Effects of intravenous amiodarone on ventricular refractoriness, intraventricular conduction, and ventricular tachycardia induction

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1 Europace (2000) 2, doi: /eupc , available online at on Effects of intravenous amiodarone on ventricular refractoriness, intraventricular conduction, and ventricular tachycardia induction P. Kułakowski, S. Karczmarewicz, G. Karpiński, M. Soszyńska and L. Ceremużyński Department of Cardiology, Postgraduate Medical School, Grochowski Hospital, Warsaw, Poland Aims Intravenous amiodarone has recently emerged as an important drug for the acute treatment of ventricular tachyarrhythmias. However, electrophysiological actions and the efficacy of the drug in the suppression of ventricular tachycardia inducibility have not yet been fully established. The present study was designed to address these issues. Methods and Results The study group consisted of 18 patients (all males, mean age years), who underwent electrophysiological study due to a history of sustained ventricular tachyarrhythmia or syncope with non-sustained ventricular tachycardia detected on ambulatory ECG monitoring. The effects of 5 mg. kg 1 or 10mg.kg 1 of intravenous amiodarone on (1) ventricular refractoriness (QTc interval, right ventricular effective refractory period and monophasic action potential duration), (2) intraventricular conduction (paced-qrs and signalaveraged QRS duration), and (3) ventricular tachycardia inducibility, were examined. The drug had no significant effect on ventricular refractoriness. However, a relatively small but significant slowing of intraventricular conduction was seen (paced-qrs duration: ms vs ms, P<0 0007; ms vs ms, P<0 0007; and ms vs ms, P<0 003, at the cycle lengths of 600, 500 and 400 ms, respectively). This effect was more evident during extrasystolic beats than during stable pacing (for example, at the cycle length of 600 ms, the magnitude of amiodarone-induced lengthening of QRS duration was ms vs ms, P<0 009, respectively). Intravenous amiodarone did not prevent induction of sustained ventricular tachycardia in any of five patients inducible at baseline. Of six patients with non-sustained ventricular tachycardia, five had sustained ventricular tachycardia or fibrillation induced after amiodarone infusion. Conclusion Intravenous amiodarone does not prolong ventricular refractoriness, slows intraventricular conduction and may facilitate inducibility of sustained ventricular arrhythmias. (Europace 2000; 2: ) 2000 The European Society of Cardiology Key Words: Intravenous amiodarone, refractoriness, intraventricular conduction. Introduction Intravenous amiodarone has recently emerged as an important drug for the acute treatment of ventricular tachyarrhythmias [1 3]. However, the data on acute electrophysiological effects and the efficacy of intravenous amiodarone during electrophysiological study are much more limited. It has been shown that, when given at the Manuscript submitted 16 June 1999, revised 15 March 2000, and accepted 1 April Correspondence: Piotr Kułakowski, MD, Department of Cardiology, Postgraduate Medical School, Grochowski Hospital, Grenadierów 51/59, Warszawa, Poland. usually recommended dose (5 mg. kg 1 body weight), intravenous amiodarone had little or no effect on the sinus cycle length, corrected QT interval, atrial, ventricular and accessory pathway refractory periods [4,5]. Small but consistent prolongation of the ventricular effective refractory period and intraventricular conduction has been achieved only by administration of a higher dose of 10 mg. kg 1 body weight [6]. None of those studies used monophasic action potential recordings to evaluate in more detail the effects of intravenous amiodarone on ventricular refractoriness. Therefore, the aim of the present study was to evaluate the effects of intravenous amiodarone, administered at a dose of 5 mg. kg 1 or 10 mg. kg 1 body weight, /00/ $35.00/ The European Society of Cardiology

