Author + information
- Received August 25, 1997
- Revision received February 17, 1998
- Accepted February 25, 1998
- Published online June 1, 1998.
- Li Zhou, MD∗,
- Bonnie P Chen, PharmD∗,†,
- Jeffrey Kluger, MD, FACC∗,†,* (, )
- Chengde Fan, BS∗,† and
- Moses S.S Chow, PharmD∗,†
- ↵*Address for correspondence: Dr. Jeffrey Kluger, Division of Cardiology, Hartford Hospital, 80 Seymour Street, PO Box 5037, Hartford, Connecticut 06102-5037
Objectives. We evaluated whether the reported difference in the ventricular defibrillation threshold (DFT) between short-term intravenous and oral amiodarone is due to the effect of amiodarone’s active metabolite desethylamiodarone (DEA).
Background. Amiodarone is frequently used in patients with implantable cardioverter-defibrillator devices (ICD). Long-term oral amiodarone raises the DFT, but intravenous amiodarone has not been shown to have this effect. DEA, an active metabolite of amiodarone, has different electrophysiologic properties than its parent compound and may be responsible for the observed different effects of intravenous and oral amiodarone on DFT.
Methods. We ascertained the DFT in 24 pigs randomized to receive intravenous amiodarone, DEA or vehicle. Defibrillation was delivered through a transvenous lead system using a biphasic waveform. The DFT was determined using an up-down DFT algorithm and defined as the average minimal energies resulting in successful defibrillation delivered from ascending and descending serial shocks.
Results. Amiodarone caused a dose-response increase in DFT (mean ± SD) from 22.7 ± 4.1 (baseline) to 26.1 ± 2.9 (10 mg/kg body weight), p = 0.11, to 34.9 ± 8.2 J (after an additional 15 mg/kg), p = 0.035. DEA (10 mg/kg) caused an increase in DFT from 20.5 ± 6.3 to 33.9 ± 13.6 J, p < 0.01. Addition of 15 mg/kg of DEA resulted in hemodynamic instability and thus DFT was not obtained. In the control group, DFT decreased from 26.8 ± 7.7 at baseline to 23.1 ± 7.4 (dose 1), p = 0.19, to 22.8 ± 6.2 J (dose 2), p = 0.18.
Conclusions. DEA increases DFT by a greater amount than its parent drug amiodarone. There is an effect of intravenous amiodarone on DFT that is dose dependent.
Advances in automatic implantable cardioverter-defibrillators (ICDs) have significantly lowered the incidence of sudden cardiac death in high risk patients (1,2).
Despite its effectiveness, patients with an ICD remain at risk of developing malignant ventricular arrhythmias (2). Unlike the ICD, antiarrhythmic agents can prevent the initiation of these arrhythmias (3,4)and are often used in combination in this patient population. Although antiarrhythmic agents can reduce the frequency of ICD shocks, they may adversely effect the energy required for successful defibrillation (defibrillation threshold [DFT]) (5–8).
Amiodarone is an antiarrhythmic agent often used in patients with an ICD. The drug–device interaction between amiodarone and an ICD is controversial (9–13). Most studies have found an increase in defibrillation energy with long-term oral amiodarone, but not with intravenous therapy. One possible explanation for the observed difference between oral and intravenous amiodarone could be that single intravenous and long-term oral amiodarone have different electrophysiologic effects (14–19). The long-term effects of amiodarone therapy may be due to an active metabolite, desethylamiodarone (DEA) (20,21). We postulate that the difference in DFT between short-term intravenous and long-term oral amiodarone may be due to the accumulation of DEA after long-term therapy.
Twenty-four domestic farm pigs (mean weight 41.8 ± 4 kg) were used in the present study. The Hartford Hospital Animal Care and Use Committee approved all procedures, and the experiment was carried out in an American Association for Laboratory Animal Service (AALAS)-approved animal laboratory. After the animals were fasted overnight, they were preanesthetized with tiletamine 100 mg/zolazepam 100 mg (Telazol 2 ml) intramuscularly followed by 5% halothane gas for initial induction and intubation. The pigs were placed supine and the temperature maintained at 37° to 38°C with a thermal blanket. The animals were intubated with an endotracheal cuffed tube and mechanically ventilated (Ohio Medical Products) with room air and supplemental oxygen. After intubation and the discontinuation of halothone, a maintenance anesthetic, pentobarbital, was given at 20 mg/kg body weight bolus followed by a 10 to 15 mg/kg per h infusion. Additional anesthesia such as isoflurane was used as needed.
