Rationale of Therapy in the Patient with Acute Myocardial Infarctionand Life-ThreateningArrhythmias: A Focus on Bretylium

BENEDICT R. LUCCHESI, PhD, MD

Experimental evidence suggests a number of Many of the new class I antiarrhythmic agents pathologic and electrophysiologic mechantsms that effectively reduce the frequency of premature may help initiate ventricular arrhythmias accom- ventricular depolarizations, but lack specific anti- panying myocardial ischemla and infarction. Early fibrillatory activity. However, the recent introduction and late phase events are associated with reentry of bretylium into clinical opens a new or an enhancement of focal mechanisms, or both. approach to preventing life-threatening ventricular These can initiate (VT) or dysrhythmias. Along with other members of class (VF), or both. The presence III, bretyllum exerts different cardiac electrophysi- of dtstinct mechanisms that may inttiate and main- ologic effects than do the other 3 classes of drugs. tain life-threatening dysrhythmias early in myo- Bretylium has been designated as class III because cardial ischemia suggest different pharmacologic it increases the action potential duration and approaches for their prevention or suppression. prolongs the effective refractory period. The other Another consideration concerns patients subjected class III drugs, including , , clofi- to coronary artery angioplasty or thrombolyttc lium and pranolium, experimentally prevent the therapy and the development of arrhythmias asso- establishment of a reentry pathway that can initiate ciated with reperfuslon of the once ischemic myo- VF. Bretylium along with these other class III agents cardium. The electrophystologic mechanisms as- is primarily anttfibrillatory rather than antiarrhythmlc. sociated with reperfusion arrhythmias are unknown, Thus, antiarrhythmic agents that reduce the fre- and little is known about appropriate therapy for quency and complexity of premature ventricular each episode of cardiac dysrhythmta. depolarizations are not necessarily antifibrillatory. Ventricular extrasystoles or VT usually precedes It is necessary to reorient our thinking about how VF. These premonitory arrhythmias are poor criteria pharmacologic interventions may influence the for the institution of antiarrhythmic drug therapy, course of events in patients at risk of developing because VF develops within 1 to 10 minutes after life-threatening ventricular arrhythmias. Because the appearance of the rhythmic dtsturbances. Borne the lethal event is most often associated with VF, it authorities suggest that all patfents with acute may be sufficient to have an agent that protects myocardial infarction should receive prophylactic against this electrophysiologic disorder even though antiarrhythmic therapy, because warning arrhyth- it does not completely prevent or suppress other mias either do not occur at all or provide insufficient ventricular arrhythmias. time to intervene pharmacologically. (Am J Cardiol 1984;54:14A-19A)

The most catastrophic event that can happen to a pa- ular complexes or episodes of ventricular tachyar- tient with acute myocardial infarction (MI) is the de- rhythmia, or both.i Because this discussion will focus velopment of primary ventricular fibrillation (VF), on patients with coronary artery disease, the term which is often associated with previous electrocardio- sudden coronary death becomes more appropriate than graphic evidence of ventricular electrical instability as the broader concept of sudden cardiac death. Within demonstrated by the occurrence of premature ventric- this context, an effort will be made to provide a rational basis for the selection of drug therapy for the prevention of recurrent episodes of life-threatening ventricular From the Department of Phermawlogy, The University of Michigan tachycardia (VT) and VF. Effective therapeutic inter- Medical School, Ann Arbor, Michigan. ventions would be most wanted for those individuals Address for reprints: Benedict R. Lucchesi, PhD, MD, Department of Pharmecology. The University of Michigan Medical School, Ann who are at high risk as determined by the presence of Arbor, Michigan 48109. coronary artery disease and left ventricular character- July 30, 1984 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 54 MA istics associated with :recurrent episodes of ventricular proposed for , which prolongs conduction time tachyarrhythmia. in the ischemic myocardial region, but not in the normal zone.2o The Necessary Substrate for Ventricular More recently, the technique of programmed elec- Tachyarrhythmia and Ventricular Fibrillation trical stimulation in the chronically ischemic canine Myocardial ischemia and MI commonly are accom- heart has been used to assess the ability of panied by the development of ventricular arrhythmias to prevent reentrant tachyarrhythmias2l The drug was or tachyarrhythmias, or