Influence of lidocaine on human muscle sympathetic nerve activity during programmed electrical stimulation and ventricular tachycardia Lidocaine directly affects conduction and refractoriness of ventricular myocardium, and may also indirectly affect these electrophysiologic properties by inhibition of cardiac sympathetic nerve traffic. Both effects may play important roles in preventing ventricular arrhythmias in humans. To determine if lidocaine has a direct effect on sympathetic nerve activity, the effects of a 100 mg lidocaine bolus followed by a 2 mg/min infusion of lidocaine on muscle sympathetic nerve activity was assessed in seven patients during programmed ventricular stimulation with single extrastimuli (premature ventricular contractions [PVCs]) in sinus rhythm, and in seven patients during induced hemodynamically stable monomorphic ventricular tachycardia. During single extrastimuli, the mean (-t SEM) area of PVC-associated bursts of sympathetic nerve activity was unaffected by lidocaine (1101 + 16 units pre-lidocaine versus 1075 it 19 units following lidocaine; p = 0.30). Likewise, the transient decrease in blood pressure with induced PVCs was similar before and after lidocaine infusion (p = 0.46). In seven patients with induced monomorphic ventricular tachycardia, tachycardia cycle length did not change after the lidocaine bolus (393 f 16 versus 399 f 17 msec; p = 0.34) but increased during lidocaine maintenance infusion (426 + 17 msec; p = 0.01). After induction of ventricular tachycardia, systolic pressure decreased from 150 + 6 to 117 f 9 mm Hg at 1 minute of tachycardia, to 109 f 6 mm Hg during the lidocaine bolus, and rebounded to 126 + 6 mm Hg during the lidocaine maintenance infusion (p = 0.04, bolus versus infusion). Sympathetic nerve activity (units/5 seconds) increased from 617 f 123 to 1775 + 274 units during ventricular tachycardia (p < 0.01 versus baseline) to 1796 t- 453 units after lidocaine bolus and to 1460 + 380 units during the lidocaine infusion (p = 0.04 versus pre-lidocaine). The change in blood pressure during ventricular tachycardia with the lidocaine maintenance infusion correlated inversely with the change in sympathetic nerve activity (r = -0.69, p = 0.002). Lidocaine appears to reduce sympathetic nerve activity indirectly by slowing ventricular tachycardia cycle length, which results in increased blood pressure during tachycardia. These data suggest that therapeutic doses of lidocaine do not directly alter sympathetic nerve activity in humans. (AM HEART J 1992;124:891.)

Kenneth A. Ellenbogen, MD, Michael L. Smith, PhD,a Larry A. Beightol, MS, and Dwain L. Eckberg, MD Richmond, Vu., and Cleveland, Ohio

Lidocaine is a class Ib antiarrhythmic drug that reduces the incidence of ventricular fibrillation during acute myocardial infarction and decreases the frequency of premature ventricular contractions (PVCs)

From the Department of Medicine. Hunter Holmes McGuire Veterans Affairs Medical Center and the Departments of Medicine and Physiology, Medical College of Virginia; and Yhe Department of Medicine, Case Western Reserve University. Supported by grants from the Department of Veterans tional Institutes of Health (HL 22296, HL30506. and

Affairs and the NaHL075561.

Received

24, 1992.

for publication

Reprint requests: Laboratory, Box 4i1139867

Kenneth 53, MCV

.Jan. 6, 1992;

accepted

April

A. Ellenbogen. MD, Cardiac Electrophysiology Station. Richmond. VA 23298.

and nonsustained ventricular tachycardia in patients.‘.” The electrophysiologic effects of lidocaine have been extensively characterized both in vitro and in vivo.sm7These electrophysiologic effects result primarily from its use-dependent blockade of open or depolarization-inactivated sodium channels with fast onset-offset kinetics. Lidocaine’s antiarrhythmic efficacy in patients is presumed to result from its direct electrophysiologic effects on the sodium channel. Limited data suggest that lidocaine may also exert indirect electrophysiologic effects by altering sympathetic input to the heart. In anesthetized, baroreceptor-denervated dogs, Miller et a1.8demonstrated that intravenous lidocaine produces a dose-dependent sustained decrease in cardiac sympathetic nerve 891