The right femoral and external jugular veins were cannulated for catheter insertion, drug infusion and blood collection. The right femoral artery was surgically exposed and an introducer was placed. Under fluoroscopic guidance, a pigtail catheter was inserted and advanced into the descending aorta for continuous monitoring of the arterial blood pressure. A tripolar transvenous endocardial catheter (CPI model 0060) was inserted through the external jugular vein for right ventricular pacing and defibrillation. Under fluoroscopic guidance, the distal spring electrode was positioned at the right ventricular apex and the proximal spring electrode at the junction of the superior vena cava and right atrium. The catheter tip and distal spring electrode provided pacing of the heart. The catheter was connected to a custom-built external defibrillator (Ventritex HVOS2) for ventricular defibrillation. The defibrillator utilizes a biphasic waveform (60/40) and has adjustable voltage levels from 50 to 990 V. The shock was delivered between the right ventricular cathode and the superior vena cava anode.
Arterial blood gases and serum sodium and potassium concentrations were monitored every 30 min and ventilation parameters adjusted to maintain an arterial pH of 7.35 to 7.45, and arterial partial pressure of carbon dioxide of 35 to 45 mm Hg. Normal saline and lactated Ringer solution were infused at a rate of 2 to 5 ml/kg per h to maintain adequate blood volume. Heparin, 150 U/kg bolus followed by 100 U/kg per h, was administered intravenously from the time of vessel cannulation.
Study protocol and drug administration (fig. 1)
The present study consisted of three groups (amiodarone, DEA and vehicle) and three treatment phases: baseline (phase 1), first dose drug infusion (phase 2), and second dose drug infusion (phase 3). The pigs were randomly assigned to the amiodarone, DEA or vehicle group, in a blinded manner. The defibrillation protocol described later was performed during each treatment phase. The baseline DFT protocol was begun 10 min after animal preparation. Approximately 10 min after the completion of the baseline phase protocol, the pig received a first dose of either amiodarone (10 mg/kg), DEA (10 mg/kg) or equal volume of vehicle (polysorbate 80, ethanol and water) over 10 minutes. Phase 2 DFT protocol was initiated 30 min after the completion of the first 10 mg/kg drug infusion. Ten minutes after the completion of phase 2, a second 15 mg/kg dose was administered over 10 min (DEA was infused over 20 min in two animals because of hemodynamic instability). The phase 3 DFT protocol was repeated 30 min after the completion of the second 15-mg/kg drug infusion.
Ventricular fibrillation (VF) was induced by pacing the right ventricle using a primary drive train at a cycle length of 270 ms for eight beats of 2-ms duration each. A secondary train of 20 pulses of 4-ms duration (100 Hz) immediately followed this for a total duration of 200 ms synchronized to the primary drive train with a 50-ms delay (WPI Stimulator). The intensity of the primary drive train was equal to four times the pacing threshold, and the intensity of the secondary train stimuli current was initially 2 mA, increased by 2 mA until sustained VF with hemodynamic collapse was induced. VF was allowed to continue for 6 to 8 s before defibrillation. All unsuccessful defibrillation shocks were immediately followed by an internal rescue shock of 860 V (50 J). In case of unsuccessful defibrillation with the rescue shock, paddles of an external defibrillator were applied to the pig’s chest and defibrillation was performed with 200 to 360 J. Defibrillation was successful when an organized heart rhythm and spontaneous circulation with a mean arterial pressure >60 mm Hg was observed. Defibrillation trials were performed approximately every 3 min, after arterial blood pressure and heart rate returned to baseline values.