2 208 P. Kułakowski et al. on ventricular refractoriness, intraventricular conduction, and inducibility of sustained ventricular tachycardia. Table 1 patients Demographic and cardiac data in 18 study n Methods Patients The initial study group consisted of 20 consecutive patients who underwent electrophysiological study in our laboratory. However, two patients did not complete the protocol: in one patient ventricular fibrillation, induced during a baseline study, was difficult to terminate (four DC shocks were needed to terminate the arrhythmia) and intravenous amiodarone was not tested; the other patient developed an allergic reaction after 100 mg of intravenous amiodarone and the infusion was not completed. Thus, the final study group consisted of 18 patients (all males, mean age years), who underwent electrophysiological study due to a history of sustained ventricular tachycardia, ventricular fibrillation not associated with ischaemia or other reversible causes, or syncope with non-sustained ventricular tachycardia detected on ambulatory ECG monitoring. The clinical characteristics of the study group are presented in Table 1. All patients gave informed written consent. The protocol of the study was approved by the local Ethics Committee. Electrophysiological study Two 6F quadripolar electrode catheters were introduced percutaneously into the femoral vein and positioned under fluoroscopic guidance in the high right atrium and the His bundle position. The third electrode, which was used for monophasic action potential recordings (7F MAP Pacing Catheter, EP Technologies) and pacing, was positioned in the right ventricular apex. Intracardiac recordings and the surface ECG were displayed and recorded using a computerized EPLab Bard system (Bard, US). Programmed ventricular stimulation was performed using a strict 12-step stimulation protocol which consisted of introducing single-, double- and tripleextrastimuli at the right ventricular apex during sinus rhythm and after eight-beat drive trains of ventricular pacing at cycle lengths of 600, 500 and 400 ms. The endpoints of the study were (1) induction of sustained ventricular tachycardia or ventricular fibrillation or (2) completion of the protocol. Sustained ventricular tachycardia was defined as a tachycardia of ventricular origin lasting 30 s or causing haemodynamic collapse. Non-sustained ventricular tachycardia was defined as >3 beats of repetitive ventricular activity that was well tolerated and lasted <30 s. Programmed ventricular stimulation and recordings of electrophysiological parameters were performed Age (years) Males 18 (100%) Structural heart disease Coronary artery disease 13 (72%) Dilated cardiomyopathy 3 (17%) No organic heart disease 2 (11%) NYHA class I 5 (28%) II 9 (50%) III 4 (22%) IV 0 Left ventricular ejection fraction <40% 6 (33%) Clinical presentation Sustained ventricular tachycardia 5 (28%) Ventricular fibrillation 1 (6%) Syncope+non-sustained ventricular tachycardia 12 (66%) on ambulatory ECG before and immediately after completion of the amiodarone infusion at a dose of 5 mg. kg 1 (first 12 patients) or 10 mg. kg 1 (remaining six patients), administered at a rate of 25 mg. min 1. A dose of 10 mg. kg 1 was tested only in six patients because, at this point, the study was terminated due to lack of an immediate antiarrhythmic efficacy of intravenous amiodarone and tendency towards more frequent side effects, namely hypotension, due to the drug. Only patients with inducible sustained or non-sustained ventricular tachycardia at baseline underwent programmed ventricular stimulation following the amiodarone infusion. The mean time from termination of the amiodarone infusion to induction of sustained ventricular arrhythmia or completion of the stimulation protocol was 21 7 min (range 8 to 9 min). In patients with no arrhythmia inducible at baseline, amiodarone was infused in order to examine drug effects on spontaneous ventricular ectopy, assessed from 10 min of ECG recording. Assessment of ventricular refractoriness and repolarization The longest interval S 1 S 2 (defined to the nearest 5 ms) at which an extrastimulus S 2, introduced during pacing at a cycle length of 600, 500 and 400 ms, failed to evoke a depolarization, was termed the effective refractory period of the ventricle. Monophasic action potential recordings were performed during sinus rhythm and at the end of a 30 s period of atrial pacing at a cycle length of 600 ms. Monophasic action potential duration was measured at 90% repolarization at a paper speed of 200 mm. s 1. The amplitude was taken from baseline to the crest of