both, because of alterations in effective only at a plasma concentration which exceeded the cellular electrophysiologic characteristics of those that usually considered to be therapeutic. These find- myocardial cells involved in the ischemic process.2 The ings were not unlike those of Horowitz et a122who used underlying alterations in cellular electrophysiologic programmed electrical stimulation to induce reentrant aspects can further be influenced by the activity of the rhythms in patients with recurrent episodes of VT and autonomic nervous syrstem.3y4 in whom the effective plasma concentrations of diso- Studies by Waldo and Kaisers and Boineau and Coxe pyramide were well beyond the upper limit of what is demonstrated that the period immediately after acute considered the therapeutic range. coronary artery occlusion was associated with transient The results of such studies might be interpreted as or sustained periods of continuous electrical activity, suggesting that currently available class I antiar- or local fibrillation, within the ischemic or infarcted rhythmic drugs might have the ability to suppress or myocardium, or both. Persistence of continuous elec- prevent reentrant ventricular rhythms, but they will trical activity beyond the T wave of the preceding im- only do so at dosages that will not be tolerated by most pulse almost always was associated with ventricular patients. The latter point is illustrated by the results of extrasystoles. Therefore, the presence of sustained Lie et a123 who studied 212 patients with acute MI electrical diastolic activity or localized fibrillation may randomized by 2 treatment groups. Among 107 patients provoke the development of VT or VF. The implication receiving (lOO-mg loading dose followed by 3 is that persistent diastolic activity within the area of mg/min for 48 hours), no episode of primary VF oc- ischemic myocardial injury spreads to the remainder of curred. This result contrasted with 9 episodes of pri- the ventricle, resulting in abnormal rhythm. The elec- mary VF among 105 patients receiving placebo (5% trophysiologic propert:ies of the ischemic myocardium, dextrose and water). Side effects occurred in 15% of the such as enhanced threshold of excitability, shortened patients treated with lidocaine and were more common refractory period, decreased conduction velocity and in older patients. increased inhomogeneity of the recovery of excitability, The major electrophysiologic effects of the class I provided a suitable substrate for initiation and per- antiarrhythmic drugs in suppressing reentrant rhythms petuation of VF.7-11 The localized areas of sustained are due to their ability to convert unidirectional block excitation function as a source of reentrant activity12J3 into bidirectional block by slowing conduction in both and suggest that a potential site of action for an anti- normal and depressed myocardial regions. The class I arrhythmic drug could be located within the ischemic drugs also prolong the effective refractory period. region or the normal myocardium so as to result in Therefore, it is theoretically possible that class I anti- electrophysiologic alterations that would decrease the arrhythmic agents might have the potential to facilitate disparity between the 2 regions or prevent the contin- the induction of reentrant rhythms, depending on the uous excitation within the ischemic zone from entering balance of their effects on conduction velocity and re- the surrounding normal myocardium. fractoriness in normal and ischemic myocardium.21T24 Recent data support the concept that early arrhyth- Class I antiarrhythmic drugs perhaps will be found to mias associated with coronary artery occlusion, and prevent recurrent episodes of VT and prevent VF only most likely the development of VF, are due to reentry at plasma concentrations that are not tolerated by a mechanism, whereas late occurring arrhythmias are significant number of patients. Failure of previous more likely the result of enhanced or abnormal auto- clinical trials to provide clear-cut evidence for a re- maticity.12-l7 duction in the frequency of primary VF despite a re- The electrophysiologic effects of lidocaine have been duction in the frequency or complexity of premature studied in the in situ canine heart in which epicardial ventricular complexes may be related to the finding that electrograms were recorded from the normal and higher plasma concentrations of the class I drugs are ischemic zones.ls Lidocaine delayed activation and required to prevent reentrant rhythms that lead to prolonged the effective refractory period of the infarcted VF. zone of the heart, without affecting these parameters Electrophysiologic abnormalities can be demon- in the normal myocardial region; the drug primarily strated in many patients who have survived an episode decreased the disparity in the effective refractory pe- of