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Prevention of primary ventricular fibrillation in acute myocardial infarction with prophylactic lidocaine
Prevention of Primary Ventricular Fibrillation in Acute Myocardial Infarction With Prophylactic Lidocaine Milford G. Wyman,
MD,
R. Michael Wyman, MD, David S. Cannom, J. Michael Criley, MD
MD,
and
Primary ventricular fibrillation (VF) during an acute myocardial infarction (AMI) occurs with a high incidence and mortality rate with or without thrombolysis. The incidence varies from 2% to 19% depending on the definition of “primary.” Primary VF in this study refers to fibrillation occurring in the absence of shock or pulmonary edema. Mortality rate, when primary VF occurs, is 2 to 4 times greater than when it does not. Prevention of VF has been impeded by the publication of the 1996 recommendations of the American Heart Association and American College of Cardiology against the use of prophylactic lidocaine based on meta-analysis studies implying toxicity. This observational study of 4,254 patients with AMI reports the incidence and mortality rates of primary VF over 32 years. Of the 4,254 patients, 4,150 received prophylactic lidocaine, and 104 patients did not receive prophylactic lidocaine due to the 1996 guidelines, after which administration of prophylactic lidocaine was governed by physician choice. The inci-
dence of primary VF was 0.5% among the 4,150 who received prophylactic lidocaine and 10% among the 104 who did not (p <0.0001). Among the 4,150 receiving prophylactic lidocaine, sinoatrial block occurred in 0.5% and complete infranodal atrial ventricular block occurred in 0.2%, all secondary to the site of infarction (concurrent serum lidocaine levels were <4g/ml). Asystole was an agonal rhythm in 4%; these patients had been off lidocaine for 48 hours. Mortality rates were 10.5% in patients without primary VF and 25% in patients with VF (p <0.001). Thus, prophylactic lidocaine markedly decreased the incidence of VF in 4,150 patients with AMI to 0.5% compared with trials before and after thrombolysis (2% to 19%) and with the 104 patients in this study who did not receive prophylactic lidocaine (10%). No lidocaine-induced sinoatrial or atrial ventricular block or asystole occurred. 䊚2004 by Excerpta Medica, Inc. (Am J Cardiol 2004;94:545–551)
rimary ventricular fibrillation (VF) precipitated by an acute myocardial infarction (AMI) continP ues to be unpredictable and frequently associated with
mortality from primary VF without inducing sinoatrial or atrial ventricular block or asystole.
an unfavorable outcome, despite early treatment with thrombolytic agents.1– 6 Lidocaine has been used for the prevention of VF since the 1960s after coronary care units became a standard setting for the treatment of AMI.7 However, the 1996 guidelines of the American Heart Association and the American College of Cardiology (AHA/ACC) for the treatment of AMI considered prophylactic lidocaine a class III indication.8 This recommendation was based on 4 metaanalyses that hypothesized that the increased mortality rate among patients who received lidocaine was due to asystole or atrial ventricular or sinoatrial block, although without supporting data.9 –12 This report embodies a 32-year observational study of 4,150 patients with AMI treated with prophylactic lidocaine, resulting in significant decreases in the incidence of and From the San Pedro Peninsula Hospital, San Pedro, California; the University of Southern California School of Medicine, Los Angeles, California; the Little Company of Mary Hospital, Torrance, California; the Good Samaritan Hospital, Los Angeles, California; and the Harbor-UCLA Medical Center, Torrance, California. Funding support for purchase of equipment was provided by The San Pedro Heart Foundation, San Pedro, California. Manuscript received February 27, 2004; revised manuscript received and accepted May 3, 2004. Address for reprints: Milford G. Wyman, MD, 3069 Crest Road, Rancho Palos Verdes, California 90275. E-mail: drwyman@earthlink. net. ©2004 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 94 September 1, 2004
METHODS The bed capacity of the community hospital varied from 135 to 200 beds between 1970 and 2002. During the first 26-year study period, all patients with suspected AMI were treated with prophylactic lidocaine on admission to the hospital. Lidocaine was administered based on a history of sustained chest discomfort for ⬎30 minutes. All attending physicians agreed to the treatment protocol, which was approved by the institutional review board. However, after publication of the 1996 AHA/ACC guidelines, physicians were given the option of withholding prophylactic lidocaine, and these patients’ outcomes were compared with those of patients who received lidocaine. The final diagnosis of an AMI was based on a history of 30 minutes of sustained chest discomfort, increased laboratory markers, and evolving electrocardiographic abnormalities. Over the 32 years of the study, enzyme determinations included aspartate aminotransferase, lactate dehydrogenase, creatine phosphokinase, creatine phosphokinase-MB, and troponin-I. ST-elevation and non–ST-elevation infarctions were included. VF was defined as primary if it occurred in the absence of pulmonary edema or shock. If VF occurred before a physician’s examination, then it was considered primary if there was no history or findings of 0002-9149/04/$–see front matter doi:10.1016/j.amjcard.2004.05.014
545
FIGURE 1. Participants and treatments. A ⴝ amiodarone; B ⴝ bretylium; B-B ⴝ  blocker; L ⴝ lidocaine; P ⴝ procainamide; PL ⴝ prophylactic lidocaine; ROMI ⴝ rule-out myocardial infarction.