An estimate of the DFT was first determined. After the delivery of a test shock at 600 V, pulse width was adjusted accordingly on the basis of the high voltage impedance. The initial shock was set at 600 V. If successful, the energy level of subsequent defibrillation attempts was reduced by 20% of the previous energy level until defibrillation failed. The estimated ventricular DFT was the lowest energy level achieving defibrillation. After the estimated DFT protocol, the step-down/step-up method of determining DFT was used. The step-down and step-up protocols used initial defibrillation energies that were 10% above and below the estimated DFT, respectively. Subsequent defibrillation energies were decreased or increased by 10% of the previous energy level in the step-down and step-up protocols, respectively. The step-down protocol was terminated when a single defibrillation energy was unsuccessful, requiring a rescue shock, and the step-up protocol continued (using a rescue shock after each failed defibrillation attempt) until a single defibrillation energy level was successful. Both the step-down and step-up protocols were performed twice, to obtain a total number of five DFT determinations (estimation, 2 step-down protocols and 2 step-up protocols) for each phase of the study. The energy, impedance and pulse duration of the defibrillation energy delivered to the myocardium were recorded as displayed on the Ventritex defibrillator. In the estimation, step-down and step-up protocols, DFT was defined as the lowest energy level, calculated in joules, that was successful in defibrillating the pig that preceded or followed the energy level that failed to defibrillate. The DFT values from the five trials were averaged for each treatment phase.
Electrocardiographic and electrophysiologic measurements
Surface electrocardiograms (ECGs) from leads I, II and aVF, heart rate and arterial blood pressure were monitored continuously and recorded on a 12-channel monitor (Electronics for Medicine). In addition, a 12-lead surface ECG was recorded during baseline and 30 min after each drug infusion. A single observer without knowledge of the randomization data measured the PR, QRS, QT and corrected QT (QTc) intervals on the ECG and cycle length with a fine ruler. Cycle length ventricular fibrillation (VFCL) was obtained from measurements from the last 2 s of VF before defibrillation. The ventricular effective refractory period (VERP) was determined after an 8-beat train at a 270-ms paced cycle length.
Amiodarone and DEA serum concentrations
After the first and second dose of amiodarone, DEA or vehicle, 6 ml of blood was obtained at 3, 15, 30, 60 and 90 min after drug infusion. The samples were centrifuged, and serum was collected and frozen at −20°C until analysis. A high performance liquid chromatographic technique was used to analytically quantitate amiodarone and DEA concentrations (22).
Mean values from each treatment phase were compared within groups using two-way analysis of variance. When significant differences were observed, a single factor analysis of variance was performed. A p value <0.05 was considered statistically significant. When significance was obtained with the single-factor analysis of variance, the Tukey honest significant difference test was used to compare the different means. Results are expressed as mean value ± SD.
Twenty-four pigs completed phase 1 and phase 2 of the protocol; however, seven of the eight animals randomized to the DEA group did not complete the second DEA dose infusion (phase 3). Five animals in the DEA group developed severe hypotension and bradycardia and died. Only one animal completed phase 3 from the DEA group. The data from phase 3 of that pig are not presented.
Ventricular DFTs (table 1)
In the amiodarone group, the DFT was increased from baseline to dose 1 by 15% (p = 0.106) and from dose 1 to dose 2 by 39% (p = 0.031). In the DEA group, the DFT was significantly increased from baseline to dose 1 by 65% (p < 0.01). In the control group, the DFT was decreased from baseline to dose 1 by 14% (p = 0.186) and dose 2 by 15% (p = 0.178).
Between group differences were determined by single-factor analysis of variance and multiple comparison tests comparing the mean changes in the DFT in the different groups (Table 1). The changes in the DFT from baseline to dose 1 of amiodarone were significantly greater than vehicle alone (3.4 ± 5.1 vs. −3.7 ± 7.2 J, p = 0.039); and from baseline to amiodarone dose 2 than the corresponding dose of vehicle (12.2 ± 7.8 vs. −4.0 ± 7.5 J, p < 0.01). Differences in the DFT from baseline to dose 1 of DEA were significantly greater than the changes in the DFT from baseline to dose 1 of vehicle (13.4 ± 10.2 vs. −3.7 ± 7.2 J, p = 0.043). In addition, changes of DFT from baseline to dose 1 of DEA were also significantly higher than in the amiodarone group (13.4 ± 10.2 vs. 3.4 ± 5.1 J, p = 0.027).
