Clin. Cardiol. 13, 534-539(1990)
Lidocaine in the Early Phase of Acute Myocardial Infarction: The Controversy Over Prophylacticor SelectiveUse M. ZEHENDER, M.D., w. U S P E R , M.D..H.JUST,
M.D.
Innere Medizin 111, Universitat Freiburg, Freiburg, West Germany
Summary: In acute myocardial infarction, lidocaine is considered the drug of choice for the treatment of malignant ventricular arrhythmias. While initially a so-called “selective” treatment strategy prevailed, in which lidocaine was administered only after the onset of certain “warning arrhythmias,” the prophylactic use of lidocaine in acute myocardial infarction has been gaining wider usage in intravenous and intramuscular application in recent years. Both therapeutic applications have been found to be problematic of late, which has led to increasingly restrictive use of lidocaine. While in selective treatment forms, the definition and prompt recognition of the socalled warning arrhythmias created especially acute problems, the prophylactic therapeutic use is problematic due to the Occurrence of sometimes serious side effects, which is to be expected as the size of the collective being treated increases. Both treatment forms also appear limited by the narrow preventive efficacy of lidocaine against malignant ventricular arrhythmias, especially against ventricular fibrillation. The current therapeutic recommendation for lidocaine in acute myocardial infarction should be limited to patients presenting with very frequent and complex ventricular arrhythmias, especially when these are elicited by an R-on-T phenomenon. Side effects and other therapeutic problems encountered when the therapeutic modality is switched or adjusted can be greatly reduced
Address for reprints: Manfred Zehender, M.D. Innere Medizin I11 University of Freiburg Hugstetterstrasse 55 D-7800 Freiburg, West Germany Received: January 20, 1990 Accepted: February 6 , 1990
by careful dosing and selection of the optimal combination substances.
Key words: acute myocardial infarction, ventricular arrhythmias, lidocaine
Introduction Lidocaine is considered the drug of choice in the treatment of ventricular arrhythmias which occur in the prehospital and early hospital phase of acute myocardial infarction.I This indication, usually differentiated under the aspect of a “prophylactic” or “selective” application, has however, come under increasing critical fire in the past few years. The (“selective”) use of lidocaine is based on a concept first described by Julian et aL2 and Lown et al. that so-called “warning arrhythmias” can be defined in the phase of acute myocardial infarction, whereby patients with an increased risk for the occurrence of lifethreatening arrhythmias can be identified, making selective antiarrhythmic therapy p o ~ s i b l e .By ~ -contrast, ~ pmponents of the “prophylactic” a p p r o a ~ h l . ~doubt . ~ - ’ ~the possibility of reliably defining the “warning arrhythmias” and identifying them early enough. The benefit of prophylactic lidocaine administration is assumed primarily based on findings of a study by Lie et (11. in the mid1970s, in which a reduction of Ventricular fibrillation in the acute infarction phase could be demonstrated following prophylactic administration of lidocaine. I s A third, much more critical standpoint meanwhile doubts both the possibility of definition and reliable recording of “warning arrhythmias” as well as the efficacy and benefit of prophylactic lidocaine administration.19-22Based on this, an antianhythmic therapy in acute myocardial infarction should be limited to patients with documented malignant arrhythmias (persistent ventricular tachycardia, ventricular fibrillation, etc.). In this report, the various aspects are discussed and a recommendation for practical procedures in acute myocardial infarction is given.
M. Zehender rt d.: Lidocaine in early AM1
Ventricular Arrhythmias in Acute Myocardial Infarction and Their Importance as Warning Arrhythmias
535
are recorded by a computerized arrhythmia recognition s y ~ t e m .Information ~ ~ . ~ ~ regarding the reliability of recognition of R-on-T arrhythmias is not available. In the prehospital infarction phase, it can certainly be assumed that the qualitative and quantitative recording of arrhythmias In more than 95 % of all patients, ventricular arrhythis less reliable. Discrepant information concerning the fremias occur during acute myocardial infarction. The frequency of primary ventricular fibrillation without precedquency and severity of infarctions correlate in a complex ing warning arrhythmias ( < 2 5 % to 80%) confirm this manner with the extent of necrotic, ischemic, and healthy deficiency from a clinical point of view. 1.34.35 myocardial areas. 1 . 2 3 - 2 6 Can these forms of arrhythmias In addition to the problem of early and reliable recogbe reliably defined and recognized as “warning arrhythnition, the problem of insufficient specificity also exists mias”? Ventricular extrasystoles, like ventricular salvos and tachycardias, occur frequently about 8- 12 h after the for R-on-T arrhythmias. About 60% of all infarction patients present with R-on-T extrasystoles, but only 3- 10% acute infarction episode.23The peak of frequency of ventricular fibrillation, which is observed in 2-10% of the of these patients experience ventricular fibrillation as a patients in the acute infarction ~ t a g e ~ . ~ ~ - ~ ~ result. . ’ ~1.4.12-14.18.19.23.27 . ~ ~ , ~ ~ This , ~ connection ~ . ~ ~ ,is ~even ~ less favorable in considering singular or polymorphic ventricular exis attained much earlier, usually in the first two hours after the onset of symptoms and thus in the prehospital trasystoles. phase. 12.23 In this phase, the occurrence of ventricular fibrillation correlates closely only with the so-called REfficacy of Lidocaine in the Prevention of on-T extrasystoles. El Sherif et al. reported on 17 postinfarction patients with early ventricular fibrillation: in 4 Ventricular Fibrillation During Myocardial of 7 patients with an eliciting R-on-T phenomenon, this Infarction occurred within the first 4 h after onset of symptoms.28 Campbell et al. even showed, in 16 of 17 patients with The validity of many investigations into the preventive ventricular fibrillation in the early infarction phase, an Reffect of lidocaine is frequently limited by an inadequate on-T phenomenon as the immediate eliciting mechanism study design and selective patient enrollment,l o , late therfor ventricular fibrillation. 23 R-on-T extrasystoles exert, apy starts,I5 and too small study cohorts. 