congestive failure on a recent previous examination. Episodes of VF were included if they occurred in the field, the emergency department, the coronary care unit, and the medical floor. The total incidence of primary VF was determined for all patients with a confirmed AMI who were treated during this 32-year period and separately for those whose physicians opted to withhold prophylactic lidocaine after publication of the 1996 AHA/ACC guidelines (Figure 1). Data collection began from onset of chest discomfort to hospital discharge. One hundred fifteen pieces of information were collected on each patient. Patients who entered the emergency department in shock and had pulmonary edema and died in ⬍1 hour were excluded from the calculation of mortality rate. Data on all patients who developed primary VF included age, gender, location at which the episode occurred, medical history, electrocardiographic site of infarct, premonitory rhythm, and total mortality. Statistical analysis: Patients with and without primary VF were compared with regard to clinical characteristics, warning arrhythmias, infarct location, and mortality rate with chi-square test. Incidences of primary VF in those patients who received prophylactic lidocaine and those who did not were compared with the chi-square test. Lidocaine was given as a 75-mg bolus over a 90-second interval followed by a 2-mg/min continuous infusion. A second bolus of 50 mg followed in 5 minutes. The infusion was discontinued after 24 hours if ectopic ventricular beats were not observed. If breakthrough ventricular arrhythmias occurred, additional 50-mg boluses were given every 5 minutes, as needed to a maximum of 325 mg. The continuous infusion was increased 1 mg/min after each bolus to a maximum of 4 mg/min.13–15 If any central nervous system side effects were noted, the dosage and infusion rates were decreased or discontinued. The lidocaine dose was halved in the presence of moderate or severe congestive heart failure (Killip’s classes II to IV). Lidocaine toxicity was graded as follows: class I ⫽ numbness of lips, hands, dizziness, slurred speech, mild sleepiness; class II ⫽ confusion, visual distur546 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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bance, agitation, somnolence, muscle twitching; class III ⫽ convulsions, unresponsiveness, conduction abnormalities; and, class IV ⫽ respiratory, cardiac arrest.13–15 If lidocaine was not effective in suppressing ventricular arrhythmias, intravenous procainamide was given with a similar multiple-bolus, continuous-infusion technique. A procainamide bolus of 100 mg was infused over 3 minutes. If ventricular extrasystoles persisted after 2 minutes, additional boluses of 100 mg were given every 5 minutes to ⱕ1 g, if necessary. Continuous infusion was increased 1 mg/min after each bolus to ⱕ6 mg/min.13,16
RESULTS During the 32-year observational study, 8,424 patients received prophylactic lidocaine; 4,254 were ultimately confirmed to have had an AMI, 4,150 of whom received prophylactic lidocaine. After 1996, 104 patients did not receive prophylactic lidocaine (Figure 1) at the discretion of their physician after the publication of the 1996 AHA/ACC guidelines.8 During this 6-year period, 798 patients with AMI were treated, 13% of whom did not receive prophylactic lidocaine. The mean age of the patients was 67 years, and 65% were men. There was a history of a myocardial infarction in 31%, a history of angina in 30%, diabetes in 21%, and previous stroke in 7%. There was a history of smoking in 27%. A typical history of AMI was recorded in 91%. There were ST-elevation infarctions with characteristic Q waves in 67% and non– ST-elevation infarctions in 33%. A diagnosis of a definite infarction required positive enzyme tests and abnormal serial electrocardiograms. The cumulative time intervals from onset of chest discomfort to hospitalization were 1 hour in 40%, 2 hours in 59%, and within 4 hours in 74%. Table 1 lists the electrocardiographic findings, old and recent infarcts, and conduction abnormalities. Arrhythmias that were identified during patients’ stay in the coronary care unit are listed in Table 2. The total incidence of primary VF in the coronary care unit was SEPTEMBER 1, 2004
TABLE 1 Electrocardiographic Findings* Infarct Site and Conduction Defects Anterior (septal, apical, lateral) Inferior-posterior Non–ST-elevation AMI Right bundle branch block Left bundle branch block Left anterior fasicular block Left posterior fasicular block Intraventricular conduction delay
TABLE 3 Degree of Pump Failure and Mortality Old
Acute
29% 18% 3% 2% 3% 3% 0.2% 1%
36% 39% 33% 7% 5% 9% 1% 2%
*A patient may have electrocardiographic findings of an acute infarct at multiple sites.
TABLE 2 Arrhythmias in Coronary Care Unit (4,254 patients) Types of Arrhythmia Atrial Sinus tachycardia ⬎100 Sinus bradycardia ⬍60 Atrial tachycardia Atrial flutter Atrial fibrillation Atrial ventricular block Nodal First-degree Second-degree (Wenckebach) Third-degree Infranodal 2:1 Complete Atrial ventricular dissociation Accelerated His rhythm ⬎60 Ventricular Ectopic ⬎5/min R on T Multifocal Pairs Ventricular tachycardia Primary Secondary VF Primary Secondary Sinoatrial block Asystole*
Incidence
Mortality Rate
27% 25% 14% 5% 13%
22% 12% 17% 23% 24%
12% 6% 3%
23% 29% 43%
0.4% 0.2%
36% 67%
0.4%
42%
31% 4% 27% 26%
17% 18% 15% 15%
15% 13%
9% 34%
0.7% 3% 0.5% 4%
24% 66% 8% 100%
*Agonal rhythms associated with pump failure.
0.7%, and 24% of these patients died. The incidence of sinoatrial block was 0.5%; second-degree atrial ventricular block type 1 progressed to third-degree block in 3%; second-degree atrial ventricular block type 2 progressed to third-degree block in 0.2%; and asystole occurred as an agonal event in 4%. Degrees of pump failure and mortality rate are presented in Table 3. Arrhythmic deaths comprised 2% of the total due to repetitive episodes of VF that ultimately did not respond to defibrillation. There were 121 patients with primary VF. Primary VF occurred in all age groups, with 25% of patients being ⬎70 years of age. Sixty-two percent developed VF before reaching the coronary care unit. Failure status increased significantly at the time of discharge in 48% of those patients with VF compared with their
Incidence Hypotension without shock Killip’s pump failure classification Class II—mild to moderate congestive failure Class III—pulmonary edema Class IV—shock Mortality rate* Shock or congestive heart failure (grade III) VF Pulmonary embolus Other Total mortality rate
Mortality Rate
7%
17%
12%
8%
16% 11%
30% 73%
454
95%
10 4 10 478
2% 1% 2% 11.2%
*Patients who were admitted with pulmonary edema and shock and died within 1 hour were excluded.
status before VF. Multiple episodes of VF separated by ⱖ1 hour occurred in 52% of patients. The incidence of primary VF in 4,150 patients who received prophylactic lidocaine was 0.5% and 10% in the 104 who did not receive prophylactic lidocaine by their physicians’ choice (p ⬍0.0001). Mortality rate for all those with primary VF irrespective of lidocaine use was 24%. Comparisons of the 4,254 patients with and without primary VF are presented in Table 4. Although there are clear differences in the 2 groups, with statistically significant risk factors in terms of “warning” arrhythmias, there was a large number of patients who had warning arrhythmias but did not develop VF. There was greater than a twofold increase in mortality rate (p ⬍0.001) in patients who developed primary VF compared with those who did not. The amounts of lidocaine and, if needed, procainamide were calculated for each patient. Fifty-eight percent of the 4,150 patients with a definite infarct received the initial bolus of 75 mg followed in 5 minutes with a 50-mg bolus and a 2 mg/min continuous infusion. The infusion was discontinued in 24 hours. Multiple boluses ⬎125 mg with an infusion of 3 to 4 mg/min were required in 42% of patients. The breakdown of lidocaine toxicity in the present study into 4 classes demonstrated a 4% incidence of class I side effects and a 3% incidence of class II side effects. Three patients had class III toxicity (0.07%); 1 had a convulsion and 2 became unresponsive. These effects were due to faulty infusion pumps. All 3 patients recovered when the lidocaine was stopped; the lidocaine levels were 5 to 6 g/ml. Twenty percent of patients were given intravenous procainamide when lidocaine was deemed ineffective. Of this group, 70% required 300 mg in divided boluses with a 2 to 3 mg/min continuous infusion. The remaining 30% of patients “resistant” to lidocaine required 400 to 1,000 mg as boluses and a continuous infusion of 5 to 6 mg/min. Detection of QRS widening or hypotension resulted in discontinuation of the drug. The boluses and infusion were decreased if the creatinine level was increased. Serum electrolytes were
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548 THE AMERICAN JOURNAL OF CARDIOLOGY姞
TABLE 4 Comparison of Patients With and Without Primary Ventricular Fibrillation Medical History
Warning Arrhythmias
Site of Infarction
Mortality Rate
VF
VF
VF
VF
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⫹ (n ⫽ 121)
0 (n ⫽ 4,133)
Arrhythmia
⫹ (n ⫽ 121)
0 (n ⫽ 4,133)
Previous AMI Angina pectoris
26% 30%
31% 30%
Premature VF ⬎5 beats/min Multifocal
41% 42%
31%* 29%*
Congestive heart failure
12%
17%
Pairs
44%
27%†
Diabetes Smoking Hypertension Chronic obstructive pulmonary disease
11% 26% 46% 7%
21%* 27% 39% 15%*
R on T Ventricular tachycardia Sinus tachycardia Sinus bradycardia Atrial tachycardia Atrial flutter Atrial fibrillation Type 1 Second-degree atrial ventricular block
17% 53% 15% 9% 7% 5% 8% 3%
3%† 27%† 27%* 25%† 14%* 5% 13% 6%
History
*p ⬍0.05; †p ⬍0.001. ⫹ ⫽ with VF; 0 ⫽ without VF.
