-Surital, S-H-Surital- Halothane, S-H-Ac-Surital, Halothnne, Acepromazine...... 141 INTRODUCTION

The genesis of the multivaried arrhythmias observed

in conjunction with the use of intravenous and inhalation

anesthetics has been the theme of many essays. Studies on both the direct and indirect effects of these drugs

centrally and peripherally have helped to clarify our understanding of their diverse actions upon cardiac rate and rhythm. Certainly, their perturbations of autonomic control have been emphasized as a major impetus in arrhythmia production. It has also become obvious, although these data are still difficult to interpret, that specific nuclei in the central nervous system, particularly the mesencephalon and hypothalamus, may alter the propensity to arrhythmia formation. Such variables as species, age, anesthetic technique and recording pro cedure must be considered when interpreting such data and most certainly is a part or one of the reasons for contradictory results. Other factors such as endogenously or exogenously administered hormonal substances, electro lytic and ac.id-base abnormalities and tension developed within the vascular system bear an important relationship to arrhythmia production and cannot be overlooked.

1 Almost invariably associated with the use of intravenous or inhalation anesthetics has been the use of prcmedicants. Among these are parasympatholytics,

ataractics, sedatives, and analgesics. These agents display their own pharmacologic actions as well as gen

erally potentiating the effects of anesthetics. This

synergism with anesthetics in many instances appears beneficial and less dangerous to the patient but in reality, may predispose an already compromised subject

to more severe problems. Locally,the excitation of cardiac muscle fibers may

result from either increases in automaticity and/or alteration in impulse conduction. Here again, anesthetics and preanesthetics display profound electrophysiologic

effects, particularly upon specific ionic conductances and the refractory process. In many instances, the anesthetic and/or preanesthetic may act in combination with endogenous hormonal substances or ionic mechanisms resulting in the production of arrhythmias. In this

regard, numerous agents have been cited as predisposing the myocardium to irregularity and thereby "sensitizing”

it to further abnormalities. As has been stated previously, numerous authors have encumbered a great deal of data on the arrhythmogenic

effects of different anesthetics and preanesthetics.

Despite these efforts, neither the precise mechanism nor a qualitative or quantitative approach to description of these arrhythmias have been attempted. Isolation of the heart from the body removes enumerable variables, the role of these variables, however, being equally as difficult to describe in the in vivo situation. In many instances, the precise mechanism of action of the drug being con sidered, may also be incompletely understood. The physiologic effects of the drugs themselves may be dose dependent, particularly with respect to the myocardium. With these thoughts in mind, it was decided to study, in a quantitatively descriptive manner, the character of the dysryhthmias associated with the inhalation anesthetic halothane as influenced by one of the commonly used preanesthetics, this being the phenothiazine derivative acetylpromazine. Other drugs commonly associated with anesthesia, such as parasyinpatholytics and ultra-short acting barbiturates used in induction to anesthesia will also be considered. The influence of arterial blood pressure and heart rate as determinants of arrhythmia formation will be discussed. To accomplish this, a two model system will be used. The ferst will take advantage of the known "sensitization" of the heart to catecholamine induced arrhythmias precipitated by halogenated hydro carbon anesthesia. The second will involve two-stage coronary artery ligation studies. From this evaluation, a more thorough understanding of the classification and 4 severity of the arrhythmias associated with the inhalation anesthetic, halothane, should evolve. The influence of several predisposing factors, heart rate and blood pres sure, should also be clarified. CHAPTER I

REVIEW OP LITERATURE

Determinants of Arrhythmia Formation

In order to understand the effects of the different anesthetic and preanesthetic drugs upon cardiac rate and rhythm one must first understand the normal electrophysio-

logic properties of the heart and the homeometric and

heterometric mechanisms under which it performs. We must also bear in mind that experimental procedures devised to produce conduction disturbances or abnormalities of

rhythm may or may not be identical to the mechanisms that

cause arrhythmias or conduction disturbances in the diseased heart. Furthermore, the electrocardiographic

identification and classification of arrhythmias and conduction disturbances contribute little if any to the

understanding of the changes which may be responsible for

the electrocardiographic abnormalities. Cardiac cells are excitable, that is, they respond

to a threshold stimulus by developing an action potential. The normal resting membrane potential is approximately a negative ninety millivolts with respect to the outside of

the cell, and that of threshold potential approximately a negative sixty-five millivolts.C121) Certain specialized

5 cardiac cells have the inherent property of rhythinicity

or automaticity. These cells reside primarily in the

sinoatrial node, atrioventricular node and all parts of the Mis Purkinje system. (121) in mammalian hearts some

part of the sinoatrial node acts as the pacemaker because its inherent rate of firing is higher than that of other

automatic tissues. The automatic rate of firing being

principally governed by the autonomic nervous system. For descriptive purposes the cardiac action poten tial has been divided into five distinct phases. This is shown diagramatically for a single automatic (Purkinje)

and nonautomatic (ventricular) fiber in Figure 1. Phase zero is the period of rapid depolarization and is indica

tive of rapid sodium transport across the cellular membrane to the inside of the cell. This phase often includes an overshoot where the membrane potential becomes positive. This positivity generally being equal to the sodium potential and calculable on the basis of the Nernst equation. Phase zero is followed by three phases of

repolarization comprising a short rapid repolarization (phase one), a plateau (phase two) and a return to the resting membrane potential (phase three). Phase one and two coincide with the period of absolute refractoriness whereas phase three is generally associated with differ

ent degrees of the relative refractory period. The period of electrical stability between each ventricular 7

ACTION POTENTIALS OF CANINE CARDIAC FIBERS AND THEIR VARIOUS PHASES

PHASE 1 + 15 m V ---- PHASE 2

PURKINJE FIBERS PHASE O PHASE 3 THRESHOLD - 6 5 mV POTENTIAL (TS) PHASE

— 2-- VENTRICULAR FIBERS

PHASE 4 -90mV

Fig. 1.--Diagramatic Representation of the Phases of the Action Potential in Automatic and Non-automatic Cardiac Tissues.

t action potential is phase four. In automatic tissue, the

location of which was described previously, this phase may

undergo spontaneous depolarization and result in the propogation of another action potential. This phase is also referred to as slow diastolic depolarization as

opposed to the sodium ion influenced systolic depolari

zation. As implied, many studies suggest that during depolarization large quantities of sodium, normally present predominantly outside the cell, enter during the

earlier phases of the action potentiaon (phase zero) , whereas much of the slower inward current that occurs

during the plateau period (phase two) is carried by cal cium ions.^^*^) phis mobilization of calcium ions is

involved in the excitation-contraction coupling process of the myocardial cell. It is also important from the

standpoint of the membrane permeability and excitability. During phase three the membrane conductance to sodium ion

decreases and potassium conductance increases transiently. This returns the membrane potential to its resting value. Once the resting membrane potential has been restored

(phase four) the excess sodium ion that entered and potassium ion that was extruded during depolarization is returned by an active transport process against a consider

able electrochemical gradient. This has been referred to

as the sodium-potassium pump mechanism. The entire action potential in cardiac muscle lasting approximately three hundred milliseconds as compared to that of nerve and skeletal muscle which is on the order of three to five milliseconds.(121) In those cardiac cells where phase four undergoes steady depolarization an increasing ratio of sodium to potassium conductance is used as a plausible explanation. It has been suggested that a gradual reduction in potass ium conductance is primarily responsible for this "pacemaker potential," however, alterations in sodium conductance may plan a minor r o l e . (54) Hoffman (H ® » H9 ) and Hoffman and Cranfield (1 ^0»121) have postulated that from an electrical standpoint arrhyth mias may develop from alterations in automaticity, alterations in conductivity, or both. If the automaticity of the sinoatrial node is depressed or if the automaticity of some other (latent) pacemaker is enhanced, specialized cardiac fibei's other than the sinoatrial node may serve as the pacemaker and initiate single or multiple ectopic impulses. Disturbances in cardiac rhythm due to conduc tion abnormalities are generally manifested as localized delay in the propogation of the cardiac action potential. Disturbances due to anatomical pathways although histo logically evident are not frequently observed as a cause of arrhythmias.(129)

The velocity with which the cardiac impulse propo- gates is determined by the magnitude of the resting 10

potential, the rate of rise of phase zero of the action

potential and the value of the threshold potential.( 2 2 0 )

Factors which slow conduction, such as, decreases in diastolic depolarization or alteration in membrane con

ductance to sodium and potassium ions may result in local failure of excitation and unidirectional or bidirectional block. lVit ej:. a_l. (286 , 287) have demonstrated that if

slow conduction is accompanied by undirectional block

reenterant excitation and arrhythmias will occur. It has also been demonstrated that decreases in the magnitude of the transmembrane potential causes decreases in the maxi mum slope of phase zero and a decrease in conduction velocity. (272) This aspect, however, is normal for pace

maker tissue in that impulses which arise as a result of phase four depolarization will have a decreased amplitude and rate of rise of phase zero and will often conduct abnormally. Also, impulses that are sufficiently pre mature to arise at a time during phase three will conduct slowly and generally are blocked.(43,272) singer et.

a]L. (247,248) have shown that automatic activity may give

rise to premature impulses which spread in fibers that are not fully repolarized and that these impulses propogate

abnormally. Alterations in automaticity may therefore be associated with abnormalities with conduction. Rosen and

Hoffman(220) have concluded from these studies that enti

ties which increase the slope of diastolic depolarization 11

I during phase four or move the threshold potential closer to the resting potential .increase the rate of automatic firing or cause ectopic impulses. Conversely, entities which decrease the slope of phase four depolarization or increase the voltage difference between the resting potential and the threshold potential have the opposite effect and suppress ectopic rhythms.(275) Furthermore, some agents may eliminate arrhythmias due to reentry by improving conduction in depressed areas (lidocaine, diphenylhydantoin) or by further depressing conduction to the point of complete block (procainamide, quinidine). Several of the more common endogenous substances which may effect the cardiac action potential are acetylcholine which slows the heart by decreasing the slope of diastolic depolarization and causing slight hyperpolari zation, catecholamines which increase heart rate by increasing the slope of diastolic depolarization and calcium fluxes in the extracellular volume.C248,265) increase in ionized calcium ion displaces the threshold potential to lower values while a decrease in calcium ion has the opposite effect. Changes in other electrolytes such as potassium and sodium may alter the maximal diastolic potential as well as the slope of diastolic depolarization. In summary arrhythmias may be due to any of a number of alterations in the cardiac actional potential due to 12 changes in automaticity ancl conductivity.

Pick(200) has sp ccifically classified the potential

for arrhythmia development into one of the following categories: 1) "Preferential" A-V path conduction; 2) Alterations in phase four depolarization; 3) Ventricular

(vascicular) origin; 4) Functional dissociation with bundle branch effects; 5) Wedensky facilitation; and 6) Supernormality of intraventricular conduction.

Other entities which may have a direct effect upon

the development of arrhythmias may be classified as intra or extracardiac. Intracardiac factors which are important may have their basis in specific receptors within the myocardium. These receptors include both the alpha and beta receptors of the sympathetic nervous system and many undescribed atrial receptors responsive to pressure and volume changes. (-*-^6) Extracardiac factors include hypo thermia^ 7)f mechanical stimulation(27)} increased pre and after loads(279)^ elevated potassium levels(66), vagomimetic effects^^^, hypoxemia and hypercarbia(218) f altered central and autonomic(^0»274) nervous system activity(168)f hydrocarbon anesthetics(273)t digitalis(27) and administration of catecholamines.(180) yhe importance of monamine oxidase, an enzyme responsible for the destruc tion of many sympathomimetic amines, must also be taken into consideration. Hypertension, arrhythmias and death have been reported in patients following the injection of 13

catecholamine releasing sympathomimetics during anesthesia or monamine oxidase inhibiting substances.(82,125)

The importance of the central nervous system in the

development and maintainence of any arrhythmia including

fibrillation cannot be over emphasized. In a recent review by Mauck and IIockman(-*-^) the difficulty of assigning any

one particular portion of the central nervous system a position of high importance concerning arrhythmia formation was emphasized. That electrical stimulation of the cere bral cortex can influence rate and rhythm was established

in the early 1870s by SchiffC231)< Recent studies by

Uvnas^^) have clarified the importance of cortical and subcortical mechanisms on cardiovascular function. Delgado and associates(55) have demonstrated that the cerebral cortex exerts important autonomic influences in addition to its sensory and motor effects. Their data support the hypothesis that autonomic responses may be evoked by electrical stimulation of discrete cerebral areas.C45) Beattie, Brow and Long(18,19) had demonstrated that stimulation of the hypothalamus could produce signifi cant arrhythmia formation. Magoun and associates (*61) have suggested that adrenergic substances are released by hypothalamic stimulation. Weinberg and Foster(^82) maintain that the posterier hypothalamus exerts its activity upon the sinus node and the lateral hypothalamus and subthalamus extert a tonic effect upon the myocardium. 14 Manning et^. al^. C163) ^as argUed that the arrhythmias

associated with hypothalamic stimulation are the result

of both sympathetic and parasympathetic influences upon the heart. They believe that the arrhythmias which they

produced were a result of vagal-induced migration of the

pacemaker toward and beyond the atrioventricular node. Recent work by Mauck ejt. aJL. (116,168,169) has clarified

much of these findings, and concluded that the majority

of abnormal rhythms due to electrical stimulation of diencephalic and mesencephalic structures are exclusively

mediated by the sympathetic division of the autonomic

nervous system. It can be concluded from these studies that the majority of arrhythmias associated with actual

organic heart disease or central nervous system disorder originate in the diencephalon specifically the hypothal amus and that these arrhythmias are induced by imbalances

in sympathetic tone.^^) The increasing knowledge of synaptic, baroreceptor and ganglionic physiology and pharmacology has made it possible to analyze the effects of anesthetics at these sights . (34 ,177) Garfield et^ al_. (86) have studied the

pharmacologic effects of ether, halothane, and cyclopro pane upon preganglionic sympathetic nerve stimulation

and concluded that these agents depress transmission through nicotinic, hexamethonium sensitive pathways.

Conversely, there appears to be little effect on impulse 15 transmission over muscarinic atropine sensitive pathways

in the cardiac sympathetic ganglia of dogs.(-^®) Biscoe and Mi liar(26) have indicated that anesthetics inhibit ganglionic transmission. Aars and Ilauge^^ have reported bradycardia and hypotension caused by inhalation anes thetics with no consistent effects on the relationships between aortic nerve activity and arterial blood pressure. Skovsted et_. aJU (251) have hypothesized that barostatic reflexes are not functionally normal during anesthesia despite the fact that stimulation of the aortic depressor nerve still effects sympathetic tone. Alper and Flacke^) have presented evidence that the primary method of action of anesthetics specifically halothane is to inhibit the response to nicotinic ganglionic receptors by its effect upon postsynaptic neurons. The importance of the sympathetic and parasympathetic divisions of the autonomic nervous system in the produc tion of arrhythmias has been ellucled to earlier. (20) Vatner et^ aT. (2 73) have shown that autonomic control upon cardiac rhythm is altered during anesthesia. They found that during anesthesia with many anesthetics basal parasympathetic tone is reduced and adrenergic tone intensified. In a more recent publication Vatner(^74) clarified the importance of both sympathetic withdrawal and parasympathetic tone on cardiac rhythm during increase in arterial blood pressure. 16 Anothea* aspect of arrhythmia production centered around autonomic control is alpha and beta receptor activity during anesthesia as compared to the unanes thetized state. Several investigators have implicated both alpha and beta receptor sensitization as the predomi nant mechanism for arrhythmia production. This has been investigated through the use of autonomic blocking agents. Somani and Lum(^56) have demonstrated the ineffectiveness of strict alpha blockers in preventing cardiac arrhythmias due to hydrocarbon-epinephrine combinations. These same investigators established the efficacy of beta blockers in the prevention of epinephrine induced arrhythmias.(73)

Alpha adrenergic effects have been shown to elicit their arrhythmogenic effects via increases in arterial blood p r e s s u r e (192) whereas beta adrenoceptor arrhythmogenicity may be enhanced by any number of perturbations which ultimately cause catecholomine release.(27) This includes pressure changes, electrolyte and acid-base imbalances, anesthesia, etc.