12.27.36.37It is not on the other hand, only very slight influence on the elicisurprising, therefore, that in the late 1960s Lown rt af. tation of rnonomorphic ventricular tachycardias within a could effectively avoid ventricular fibrillation by aggres~ l i n i ~oraexperimental 1 ~ ~ ~ ~myocardial ~ ~ ~ ~infarction.26The sive administration of lidocaine to 130 patients with discrepancy arises from the fact that R-on-T extrasystoles infarction-associated “warning arrhythmias,”2 but conpotentiate the heterogeneity of the excitation state of the secutive studies by Pantridge et al. 38 or Chopra et al. 3y individual myocardial cells, a fact which promotes the occould not confirm corresponding therapeutic success or currence of ventricular fibrillation, but which is of suboreven, like Darby er al. ,40 reported contrary results. dinate importance as a starting mechanism for the reentry A first systematic approach was given by Lie et al. in circle which i s usually at the base of monomorphic the mid-l970s, when they observed a ninefold higher risk tachycardias. A clear difference in the above findings is of ventricular fibrillation in the placebo group in a also given for patients with chronic coronary heart disprophylactic lidocaine administration to 2 12 randomized ease. The knowledge concerning eliciting mechanisms infarction patients. Here, too, the marked patient selec(very rarely R-on-T phenomena) and trigger arrhythmias tion must be noted (only patients under 70 years of age for ventricular fibrillation ( >90% ventricular tachywith transmural infarction and early admittance, exclusion cardias) collected in these patients, especially during longof patients with heart failure, conduction impairment, etc.). term electrocardiography, cannot be applied to the acute The same team was not able to demonstrate prophylacinfarction ~ i t u a t i o n . ~ O - ~ ~ tic efficacy of lidocaine following intramuscular adminisAccording to available literature, only the occurrence tration in a subsequent study on hospitalized infarction paof R-on-T arrhythmias elicits sensitivity sufficient to det i e n t ~ .Consecutive ~~ studies, in which lidocaine was fine the so-called “warning arrhythmias” in acute myadministered in the prehospital phase, showed a tendenocardial infarction. Nevertheless, Pantridge et al. 33 concy to promote only the preventive effects of lidofirmed that, according to various authors, a lack of such caine.4,11,’2,42 Wennerblom et al. monitored 54 infarction warning arrhythmias can be observed in 20-80% of the patients for 3 h after intramuscular injection of 300 mg patients. lidocaine, but did not observe ventricular fibrillation in The question arises as to the degree with which such any patient in either the placebo or treated group.37Likearrhythmias can reliably be recorded in acute myocardial wise, in a randomized controlled investigation by Dunn infarction. According to observations by individual et al., the patient group of 402 was too small to confirm authors, only 7-16% of all complex forms of arrhythmia a preventive drug effect; only 3 patients suffered from ven(ventricular pairs and tachycardias) are recorded in the intricular fibrillation (all in the placebo group). Other comtensive medical care unit by personnel, and about 75% plex forms of arrhythmia (ventricular pairs and
536
Clin. Cardiol. Vol. 13, August 1990
tachycardias) were clearly reduced by lidocaine (by 60%) (placebo group 19%).11,12 Currently, the largest controlled study by Koster and Dunning4 reports a 40% reduction in ventricular fibrillation after prophylactic administration of lidocaine. In the total 2987 patients pretreated with intramuscular lidocaine, ventricular fibrillation occurred within the first 60 minutes after administration in 8 cases (0.3%);the frequency in the placebo group (3037 patients) was 17 patients (0.5%),and thus was not statistically significantly different. Ventricular fibrillation occurred in only 2 of 2987 patients after therapeutic lidocaine levels were attained, while the incidence in the placebo group was six times higher. The practical consequences of this study are somewhat sobering, not only because the total rate of ventricular fibrillation is clearly lower than in earlier studies. Taking the effectivenessof lidocaine into account, 300 patients would have to be prophylactically treated in order to avoid ventricular fibrillation in only one patient! When additional investigations by Carmth et af. are considered, in which the prognosis of an intensive care monitored infarction patient does not deteriorate due to single ventricular fibrillation as long as immediate defibrillation and, if necessary, reanimation follow, the therapeutic benefit of lidocaine is reduced to an even greater extent. 12.19.36 A question arises concerning the cause of the frequent therapeutic failure of lidocaine, especially in early infarction arrhythmia. Chopra et al.39 and Epstein et al.42 document, very clearly, a reduced efficacy of lidocaine, especially against early onset ventricular extrasystoles (such as R-on-T extrasystoles), which is attributed among other things to a brief, inadequate blood level of electrophysiological mechanisms l i d ~ c a i n or e ~different ~ of early and late infarction arrhythmia^.^^.^' Likewise, some authors point to the influence of the ~ a g o t o n and e~~ sympathotone for the genesis of arrhythmias and the failure of lidocaine in the early infarction phase.33.46*47 In this connection, Pantridge et al. 2s.33.38 impressively document a >50% reduction in the antiarrhythmicefficacy of lidocaine in infarction patients with elevated sympathotone (heart rate >90/min). Experience shows that these patients profit from the administration of beta-blocking substance^^^.^^ as long as the clinical contraindications to these substances are considered (e.g., decompensated left heart failure, posterior wall infarction with septum involvement).
Side Effects and Risks of Preventive Lidocaine Therapy The incidence of adverse events during antiarrhythmic therapy with lidocaine is generally cited as 739%. However, these are usually direct side effects of the local anesthetic effect of lidocaine, which possesses a high affinity to central and peripheral nervous structures due to its lipophilic properties. The patients 1s9*1s*16.21,27
complained most frequently of dizziness, giddiness, tremors and paresthesias, and impairments in vision, speech, and coordination. 13-1s.18.21.27.41.50 The onset of these adverse events is time dependent and correlates very closely with the rate of injection and the cumulative lidocaine dosage. It shows only a poor relationship to the plasma level of lidocaine.21Less frequent and considerably more serious, on the other hand, is the occurrence of marked h y p o t e n s i ~ n ,grand ~ ~ , ~ma1 ~ seizures,52sinus arrest and AV conduction impairmentss6 and AV conduction acceleration with atrial f i b r i l l a t i ~ n , ~ ~ allergic reactionsS8and respiratory arrests9 (as well as a high mortality reported under lidocaine in individual these side studies).l 2 In spite of controversial findings,21.26 effects appear elevated in acute myocardial infarction and are especially high in patients with cardiogenic shock and heart failure, or in patients older than 70 years of age. l 6 However, it must be considered that the two patient groups last cited represent 32% or 22%, respectively, of the infarction patients in an intensive care unit. The frequency of serious side effects under lidocaine in infarction patients was probably underestimated in the past, in spite of numerous casuistics. This was made clear in a prospective, randomized, double-blind study on intensive care patients published recently by Rademaker et aL2I Of the 285 enrolled patients who were treated with, among other things, 2 x 100 mg bolus injections of lidocaine with subsequent drip infusion of about 4 g/24 h, lifethreatening episodes developed in 5 patients. Two patients each showed drug-dependent sinus arrest or seizure; one patient suffered respiratory arrest. All events occurred in the lidocaine group within the first 24 h after start of therapy.
