LABORATORY INVESTIGATION VENTRICULAR FIBRILLATION Effects of encainide and its metabolites on energy requirements for defibrillation

Encainide, a class IC antiarrhythmic agent, has been associated with proarrhythmic responses of ventricular tachycardia and fibrillation requiring defibrillation in patients. We examined the short-term effects of intravenous encainide and its two major metabolites, O-demethyl-encainide (ODE) and 3-methoxy-ODE (MODE), on the energy requirements for successful defibrillation in 25 pentobarbital-anesthetized, open-chest dogs. Truncated exponential (60% tilt) defibrillation shocks were administered through right atrial spring and left ventricular epicardial patch electrodes identical to those used in man with the automatic implantable defibrillator. At baseline multiple shocks of varying energy were applied to construct curves of percent successful defibrillation as a function of energy (DF curves) for each animal. Encainide, ODE, or MODE was then infused in loading and maintenance doses to achieve QRS widening of 20% to 50%. Saline was administered to animals serving as controls. Determination of the DF curve was repeated, after which the infusion was discontinued. After 1 hr washout period, an additional DF curve was constructed. The data were analyzed by logistic regression, and the energies required for 50% successful defibrillation (E50) were compared. No significant differences existed between the four groups in body or heart weight, extent of QRS widening, or baseline E50 values. After administration of encainide and ODE, the E50 increased by 129 ± 43% (p < .001) and 76 + 34% (p < .005), respectively. Return of E50 toward baseline was observed after the washout periods in both groups (p < .025), demonstrating the reversibility of the drugs' effects. No significant increase in E50 was observed after administration of MODE, and the results were not statistically different from those in the control group. We conclude that both encainide and ODE greatly increase the energy required for successful defibrillation, while MODE does not exert a significant effect. Also, their effect on defibrillation cannot be predicted by plasma drug concentration, extent of QRS widening, or increase in ventricular refractoriness. Circulation 73, No. 6, 1334-1341, 1986. ENCAINIDE is a potent class IC antiarrhythmic drug that is effective in the treatment of ventricular ectopy'4 and ventricular tachycardia refractory to conventional drug therapy.7-'"When administered by short-term infusions to anesthetized dogs'2 and man,'3 encainide prolongs His-Purkinje system and intraventricular conduction, while not significantly altering atrioventricuFrom the Division of Cardiology, Stanford University Medical Center, Stanford, CA. Supported in part by a gift from Intec Systems, Inc., Pittsburgh. Address for correspondence: Roger A. Winkle, M.D., Cardiovascular Medicine, 770 Welch Rd., Suite 100, Palo Alto, CA 94304. Received June 21, 1985; revision accepted March 20, 1986. Eric Fain is an American Heart Association Medical Student Research Fellow. Dr. Dorian is supported by a grant from the Medical Research Council of Canada. His present address is: Division of Cardiology, Toronto Western Hospital, Toronto, Canada M5T 2S8. Dr. Davy is supported by a grant from the Foundation pour La Recherche Medicale. His present address is: Service de Cardiologie, Hopital A. Beclere, 157 rue de la Porte de Trivaux, 92141 Clamart, France. lar nodal function or ventricular refractory periods. During long-term oral therapy, encainide is metabolized to two major metabolites, O-demethyl encainide (ODE) and 3-methoxy-O-demethyl encainide (MODE), which accumulate in the plasma to steadystate concentrations fivefold higher than those of the parent drug.'4 The electrophysiologic effects of longterm oral therapy differ from those observed after short-term intravenous administration in that atrioventricular nodal, His-Purkinje, and intraventricular conduction are depressed and atrial and ventricular refractoriness are increased after long-term oral encainide.'5 These differences are thought to be due to the accumulation ofODE and MODE,"I ' which are also believed to be responsible in part for encainide's antiarrhythmic action.4' 6, 9. 1, 15, 16 Alteration of energy requirements for successful defibrillation by antiarrhythmic drugs has become increasingly important with the introduction and success CIRCULATION 1334 by gest on A ril 7, 2017 http://ciajournals.org/ D ow nladed from LABORATORY INVESTIGATION-VENTRICULAR FIBRILLATION of the automatic implantable cardioverter/defibrillator, since the majority of patients receiving this device will undergo concurrent drug therapy for control of their arrhythmias. Past studies have shown that antiarrhythmic drugs such as lidocaine, quinidine, clofilium, bretylium, propranolol, and procainamide have differing effects on defibrillation, with some increasing, some decreasing, and others having no significant effect on energy requirements. 1-21 The defibrillator has the capacity to deliver only a limited amount of energy, and a drug that has the potential to cause the maximum available energy to be unsuccessful in defibrillating the patient could be responsible for the ultimate failure of the device, while agents decreasing energy requirements would improve its effectiveness. Encainide has been associated with an arrhythmogenic response of sustained ventricular tachycardia or ventricular fibrillation in a significant number of patients.4 10,22 24 Many of these tachyarrhythmias have been difficult to terminate by electrical defibrillation. Therefore, we attempted to determine the effects of encainide, ODE, and MODE on defibrillation with an internal lead system identical to that used with the automatic implantable cardioverter/defibrillator. Materials and methods Animal preparation. The experiments were conducted in 25 mongrel dogs of both