The importance of catecholamines whether of endo genous or exogenous origin associated with anesthesia cannot be overemphasized.(56) Many investigators have taken advantage of their arrhythmogenic characteristics in order to delineate the genesis of abnormal rhythms.(®2>100,180,206) price(203) ^as demonstrated that anesthetized dogs secrete epinephrine and small 17 quantities of norepinephrine, presumably from the adrenal medulla. He has also shown that this secretion is increased by ten-fold during anesthesia and laporatomy. In man the predominant amine appears to be norepinephrine. The electrophysiologic effects of these agents has been previously discussed. Hoffman ert. a_l. C122) have studied fibrillatory thresholds in dogs and concluded that both epinephrine and norepinephrine produce similar increases in vulnerability immediately following their injection intravenously. These changes in vulnerability occur simultaneously with alterations in resting excitability and are dose related. Recently Moore et. al^ C180) have studied the arrhythmias produced by catecholamines in anesthetized dogs. They suggest that coupled rhythms produced by the intravenous injection of microgram doses of epinephrine may result from premature depolarization of peripheral Purkinje fibers. They also conclude that autonomic innervation may be unnecessary for some dys rhythmias since coupled rhythms could be produced in denervated heart-lung preparations. These rhythms may have been pressure sensitive although increases in pres sure were not necessary for their initiation. Other studies by Murphy et^. a]^. C186) have demonstrated that injection of as little as five micrograms of epinephrine in cyclopropane anesthetized dogs will cause potassium concentrations to increase by one hundred per cent as 18 compared to resting levels. Ventricular tachycardia always occurred at the time of rapid ascent of the potas

sium levels. (194) inte restingly this phenomena and

resultant arrhythmia formation could be eliminated by

prior treatment with dibenamine. Katz and KatzC135) have

shown contradictory results to these findings and demon

strated no correlation between the absolute rise in plasma

potassium concentrations and arrhythmogenicity. In addition other sympathomimetic agents which do not produce hyperkalemia are capable of producing arrhythmias.(134) From these findings it becomes clear that arrhythmias

associated with catecholamine administration are dose

dependent, pressure sensitive and may occur under varying degrees of autonomic innervation and to assume a common mechanism is operating may be dangerous. The role of arterial blood pressure in the produc

tion of arrhythmias has been the theme of many monographs and reviews . * 1°5) Levy^15**) wrote, "Throughout a

long series of experiments with adrenalin the onset of ventricular fibrillation has borne no relation to the height of which the blood pressure has been raised and the supposition of a casual relationship is thereby largely negatived." Since that time many other experiments by a great many more investigators have reached a similar conclusion although they felt the point required further investigation. M oe^ ^} has pointed out that prevention 19

or arterial pressure elevation protected the heart

against epinephrine induced fibrillation. Hoffman and

Cranefield^^'} have shown that increased arterial pres sure induces stretch in myocardial tissues which decreases

resting potential and increases multifocal pacemaker activity in the sinoatrial node. Vick(279) ]ias shown that

after administration of epinephrine or metaraminol a new or increased pacemaker activity is seen independent of the beating of the ventricle. Innes and SandersC127) have

observed that a sudden rise in tension in cat papillary muscle increases its sensitivity to induction of automaticity by epinephrine. The rate of rise of tension appearing to be the important factor. Moreover, the

"sensitization" of the ventricle to epinephrine when higher tensions were maintained decreased gradually. They concluded that the sudden application of tension results in a shorter muscle length than will slow application of an equal tension. The sensitizing factor, therefore, is not cardiac muscle length but the rapidity with which the length is increased. The short duration of sensitization being due to accommodation of some factor resisting stretch, such as viscosity. They suggested that the sensitization of cardiac muscle to epinephrine by rapidly increasing tension may account for ventricular arrhyth mias which are induced by epinephrine in the presence of anesthetics. The increasing tension developed within the 20 muscle should cause progressively increasing sensitivity to the induction of automaticity by epinephrine.CIS?) In a recent publication Verrier et. a l .(2 76,2 77) have questioned the importance of arterial blood pressure and the predisposition to ventricular arrhythmias. They argue that, in the majority of studies conducted, the hypertension resulted from the infusion of pressor agents or increased adrenergic discharge, factors themselves capable of altering ventricular vulnerability. This argu ment was based upon their inability to produce ventricular arrhythmias with an equipressor dose of the alpha stimu lator phenylephrine. Furthermore, increases in arterial blood pressure caused by phenylephrine injection or by aortic occlusion consistently increased the fibrillatory threshold. In support of these findings Kezdi^^) has indicated that acute withdrawl of sympathetic tone in the aortic arch and carotid sinus follows pressure elevation.

It would appear that increases in arterial pressure has varied effects upon ventricular automaticity. Whether results in anesthetized animals involving neural reflex mechanisms are applicable to the conscious state deserves a more in-depth evaluation.

In conjunction with changes in arterial blood pressure alterations in heart rate are equally as import ant. The single most important cause of alterations in heart rate is the action of autonomic mediators discussed 21 previously. Alterations in automaticity induced by acetyl

choline and the catecholamines are the principle means

whereby heart rate is adapted to meet the changing needs. These agents also represent an important cause of arrhyth mia production. Acetylcholine depresses automaticity in the sinus node and other specialized atrial tissues by decreasing the slope of phase four depolarization and increasing the maximum diastolic potential. This acts to reduce heart rate. If depression of supraventricular pacemaker activity is sufficient the pacemaker will shift to the atrio-ventricular node or His Purkinje system. Catecholamines on the other hand, increase the slope of phase four depolarization of all automatic cells through out the heart. Development of ectopic tachyarrhythmias being a common sequel of this action.(278) other determi nants such as increases in blood pressure and therefore myocardial tension and increased myocardial oxygen demand occur as a result of increased heart rates. Although changes in heart rate may incite any of these factors to a predominant role in the formation of an arrhythmia it generally does not do so until rate becomes excessive. In the dog this is generally in excess of one hundred and eighty beats per minute.(121)

Hypoxia and hypercarbia have long been thought to increase the vulnerability of the canine ventricle to fibrillation. *269) Respiratory acidosis stimulates 22 vasomotor areas in the brain stem resulting in an in creased sympathetic outflow and myocardial and adrenal catecholamine release. Similar results have been reported in cases of respiratory alkalosis. Joas and Stevens Cl30) however, have reported an increase in the fibrillatory dose of epinephrine when respiratory acidosis was present in animals anesthetized with halothane, fluroxine or forane. In support of these findings Rogers et^. al. (2^8) has

found that respiratory acidosis with hypoxia resulted in a striking increase in the amount of current required to initiate fibrillation in dog ventricles. The protection afforded by hypercarbia and hypoxia is both consistant and in conflict with the results of others. Ueda et. al. (270) wooing with pentobarbital anesthetized dogs found that addition of carbon dioxide to the inspired gases increased the dose of epinephrine necessary to in duce arrhythmias. Virtue(282) foun(j that dogs were more sensitive to epinephrine induced arrhythmias during cyclopropane anesthesia and respiratory alkalosis rather than respiratory acidosis. In man, hypercarbia has caused arrhythmias during cyclopropane anesthesia. Gerst et. al.(87) have reported that respiratory acidosis produces no significant change in ventricular fibrillatory thres hold although supraventricular arrhythmias did occur.

Conversely, a decrease in ventricular fibrillatory thres hold has been noted with metabolic acidosis.(159) ^he 23

effects of metabolic alkalosis however, have not been studied. Hypercarbia and hypoxia also have variable

effects upon cardiac elcctrophysiologic parameters. Thus, their resultant effect upon ventricular fibrillatory threshold cannot be predicated on this basis. For example, hypoxia results in shortening of the action potential, whereas hypercapnic acidosis causes an increase in the duration of the cardiac action potential. These studies suggest that in cases of respiratory acidosis and hypoxia, possibly due to anesthesia, one should be cautious to attribute ventricular arrhythmias to blood gas abnormali ties solely and should carefully evaluate other parameters.

In summary, many factors must be taken into con sideration when considering the cause of an arrhythmia particularly when induced by anesthesia, catecholamines or both. Many of these factors are interrelated and must be considered as part of the overall effect in order to accurately determine the proper role to assign each determinant in the formation of an arrhythmia. Thiobarbiturates and Arrhythmias The first barbiturate introduced into medicine as a hypnotic was barbital or diethylbarbiturac acid. Since then more than 2500 barbiturate derivatives have been synthesized with only about a dozen remaining in common clinical use because of their durations of action. Barbiturates are formed by the condensation of urea and 24 malonic acid. To obtain hypnotic action both hydrogen substitutions in the number five position must be replaced. The molecularity of the substitution conferring either sedative or convulsant activity. For example, substitution of long chain molecules in the number five position may lead to convulsant activity. Substitution of a sulfur atom for the carbonyl oxygen at the number two position yields the ultra-short acting thiobarbiturates as distinct from the oxybarbiturates. This substitution results in high fat solubility, rapid onset of action and a short duration of action depending upon the total dose administered. Only those thiobarbiturates with a relatively high molecular weight have become popular, primarily because of their higher safety margin. The most commonly used thiobarbiturates are thiopental sodium (Pentothal Sodium) and thiamylal sodium (Surital). In general the thiobarbiturates like other local anesthetics, hypnotics, etc. are depressents affecting nervous tissue as well as skeletal, smooth and cardiac muscles.(229) -phe electrophysiologic effects of the thiobarbiturates, in particular thiamylal, have not been well documented. The oxybarbiturates, however, demonstrate little effect upon the resting membrane potential when administered in moderate doses. Higher concentrations however, elevate the membrane threshold.(266)

Repolarization of the cardiac action potential as well as 25 a negative chronotropic effect have also been demon strated in rabbit hearts after administration of phento- barbital. Thesleff^2^ 1) has observed that a variety of anesthetics including thiobarbiturates, reduced the sodium conductance at concentrations below those affecting the resting membrane potential. Shanes(237) and Seeman^2* ^ demonstrated that lipid-soluble anesthe tics can disorder the membrane resulting in electrical stabilization. Thiobarbiturates also selectively depress transmission in sympathetic ganglia although their effect is not as potent as the longer acting barbiturates.(78)

This depressant effect upon sympathetic ganglia however, is often masked by the ability of thiobarbiturates to release norepinephrine from stores in vascular smooth muscle.C36) Similarly, after the injection of a thiobarbiturate plasma catecholamine levels in dogs usually rise predominately due to adrenal medullary release.(49)

The effects of barbiturates upon the central- nervous system is poorly understood but appears to be at all levels of the neuroaxis. The cerebral cortex and reticular activating system appear the most sensitive. Thiobar biturates in particular appear to accumulate in the thalamus and cerebral cortex.Their mechanism of action has not been described. Aldridgehas demonstr ated that barbiturates inhibit oxidative phosphorylation and activate adenosine triphosphatase in vitro. The 26

importance of these findings and mechanism of action however, remains obscure. Whatever their method of action it appears to be their effect on the reticular activating system that produces sedation and anesthesia. (^* 142)

The cardiovascular alterations of the barbiturates not only varies between the oxybarbiturates and thio barbiturates but has been demonstrated clinically to be somewhat dose dependent. The action of the oxybarbitu rates is primarily depressant in activity.(-^) Sodium pentobarbital, for example, depresses vasomotor centers centrally, baroreceptor reflexes, vascular smooth muscle, myocardium and sympathetic ganglia as well as demonstrating an atropine-like activity.( ^ *^0*9^ ^ »196) The result ant effects being that cardiac output is increased, decreased or unchanged. In those studies in which cardiac output was increased the effect was attributed to increases in heart rate. Few reports describing the cardiovascular effects of thiamylal are available. Greis eimer et.a_l. (93) and Dobkin and Wyant(6®) demonstrated that cardiac output increased or remained unchanged. The latter authors observed that thiamylal caused myocardial depression and a decrease in arterial blood pressure in man after rapid injection. Recent studies by Sawyer e_t. al. (228) an(j

D u n n e (^9) in miniature swine have shown peripheral vascu lar resistance to be increased as well as arterial blood pressure. Price e_t. al_. (204) reported similar results in 27 clogs. These findings could be expected to increase myo cardial wall tension, work and oxygen consumption.

Thiamylal sodium and other thiobarbiturates when injected intravenously in anesthetic dosages have been

shown to induce cardiac arrhythmias in d o g s . (94,95)

Gruber and associates(95) related this to the direct cardiotoxic effects of the drug itself and the duration of the sustained increase in arterial blood pressure. More e£. ajU (1^9) lJSing dogs demonstrated that sudden elevation of pressure in the denervated heart-lung preparation may cause premature ventricular contractions and often bigeminal rhythms. The concomitant release of catecholamines induced by the thiobarbiturates could be expected to compound this problem to the point of ventri cular fibrillation. Verrier et. al. however anes thetized dogs with intravenous alpha chloralose and concluded that an acute rise in arterial blood pressure decreases susceptability to ventricular fibrillation and that this effect is mediated through reflex withdrawal of cardiac sympathetic tone.

Arrhythmias produced by the intravenous adminis tration of thiobarbiturates are more prevalent at light as opposed to deeper levels of anesthesia. It has also been demonstrated that adrenalectomy or ventilation with one hundred per cent oxygen has little palliative effect

upon this r e s p o n s e . (94) These points tend to negate the 28

importance of the norepinephrine releasing qualities of the thiobarbiturates referred to earlier in this dis cussion. In subsequent studies it was established that coronary vasodialator drugs (amylnitrate, glyceryl- trinitrate) relieved the arrhythmias caused by intravenous thiamylal even in the face of ventilatory insufficiency. Gruber et^. al^. (95) have therefore attributed arrhythmias to the vasoconstrictive properties of the thiobarbiturates as opposed to the eventual vasodilatory action of the oxybarbiturates although other authors have questioned his methods. Thus coronary vasoconstriction produced by the thiobarbiturates has been implicated as one of the major causes for arrhythmia production and myocardial hypoxia. Similar studies by the same authors with barbiturates have concluded that the major factors responsible for arrhyth mia formation are: 1) vasoconstriction caused by the sulfur analogues of barbituric acid whereas the oxygen analogues cause vasodilatation; 2) increased arterial blood pressure which increases myocardial wall tension, work load and oxygen consumption; 3) decreased ventilation although it may be a relatively minor cause. The last of these factors is made less important by the finding that arrhythmias were just as prominent during ventilation with pure oxygen as with one hundred per cent helium. Similarly, if cardiac arrhythmias were not present immedi ately following the intravenous injection of thiamylal 29 they could be induced by any maneuver which would elevate the arterial blood pressure. In conclusion it would appear that the major impetus for arrhythmia formation when administering intravenous thiobarbiturates is reduced coronary arterial flow and increased myocardial wall tension. Both factors tending to increase myocardial excitability. Atropine and Arrhythmias Atropine, an antimuscarinic, is a racemic mixture of d and ^-hyossyamine. The antimuscarinic activity residing primarily in the £- form. As an example of the differences in potencies between the two the -form has been shown to demonstrate as much as fifty times the central nervous ‘ system excitation as the d-form.^1) Atropine can inhibit all muscarinic actions of acetylcholine and other choline • esters. The peripheral effects of atropine effecting exocrine glands, smooth and cardiac muscles.^ B e s i d e s its antimuscarinic activity peripherally atropine has potent central effects and has demonstrated mild local anesthetic action.(47,79) The mechanism by which atro pine acts is by competitive antagonism of acetylcholine. This blockade can be overcome by increasing the concentra tion of acetylcholine at the receptor sights. Concerning cardiac rate and rhythm the effects of atropine are of interest because of their actions centrally and directly upon the cardiovascular system. Atropine 30

has a stimulatory effect upon the medulla and higher cerebral centers . (14?»1^7 * 198) Large doses of atropine

have caused restlessness and excitation in unanesthetized dogs. Exley et^. al_. (^9) have shown that atropine and

especially scopolamine, depress the reticular activating system. Ostfeld and Arguete(1°^) demonstrated that atro

pine may also antagonize hypothalamic and reticular

formation activation by sympathomimetic amines. Direct depression of various types of neurons in the spinal cord

of cats has also been examined.(7®) The effects of atropine upon the cardiovascular system are a direct consequence of its parasympatholytic activity.(^2,90,193,240) jn jow dosages atropine has been

shown to further augment bradycardias due to its stimu latory effect upon vagal nuclei.(9) in larger dosages, however, (.02 mg/lb) atropine increases heart rate and completely counteracts the peripheral vasodilatation and

fall in blood pressure caused by acetylcholine. ( ^ ° ) The effect upon arterial blood pressure is not marked with minimal increases in systolic and diastolic pressures being noted.(46) Atropine has also been advocated as a coronary

artery dialator although this effect has not been analyzed closely. Its use in bradyarrhythmias as xvell as first and second degree heart block has been advocated by many researchers.(104,267)

Recently a great deal of controversy has evolved 31

over the use of atropine as the drug of choice in bradyarrhythmias.C91,104,131,165,184,267) Electrophysiologic

studies in canine hearts have shown that slower heart rates are accompanied by a more homogenous recovery of ventri

cular excitability and higher ventricular fibrillation threshold. (102) Vagal stimulation per se increases

electrical stability in both non-ischemic and ischemic myocardium. (^ »®1 » > 181) Bailey and Associates^3*)

have demonstrated that acetylcholine prolongs diastolic depolarization and increases rise time, amplitude and conduction velocity of action potentials in the His- Purkinje system of canine ventricles. This effect being associated with cardiac cellular electrical stability. In contrast to these findings increasing heart rates result in electrophysiologic changes indicative of greater electrical instability of the ventricle, particularly in ischemic hearts. (140) Scherlag et. al^. (23°) has postula ted that reenterant arrhythmias are more likely to occur when a greater number of impulses encounter delays such as decremental conduction or local block due to myocardial ischemia. Thus, atropine may potentiate arrhythmia forma tion solely by increasing heart rate.