Selective Versus Prophylactic Treatment Strategies The findings presented are summarized in their consequences in a recently published randomized study by Wyse et d Z 2 The authors compared for the first time a prophylactic with a selective application of lidocaine in 333 intensive care infarction patients. The occurrence of long-lasting ventricular tachycardias and ventricular fibrillation in only two patients confirm here, also, the low incidence of such events documented in recent s t ~ d i e s . ~ , ~ Causes ~ . ~ ~ cited . ~ ~ may . ~ ~include . ~ ~ improved infarction therapy, including interventional possibilities (thrombolytic therapy, etc.). Both patients with malignant tachyarrhythmias belonged to the group of selectively treated patients; the difference compared with the prophylactically treated patients was, however, not significant. By contrast, adverse events occurred in 44% of the prophylactically treated patients, which was three times the rate in the selectively treated group, and serious adverse events occurred with a rate of 17%, which is 10 times the rate of the group of selectively treated patients.
M . Zehender et al. : Lidocaine in early AM1
Lidocaine Therapy in Patients Considered for Thrombolytic Therapy Since thrombolytic therapy is currently applied in 1020% of all infarction patients, the question of appropriate prophylactic or selective lidocaine therapy arises for this patient group as well. To date, no systematic data are available on the efficacy of lidocaine in corresponding reperfusion arrhythmias. The first findings on the frequency and severity of ventricular arrhythmias occurring after successful reperfusion therapy do not, however, show any difference compared with patients unsuccessfully reperfused.60At the same time, the majority of the observed arrhythmias were so-called idioventricular forms of arrhythmia, which have no prognostic importance according to clinical experience, and progress only very rarely to malignant forms. Insofar as early onset ventricular arrhythmias or the occurrence of ventricular tachycardias and ventricular fibrillation require corresponding therapy, it must be considered that particularly patients with occluded right coronary arteries present with an elevated incidence of pathological sinus bradycardia and hypotension during reperfusion. This could, however, be aggravated by lidocaine therapy.
Summary and Therapeutic Recommendations We must conclude that none of the treatment strategies discussed for the prevention of infarction-related ventricular fibrillation can be considered optimal. Ppphylactic lidocaine therapy has no clinical benefit as evidenced by the currently relatively low incidence of ventricular fibrillation in acute myocardial infarction and the limited efficacy of lidocaine, especially in the early infarction phase, and also in light of the occurrence of side effects, which cannot be overlooked. Selective lidocaine therapy also has been shown to be hardly effective, since a reliable definition and early recognition of “warning arrhythmias” is not now clinically possible or guaranteed. Clearly, lidocaine, should therefore be used more restrictively in acute myocardial infarction. It must be noted especially that a causal therapy of infarction-related myocardial ischemia with thrombolytic, vasodilating, antianginal, and sympatholytic substances must take precedence over the therapy of ventricular arrhythmias which arise secondarily. Indications for antiarrhythmic therapy with lidocaine should be limited to infarction patients with recurrent, intermittent ventricular tachycardias ( >4 beats, at least three episodes per hour) and frequent R-on-T arrhythmias, especially when a relationship to the occurrence of complex arrhythmias can be recognized, as well as after the occurrence of persistent ventricular tachycardias and/or ventricular fibrillation. This applies to the prehospital phase as well as to any further course of hospitalization. Therapeutic lidocaine dosage should be administered as a slow bolus injection (where possible 100 mg/lO min or
537
200 mg/20 min) and not exceed 3-4 g/24 h to avoid side effects. The maximum effect is attained by the end of the bolus phase. In the event of therapy-resistant ventricular tachycardia and/or ventricular fibrillation and optimized infarction therapy, an additional bolus administration of propafenone, 70 mg, is indicated, depending on the clinical stability of the patient. For patients with very frequent malignant forms of arrhythmia and especially in the presence of greatly reduced ventricular ejection fraction, we ppfer an immediate switch to intravenous amiodarone therapy (200 mg amiodarone over 3 h, subsequently 1200 mg/24 h). Lidocaine therapy is maintained in decreasing doses (reduction of the daily dose by 1 g every 12 h). During the prehospital phase, administration of combination antiarhythmics should be subjected to very restrictive consideration of the therapeutic indications due to the lower surveillance opportunity arld, if persistent ventricular tachycardia occurs, preference should be given to early cardioversion. Intramuscular administration of lidocaine or of other antianhythmics is of very limited or no practical importance in this connection from the aspect of possible thrombolytic therapy and the lack of evidence of clinically relevant therapeutic advantages. The necessity of continuing lidocaine therapy should continually be critically examined in all hospitalized phases of infarction depending on the form of arrhythmia on which the therapeutic indication is based, and should not exceed a total duration of 2-3 days where possible. For patients in whom continued antiarrhythmic therapy appears necessary (e.g., in recurrent ventricular fibrillation), attention must be paid to the overlapping dosage scheme, since the saturation phase of certain antiarrhythmic drugs (such as amiodarone) may clearly exceed the half-life of lidocaine. In these patients, intensive care monitoring should be provided in the transfer phase, since a prognosis of the antiarrhythmic efficacy of other, even closely related antiarrhythmics following lidocaine administration is ~ n r e l i a b l eIf. ~possible, ~ withdrawal of lidocaine should also be done under intensive care monitoring for patients in whom continued antiarrhythmic therapy does not appear to be necessary.