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Table

1.Lidocaine-PVC patient descriptors Patient No.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 Mean

f SEM

American

EF (PO) 35 45 45 42 40 41 60 45 50 30 30 35 45 40 41 + 3

Cardiac disease

VT cycle length (msec)

CMYO CAD, MI CAD, HTN CAD AR, MI CAD CAD CAD CAD, AR CAD, MI CAD, MI CAD, MI CAD, MI CAD, MR

320 300 400 400 315 380 370 315 * 20

Medications

Iso, Nif Dilt, En Dilt Prop Iso, Nif Nif, En Dilt Cap, Amio Fur, Dilt Dig, Fur Fur, Iso, Nif, Quin, Mex Fur, Cap, Amio, Dilt Amio

October 1992 Heart Journal

Lidocaine Cdmli 3.5 1.4 3.1 2.0 2.6 3.1 5.0 2.6 4.0 3.5 3.2 2.7 3.1 i 0.3

Amio, Amiodarone; AR, aortic regurgitation; CAD, coronary artery disease: Cap, captopril; CMYO, cardiomyopathy; Dig, dig&n; Dilt, diltiazem; EF, ejection fraction; En, enalapril: Fur, furosemide; HTN, hypertension; Iso, isosorhide; Ma, mexiletine; MI, myocardial infarction; MR, mitral regurgitation; Nif, nifedipine; Prop, propranolol: Quin, quinidine; VT, ventricular tachycardia

activity. Preliminary results from other investigatorsg, lo suggest that procainamide and lidocaine may inhibit reflex sympathoexcitation in humans. Previously, well and others12 have reported transient increases in cardiac, renal, and muscle sympathetic nerve traffic following a single ventricular extrastimulus. During ventricular tachycardia, there is a marked and sustained increase in sympathetic tone.13-15In the present study, we sought to determine whether lidocaine alters the sympathetic responses caused by a single extrastimulus or during sustained ventricular tachycardia. We recorded efferent muscle sympathetic nerve activity from the peroneal nerve before and after a 100 mg lidocaine bolus and a 2 mg/min lidocaine infusion in patients during either introduction of single premature ventricular extrastimuli (PVCs) during sinus rhythm or during induced sustained monomorphic ventricular tachycardia. METHODS

We studied 14 patients referred for electrophysiology study to evaluate a documented or suspected cardiac arrhythmia. Sevenpatients were referred for evaluation of nonsustained ventricular tachycardia and seven patients were referred for evaluation of sustained monomorphic ventricular tachycardia. All patients gave verbal and written informed consentto a protocol approved by the Committee for the Conduct of Human Researchat both the Medical College of Virginia and the Hunter Holmes McGuire Veterans Affairs Medical Center. The protocol was performed after the clinically indicated electrophysiology study. All studieswere performed with patients in a

fasting, nonsedated state. Patients had undergone coronary arteriography and left ventriculography before the electrophysiology study. Electrophysiology study. In each patient two or three multipolar catheters were introduced percutaneously into the femoral vein and were positioned in the right atria1 appendage, right ventricular apex, and near the tricuspid valve to record a His bundle potential. Programmed electrical stimulation wasperformed with a custom-designed, programmable stimulator (DTU-201, Bloom Associates, Philadelphia, Pa.) at a pulse width of 2 msecand an amplitude of twice diastolic threshold. One to three programmed extrastimuli were delivered to the right ventricular apex and outflow tract at two drive cycle lengths. During each study, surface electrocardiograms(leads I, II, III, and VI) and intracardiac electrograms(right atria1 [RA], right ventricular [RV], and His bundle) were recorded and displayed on a 16-channelphysiologic recorder (Model VR-16, PPG Biomedical Systems, Cardiovascular Division, Pleasantville, N.Y.), an oscilloscope,and an FM tape recorder (model 3968A, Hewlett-Packard Co., Cupertino, Calif.). Arterial pressurewasmonitored with a 5F or 6F sheath in the femoral artery. Sympathetic nerve recordings. Multiunit postganglionic musclesympathetic nerve activity was recorded with a microelectrode inserted into a peroneal nerve near the fibular head, asdescribede1sewhere.l”The nerve signalwas processedby a preamplifier and an amplifier (Nerve Traffic Analyzer, Model 662C-3, University of Iowa Bioengineering, Iowa City, Iowa) with a total gain of 70,000.Amplified signalswerebandpassfiltered (700 to 2000Hz), rectified, and electronically discriminated from baselinenoise. Raw nerve signalswere integrated by a resistance-capacitance circuit with a time constant of 0.1 second.Recordings were consideredacceptablewhen spontaneous,pulse-syn-