In addition to increases in heart rate increases in myocardial wall tension accompanying increased rate (Bowditch effect) may result in gerater oxygen demand.(165,211,212) This could further increase the 32 tendency towards myocardial hypoxia and favor reentcrant mechanisms. The enflux of potassium ion from myocardial cells may also be an important factor in promoting ventri cular irritability. ^ ^ Berkowitz (^) has demonstrated ventricular extrasystoles in man in the absence of coronary artery disease after the administration of atropine. Epstein et^. studying acute coronary ligation in dog models, demonstrated that atropine increased the incidence of arrhythmias and lowered the ventricular fibrillation threshold. They also demonstrated a greater disparity in refractory periods between normal and ischemic tissues at faster than at slower rates after atropine administration. Although atropine may predispose the canine ventricle to arrhythmias by increasing the degree of myocardial oxygen consumption and myocardial hypoxia and favoring reentry mechanisms the drug has been useful in controlling many so called innocuous arrhythmias by overdrive sup pression. (19?) Atropine has also been shown highly effective against less serious arrhythmias during coronary occlusion but much less effective when the arrhythmia was associated with the eventual development of ventricular fibrillation. The use of atropine, therefore appears predicated upon the type and cause of the particular arrhythmia and should not be used in routine treatment of arrhythmias. Halothane and Arrhythmias Malogenated and nonhalogenatcd hydrocarbons devel oped for use as inhalation anesthetics have been the source of many experimental and clinical investigations since the advent of diethylether. The halogenated hydrocarbons in particular have become increasingly popu lar because of their non-explosive characteristics and high therapeutic ratios as compared with ether. In most instances however, these agents have fallen short of the anesthetic qualities that are inherent to ether. Early work with halogenated substances indicated that chlorine substitution of several relatively simple hydrocarbons had the ability to sensitize the myocardium to ventricu lar arrhythmias and fibrillation.(05>3.53) Similar findings were reported by Robbins(215) while working with flouri- nated hydrocarbons and ethers, Chenoweth^^ has reported that several unsubstituted hydrocarbons such as methane, butane and benzene have similar capabilities. This pheno mena since referred to as "myocardial sensitization" to arrhythmias by halogenated hydrocarbons particularly in the presence of high catecholamine levels has been sup ported by several authors and the source of several monographs investigating its mechanism.(146,167,185)

In 1956 R a v e n t o s (23-0) reported on the action of a new halogenated hydrocarbon, 2-bromo-2-chloro-1:1:1-tri- fluoroethane or FluOthane also referred to as halothane. 34

This agent was non-explosive, more potent than ether or chloroform and had about twice the therapeutic ratio of

that of e t h e r . (28,175) Although Raventos(210) was unable to describe little physiologic change in cardiovascular function except hypotension Deutsch ejt_. a_l_* (^) has shown that halothane reduces not only systemic arterial blood pressure but also cardiac contractile force, cardiac output and total peripheral resistance. The last of the findings has been questioned recently by Sawyer et/al,(228) studying the effects of halothane on peripheral vascular resistance in miniature swine. These authors have shown an initial increase in this parameter. The concensus however, along with the evidence that halothane has a vasodilatory effect upon vascular smooth muscle in canine aortic strips, remains that halothane depresses peripheral vascular res istance.(4» 29 ,162 ,207) Although many para meters of cardiovascular function are depressed,

S h i m a s a t o ,(246) evaluating the effects of halothane in intact closed chest dogs concluded that the mechani cal efficiency of the heart is not altered. He concluded that the ventricles operate at different functional levels during various concentrations of halothane anes thesia in the presence of a decrease in myocardial contractility. As alluded to earlier, halothane like other chlorinated and fluoronated hydrocarbons also has the capability of sensitizing the ventricular myocardium 35 to arrhythmias. > 255) pronounced electrophysiologic alterations upon Purkinje and ventricular action poten tials have also been reported. Halothane has several distinct effects both centrally and peripherally that result in its profound (2 511 cardiovascular actions. Skovsted et^. al. v have demonstrated that soon after exposure to halothane sympathetic rhythm becomes disruped to almost continuous firing. This was interpreted as indicating that the major site of action was above the spinal cord. Subse quent studies in decerebrated cats have suggested a medullary sight of action.(205) Halothane also influences the efferent arm of the reflex arc and has been shown to decrease sympathetic ganglionic transmission.This finding combined with the paradox that postganglionic activity is still increased suggested that halothane may depress the hearts ability to respond to accelerator stimuli. From these studies it was concluded that the barostatic reflexes are not functioning normally during halothane anesthesia despite the fact that stimulation of the aortic depressor nerve still depresses sympathetic tone. Similar conclusions have been reached by Aars and

Hauge^-) and Bristow e_t. aJU in rabbits, dogs and man. The concensus is that halothane produces bradycardia and hypotension but has no consistent or slight depressive effects upon barostatic reflexes and that the cardio 36 vascular depression produced is largely due to its action on peripheral sights. In support of this contention ltfollman^®^ has demonstrated a direct vasodilator action on vascular smooth muscle induced by halothane. Price and Price (207) anc| piack and M c A r d l e ^ ^ have described a reduction in the normal vascular response to catechola mines particularly norepinephrine. The effect of halothane upon canine ventricular automaticity has been studied by Atlee and Rusy(^), Logic and Morrow*-15®}, Flacke and Alper^81) and Hauswirth.(112) The later authors* 112) have demonstrated direct depres sion of the sino-atrial node and rationalized that the same mechanism may be responsible for atrio-ventricular rhythms occurring during the administration of halothane. Atlee and Rusy*-1*^ demonstrated that halothane exerted its greatest effect by slowing conduction between the atria and bundle of His; there was also some slowing of conduction in the ventricle. They suggested that the arrhythmias seen with halothane are primarily due to impaired conduction. Logic and Morrow*^15®} described the effects of halothane upon the time-dependent conductance of pacemaker fibers to potassium. Halothane was found to produce a membrane stabilizing effect. In this regard it is now known that biological membranes are expanded by many inhalation anesthetics. Studies upon biomembrane expansion using erthrocytes have demonstrated that agents 37 such as chloroform, cyclopropane and halothane have anti- hemolytic effects and thereby stabilize the cell. As a consequence of membrane expansion, membrane assoc iated enzymes and proteins can be either stimulated or inhibited. The pathways for facilitated fluxes of solutes across these membranes may also be depressed. The sodium conductance most certainly being affected. The so called "fluidization" of the membrane by lipid soluble agents may also alter membrane responses, particularly because of its positive effect upon neurosecretion. While anes thetics may stimulate neurosecretion the overall effect of these compounds on the junctional or synaptic trans mission is depression. Neutral anesthetics have also been shown to increase membrane bound calcium and stabilize or increase passive ion fluxes. These studies emphasize the complexity of halothanes effect upon cellular membranes. Hauswirth (HO) has shown that halothane markedly increases the internal- longitudinal resistance of cardiac fibers and that the input capacitance is significantly reduced. These findings support the same author's obser vations that halothane decreases conduction velocity and shortens the action potential significantly in ventricular and Purkinje fibers. (Figure 2) (109) Moreover, the ex posure of the heart to the action of catecholamines contributes even more to abnormal activity. CHI) Reynolds et. al.(214) kas also demonstrated the suppression of 38

ELECTRO PHYSIOLOGIC EFFECTS OF HALOTHANE ON CANINE CARDIAC FIBERS

PURKINJE CONTROL FIBERS —HALOTHANE

1 VENTRICULAR FIBERS

Fig. 2.--Diagramatic Representation of the Effects of Halothane on Canine Cardiac Fibers. 39 of normal escape pacemaker activity showing that halothane depresses spontaneous phase four depolariza tion in Purkinje fibers in vitro. The electrophysiologic predisposition to arrhythmia formation from exposure to halothane may therefore be explained by: 1) a decreased conduction velocity, which is mainly due to an increase in internal resistance; 2) a marked shortening of the refractory period; and 3) a pronounced disparity of the refractory periods bet\>reen Purkinje and ventricular fibers. 00 9 , U O , 132)

One property of many of the halogenated inhalation anesthetics has been the ability to produce ventricular arrhythmias particularly in the presence of catechola mines .(40» 52, 133,171,173,203 , 261) Volatile anesthetics have been shown to sensitize mechanical stretch receptors and afferent nerve endings.(199) volatile anesthetics in their neutral form can also produce muscle contracture.(258)

Price et. al_. (208) pro

A n d e r s o n (2^5) h a s suggested that inhalation anesthetics produce at least two effects, the sum of which may vary depending on the anesthetic or anesthetic combination employed. They believe that in addition to anesthetizing tissues and cells anesthetics can also sensitize the

myocardium via their fluidizing effects upon the membrane and membrane bound calcium. Hall^-®^ has demonstrated an

increase in canine left ventricular sensitivity to the effects of epinephrine and Joas and Stevens £130) jiave

compared the dosage of epinephrine needed to produce arrhythmias in awake versus halothane anesthetized animals. These authors also pointed out that as the depth of halo thane anesthesia increases more epinephrine is needed to

produce an arrhythmia, Dresel and Sutter^^ have con cluded that the arrhythmias formed by sensitization are not due to increased automaticity but to reentry mechanisms. Although this sensitizing effect to epinephrine appears to be due to the direct effect upon the ventricu lar myocardium Hashimoto and Hashimoto£1^7»108) have

demonstrated that cardiac arrhythmias induced by halothane, after induction with pentobarbital sodium, could be abolished when heart rate was returned to control levels

or above by driving the atrium. Thus emphasizing the

importance of heart rate in halothane induced arrhythmia formation. Recently, Vick^^*0 has provided evidence that

halothane arrhythmias are dependent upon supraventricular input. He concluded that the arrhythmias caused by halo thane sensitization are maintained by a self-sustaining mechanism closely related to the increased automaticity

caused by epinephrine. Hashimoto and Hashimoto£1®®) have 41 supported these findings and hypothesized that the decrease of supraventricular input by halothane results in favor able conditions for the ventricle to produce arrhythmias.

Their study indicated that the level of supraventricular input is more important than the direct effect of halo thane on the ventricle itself. The mechanism of sensiti zation is due to halothane depression of sinus node activity. These studies indicate that halothane may have both protective and potentially dangerous effects upon cardiac rhythm. Certainly such factors as heart rate and blood pressure and thereby barostatic reflex activity are important considerations in evaluating the potential arrhythmogenicity of this agent.(134,171) ^he effects of other drugs used for restraint in the evaluation of halothane should also be considered. The influence of each of these factors in the intact closed chest patient exposed to halothane alone has not yet been examined. Phenothiazines and Arrhythmias The phenothiazine tranquilizers as a class are among the most widely used drugs in human and veterinary medicine today. Because of their profound mental calming effect in man and animals they have been classified as one of the major tranquilizers and used to combat psychosis in man.j^g phenothiazine molecule is a three ringed structure formed by the linkage of two benzine rings by 42

a sulfur and a nitrogen.i» Substitution at the 10-N and 2 position causes molecular asymmetry and increases pharmocologic activity. The many substitutions possible

at these sights has led to the formation of several dozen phenothiazine derivatives of which only about ten

enjoy a great deal of popularity. These are the drugs containing an aliphatic, piperidine or piperazine

(piperazinyl) group in the 10-N position. Although the

phenothiazine nucleus itself has little central nervous

system depressant effect its derivatives demonstrate this capability as well as many other properties. As a group the phenothiazine derivatives display gangliolytic,

adrenolytic, antiedema, antipyretic, anticonvulsant,

antiemetic, antihistiminic, antipruritic, antishock, antifibrillatory and antiarrhythmic properties.*^24)

The last of these several properties has been compared to the effects of quinidine. * 124) indeed many of the

phenothiazine derivatives have been shown to contain

potent local anesthetic effects although few have been used for this purpose.»149) Figure 3 illustrates the

basic structure of the phenothiazine molecule and its

active substitution sights. The substitution necessary, to produce several of the more common phenothiazine tranquilizers are also listed.

Recently a great deal of emphasis has been placed upon the possible role of the central nervous system and 43 the psychosomatic basis of cardiac arrhythmias. Parti cular emphasis has been placed upon the hypothalamus and

its control of many vegetative functions in this regard.

The effects of the phenothiazine derivatives as potential

antiarrhythmics has been investigated by Dunbar^^, Harvey and Levine , Katz and PickC-*3^), and Arora^) but these are not fully described. In 1953, Courvoisier

et. al_. (4 ^ found that chlorpromazine impaired the ability of animals to make a conditioned response. Similar findings were soon described by Cook and Weidley (4-*-) in rats and man. Although phenothiazine derivatives have been reported not to alter motor cortex response to direct stimulation they do produce changes at all levels of the cerebrospinal axis . (2,14,85,145) ^he Uptake of

S^S phenothiazine in the different parts of the brain of cats, monkeys and humans has demonstrated that the main action of the drug is upon the brain stem, Auto radiographic studies have specifically selected the reticular activating system and to a lesser extent the sensory portions of the cerebral cortex as the major sights of drug accumulation. The reticular activating system in particular has been shown to act as a moderator for most impulses ascending the spinal cord to connec tions in the thalamus and sensory cortex.(-*-4 3 ) Dobkin(33) demonstrated that vasomotor and therefore cardioregulatory reflexes mediated either by the hypothalamus or the PHENOTHIAZINE NUCLEUS AND SEVERAL COMMON COMPOUNDS

8 10 R.

CHLORPROMAZINE R 1 = -c h 2 - c h 2 - c h 2 -n (c h 3 )2 R2 =-C l PROMAZINE Rl =-CHg-CHg -CH2 -N(CH3 )2 R2 = -H AC ET YLPROMAZIN E R1 = c h ^ -c h2 -c h 2 -N(CI-^)2 hci R2 = c o - c h 3 THIORIDAZINE -c h 2 -c h 2 - < R 1 = N R2 = -SH~ CH-

Fig. 3.--Basic Structure of the Phenothiazine Molecule and Several of its Derivatives. 45 brain stem arc depressed by relatively low dosages of chlorpromazine. Hypertensive responses following stimu lation of the hypothalamic pressor regions are also diminished by the drug. Decorticate animals being particularly sensitive to these depressant effects.