Site Anterior Inferior Posterior Non–ST-elevation AMI
⫹ (n ⫽ 121)
0 (n ⫽ 4,133)
⫹ (n ⫽ 121)
0 (n ⫽ 4,133)
36% 50%
36% 39%
24%
10.5%†
14%
33%†
determined for each patient, and replacement of potassium and magnesium was instituted as needed. Amiodarone,  blockers, or bretylium was given to 2% of patients when lidocaine and procainamide were ineffective.
DISCUSSION Five conclusions have been drawn from the results of this and other studies: (1) the incidence of primary VF before and during the thrombolytic era is unchanged and continues to be excessive; (2) primary VF is unpredictable; (3) when primary VF occurs, it portends poor outcomes in morbidity and mortality rates; (4) lidocaine is effective for preventing primary VF; and (5) lidocaine is not associated with an increased incidence of conduction defects when given properly. The incidence of primary VF continues to be disturbingly high but varies from 2% to 19% in published studies for multiple reasons. The definition of “primary” in many studies exclude patients with clinical or x-ray evidence of congestive heart failure.17–19 In addition, studies have excluded patients with previous myocardial infarction or patients who developed late VF, with “late” being defined as fibrillation occurring 48 to 72 hours after admission.6,17,18 The most significant factor that affects incidence is the interval from onset of chest discomfort to hospital admission.18 –20 The incidence decreases exponentially as each hour elapses from onset. Pantridge et al18 reported an incidence of 19% in 294 patients seen within 1 hour of onset. The reported 60% incidence of prehospital mortality from acute coronary syndromes supports the contention that VF is prevalent in the early minutes to hours after onset of chest pain.21 Many published studies have evaluated the incidence of VF for ⱕ2 hours.19,22 Studies have reported the incidence of combined VF and sustained ventricular tachycardia; others have not distinguished primary from secondary or cardiac arrest.2– 6,23,24 This particular study has eliminated these reasons for a decreased incidence. This study includes (1) patients with Killip’s class II failure, patients with previous infarcts, and all patients with primary VF who received prophylactic lidocaine from hospital admission to discharge; and (2) a large proportion of patients who had a brief interval from symptom onset to hospitalization, 40% within 1 hour, 59% within 2 hours, and 74% within 4 hours. Thus, one would expect our patient cohort to have an untreated incidence of primary VF at the high end of the 2% to 19% range. Primary VF is unpredictable; the so-called warning or premonitory arrhythmia theory has been unreliable.25,26 Although warning arrhythmias emerged as a statistically significant risk factor in the study, the warning arrhythmia could not be used as a method to differentiate the patient who required lidocaine. Medical history did not provide a reliable indicator for the patient who was at high risk for developing primary VF. Until a reliable, simple tool for risk stratification
can be found, prophylactic treatment of all patients appears preferable. The occurrence of primary VF portends poor outcomes in morbidity and mortality rates. An important finding in this study was the twofold increase in mortality rate in the patients who developed primary VF versus those who did not (p ⬍0.001). This increase in mortality rate has been a consistent finding in other published studies, varying from 2 to 4 times greater than that in patients without fibrillation.17,24,27–30 Mortality data will be affected by the different definitions of primary VF. Morbidity rate will be affected by the number of recurrences of primary VF; in this study 52% of patients had ⱖ1 episodes of primary VF separated by ⱖ1 hour. Each episode could result in a further decrease of ventricular function. Our finding that 48% of patients with primary VF developed worsening heart failure supports this hypothesis. Lidocaine is effective. The use of prophylactic lidocaine in this 32-year observational study of 4,150 patients with AMI resulted in an incidence of 0.5% for primary VF, which is 4 to 20 times lower than in studies before and after the thrombolytic era of treatment.1– 6,17,24 –30 Lidocaine was not used in 104 patients prophylactically after the publication of the 1996 AHA/ACC guidelines. In this 6-year period, 10 patients developed primary VF, an incidence of 10% (p ⬍0.0001), compared with the 4,150 patients who received prophylactic lidocaine, an incidence of 0.5% for primary VF. There was no difference between the 104 patients who did not receive prophylactic lidocaine and the 4,150 who did in terms of medical history, warning arrhythmias, or time of onset of chest discomfort to hospitalization. Lidocaine toxicity was broken down into 4 classes, with 3 patients developing severe central nervous system side effects (1 had convulsions and 2 were unresponsive) due to faulty infusion pumps. All 3 patients recovered when lidocaine was discontinued. No class IV or cardiac toxic effects occurred. It was our contention and finding that, by stopping the lidocaine when central nervous system symptoms were noted, the cardiac toxic effects were averted. The low incidences of sinoatrial block (0.5%) and infranodal complete atrial ventricular block (0.2%) were due to the infarct and not to lidocaine toxicity; the concentration of serum lidocaine was ⬍4 g/ml in these patients. All patients with asystole had been off lidocaine for 48 hours and had agonal rhythms. The smallest amounts of lidocaine, rather than a preset infusion rate, were given to control the ventricular ectopic beats in the first 24 hours. The increased mortality rate due to lidocaine that was suggested in the AHA/ACC guidelines was ascribed to sinoatrial, atrial ventricular block, or asystole. The 1996 AHA/ACC guidelines recommending against the prophylactic or routine use of lidocaine were based on mortality data in meta-analytic studies, primarily the study by MacMahon et al,9 despite the article concluding as follows: “Because of the small numbers of reported events, the short follow-up periods, and the unavailability of data for some specific
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causes of death, even an overview of all the trial results does not provide good evidence as to whether prophylactic lidocaine is likely to be helpful or harmful. To answer this question reliably, future trials will need to utilize large numbers of patients and prolonged follow-up.” In addition to the meta analysis of MacMahon et al,9 the AHA/ACC guidelines cited 3 additional metaanalytic studies, presumably to support their contention that prophylactic lidocaine is associated with an increased mortality rate. First is the meta-analysis by Hine et al10 who examined 6 studies published between 1970 and 1973. The individual studies showed no adverse effects while lidocaine was administered, but the combination of the studies suggested a statistically significant increase in deaths occurring during treatment. At time of discharge, the mortality rate was the same in the 2 groups. The metaanalysis by Hine et al10 was completely silent on cause of death; nor were any data on sinoatrial or atrial ventricular block or asystole provided. Nevertheless, the AHA/ACC guidelines committee inferred that the cause of death was lidocaine, ignoring the marked variation in the doses of the boluses, the continuous infusion rates in the reported studies, and the intramuscular route of the bolus