sexes weighing 16.6 to 28.2 kg (mean 21.8 + 2.9) that were premedicated with 2 mg/kg body weight intramuscular morphine and anesthetized with 20 to 25 mg/kg body weight intravenous sodium pentobarbital. Additional doses of approximately 100 mg/hr were administered as required to maintain a level of surgical anesthesia. Previous work by Babbs25 has demonstrated that the ventricular defibrillation "threshold" is not significantly affected by anesthesia with sodium pentobarbital. The dogs were ventilated with humidified room air by a Harvard respirator pump. Normal saline was infused at a rate of 2 to 5 ml/kg/hr to prevent volume depletion. A polyethylene catheter in the femoral artery allowed continuous monitoring of systemic arterial pressure and blood sampling. The femoral vein of each dog was cannulated for the infusion of drug or placebo (saline). Arterial blood gases (pH, 02, and CO2 tension) were determined every 30 min by a Coming 165 pH/blood gas analyzer and the rate and volume of respiration was adjusted to maintain oxygen tension greater than 85 mm Hg and pH between 7.36 and 7.44. Sodium bicarbonate was administered when necessary. Electrocardiographic leads I, II, and aVF were monitored and displayed along with systemic pressure on a Beckman Instruments oscilloscope. Intravenous succinylcholine (Anectine, 20 mg/ml), 1 mg/kg, was given before opening the chest cavity. A left thoractomy was performed through the fourth intercostal space, and the heart was suspended in a pericardial cradle. The internal defibrillating lead system, identical to the type used with the Intec Systems AID-B, was then implanted. A 13.5 cm2 titanium mesh patch electrode (cathode) was sutured directly to the epicardial surface of the left ventricle. A titanium spring lead (anode) with approximately 10 cm2 surface area was inserted into the right atrium via the right atrial appendage. The stimulating/fibrillating electrode consisted of two 1.5 mm diameter 80% platinum, 20% iridium electrodes embedded 1 cm apart in acrylic, and was sutured to the right ventricular epicardium. Measurements. All ventricular fibrillation/defibrillation trials were recorded on a Gould ES 10000 Electrostatic Recorder at paper speeds of 5 to 25 mm/sec. QRS intervals from surface electrocardiographic leads were measured at 250 mm/sec. After 2 min of constant right ventricular pacing at a basic cycle length of 300 to 400 msec, programmed premature extrastimuli (S2) at twice late diastolic threshold were introduced after every eighth paced beat (S,). The longest SI-S2 interval (to the nearest 2 msec) at which S2 consistently failed to capture the ventricle was considered the ventricular effective refractory period (VERP). At the conclusion of the experiment the heart was removed and its weight was recorded. Fibrillation/defibrillation trials. Fibrillation was induced by a 1 to 2 sec train of rectified 60 Hz elecrical current of 10 to 15 V via the right ventricular epicardial electrode. The internal lead system was connected to a battery-operated external cardioverter-defibrillator (Intec Systems, Pittsburgh, PA) that could be preset to deliver an amount of energy variable from 1 to 40 J in 1 to 2 J increments. The defibrillating pulse was a truncated exponential with 60% tilt. The shock was delivered through a 0.25 Q1 resistor in series with the internal lead system and the waveform was displayed on a Tektronix 7623A storage oscilloscope. The peak current, end current, and duration of the pulse were recorded for each trial to allow calculation of delivered energy. The heart was allowed to fibrillate for a total of 15 sec before the defibrillating shock was given. When defibrillation was unsuccessful a rescue shock of higher energy (up to 30 J) followed in less than 10 sec. A backup Hewlett-Packard 7802C defibrillator with a capacity to deliver up to 400 J through 5 cm paddles applied directly to the heart was used if necessary. Fibrillation/defibrillation trials were performed every 3 min during each phase, and only the first shock was used for analysis. Protocol. The experiment was divided into three phases. Baseline phase. Five energy levels in 1 to 2 J increments were chosen based on the animal's weight and our past experience. Each of these five energy levels was tested five times in balanced random order by referring to a standard table of random numbers. 26 Drug phase. A drug or saline loading dose was given over 20 min, immediately followed by a maintenance infusion that was administered until completion of the drug phase. Four of the five energy levels used in the baseline phase, which optimally defined the baseline percent successful defibrillation vs energy curve, were chosen to be retested in this phase of the experiment. After the loading dose and 10 min of the maintenance infusion, each of these energies was applied five times in balanced random order for a total of 20 trials. The drug phase was terminated prematurely if twice during the drug infusion the heart could not be defibrillated with repeated rescue shocks of up to 30 J and higher energy shocks (50 to 100 J) via the direct heart defibrillating paddles of the backup defibrillator were required. Washout phase. At the conclusion of the drug phase the maintenance infusion was discontinued and no shocks were administered. After 60 min three of the four energy levels used in the drug phase were each administered five times in balanced random order for a total of 15 trials (in two dogs receiving encainide only two energy levels were used). Drug infusions. Initial estimation of encainide, ODE, and MODE dosages was based on previous pharmacokinetic and electrophysiologic studies27 and were titrated as needed to achieve a QRS interval increase of 20% to 50%. The drugs were administered at the following infusion rates (loading and mainVol. 73, No. 6, June 1986 1 335 by gest on A ril 7, 2017 http://ciajournals.org/ D ow nladed from