Several conflicting views describing the mechanism of action of the phenothiazine tranquilizers centrally have been offered by Bovet et^. aT. C31) f Himwich and Rinaldi (115) and Killaml-^^ These theories may differ due to vari ability in species responses, techniques used and variations in dosages of drugs tested. None however, has adequately explained the role of these agents as centrally acting antiarrhythmics. The physiological effects of the phenothiazine derivatives particularly chlorpromazine, but including acetylpromazine, have been well documented.£38,42,92,99, 150,174,183,249 ,289) The hemodynamic effects of these drugs being complex because of their direct effects upon the heart and peripheral circulation. In therapeutic dosages the phenothiazine tranquilizers demonstrate slight ganglionic blocking activity, weak peripheral cholinergic blocking activity and strong adrenergic blocking activity.

In the dog an atropine-like effect has also been de scribed. (92) jn man, and a wide variety of animal species the intravenous administration of several of the pheno thiazine tranquilizers will result in orthostatic hypo 46 tension and tachycardia.(22) Inhibition of centrally

mediated pressor reflexes and o C -adrenergic receptor bloclcade are believed to be the cause. Finkelstein and Spencer(80) have demonstrated the effects of chlorproma

zine on heart muscle and its influence upon the inotropic

action of several sympathomimetic amines. These studies varified the antiadrenergic effects of previous workers

and illustrated the negative inotropic effects upon the myocardium of chlorpormazine itself. Similar findings

have been reported by Melville(^74) , Wendkos(284) and

Hollander ejt. al^. (-*-24) us^ng ^ 0 phenothiazine thiorida

zine. Concomitant with the decrease in inotropy is an increase in coronary arterial flow. Singh^^-* most accurately described this effect in 1969 using close intracoronary injections in dogs. These effects may be assumed to lead to decreased myocardial tension, oxygen

consumption and work load.

Singh(249) ^ singh and Sharma (2-50) f Yoshitani (290)

and Sato and Tanabe(22?) have described the antiarrhythmic activity of 10-N substituted phenothiazines. Substitution with a four carbon atom straight chain at this sight is responsible for maximum antiarrhythmic activity. Substitution at the 2 position (Figure 3) produced a less active antiarrhythmic form. Next in order of antiarrhythmic potency were those derivatives which had approximately three or five carbon atoms in the 10-N 47 position. This was followed by similar derivatives with

OCHg or Cl groups at position 2. The introduction of an amino group in the side chain at the 10-N position was found to reduce the antiarrhythmic activity considerably as observed with the phenothiazines prothipendyl, methoxy- promazine, levopromazine and multergan. From these findings it is obvious that straight chain unsubstituted carbon atoms in the 10-N position contain the most potent antiarrhythmic properties. It is interesting to note that these substitutions also lead to the most potent central nervous system depressant effects. (^2)

Electrocardiographically 10-N substituted pheno thiazine derivatives have demonstrated flattening of the T wave and ST segment. Prolongation of the QRS, PR and QT intervals have also been preported. ^ » 259)

Based upon these findings a model has been proposed comparing the effects of the phenothiazines to that of quinidine . ^ * 264) reasoning being based upon the potent local anesthetic effects of many of the pheno thiazine tranquilizers and the almost total similarity in tissue response characteristics in isolated perfussion studies. Hollander and Besch^23) in a comparison of the electrophysiological properties of quinidine and thiori dazine concluded that the only difference in their effect was an increase in electrical stimulation threshold exhibited by quinidine. Arita and SurawiczCS) have studied 48 the electrophysiologic effects of phenothiazines on canine ventricular and Purkinje tissue. Their findings indicate that the phenothiazine derivatives 1) decrease resting membrane potentials in Purkinje tissue but not ventricular muscle; 2) decrease the maximum rate of rise (dv/dt) of phase zero of the action potential. This effect being more pronounced at rapid heart rates thus indicating a dependence of dv/dt on time; 3) decreased the amplitude and duration of phase two of the action potential; 4} prolonged phase three of the action potential. All effects were augmented by increasing concentrations of drug and were more pronounced in Purkinje than in ventricular muscle fibers (Figure 4). Similar findings have been reported by Hollander and Cain(^4) even when the tissues had been exposed to varying quantities of norepinephrine. These effects have been found to be reversible by prior treatment of the tissue bath with increasing concentra tions of sodium ion.(^) This has led to the conclusion that phenothiazine derivatives retard the reaction of the rapid sodium-carrying system thereby decreasing the maximum available sodium conductance,( ^ *22S) Previous studies by Kelly et^. al^ (138) have sug gested that another prominent effect of phenothiazine derivatives upon the myocardial action potential may be a decrease in slow diastolic depolarization (SDD). The concept has been supported clinically by the prolongation ELECTROPHYSIOLOGIC EFFECTS O F PHENOTHIAZINES ON CANINE CARDIAC FIBERS

PURKINJE CONTROL FIBERS — PHENOTHIAZINE

VENTRICULAR FIBERS

3 V

Fig. 4.--Diagramatic Representation of the Effects of Phenothiazines on Canine Cardiac Fibers. 50 of the PR and QT intervals which occurs when conduction and depolarization rates of action potentials decrease.( ^ * 249)

This finding does not fully explain the significance of the phenothiazine derivatives on slow diastolic depolari zation, however Balzer et. a]^. (15) demonstrated the phenothiazines reduce the efflux of potassium from tissue slices. This would shorten diastolic depolarization if the hypothesis porposed by Deck and Trautwein(54) correct in that gradual reduction in potassium conductance is principally responsible for the pacemaker potential. Domato et^. a_l. (^) however have pointed out the importance of sodium conductance and the rate of slow diastolic depolarization. It has also been shown that the tran- quilizing concentration necessary to depress the potassium conductance of the action potential is generally about ten times higher than that required to depress the sodium conductance channel. (H 4 »144)

The term membrane stabilizer was first introduced by Guttman(^} who in 1940 found that calcium or magne sium ions prevented or stabilized the resting membrane potential of the nerve membrane from depolarization. Shanes (237) broadened this concept to include any com pound which inhibited a change in the resting membrane potential. Phenothiazines have been implicated as causing membrane stabilization as mentioned previously and have been classified as membrane stabilizers by Shanes.(^38) 51

Contrary to published reports of the inhibitory effects of phenothiazine derivatives upon calcium uptakeC13,15) it has been demonstrated that phenothiazines actually increase the rate of uptake of calcium by muscle microsomes.(68) Promazine, prochlorperazine, triflupromazine and perphenazine being of equal potency in this respect but less effective than chlorpromazine. When the activa ting cation potassium was added however, a decrease in calcium uptake was observed. Further studies have demon strated that chlorpormazine renders frog sartorius muscle inexcitable to S ugm/ml boluses of acetylcholine, reduces efflux of potassium from brain slices and decreases potassium uptake by sodium loaded liver slices. Another purported membrane stabilizing effect of pheno thiazine derivatives has been their ability to increase the membrane area of erythrocytes thus protecting them against osmotic lysis.(149) The membrane of subcellular organelles are also stabilized or protected by low con centrations of these same drugs.(I?®) It is interesting to note that the concentrations of phenothiazine deriva tives which cause fifty per cent antihemolysis are identical to the nerve-blocking concentrations in frog sciatic nerve preparations.(233,235) Similar observations upon membrane stability have demonstrated that phenothia zine tranquilizers exhibit surface-active properties principally at low concentrations.(233) The reduction of 52

spontaneous loss of catecholamines from catecholamine granules has also recently been established.(77) in

summary, since it has been known that lipid-soluble anesthetics and phenothiazine tranquilizers can "fluidize" and disorder the membrane it is probably more appropriate to refer to them as electrical stabilizers. Clinically the use of the phenothiazine tranquilizers as antiarrhythmics has enjoyed a wide variety of opinion. This eminates from the marked and diverse physiological effects of the many derivatives available. Most prominant among these being hypotension although everything from drowsiness to agranulocytosis and Parkinsonism has been attributed as a side effect. As a group their negative inotropic, chronotropic and dromotropic effects as well

as their effects upon the peripheral circulation has been alluded to previously. Their clinical usage as anti arrhythmics, however, has led to a great deal of contro versy. (7,23,40,59,148,189,190,232,239,257,260,291)

Kelly et^. aJU , Leestma and Koenig^1^2^, Surawicz and Lasseter(259) an

The 10-N cyclopentyl phenothiazines producing A-V nodal rhythms when injected into the circumflex branch of the left coronary artery. Sato and Tanabe^27) on the other hand have demonstrated the beneficial effects of pheno thiazines on clinical extrasystoles and tachycardias. Their effects upon experimentally induced atrial dys rhythmias such as atrial fibrillation and flutter has proven their potency to be equal in magnitude if not greater than that of quinidine as judged by the average percentage reduction in the duration of fibrillation. In clinical patients with auricular fibrillation, however, sinus rhythm was reestablished in only twenty per cent of the cases studied. These discrepancies may be based upon not only the membrane stabilizing qualities of the phenothiazines but also the effects which could facilitate re-enterant activity. Among these are decreased conduc tion velocity in all types of myocardial fibers, shortening of the effective refractory period in the Purkinje fibers, altered relation between the action potential duration between the Purkinje and ventricular fibers and altered effective refractory periods between Purkinje and ventri cular fibers. In conclusion, it is obvious that variations in the potency of a drug in different types of arrhythmias and the sudden reversion of an arrhythmia to normal sinus rhythm is hard to explain on the basis of the unitary concept of cardiac arrhythmias. Experimental or clinical

arrhythmias produced by different techniques or diseases

respectively may have different mechanisms and conse quently vary in their response to the different anti-

arrhythmics including the phenothiazine derivatives. Experimental Models for Arrhythmia Production

The production of cardiac arrhythmias has fascinated

investigators of the cardiovascular system for many^ years.(52) parly studies on alterations of heart rate

and rhythm were confined to the frog and turtle but as techniques improved studies rapidly advanced to the dog and cat and even man himself. Although several investi gators have questioned the applicability of using species

other than man for the study of cardiac arrhythmias few can deny their merit in dilineating the determinants of arrhythmia formation.(129,151,172) Certainly the dog and

cat remain the most popular experimental animals in the

study of cardiac arrhythmias and many inferences between these species and man have been drawn. Whether the variables which act to produce arrhythmias in the isolated

or intact dog or cat preparation act similarly in those in man is questionable. Hopefully studies on isolated perfusions and the use of cardiac pacing techniques have helped to eliminate this problem. In any general discussion of the initiation of cardiac arrhythmias, the relative merits of the ectopic 55 focus and circus movement theories, in connection with both auricular and ventricular disorders is bound to arise. This particular facet of arrhythmia production will not be dealt with here. Instead, the purpose of this section of the review will be to list the more popular methods used in the production of cardiac arrhythmias in experi mental animals and describe the techniques used in the production of arrhythmias via two-stage coronary artery ligation and hydrocarbon sensitization to epinephrine. The more popular of the various types of experimental models used in the production of cardiac arrhythmias are listed in Table 1. It must be remembered that although these various techniques have greatly increased the understanding of arrhythmia production and maintenance it is still uncertain if any one model adequately describes the situation in the unanesthetized intact animal and more specifically in the diseased human heart.

The more popular of the techniques used in the production of cardiac arrhythmias are centered around the production of various forms of damage to the myocar dium (Table 1). These include such procedures as anoxia

(anoxemia)^ 2 1 3 ) ^ exposuer to barium chloride C1S3,223,254) ^ veratrum alkaloids( 2 4 4 ) , aconitine£209»242,262)^ chloroform^^^ , digitalis £182) ( an(j coronary artery ligation . (103,201 ,217 , 252) ^11 of these studies indicate that these agents or techniques can induce and sustain 56

TABLE 1

TECHNIQUES USED IN THE PRODUCTION OF CARDIAC ARRHYTHMIAS

A. Alterations in Neurologic Parameters 1. CNS stimulation 2. Vagal stimulation 3. Sympathetic stimulation 4. Digitalis Glycosides B. Electrical Stimulation of Atria or Ventricles 1. Auricular stimulation 2. Ventricular stimulation *3. Pacing of Atrial or Ventricles C. Pharmacologic Methods that Alter Electrophysiologic Properties of the Myocardium 1. Catecholamines Epinephrine Norepinephrine 2. Acetylcholine 3. Acetyl-B-raethylcholine *4. Halogenated hydrocarbons and Epinephrine Chloroform Cyclopropane 5. Alterations of ionic milieu: hyperkalemia, hypokalemia, hypercalcemia, B hypocalcemia, hypercapnia D. Myocardial Damage 1. Anoxia (anoxemia) 2. Barium Chloride 3. Chloroform 4. Veratrum Alkaloids 5. Aconitine *6 . Digitalis Glycosides 7. Coronary Artery Occlusion Acute ligation *Two-stage ligation

^Currently popular techniques 57

automaticity in non-pacemaker isolated or intact myo

cardial preparations. The criticism being that until recently there has been little uniformity in the prepara tions or dosages of the drugs employed by the different investigators. This has led to a great deal of controversy in reported results. For example, although Levyd-53) had

come to the conclusion that anoxemia reduced the liability

of the heart to ventricular fibrillation caused by chloro

form and epinephrine, Resnik^l3) demonstrated that

denervated anoxemia dogs stimulated by a faradic current were predisposed to auricular fibrillation. Prolonged anoxemia however, produced an increase in fibrillatory threshold. Smith and Wilson(253) used somewhat different

conditions. They injected mecholyl into anoxemic dogs

and observed a high incidence of auricular and ventricu lar arrhythmias. Another example are studies with the cardiotoxic agent aconitine. Masuda and co-workers(166) have noted repetitive contractions when 10" 8 gm/ml of aconitine was dripped in the canine ventricle. Totuka^*^

achieved repetitive contractions of atrial muscle after a single mechanical stimulation and exposure to aconitine

in 10"8 gm/ml, 10"8 gm/ml doses and mechanical stimulation were needed to induce ventricular activity. Although studies such as these have indicated that atrial tissue may be more sensitive to specific toxic agents such as aconitine, little information is available as to the dose 58 response effect that may exist after exposure to aconitine or any other cardiotoxic agent. In the anoxemic studies referred to earlier, little effort was made to quantitate the degree of hypoxia in the models used, the formation of the arrhythmia being the decisive factor. Certainly the development of a casual relationship between the type of arrhythmia produced and the amount of drug or type of preparation is difficult to establish from these studies.

Also in preparations where intact animals were used the influence of arterial pressure and autonomic control was often overlooked or considered secondary to the primary goal. Arguments similar to those used above can be levied against many other techniques used in the production of either auricular or ventricular arrhythmias. Techniques such as, stimulation of discrete central nervous system centers(51>231)^ 0£ sympathetic and parasympathetic neurons (*53»216) t alterations of blood pressure (153) an(j cardiac pacingC151,?00) produce arrhythmias electrocardiographically indistinguishable from those seen clinically. These techniques demonstrate the importance of various influences but do little to illuminate the roles of the. determinants of arrhythmias in the spontaneously occurring disease. Cardiac pacing, for example, alters autonomic activity upon the heart but does so as a result of the arrhythmia. In many clinical patients however, it is 59

either the distortion or loss of normally balanced autonomic influences on the conduction system that is responsible for electrical instability and arrhythmia formation.(129)

Of the techniques listed in Table 1, the two which appear to have the most clinical bearing are the two- stage coronary artery ligation model developed by Harris(103) and the hydrocarbon sensitization technique developed by L e v y ^ ^ ^ and expanded upon by Meek et. al. (122) Coronary artery disease and acute myocardial infarction are responsible for over fifty per cent of the deaths in the United States each year. (191) Although it may be argued that coronary artery occlusion models are much more acute than the spontaneously occurring disease it is reasonable to assume that the same determinants which act acutely are important in the more chronic situation. Similarly, there is no question as to the importance of describing the relative arrhythmogenicity and determinants thereof of the different inhalation anesthetic agents used clinically today. Prior to work conducted by Harris(103) the few experimental studies on ventricular ectopic activity following coronary artery occlusion was confined to observations made within a brief period after occlusion.

