Efficacy and safety of intravenous tocainide compared with intravenous lidocaine for acute ventricular arrhythmias immediately after cardiac surgery

ARRHYTHMIAS AND CONDUCTION DISTURBANCES

Efficacy and Safety of Intravenous Tocainide Compared with Intravenous Lidocaine for Acute Ventricular Arrhythmias Immediately After Cardiac Surgery JOEL MORGANROTH, MD, IOANNIS P. PANIDIS, MD, SALLY HARLEY, RN, JEANNE JOHNSON, EMIL SMITH, PhD, and HORACE MacVAUGH, MD

in this double-blind parallel study, 99 patients with acute ventricular tachyarrhythmias after open-heart surgery were given either tocainide (50 patients) or tidocaine (49 patients) intravenously as 2 bolus injections 15 minutes apart, plus a fixed-rate infusion that started at the first bolus. If needed, a third bolus was administered and simultaneously the infusion rate was doubled. The boluses and initial infusion rate for tocainide treatment were, respectively, 250, 250 and 125 mg and 1.04 mg/min, and for Iidocaine treatment, 100, 50 and 50 mg and 2.08 mg/min. When efficacy was defined as 80 % or greater reduction in single Ventricular premature complexes (VPCs) or complete abolition of ventricular couplets or ventricular tachycardia, no difference in efficacy between the 2 treatments was found by bedside electrocardiographic monitoring. By computer analysis of 24-hour taped electrocardiograms and a regression analysis of the proportion of patients responding favorably to treatment, it was estimated that an 80% or greater reduction of single VPCs

occurred in 55% of patients during tocainide treatment and in 48% of patients during lidocaine treatment; abolition of couplets occurred in 74% and 68% of patients, respectively; and abolition of ventricular tachycardia in 87 % and 73 % of patients, respectively. These treatment-related differences were different (p <0.004). Adverse reactions occurred in 5 patients (10 % ) given tocainide (hypotension in 4; junctional rhythm in 1 patient; and nausea-vomiting in 1) and led to discontinuation of treatment in 3 patients. Adverse reactions were reported in 9 patients (18 %) given lidocaine (hypotension, 4; central nervous system depression, 2; bradycardia, 2; nausea-vomiting, 1; increased frequency of VPCs, 1) and led to discontinuation of treatment in 4 patients. Thus, tocainide was at least as effective, if not more effective, than Iidocaine when administered intravenously for the treatment of acute ventricular arrhythmias occurring immediately after cardiac surgery. (Am J Cardiol 1984;54:1253-1258)

Tocainide is a primary amine analog of lidocaine which, in contrast to lidocaine, can be administered both orally and intravenously. Orally administered tocainide is effective in suppressing both chronic stable ventricular arrhythmias 1-3 and life-threatening ventricular arrhythmias refractory to conventional antiarrhythmic drug therapy. 4-7 Intravenously administered tocainide has been used successfully in the treatment of ventricular arrhythmias after acute myocardial infarction

without adverse hemodynamic or serious side effects. 8-1° This study compares therapeutic efficacy and safety of intravenous (i.v.) tocainide and i.v. lidocaine in patients with acute ventricular arrhythmias occurri'~g immediately after cardiac surgery.

Methods Patients: Before cardiac surgery, 316 patients consented in writing to participate in the study. The study population consisted of 99 patients from this group who fulfdled the entry criteria. There were 73 men and 26 women, aged 34 to 75 years (mean 59). Criteria for entry into the study included the occurrence of more than 5 ventricular premature complexes (VPCs) per minute or any ventricular couplets or ventricular tachycardia (VT) within 24 hours after surgery. The primary diagnosis was coronary artery disease in 78 patients, valvular heart disease in 20 and atrial septal defect in 1 patient (Table

From the Likoff Cardiovascular Institute of Hahnemann University School of Medicine, the Lankenau Hospital, Philadelphia, Pennsylvania, and the University of Massachusetts School of Medicine, Worcester, Massachusetts. Manuscript received May 21, 1984; revised manuscript received July 27, 1984, accepted July 30, 1984. Address for reprints: Joel Morganroth, MD, Likoff Cardiovascular Institute, Hahnemann University Hospital, 230 North Broad Street, Philadelphia, Pennsylvania 19102. 1253