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chronous bursts with signal-to-noise ratios > 3:l were obtained. Muscle sympathetic nerve activity was identified by its relation to cardiac and respiratory activity, its tendency to increase during held expiration and Valsalva straining, and its unresponsiveness to arousal stimuli or skin stroking (which trigger skin, but not muscle sympathetic bursts). Data analysis. Sympathetic nerve activity was quantified off-line by custom programs written for signal processing software (CODAS, DATAQ Instruments, Inc., Akron, Ohio). The programs were designed to integrate the nerve traffic signal above the baseline noise level over discrete periods of time (2 or 5 seconds). Sympathetic traffic integrations were normalized to permit comparisons among different patients; the largest 5-second integration voltage during the initial rest period was assigned a value of 1000, and all other integration voltages were normalized against this standard. The nerve signal was offset 1.3 seconds to account for the nerve conduction delay. Experimental protocols. Two experimental protocols were used. In the PVC protocol, seven patients without inducible sustained ventricular tachycardia (VT) were studied during programmed electrical stimulation in normal sinus rhythm with a single ventricular extrastimulus. The coupling interval of the extrastimulus was decreased by 20 to 50 msec until the electrically excitable diastolic period had been scanned at least twice. Each patient was then given a 100 mg bolus of lidocaine, followed by a 2 mg/min continuous infusion. After 5 minutes of infusion, programmed electrical stimulation was repeated. A plasma lidocaine level was obtained in six of seven patients approximately 10 minutes after the infusion was started. In the VT protocol, seven patients were studied during induced sustained hemodynamically stable (e.g., without presyncope or syncope) monomorphic VT. A 100 mg bolus of lidocaine was given 2 minutes after the induction of VT, followed by a 2 mg/min infusion. A lidocaine level was obtained in six of the seven patients 10 minutes after the start of infusion. Blood pressure and sympathetic nerve traffic were measured continuously before, during, and after induction of tachycardia. In three patients, VT spontaneously terminated during the lidocaine maintenance infusion. Lidocaine levels were measured from a plasma sample drawn through a peripheral intravenous line. Lidocaine was assayed using fluorescence polarization immunoassay. Reproducibility tests yielded coefficients of variation of 5 ‘c. Recovery of lidocaine varied from 96% to 100 5;. Lidocaine measurements by this assay compared with lidocaine measurements by high-pressure liquid chromatography yielded a correlation coefficient of 0.94. With this assay. therapeutic lidocaine levels vary from 1.5 to 5 ~g/ml.‘” Statistical analysis. All averaged data are presented as mean t SEM. Paired t test analysis was used to compare sympathetic and blood pressure responses to PVCs before and after lidocaine infusion. A polynomial regression analysis was applied to generate a relation between sympathetic activity and coupling intervals over the entire range

Lidocaine

”

on adrenergic

activity

893

m C 3

1600

3 2 .c f 0

1300

% 3 .r a

1000

E 0 F 2

1

700 20

40

coupling

60

interval,

SO

% of R-R

1

interval

Fig. 1. Relation betweensympathetic burst amplitude (Y axis) and coupling interval of induced ventricular premature beats (X axis) in sevenpatients. Each solid circle is the mean burst amplitude at one tested coupling interval in one patient before lidocaine infusion (n = 77). Each open circle is the mean burst amplitude at one tested coupling interval in one patient after lidocaine infusion (n = 59). Note that the burst amplitude increased as the coupling interval decreasedin all patients before and after lidocaine. The dashed line shows pre-lidocaine data (r = 0.61, p < O.OOl),while the solid line showsthe postIidocaine data (r = 0.70, p < 0.001). Each curve was described by a second-orderpolynomial. The lines were not significantly different (p > 0.05).