in 1 study. The 2 other reports, by Teo et al11 and DeSilva et al,12 did not support the guidelines’ thesis. Neither showed any increase in mortality rate when prophylactic lidocaine was used. DeSilva et al12 concluded that lidocaine prophylaxis prevents VF in AMI. Therefore, it can be concluded that there are no credible data in any of the meta-analyses cited in the guidelines to indicate that sinoatrial or atrial ventricular block, asystole, or that increased mortality rate was caused by the use of prophylactic lidocaine. In marked contrast, the recent United States portion of the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO I) and II-B studies and the present study specifically showed no increase in sinoatrial or atrial ventricular block, asystole, or any increase in mortality rate in patients who received lidocaine prophylactically versus those who did not. Moreover, the GUSTO I and II-B studies showed a decrease in VF with prophylactic lidocaine.5 This study of 32 years of using prophylactic lidocaine was an observational study and could not be conducted as a randomized controlled evaluation in this community hospital. Ninety-seven percent of the patients in this study, ⬍50% of whom were eventually diagnosed as having had an AMI, received prophylactic lidocaine. Patients who did not have an AMI had no toxic effect from the prophylactic dose, but these patients and those with an AMI who received increasing doses based on the continued presence of warning arrhythmias received the medication in the absence of reliable data to support this approach. The untested hypothesis was based on the assumption that it is necessary to have a sensitive substrate, such as recent ischemic or necrotic myocardium, plus the ectopic ventricular beat to precipitate VF. The method used in 550 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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this study clearly overtreats a substantial number of patients, but it has been effective and safe. A randomized study is necessary to resolve unanswered questions of dosing schedule and whether other drugs would be more effective for preventing the continued substantial incidence and mortality rate of primary VF and sustained ventricular tachycardia. Acknowledgment: We acknowledge the excellent care afforded the patients by the CCU nurses from the inception of the unit in 1966 to the present. We thank Sarah Wyman for preparing this manuscript. Statistical support was provided by Nancy Berman, PhD, and Peter D. Christenson, PhD, Department of Bio-Statistics, General Clinical Research Center, Harbor-UCLA Medical Center, Torrance, California. We are grateful for the computer support provided by the Research and Education Institute, Harbor-UCLA Medical Center; Torrance, California, with data input provided by Paul Ko, MD, and Anna Kim, BS.
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fibrillation following administration of thrombolytic treatment: the EMIP experience. Eur Heart J 1996;17:213–224. 2. The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993;329: 673– 682. 3. Newby KH, Thompson T, Stebbins A, Topol EJ, Califf RM, Natalie A. Sustained ventricular arrhythmias in patients receiving thrombolytic therapy incidence and outcomes. Circulation 1998;98:2567–2573. 4. Third International Study of Infarct Survival Collaborative Group. A randomized comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs aspirin alone among 41,299 cases of suspected acute myocardial infarction. ISIS-3. Lancet 1992;339:753–770. 5. Alexander JH, Granger CB, Sadowski Z, Aylward PE, White HD, Thompson TD, Califf RM, Topol EJ. Prophylactic lidocaine use in acute myocardial infarction; incidence and outcomes from two international trials. Am Heart J 1999; 137:799 – 805. 6. Berger PB, Ruocco NA, Ryan TJ, Frederick M, Podrid PJ, TIMI Investigators. Incidence and significance of ventricular tachycardia and fibrillation in the absence of hypotension or heart failure in acute myocardial infarction treated with recombinant tissue-type plasminogen activator: results from the Thrombolysis In Myocardial Infarction (TIMI) Phase II trial. J Am Coll Cardiol 1993;22:1773– 1779. 7. Lown B, Fakhro AM, Hood WB Jr, Thorn GW. The coronary care unit—new perspectives and directions. JAMA 1967;199:188 –198. 8. Ryan TJ, Anderson JL, Antman EM, Braniff BA, Brooks NH, Califf RM, Hillis LD, Hiratzka LF, Rapaport E, Riegel BJ, et al. ACC/AHA guidelines for the management of patients with acute myocardial infarction. J Am Coll Cardiol 1996;28:1328 –1428. 9. MacMahon S, Collins R, Peto R, Koster RW, Yusuf S. Effects of prophylactic lidocaine in suspected acute myocardial infarction: an overview of results from the randomized, controlled trials. JAMA 1988;260:1910 –1916. 10. Hine LK, Laird N, Hewitt P, Chalmers TC. Meta-analytic evidence against prophylactic use of lidocaine in acute myocardial infarction. Arch Intern Med 1989;149:2694 –2698. 11. Teo KK, Yusuf S, Furberg CD. Effects of prophylactic antiarrhythmic drug therapy in acute myocardial infarction: an overview of results from randomized controlled trials. JAMA 1993;270:1589 –1595. 12. DeSilva RA, Lown B, Hennekens CH, Casscells W. Lignocaine prophylaxis in acute myocardial infarction: an evaluation of randomized trials. Lancet 1981; 2:855– 858. 13. Wyman MG, Hammersmith L. Comprehensive treatment plan for the prevention of primary ventricular fibrillation in acute myocardial infarction. Am J Cardiol 1974;33:661– 667. 14. Wyman MG, Lalka D, Hammersmith L, Cannom DS, Goldreyer BN. Multiple bolus technique for lidocaine administration during the first hours of an acute myocardial infarction. Am J Cardiol 1978;41:313–317. 15. Wyman MG, Slaughter RL, Farolino DS, Farolino DA, Gore SA, Cannom DS, Goldreyer BN, Lalka D. Multiple bolus technique for lidocaine administration in acute ischemic heart disease. II. Treatment of refractory ventricular arrhythmias and the pharmacokinetic significance of severe left ventricular failure. J Am Coll Cardiol 1983;2:764 –769.
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16. Lalka D, Wyman MG, Goldreyer BN, Ludden TM, Cannom DS. Procainamide accumulation kinetics in the immediate post-myocardial infarction period. J Clin Pharmacol 1978;18:397– 401. 17. Volpi A, Maggioni A, Franzosi MG, Pampallona S, Mauri F, Tognoni G. In-hospital prognosis of patients with acute myocardial infarction complicated by primary ventricular fibrillation. N Engl J Med 1987;317:257–261. 18. Pantridge JF, Webb SW, Adgey AAJ. Arrhythmias in the first hours of acute myocardial infarction. Prog Cardiovasc Dis 1981;23:265–278. 19. Valentine PA, Frew JL, Meshford ML, Sloman JG. Lidocaine in the prevention of sudden death in the pre-hospital phase of acute infarction. N Engl J Med 1974;291:1327–1331. 20. O’Doherty M, Tayler DI, Qunn E, Vincent R, Chamberlain DA. Five hundred patients with myocardial infarction monitored within one hour of symptoms. BMJ 1983;286:1405–1408. 21. Dalzell GW, Cunningham SR, Wilson CM, Allen JD, Anderson J, Adgey AAJ. Ventricular fibrillation: the Belfast experience. Br Heart J 1987;58:441– 446. 22. Koster RW, Dunning AJ. Intramuscular lidocaine for prevention of lethal arrhythmias in the prehospitalization phase of acute myocardial infarction. N Engl J Med 1985;313:1105–1110. 23. The International Study Group. In-hospital mortality and clinical course of 20,291 patients with suspected acute myocardial infarction randomized between alteplase and streptokinase with or without heparin. Lancet 1990;336:71–75.