The paucicity of experimental studies being attributable to the high rate ofearly mortality via ventricular 6 0 fibrillation and the cessation of ectopic ventricular

activity within ten to twenty minutes in those hearts that survived. The early development of ectopic ventri cular activity and fibrillation in dogs due to acute coronary artery ligation has been described by Lewis(155)^

PorterC201) an(j Robinson and Herrman. (217) They observed

that fibrillation due to ligation of one of the two major rami of the left coronary artery occurred no later than the tenth minute after occlusion. Ventricular fibrilla tion being initiated by a paroxysm of ventricular ectopic systoles accelerating in frequency. In several trials the ventricular premature systoles ceased entirely after an initial period of increased activity and continued at a slow rate of about one to five per minute for up to thirty minutes. Moe et. elL.(179) has demonstrated a casual relationship between vintricular premature systoles and the initiation of ventricular fibrillation in acute cases of coronary artery ligation. In the early 1950s Harris(103) introduced his technique of two-stage ligation of the coronary artery. The left coronary artery was dissected free and partially ligated at varying distances from the aorta. This was facilitated by incorporating a twenty guage needle in the first ligature tightened around the coronary artery and then removing the needle. After a period of one hour had elapsed a second ligature was tightened around the artery. 61 Later the waiting period was shortened to thirty minutes.

The second ligature completely and permanently closing the artery. The relationship of early mortality and development of ectopic ventricular discharges was found to be crucial to the distance of the ligature from the ostium of the left coronary artery. Tightening of the second ligature at 2.6-3.0 cm. from the aorta prevented the immediate loss of animals from ventricular fibrilla tion and resulted in less than twenty-five per cent total mortality rate. The reason for the protection against immediate ventricular ectopic rhythms still remaining a mystery. Following the final stage of occlusion there was a period of four to eight hours with little or no ectopic activity. After this quiescent period ectopic impulses developed rapidly. This high ectopic rate persisting for twenty-four to forty-eight hours postoperatively and then subsiding slowly over the next three to•four days. The animals body temperature increased inconsistently with ventricular ectopic frequency. All hearts developed gross infarcts. The ectopic foci appeared to be originating from one of three sights: 1) a thin band of tissue surrounding the ischemic area, 2) a thin band of tissue between th.e ischemic myo cardium and the spared endocardium, 3) a thin sheet of tissue between the ischemic muscle and a spared epicardial layer. The electrocardiograph indicating a predominant 62

single focus in most instances. Other excitable factors besides anoxia and the injury potential were attributed to sympathoadrenal stimulation and histamine release.

More recently Gillis et_. al_, (88) have used the Harris model in testing the efficacy of several peripherally and centrally acting antiarrhythmic drugs. Their studies indicate that drugs that depress the central nervous system, specifically sympathetic nerve activity, may be effective for the treatment of ventricular arrhythmias due to myocardial infarction. The second model to be described and probably the most complex in regards to possible physiologic effects originates from the investigations of Levy.(153) j^e combined chloroform and epinephrine to produce arrhyth mias in the cat. Both these agents are capable of inciting cardiac irregularities in themselves. Studies since that time have emphasized the arrhythmogenic effect of many hydrocarbon anesthetics (185) an(j use 0£ sympathomimetic amines.(18°) Although the variables involved are complex and seemingly difficult to control, experiments using intact animals have revealed the individual determinants important in arrhythmia formation. The model is created by exposing the animal to what is referred to as a "sensitizing" agent, generally an inhalation anesthetic. This is a poor choice of words in that most of the so called sensitizing agents are 63 depressant on the myocardium and have been classified as membrane stabilizers by Shanes.(237) After the animal has been maintained at a specific anesthetic concentra tion for a given period it is administered boluses of epinephrine intravenously. In this manner the importance of sympathetic activity, plasma catecholamine levels(180)^ arterial blood pressure(153)^ electrolyte imbalancesC134)i hypoxia and hypercarbiaC221) have been studied in rela tion to arrhythmia development. The concentration of the anesthetic delivered and the amount of epinephrine administered have also been evaluated. The great diffi culty in interpreting these studies has been the laclc of a standardized boluses of epinephrine and a quantitative approach to the evaluation of the effects of the diffe rent determinants. It is not enough in judging an anesthetic merely to note that the heart shows irregulari ties of rhythm. One should also have the ability to clearly define the determinants and quality of the arrhythmia. In conclusion, it does not appear that any of the techniques used to produce cardiac arrhythmias is com pletely free of critizism. On the other hand, all have aided in our knowledge of arrhythmia development and maintenance. They have also helped in the refinement of new antiarrhythmic agents. The quantitative effects of the different physiologic factors in the production and 64 maintenance of arrhythmias still remains to be ascer tained. This is particularly applicable when speaking of inhalation anesthetics. CHAPTER II

MATERIALS AND METHODS

Eighty-four dogs judged to be in good health upon physical examination, electrocardiogram, and lateral and dorso-ventral radiographs of the thorax were divided into one of ten categories. These dogs were adults of either sex with weights ranging from 17 to 2 0 kg. The groups studied were: Group 1 . Six dogs were chosen to serve as controls. These animals were trained to remain in lateral recumbancy after placement of an intravenous catheter in the jugular vein and electrodes forming lead aVf of the electro cardiogram. Four dogs in this group were monitored for changes in arterial blood pressure. This was accomplished by prior surgical placement of a number eight polyethy lene catheter in the carotid artery. The catheter was then exteriorized at the nape of the neck. The placement of the arterial catheter was facilitated by halothane anesthesia approximately twenty-four hours previous to any recordings. Recordings of the electrocardiogram were monitored before, during and for variable periods of time 65 66 after the administration of 5, 10, 20, 40, 80, 160, 300,

and BOO ugm boluses of epinephrine per dog, given intra venously. A minimum amount of restraint was used when necessary. The dogs heart rate and blood pressure, in those which were monitored, were allowed to return to control levels for a period of at least ten minutes prior to the administration of another incremental dose of epinephrine. Group 2. Six dogs were anesthetized with a dose of 5 mg/lb thiamylal sodium given as an intravenous bolus. (Thiamylal will be referred to as Surital in the Figures.) They were then intubated with a cuffed endotracheal tube and maintained in an anesthetic state with repeated doses of

thiamylal sodium given to effect. Polyethylene catheters were surgically placed in the jugular vein and carotid artery for drug administration and arterial blood pressure monitoring respectively. Electrocardiograms were monitored with leads corresponding to the X, Y, and Z planes. These correspond to electrocardiographic leads I, aV£, and V-^g respectively. Again, incremental microgram doses of epinephrine were administered via the intravenous cathe ter as in the control group (5, 10, 20, 40, 80, 160, 300, 500). Heart rate and blood pressure were allowed to return to control values after each dosage of epinephrine (15 minutes) before'the experiment was allowed to continue. 68 80, 160, 300 and 500 of epinephrine were administered intravenously. Adequate time between measurements was allowed so that the heart rate and pressure could return to pre-drug administration levels.

Group 5. Fourteen dogs were atropinized intravenously

(0.01 mg/lb) after being anesthetized and prepared simi larly to those animals in Group 4. They were then monitored and subjected to the same incremental dosages of epinephrine as in Group 4.

Group 6 . Six dogs were given the ataractic acetylpromazine (0.4 mg/lb as a premedicant approximately twenty minutes prior to induction to anesthesia with thiamylal sodium (5 mg/lb). The dose of acetylpromazine was derived from previous studies by Singh C249) an(j found be the approximate minimum effective dose needed to prevent minor ventricular arrhythmias. Intubation was accomp lished with a cuffed endotracheal tube and anesthesia maintained with a 1 to 1.5 per cent concentration of halothane in oxygen. A twenty minute stabilization period was allowed during which time jugular vein and carotid artery were exposed and polyethylene catheters placed as previously described. This time, however, 5, 10, 20, 40, 60, 80, 160, 300, 500, 1000, and 5000 microgram boluses of epinephrine were administered intravenously. Adequate 69

time was allowed between boluses of epinephrine for heart rate and blood pressure to return to pre-drug administration levels. Group 7 . Eight dogs were anesthetized and prepared similarly to those dogs in Group 6 . They were then given an intra venous bolus of acetylpromazine (0.4 mg/lb). This was done in order to quantitate the effects of this drug upon heart rate and blood pressure. A suitable period of time \\ras allowed to pass until heart rate and blood pressure stabilized (approximately twenty minutes). These dogs were then monitored as in the previous groups and administered incremental microgram boluses of epinephrine as in Group 6 .

Group 8 . Nine dogs were prepared as in Group 4 and studied independently before exposure to epinephrine. The pur pose being to evaluate the influence of arterial blood pressure upon predisposition to arrhythmia formation.

These animals were initially exposed to incremental micro gram boluses of epinephrine as were the dogs in Groups 1 through 8 . When the dosage of epinephrine needed to establish multifocal ventricular tachycardia had been established, drug administration was stopped. The dogs were then divided into two sub-groups. In the first group (three dogs) arterial blood pressure was increased 70 via administration of phenylephrine (0.10 mg/lb) approxi mately ten minutes prior to epinephrine administration. In the second group, arterial blood pressure was reduced prior to epinephrine administration by one of three techniques; 1) venous occlusion via placement of balloon tipped catheters in the anterior and posterior vena cavae approximately two to three centimeters from the heart (2 dogs). The placement of these catheters being facili tated by fluoroscopy with image intensification, 2) administration of nitroglycerin (.01 mg/lb) intravenously (2 dogs), 3) administration of pentolinium tartrate intravenously until blood pressure had been lowered by approximately 40 mmHg (2 dogs). The dosage of epinephrine needed to produce multifocal ventricular tachycardia in both these sub-groups was then compared to the dosage of epinephrine needed to produce the same arrhythmia prior to arterial pressure alteration as outlined above.

Group 9 . Four dogs were induced to anesthesia with thiamylal sodium (S mg/lb) intubated and maintained in a surgical plane of anesthesia with a 1 to 1.5 per cent concentration of halothane as in Group 4. A twenty minute period was allowed for equilibration during which time polyethylene catheters were placed in the jugular vein and carotid artery. This was done in order to facilitate intravenous injections and arterial blood pressure recordings 71 respectively. The dogs were then subjected to incre mental intravenous boluses of epinephrine as in Group 4.

Heart rate and blood pressure were allowed to return to control values before larger increments of epinephrine were administered. This was continued until the ventri cular fibrillatory dose of epinephrine had been reached. The dog was electrically defibrillated and allowed a thirty minute stabilization period. The spinal cords and vagus nerves of these animals were then transected at the atlanto-occipital junction and at the cervical region respectively. All animals were artificially ventilated with one per cent halothane in oxygen. The mean dose of epinephrine needed to produce ventricular fibrillation was then reestablished. The dogs were again electrically defibrillated and allowed a thirty minute stabilization period. At this time acetylproma zine (0.4 mg/lb) was administered as an intravenous bolus. Incremental doses of epinephrine were then administered as described for Group 7 until ventricular fibrillation or a dose of 1000 ugm of epinephrine had been reached.

Group 10. Four dogs were induced to anesthesia with thiamylal sodium (5 mg/lb) intubated and maintained in a surgical plane of anesthesia with a 1 to 1.5 per cent concentration of halothane as in Group 4. The thoracic cavity was then aseptically entered through a left lateral thorocotomy 72 at the fourth intercostal space. The pericardium was opened and the left anterior descending coronary artery isolated and occluded in two stages according to the method described by Harris.(103) ^he pericardium and chest were then closed and a polyethylene catheter for measurement of arterial blood pressure surgically placed in the carotid artery. This catheter was exteriorized at the nape of the nec.lt. These animals were studied the following day, twenty-four to forty-eight hours after coronary artery occlusion, in the unanesthetized state before and after the administration of 0.5 mg/lb of acetylpromazine intravenously. This dose of acetyl promazine is not that disimilar from that used in Groups 6, 7, and 8 and was used for the sake of convenience.

All animals in this group had been trained to lie quietly while ECG recordings (leads I, aV£, II, III) and arterial blood pressure were being recorded. The arrhythmia produced by coronary artery ligation was quantitated by counting every beat during a three minute period and noting the number which were normal in origin. Electrocardiographic recordings were taken for variable periods before and after the admimistration of acetylpromazine. This drug was rapidly administered intravenously via a catheter placed in the cephalic vein. A stabilization period of approximately twenty minutes was allowed to pass before the first measurements were 73 recorded. Thereafter, recordings were obtained at approximately two hour intervals for eight hours. Boluses injections of epinephrine administered intravenously in a constant 5 cc volume of phsyiologic saline were chosen in preference to a constant infusion technique in those dogs receiving epinephrine. This method was chosen based upon the discrepancies and inaccuracies of previous dose-response data collected on a preliminary study in eighteen dogs of various weights. Bolus injections have been shown to be effective and are acceptable providing the drug is administered rapidly and in close proximity to the heart.(172) in these studies all injections were made into the right atrium by rapid injection. Dogs of similar weights were used so as to minimize this variable and its effect upon response. Electrocardiographic and pressure fluctuations were recorded by a multi-channeled direct writing Brush recording system, which was flat from DC to 60 hertz. These parameters were monitored on a six channel oscillo scope for constant visual observation. Arterial blood pressure recordings were facilitated by use of a P23 AA statham pressure transducer. Alterations in blood pressure were examined for mean systolic and diastolic changes as well as mean arterial pressure alterations before and after epinephrine administration in Croups 1 through 8. Arterial blood 74 pressure in Group 9 was monitored for mean value changes only.

In Groups 2 through 8 electrocardiographic leads

I, ^io* anc* ^3 were recorded for comparison of rate and rhythm before and after the administration of epin ephrine. Because Groups 1 and 9 were recorded in the unanesthetized state, electrocardiographic leads I, aV^.,

II and III were selected because of the ease with which they could be obtained. In some instances only one + electrocardiographic lead could be obtained and then lead aV£ or II was selected. Heart rate was monitored in all groups as to mean value changes before and after epinephrine administration in Groups 1 through 9. Arrhythmias were classified as one of the following: (Figure 5)

1. Normal Sinue Rhythm (control)

2. Sinus Tachycardia

3. Bigeminy

4. Extrasystole 5. Ventricular Tachycardia

6. Multifocal Ventricular Tachycardia 7. Ventricular Fibrillation Dogs in group ten were observed for mean heart rate changes, and number of normally conducted beast as pre viously described. Venous blood samples for acid-base determination Fig. 5 -Classification of Arrhythmias Associated with the Administration of Epinephrine and Anesthesia. LEGEND

(ST) SINUS (ST) (VT) TACHYCARDIA

(BG) BIGEMINY

(ES) EXTRASYSTOLE M - l t M i fte (VT) VENTRICULAR TACHYCARDIA (BG) (MVT) (MVT) MULTIFOCAL f I I l ! i ! ; . . I- VENTRICULAR TACHYCARDIA . (F) FIBRILLATION

(ES) (F) 77 were collected anaerobically at random from several animals in each group. This was facilitated by the prior placement of the venous catheter. Blood samples were collected into heparinized syringes and analyzed within ten minutes of collection. Measurements were made on an automatic analyzer which measured pH with a reproducibility of ^ .002 pH and pCC^ with a repeatability of 0.2 mmHg. The bicarbonate was calculated from the Henderson- Hasselbach equation for carbonic acid. Base excess was extrapolated from the Siggard-Anderson nomogram which has been shown to be applicable to the canine. All data was analyzed by paired and grouped students t-tests with the criterion for significance being P 0.05. CHAPTER III

RESULTS

The cardiovascular response to epinephrine can be

divided into three phases based upon alteration in heart rate or arterial blood pressure. The first phase can be classified as a period of rapid response during which

time both heart rate and arterial blood pressure increase rapidly. The magnitude of these increases are dependent upon the dose of epinephrine administered. Alterations in systolic and diastolic pressure are characterized by larger increases in systolic than in diastolic pressure. This results in an increased pulse pressure. The second phase is a period of adjustment. During this period heart rate and blood pressure readjust themselves to new levels depending upon the amount of epinephrine administered and previous drug exposure. It is this period which

appears to be the most indicative of the degree of auto nomic control. This period is also marked by a further

increase of the pressure pulse due primarily to a fall in

diastolic pressures and a resultant fall in mean arterial blood pressure. Phase three is the period of gradual return towards control values and is time dependent

78 79 varying with the dosage of epinephrine. After heart rate and blood pressure have reestablished themselves at relatively stable levels there is a gradual return to control values. Because all dogs in all groups responded similarly to epinephrine administration during the first phase (period of rapid response) most of the results will be in reference to phase two unless otherwise indicated.