Hemodynamic effects (table 4)
In the amiodarone group the mean blood pressure was significantly lower from baseline to dose 2 by 13% (p = 0.013), but not when compared with dose 1 or from dose 1 to dose 2. There was no significant difference in mean blood pressure from baseline to dose 1 in the DEA group. In the control group there was a significantly lower mean blood pressure of 9% from dose 1 to dose 2 (p = 0.014), but no change from baseline to dose 1 or baseline to dose 2. In addition, the mean blood pressures were similar between control and amiodarone groups at baseline and dose 1 and dose 2, as well as between control and DEA groups and amiodarone and DEA groups. There was no significant correlation in the percent change in mean blood pressure compared with percent change in DFT in any of the three groups (Fig. 2).
ECG and electrophysiologic variables (table 5)
In the amiodarone group, the QTc and RR intervals, VFCL and VERP were significantly increased from baseline to dose 1 by 6% (p < 0.001), 22% (p < 0.001), 24% (p < 0.001) and 12% (p = 0.017), respectively. These variables also significantly increased from baseline to dose 2 by 7% (p < 0.01), 40% (p < 0.0001), 39% (p < 0.0001) and 29% (p = 0.022), respectively. In addition, RR intervals and VFCL were further increased from amiodarone dose 1 to dose 2 by 14% (p = 0.023) and 11% (p < 0.01), respectively. There were no significant changes in QRS intervals during the treatment phases in the amiodarone group.
In the DEA group, the QRS and QTc intervals, VFCL and VERP were significantly increased from baseline to after DEA dosing by 24% (p = 0.01), 7% (p = 0.049), 32% (p < 0.001) and 16% (p = 0.018), respectively. The RR intervals did not change significantly in the DEA group.
In the control group, there were no significant changes from baseline in the RR, QRS or QTc intervals, VFCL or VERP during the vehicle phases.
Despite changes in QTC and VERP after amiodarone dose 1 and dose 2, there was no correlation between those values and changes in DFT (r = 0.0008 and 0.0975, respectively, p = 0.99 and p = 0.69, respectively). Similarly, the increase in VERP after DEA did not correlate with DFT (r = 0.175, p = 0.71).
Serum drug concentrations (table 6)
Seven pigs in the amiodarone group had serum amiodarone and DEA concentrations measured after both dose 1 and dose 2. All animals in the DEA groups had serum DEA measured. The amiodarone concentrations remained relatively constant at 0.78 ± 0.4 to 0.61 ± 0.3 and 1.42 ± 0.7 to 1.25 ± 0.6 μg/ml at 60 and 90 min after the first and second dose of amiodarone, respectively. These concentrations corresponded to the approximate time of the DFT determinations. The DEA concentrations after amiodarone administration (i.e., converted from amiodarone) were constant at 0.044 ± 0.024 to 0.046 ± 0.021 μg/ml after 60 to 90 min after the first dose of amiodarone and remained low but significantly higher at 0.095 ± 0.054 to 0.092 ± 0.055 μg/ml after the second dose of amiodarone. In the DEA group, the DEA concentrations were 0.49 ± 0.3 to 0.34 ± 0.2 μg/ml after 60 to 90 min.
Amiodarone and DEA effects on ventricular DFTs
The present study demonstrates that DEA has greater effects on DFT than its parent drug amiodarone. DEA increased the DFT by 65% from baseline, compared with a reduction in DFT of 14% in the control group. Amiodarone increased the DFT by 15% from baseline after the first dose of 10 mg/kg and by 54% from baseline after an additional 15 mg/kg (cumulative dose of 25 mg/kg). The increase in DFT with intravenous amiodarone appeared to be concentration dependent. Significant increases in DFT only occurred with amiodarone plasma concentrations of 1.42 ± 0.7 μg/ml and not with a concentration of 0.78 ± 0.4 μg/ml. Although there was a significant increase in the concentrations of DEA converted from amiodarone from dose 1 to dose 2, it is unlikely that the increase in DFT was caused by the presence of DEA converted from amiodarone, because DEA concentrations were only 0.095 ± 0.054 to 0.092 ± 0.055 μg/ml. On the basis of amiodarone concentration and DFT effect, at the amiodarone therapeutic range of 1.0 to 2.5 μg/ml (23,24)after long-term oral dosing in patients, amiodarone can contribute to the increase in DFT. Also, in the present study the DFT dramatically increased in the DEA group, with DEA plasma levels of 0.49 ± 0.3 μg/ml; levels that are readily achieved during oral amiodarone therapy (13,24). These results suggest that the observed increased DFT after long-term oral amiodarone dosing may be due to both amiodarone and DEA concentrations (8–10,12,13,25).