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Julippe C, Preston L, Carlier J, Kulbertus HE. Incidence, clinical significance and prognosis of ventricular fibrillation in the early phase of myocardial infarction. Eur Heart J 1986;7:945–951. 25. El-Sherif N, Myerburg RJ, Sherlag BJ, Befler B, Aranda JM, Castelleanes A, Lazzara R. Electrocardiographic antecedents of primary ventricular fibrillation. Br Heart J 1976;38:415– 422. 26. Lie KI, Wellens HJJ, Downar E, Durrer D. Observations on patients with primary ventricular fibrillation complicating acute myocardial infarction. Circulation 1975;52:755–759. 27. Conley MJ, McNeer JF, Lee KL, Wagner GS, Rosati RA. Cardiac arrest complicating acute myocardial infarction; predictability and prognosis. Am J Cardiol 1977;39:7–12. 28. Goldberg RJ, Szklom M, Tonascia JA, Kennedy HL. Acute myocardial infarction prognosis complicated by ventricular fibrillation or cardiac arrest. JAMA 1979;241:2024 –2027. 29. Chiriboga D, Yarzebski J, Goldberg RJ, Gore JM, Alpert JS. Temporal trends and case fatality rates of primary ventricular fibrillation complicating acute myocardial infarction. A community wide perspective. Circulation 1994;89:998 – 1003. 30. Lawrie DM. Ventricular fibrillation in acute myocardial infarction. Am Heart J 1969;78:1424 –1425.
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MD,
R. Michael Wyman, MD, David S. Cannom, J. Michael Criley, MD
MD,
and
Primary ventricular fibrillation (VF) during an acute myocardial infarction (AMI) occurs with a high incidence and mortality rate with or without thrombolysis. The incidence varies from 2% to 19% depending on the definition of “primary.” Primary VF in this study refers to fibrillation occurring in the absence of shock or pulmonary edema. Mortality rate, when primary VF occurs, is 2 to 4 times greater than when it does not. Prevention of VF has been impeded by the publication of the 1996 recommendations of the American Heart Association and American College of Cardiology against the use of prophylactic lidocaine based on meta-analysis studies implying toxicity. This observational study of 4,254 patients with AMI reports the incidence and mortality rates of primary VF over 32 years. Of the 4,254 patients, 4,150 received prophylactic lidocaine, and 104 patients did not receive prophylactic lidocaine due to the 1996 guidelines, after which administration of prophylactic lidocaine was governed by physician choice. The inci-
dence of primary VF was 0.5% among the 4,150 who received prophylactic lidocaine and 10% among the 104 who did not (p <0.0001). Among the 4,150 receiving prophylactic lidocaine, sinoatrial block occurred in 0.5% and complete infranodal atrial ventricular block occurred in 0.2%, all secondary to the site of infarction (concurrent serum lidocaine levels were <4g/ml). Asystole was an agonal rhythm in 4%; these patients had been off lidocaine for 48 hours. Mortality rates were 10.5% in patients without primary VF and 25% in patients with VF (p <0.001). Thus, prophylactic lidocaine markedly decreased the incidence of VF in 4,150 patients with AMI to 0.5% compared with trials before and after thrombolysis (2% to 19%) and with the 104 patients in this study who did not receive prophylactic lidocaine (10%). No lidocaine-induced sinoatrial or atrial ventricular block or asystole occurred. 䊚2004 by Excerpta Medica, Inc. (Am J Cardiol 2004;94:545–551)
rimary ventricular fibrillation (VF) precipitated by an acute myocardial infarction (AMI) continP ues to be unpredictable and frequently associated with
mortality from primary VF without inducing sinoatrial or atrial ventricular block or asystole.
an unfavorable outcome, despite early treatment with thrombolytic agents.1– 6 Lidocaine has been used for the prevention of VF since the 1960s after coronary care units became a standard setting for the treatment of AMI.7 However, the 1996 guidelines of the American Heart Association and the American College of Cardiology (AHA/ACC) for the treatment of AMI considered prophylactic lidocaine a class III indication.8 This recommendation was based on 4 metaanalyses that hypothesized that the increased mortality rate among patients who received lidocaine was due to asystole or atrial ventricular or sinoatrial block, although without supporting data.9 –12 This report embodies a 32-year observational study of 4,150 patients with AMI treated with prophylactic lidocaine, resulting in significant decreases in the incidence of and From the San Pedro Peninsula Hospital, San Pedro, California; the University of Southern California School of Medicine, Los Angeles, California; the Little Company of Mary Hospital, Torrance, California; the Good Samaritan Hospital, Los Angeles, California; and the Harbor-UCLA Medical Center, Torrance, California. Funding support for purchase of equipment was provided by The San Pedro Heart Foundation, San Pedro, California. Manuscript received February 27, 2004; revised manuscript received and accepted May 3, 2004. Address for reprints: Milford G. Wyman, MD, 3069 Crest Road, Rancho Palos Verdes, California 90275. E-mail: drwyman@earthlink. net. ©2004 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 94 September 1, 2004
METHODS The bed capacity of the community hospital varied from 135 to 200 beds between 1970 and 2002. During the first 26-year study period, all patients with suspected AMI were treated with prophylactic lidocaine on admission to the hospital. Lidocaine was administered based on a history of sustained chest discomfort for ⬎30 minutes. All attending physicians agreed to the treatment protocol, which was approved by the institutional review board. However, after publication of the 1996 AHA/ACC guidelines, physicians were given the option of withholding prophylactic lidocaine, and these patients’ outcomes were compared with those of patients who received lidocaine. The final diagnosis of an AMI was based on a history of 30 minutes of sustained chest discomfort, increased laboratory markers, and evolving electrocardiographic abnormalities. Over the 32 years of the study, enzyme determinations included aspartate aminotransferase, lactate dehydrogenase, creatine phosphokinase, creatine phosphokinase-MB, and troponin-I. ST-elevation and non–ST-elevation infarctions were included. VF was defined as primary if it occurred in the absence of pulmonary edema or shock. If VF occurred before a physician’s examination, then it was considered primary if there was no history or findings of 0002-9149/04/$–see front matter doi:10.1016/j.amjcard.2004.05.014
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FIGURE 1. Participants and treatments. A ⴝ amiodarone; B ⴝ bretylium; B-B ⴝ  blocker; L ⴝ lidocaine; P ⴝ procainamide; PL ⴝ prophylactic lidocaine; ROMI ⴝ rule-out myocardial infarction.