References I. Harrison DC: Should lidocaine be administred routinely to all patients after acute myocardial infarction? Circulation 58, 581 ( 1978) 2. Julian DG, Valentine PA, Miller GG: Disturbances of rate, rhythm and conduction in acute myocardial infarction. Am J Med 37, 915 (1964) 3. Lown B, Fakhro AM, Hood WB, Thorn GW: The coronary care unit. New perspectives and directions. J Am Med Assoc 199, 188 (1967) 4. Koster RW, Dunning AJ: Intramuscular lidocaine for prevention of lethal anhythmias in the prehospitalizationphase of acute myocardial infarction. N Engl J Med 18, I105 (1985) 5 . Kostuk WJ, Beanlands DS: The prophylactic use of lidocaine in the prevention of ventricular arrhythmias in acute myocardial
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infarction. In Lidocaine in the Treatment of Ventricular Arrhythmias (Eds. Scott DB, Julian DG). Livingstone, Edinburgh and London (1971) 82 6. Mounsey P: Intensive coronary care: Arrhythmias after acute myocardial infarction. Am J Cardiol 20, 475 (1967) 7. Pentecost BL, Mayne NMC: Results of a general hospital comnary care service. Br Med J I,830 ( I 968) 8. Thomas M, Jewitt DE. Shillingford JP: Analysis of 150 patients with acute myocardial infarction admitted to an intensive care and study unit. Br Med J 1, 787 (1968) 9. Bleifeld W, M e n W. Heinrich KW, Effert S: Controlled trial of prophylactic treatment with lidocaine in acute myocardial infarction. Eur J Clin Pharmacol 6, I19 (1973) 10. Borak J, Veilleux S: Prophylactic lidocaine: Uncertain benefits in emergency settings. Ann Emerg Med 1 I , 493 (1982) 11. Dunn HM, Kinney CD, Campbell NPS, Shanks RG, Adgey AAJ: Prophylactic lidocaine in suspected acute myocardial infarction. Int J Cardiol 5 , 96 (1984) 12. Dunn HM, McComb JM, Kinney CD. Campbell NPS. Shanks RG. MacKenzie G, Adgey AAJ: Prophylactic lidocaine in the early phase of suspected myocardial infarction. Am Hean J I10, 353 (1985) 13. Noneman JW, Rogers JF: Lidocaine prophylaxis in acute myocardial infarction. Medicine 57, 501 (1978) 14. O'Brien KP, Taylor PM, Croxson R: Prophylactic lignocaine in hospitalized patients with acute myocardial infarction. Med J Aust 2 (suppl), 36 (1973) 15. Pitt A, Lipp H, Anderson ST: Lignocaine given prophylactially to patients with acute myocardial infarction. Lancer I , 612 (1971) 16. Ribner HS, Isaacs ES, Frishrnan WH: Lidocaine prophylaxis against ventricular fibrillation in acute myocardial infarction. Progr Cardiovasc Dis 21, 287 (1979) 17. Singh JB, Kocot SL: A controlled trial of intramuscular lidocaine in the prevention of premature ventricular contractions associated with acute myocardial infarction. Am Heart J 91, 430 (1976) 18. Lie KI. Wellens HJ, van Capelle FJ. Durrer D: Lidocaine in the prevention of primary ventricular fibrillation. N Engl J Med 291, 1324 (1974) 19. Carmth JE, Silverman ME: Ventricular fibrillation complicating acute myocardial infarction: Reasons against the routinous use of lidocaine. Am Heart J 104, 545 (1982) 20. Lofmark R , Orinius E: Restricted lignocaine prophylaxis in acute myocardial infarction. Acta Med Scand 201, 89 (1977) 21 Rademaker AW, Kellen J , Tam YK, Wyse DG: Character of adverse effects of prophylactic lidocaine in the coronary care unit. Clin Pharmacol Ther 40, 71 (1986) 22 Wyse DG,Kellen J, Rademaker AW: Prophylactic versus selective lidocaine for early ventricular arrhythmias of myocardial infarction. J Am Coll Cardiol 12, 507 (1988) 23. Campbell RWF, Murray A, Julian DG: Ventricular arrhythmias in the first 12 hours of acute myocardial infarction. Br Heart J 46, 351 (1981) 24. De Soyza, Bissett JK,Kane JJ, Murphy ML, Doherty JE: Ectopic ventricular prematurity and its relationship to ventricular tachycardia in acute myocardial infarction in man. Circulation 50, 529 (1974) 25. Pantridge JF, Webb SW, Adgey AAJ, Geddes JS: The first hour after the onset o f myocardial infarction. Progr Cardiol 3, 173 (1974) 26. Williams DO, Scherlag BJ, Hope RR, El-Sherif N, Lazzara R: The pathophysiology of malignant ventricular arrhythmias during acute myocardial ischemia. Circulation 50, I 163 (1974) 27. Mogensen L: Ventricular tachyarrhythmias and lignocaine prophylaxis in acute myocardial infarction. Acta Med Scand 513 (suppl) I (1976)
28. El-Sherif N, Mycrburg RJ, Scherlag BJ, Bcfclcr B, Aranda JM, Castellanos A, Lazzard R: Electrocardiographic antecedents of primary ventricular fibrillation, value of the R-on-T phenomenon in myocardial infarction. Br H e m J 38, 415 (1976) 29. Dhingra RC, Deedwania PC, Cummings JM: Electrophysiologic effects of lidocaine on sinus node and atrium in patients with and without sinoatrial dysfunction. Circulation 57, 448 (1978) 30. Hohnloser S, Kasper W, Zehender M, Meinertz T, Just H: LangzeitelektrokardiographischeBeobachtungen beim plijtzlichen Herztod. Intensivmed 26, 250 (1989) 3 I. Panidis JP, Morganroth J: Sudden death in hospitalized patients: Cardiac rhythm disturbances detected by ambulatory electrocardiographic monitoring. J Am ColI Carifiol2.798 (1983) 32. Pratt CM, Francis MJ, Luck JC, Wyndhani CR, Miller RR, Quinones MA: Analysis of ambulatory electrocardiograms in 15 patients during spontaneous ventricular fibrillation with special reference to preceding arrhythmic event. J Am CONCurdid 2, 789 (1983) 33. Pantridge JF, Adgey AAJ, Geddes JS, Webb SW: 7he Acute Coronury Attack. Pitman Medical Publishing, Turnbridge Wells, Kent (1975) 7-1 17 34. Bennett MA, Pentecost BL: Warning of cardiac arrest due to ventricular