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TOCAINIDEAND LIDOCAINE FOR VENTRICULAR ARRHYTHMIAS

TABLE I

Clinical Characteristics of Patients Treated with Tocainlde or Lidocaine Tocainide Group*

Lidocaine Group*

No. of pts. Mean age (yr)

50 60

49 58

Men Women

42 8

31 18

Mean weight (kg)

77

76

CAD VHD CAD and VHD Atrial septal defect Healed MI Systemic hypertension Preop ECG conduction abnormalities Arterial pressure (mm Hg) before entry Systolic (mean 4- SEM) Diastolic (mean 4- SEM) Heart rate (beats/min, 4- SEM) Type of surgery CABG1" VR CABG and VR Duration of surgery (min)

42 6 2 0 23 21 9

36 9 3 1 18 20 10

124 4- 2.2

119 4- 2.0

76 4- 1.3

72 4- 1.5

72 4- 1.6

74 4- 2.3

IABP

42 6 2 181 4- 54

1

36 9 3 191 4- 51

2

• Difference not significant by unpaired t test or chi-square analysis between the 2 groups for all parameters except for number of female patients (p <0.05). 1 No significant difference between the 2 groups for number of

vessels bypassed. CABG = coronary artery bypass grafting; CAD = coronary artery disease; ECG = electrocardiographic; IABP = intraaortic balloon pump; MI = myocardial infarction; Preop = preoperative; SEM = standard error of the mean; VHD = valvular heart disease; VR = valve replacement,

I). Seventy-eight patients underwent coronary artery bypass surgery (1 to 6 anastamotic sites), 15 patients underwent isolated aortic or mitral valve replacement, 5 patients underwent valve replacement in addition to coronary artery bypass surgery and 1 patient had repair of an atrial septal defect. All antiarrhythmic medications including ~-adrenergic blocking agents were withdrawn before surgery and were not allowed during the course of the study. Exclusion criteria were: younger than age 18 years, heart rate less than 45 beats/min, renal insufficiency (creatinine >2.5 mg/ml), second- or third-degree atrioventricular block or serious sinoatrial node disorder in the absence of an artificial pacemaker, known allergy to amide-type local anesthetic agents, hepatic insufficiency, concurrent illness that might interfere, and pregnancy. Study design: Patients who entered the study were treated in a double-blind, parallel manner and were given either i.v. tocainide hydrochloride (50 patients) or i.v. lidocaine hydrochloride (49 patients) in randomized order. Patients treated with tocainide received an initial bolus of 250 mg and a second bolus of 250 mg 15 minutes later, each dose administered over 1 to 2 minutes, plus an i.v. infusion at 1.04 mg/min started at the time of the first bolus injection. If this regimen was judged therapeutically ineffective using bedside electrocardiographic monitoring, a third bolus of 125 mg of tocainide was given, but not sooner than 5 minutes after the second bolus, and the rate of i.v. infusion was increased to 2.08 mg/min. Patients treated with lidocaine received a first bolus of 100 mg and a second bolus of 50 mg 15 minutes later, plus a continuous i.v. infusion of 2.08 mg/min started at the time of the first bolus injection. If this regimen was judged clinically ineffective, a third bolus of 50 mg of lidocaine was administered and the i.v. infusion rate was doubled to 4.16 mg/min.

TABLE II

Ventricular Arrhythmias at Entry into Study of Patients Treated with Tocainide or Lidocaine Tocainide Group*

Type of arrhythmia Unifocal VPCs > 5 beats/min Multiform VPCs Ventricular couplets VT Unifocal VPCs and couplets Unifocal VPCs and VT Multiform VPCs and couplets Ventricular couplets and VT Unifocal VPCs, couplets and VT Time of onset of arrhythmias after surgery (min)

(n = 50)

Lidocaine Group * (n = 49)

14 1 8 12 7 0 5 1 2

20 0 8 10 3 3 1 2 2

214 4- 234

216 4- 206

• Difference not significant by unpaired t test or chi-square analysis

between the 2 groups for all parameters. VPCs = ventricular premature complexes; VT = ventricular tachycardia.