congestive failure on a recent previous examination. Episodes of VF were included if they occurred in the field, the emergency department, the coronary care unit, and the medical floor. The total incidence of primary VF was determined for all patients with a confirmed AMI who were treated during this 32-year period and separately for those whose physicians opted to withhold prophylactic lidocaine after publication of the 1996 AHA/ACC guidelines (Figure 1). Data collection began from onset of chest discomfort to hospital discharge. One hundred fifteen pieces of information were collected on each patient. Patients who entered the emergency department in shock and had pulmonary edema and died in ⬍1 hour were excluded from the calculation of mortality rate. Data on all patients who developed primary VF included age, gender, location at which the episode occurred, medical history, electrocardiographic site of infarct, premonitory rhythm, and total mortality. Statistical analysis: Patients with and without primary VF were compared with regard to clinical characteristics, warning arrhythmias, infarct location, and mortality rate with chi-square test. Incidences of primary VF in those patients who received prophylactic lidocaine and those who did not were compared with the chi-square test. Lidocaine was given as a 75-mg bolus over a 90-second interval followed by a 2-mg/min continuous infusion. A second bolus of 50 mg followed in 5 minutes. The infusion was discontinued after 24 hours if ectopic ventricular beats were not observed. If breakthrough ventricular arrhythmias occurred, additional 50-mg boluses were given every 5 minutes, as needed to a maximum of 325 mg. The continuous infusion was increased 1 mg/min after each bolus to a maximum of 4 mg/min.13–15 If any central nervous system side effects were noted, the dosage and infusion rates were decreased or discontinued. The lidocaine dose was halved in the presence of moderate or severe congestive heart failure (Killip’s classes II to IV). Lidocaine toxicity was graded as follows: class I ⫽ numbness of lips, hands, dizziness, slurred speech, mild sleepiness; class II ⫽ confusion, visual distur546 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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bance, agitation, somnolence, muscle twitching; class III ⫽ convulsions, unresponsiveness, conduction abnormalities; and, class IV ⫽ respiratory, cardiac arrest.13–15 If lidocaine was not effective in suppressing ventricular arrhythmias, intravenous procainamide was given with a similar multiple-bolus, continuous-infusion technique. A procainamide bolus of 100 mg was infused over 3 minutes. If ventricular extrasystoles persisted after 2 minutes, additional boluses of 100 mg were given every 5 minutes to ⱕ1 g, if necessary. Continuous infusion was increased 1 mg/min after each bolus to ⱕ6 mg/min.13,16
RESULTS During the 32-year observational study, 8,424 patients received prophylactic lidocaine; 4,254 were ultimately confirmed to have had an AMI, 4,150 of whom received prophylactic lidocaine. After 1996, 104 patients did not receive prophylactic lidocaine (Figure 1) at the discretion of their physician after the publication of the 1996 AHA/ACC guidelines.8 During this 6-year period, 798 patients with AMI were treated, 13% of whom did not receive prophylactic lidocaine. The mean age of the patients was 67 years, and 65% were men. There was a history of a myocardial infarction in 31%, a history of angina in 30%, diabetes in 21%, and previous stroke in 7%. There was a history of smoking in 27%. A typical history of AMI was recorded in 91%. There were ST-elevation infarctions with characteristic Q waves in 67% and non– ST-elevation infarctions in 33%. A diagnosis of a definite infarction required positive enzyme tests and abnormal serial electrocardiograms. The cumulative time intervals from onset of chest discomfort to hospitalization were 1 hour in 40%, 2 hours in 59%, and within 4 hours in 74%. Table 1 lists the electrocardiographic findings, old and recent infarcts, and conduction abnormalities. Arrhythmias that were identified during patients’ stay in the coronary care unit are listed in Table 2. The total incidence of primary VF in the coronary care unit was SEPTEMBER 1, 2004
TABLE 1 Electrocardiographic Findings* Infarct Site and Conduction Defects Anterior (septal, apical, lateral) Inferior-posterior Non–ST-elevation AMI Right bundle branch block Left bundle branch block Left anterior fasicular block Left posterior fasicular block Intraventricular conduction delay
TABLE 3 Degree of Pump Failure and Mortality Old
Acute
29% 18% 3% 2% 3% 3% 0.2% 1%
36% 39% 33% 7% 5% 9% 1% 2%
*A patient may have electrocardiographic findings of an acute infarct at multiple sites.
TABLE 2 Arrhythmias in Coronary Care Unit (4,254 patients) Types of Arrhythmia Atrial Sinus tachycardia ⬎100 Sinus bradycardia ⬍60 Atrial tachycardia Atrial flutter Atrial fibrillation Atrial ventricular block Nodal First-degree Second-degree (Wenckebach) Third-degree Infranodal 2:1 Complete Atrial ventricular dissociation Accelerated His rhythm ⬎60 Ventricular Ectopic ⬎5/min R on T Multifocal Pairs Ventricular tachycardia Primary Secondary VF Primary Secondary Sinoatrial block Asystole*
Incidence
Mortality Rate
27% 25% 14% 5% 13%
22% 12% 17% 23% 24%
12% 6% 3%
23% 29% 43%
0.4% 0.2%
36% 67%
0.4%
42%
31% 4% 27% 26%
17% 18% 15% 15%
15% 13%
9% 34%
0.7% 3% 0.5% 4%
24% 66% 8% 100%
*Agonal rhythms associated with pump failure.
0.7%, and 24% of these patients died. The incidence of sinoatrial block was 0.5%; second-degree atrial ventricular block type 1 progressed to third-degree block in 3%; second-degree atrial ventricular block type 2 progressed to third-degree block in 0.2%; and asystole occurred as an agonal event in 4%. Degrees of pump failure and mortality rate are presented in Table 3. Arrhythmic deaths comprised 2% of the total due to repetitive episodes of VF that ultimately did not respond to defibrillation. There were 121 patients with primary VF. Primary VF occurred in all age groups, with 25% of patients being ⬎70 years of age. Sixty-two percent developed VF before reaching the coronary care unit. Failure status increased significantly at the time of discharge in 48% of those patients with VF compared with their
Incidence Hypotension without shock Killip’s pump failure classification Class II—mild to moderate congestive failure Class III—pulmonary edema Class IV—shock Mortality rate* Shock or congestive heart failure (grade III) VF Pulmonary embolus Other Total mortality rate
Mortality Rate
7%
17%
12%
8%
16% 11%
30% 73%
454
95%
10 4 10 478
2% 1% 2% 11.2%
*Patients who were admitted with pulmonary edema and shock and died within 1 hour were excluded.