3 Effects of intravenous amiodarone 209 the plateau phase. The mean value of five consecutive measurements was calculated. The QT interval duration was measured at a paper speed of 100 mm. s 1. The corrected QT interval was calculated using Bazett s formula as QT/(sinus cycle length in s) 1/2. Assessment of intraventricular conduction Intraventricular conduction was assessed using paced- QRS duration at the cycle lengths of 600, 500 and 400 ms (the duration of the last QRS complex of each pacing train was used). In order to examine the effects of intravenous amiodarone on intraventricular conduction during premature stimulation, the QRS duration of paced extrasystolic beats (S 2 ), introduced 20 ms outside the effective refractory period, was assessed. The measurements were performed from the pacing spike to the end of a paced-qrs complex at a paper speed of 100 mm. s 1. The ECG lead (the same before and after amiodarone) with the sharpest QRS complex end (not merging with a T-wave) was chosen for analysis. Intraventricular conduction during sinus rhythm was measured as the signal-averaged QRS duration (recorded using an FD-3 solid state Holter recorder and analysed at a high pass filter setting of 40 Hz, using Excel-2 software, Oxford, UK). All electrophysiological parameters were analysed in a blinded manner before and after amiodarone infusion. Intra- and inter-observer (P.K. vs G.K.) variability was <7%. Assessment of haemodynamic parameters Heart rate and systolic blood pressure were measured before and after termination of the amiodarone infusion. Table 2 Effects of intravenous amiodarone on ventricular refractoriness and repolarization Parameter (ms) Baseline After amiodarone parameters were tested with the use of Pearson s correlation coefficient. A two-tailed P value <0 05 was required for statistical significance. Results Effects on haemodynamic parameters P value QTc interval ns ERP of RV ns Pacing at CL of 600 ms ERP of RV ns Pacing at CL of 500 ms ERP of RV ns Pacing at CL of 400 ms MAP duration ns Sinus rhythm MAP duration ns Pacing at CL of 600 ms ERP of RV=effective refractory period of right ventricle; CL=cycle length, MAP=monophasic action potential. Amiodarone infusion had no effect on the heart rate (75 11 at baseline vs beats. min 1 after amiodarone, ns), but caused a significant decrease in systolic blood pressure ( at baseline vs after amiodarone, P=0 03). Amiodarone plasma levels A blood sample for determination of the plasma levels of amiodarone and desethylamiodarone was drawn immediately after completion of the amiodarone infusion. Statistical methods Continuous variables are presented as the mean value 1 standard deviation. The paired t-test was used to compare the haemodynamic and electrophysiological parameters before and after the amiodarone infusion. The unpaired t-test was used to compare amiodaroneinduced changes in haemodynamic and electrophysiological variables between patients who received 5mg.kg 1 and 10 mg. kg 1 of amiodarone, and between patients with and without amiodarone-induced aggravation of arrhythmia. The correlations between the amiodarone dose, amiodarone plasma levels and amiodarone-induced changes in the electrophysiological Effects on ventricular refractoriness and repolarization (Table 2) Amiodarone infusion had no significant effect on either ventricular repolarization or refractoriness at any pacing cycle length. Effects on intraventricular conduction (Table 3 and Fig. 1) Amiodarone significantly increased the QRS duration at all pacing cycle lengths, both during stable pacing and during extrasystolic paced beats. Details are presented in Table 3. The magnitude of the amiodarone-induced increase in the QRS duration was significantly greater during premature ventricular stimulation than during stable pacing ( msvs ms, P=0 009, ms vs ms, P=0 03; and msvs ms, P=0 01, pacing cycle lengths of 600, 500, and 400 ms, respectively) (Fig. 1). The