Treatment with either drug was terminated when an adverse reaction developed, when treatment was judged ineffective after the previously described sequences or when the patient was transferred out of the surgical intensive care unit. Patients in whom treatment was judged ineffective were not subsequently treated with the alternate drug. The antiarrhFthmic efficacy of each regimen was evaluated by 2 independent methods. First, at the time of treatment, the nurses in the intensive care unit used continuous electrocardiographic monitoring at the bedside to judge whether the treatment was effective. Efficacy was defined as 80% or more reduction in single VPC frequency or, if present, complete abolition of ventricular couplets or tachycardia. Second, a computer-generated analysis of a 24-hour Holter recording of the electrocardiograms was begun on all consenting patients on arrival in the surgical intensive care unit. A reel-to-reel tape recorder (model 445B electrocardiocorder; DelMar Avionics) was used and a research quality computer analysis of taped recordings was performed (Cardio-Data Systems of United Medical Corporation). Quality control details of this research Holter analysis service have been previously established. 11 Supine blood pressure and heart rate were recorded during the study at 5-minute intervals for 15 minutes after each bolus injection and then at hourly intervals for the remainder of the study. Laboratory evaluation: All prospective subjects were examined and interviewed before surgery. A 12-lead electrocardiogram was taken and blood and urine samples were obtained for clinical laboratory screening (SMA-6, hematology and routine urinalysis) before surgery and at the conclusion of drug treatment. For the determination of tocainide and lidocaine blood levels, 4-ml blood samples were collected at 1 hour after the beginning of treatment, immediately before any increase in infusion rate and at the end of treatment. The samples were analyzed by Astra Pharmaceutical Products. Tocainide blood levels were measured by high-pressure liquid chromatography, 12 while gas chromatography was used for determination of lidocaine blood levels. 13 Statistical analysis: Antiarrhythmic efficacy was defined as 80% or greater suppression of single VPCs and complete abolition of complex ventricular arrhythmias using previously reported guidelines. 14 Differences in clinical characteristics and subjective assessment of antiarrhythmic efficacy between the 2 treatment groups were analyzed using the unpaired t test and the chi-square analysis or Fisher exact probability test where appropriate.

DeGember 1, 1984

The data on ventricular arrhythmias from the computer analysis of the taped electrocardiograms were tabulated for statistical analysis. An analysis was performed in which each patient in each treatment group was considered a responder or a nonresponder at each 1-hour interval for 24 hours after the start of treatment; the percentage of responders in each group was then calculated for each interval. When treatment was terminated with the arrhythmia abolished or still present, its absence or presence was assumed for the remainder of the 24 hours. For each treatment group, the relation between the proportion of responders and time after start of treatment was fit to the following equation using the least squares method: Y = A(1-e-SX), where Y ffi percent responders, X = time after start of treatment, A = ultimate percentage of responders (value of the asymptote) and B = rate constant. The standard errors for the estimates of A and B were obtained and the estimates were compared by t test. Results Comparison of the group of patients treated with tocainide and the group treated with lidocaine revealed no differences in clinical or surgical variables except for a greater number of women in the lidocaine group (p <0.05) (Table I). All 50 patients treated with tocainide received both the initial and the second boluses of 250 mg each and the continuous i.v. infusion at a rate of 1.04 mg/min for 22 minutes to 24 hours; 31 of these 50 patients required the third bolus of 125 mg of tocainide and had the rate of infusion increased to 2.08 mg/min for a duration of 5 minutes to 20 hours and 40 minutes. All of the 49 patients treated with lidocaine received the initial and second boluses and had a continuous i.v. infusion at a rate of 2.08 mg/min for 10 minutes to 24 hours and 20 minutes; 27 of the 49 patients required the third bolus of 50 mg and had their infusion rate increased to 4.16 mg/min for 8 minutes to 16 hours and 20 minutes. A n t i a r r h y t h m i c e f f i c a c y of t o e a i n i d e and lidocaine: Arrhythmias before treatment: There were no statistically significant differences between the 2 treatment groups with respect to the type and frequency of the ventricular arrhythmias present at entry into the study (Table II). Clinical assessment of efficacy: The lower rate of drug infusion was considered effective by the judgment of the nursing staff in 19 of 50 patients (38%) treated with tocainide and in 22 of 49 patients (45%) treated with lidocaine (difference not significant [NS]). At the higher infusion rates, treatment was effective in 22 of the 31 patients (71%) given this infusion of tocainide and in 13 of the 27 patients (48%) given this infusion of lidocaine (NS). When the overall effectiveness of the agents was determined by combining the observations at both rates of infusion, tocainide was found effective in 41 of 50 patients (82%) and lidocaine in 35 of 49 patients (71%) (NS). Efficacy analysis by Holter monitoring: In 3 of the 99 patients, the Holter-type recordings were of poor quality and were not included in this analysis. The frequency of ventricular arrhythmias both before and for hourly intervals up to 24 hours after the start of the treatment were obtained by analysis of the taped electrocardiogram from the remaining 96 patients.