status before VF. Multiple episodes of VF separated by ⱖ1 hour occurred in 52% of patients. The incidence of primary VF in 4,150 patients who received prophylactic lidocaine was 0.5% and 10% in the 104 who did not receive prophylactic lidocaine by their physicians’ choice (p ⬍0.0001). Mortality rate for all those with primary VF irrespective of lidocaine use was 24%. Comparisons of the 4,254 patients with and without primary VF are presented in Table 4. Although there are clear differences in the 2 groups, with statistically significant risk factors in terms of “warning” arrhythmias, there was a large number of patients who had warning arrhythmias but did not develop VF. There was greater than a twofold increase in mortality rate (p ⬍0.001) in patients who developed primary VF compared with those who did not. The amounts of lidocaine and, if needed, procainamide were calculated for each patient. Fifty-eight percent of the 4,150 patients with a definite infarct received the initial bolus of 75 mg followed in 5 minutes with a 50-mg bolus and a 2 mg/min continuous infusion. The infusion was discontinued in 24 hours. Multiple boluses ⬎125 mg with an infusion of 3 to 4 mg/min were required in 42% of patients. The breakdown of lidocaine toxicity in the present study into 4 classes demonstrated a 4% incidence of class I side effects and a 3% incidence of class II side effects. Three patients had class III toxicity (0.07%); 1 had a convulsion and 2 became unresponsive. These effects were due to faulty infusion pumps. All 3 patients recovered when the lidocaine was stopped; the lidocaine levels were 5 to 6 g/ml. Twenty percent of patients were given intravenous procainamide when lidocaine was deemed ineffective. Of this group, 70% required 300 mg in divided boluses with a 2 to 3 mg/min continuous infusion. The remaining 30% of patients “resistant” to lidocaine required 400 to 1,000 mg as boluses and a continuous infusion of 5 to 6 mg/min. Detection of QRS widening or hypotension resulted in discontinuation of the drug. The boluses and infusion were decreased if the creatinine level was increased. Serum electrolytes were
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548 THE AMERICAN JOURNAL OF CARDIOLOGY姞
TABLE 4 Comparison of Patients With and Without Primary Ventricular Fibrillation Medical History
Warning Arrhythmias
Site of Infarction
Mortality Rate
VF
VF
VF
VF
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⫹ (n ⫽ 121)
0 (n ⫽ 4,133)
Arrhythmia
⫹ (n ⫽ 121)
0 (n ⫽ 4,133)
Previous AMI Angina pectoris
26% 30%
31% 30%
Premature VF ⬎5 beats/min Multifocal
41% 42%
31%* 29%*
Congestive heart failure
12%
17%
Pairs
44%
27%†
Diabetes Smoking Hypertension Chronic obstructive pulmonary disease
11% 26% 46% 7%
21%* 27% 39% 15%*
R on T Ventricular tachycardia Sinus tachycardia Sinus bradycardia Atrial tachycardia Atrial flutter Atrial fibrillation Type 1 Second-degree atrial ventricular block
17% 53% 15% 9% 7% 5% 8% 3%
3%† 27%† 27%* 25%† 14%* 5% 13% 6%
History
*p ⬍0.05; †p ⬍0.001. ⫹ ⫽ with VF; 0 ⫽ without VF.
Site Anterior Inferior Posterior Non–ST-elevation AMI
⫹ (n ⫽ 121)
0 (n ⫽ 4,133)
⫹ (n ⫽ 121)
0 (n ⫽ 4,133)
36% 50%
36% 39%
24%
10.5%†
14%
33%†
determined for each patient, and replacement of potassium and magnesium was instituted as needed. Amiodarone,  blockers, or bretylium was given to 2% of patients when lidocaine and procainamide were ineffective.
DISCUSSION Five conclusions have been drawn from the results of this and other studies: (1) the incidence of primary VF before and during the thrombolytic era is unchanged and continues to be excessive; (2) primary VF is unpredictable; (3) when primary VF occurs, it portends poor outcomes in morbidity and mortality rates; (4) lidocaine is effective for preventing primary VF; and (5) lidocaine is not associated with an increased incidence of conduction defects when given properly. The incidence of primary VF continues to be disturbingly high but varies from 2% to 19% in published studies for multiple reasons. The definition of “primary” in many studies exclude patients with clinical or x-ray evidence of congestive heart failure.17–19 In addition, studies have excluded patients with previous myocardial infarction or patients who developed late VF, with “late” being defined as fibrillation occurring 48 to 72 hours after admission.6,17,18 The most significant factor that affects incidence is the interval from onset of chest discomfort to hospital admission.18 –20 The incidence decreases exponentially as each hour elapses from onset. Pantridge et al18 reported an incidence of 19% in 294 patients seen within 1 hour of onset. The reported 60% incidence of prehospital mortality from acute coronary syndromes supports the contention that VF is prevalent in the early minutes to hours after onset of chest pain.21 Many published studies have evaluated the incidence of VF for ⱕ2 hours.19,22 Studies have reported the incidence of combined VF and sustained ventricular tachycardia; others have not distinguished primary from secondary or cardiac arrest.2– 6,23,24 This particular study has eliminated these reasons for a decreased incidence. This study includes (1) patients with Killip’s class II failure, patients with previous infarcts, and all patients with primary VF who received prophylactic lidocaine from hospital admission to discharge; and (2) a large proportion of patients who had a brief interval from symptom onset to hospitalization, 40% within 1 hour, 59% within 2 hours, and 74% within 4 hours. Thus, one would expect our patient cohort to have an untreated incidence of primary VF at the high end of the 2% to 19% range. Primary VF is unpredictable; the so-called warning or premonitory arrhythmia theory has been unreliable.25,26 Although warning arrhythmias emerged as a statistically significant risk factor in the study, the warning arrhythmia could not be used as a method to differentiate the patient who required lidocaine. Medical history did not provide a reliable indicator for the patient who was at high risk for developing primary VF. Until a reliable, simple tool for risk stratification
can be found, prophylactic treatment of all patients appears preferable. The occurrence of primary VF portends poor outcomes in morbidity and mortality rates. An important finding in this study was the twofold increase in mortality rate in the patients who developed primary VF versus those who did not (p ⬍0.001). This increase in mortality rate has been a consistent finding in other published studies, varying from 2 to 4 times greater than that in patients without fibrillation.17,24,27–30 Mortality data will be affected by the different definitions of primary VF. Morbidity rate will be affected by the number of recurrences of primary VF; in this study 52% of patients had ⱖ1 episodes of primary VF separated by ⱖ1 hour. Each episode could result in a further decrease of ventricular function. Our finding that 48% of patients with primary VF developed worsening heart failure supports this hypothesis. Lidocaine is effective. The use of prophylactic lidocaine in this 32-year observational study of 4,150 patients with AMI resulted in an incidence of 0.5% for primary VF, which is 4 to 20 times lower than in studies before and after the thrombolytic era of treatment.1– 6,17,24 –30 Lidocaine was not used in 104 patients prophylactically after the publication of the 1996 AHA/ACC guidelines. In this 6-year period, 10 patients developed primary VF, an incidence of 10% (p ⬍0.0001), compared with the 4,150 patients who received prophylactic lidocaine, an incidence of 0.5% for primary VF. There was no difference between the 104 patients who did not receive prophylactic lidocaine and the 4,150 who did in terms of medical history, warning arrhythmias, or time of onset of chest discomfort to hospitalization. Lidocaine toxicity was broken down into 4 classes, with 3 patients developing severe central nervous system side effects (1 had convulsions and 2 were unresponsive) due to faulty infusion pumps. All 3 patients recovered when lidocaine was discontinued. No class IV or cardiac toxic effects occurred. It was our contention and finding that, by stopping the lidocaine when central nervous system symptoms were noted, the cardiac toxic effects were averted. The low incidences of sinoatrial block (0.5%) and infranodal complete atrial ventricular block (0.2%) were due to the infarct and not to lidocaine toxicity; the concentration of serum lidocaine was ⬍4 g/ml in these patients. All patients with asystole had been off lidocaine for 48 hours and had agonal rhythms. The smallest amounts of lidocaine, rather than a preset infusion rate, were given to control the ventricular ectopic beats in the first 24 hours. The increased mortality rate due to lidocaine that was suggested in the AHA/ACC guidelines was ascribed to sinoatrial, atrial ventricular block, or asystole. The 1996 AHA/ACC guidelines recommending against the prophylactic or routine use of lidocaine were based on mortality data in meta-analytic studies, primarily the study by MacMahon et al,9 despite the article concluding as follows: “Because of the small numbers of reported events, the short follow-up periods, and the unavailability of data for some specific