fibrillation and tachycardia. h n c e t I , 1351 (1972) 35. Dhurandhar RW, Macmillan RL, Brown KWG: Primary ventricular fibrillation complicating acute myocardial infarction. Am J Cardiol 27, 347 (1971) 36. Church G, Biem RO: Intensive care-a practical system for a small hospital without a house staff. N EnglJ Med 281, I 155 ( 1969) 37. Wennerblom B, Holmberg S, Ryden L, Wedel H: Antiarrhythmic efficacy and side effects of lidocaine given in thc prehospital phase of acute myocardial infarction. Eur HeartJ 3 , 5 16 (1982) 38. Pantridge JF: Emergency treatment of cardiac arrhythmias in myocardial infarction. In Lidocaine in the Treatment of Ventricular Arrhythmias: Proceedings of. Symposium (Eds. DB Scott, DG Julian). Livingstone, Edinburgh (1971) 77 39. Chopra MP, Thadani U, Portal RW, Aber CP: Lignocaine therapy for ventricular ectopic activity after acute myocardial infarction: A double-blind trial. Br Med J I , 213 (1971) 40. Darby S, Bennett MA, Creuickshank JC, Pentecost BL: Trial of combined intramuscular and intravenous lignocaine in prophylaxis of ventricular tachyarrhythmias. Lancet I , 817 (1972) 41. Lie KI, Liem KL, Durrer D: A double-blind randomized study of intramuscular lidocaine in preventing primary ventricular fibrillation. Am J Ccrrdiol 39, 275 (1977) 42. Valentine PA, Frew JL, Mashford ML, Sloman JG: Lidocaine in the prevention of sudden death in the pre-hospital phase of acute infarction. A double-blind study. N Engl J Med 294, 1327 ( 1974) 42. Epstein SE, Beiser GD, Rosing DR, Talano J V , Kanh RB: Experimental acute myocardial infarction: Characterization and treatment of the malignant premature ventricular contraction. Circulation 47, 446 (1973) 43. Gamble OW, Cohn K: Effect of propranolol, procainamide, and lidocaine on ventricular automaticity and re-entry in experimental myocardial infarction. Circulation 46, 498 (1972) 44. Kelzner J, Wolf M, Kosowsky BD, Lown B: Ventricular ectopic rhythms following vagal stimulation in dogs with acute myocardial infarction. Circulation 47, 44 ( 1973) 45. Scherlag BJ, Helfant RH, Haft J1, Damato AN: Electrophysiology underlying ventricular arrhythmias due to coronary ligation. Am J Phys 219, 1665 (1970) 46. Lown B, Klein MD, Hershberg PI: Coronary and precoronary care. Am J Med 46, 705 (1969)
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47. Robison SL, Schroll M, Hamson DC: The circulatory response to lidocaine in experimental myocardial infarction. Am J Med Sci 258, 260 (1969) 48. Snow PJD: Effect of propranolol in myocardial infarction. Luncet 2, 551 (1965) 49. Webb SW, Adgey AAJ, Pantridge JF: Autonomic disturbance at onset of acute myocardial infarction. Br Med J 3, 89 (1972) 50. Gianelly R, von der Groeben JO, Spivack AP, Hamson DC: Effect of lidocaine on ventricular arrhythmias in patients with coronary artery disease. N Engl J Med 277, 1215 (1967) 51. Jewitt DE, Kishon Y, Thomas M: Lignocaine in the management of arrhythmias after acute myocardial infarction. Lancet I , 266 (1968) 52. Klein HO. Jutrin I, Kaplinsky E: Cerbral and cardiac toxicity of a small dose of lignocaine. Br Heart J 37, 775 (1975) 53. Cheng TO, Wadhwa K: Sinus standstill following intravenous lidocaine administration. J Am Med Assoc 223, 790 (1973) 54. Conley MJ, McNeer JF, Lee KL, Wagner GS, Rosati RA: Cardiac arrest complicating acute myocardial infarction. Predictability and prognosis. Am J Curdiol 39, 7 (1977) 55. Manyari-Ortega DE, Brennan FJ: Lidocaine-induced cardiac asystole. Chest 74, 227 (1978) 56. Roos JC, Dunning AJ: Effects of lidocaine on impulse formation and conduction defects in man. Am HeurtJ 86,686 (1975) 57. Sinatra ST, Jeresaty RM: Enhanced atrioventricular conduction in atrial fibrillation after lidocaine administration. J Am Med Assoc 237, 1356 (1977)
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58. Zehender M, Geibel A, Treese N , Hohnloser S, Meinertz T, Just H: Prediction of efficacy and tolerance of oral mexiletine by intravenous lidocaine application. CIin Phurmucol Thrr 44, 389 (1988) 59. Grenadier E, Alpan G, Keidar S, Palant A: Respiratory and cardiac arrest after the administration of lidocaine into the central nervous system. Eur J Curdiol 2, 235 (1981) 60. Theroux P, Morisette D, Juneau M , de Guise P. Pclleticr G, Waters DD: Influence of fibrinolysis and percutaneous transluminal coronary angioplast on the frequency of ventricular premature complexes. Am J Curdiol 63, 797 (1989) 61. Antonelli D, Ben-Ami M, Weiss Z: Sinus standstill following accidental lidocaine overdose. Am Heart J 107, 1042 (1984) 62. Lawrie DM, Higgins MR, Godman MJ, Oliver MF, Julian DG, Donald KW: Ventricular fibrillation complicating acute myocardial infarction. Lance? 2, 523 (1968) 63. Marriott HJL, Bieza CF: Alarming ventricular acceleration after lidocaine administration. Chest 61, 682 (1972) 64. Romhilt DW, Bloomfield SS, Chou TC, Fowler NO: Unreliability of conventional electrocardiographic monitoring for arrhythmia detection in coronary care units. Am J Curdiol 31, 457 (1973) 65. Vetter NJ, Julian DG: Comparison of arrhythmia computer and conventional monitoring in coronary care unit. Lrrncet 1. I151 ( 1975) 66. Wysman MG, Hammelsmith L: Comprehensive treatment plan for the prevention of primary ventricular fibrillation in acute myocardial infarction. Am J Curdiol 33, 661 (1974)
Lidocaine in the Early Phase of Acute Myocardial Infarction: The Controversy Over Prophylacticor SelectiveUse M. ZEHENDER, M.D., w. U S P E R , M.D..H.JUST,
M.D.