THE AMERICAN JOURNAL OF CARDIOLOGY

Volume 54

1255

In all, 72 patients exhibited single VPCs before treatment. Of these, there was 80% or greater reduction in VPCs in 55% of 36 patients treated with tocainide and in 48% of 36 patients treated with lidocaine (p <0.004) (Fig. 1A). Complete abolition of single VPCs was observed in 38% of the tocainide group and in 20% of the lidocaine group (p <0.001) (Fig. 1B). Of the patients who entered the study with ventricular couplets, 33 were treated with tocainide and 28 were treated with lidocaine. Complete abolition of ventricular couplets occurred in 74% of the patients treated with tocainide compared with 68% treated with lidocaine (p <0.001) (Fig. 2). Finally, complete abolition of the VT was observed in 87% of 24 patients treated with tocainide compared with 73% of 20 patients treated with lidocaine (p <0.001) (Fig. 3). L a b o r a t o r y findings: No significant differences in blood pressure and heart rate were observed between the 2 treatment groups during either the low or the high rates of infusion. Treatment with tocainide rapidly produced and then maintained blood levels of about 3 to 10 #g/ml, whereas treatment with lidocaine produced and sustained blood levels of about 1 to 5 #g/ml (Fig. 4). There were no changes in the clinical laboratory test

A

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Legend X TOCAINIDE ~. LIDOCAINE

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1256

TOCAINIDE AND LIDOCAINE FOR VENTRICULAR ARRHYTHMIAS

T A B L E III

A d v e r s e Reactions in Patients T r e a t e d with T o c a i n i d e or Lidocaine Tocainide Group 5 of 50 Pts. ( 1 0 % )

No. and type of specific reaction Hypotension Nausea, vomiting Increasing drowsiness Junctional rhythm Bradycardia Increased VPC frequency Total

Lidocaine Group 9 of 49 Pts. ( 1 8 % )

4 (3)" 1 . :1"

4 (2) ° 1 2 (2)"

...

"2 "

6"(3i •

1 10 (4)*

• Number of patients who required drug discontinuation. VPCs = ventricular premature complexes.

results that could be ascribed to treatment with either tocainide or lidocaine. Adverse reactions: A total of 6 adverse reactions were observed in 5 patients treated with tocainide and a total of 10 adverse reactions were seen in 9 patients treated with lidocaine (Table III). The most common reactions were cardiovascular in nature, and included hypotension (in 4 patients given tocainide and in 4 given lidocaine), bradycardia (in 2 patients given lidocaine), i episode of junctional rhythm (1 patient given tocain-

ide; blood level 21 #g/ml) and 1 episode of increased frequency of V P C s (in I patient given lidocaine). Gastrointestinaladverse effects (nausea and vomiting) were possibly related to treatment in 1 patient given tocainide and i given lidocaine.Finally, 2 patients treated with lidocaine experienced a slowly developing depression of the central nervous system that was manifested as drowsiness and sedation leading to slurred speech in i patient and impaired responsiveness in the other. Both patients improved rapidly after discontinuation of lidocaine treatment. Discontinuation of tocainide therapy was required in 3 patients because of sustained hypotension, whereas lidocaine was discontinued in 2 because of sustained hypotension, as well as in the 2 patients with central nervous system depression. Discussion

The results of this study suggest that i.v. tocainide can be used to effectively and safely suppress acute ventricular arrhythmias immediately after cardiac surgery. Comparison of tocainide and lidocaine: Intravenous tocainide has been effective in the treatment of

TOCAINIDE 80,

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xxXXxx X

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RELATIVE TIME (HOURS}

FIGURE 4. Blood levels (p.g/ml) attained 1 hour after the start and at the end of tocainide and lidocaine infusion, when in some patients the rate of infusion was increased.