4 210 P. Kułakowski et al. Table 3 Effects of intravenous amiodarone on intraventricular conduction Parameter (ms) Baseline After amiodarone P value Signal-averaged QRS duration sinus rhythm ns Paced-QRS (S 1 )durationatclof600ms Paced-QRS (S 1 )durationatclof500ms Paced-QRS (S 1 )durationatclof400ms Extrabeat paced-qrs (S 2 ) duration after a basic drive at CL of 600 ms Extrabeat paced-qrs (S 2 ) duration after a basic drive at CL of 500 ms Extrabeat paced-qrs (S 2 ) duration after a basic drive at CL of 400 ms S 1 =basic drive; S 2 =single extrastimulus; rest of abbreviations as in Table 2. Delta QRS (ms) P = P = 0 03 P = 0 01 results are summarized in Fig. 3 and the original recordings from a representative patient are presented in Fig. 2. Amiodarone-induced changes in the haemodynamic and electrophysiological parameters measured were similar in patients with and without arrhythmia aggravation CL (ms) 400 Figure 1 Comparison of the degree of amiodaroneinduced prolongation of intraventricular conduction (delta QRS) during stable pacing (S 1 ) at the cycle lengths of 600, 500 and 400 ms ( ) and during extrasystolic (S 2 ) paced- QRS ( ). signal-averaged QRS duration during sinus rhythm was similar prior to and after drug infusion (Table 3). Effects on inducibility of sustained ventricular tachycardia (Fig. 3) At baseline, five patients had inducible sustained monomorphic ventricular tachycardia, six non-sustained ventricular tachycardia, and in the remaining seven patients no ventricular arrhythmia was induced. Sustained ventricular tachycardia was haemodynamically well tolerated in all patients and was terminated by introducing one extrastimulus in two patients, and overdrive pacing in the remaining three patients. No patient had unstable ventricular tachycardia or ventricular fibrillation inducible at baseline. After the amiodarone infusion, all five patients with sustained ventricular tachycardia inducible at baseline, remained inducible. In three of these patients, the arrhythmia was not haemodynamically tolerated and required DC shock for termination. Of six patients with non-sustained ventricular tachycardia inducible at baseline, five cases of rapid hypotensive ventricular tachycardia were induced following the amiodarone infusion and required DC cardioversion (Table 4). Altogether, in eight patients, amiodarone promoted induction of sustained, unstable ventricular tachyarrhythmia. The Amiodarone effects on spontaneous ventricular ectopy in patients without inducible sustained or non-sustained ventricular tachycardia at baseline In seven patients who had no inducible ventricular arrhythmia at baseline, amiodarone had no significant effect on the frequency of spontaneous ventricular ectopic beats ( beats. 10 min 1 at baseline vs beats. 10 min 1 after amiodarone, ns). Comparison of the effects of two different doses of amiodarone on haemodynamic and electrophysiological parameters (Table 5) Amiodarone infused at a dose of 10 mg. kg 1 body weight tended to lengthen intraventricular conduction to a greater extent than 5 mg. kg 1 of amiodarone, however, the difference did not reach statistical significance. These effects were particularly evident in respect of amiodarone-induced prolongation of the QRS duration during extrasystolic beats. The changes in ventricular refractoriness were small and similar in both dosage groups. The fall in systolic blood pressure tended to be greater following administration of the higher dose of amiodarone ( mmhg after 5 mg. kg 1 of amiodarone vs mmhg after 10 mg. kg 1 of amiodarone, P=0 07). Relationship between plasma amiodarone levels and clinical and electrophysiological parameters The mean total dose of amiodarone in 12 patients receiving 5 mg. kg 1 of the drug was mg vs