of coupling intervals. Repeated measuresanalysis of variancewith contrast analysiswasusedto compareresponses at each stage of VT. In each analysisp < 0.05 was considered significant. RESULTS PVC protocol. A summary of clinical data for the seven patients is shown in Table I (patients No. 1 to 7). Six of the seven patients had underlying angiographically documented coronary artery disease (two with a previous myocardial infarction), and one had an idiopathic dilated cardiomyopathy. Their mean age was 52 rf: 3 years. Before the infusion of lidocaine, systolic blood pressure was 128 + 7 mm Hg and baseline diastolic blood pressure was 81 t 5 mm Hg. Lidocaine infusion did not significantly alter baseline blood pressures (systolic: 124 -t 8 mm Hg; diastolic: 80 rf: 4 mm Hg; p = 0.36 and 0.59, respectively). Moreover, lidocaine infusion did not affect baseline sympathetic burst activity (42 f 7 bursts/min versus 40 -+ 8 bursts/min, p = 0.52). PVCs elicited a transient fall in blood pressure; the mean fall in diastolic blood pressure induced by single PVCs was -14 f 1 mm Hg during baseline and -16 -+ 1 mm Hg after lidocaine infusion (p = 0.46).

894

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American

October 1992 Heart Journal

. * I 450

I

7

r-5

*

160

I 1

I

l-

600 control

vr

lidocaine bolus

lidocaine infusion

Fig. 2. The meanchangesin ventricular tachycardia cycle length (in msec),systolic pressure(in mm Hg), and muscle sympathetic nerve activity (units) after the induction of ventricular tachycardia, following the administration of the lidocaine bolus, and during the lidocaine infusion. *p < 0.05.

dial infarction and two had coexistent valvular heart disease.All patients had mild to moderate congestive heart failure, but no patient had class IV heart failure. Their mean age was 64 i 1 years. Four patients had VT with a right bundle branch morphology and three had VT with a left bundle branch morphology. Before the induction of VT, systolic blood pressure was 150 f 6 mm Hg and diastolic blood pressure was 77 * 2 mm Hg. The baseline muscle sympathetic nerve activity was 817 +- 123 units/5 sec. Lidocaine effects are summarized in Fig. 2 (mean data at minute 2 of VT, following the lidocaine bolus, and 2 minutes after lidocaine infusion was begun). Sample patient data are shown in Fig. 3, A to D. One minute after the induction of VT (immediately before lidocaine infusion), the cycle length of VT was 393 ? 18 msec. Systolic and diastolic blood pressure decreased to 117 +- 9 and 77 + 5 mm Hg (p < 0.01 and p < 0.01, respectively, versus baseline). Mean muscle sympathetic nerve activity increased to 1775 t 274 units/5 set (p = 0.02 versus baseline). Immediately following the lidocaine bolus, systolic and diastolic blood pressure decreased slightly to 109 -t 6 mm Hg and 75 -t 4 mm Hg (p = 0.20 and p = 0.42, respectively, versus pre-lidocaine), while sympathetic nerve activity was unchanged (1798 -t 458 units/5 set; p = 0.92 versus VT baseline before bolus). The cycle length of VT did not change significantly during the bolus (393 t 18 versus 399 +- 17 msec, p = 0.34). During the lidocaine maintenance infusion, the cycle length of VT slowed to 428 t 16 msec (p = 0.01 versus bolus). Mean systolic and diastolic blood pressure increased to 126 + 7 mm Hg and 81 t 4 mm Hg (p = 0.04 and p = 0.1 I versus bolus, respectively). Sympathetic nerve activity decreased to 1460 i 380 units (p = 0.04 versus pre-lidocaine). The lidocaine-induced (probably via tachycardia cycle length slowing) increase in systolic pressure correlated inversely with the fall in sympathetic nerve activity (r = -0.69, p = 0.002). DISCUSSION

PVCs consistently elicited a burst of sympathetic activity. The mean PVC-associated sympathetic burst area was 1101 +- 16 units before lidocaine infusion and 1075 f 19 units after lidocaine infusion (p = 0.30; Fig. 1). PVC-associated burst amplitude increased as an inverse function of coupling interval, and this relation was unchanged by lidocaine infusion (Fig. 1). Ventricular tachycardia protocol. A summary of clinical data for the seven patients in this phase of the protocol is shown in Table I (patients No. 8 to 14). All seven patients had angiographically documented coronary artery disease; five had a previous myocar-

Most antiarrhythmic drugs have direct electrophysiologic effects on cardiac tissue by sodium or calcium channel blockade, or by altering repolarization. Antiarrhythmic drugs may also have indirect electrophysiologic effects by altering autonomic tone. Previous studies in animals8 and in humans9 have revealed that intravenous lidocaine decreases sympathetic nerve activity in various regional beds. These observations have prompted speculation that changes in sympathetic nerve activity may contribute to lidocaine’s antiarrhythmic activity. Our data suggest that therapeutic doses of lidocaine do not alter baseline sympathetic nerve activity and do not

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VT onset

control

1

I electracardiogrom

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blood

blood

pressure.

pressure.