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causes of death, even an overview of all the trial results does not provide good evidence as to whether prophylactic lidocaine is likely to be helpful or harmful. To answer this question reliably, future trials will need to utilize large numbers of patients and prolonged follow-up.” In addition to the meta analysis of MacMahon et al,9 the AHA/ACC guidelines cited 3 additional metaanalytic studies, presumably to support their contention that prophylactic lidocaine is associated with an increased mortality rate. First is the meta-analysis by Hine et al10 who examined 6 studies published between 1970 and 1973. The individual studies showed no adverse effects while lidocaine was administered, but the combination of the studies suggested a statistically significant increase in deaths occurring during treatment. At time of discharge, the mortality rate was the same in the 2 groups. The metaanalysis by Hine et al10 was completely silent on cause of death; nor were any data on sinoatrial or atrial ventricular block or asystole provided. Nevertheless, the AHA/ACC guidelines committee inferred that the cause of death was lidocaine, ignoring the marked variation in the doses of the boluses, the continuous infusion rates in the reported studies, and the intramuscular route of the bolus in 1 study. The 2 other reports, by Teo et al11 and DeSilva et al,12 did not support the guidelines’ thesis. Neither showed any increase in mortality rate when prophylactic lidocaine was used. DeSilva et al12 concluded that lidocaine prophylaxis prevents VF in AMI. Therefore, it can be concluded that there are no credible data in any of the meta-analyses cited in the guidelines to indicate that sinoatrial or atrial ventricular block, asystole, or that increased mortality rate was caused by the use of prophylactic lidocaine. In marked contrast, the recent United States portion of the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO I) and II-B studies and the present study specifically showed no increase in sinoatrial or atrial ventricular block, asystole, or any increase in mortality rate in patients who received lidocaine prophylactically versus those who did not. Moreover, the GUSTO I and II-B studies showed a decrease in VF with prophylactic lidocaine.5 This study of 32 years of using prophylactic lidocaine was an observational study and could not be conducted as a randomized controlled evaluation in this community hospital. Ninety-seven percent of the patients in this study, ⬍50% of whom were eventually diagnosed as having had an AMI, received prophylactic lidocaine. Patients who did not have an AMI had no toxic effect from the prophylactic dose, but these patients and those with an AMI who received increasing doses based on the continued presence of warning arrhythmias received the medication in the absence of reliable data to support this approach. The untested hypothesis was based on the assumption that it is necessary to have a sensitive substrate, such as recent ischemic or necrotic myocardium, plus the ectopic ventricular beat to precipitate VF. The method used in 550 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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this study clearly overtreats a substantial number of patients, but it has been effective and safe. A randomized study is necessary to resolve unanswered questions of dosing schedule and whether other drugs would be more effective for preventing the continued substantial incidence and mortality rate of primary VF and sustained ventricular tachycardia. Acknowledgment: We acknowledge the excellent care afforded the patients by the CCU nurses from the inception of the unit in 1966 to the present. We thank Sarah Wyman for preparing this manuscript. Statistical support was provided by Nancy Berman, PhD, and Peter D. Christenson, PhD, Department of Bio-Statistics, General Clinical Research Center, Harbor-UCLA Medical Center, Torrance, California. We are grateful for the computer support provided by the Research and Education Institute, Harbor-UCLA Medical Center; Torrance, California, with data input provided by Paul Ko, MD, and Anna Kim, BS.
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fibrillation following administration of thrombolytic treatment: the EMIP experience. Eur Heart J 1996;17:213–224. 2. The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993;329: 673– 682. 3. Newby KH, Thompson T, Stebbins A, Topol EJ, Califf RM, Natalie A. Sustained ventricular arrhythmias in patients receiving thrombolytic therapy incidence and outcomes. Circulation 1998;98:2567–2573. 4. Third International Study of Infarct Survival Collaborative Group. A randomized comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs aspirin alone among 41,299 cases of suspected acute myocardial infarction. ISIS-3. Lancet 1992;339:753–770. 5. Alexander JH, Granger CB, Sadowski Z, Aylward PE, White HD, Thompson TD, Califf RM, Topol EJ. Prophylactic lidocaine use in acute myocardial infarction; incidence and outcomes from two international trials. Am Heart J 1999; 137:799 – 805. 6. Berger PB, Ruocco NA, Ryan TJ, Frederick M, Podrid PJ, TIMI Investigators. Incidence and significance of ventricular tachycardia and fibrillation in the absence of hypotension or heart failure in acute myocardial infarction treated with recombinant tissue-type plasminogen activator: results from the Thrombolysis In Myocardial Infarction (TIMI) Phase II trial. J Am Coll Cardiol 1993;22:1773– 1779. 7. Lown B, Fakhro AM, Hood WB Jr, Thorn GW. The coronary care unit—new perspectives and directions. JAMA 1967;199:188 –198. 8. Ryan TJ, Anderson JL, Antman EM, Braniff BA, Brooks NH, Califf RM, Hillis LD, Hiratzka LF, Rapaport E, Riegel BJ, et al. ACC/AHA guidelines for the management of patients with acute myocardial infarction. J Am Coll Cardiol 1996;28:1328 –1428. 9. MacMahon S, Collins R, Peto R, Koster RW, Yusuf S. Effects of prophylactic lidocaine in suspected acute myocardial infarction: an overview of results from the randomized, controlled trials. JAMA 1988;260:1910 –1916. 10. Hine LK, Laird N, Hewitt P, Chalmers TC. Meta-analytic evidence against prophylactic use of lidocaine in acute myocardial infarction. Arch Intern Med 1989;149:2694 –2698. 11. Teo KK, Yusuf S, Furberg CD. Effects of prophylactic antiarrhythmic drug therapy in acute myocardial infarction: an overview of results from randomized controlled trials. JAMA 1993;270:1589 –1595. 12. DeSilva RA, Lown B, Hennekens CH, Casscells W. Lignocaine prophylaxis in acute myocardial infarction: an evaluation of randomized trials. Lancet 1981; 2:855– 858. 13. Wyman MG, Hammersmith L. Comprehensive treatment plan for the prevention of primary ventricular fibrillation in acute myocardial infarction. Am J Cardiol 1974;33:661– 667. 14. Wyman MG, Lalka D, Hammersmith L, Cannom DS, Goldreyer BN. Multiple bolus technique for lidocaine administration during the first hours of an acute myocardial infarction. Am J Cardiol 1978;41:313–317. 15. Wyman MG, Slaughter RL, Farolino DS, Farolino DA, Gore SA, Cannom DS, Goldreyer BN, Lalka D. Multiple bolus technique for lidocaine administration in acute ischemic heart disease. II. Treatment of refractory ventricular arrhythmias and the pharmacokinetic significance of severe left ventricular failure. J Am Coll Cardiol 1983;2:764 –769.
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