December 1, 1984 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 54

ventricular arrhythmias after acute myocardial infarction and under these conditions a mean half-life of about 14 hours was observed.8,9,15Intravenous lfdocaine, on the other hand, has been used successfully in the prophylaxis of acute ventricular arrhythmias, especially ventricular fibrillation, after acute myocardial infarction. 16,17 Although lidocaine is the i.v. antiarrhythmic agent most commonly used in the treatment of acute ventricular arrhythmias after surgery, no recent controlled studies are available to confirm its specific efficacy in this setting. In the present study the efficacy of i.v. tocainide in the treatment of acute ventricular arrhythmias after cardiac surgery was compared with i.v. lidocaine administered according to widely used procedures. 16,17 ]~ocainide is approximately half as potent on a weight basis as lidocaine ls,19 and tocainide blood levels achieved in this study (3 to 10 #g/ml) were approximately twice the plasma levels attained with lidocaine (1 to 5 #g/ml). The antiarrhythmic efficacy of i.v. tocainide and lidocaine was assessed in a double-blind, parallel manner in 2 groups of patients with similar clinical characteristics and ventricular arrhythmias at entry into the study. Subjective assessment of efficacy at the time of treatment, defined as 80% or greater suppression of single VPCs and abolition of higher forms of ventricular arrhythmias, 14 revealed no significant difference between the 2 treatments: A favorable response was achieved in 41 of 50 patients (82%) treated with tocainide and in 35 of 49 patients (71%) treated with lidocaine (NS). An objective assessment of efficacy, obtained independently from a computer-generated analysis of the electrocardiograms taped before and during treatment, 11 and using a regression analysis to estimate the proportion of patients responding favorably to treatment, revealed that i.v. tocalnide was probably more effective than lidocaine in suppressing single VPCs and in abolishing both ventricular couplets and VT. Electrophysiologic and hemodynamic effects of tocainide: The effects of tocainide on the conduction system are similar to those of lidocaine. 2° Animal studies 19 and studies in healthy volunteers 21 and in patients with coronary artery disease 22 showed no significant effects of tocainide on the sinus node function, effective refractory periods or intraventricular conduction times. No adverse effects on atrioventricular conduction were observed in patients with an intraventricular conduction disturbance or a prolonged AV interval. 22 The PR and QRS intervals as measured on the surface electrocardiogram are not significantly affected by tocainide; the QT interval may decrease even slightly in s o m e c a s e s . 20,23 If/~-blocking drugs are used concomitantly with tocainide, 24 asystole may develop in patients with sinus node dysfunction. Thus, all patients with significant sinus node or atrioventricular node dysfunction were excluded from the study, and fl-blocking drugs were discontinued before the study. No patient had any electrophysiologic adverse effects, except for 1 who had a junctional rhythm associated with high levels of tocainide.

1287

A small but statistically significant increase in aortic and pulmonary arterial pressures and in pulmonary and systemic vascular resistance have been observed during i.v. administration of tocainide in patients with heart disease 25,26 and is not associated with clinical evidence of congestive heart failure, even in patients with compensated left ventricular dysfunction.26,27 Four of the 50 patients treated with tocainide had hypotension, and tocainide treatment was discontinued in 3 of them. Although these hypotensive episodes may have been related to treatment and were severe enough that treatment was terminated, it is difficult to be certain of the precise cause of hypotension in view of the altered postoperative cardiovascular status in patients after cardiac surgery. No direct, clinically overt worsening of left ventricular function was observed in any of the patients in this study. Adverse effects: Adverse reactions involving the central nervous system and gastrointestinal tract are the most common side effects reported in patients treated orally with tocainide. 28,29 In the present study, nausea and vomiting did develop in 1 patient treated with tocainide, but neurologic adverse effects were not observed in any of the patients treated with tocainide. However, 2 patients treated with lidocaine had increasing drowsiness that required discontinuation of treatment. No aggravation of ventricular arrhythmias was observed in any patient treated with tocainide, although 1 patient treated with lidocaine had an increased frequency of VPCs. A proarrhythmic effect has been observed in approximately 10% of patients treated with antiarrhythmic agents. 3° Ventricular fibrillation has been reported previously in 2 patients given tocainide. 31 Clinical implications: Although the antiarrhythmic efficacy of i.v. lidocaine in postsurgical arrhythmias has not been confirmed by recent, clinically controlled studies, it remains the most frequently used i.v. antiarrhythmic agent in the short-term treatment of these acute ventricular arrhythmias. In this double-blind, comparative, parallel study, i.v. tocainide was found to be as effective, if not more effective, than lidocaine, when both were used in the treatment of acute ventricular arrhythmias immediately after cardiac surgery. Similar to lidocaine, tocalnide lacks significant negative inotropic effects and is, therefore, a useful agent in patients with compromised left ventricular f u n c t i o n . 26,27 In addition, tocainide has favorable electrophysiologic properties, a low proarrhythmic propensity and often decreases the QT interval on the electrocardiogram.2° Compared with lidocaine, tocainide has a longer halflife, less central nervous system adverse effects and is available for oral administration. Orally administered tocainide has been an effective antiarrhythmic agent with a therapeutic response that is frequently predicted by the response to i.v. lidocaine. 32-36 References 1. Winkle RA, Meffln PJ, Fitzgerald JW, Harrison DC. Clinical efficacy and pharmacokinetics of a new orally effective antiarrhythmlc, tocalnlde. Circulation 1976;54:884-889. 2. Woosley RL, McDevltt DG, Nles AS, Smith RF, Wilkinson GR, Oate= JA. Suppressionof ventricular ectopic depolarizationsby tocalntde.Circulation 1977;56:980-984. 3. Bastlan BC, MacFadane PW, McLauchlan JH, Ballantym) D, Clark P, HIIII=