Group 1 (Control The mean value for heart rate and blood pressure for those animals in Group 1 were 88* 18 and 124* 18 mmHg respectively. Upon injection of 5 ugm of epinephrine heart rate increased slightly or remained unchanged. Mean arterial blood pressure followed the pattern pre viously described with an overall increase of approximately 5 mmHg. Upon administration of 10 ugm of epinephrine heart rate decreased in most dogs while blood pressure increased an average of 10 mmHg. At a mean dose of approximately 15 ugm ( 1 mg/kg) of epinephrine ventri cular extrasystoles or a ventricular rhythm developed. Heart rates during this time were approximately one half of their control values. Mean arterial blood pressure on the other hand, continued to increase and was characterized by a widened pressure pulse. This pattern continued (decreased heart rate; increased mean arterial blood pres sure) until a dose of approximately 160 ugm ( % 10 mg/kg) of epinephrine had been reached. At this point four dogs 80 developed a rapid ventricular tachycardia of 272*34 beats per minute while two others remained in slow ventricular rhythm of 54-15 beats per minute. Mean arterial blood pressure at this dose of epinephrine increased approxi mately 60 mmHg from control values. As the dosage of epinephrine increased past 160 ugm all dogs developed rapid ventricular tachycardia. This was soincident with progressively higher initial (phase one) and secondary mean arterial pressure values. Although mean arterial pressure never fell below control values during phase two of the response to epinephrine its value always decreased from the initial peak. This was particularly evident if a slow ventri

cular rhythm developed. None of the animals in this group died but all developed fast ventricular tachycardia primarily unifocal in nature. The control electrocardio

gram and response to varying doses of epinephrine are shown in Figure 6. Figure 7 demonstrates alterations in cardiac rhythm coincident with arterial blood pressure fluctuations. Group 2 (Thiamylal) The mean values for heart rate and blood pressure

for animals in Group 2 were 150il9 and 142il7 respectively. The response to a 5 ugm bolus of epinephrine intravenously was an increase in mean arterial blood pressure to approxi mately 165tl2 mmHg and the establishment of a bigeminal Fig. 6.--Control Electrocardiagram and Respons to Varying Doses of Epinephrine in the Dog. 82 GROUP t M - 2 CONTROL t-^r* ECG a F \

fi ,n .• n . n ... n.~n— n.

I , 20Mgm *, v- /I— M' l<—W il*""

i i.. Ju_— L Jl— Jl-- II— Jl_ j n . - n n _ n _ n ti -..il

E-.b h yilK'/tSWW 40(Jgm "T* W m r a

1 . t i V

^ J u ■i. Ln ; h- ' n -1 fl I n ; fi ;fi ,

160|igm

lU-.h. n-^-lL

| ...... ”"T , 1 ■■ i ...... _____ 1____ -— r .. •••[--- <

~i*ir i t il ?^

ARTERIAL BLOOD PRES.

__ 2 0 m m H g

'10 85 rhythm in four dogs. Heart rate and blood pressure reestablishing itself at 142t26 and 151119 mmHg before returning to control values. The majority of dogs in this group responded to increasing doses of epinephrine by establishment of bigeminy, slower heart rates and gradual increases in mean arterial blood pressure until a dose of 160 ugm of epinephrine had been given. At this point ventricular tachycardia or multifocal ventricular tachycardia became the predominant rhythm. Heart rate increasing to a rate above 230 beats per minute in most dogs. Mean arterial blood pressure continued to increase in all instances. One dog died at a dose of 160 ugm of epinephrine and a heart rate and mean arterial blood pressure of 210 and 162 mmHg respectively. The remaining dogs survived the final dosage of 500 ugm of epinephrine displaying multifocal ventricular tachycardia and eleva ted arterial pressures. Group 3 (Halothane) Animals in group three had control heart rates of

107-13 beats per minute and mean arterial pressures of 92tl3 mmHg after the stabilization period with halothane. The response to a 10 ugm bolus of epinephrine was marked by the initial rapid increase in both heart rate and blood pressure described previously. This was followed by a change in heart rate to 87il3 beats per minute and an arterial blood pressure of 123tl4 mmHg. Premature 86 ventricular contractions were evident even at this low dosage. As the dose of epinephrine was increased multi focal ventricular tachycardia and ventricular fibrilla tion rapidly developed. All dogs developed ventricular* fibrillation at or before a dosage of 80 ugm of epineph rine. The mean lethal dose being 60.7 ugm of epinephrine or approximately 2.3 ug/kg. Mean arterial blood pressure increased as the dose of epinephrine increased similar to previous groups. Group 4 (Surital-Halothane) and Group 5 (Surital-Halothane-Atropine) Because these two groups are similar in every respect as pertains to their preparation and experimental design except that those animals in group five received atropine (0.01 mg/lb) they will be considered together.

The mean heart rate for animals in group four was 142tl7 beats per minute. The mean heart rate for those animals in group five was 138tl6 before the administration of atropine and 151^23 after the administration of atropine intravenously. The absence of a significant effect in mean heart rate change was due to the wide variability in control heart rate values. All dogs, however, demon strated an increase in heart rate of approximately 15 beats per minute. Mean arterial blood pressure in those animals in group five increased approximately 13t mmHg after the administration of atropine. Control mean arterial blood pressure was 116tl2 mmHg, 87

The response to a 5 ugm bolus of epinephrine administered intravenously was sinus tachycardia and bigeminy. Mean arterial blood pressure increased approxi mately 12 mmHg in both groups before the onset of an arrhythmia. As the dosage of epinephrine increased, the predominant arrhythmias noted in both groups were bigeminy, multifocal ventricular tachycardia, and ventricular fibrillation. Those dogs which had been given atropine progressed to multifocal ventricular tachycardia and fibrillation more rapidly than dogs in group four. The mean dose of epinephrine needed to produce ventricular fibrillation for dogs in group four being 62.4 ugm of epinephrine as opposed to SI.4 ugm of epinephrine for those dogs in group five. This difference was insignifi cant when analyzed statistically (P .05).

The dose of atropine chosen was based upon that dosage used commonly in clinical practice. It can be questioned if all the dogs were truly atropinized at this dosage because of the inadequate evidence for cardiac vagolytic effect. The data suggest, however, that atropine at the dosage used does have an effect upon cardiac rhythm. Heart rate and arterial pressure values increased progressively from control values with increasing doses of epinephrine. The change in arterial blood pressure appearing to have the same general pattern as that descri bed for previous groups but being maintained at higher 88 mean values during phase two of the epinephrine response.

Group 6 (Acetylproma.zine-Surital-Halothane) Group-7 (Surital-Halothane-Acetyipromazine)

The results of these two groups will be discussed simultaneously because of their similarity. The only difference between the groups is the time at which acetylpromazine was administered. This was done in order to quantitate the effects of acetylpromazine upon mean arterial blood pressure. The mean heart rate for the two groups before acetylpromazine administration was 108tll beats per minute that after being approximately 120 beats per minute. Mean arterial blood pressure decreased 20^6 mmHg after acetylpromazine administration. The control mean being approximately 125-14 mmHg. The response of cardiac rhythm to increasing boluses of epinephrine in these groups was predominately sinus and ventricular tachycardia. In several instances pre mature ventricular contractions were noted. In only one instance did multifocal ventricular tachycardia arise and this was after 5000 ugm bolus of epinephrine. Out of the fourteen animals in both groups one died at a dose of 1000 ugm of epinephrine. Heart rate increased to progressively larger values as the dose of epinephrine increased. Mean arterial blood pressure, however, was unique as compared to the previous groups. Upon administration of epinephrine blood pressure initially increased as expected dependent upon the dose administered. During phase two, however, pulse pressure widened to a much greater degree than was seen previously with a corresponding decrease in blood pressure. In all instances mean arterial blood pressure fell below con trol values before returning to control values. This pattern continued until a dose of approximately 160 ugm of epinephrine had been reached. At this point blood pressure began a type of sinusoidal oscillation slightly above control values. This was coincident with accelera tions and decelerations in heart rate. At times of high pressure values the rhythm would often change to a ventricular focus (Figure 8). Alterations in cardiac rhythm with increasing doses of epinephrine for groups one through seven are shown in figures 9 through IS. The shaded area respresents the control number of dogs in each group before epinephrine administration. Figure 16 is a three dimensional plot of groups one through seven versus the arrhythmia developed and the corresponding dose of epinephrine needed to pro duce that rhythm. Figure 17 is a diagram of the rhythmic response of each individual dog in each group to the different boluses of epinephrine. Table 2 gives the mean values of the changes in heart rate from control values due to intravenous epinephrine administration. Table 3 gives the mean dose of epinephrine needed to produce the arrhythmia listed for each of the seven groups. Fig. 8— EFFECTS OF EPINEPHRINE ON THE RELATIONSHIP BETWEEN HEART RATE AND BLOOD PRESSURE IN HALOTHANE ANESTHETIZED DOGS GIVEN ACETYLPROMAZINE. _20mm Hg

# ^ Aomlrvlitration ot 300pgm of Epinephrino LVf

' e cg leao : - - ■ • • : i

4*1 j M l i NJIti avF

.JlMEfete) . Fig. 9.--Effects of Definitive Doses of Epinephrine on Cardiac Rhythm in Unanesthetized Dogs. CONTROL tLgm OF EPINEPHRINE

C 5 10 20 30 40 SO 60 70 80 90 100 160 300 500 1000 5000

S i • • • (ST) • • • • !vtw!m y ! •a v a 'Iv !*

(BG)

• • • • (ES) • • • •

• • • • • • • (VT) • • • • • • • •

(MVU

(F) Fig. 10.--Effects of Definitive Doses of Epinephrine on Cardiac Rhythm in Dogs as Influenced by Surital. SURITAL fi.gm OF EPINEPHRINE

•

(ST) m ■

• • • (BG) • • • •

• • . (ES)

• • • • • (VT) •

• • (MVT) • • • • • • • 0 •

• (F) Fig. 11.--Effects of Definitive Doses of Epinephrine on Cardiac Rhythm in Dogs as Influenced by Halothane. HALOTHANE |xgm OF EPINEPHRINE

C 9 10 20 30 40 50 60 70 80 90 100 160 300 500 1000 5000 IS • • (ST) lllll • • ilss!• •

• (BG)

• • • • (ES) • • • • •

(VT)

• • • • (MVT) • •

• • • • (F) • • Fig. 12.--Effects of Definitive Doses of Epinephrine on Cardiac Rhythm in Dogs as Influenced by Surital and Halothane. SURITAL-HALOTHANE fxgm OF EPINEPHRINE

C 5 10 20 30 40 50 60 70 80 90 100 160 300 500 1000 5000 • •• • •• • • • • • •• • •• • • (ST) • • • m m • •• • • • •• • • • • • • • • • • • • • • • • • • (BG) • • •

• • • • • t (ES) • •

• • (VT)

• • • • • • • • • • • • • (MVT) • • • • • • • • • • (F) • • • • Fig. 1 3 -Effects of Definitive Doses of Epinephrine on Cardiac Rhythm in Dogs as Influenced by Surital, Halothane and Atropine. SURITAL-HALOTHANE - ATROPINE p.gm OF EPINEPHRINE

C 5 10 20 30 40 50 60 70 80 90 100 160 300 500 1000 5000 • • • • • • (ST) :***: • • it*:#! • •

(BG) • • • • • • • •

• • (ES)

(VT)

• • • • • • • •

(MVT) • • • •

C 5 10 20 30 40 50 60 70 80 90 100 16Q 300 500 1000 5000 ill • • •_ • • • • • • • • • • • (ST) ili • • • • • • • • • • • • • • 111 • • • • • • • • • • • • • •

(BO)

(ES)

(VT)

• (MVT)

• (F) Fig. IS.--Effects of Definitive Doses of Epinephrine on Cardiac Rhythm in Dogs as Influenced by Surital, Halothane and Acepromazine. SURITAL-HALOTHANE-ACEPROMAZIN E |igm OF EPINEPHRINE

C 5 10 20 30 40 50 60 70 80 90 100 160 300 500 1000 5000 • 9 • 9 • • • 9 • 9 • 9 9 9 i s • • • • • • • • • • • • 9 9 (ST) • 9 • • • • • • • • • 9 9 9 9 • • • 9 • • • 9

(BG)

•• 9 9 9 9 (ES)

J (VT)

(MVT)

(F) Fig. 16.--Three Dimensional Representation of Anes thetic Regimen versus Dose of Epinephrine versus Arrhythmia Formed, tOOO^gm 1000pgm Fig. 17.--Specific Arrhythmias Associated with Various Anesthetic Regimens and Dosages of Epinephrine. CATEGORIES I 2 3 4 5 6 7 GROUPS — C (6) S(6) H{6) S - H (21) A-S-H04) Ae-S-H(6) S-H-Ac(8) . NORMAL I 0- 1 1 1 1 1 1 1 1 SINUS RYTHM 2 ST 2 3 3 3 3 2222222 Z 5- 1 2 2 333333 2 2 4 4 3 BG 1 4 4 4 4 3 3 3 3 3 4 4 4 222222 222 4 ES 3 10- 33333333 33333333 5 4 9 4 4 2 2 4 4 4 666 7 4 66 5 VT 22 3333333 4 4 4 4 3 3 3 3 4 4 4 4 333333 4 2 0 - 3333 444 6666 2 2 6 MV T 5 5 3 0 6 6 9 777 7777 3 3 3 3 3 6 6 6 6 3 44 9 666 6665666 2 2 2 2 2 2 2 7 F 3 - 4 0 - 5 5 7 7 666666 7 7 7 2 4 5 7 7 7 7 3 3 3 4 3 666666 66666 2 2 222 22 s leo- 5 9 9 6 777777 77 2 4

3 999 66 222222 7 8 0 - 5 6 6 7 77777 7 2 4 4

66666 222222 6 160- 5 7 7 7 7 2 4 4

9 32 0- 22222 5 6 7 7 7 2 4 4 4 10 900- 5 6 7 7 7 5 5

5 5 5 5 9 11 1 0 0 0 - 7 7 7 7 5 TABLE 2

MEAN HEART RATE ALTERATIONS AFTER THE INITIAL PRESSURE PEAK DUE TO THE ADMINISTRATION OF EPINEPHRINE INTRAVENOUSLY

C 5 10 20 40 60 80 160 320 500 1000

c 88-11 98-6 71*7 56*6 51*6 49*7 43*17 272*34 284*31 342*67 *54*15

s 150-19 142-26 136-19 127*13 124*12 122*13 123*21 121*27 240*36 295*54

H 107-13 132-17 87-13 112*32 220*54 246*28

S-H 142-17 148-17 156-18 159*23 181*23 232*25

S-H-A 151-23 156-24 158-16 160*18 240*35 238*41

S-H-Ac 120-15 125-18 121*22 153*16 165*12 164*14 180*23 241*31 245*37 250*16 243*18

Ac-S-H 123-14 128-15 133*22 155*18 160*11 165*17 185*25 231*42 230*35 236*21 240*14

^Several dogs displayed slow ventricular rhythm at this dosage of epinephrine. TABLE 3

MINIMUM, MAXIMUM AND MEAN DOSE OF EPINEPHRINE (ugm) NEEDED TO PRODUCE A DYSRRHYTHMIA

r - GROUP 1 2 3

Min Max X Min Max X Min Max X l i 1 ST 5 10 • 5.7 S 1 5 1 5 5 5 5 I I V 1 ' BG 5 , 80 1 23.2 ♦10 10 10 | i 1 ES 10 20 ] 15.0 5 , 10 l 7.5 10 20 14.4 i VT 10 500 [175.2 10 ' 80 1 51. 7 l 1 i MVT I 80 1 500 ! 288. 3 20 60 33.3 i 1 i ! I VF I A 60. 7 i i I 1 _ ....