Innere Medizin 111, Universitat Freiburg, Freiburg, West Germany
Summary: In acute myocardial infarction, lidocaine is considered the drug of choice for the treatment of malignant ventricular arrhythmias. While initially a so-called “selective” treatment strategy prevailed, in which lidocaine was administered only after the onset of certain “warning arrhythmias,” the prophylactic use of lidocaine in acute myocardial infarction has been gaining wider usage in intravenous and intramuscular application in recent years. Both therapeutic applications have been found to be problematic of late, which has led to increasingly restrictive use of lidocaine. While in selective treatment forms, the definition and prompt recognition of the socalled warning arrhythmias created especially acute problems, the prophylactic therapeutic use is problematic due to the Occurrence of sometimes serious side effects, which is to be expected as the size of the collective being treated increases. Both treatment forms also appear limited by the narrow preventive efficacy of lidocaine against malignant ventricular arrhythmias, especially against ventricular fibrillation. The current therapeutic recommendation for lidocaine in acute myocardial infarction should be limited to patients presenting with very frequent and complex ventricular arrhythmias, especially when these are elicited by an R-on-T phenomenon. Side effects and other therapeutic problems encountered when the therapeutic modality is switched or adjusted can be greatly reduced
Address for reprints: Manfred Zehender, M.D. Innere Medizin I11 University of Freiburg Hugstetterstrasse 55 D-7800 Freiburg, West Germany Received: January 20, 1990 Accepted: February 6 , 1990
by careful dosing and selection of the optimal combination substances.
Key words: acute myocardial infarction, ventricular arrhythmias, lidocaine
Introduction Lidocaine is considered the drug of choice in the treatment of ventricular arrhythmias which occur in the prehospital and early hospital phase of acute myocardial infarction.I This indication, usually differentiated under the aspect of a “prophylactic” or “selective” application, has however, come under increasing critical fire in the past few years. The (“selective”) use of lidocaine is based on a concept first described by Julian et aL2 and Lown et al. that so-called “warning arrhythmias” can be defined in the phase of acute myocardial infarction, whereby patients with an increased risk for the occurrence of lifethreatening arrhythmias can be identified, making selective antiarrhythmic therapy p o ~ s i b l e .By ~ -contrast, ~ pmponents of the “prophylactic” a p p r o a ~ h l . ~doubt . ~ - ’ ~the possibility of reliably defining the “warning arrhythmias” and identifying them early enough. The benefit of prophylactic lidocaine administration is assumed primarily based on findings of a study by Lie et (11. in the mid1970s, in which a reduction of Ventricular fibrillation in the acute infarction phase could be demonstrated following prophylactic administration of lidocaine. I s A third, much more critical standpoint meanwhile doubts both the possibility of definition and reliable recording of “warning arrhythmias” as well as the efficacy and benefit of prophylactic lidocaine administration.19-22Based on this, an antianhythmic therapy in acute myocardial infarction should be limited to patients with documented malignant arrhythmias (persistent ventricular tachycardia, ventricular fibrillation, etc.). In this report, the various aspects are discussed and a recommendation for practical procedures in acute myocardial infarction is given.
M. Zehender rt d.: Lidocaine in early AM1
Ventricular Arrhythmias in Acute Myocardial Infarction and Their Importance as Warning Arrhythmias
535
are recorded by a computerized arrhythmia recognition s y ~ t e m .Information ~ ~ . ~ ~ regarding the reliability of recognition of R-on-T arrhythmias is not available. In the prehospital infarction phase, it can certainly be assumed that the qualitative and quantitative recording of arrhythmias In more than 95 % of all patients, ventricular arrhythis less reliable. Discrepant information concerning the fremias occur during acute myocardial infarction. The frequency of primary ventricular fibrillation without precedquency and severity of infarctions correlate in a complex ing warning arrhythmias ( < 2 5 % to 80%) confirm this manner with the extent of necrotic, ischemic, and healthy deficiency from a clinical point of view. 1.34.35 myocardial areas. 1 . 2 3 - 2 6 Can these forms of arrhythmias In addition to the problem of early and reliable recogbe reliably defined and recognized as “warning arrhythnition, the problem of insufficient specificity also exists mias”? Ventricular extrasystoles, like ventricular salvos and tachycardias, occur frequently about 8- 12 h after the for R-on-T arrhythmias. About 60% of all infarction patients present with R-on-T extrasystoles, but only 3- 10% acute infarction episode.23The peak of frequency of ventricular fibrillation, which is observed in 2-10% of the of these patients experience ventricular fibrillation as a patients in the acute infarction ~ t a g e ~ . ~ ~ - ~ ~ result. . ’ ~1.4.12-14.18.19.23.27 . ~ ~ , ~ ~ This , ~ connection ~ . ~ ~ ,is ~even ~ less favorable in considering singular or polymorphic ventricular exis attained much earlier, usually in the first two hours after the onset of symptoms and thus in the prehospital trasystoles. phase. 12.23 In this phase, the occurrence of ventricular fibrillation correlates closely only with the so-called REfficacy of Lidocaine in the Prevention of on-T extrasystoles. El Sherif et al. reported on 17 postinfarction patients with early ventricular fibrillation: in 4 Ventricular Fibrillation During Myocardial of 7 patients with an eliciting R-on-T phenomenon, this Infarction occurred within the first 4 h after onset of symptoms.28 Campbell et al. even showed, in 16 of 17 patients with The validity of many investigations into the preventive ventricular fibrillation in the early infarction phase, an Reffect of lidocaine is frequently limited by an inadequate on-T phenomenon as the immediate eliciting mechanism study design and selective patient enrollment,l o , late therfor ventricular fibrillation. 23 R-on-T extrasystoles exert, apy starts,I5 and too small study cohorts. 