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mmtiq

integrated sympathetic

integrated sympathetic

“e”roqram

neurogrom

muscle activity.

sympathetic 2 s reset

muscle

sympathetic

activity.

A

b-4

2 9 reset

B

set-i

sustoined

t-4

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set+

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t electracardiogrom

200 blood

160

pressure,

blood

120

mdg

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pressure,

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“CXIrOgPZm

muscle activity.

sympathetic 2 s

C

muscle reset

activity,

k4

set+

sympathetic 2 s

D

reset

k4

seci

Fig. 3. Simultaneous recordingsof electrocardiographic rhythm (top panels in each), blood pressure(in mm Hg; second panels in each), integrated sympathetic nerve activity (third panels in each), and integrated musclesympathetic activity reset every 2 seconds(bottom panels in each). Data are shownduring normal sinusrhythm with PVCs for control period (A), following induction of a monomorphicVT (B), after a bolus lidocaine infusion (C), and during the lidocaine maintenance infusion (D).

inhibit sympathetic responses to arterial pressure reductions caused by induced single ventricular extrastimuli or induced monomorphic VT. Sympathetic activity did decrease after lidocaine infusion during VT; however, this decrease was concomitant with an increase in blood pressure, suggesting that the change in nerve traffic was baroreflex-mediated. Therefore, unlike some other antiarrhythmic agents,

the electrophysiologic effects of lidocaine do not appear to be mediated directly through alterations in sympathetic nerve activity. Relation to previous studies. Well and othersI have previously analyzed muscle sympathetic nerve responses to single ventricular extrastimuli in healthy volunteers and in anesthetized animals. These studies have shown that increased sympathetic responses to

696

Ellenbogen et al.

premature ventricular beats are a function of their timing within the cardiac cycle. The most premature beats lead to the largest reductions of arterial pressure and the largest amplitude bursts of sympathetic nerve traffic. Postpremature beat sympathetic surges are mediated by reductions in baroreceptor input, because they do not occur after sinoaortic baroreceptor denervation. l2 In studies of induced VT, an increased release of catecholamines and an increased muscle sympathetic nerve activity have been reported.13-15 Increased sympathetic activation leads to increased forearm vascular tone and to shortening of ventricular refractory periods. Both induced premature ventricular extrastimuli and induced VT are associated with increased regional (e.g., cardiac and renal beds) as well as “global” sympathoexcitation. We therefore used these two clinical situations to test the hypothesis that lidocaine inhibits sympathetic nervous outflow. Miller et a1.8 found that graded doses of lidocaine produced dose-dependent decreases in cardiac sympathetic activity in anesthetized sinoaortic denervated vagotomized dogs. Our study did not show this lidocaine effect on baseline sympathetic nerve activity. These differences are most likely the result of one of two distinctions between the two studies. First, the baseline sympathetic activity in the dogs of Miller et al. was extremely high as a result of general anesthesia, thoracotomy, and baroreceptor denervation.18 Lidocaine may have significant sympathoinhibitory effects when sympathetic activity is extremely high. Second, the plasma lidocaine levels were much higher in the study of Miller et a1.8 (5.2 to 7.5 pg/ml versus 2.6 to 3.5 pg/ml); therefore lidocaine may have sympathoinhibitory effects only at higher doses. The findings of a recent preliminary report by Ebert and Mohantyg indicated that lidocaine may produce sympathoinhibition in healthy conscious humans. Although they observed a significant difference in baseline sympathetic nerve activity, the physiologic relevance of this subtle difference (15 t 2 versus 11 + 2 bursts/100 heart beats) is uncertain. More importantly, they found a difference in sympathetic nerve activity and blood pressure response to the cold pressor test. The cold pressor test is a complicated stimulus producing direct sympathoexcitation, presumably through cutaneous afferent signals. The lidocaine-induced reduction of sympathetic response to the cold pressor test may be the result of the membrane stabilizing effects of lidocaine. a local anesthetic, on these cutaneous nerve fibers. Thus this finding may not be relevant to the antiarrhythmic effects of lidocaine. Leimbach et al.lg reported no increase in muscle sympathetic nerve activity in humans following lidocaine boluses of 50 and 100 mg.