5 Effects of intravenous amiodarone 211 (a) MAP 292 ms 90% of repolarization MAP 287 ms 90% of repolarization (b) S1 S1 S2 V2 S1 S1 S2 198 ms 222 ms V2 210 ms 242 ms Figure 2 a and b mg in six patients who received 10 mg. kg 1 (P=0 001). However, the mean plasma amiodarone levels were similar in the two groups ( μg.ml 1 vs μg.ml 1, respectively, ns). There was no significant difference between the total amiodarone dose and amiodarone plasma levels in patients with and without amiodarone-induced aggravation of arrhythmia ( mg vs mg, ns, and μg.ml 1 vs μg.ml 1, ns, respectively). No significant correlation was found between the total amiodarone dose or amiodarone plasma level and druginduced changes in the electrophysiological parameters measured. Desethylamiodarone was not detected in eight patients. In the remaining patients, plasma levels of desethylamiodarone were very low, not exceeding 0 09 μg.ml 1. Discussion The present study has shown that intravenous amiodarone: (1) has no immediate significant effects on ventricular refractoriness, (2) lengthens intraventricular conduction, and (3) may facilitate induction of haemodynamically unstable sustained ventricular tachycardia. Electrophysiological actions of intravenous amiodarone To date, few studies have examined the electrophysiological effects of intravenous amiodarone in patients with ventricular tachyarrhythmias [4 6]. In two studies [4,5] a dose of 5 mg. kg 1 of amiodarone had no significant effect on ventricular refractoriness, whereas Morady et al. [6] showed that 10 mg. kg 1 of amiodarone, infused at a rapid rate of 50 mg. min 1, slightly but significantly prolonged the effective refractory period of the right ventricle. The present study, using monophasic action potential recordings for the first time in such a group of patients, supports the findings of Gomes et al. [4] and Singh et al. [5] that intravenous amiodarone administered at usual doses, has no significant effect on ventricular refractoriness. The discrepancies between the findings of Morady et al. [6] and our results may be

6 212 P. Kułakowski et al. (c) I II III avr avl avf V 1 V 2 V 3 V 4 V 5 V (d) I II III avr avl avf V 1 V 2 V 3 V 4 V 5 V Figure 2 c and d. Figure 2 Original ECG tracings from a patient with dilated cardiomyopathy and a history of syncope and non-sustained ventricular tachycardia on ambulatory ECG monitoring. (a) Original monophasic action potential (MAP) recordings. Left panel. Baseline MAP duration at 90% of repolarization is 292 ms (pacing at a cycle length of 600 ms, paper speed 200 mm. sec 1, magnification 16, MAP amplitude is 10 5 mv). Right panel. After amiodarone MAP duration is 287 ms (paper speed 200 mm. sec 1, pacing at the cycle length of 600 ms, magnification 16, MAP amplitude is 6 05 mv). (b) Original ECG tracings during ventricular pacing at a cycle length of 600 ms showing amiodarone-induced prolongation of paced-qrs complex (paper speed 100 mm. sec 1 ). Left panel. At baseline, paced-qrs duration is 198 ms, and paced-extrasystolic QRS 222 ms. Right panel. After amiodarone, paced-qrs duration increased to 210 ms, and paced extrasystolic QRS increased to 242 ms. (c) A 12-lead ECG during baseline programmed ventricular stimulation. Only short runs (four QRS complexes) of polymorphic non-sustained ventricular tachycardia were induced (pacing at the cycle length of 600 ms, triple extrastimuli). (d) A 12-lead ECG during programmed ventricular stimulation on amiodarone. Sustained ventricular tachycardia (cycle length of 276 ms) was induced using triple extrastimuli during sinus rhythm. The tachycardia was haemodynamically unstable and DC shock was required. 8000

7 Effects of intravenous amiodarone 213 Table 4 Programmed ventricular stimulation data in five patients with non-sustained ventricular tachycardia at baseline and amiodarone-induced arrhythmia aggravation Patient Baseline stimulation Stimulation on amiodarone nsvt characteristics Mode of induction svt characteristics Mode of induction CL (ms) No. of QRS complexes Drive train CL (ms) No. of extrastimuli Protocol stage CL (ms) Clinical type Mode of termination Drive train CL (ms) No. of extrastimuli Protocol stage Triple XI 161 VT VF DC shock 400 Double VIII Double IV 180 VT VF DC shock 600 Double IV Triple X 205 VT VF DC shock 400 Double VIII Triple XII 199 Hypotensive VT DC shock 400 Double VIII Triple X 276 Hypotensive VT DC shock SR Triple IX nsvt=non-sustained ventricular tachycardia; svt=sustained ventricular tachycardia; CL=cycle length; no.