Some animal experiments have reported conflicting results in the effects of intravenous amiodarone on DFT (10–12). We report a modest change in DFT after 10 mg/kg of amiodarone, which corroborates the observation by Arredondo et al. (10)who reported that 10 mg/kg of intravenous amiodarone increased DFT by 32%. Frame (12)did not observe any changes in DFT after a lower dose (5 mg/kg) of amiodarone, which is consistent with our observed dose-dependent effect of amiodarone on DFT. In contrast, Fain et al. (11)found that DFT decreased by 22% after the administration of 10 mg/kg of amiodarone. The reasons for these differences are not readily apparent but may relate to different experimental models, shock waveforms used and species differences.
Proposed mechanisms for amiodarone and DEA effects on DFT
The mechanisms responsible for the DFT changes in amiodarone and DEA are unknown. Agents that slow ventricular conduction have been shown to increase DFT (5–7,26,27). Amiodarone and DEA slow conduction velocity of the Purkinje and ventricular muscle fibers (28–30). Therefore, the observed effects of amiodarone and DEA in the present study may be due to sodium channel blocking action. In addition, DEA has been shown to slow ventricular conduction to a greater extent than amiodarone (20).
Drugs that prolong repolarization by blocking outward potassium channels can decrease DFT (31). Although QTc and VERP were increased after administration of intravenous amiodarone at both the 10-mg/kg and additional 15-mg/kg doses, we observed an increase in DFT. This observation differs from the suggestion of Ujhelyi et al. (32)that drugs that increase repolarization decrease the DFT independent of sodium channel blockade.
Another relevant observation in the present study was the dose-dependent reduction in heart rate with amiodarone. This effect is consistent with amiodarone’s noncompetitive beta-adrenergic blocking effects (23,24). Ruffy et al. (33)has demonstrated that the beta blocker propranolol increased DFT. Thus, the beta-adrenergic blocking effects of amiodarone may contribute to its effect on increasing DFT (33).
Although amiodarone caused a significant decrease in mean blood pressure, this did not correlate with changes in DFT as previously suggested (34).
The defibrillation system used in the present study represents one manufacturer and may be different from a patient’s ICD. It was previously demonstrated that DFTs were affected by the type of waveforms delivered and the defibrillation system itself (35). In addition, a porcine model with a healthy cardiovascular system may not be directly applicable to humans.
The present investigation did not directly measure the action potential duration or ventricular conduction velocity to better address the mechanism for the observed changes on DFT.
The importance of DFTs has been highlighted by the significant increase in sudden cardiac death in ICD recipients who had marginal DFTs at implantation (36). Because amiodarone is frequently used in this patient population, the results of our study may have clinical importance. In the present study, low dose intravenous amiodarone (10 mg/kg) modestly increased DFT, which may not be clinically significant. However, the high cumulative dose (25 mg/kg) of amiodarone and DEA significantly increased the DFT at serum concentrations achieved clinically. These results suggest that high intravenous doses of amiodarone and long-term oral amiodarone therapy with the accumulation of DEA may alter the DFT in patients with ICDs.
☆ This study was supported by a grant from Wyeth Ayerst Laboratories, Philadelphia, Pennsylvania. Cardiac Pacemaker Inc., St. Paul, Minnesota and Ventritex, Sunnyvale, California, respectively, provided the leads and defibrillation equipment used in this study.
- defibrillation threshold
- electrocardiogram, electrocardiographic
- implantable cardioverter-defibrillator
- corrected QT interval
- ventricular effective refractory period
- ventricular fibrillation
- cycle length ventricular fibrillation
- Received August 25, 1997.
- Revision received February 17, 1998.
- Accepted February 25, 1998.
- by the American College of Cardiology
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