out-of-hospital cardiac arrest not associated with riods of the 2 myocardial regions. Subsequent studieslg acute MI.zkss The continued presence of an electrically showed that lidocaine affects intraventricular conduc- unstable myocardial substrate is suggested by the tion as do and . Therefore, lid- finding that VT will develop in 81% of such patients in ocaine may abort reentrant ventricular arrhythmias by response to programmed electrical stimulation. The depressing the conduction velocity within the region of ability to induce VT by electrical stimulation is rarely, myocardial injury to the point of extinction of the if ever, observed in patients who do not possess under- reentrant wave-front. A similar mechanism has been lying heart disease, 29 thus emphasizing the importance WA BRETYLIUM TOSYLATE SYMPOSIUM of a vulnerable substrate for the initiation and main- myocardial tissue over time and show little correlation tenance of lethal tachyarrhythmia. between concentration of drug in the plasma and ther- The importance of the presence of a vulnerable apeutic efficacy. myocardial substrate for the development of sudden Considering the magnitude of the problem of sudden coronary death has been emphasized by the observation coronary death, there is a need for an intensive program of Schuster and Bulkley.30They identified 2 groups with aimed at the development of new therapeutic inter- early postinfarction angina: those with ischemia at a ventions as the only practical approach to the reduction distance and those with ischemia in the infarct zone. in mortality among those identified to be at risk. The Patients with ischemia at a distance constitute a subset ideal antiarrhythmic, or to be more precise, antifibril- of hemodynamically stable patients who face an unex- latory agent, does not exist. Despite extensive clinical pectedly high mortality because of a persistently studies, it is not possible to demonstrate that 11 of the ischemic myocardium which provides the proper sub- newer pharmacologic agents possess any promise as strate for the genesis of reentrant rhythms and the de- being the ideal agent for the prevention of sudden cor- velopment of VF. onary death. May et a132recently reviewed the results of 14 clinical trials involving 3,625 patients with docu- Evaluating the Antiarrhythmic vs the mented MI who were treated with 1 of 4 antiarrhythmic Antifibrillatory Action of Pharmacologic drugs including quinidine, disopyramide, procainamide Interventions and lidocaine. Despite the fact that each agent has been The presence of a vulnerable substrate needed for the reported to suppress ventricular arrhythmias in the genesis of life-threatening tachyarrhythmias is sup- acute phase of MI, and lidocaine may reduce the inci- ported by the use of programmed electrical stimulation dence of in-hospital VF, not 1 of the trials has demon- to elicit ventricular arrhythmias, as already discussed strated that suppression of ventricular premature herein, and has led to the use of provocative testing complexes is accompanied by a statistically significant procedures in the identification of pharmacologic agents reduction in overall mortality. for prophylactic management of patients determined Ruskin et al33employed electrophysiologic testing in to be at high risk of sudden coronary death. In most 98 patients who had survived an episode of cardiac ar- patients with recurrent sustained VT, the arrhythmia rest. Six of the 98 patients had been taking antiar- occurs sporadically; therefore, empiric selection of rhythmic drugs at the time of cardiac arrest. Before the therapy is marked by fallibility in both the choice and administration of antiarrhythmic therapy, no patient the dose of . Electrophysiologic had a documented episode of VT or symptoms sugges- testing is believed to provide an objective basis on which tive of it. After therapy was initiated, however, cardiac rational pharmacologic therapy can be selected,al be- arrest occurred with documented VF or VT within 3 to cause recurrent VT can be reproducibly initiated by 5 months in the 6 patients. Electrophysiologic testing programmed electrical stimulation in most patients demonstrated that these patients were more susceptible with chronic ischemic heart disease. to inducible VT while taking antiarrhytbmicdrugs than The use of an electrophysiologic protocol for drug in the absence of drug therapy. When the drugs were selection is based on several assumptions: (1) the withdrawn for 48 hours, no patient responded to elec- tachycardia produced in the laboratory by programmed trophysiologic testing with the induction of ventricular stimulation is identical to clinical tachyarrhythmia; (2) tachyarrhythmias.The clinical implication of this study the response to drug therapy in the laboratory predicts is significant and provides strong circumstantial evi- the clinical response; and (3) the