1258

4. 5. 6. 7. 8.

9. 10. 11. 12. 13. 14.

15. 16. 17. 18. 19.

TOCAINIDEAND LIOOCAINE FOR VENTRICULAR ARRHYTHMIAS

WS, Rae AP, Hutton I. A prospectiverandomizedVial of tocalnldeIn patients following myocardial Infarction. Am Heart J 1980;100:1017-1022. Winkle RA, Meffln PJ, Harrison DC. Long*term tocalnide therapy for vantricular arrhythmias. Circulation 1978;57:1008-1016. Ryan W, Engler R, LeWlnter M, Karllner JS. Efficacy of a new oral agent (tocalnide) in the acute ~reatmantof refractory ventricular arrhythmlas. Am J Cardiol 1979;43:285-291. Young MD, Hadidlan Z, Horn HR, Johnson JL, Vassallo HG. Treatment of ventrlcular arrhythmias with oral tocainide. Am Heart J 1980;100:10411045. Podrld PJ, Lown B. Tocainide for refractory symptomatic ventrlcular arrhythmlas. Am J Cardiol 1982;49:1279-1286. Ryden L, Amman K, ComadsonTB, Hofvandahi S, Modansen O, Smedgard P. Prophylaxis of ventricular tachyarrhythmlas with intravenous and oral tocainide in patients with and recovering from acute myocardial infarction. Am Heart J 1980;100:1006-1012. Nyquiat O, Fersseii G, NerdlanderR, Schanck-GtmtafssooK. Hemndynamic and antlarrhythmic effects of tocainide in patients with acute myocardial infarction. Am Heart J 1980;100:1000-1005. Sonnhag C. Efficacy and tolerance of tocalnide during acute and long-term treatment of chronic ventricular arrhythmlas. Eur J Clin Pharmacol 1980; 18:301-310. Klein M, Baker S, Feldman C, Hubelbank M, Lane B. A validationtechnique for computerized Holtar tape processing systems used In drug efficacy testing. IEEEProc Comput Cardiol Conference, 1977. Wolshln EM, Cavanaugh MH, Manion CV, Meyer MB, Mileno E, Reardon CR, and Woishln SM. Assay of tocainide in blood by high-pressure liquid chromatography. J Pharm Sci 1978;67:1692-1685. Kanflaghan JIB.The determinationof lidocaineand prllocaine in whole blood by gas chromatography. Anesthesiology 1968;29:110-112. Merganroth J, Mlchelson ER, Horowllz LN, Josophson ME, Peadman AS, Dunkman WB. Limitations of routine Iong*tarm electrocardiographic monitoring to assess vantrlcular ectopic frequency. Circulation 1978;58: 408-414. Grafner C, ConradsonTB, Hofvendahl S, Ryden L. Tocalnlde kinetics after intravenous and oral administration in healthy subjects and in patients with acute myocardial infarction. Clin Pharmacol Ther 1980;27:64-71. Lie KI, Well(ms HS, Van Capelle FJ, Durrar D. Lidocaine in the prevention of primary ventricular fibrillation. N Engl J Med 1974;291:1324-1326. deSIIva RA, Hennekens CH, Lown B, Casscells W. Lignocaine prophylaxis in acute myocardial infarction: an evaluation of randomized trials. Lancet 1981;2:855-858. Moore EN, Spear JF, Horowltz LN, Feldman HS, Moiler RA. Electrophysiological properties of a new antiarrhythmic drug-tocainide. Am J Cardiol 1978;41:703-708. Coltart DJ, Berndt TB, Kernoff R, HarrisOn DC. Antiarrhythmic and circulatory effects of Astra W36095. Am J Cardiol 1974;34:35-41.