♦Represents data from only one dog. Ill

Table 3--Continued

4 5 6 7

Min Max X Min Max X Min Max X Min Max X i 1 5 20 | 7. 3 5 t 10 ‘ 6.5 5 160 | 49.0 5' 160,' 49.0 i 1 i i 10 60 ! 17.4 5 < 11. 5 i i i 2 0 I i 1 40 < 5; 7.5 4 0 160 96. 7 10 21. 25 1 0 1 1 1 J i i I1 20 40 | 30.0 i i 300 5000 I -300 300 j5000| -300 i i l * 10 80 1 41. 7 1 0 60 1 37. 8 5000 ' i ! I I ■ 10 160 | 62.4 20 ! 80 1 51.4 * i o o o ; I \ 1 \ i i i . I. i i 112

Group 8 (Surital-Halothane-Pressure Alterations') Mean arterial blood pressure could be raised to the desired level via the intravenous administration of phenylephrine. At the particular dosage used mean arterial blood pressure increased approximately 62^15 mmHg. The mean dosage of epinephrine needed to produce multi focal ventricular tachycardia at this pressure being

reduced from a control value of 50.0 ugm to 7.5 ugm. In one animal the experiment was repeated giving an intra venous bolus of 10 mg of phenylephrine. This resulted in a rapid increase in blood pressure and heart rate re sulting in ventricular fibrillation (Figure 18). The ability of inflow occlusion and nitroglycerin to abolish an arrhythmia is illustrated in Figures 19 and 20. Their effect being to decrease mean arterial blood pressure. The onset of sinus rhythm generally marked by an increase in heart rate. The dose of epineph rine needed to produce multifocal ventricular tachycardia when either of these techniques were used was correspon dingly increased from a mean dose of 50.0 ugm to greater than 160 ugm for venous inflow occlusion and 80 ugm of epinephrine for nitroglycerin. Similar results were noted when pentolinium tartrate, a ganglionic blocking agent, was used to reduce arterial blood pressure. In this instance however, the mean dose of epinephrine needed to produce multifocal ventricular tachycardia was increased 113

i ' T I | |~Tj: j : | i_.*,10.mgJ.ph.fiJi.yi ephr LneJ— ; ARTERIAL! BLOOD. ..PRESSURE .

T* i I L ------______i

i 20mm Hg i ...... t !-- _xo GC 3 9 0 0 i „ ~i ""' ’ ... 1 I E C G I — ~ T " T '” : I i

. j ■ ■ > *

7(£Pp*«t*N PI

TjME (sec!) |__! ;U:.:. - f t — ft-— ft - h.:_" .h :r-~ti ‘ ~ h 1 h : - tr:~:vli ft ‘ ~ti ~ fi-— fH — ft Fig. 18.--Effect of the Pressor Agent Phenylephrine upon Cardiac Rhythm in the Presence of Halothane. ARTERIAL BLOOD PRESSURE * Inf low ocdusion

2 0 m m H g

E G G 1

i 1 * 1 ‘I A 4 .

' I avF

T I M E (sec)

Fig. 19.--Effects of Inflow Occlusion Upon Arterial Blood Pressure and Cardiac Rhytym. Fig. 20.--Effect of Nitroglycerin Upon Arterial Blood Pressure and Cardiac Rhythm ARTERIALi ! BLOOD PRESSURE , * 04 mg Nitroglycerin > IV. 1

' *

_20mm Hg; _ ,_ j j j

I * j > - I * — ^ ] » 0 Q > » EC6 I

n i H U n n

t i

TIME(m c ) 116 117 to a mean value of 65.0 ugm from 40.0 ugm in the pre- pentiolinium state. The decrease in arterial pressure was approximately 23*7 mmHg in the dogs studied. Table 4 illustrates the changes in mean arterial blood pressure due to each of the pressure perturbations and the corresponding alteration in the dose of epineph rine needed to produce multifocal ventricular tachycardia. Group 9 CSurital-Halothane-Denei ation-Acetylpromazine)

This group of dogs was studied in order to ascer tain whether the primary sight of action of acetylpromazine was peripheral or central in action. Initial heart rate and mean arterial blood pressure values were 138*14 and 139*10 respectively. The mean dose of epinephrine needed to produce ventricular fibrillation being 40.0 ugm. After transection of the spinal cord and vagi, heart rate and mean arterial blood pressure decreased to 123*15 beats per minute and 63*12 mmHg respectively. The mean ventricular fibrillatory dose of epinephrine increasing to approximately 65 ugm. The response to an intravenous bolus of epinephrine was marked by a dramatic increase of both heart rate and blood pressure. After the adminis tration of acetylpromazine intravenously (0.4 mg/lb) heart rate remained relatively unchanged at 124*13 beats per minute whereas mean arterial blood pressure decreased to 41*8 mmHg. The response to increasing boluses of epinephrine being marked by increases of mean arterial TABLE 4

EFFECT OF ALTERATIONS IN MEAN ARTERIAL BLOOD PRESSURE ON THE DOSAGE OF EPINEPHRINE NEEDED TO PRODUCE MULTIFOCAL VENTRICULAR TACHYCARDIA (MVT) AFTER ADMINISTRATION OF SURITAL AND HALOTHANE

Group Mean Arterial Dose of Mean Arteral Dose of Blood Pressure Epineph Blood Pressure Epineph Before Alter rine (ugm) After Alter rine (ugm) ation Needed to ation Needed to Produce Produce MVT MVT

Phenylephrine 123-18 50.0 194-21 7.5

Inflow Occlusion 114-15 50.0 45-9 >160.0* (2)

Nitroglycerin 119-12 50.0 91-11 80.00 (2)

Pentolinium 124-17 40.0 101-9 65.0 (2)

*The amount of epinephrine needed to produce MVT appeared to be dependent upon the severity and duration of inflow occlusion. **Number of dogs used. 119 blood pressure and sinus tachycardia. At doses of epineph rine greater than 300 ugm a rapid bigeminal rhythm developed. All four dogs survived the final dose of

1000 ugm of epinephrine without developing ventricular fibrillation. Group 10 (Coronary Artery Occlusion) The development of ventricular ectopic activity did not develop until approximately three hours after complete surgical ligation of the left coronary artery.

The ectopic activity at this time was generally ventri cular extrasystoles. This activity increases in appearance so that by approximately eight hours post ligation all beats were of an idioventricular origin. Ectopic acti vity intermixed with periods of complete multifocal activity (Figure 21). The maximal activity of abnormal beats appeared between ten and forty-eight hours postoperatively. After this time there was a gradual diminution of ectopic activity until by the fifth day almost all abnormal ventricular activity had subsided.

The mean value of abnormally conducted beats, in a three minute period, twenty-four hours post ligation was 486±21.5. The number of normally conducted beats aver aging 45tl3. After the administration of acetylpromazine

(0.5 mg/lb) the number of normally conducted beats in creased to 99±16 per three minute period. The heart rate did not change significantly during this period. The CORONARY LIGATION MCL-5

CONTROL

ECG aVF

POST U GAT I ON

3hr

8 hr

24 hr r

TIME (sec.)

Fig- 21---Effect of Two Stage Ligation of the Left Coronary Arthery Upon Cardiac Rhythm. 121 peak antiarrhythmic effect appeared to occur approxi mately fifteen to twenty-five minutes after administration of the drug with a mean duration of approximately forty- five minutes. An experiment demonstrating the effects of acetylpromazine on the cardiac rhythm is shown in Figure 22. Table 5 gives the mean values and standard errors for the changes in heart rate and arterial blood pressure before and after the administration of acetylpromazine. Mean blood gas values for the different groups are shown in Table 6 . Analysis of venous blood gases showed no significant differences between groups two through nine after the stabilization period with the anesthetic technique used. These groups did display high venous oxygen partial pressures indicative of the pure oxygen being breathed. There was a slight tendency towards respiratory acidosis which may be attributed to the respiratory depression. Groups one and ten breathed room air and therefore have relatively normal venous blood gases. The negative bases excess being normal for the dog. Fig. 22."-Effect of Acetylpromazine Upon Arrhythmias Initiated by Two-Stage Ligation of the Left Coronary Artery. 123

CORONARY LIGATION M C L-8

CONTROL RECORD 24hrs POST LIGATION

E C G I

a vF

n u

RECORDING 20min. POST .5mg/lb. ACETYLPROMAZINE

E C G 1

avF

n - i

TIME (sec.) —”— ■»- $ 124

TABLE 5

EFFECT OF ACETYLPROMAZINE (0.5 mg/lb) ON CARDIAC MEAN BLOOD PRESSURE AND HEART RATE IN UNANESTHETIZED CORONARY LEGATED DOGS

Before Acetylpromazine After Acetylpromazine Administration and During Administration Ventricular Arrhythmia

Mean Blood Heart Mean Blood Heart Pressure Rate Pressure Rate (mmHg) (beats/min) (mmHg) (beats/min)

118+14 162±7.2 97±15 172+14.3 TABLE 6

MEAN AND STANDARD ERROR VALUES FOR VENOUS BLOOD GAS SAMPLES IN GROUPS 1 THROUGH 11

GROUP 1 2 3 4 5 6 8 9 11

. PH 7.32+03 7.29±05 7.30*04 7.30*05 7.31+03 7.28+04 7.31+03 7.29*04 7.30+02

P°2 41-5 113t21 131*27 123+23 111+26 107+26 121+23 132+26 39+4 PCO2 42+6 49+4 50+5 47+3 50+7 49+6 51+6 54+7 40+7

hco3 * 21±3 22+3 19*4 22t4 21*5 21t3 22+4 2lt4 18+5

tco2 22+3 23t2 22+4 24t3 22*3 23t2 24-4 23-5 19+6

BE -5t2 -7±3 -6+4 -7t2 -7*4 -8*4 -6+3 -7+4 -5+3 125 CHAPTER IV

DISCUSSION

Since its description by Raventos^lO) in 1955 halothane has become the most popular inhalation anes

thetic in clinical usage today. Equally as popular has been its introduction as the sole source of general anesthesia in many experimental procedures. The halothane-epinephrine model for arrhythmia development recently superceeding the cyclopropane-epinephrine pre paration as a method of studying the possible mechanisms of arrhythmia formation and potential use of antiarrhythmics. As noted previously, little or no attention has been given to the uniformity in dosage of epinephrine employed by many investigators when studying halothane sensitization and arrhythmia development. Neither has there been an attempt to qualitatively describe the type of arrhythmia produced when definitive doses of epineph rine have been administered. Furthermore, although arterial blood pressure has been alluded to as a decisive factor in the induction of cyclopropane-epinephrine in duced arrhythmias little evidence exists describing its role in halothane induced arrhythmias. Other considera-

126 127 tions to be evaluated are the possible effects of the anticholinergics and thiobarbiturates commonly used as premedicants and induction agents respectively to halo thane anesthesia. That the unanesthetized dog responds differently than the dog anesthetized with halothane or halothane as influenced by a thiobarbiturate, anticholinergic or phenothiazine tranquilizer is evidenced by close exami nation of figures 9 through 15. The absolute quality and quantity of these arrhythmias are indicative of the effects of the premedicants or anesthetics used. Evalua tion of these figures permits their division on the basis of arrhythmia produced into two gross categories. Those responding to intravenous boluses of epinephrine with unifocal ventricular rhythms or those responding with multifocal ventricular rhythms and ventricular fibrilla tion. The predominant rhythm of the control dogs to low doses of epinephrine was sinus tachycardia or extra systoles. This progressed to ventricular tachycardia as the dose of epinephrine increased. The only difference between these dogs and those given halothane being the early development of multifocal ventricular tachycardia and fibrillation in the latter group. Those dogs given Surital developed a much higher incidence of bigeminal or coupled rhythms than any of the other groups. Recently Claborn and SzabuniewiczC40) have reported 128 a similar tendency to bigeminal rhythms in over eighty per cent of dogs anesthetized with Surital and in forty per cent of dogs anesthetized with thiopental. Gruber and associatesC15) have attributed bigeminy due to thiobarbiturates to several causes including a direct cardiotoxic effect of thiobarbiturates resulting in coronary artery vasoconstriction, increased arterial blood pressure and to a lesser extent, depressed venti lation. Nickerson and Nomaguchi(192) using cyclopropane anesthetized dogs showed that bigeminal rhythms were precipitated when arterial blood pressure was rising, due to injected epinephrine, rather than when arterial pres sure was at its peak. D r e s e l ( ^ > ^ ) again using cyclo propane anesthetized dogs, found epinephrine induced bigeminal rhythms to be pressure sensitive and dependent upon the level of systolic pressure attained. Similar results have been formulated by Moore ejt. aJ. (180) intact dogs anesthetized with cyclopropane. Innes(l^) and others(137,171) have expanded these studies and demonstrated that increasing tensions developed within the myocardium progressively increased its sensitivity to induction of automaticity by epinephrine. Furthermore, Birnbaum ejt. al. (24) have observed shortening of the re fractory period when stretch was applied to rabbit auricles. It is interesting to note that in those studies where inhalation anesthetics were used in the description 129 of bigeminal rhythms a thiobarbiturate was used for in duction. Bigeminal or coupled rhythms may, therefore, be closely associated with the use of thiobarbiturates.C195)

That they are also pressure sensitive was established in this study by their rapid elimination due to a hypotensive manuever. The importance of coronary artery vasocon striction is as yet to be determined. That increased intraluminal pressure is not the only cause of the rhythms is emphasized by the development of coupled rhythms in isolated Purkinje fiber muscle preparations.(180) The ability of atropine to alter the rhythmic re sponse of the heart to Surital and halothane is inte resting in that bigeminy was again the predominant arrhythmia witnessed at lower doses of epinephrine. As the dosage of epinephrine increased cardiac rhythm rapidly progressed to multifocal ventricular tachycardia and ventricular fibrillation with a relative paucity of minor ventricular arrhythmias. This indicates that although epinephrine increases ventricular automaticity the sever ity of the arrhythmia produced is dependent upon the degree of supraventricular input. This conclusion must be con sidered carefully in that the level of supraventricular input appear critical. The mean dose of epinephrine needed to produce ventricular fibrillation is greater in dogs anesthetized with halothane alone than with Surital and halothane or surital, halothane and atropine. This 130 finding is indicative of the lower supraventricular activ ity in the halothane anesthetized dog as compared to the latter two groups. The higher incidence of ventricular extrasystoles seen in those animals anesthetized with halothane also is indicative of low supraventricular input allowing time for idioventricular rhythms to develop. The relative absence of ventricular extrasystoles in those animals receiving atropine indicates atropine may have a protective quality at lower doses of epinephrine admini stration. This finding is explainable on the basis of overdrive suppression of ectopic ventricular foci due to atropine's ability to reduce parasympathetic tone, thus reducing the possibility of the ventricles responding to reentry or other types of abnormal impulses, As the dosage of epinephrine increases a critical point is reached at which the effects of atropine can no longer override the excitable effects of epinephrine upon the ventricular myocardium in the presence of halothane. At this point atropine or any other agent which augments supraventricular input may actually decrease the amount of epinephrine needed to produce an arrhythmia. Hashimoto and HashimotoC108) and Vick^278) have come to a similar conclusion based upon studies in intact dogs initially anesthetized with pentobarbital sodium and subsequently exposed to halothane. In experiments in which the sinus node was destroyed and the atria driven at various rates 1 3 1 they concluded that minor arrhythmias produced by ex posure to halothane were dependent on the supraventricular input. That the dose of epinephrine needed to produce ventricular fibrillation is independent of this effect and due to epinephrine's actions directly upon the ven tricle is evidenced by the rapid development of multifocal ventricular tachycardia and ventricular fibrillation in those dogs receiving halothane (Table 3) . Hauswirth^O®) has concluded that halothane particularly in the presence of sympathomimetic amines causes a pronounced disparity

of the refractory period between Purkinje and ventricular

fibers, a marked shortening of the refractory period and a decrease in conduction velocity. Although these results suggest the importance of supraventricular input in the production of ventricular arrhythmias of various types they do not elucidate the relative importance of arterial blood pressure. The role of arterial blood pressure in the production of many ven tricular rhythms associated with epinephrine and hydro carbon anesthetics has yet to be resolved. Levy^33) in 1914, using chloroform anesthetized dogs felt that although increases in blood pressure were important no correlation could be drawn between ventricular fibrillatory threshold and the height to which the blood pressure rose. Since that time, Moe et^ al.(179), Nickerson and Nomaguchi, Innes et^. al^. C127) an(j vick^79) have all 132 established that arterial blood pressure elevation is an important factor in the production of arrhythmias associ ated with chloroform and cyclopropane anesthesia. A sudden rise in pressure not being necessary but an eleva tion of mean arterial pressure quite effective provided it is long enough in duration. Recently a study on the effect of acute blood pressure elevation on the ventri cular fibrillation threshold in dogs has come to the opposite conclusion.(276) This study indicates that increases in mean arterial blood pressure actually in creases the ventricular fibrillatory threshold in the dog. The discrepancy between this study and previous work may be explained by the fact that techniques used for increases in pressure by previous investigators were dependent upon agents capable of increasing adrenergic tone. A few investigators have not dealt with arterial pressure at all in their description of ventricular activ ity in the presence of halothane. Arterial pressure is not made reference to in Hashimoto and Hashimoto's(108) study and in a recent publication on the prevention of chloroform and thiobarbiturate cardiac sensitization to catecholamines in dogs by Claborn and Szabuniewicz arterial blood pressure is not even mentioned. It becomes clearly obvious by evaluation of the dogs in groups six and seven of the results that arterial blood pressure must 133 be evaluated if a complete understanding of arrhythmia formation is to be appreciated. This point is further emphasized by the effects of alterations in blood pres sure upon the dose of epinephrine needed to produce an arrhythmia (group eight). The majority of information presented thus far indicated that when halothane is used in the anesthetic regimen the degree of supraventricular input is a cricital factor in arrhythmia production. Alterations in arterial blood pressure however may incite arrhythmia formation j and decrease the dose of epinephrine needed to elicite ventricular tachycardia and fibrillation. The effects of the phenothiazine tranquilizer acetylpromazine, a known hypotensive and adrenolytic, help to clarify this effect.