ability to prevent dence that antiarrhythmic drugs can contribute to ep- electrically induced VT by drug treatment predicts the isodes of cardiac arrest. inability of the heart to develop VF, especially if an The recurrence rate of sudden death is extremly high ischemic episode superimposes on a vulnerable sub- (30 to 40%), especially among those whose cardiac arrest strate. Is the prevention of electrically induced ar- was not associated with acute MI. Treatment with an rhythmias by drug therapy synonomous with the pre- antiarrhythmic agent would seem essential. In such vention of sudden coronary death? Probably not. patients, programmed electrical stimulation can often Although the first and second assumptions may be es- induce sustained VT or VF, or both. What is unclear, tablished, the third is not, because an acute ischemic however, is whether a drug that prevents electrically episode is not part of the testing procedure. The true induced arrhythmias in a patient rescued from cardiac efficacy of an intervention can only be determined by arrest will also be effective in preventing spontaneous looking at its potential to prevent sudden coronary recurrence of sudden coronary death. Roy et alN re- death. Programmed electrical stimulation and acute ported their long-term experience after electrophysio- pharmacologic testing may not be valuable in helping logic testing in 119 patients resuscitated from cardiac to identify those at risk of sudden coronary death and arrest. Repeat electrophysiologic testing was performed in establishing treatment regimens. The identification in 60 patients after initiating therapy and 41 were not of a truly effective agent will be determined by its ability inducible. The rate of recurrent sudden death in the 41 to prevent VF, an end point seldom achieved during patients over a follow-up period of 17 months was 15%. provocative testing procedures. It may also be true that The long-term recurrence rate of sudden death in pa- a drug fails to prevent the initiation of tachyarrhythmia tients who remained inducible was 21% (4of 19). There by programmed electrical stimulation may still suc- were 47 sudden death survivors in whom sustained ar- cessfully prevent a spontaneous recurrence. This would rhythmiascould not be induced. Ten of 29 (34%) treated be especially true of those agents that accumulate in patients had recurrent sudden death as did 5 of 18 who July 30. 1984 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 54 17A received no specific antiarrhythmic therapy. There were TABLE I Classification of Antiarrhythmic Drugs 9 patients who received amiodarone and in whom Class Drugs catheter-induced arrhythmias could not be prevented when reevaluated after acute.administration. Only 1 of I Quinidine, procainamide, disopyramide, penytoin, lidocaine the 9 patients on amiodarone therapy experienced re- , current sudden deatlh. These studies suggest that suc- , , lorcainide, , ethmozin, cessful abolition of inlduced arrhythmias is a meaningful , pirmenol , timolol, , , way of assessing drug efficacy and that amiodarone 111 Bretylium: sotalol, amiodarone, clofilium, pranolium might be reserved for patients whose condition is re- IV Verapamll, , fractory to standard antiarrhythmic agents. Invasive electroph,ysiologic testing currently may be the best approach in selecting effective antiarrhythmic therapy in patients who have had a life-threatening ventricular arrhythmia. The appropriate means of de- vors of acute MI, therapy with the /3-adrenergic termining therapy in patients who are at high risk of blocking agents may not be applicable to all survivors sudden death but who only demonstrate nonsustained with acute MI or to those patients rescued from sudden VT and complex ventricular ectopic depolarizations coronary death but in whom MI has not occurred. De- remains uncertain. Spielman et aP5 reported that spite dramatic progress, the need for alternative phar- electrophysiologie-testing ismore effective than em- macologic interventions for patients at risk of sudden pirical drug selection in high-risk patients who have not coronary death is clearly recognized. manifested recurrent VT or out-of-hospital cardiac The recent introduction of bretylium into clinical arrest. cardiology has suggested a new approach to the pre- vention of life-threatening ventricular arrhythmias. The Antiarrhythmic vs Antifibrillatory Drugs precise mechanism by which bretylium produces its There has been an “explosive” appearance of new antifibrillatory effect is unknown, but its cellular elec- ant&rhythmic agents (Table I) that are reported to be trophysiologic effects differ significantly from those of effective in reducing the frequency of premature ven- the class I and class II antidysrhythmic drugs. Bretyl- tricular complexes, but most lack specificity with re- ium has been classified as belonging to a group of agents spect