12.27.36.37It is not on the other hand, only very slight influence on the elicisurprising, therefore, that in the late 1960s Lown rt af. tation of rnonomorphic ventricular tachycardias within a could effectively avoid ventricular fibrillation by aggres~ l i n i ~oraexperimental 1 ~ ~ ~ ~myocardial ~ ~ ~ ~infarction.26The sive administration of lidocaine to 130 patients with discrepancy arises from the fact that R-on-T extrasystoles infarction-associated “warning arrhythmias,”2 but conpotentiate the heterogeneity of the excitation state of the secutive studies by Pantridge et al. 38 or Chopra et al. 3y individual myocardial cells, a fact which promotes the occould not confirm corresponding therapeutic success or currence of ventricular fibrillation, but which is of suboreven, like Darby er al. ,40 reported contrary results. dinate importance as a starting mechanism for the reentry A first systematic approach was given by Lie et al. in circle which i s usually at the base of monomorphic the mid-l970s, when they observed a ninefold higher risk tachycardias. A clear difference in the above findings is of ventricular fibrillation in the placebo group in a also given for patients with chronic coronary heart disprophylactic lidocaine administration to 2 12 randomized ease. The knowledge concerning eliciting mechanisms infarction patients. Here, too, the marked patient selec(very rarely R-on-T phenomena) and trigger arrhythmias tion must be noted (only patients under 70 years of age for ventricular fibrillation ( >90% ventricular tachywith transmural infarction and early admittance, exclusion cardias) collected in these patients, especially during longof patients with heart failure, conduction impairment, etc.). term electrocardiography, cannot be applied to the acute The same team was not able to demonstrate prophylacinfarction ~ i t u a t i o n . ~ O - ~ ~ tic efficacy of lidocaine following intramuscular adminisAccording to available literature, only the occurrence tration in a subsequent study on hospitalized infarction paof R-on-T arrhythmias elicits sensitivity sufficient to det i e n t ~ .Consecutive ~~ studies, in which lidocaine was fine the so-called “warning arrhythmias” in acute myadministered in the prehospital phase, showed a tendenocardial infarction. Nevertheless, Pantridge et al. 33 concy to promote only the preventive effects of lidofirmed that, according to various authors, a lack of such caine.4,11,’2,42 Wennerblom et al. monitored 54 infarction warning arrhythmias can be observed in 20-80% of the patients for 3 h after intramuscular injection of 300 mg patients. lidocaine, but did not observe ventricular fibrillation in The question arises as to the degree with which such any patient in either the placebo or treated group.37Likearrhythmias can reliably be recorded in acute myocardial wise, in a randomized controlled investigation by Dunn infarction. According to observations by individual et al., the patient group of 402 was too small to confirm authors, only 7-16% of all complex forms of arrhythmia a preventive drug effect; only 3 patients suffered from ven(ventricular pairs and tachycardias) are recorded in the intricular fibrillation (all in the placebo group). Other comtensive medical care unit by personnel, and about 75% plex forms of arrhythmia (ventricular pairs and
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tachycardias) were clearly reduced by lidocaine (by 60%) (placebo group 19%).11,12 Currently, the largest controlled study by Koster and Dunning4 reports a 40% reduction in ventricular fibrillation after prophylactic administration of lidocaine. In the total 2987 patients pretreated with intramuscular lidocaine, ventricular fibrillation occurred within the first 60 minutes after administration in 8 cases (0.3%);the frequency in the placebo group (3037 patients) was 17 patients (0.5%),and thus was not statistically significantly different. Ventricular fibrillation occurred in only 2 of 2987 patients after therapeutic lidocaine levels were attained, while the incidence in the placebo group was six times higher. The practical consequences of this study are somewhat sobering, not only because the total rate of ventricular fibrillation is clearly lower than in earlier studies. Taking the effectivenessof lidocaine into account, 300 patients would have to be prophylactically treated in order to avoid ventricular fibrillation in only one patient! When additional investigations by Carmth et af. are considered, in which the prognosis of an intensive care monitored infarction patient does not deteriorate due to single ventricular fibrillation as long as immediate defibrillation and, if necessary, reanimation follow, the therapeutic benefit of lidocaine is reduced to an even greater extent. 12.19.36 A question arises concerning the cause of the frequent therapeutic failure of lidocaine, especially in early infarction arrhythmia. Chopra et al.39 and Epstein et al.42 document, very clearly, a reduced efficacy of lidocaine, especially against early onset ventricular extrasystoles (such as R-on-T extrasystoles), which is attributed among other things to a brief, inadequate blood level of electrophysiological mechanisms l i d ~ c a i n or e ~different ~ of early and late infarction arrhythmia^.^^.^' Likewise, some authors point to the influence of the ~ a g o t o n and e~~ sympathotone for the genesis of arrhythmias and the failure of lidocaine in the early infarction phase.33.46*47 In this connection, Pantridge et al. 2s.33.38 impressively document a >50% reduction in the antiarrhythmicefficacy of lidocaine in infarction patients with elevated sympathotone (heart rate >90/min). Experience shows that these patients profit from the administration of beta-blocking substance^^^.^^ as long as the clinical contraindications to these substances are considered (e.g., decompensated left heart failure, posterior wall infarction with septum involvement).
Side Effects and Risks of Preventive Lidocaine Therapy The incidence of adverse events during antiarrhythmic therapy with lidocaine is generally cited as 739%. However, these are usually direct side effects of the local anesthetic effect of lidocaine, which possesses a high affinity to central and peripheral nervous structures due to its lipophilic properties. The patients 1s9*1s*16.21,27
complained most frequently of dizziness, giddiness, tremors and paresthesias, and impairments in vision, speech, and coordination. 13-1s.18.21.27.41.50 The onset of these adverse events is time dependent and correlates very closely with the rate of injection and the cumulative lidocaine dosage. It shows only a poor relationship to the plasma level of lidocaine.21Less frequent and considerably more serious, on the other hand, is the occurrence of marked h y p o t e n s i ~ n ,grand ~ ~ , ~ma1 ~ seizures,52sinus arrest and AV conduction impairmentss6 and AV conduction acceleration with atrial f i b r i l l a t i ~ n , ~ ~ allergic reactionsS8and respiratory arrests9 (as well as a high mortality reported under lidocaine in individual these side studies).l 2 In spite of controversial findings,21.26 effects appear elevated in acute myocardial infarction and are especially high in patients with cardiogenic shock and heart failure, or in patients older than 70 years of age. l 6 However, it must be considered that the two patient groups last cited represent 32% or 22%, respectively, of the infarction patients in an intensive care unit. The frequency of serious side effects under lidocaine in infarction patients was probably underestimated in the past, in spite of numerous casuistics. This was made clear in a prospective, randomized, double-blind study on intensive care patients published recently by Rademaker et aL2I Of the 285 enrolled patients who were treated with, among other things, 2 x 100 mg bolus injections of lidocaine with subsequent drip infusion of about 4 g/24 h, lifethreatening episodes developed in 5 patients. Two patients each showed drug-dependent sinus arrest or seizure; one patient suffered respiratory arrest. All events occurred in the lidocaine group within the first 24 h after start of therapy.