American

October 1992 Heart Journal

Our data corroborate those of Leimbach et al. and extend their findings to the clinical electrophysiologg laboratory with induced ventricular ectopy and VT. The discrepancies in studies showing a lidocaine effect appear to be related to differences in the lidocaine dose, in baseline sympathetic activity, and in the stimulus used to elicit sympathetic activation. Relevance to mechanisms of sudden death. Studies conducted in humans and in animals provide indirect evidence to suggest that sympathetic mechanisms contribute to the occurrence of ventricular arrhythmias and sudden death.“OmZs In patients with the idiopathic long QT interval syndrome or after myocardial infarction, B-blockers have been shown to reduce the incidence of sudden cardiac death.‘“, 15 Amiodarone and sotalol are two of the most effective drugs for suppressing ventricular arrhythmias, and both have antiadrenergic effects.““, 27 Published evidence indicates that sympathetic mechanisms promote ventricular arrhythmias, and that antiarrhythmic drugs may work in part by opposing sympathoexcitation. In our study, lidocaine was given according to standard clinically practiced regimens, and therapeutic levels of lidocaine were measured in all 12 patients in whom serum was available for analysis. The infusion was not associated with a significant decrease in blood pressure, and the measured sympathetic burst amplitude associated with coupled PVC% was not affected by lidocaine. Similarly, the mean sympathetic nerve activity did not change following a 100 mg bolus of lidocaine during VT. After the lidocaine maintenance infusion, VT cycle length increased or the tachycardia terminated. systolic blood pressure increased, and sympathetic nerve activit.y decreased. Since lidocaine did not appear to influence sympathetic activity directly, it, is likely that the decrease in sympathetic nerve activity was baroreflex-mediated and was the result, of the increase in blood pressure caused by the change in tachycardia cycle length. Therefore our data suggest that the therapeutic benefits of lidocaine are unrelated to effects on the control of sympathetic nerve activity. Limitations. The present study has several limitations. Only one lidocaine dosing regimen was administered, and the effects of lidocaine on sympathetic nerve activity may have been greater at higher plasma lidocaine levels. We did not measure preload and thus cannot comment on any potential role of cardiopulmonary baroreceptors in mediating lidocaine’s effects. We also did not assess the effect of lidocaine on additional sympathetic stimuli such as lower body negative pressure or the cold pressor test. It is possible that other sympathetic stimuli, especially those that arouse maximal sympat,hoexcitation, may have provided a better opportunity to

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demonstrate asympathoinhibitoryeffect of lidocaine. Slowing of tachycardia cycle length by lidocaine and the subsequent increase in arterial pressure may have obfuscated its direct effect on sympathetic nerve traffic. Finally, four of the seven patients with sustained VT were taking other antiarrhythmic drugs at the time of their study. The responses of these four patients were similar to those of the other patients, both qualitatively and quantitatively. A major limitation of this study is the confounding effect of antiarrhythmic drugs present in four patients. It is possible that antiarrhythmic drugs may suppress baseline sympathetic nerve activity and may therefore mask any lidocaine-induced sympathoinhibition. Several relevant points may be noted. First, baseline sympathetic nerve activity was not different in patients receiving long-term antiarrhythmic therapy. Second, the changes in sympathetic nerve activity in patients taking or not taking antiarrhythmic drugs were similar. The stimulus to sympathoexcitation was considerable in these patients, as noted by a drop in systolic and diastolic blood pressure. Finally, it is possible but unlikely that lidocaine would reduce cardiac sympathetic tone without altering peroneal efferent traffic. Our data demonstrate that therapeutic doses of lidocaine do not have a direct effect on muscle sympathetic nerve activity during sustained VT or during programmed electrical stimulation with single ventricular extrastimuli. Lidocaine slows tachycardia cycle length, leading to higher arterial pressure and decreased arterial baroreceptor-mediated sympathetic nerve activity. It is likely that lidocaine’s major electrophysiologic action at doses used in clinical settings is primarily a direct electrophysiologic effect. We thank Regina Rogers, RN, Mary Lynn Martin, Sheehan, RN, and Alan Cycan, RN, for their excellent tient care. We also acknowledge the statistical advice tation of Douglas T. F. Simmons.