to antifibrillatory activity. Thus, current proce- that are placed in class III because they have the prop- dures used to identify an agent capable of preventing erty of increasing the ventricular action potential du- sudden cardiac .death may be inadequate if the end ration and prolonging the effective refractory period. point is something other than VF. The antiarrhythmic Others considered to be class III antidysrhythmic agents drugs currently available in the United States for the include amiodarone, sotalol, clofilium and prano- long-term management of patients with life-threatening lium.37 arrhythmias are quinidine, procainamide, disopyram- ide, propranolol, timolol, metoprolol and . Indirect and Direct Cardiac Actions of Bretylium None is considered entirely suitable for long-term Alterations in adrenergicneuronal function:The prophylactic use in the prevention of sudden coronary acute single dose of bretylium leads to a biphasic car- death. Of the new class I agents including aprindine, diovascular response in both experimental animals and tocainide, mexiletine, encainide, ethmosin, flecainide man.384o The initial displacement of and pirmenol, none is known specifically to prevent VF from adrenergic nerve terminals results in an increase in either the experimental animal or man. There are in arterial blood pressure, vascular resistance and heart limited published preclinical data with respect to many rate and may augment the frequency of ventricular of these agents, and already several are proving to have premature complexes. The initial response begins to serious toxic effects. dissipate by 20 tc 30 minutes and blood pressure, vas- Studies recently reviewed by Singh and Venkateshss cular resistance and heart rate begin to decrease as pe- demonstrate a clear rationale for the prophylactic use ripheral sympathetic tone decreases secondary to the of fl- blocking agents (propranolol adrenergic neuronal blocking effects of bretylium and timolol) in subsets of patients with ischemic heart (chemical sympathectomy). The latter effect predom- disease for the purpose of reducing the incidence of inates during the chronic phase of therapy and may be sudden death and the recurrence of MI. Although the circumvented by the previous administration of a tri- beneficial result is attributed to the establishment of cyclic antidepressant drug, e.g., or dox- P-adrenergic receptor blockade, the exact mechanism epin, which effectively blocks the uptake mechanism of the salutary effect is not known. The antiischemic in adrenergic neurons, thereby preventing bretylium effects that accrue as a result of inhibiting adrenergic from gainii access to the adrenergic nerves. Therefore, responses of cardiac @receptors may serve to prevent the catecholamine release and subsequent sympatho- the initiating triggering event from acting on a vulner- lytic effects of bretylium can be prevented without af- able myocardial substrate. Therefore, a primary anti- fecting the electrophysiologic effects of the quaternary arrhythmic or antifibrillatory action may not be present amine on the heart.4cr41 The complicating effects of in many members of this class, despite their ability to catecholamine release can be minimized or prevented reduce the incidence of lethal arrhythmic events in by pretreatment with a tricyclic antidepressant40p41 or patients with ischemic heart disease. Despite their by the previous administration of a /3-adrenergic re- demonstrated efficacy in reducing morbidity in survi- ceptor antagonist.42 18A BRETYLIUM TOSYLATE SYMPOSIUM

Direct Electrophysiologic Effects of Bretylium to increase the current required to achieve ventricular The direct electrophysiologic effects of bretylium defibrillation in the experimental anima1.55 However, resulting in prolongation of the ventricular refractory bretylium decreases the electrical threshold for suc- period can be demonstrated with long-term drug ad- cessful defibrillation.56 ministration and in the absence of endogenous cate- Haynes et a157 compared the immediate and short- cholamine release.43 The direct electrophysiologic and term effects of bretylium and lidocaine in the manage- antifibrillatory effects of bretylium were noted to par- ment of 146 victims of out-of-hospital VF in a allel the myocardial rather than the serum concentra- randomized blinded trial. The administration of tions of the drug, with the peak response occurring 3 to bretylium (500 mg intravenously) or lidocaine (100 mg 6 hours after intravenous administration. Our data intravenously) followed by resuscitative measures re- suggest that the kinetics of the electrophysiologic and sulted in the development of an organized cardiac antifibrillatory effects of bretylium parallel those of rhythm in most patients (89 and 93% in the bretylium drug accumulation in myocardial tissue, whereas the and lidocaine groups, repsectively). The