Selective Versus Prophylactic Treatment Strategies The findings presented are summarized in their consequences in a recently published randomized study by Wyse et d Z 2 The authors compared for the first time a prophylactic with a selective application of lidocaine in 333 intensive care infarction patients. The occurrence of long-lasting ventricular tachycardias and ventricular fibrillation in only two patients confirm here, also, the low incidence of such events documented in recent s t ~ d i e s . ~ , ~ Causes ~ . ~ ~ cited . ~ ~ may . ~ ~include . ~ ~ improved infarction therapy, including interventional possibilities (thrombolytic therapy, etc.). Both patients with malignant tachyarrhythmias belonged to the group of selectively treated patients; the difference compared with the prophylactically treated patients was, however, not significant. By contrast, adverse events occurred in 44% of the prophylactically treated patients, which was three times the rate in the selectively treated group, and serious adverse events occurred with a rate of 17%, which is 10 times the rate of the group of selectively treated patients.
M . Zehender et al. : Lidocaine in early AM1
Lidocaine Therapy in Patients Considered for Thrombolytic Therapy Since thrombolytic therapy is currently applied in 1020% of all infarction patients, the question of appropriate prophylactic or selective lidocaine therapy arises for this patient group as well. To date, no systematic data are available on the efficacy of lidocaine in corresponding reperfusion arrhythmias. The first findings on the frequency and severity of ventricular arrhythmias occurring after successful reperfusion therapy do not, however, show any difference compared with patients unsuccessfully reperfused.60At the same time, the majority of the observed arrhythmias were so-called idioventricular forms of arrhythmia, which have no prognostic importance according to clinical experience, and progress only very rarely to malignant forms. Insofar as early onset ventricular arrhythmias or the occurrence of ventricular tachycardias and ventricular fibrillation require corresponding therapy, it must be considered that particularly patients with occluded right coronary arteries present with an elevated incidence of pathological sinus bradycardia and hypotension during reperfusion. This could, however, be aggravated by lidocaine therapy.
Summary and Therapeutic Recommendations We must conclude that none of the treatment strategies discussed for the prevention of infarction-related ventricular fibrillation can be considered optimal. Ppphylactic lidocaine therapy has no clinical benefit as evidenced by the currently relatively low incidence of ventricular fibrillation in acute myocardial infarction and the limited efficacy of lidocaine, especially in the early infarction phase, and also in light of the occurrence of side effects, which cannot be overlooked. Selective lidocaine therapy also has been shown to be hardly effective, since a reliable definition and early recognition of “warning arrhythmias” is not now clinically possible or guaranteed. Clearly, lidocaine, should therefore be used more restrictively in acute myocardial infarction. It must be noted especially that a causal therapy of infarction-related myocardial ischemia with thrombolytic, vasodilating, antianginal, and sympatholytic substances must take precedence over the therapy of ventricular arrhythmias which arise secondarily. Indications for antiarrhythmic therapy with lidocaine should be limited to infarction patients with recurrent, intermittent ventricular tachycardias ( >4 beats, at least three episodes per hour) and frequent R-on-T arrhythmias, especially when a relationship to the occurrence of complex arrhythmias can be recognized, as well as after the occurrence of persistent ventricular tachycardias and/or ventricular fibrillation. This applies to the prehospital phase as well as to any further course of hospitalization. Therapeutic lidocaine dosage should be administered as a slow bolus injection (where possible 100 mg/lO min or
537
200 mg/20 min) and not exceed 3-4 g/24 h to avoid side effects. The maximum effect is attained by the end of the bolus phase. In the event of therapy-resistant ventricular tachycardia and/or ventricular fibrillation and optimized infarction therapy, an additional bolus administration of propafenone, 70 mg, is indicated, depending on the clinical stability of the patient. For patients with very frequent malignant forms of arrhythmia and especially in the presence of greatly reduced ventricular ejection fraction, we ppfer an immediate switch to intravenous amiodarone therapy (200 mg amiodarone over 3 h, subsequently 1200 mg/24 h). Lidocaine therapy is maintained in decreasing doses (reduction of the daily dose by 1 g every 12 h). During the prehospital phase, administration of combination antiarhythmics should be subjected to very restrictive consideration of the therapeutic indications due to the lower surveillance opportunity arld, if persistent ventricular tachycardia occurs, preference should be given to early cardioversion. Intramuscular administration of lidocaine or of other antianhythmics is of very limited or no practical importance in this connection from the aspect of possible thrombolytic therapy and the lack of evidence of clinically relevant therapeutic advantages. The necessity of continuing lidocaine therapy should continually be critically examined in all hospitalized phases of infarction depending on the form of arrhythmia on which the therapeutic indication is based, and should not exceed a total duration of 2-3 days where possible. For patients in whom continued antiarrhythmic therapy appears necessary (e.g., in recurrent ventricular fibrillation), attention must be paid to the overlapping dosage scheme, since the saturation phase of certain antiarrhythmic drugs (such as amiodarone) may clearly exceed the half-life of lidocaine. In these patients, intensive care monitoring should be provided in the transfer phase, since a prognosis of the antiarrhythmic efficacy of other, even closely related antiarrhythmics following lidocaine administration is ~ n r e l i a b l eIf. ~possible, ~ withdrawal of lidocaine should also be done under intensive care monitoring for patients in whom continued antiarrhythmic therapy does not appear to be necessary.
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