20. Anderson JL, Mason JW, Winkle RA, Meffin PJ, Fowles RE, Peters L, Harrison DC. Clinical electrophysiologlcal effects of tocalnide. Circulation 1978;57:685-691. 21. Swedberg K, Pehrson J, Ryden I. Electrocardiographicand hemodynamic effects of tocainide (W-36095) in man. Eur J Clin Pharmacol 1978;14: 15-19. 22. Horowltz LN, Josophson ME, Farshidl A. Human electropharmacology of tocainide a lidocalne congener. Am J Cardiol 1978;42:276-280. 23. Maloney JD, Nissen RG, Moolgan MJ. Open clinical studies at a referral canter: chronic maintenance tocalnide therapy in patients with recurrent sustained vantricular tachycardla refractory to conventional antiarrhythmic agents. Am Heart J 1980;100:1023-1030. 24. Ikram H. Hemodynamic and electrophysiologic interactions between antiarrhythmic drugs and beta-blockars, with special reference to tocainlde. Am Heart J 1980;100:1076-1080. 25. Harrison DC, Meffin PJ, Winkle RA. Clinical pharmacology and antiarrhythmic actions of tocainide. Br Heart J 1978;40:83-87. 26. Winkle RA, Anderson JL, Peters F, Meffin PJ, Fowles RE, Harrison OC. The hemodynamic effects of intravenous tocainide in patients with heart disease. Circulation 1978;67:787-792. 27. Schwartz M, Covino B, Duce B, Narang R, Fiore J, Merkeils M, Rizvl S, Smith E. Acute hemodynamlc effects of tocainlde in patients undergoing cardiac catheterization. J Clin Pharmacol 1979;19:100-107. 28. Horn HR, Hadldian Z, Johnson JL, Vassailo HG, Williams JH, Young MD. Safety evaluation of tocainide in the American Emergency Use Program. Am Heart J 1980; 100:1037-1040. 29. ZIpes DP, Troup PJ. New antiarrhythmic agents. Am J Cardiol 1978;41: 1005-1024. 30. Veleblt V, Podrld P, Lown B, Cohen BH, Graboys TB. Aggravation and provocation of ventricular arrhythmias by antlarrhythmic drugs. Circulation 1982;65:886-894. 31. Eogler RL, LeWlnter M. Tocainide-inducedventricular fibrillation. Am Heart J 1981;101:494-496. 32. Klein MD, Levlne PA, Ryan TJ. Antiarrhythmic efficacy, pharmacokinetics and clinical safety of tocainide in convalescent myocardial infarction patients. Chest 1980;77:726-730. 33. Winkle RA, Mason JW, Harrison DC. Tocainidefor drug*resistantventrlcuiar arrhythmias: efficacy, side effects, and lidocaine responsiveness for predicting tocainide success. Am Heart J 1980; 100:1031- 1036. 34. HaffaJee Cl, Alpert JS, Dalen JE. Tocainide for refractory ventricular arrhythmias of myocardial infarction. Am Heart J 1980;100:1013-1016. 35, MoDevltt DG, Nles AS, WilkinSOn GR, Smith RF, Woosley RL, Oates JA. Antiarrhythmic effects of a lidocaine congener, tocainide, 2-amino-2'-6'propionoxylidide, in man. Clin Pharmacol Ther 1976;19:396-402. 36. RodenDM, Reele SB, Hlggins SB, Carr RK, Smith RF, Oates JA, Woostay RL. Tocainide therapy for refractory ventricular arrhythmias. Am Heart J 1980;100:15-22.