=number; VT VF=VT rapidly degenerating into VF; DC=direct current; SR=sinus rhythm. Sustained VT n = Sustained VT or VF n = 10 Baseline PVS Non-sustained VT n = 6 PVS on amiodarone 1 Non-sustained VT n = 1 No arrhythmia n = 7 Figure 3 Results of programmed ventricular stimulation before and after amiodarone infusion. Abbreviations: PVS=programmed ventricular stimulation; VT= ventricular tachycardia; VF=ventricular fibrillation. explained in part by differences in the amiodarone infusion rate (the latter being slower in our patients) and differences in patients characteristics. It should be stressed, however, that amiodarone-induced changes in the effective refractory periods, detected by Morady et al. [6], although significant, were relatively small (from ms to ms) and the clinical importance of this finding is unclear. Another electrophysiological parameter, intraventricular conduction, was significantly lengthened following the amiodarone infusion. This effect was evident during pacing, but not during sinus rhythm, which is in agreement with the results of other studies that amiodarone-induced slowing of conduction is present during faster rates [6]. The dose of 10 mg. kg 1 of amiodarone produced a greater lengthening of intraventricular conduction than the dose of 5 mg. kg 1, which suggests that slowing of conduction following amiodarone infusion is also dose-dependent. We have also observed that prolongation of intraventricular conduction was significantly greater following closely coupled extrasystolic beats than during stable pacing, suggesting a greater influence of intravenous amiodarone on electrical restitution than on steady-state rate-dependence. This may be of clinical importance since ventricular ectopic beats may trigger sustained ventricular tachyarrhythmias. Whether this effect could contribute to the antiarrhythmic efficacy or proarrhythmic effects of intravenous amiodarone, needs to be further evaluated. The magnitude of the amiodarone-induced prolongation of intraventricular conduction is relatively small compared with class IA and IC antiarrhythmic agents [7] or prolonged oral amiodarone therapy [8] which further questions the clinical significance of this mechanism of amiodarone action. What are, then, the electrophysiological mechanisms of action of intravenous amiodarone in patients with ventricular tachyarrhythmias? It has been postulated that the efficacy of intravenous amiodarone may be attributed to its antisympathetic [4,5,9] or calcium channel blocking properties [4,5,10]. Another potential antiarrhythmic action of intravenous amiodarone may be a reduction of dispersion of repolarization and conduction velocities. This mechanism has been suggested in an animal model by Mayuga et al. [11] However, more work needs to be done to assess precisely the mechanisms of antiarrhythmic action of intravenous amiodarone. Available data suggest that class III effects of amiodarone become important only during long-term treatment whereas its immediate efficacy is attributed to class II or class IV properties. Efficacy of intravenous amiodarone during electrophysiological study Although the present study included a relatively small number of patients, some preliminary conclusions concerning the drug effects on inducibility of sustained ventricular tachyarrhythmias can be drawn. Intravenous amiodarone seems to be ineffective in preventing inducibility of sustained ventricular tachycardia and may

8 214 P. Kułakowski et al. Table 5 Absolute amiodarone-induced changes (Δ) in the electrophysiological variables studied in the 5 mg. kg 1 vs 10 mg. kg 1 dosage groups Parameter (ms) 5 mg. kg 1 10 mg. kg 1 P value Δ Signal-averaged QRS duration sinus rhythm ns Δ Paced-QRS (S 1 )durationatclof600ms ns Δ Paced-QRS (S 1 )durationatclof500ms ns Δ Paced-QRS (S 1 )durationatclof400ms ns Δ Extrabeat paced-qrs (S 2 ) duration after drive at CL of 600 ms Δ Extrabeat paced-qrs (S 2 ) duration after drive at CL of 500 ms Δ Extrabeat paced-qrs (S 2 ) duration after drive at CL of 400 ms ns Δ QTc interval ns Δ ERP of RV ns Pacing at CL of 600 ms Δ ERP of RV ns