lidocaine- kinetics of catecholamine release and serum concen- treated group showed a slightly greater tendency tration of the drug are dissimilar. These studies dem- towards conversion to asystole (46 vs 34%), whereas onstrate the marked time and dose-dependent differ- bretylium-treated patients had a somewhat greater ences in response to bretylium. The delayed response tendency towards recurrent VF (49 vs 39%). Chemical in the increase in the ventricular refractory period and defibrillation was not observed with either of the drug fibrillation threshold with small doses might be con- treatments. There was no difference with respect to the verted to a more immediate response by a larger initial number of patients successfully defibrillated in each of dose which results in a more rapid accumulation of the the groups. Therefore, the investigators did not observe drug in myocardial tissue. The limitation in the rate of any significant differences between the 2 groups of pa- administration of bretylium is due to the concomitant tients in the response to defibrillation, in resuscitation effects on the adrenergic neuronal stores of norepi- or in mortality. nephrine. Nowak et a1s8 conducted a randomized double-blind The electrophysiologic effects of intravenous brety- study comparing bretylium with saline solution (in lium on the conduction of premature impulses and ex- addition to Advanced Cardiac Life Support protocol citation threshold in the normal and ischemic drugs and procedures) as a first-line drug in patients myocardium have been described.44F45 There was a with cardiopulmonary arrest. They concluded that the significant delay in the conduction of impulses from aggressive use of bretylium (10 mg/kg) as a first-line normal myocardial tissue to the border of the ischemic agent in the treatment of out-of-hospital VF signifi- heart muscle and a decrease in the disparity between cantly increases the chances for successful resuscitation. excitation thresholds of adjoining ischemic and normal Furthermore, the administration of bretylium followed myocardial regions. As noted by others,4244 the elec- by lidocaine reduced the incidence of recurrent VF. trophysiologic effects of bretylium were delayed in their The observation that VF develops in 40% of patients appearance, once again suggesting the need for the drug with acute MI with significant warning arrhythmias to accumulate in myocardial tissue. However, the effects suggests that an effective antiarrhythmic drug should of bretylium on the VF threshold and defibrillation be employed as a routine prophylactic measure. Clinical threshold occur within minutes of administration. studies in the setting of acute MI provide convincing The most prominent electrophysiologic actions of evidence that bretylium is effective in reducing the in- bretylium are an increase in the threshold current re- cidence of VF.59-63 quired to induce VF and a prolongation in the ventric- Prospects for the Future ular effective refractory period,46-50 an effect that is more prominent than that observed with other currently There has been substantial progress in recent years available antiarrhythmic drugs grouped under class with respect to identifying subsets of patients who are I.47-5oA most interesting observation is the spontaneous at risk of sudden coronary death. Both surgical and conversion of VF to sinus rhythm after the adminis- electrical means of preventing sudden death in the most tration of bretylium.sl Chemical defibrillation has not difficult-to-manage patient groups have been attempted been observed with other antiarrhythmic agents and is with impressive results. However, a critical need re- a property possessed by bretylium and other investi- mains for the development of more reliable and effective gational drugs grouped as class III antiarrhythmic therapeutic agents capable of preventing VF. The re- agents.37vs2 The ability of bretylium to exert an antifi- sults being reported with amiodarone,s4965 clofilium66 brillatory effect is unlikely to be a result of its actions and sotalo1,s796s all members of class III; suggest that on the sympathetic nervous system, because guaneth- these agents have electrophysiologic effects that will idine, a compound that exerts similar actions on the prevent induction of a reentrant rhythm and develop- sympathetic nervous system, does not possess an anti- ment of a lethal arrhythmia when a triggering event is fibrillatory action when studied in the experimental superimposed on the vulnerable substrate of an ische- animal.48,53 Bretylium is equally as effective in the heart mic myocardium. of -treated animals53 and in the denervated heart54 as it is in the normal heart. Several currently References available drugs (quinidine, lidocaine, phenytoin, diso- 1. BlOger JT, Dresdsle RJ, Helssenbultel RH, Weld FM, WI AL. 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