At the dosage of acetylpromazine used the arrhythmogenic effect of low doses of epinephrine in the halothane sensitized dog could be almost entirely abolished. This finding is coincident with marked decreases in mean arterial blood pressure from control values. As the dose of epinephrine increases the production of arrhyth mias ensues but only to a significant degree at dosages of epinephrine greater than 160 ugm. The fact that all but one of these dogs did not develop ventricular fibril lation may be attributed to acetylpromazine*s anti arrhyth mic effect. A point further emphasized by the response of coronary ligation dogs to the intravenous administration of acetylpromazine. Phenothiazines have been shown to exert strong adrenergic and weaker peripheral cholinergic blocking activity. (92) Gangl ionic blocking action also being attributed to this class of drugs. Phenothiazines in general have been classified as membrane stabilizers by Weidmann^^-O anci Shanes (237) ancj on this basis have been used in the clinical treatment of both atrial and ventri cular arrhythmias. Although investigators have noted the protective action of this agent no one has described whether this effect is primarily central or peripheral to the central nervous system.(249) Sharma and Arora(^9) Arora and Madan(^), Madan and Pendse(160), an(j Arita and

Surawicz(S) have indicated that this antiarrhythmic effect is primarily peripheral in nature and electrophysiologic in character. Kelly(l^), Leestma and Koenig(152) t

Surawicz and Lasseter(259) an(j Hurst and Logue^^^ on the other hand have reported ventricular, tachycardias and fib rillation with the use of phenothiazine tranquilizers. An alternative argument to its peripheral action may be that phenothiazines exert their antiarrhythmic effect via its action upon the central nervous system. D u n b a r t Harvey and Levine(106) 9 Katz and Pick^SG)^ Arora^-^ and more recently, Gillis £t. al. (**S0 have emphasized the importance of the central nervous system and the psycho somatic basis of cardiac arrhythmias. Gillis et. al.(®9) 135 using chlordiazepoxide demonstrated that drugs which de

press the central nervous system may be effective for the treatment of ventricular arrhythmias. Analysis of the dogs in group seven would appear to indicate that the primary sight of antiarrhythmic action of the phenothiazine acetylpromazine is peripheral to the central nervous system, based upon their response to epinephrine. That acetylpromazine does exert a slight central antiarrhythmic

effect however cannot be ruled out on the basis of these

studies. From these data it would appear that the immediate

response of the heart to the possibility of arrhythmia formation may be a reflection of its autonomic innerva tion. The effects of anesthetics and preanesthetics upon electrophysiologic properties of the heart being secondary

in importance. Braunwald(33) an(j Vatner et_. al. (276) have

offered convincing evidence that autonomic control of the dog heart is altered during anesthesia with pentobarbital. The primary mechanism involved with carotid sinus slowing of the heart in the conscious dog being predominantly vagally mediated while in anesthetized dogs withdrawal of sympathetic tone appears to be responsible. (4,20,25,34, 76,160,171) Other studies have shown that during anes thesia the carotid sinus reflex may be facilitated or depressed by electrical stimulation of areas of the brain above the medulla. ,117,283) Thus, general anesthesia 136

could not only delay integration of information in the

brain but also alter the facilitation and inhibitation of

the reflex that exists in the conscious state. Altera tions in autonomic control although not measured directly

in these studies may be inferred by both changes in heart rate and blood pressure due to intravenous administration of epinephrine clearly emphasizing the importance of an intact autonomic nervous system. This effect upon auto

nomic regulation most accurately depicted by phase two of the response to epinephrine (Figure 23). Control dogs

responded to increasing boluses of epinephrine during phase two by characteristic increases in mean arterial blood pressure and corresponding decreases in heart rate.

This finding also being true for those dogs anesthetized with Surital. Techniques in unanesthetized dogs involving occlusion of the aorta, elevation of blood pressure with

angiotensin or phenylephrine or by electrical stimulation of the carotid sinus nerves have associated this response to an increase in vagal tone. Verrier et. al. (276) have offered evidence indicating that acute withdrawal of sympathetic tone following pressure elevation may also play a part. This finding is supported in that, beta- adrenergic blockade but not vagotomy abolished a rise in ventricular fibrillatory threshold seen in response to acute pressure elevation in conscious dogs. These findings in combination with the response of conscious dogs in Fig. 23.-- Diagramitic Response of Heart Rate (HR) and Blood Pressure (BP) to Epinephrine in the Presence of Varying Anesthetic Regimens. DIAGRAMMATIC REPRESENTATION OF HEART RATE (HR) AMD MEAN ARTERIAL BLOOD PRESSURE CHANGES DUE TO A 20pnng DOSE OF EPINEPHRINE PHASE 1 PHASE 2 PHASE 3

HR o r S-H o r S-H-A BP

HR Ac-S-H

S-H-Ac BP

C-CONTROL H-HALOTHANE S SURITAL Ac - ACETYLPROMAZINE 139

this study indicate that the reflex heart rate response may be mediated by a combination of sympathetic with drawal and augmentation of vagal restraint. This response explains why none of the control dogs died even at a dos age of 500 micrograms of epinephrine. Similar rationali zation can be used for the response to surital except for the fact that this agent is known to release catecholamines probably of adrenal origin. This effect would have a tendency to minimize heart rate depression and increase the blood pressure response to epinephrine (Table 7). Obviously the decreases in susceptability to ventricular fibrillation noted in this study using surital and by Verrier et. al. (276) using alpha chloralose anesthetized

dogs, an agent noted to have minimal effects upon auto nomic regulation, are due to the limited ability, at the doses used, of these agents to alter sympathetic and parasympathetic responses. Halothane anesthetized dogs responded to intravenous boluses of epinephrine during phase two of the epineph rine response period by increases in both heart rate and arterial blood pressure (Figure 240• Halothane has been shown to have a negative chronotropic effect on the pace maker fibers of the sinoatrial node, which is not antagonized by atropine. (^ 2) jt has also been suggested by Reynolds et^. aT. (214) an(j Hauswirth(^l^) that halothane can suppress automaticity in both dominant and latent TABLE 7

MEAN ARTERIAL PRESSURE ALTERATIONS AFTER THE INITIAL PRESSURE PEAK DUE TO THE ADMINISTRATION OF EPINEPHRINE INTRAVENOUSLY

C 10 20 40 80 160

c 124-18 133-22 144-26 165-28 172-27 184-28

S 142-17 156-23 160-26 183-27 192-25 194-27

S-H 118-17 132-16 154-22 172-19

S-H-Ac 103-14 83-12 37-10 34-13 78-7 86-13 141

7J Fig. 24.--Changes in Heart Rate vs. Mean Arterial Blood Pressure for Several of the Groups Studied, C-Control, S-Surital, S-H-Surital, Halothane, S-H-Ac- Surital, Halothane, Acepromazine. pacemakers. This work however does not consider autonomic and other influences operating in the intact preparation. Skovsted et^. al. (251) have concluded that halothane

produces only slight depression in sympathetic activity and does not extinguish barostatic reflexes. The same authors admit that barostatic reflexes are not functionally normal during halothane anesthesia and that augmentation or withdrawal of sympathetic tone to the heart is depressed. Other work has pointed out that soon after exposure to halothane the sympathetic rhythm becomes disrupted to almost continuous firing. In support of this finding Vatner et^. aJ. (274) concluded that anesthetized dogs display a reduction in parasympathetic tone and augmenta tion of sympathetic tone as compared to unanesthetized dogs. Altee and Rusy(*®) have suggested that arrhythmias seen with halothane are in part due to direct depression of atrio-ventricular conduction. These data would appear to suggest that halothane predisposes the heart in the intact dog to ventricular arrhythmias and fibrillation primarily via its effects upon autonomic control and secondarily through its direct effects upon specialized conduction or ventricular tissue. The inability of the halothane anesthetized dog to acutely withdraw sympathetic tone, shown to be critical to an increase in ventricular fibrillation threshold by Verrier et. al.. (277) may cxuciai, Reduction in para- 143 sympathetic tone may further augment this situation.

These effects compounded by halothane's ability to slow atrio-ventricular conduction may further impare impulses from higher centers thus allowing lower order pacemakers whose automaticity has not been depressed to emerge. Although the determinants of arrhythmia formation due to halothane anesthesia have been discussed, the in citing factor is absent. That this factor may be pressure is well illustrated by the response of halothane anes thetized dogs to the phenothiazine tranquilizer acetylpromazine (Figure 24). This point, further exempli fied by the laterations in dosages of epinephrine observed in those dogs in which pressure was altered. If autonomic control were intact the effect of a fall in arterial pressure should be to decrease parasympathetic activity to the heart and further increase the susceptability to ventricular fibrillation. Only one of the dogs in group six died however, and this was at a dose of 1000 micrograms of epinephrine. Further support of the importance of blood pressure in arrhythmia development being the almost complete absence of idoventricular rhythms in dogs administered acetylpromazine until a dose greater than

160 micrograms of epinephrine had been reached. This emphasizes the ability of epinephrine to elicit arrhyth mias in halothane anesthetized dogs in the presence of acetylpromazine but not until the effect of epinephrine 144 is directly upon the ventricle. In those studies dosages of 160 micrograms of epinephrine or greater held special significance. It appears it is at this dosage that both control and surital anesthetized dogs demonstrate drastic increases in heart rate (Table 2). It is also at dosages of this magnitude or greater that ventricular arrhythmias develo ped in the halothane anesthetized dog given acetylproma zine. Considering that most of the dogs weight approximately 17 to 20 Kg. this would coincide with an approximate dosage of 10 micrograms per kilogram. This same dosage was found by Nickerson and NomaguchiC192) to be critical in the dissociation of pressor and arrhythmia blocking actions. * These findings lend support to the contention that autonomic control is the important variable in the production of ventricular arrhythmias and that arterial pressure is an important determinant in their appearance. When the dosage of epinephrine exceeds a particular limit other mechanisms must become respons ible for protection from ventricular fibrillation. These mechanisms appear to be related to alterations upon the electrophysiologic properties of the heart. CHAPTER V

SUMMARY

A qualitative and quantitative analysis of the arrhythmias associated with several anesthetic combi nations and epinephrine administration was made in dogs.

These combinations were as follows: 1. Control (Unanesthetized)

2. Thiamylal (Surital) 3. Halothane 4. Surital-Halothane 5. Surital-Halothane-Atropine

6 . Acetylpromazine-Surital-Halothane 7. Surital-Halothane-Acetylpromazine

The rhythms described were placed into the following categories: 1. Normal Sinus Rhythm 2. Sinus Tachycardia (ST)

3. Bigeminy (BG) 4. Extrasystole (ES) 5. Ventricular Tachycardia (VT)

6 . Multifocal Ventricular Tachycardia (MVT) 7. Ventricular Fibrillation (VF) 146 These rhythms were produced by several predetermined intravenous bolus injections of epinephrine varying from 5 to 1000 ugms. Blood pressure and venous blood gas samples were monitored throughout the experimental procedure. Unanesthetized dogs responded to increasing boluses of epinephrine by the production of sinus tachycardia progressing to slow then fast ventricular tachycardia. The slow ventricular tachycardia was associated with in creases in mean arterial blood pressure and was most likely due to the barostatic reflex increase in vagal tone due to increases in arterial blood pressure. Fast ventricular tachycardia was produced with boluses of epinephrine in excess of 160 ugm (10 ugm/kg) Those dogs receiving thiamylal sodium responded to increasing boluses of epinephrine by the production of

BG progressing to VT and MVT. The production of BG appeared to be most prevalent shortly after the admini stration of thiamylal and was eliminated by spontaneous ventilation or venous inflow occlusion. The later of these findings supports the important role which arterial pressure has in the production of this rhythm although it may not be the only factor involved. None of the dogs in the fiTst two groups developed VF. Those dogs anesthetized with halothane and adminis tered epinephrine intravenously progressed rapidly from 147 ST to MVT and VF. The mean dose of epinephrine needed to produce VF was approximately 60 ugm (3 ugm/kg). Those dogs induced to anesthesia with thiamylal and then administered halothane showed a similar response with a predominance of BG. When atropine was added to this anesthetic regimen there was a relative paucicity of BG and ES. This could have been due to overdrive suppres sion and supports the contention that supraventricular input is important in the production of halothane arrhythmias and fibrillation. Acetylpromazine in combination with thiamylal and halothane lowered mean arterial blood pressure from control values and reduced the variety of arrhythmias recorded. Increasing boluses of epinephrine resulting in the production of ST and VT. Only one dog developed

VF of those dogs given acetylpromazine. The action of acetylpromazine appeared to be prim arily peripheral to the central nervous system based upon findings in denervated and two-stage coronary artery ligation preparations. Its protective action from VF in the presence of halothane appeared to be primarily due to its effect upon arterial blood pressure although a direct myocardial effect cannot be eliminated. It was demonstrated by venous inflow occlusion, nitroglycerin intravenously and phenylphrine intravenously that arterial blood pressure and therefore myocardial 148 wall tension is important in the production of ventri cular arrhythmias and VF in intact dogs given epinephrine. Whether endogenous catecholamine levels approximate the boluses used in this study is doubtful. Exogenous catecholamines, however, must be administered cautiously. The determinants of cardiac arrhythmias Csupraventricular input, arterial blood pressure) exemplified by these

studies. It appears from these studies that the underlying factor in the production of arrhythmias and ventricular fibrillation is alterations in the ability of the autono mic nervous system to respond to perturbations in hemo dynamic parameters and a reversal of the regulatory roles of the parasympathetic and sympathetic nervous systems during anesthesia. In the unanesthetized dog an increase in arterial blood pressure triggers the reflex augmenta tion of vagal activity and the withdrawal of sympathetic

tone. The anesthetized dog responds to increases in arterial blood pressure by the delayed withdrawal of

sympathetic tone and secondarily by increasing para sympathetic tone. This effect is particularly evidenced by halothane anesthesia and much less so with thiamylal.. This response is similar to that witnessed in dogs with experimentally induced and spontaneously occurring con gestive heart failure. Anesthesia may reduce the dogs ability to maintain cardioregulatory homeostasis similar 149 to those patients in heart failure. Finally, it was demonstrated that the dose of epinephrine needed to a purely ventricular effect was approximately 10 ugm/kg. BIBLIOGRAPHY

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