Pacing at CL of 500 ms Δ ERP of RV ns Pacing at CL of 400 ms Δ MAP duration ns Sinus rhythm Δ MAP duration ns Pacing at CL of 600 ms Abbreviations: as in Tables 2 and 3. facilitate induction of unstable sustained ventricular tachyarrhythmias in patients with baseline nonsustained ventricular tachycardia. However, the electrophysiological mechanism of that proarrhythmic action is unclear: in our study the amiodarone-induced changes in all electrophysiological parameters evaluated were similar in patients with and without proarrhythmia. One of the possible mechanisms may be amiodarone-induced hypotension, which may enhance adrenergic drive to the heart, may shorten the cycle length of ventricular tachycardia and increase the possibility of haemodynamic collapse [12]. In our study, the patients with arrhythmia aggravation tended to have a greater fall in systolic blood pressure than the patients with no proarrhythmic effects, although the difference was not statistically significant. The problem of amiodarone-induced hypotension may probably be solved, at least in part, by using water solutions instead of hypotensive dilutents polysorbate 80 and benzyl alcohol. A preliminary report has suggested such a benefit [13]. The mean time from termination of amiodarone infusion to induction of sustained ventricular arrhythmia or termination of the stimulation protocol was 21 7 min. Probably more time is needed for antiarrhythmic effects of intravenous amiodarone to occur and it is possible that antiarrhythmic action had not commenced at the time of electrophysiological testing. However, an antiarrhythmic agent which is used for acute treatment of life-threatening arrhythmias should be characterized by a rapid onset of action, occurring within seconds or a few minutes rather than hours. The present study suggests that a delay in the antiarrhythmic action of intravenous amiodarone exceeds 27 min, which is in agreement with the findings of Hohnloser et al. [14] who noticed the corrected QT interval prolongation 6 h after the start of amiodarone infusion. The data in the literature on the efficacy of intravenous amiodarone in the electrophysiology laboratory are very scarce. In the study by Morady et al. [6], in only two of eight patients with inducible sustained ventricular tachycardia at baseline, did amiodarone prevent induction of that arrhythmia. In a recent review on intravenous amiodarone no data on the effects of the drug on inducibility of ventricular tachycardia are provided [15]. The present study confirms the results of previous reports [6,16], which have documented a lack of a relationship between amiodarone plasma levels and drug efficacy or amiodarone-induced changes in electrophysiological parameters. Interestingly, in our study amiodarone plasma levels in patients who received the dose of 5 mg. kg 1 were similar to those in patients who received the higher dose of the drug. Thus, at least in the early phase of therapy with intravenous amiodarone, plasma levels should not be routinely used for the assessment of drug efficacy. Intravenous amiodarone has recently emerged as an important drug for the acute treatment of ventricular tachyarrhythmias [1 3,15]. However, due to ethical reasons, these studies were not placebo-controlled, and only in one study [1] was amiodarone directly compared with another antiarrhythmic agent, bretylium. Moreover, the doses used by other authors were similar or even smaller than those tested in the present study. Therefore, we believe that there is a need for more studies to assess precisely and definitively the electrophysiological mechanism of action and the efficacy of