RN, Helen help in paand consul-

REFERENCES

1. Koster RW, Dunning AJ. Intramuscular lidocaine for prevention of lethal arrhythmias, in the prehospitalization phase of acute myocardial infarction. N Engl J Med 1985;313:1105-10. 2. Lie KJ, Wellens HJJ, Van Champell FS, et al. Lidocaine in the prevention of primary ventricular fibrillation. A double-blind randomized study of 212 consecutive patients. N Engl J Med 1974;2291:1324-6. 3. Morganroth J, Panidis IP, Harley S, Johnson J, Smith E, MacVaugh H. Efficacy and safety of intravenous tocainide compared with intravenous lidocaine for acute ventricular arrhythmias immediately after cardiac surgery. Am J Cardiol 1987;54:1253-8. 4. Gianelly R, Von der Groeben JO, Spivack AP. Effect of lidocaine on ventricular arrhythmias in patients with coronary heart disease. N Engl J Med 1967;277:1215-9. 5. Bigger JT, Mandel WJ. Effect of lidocaine on the electrophys-

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12. Herre JM, Thames MD. Responses of sympathetic nerves to programmed ventricular stimulation. J Am Co11 Cardiol 1987;9:147-53. 13. Morady F, Halter JB, DiCarlo LA, Baerman JM, de Buitleir M. The interplay between endogenous catecholamines and induced ventricular tachycardia during electrophysiologic testing. AM HEART J 1987;113:227-33. 14. Ellenbogen KA, Smith ML, Thames MD, Mohanty PK. Changes in regional adrenergic tone during sustained ventricular tachycardia associated with coronary artery disease or idiopathic dilated cardiomyopathy. Am J Cardiol 1990; 651334-8. 15. Smith ML, Ellenbogen KA, Beightol LA, Eckberg DL. Human sympathetic neural responses to induced ventricular tachycardia. J Am Co11 Cardiol 1991;18:891-7. RH. A compendium of therapeutic and 16. Baselt RC, Cravey toxic concentrations of toxicologically significant drugs in human biofluids. J Anal Toxic01 1977;1:81-103. 17. Fagius J. Muscle nerve sympathetic activity following ectopic heart beats-a note on the burst pattern of sympathetic impulses. J Auton Nerv Syst 1988;22:243-5. 18. Selleren J. Ponten J. Wallin BG. Percutaneous recording of muscle nerve sympathetic activity during propofol, nitrous oxide and isoflurance anesthesia in humans. Anesthesiology 1990;73:20-7. 19. Leimbach WN Jr, Kempf J, Mark AL. Intraneural recordings of sympathetic nerve activity in humans before and after lidocaine [Abstract]. Clin Res 1985;33:811A. 20. Schwartz PJ, Vanoli E, Stramba-Badiale M, Defeorari GM, Billman GE, Foreman RD. Autonomic mechanisms and sudden death. New insights from analysis of baroreceptor reflexes in conscious dogs with and without a myocardial infarction. Circulation 1989;78:969-79. 21. Martins JB. Sympathetic influences in myocardial ischemia: possible mechanisms of arrhythmogenesis. In: Zipes DP, ed. Cardiology clinics. Philadelphia: WB Saunders, 1983:51-61. 22. Kleiger RE, Miller JP, Bigger JT Jr, et al. Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. Am J Cardiol 1987;59:256-62. 23. Freeman RA, Swerdlow CO, Echt DS, Winkle RA, SoderholmDifatte V. Mason JW. Facilitation of ventricular tachycardia induction by isoproterenol. Am J Cardiol 1984;54:765-70. 24. Milne JR, Ward DE, Spurrel AJ, et al. The long QT syndrome: effects of drugs and left stellate ganglion block. AM HEART J 1982;104:194-8. 25. Yusuf S, Pete R, Lewis J, Collins R, Sleight P. Beta-blockade during and after myocardial infarction: an overview of the randomized trials. Proa Cardiovasc Dis 1985:24:336-67. 26. Mason JW. Amiodarone. N Engl J Med 1987;316:455-66. 27. Singh BN. Sotalol; a beta-blocker with unique antiarrhythmic effects. AM HEART J 1987;114:121-39.