9 Effects of intravenous amiodarone 215 intravenous amiodarone in prevention and termination of ventricular tachyarrhythmias. Study limitations The study group was relatively small and the results should be interpreted with caution. However, the lack of any effect of the drug on ventricular refractoriness and inducibility of sustained ventricular tachycardia as well as an increase in inducibility of sustained ventricular arrhythmias in patients with non-sustained arrhythmias at baseline are striking. Monophasic action potential recordings were performed only during sinus rhythm and during atrial pacing at the cycle length of 600 ms because at faster rates of atrial pacing or during application of extrastimuli, amiodarone-induced atrioventricular block precluded ventricular capture in a significant proportion of patients. Therefore, it cannot be excluded that amiodarone may prolong monophasic action potential duration at faster pacing rates, in a rate-dependent manner. However, this seems unlikely, since right ventricular effective refractory periods were not affected by amiodarone at any pacing rate studied. In the present study, the efficacy of amiodarone was assessed using programmed ventricular stimulation and, therefore, it may not be comparable to the efficacy of intravenous amiodarone in terminating spontaneous ventricular tachycardia or preventing spontaneous recurrences of ventricular tachyarrhythmias, recently demonstrated in multicentre United States studies [1 3]. The present study was supported by governmental research KBN grant No. 4 P05B and by research grant from the Medical Centre of Postgraduate Education, Grant No /88. References [1] Kowey PR, Levine JH, Herre JM, et al. Randomised, doubleblind comparison of intravenous amiodarone and bretylium in the treatment of patients with recurrent, hemodynamically destabilizing ventricular tachycardia or fibrillation. Circulation 1995; 92: [2] Scheinman MM, Levine JH, Cannom DS, et al. Dose-ranging study of intravenous amiodarone in patients with lifethreatening ventricular tachyarrhythmias. Circulation 1995; 92: [3] Levine JH, Massumi A, Scheinman M, et al. Intravenous amiodarone for recurrent sustained hypotensive ventricular tachyarrhythmias. J Am Coll Cardiol 1996; 27: [4] Gomes JAC, Kanf PS, Hariman RJ, El-Sherif N, Lyons J. Electrophysiologic effects and mechanisms of termination of supraventricular tachycardia by intravenous amiodarone. Am Heart J 1984; 107: [5] Singh BN, Nademanee K, Kannan R, Ikeda N. The clinical results of amiodarone in cardiac arrhythmias: optimal dosing. PACE 1984; 7: [6] Morady F, DiCarlo LA, Krol RB, Baerman JM, Buitleir de M. Acute and chronic effects of amiodarone on ventricular refractoriness, intraventricular conduction and ventricular tachycardia induction. J Am Coll Cardiol 1986; 7: 148. [7] Kulakowski P, Bashir Y, Heald S, et al. Effects of procainamide on the signal-averaged electrocardiogram in relation to the results of programmed ventricular stimulation in patients with sustained monomorphic ventricular tachycardia. J Am Coll Cardiol 1993; 21: [8] Borbola J, Denes P. Oral amiodarone loading therapy. 1. The effect on signal-averaged electrocardiographic recordings and on the QTc in patients with ventricular tachyarrhythmias. Am Heart J 1988; 115: [9] Du X-J, Murray DE, Dart AM. Sympatholytic action of intravenous amiodarone in the rat heart. Circulation 1995; 91: [10] Kojima S, Wu ST, Wikman-Coffelt J, Parmley WW. Acute amiodarone terminates ventricular fibrillation by modifying cellular Ca+ + homeostasis in isolated perfused rat hearts. J Pharm Exp Ther 1995; 275: [11] Mayuga RD, Singer DH. Effects of intravenous amiodarone on electrical dispersion in normal and ischaemic tissues and on arrhythmia inducibility: monophasic action potential studies. Cardiovasc Res 1992; 26: [12] Gough WB, Zeiler RH, Barecca P, et al. Hypotensive action of commercial intravenous amiodarone and polysorbate 80 in dogs. J Cardiovasc Pharmacol 1982; 4: [13] Gallik DM, Meissner MD, Communale M, Singer I, Hanin L. Favorable hemodynamic effects of Amio-AqueousR, a new formulation of intravenous amiodarone (Abstr). Circulation 1997; 96: [14] Hohnloser SH, Meinertz T, Demmbacher T, et al. Electrocardiographic and antiarrhythmic effects of intravenous amiodarone. Results of a prospective placebo-controlled study. Am Heart J 1991; 121: [15] Kowey PR, Marinchak RA, Rials SJ, Filart RA. Intravenous amiodarone. J Am Coll Cardiol 1997; 29: [16] Venkatesh N, Somani P, Bersohn M, et al. Electropharmacology of amiodarone: absence of relationship to serum, myocardial, and cardiac sarcolemmal membrane drug concentrations. Am Heart J 1986; 112: