Takotsubo cardiomyopathy and flecainide toxicity: a case report and brief literature review.

OBJECTIVE: Takotsubo syndrome, also known as stress cardiomyopathy, is predominantly reported in postmenopausal women and it is often triggered by a physical or emotional stressor. CASE REPORT: We present the case of a 44-year-old Caucasian woman admitted to the emergency department after voluntary intake of 20 tablets of flecainide 150 mg to commit suicide. During the in-hospital stay in the Cardiac Intensive Care Unit, the patient developed Takotsubo syndrome. CONCLUSIONS: The relative role of flecainide as a possible trigger of the syndrome is discussed in the context of the current literature evidence.

Flecainide-induced QRS complex widening correlates with negative inotropy.

BACKGROUND: The negative inotropic effect of Class IC antiarrhythmic drugs limits their use for acute cardioversion of atrial fibrillation (AF). OBJECTIVE: The purpose of this study was to examine, in an intact porcine model, the effects of pulmonary and intravenous (IV) administration of flecainide on left ventricular (LV) contractility and QRS complex width at doses that are effective in converting new-onset AF to sinus rhythm. METHODS: Flecainide (1.5 mg/kg bolus) was delivered by intratracheal administration and compared to 2.0 mg/kg 10-minute IV administration (European Society of Cardiology guideline) and to 0.5 and 1.0 mg/kg 2-minute IV doses in 40 closed-chest, anesthetized Yorkshire pigs. Catheters were fluoroscopically positioned in the LV to monitor QRS complex width and contractility and at the bifurcation of the main bronchi to deliver intratracheal flecainide. RESULTS: Peak flecainide plasma concentrations (Cmax) were similar, but the 30-minute area under the curve (AUC) of plasma levels was 1.4- to 2.8-fold greater for 2.0 mg/kg 10-minute IV infusion than for the lower, more rapidly delivered intratracheal and IV doses. AUC for LV contractility (ie, negative inotropic burden) was 2.2- to 3.6-fold greater for 2.0 mg/kg 10-minute IV dose than for the lower, more rapidly delivered doses. QRS complex widening by flecainide was highly correlated with the decrease in LV contractility (r2 = 0.890, P <.0001, for all IV doses; r2 = 0.812, P = .01, for intratracheal flecainide). CONCLUSION: QRS complex widening in response to flecainide is strongly correlated with decrease in LV contractility. Rapid pulmonary or IV flecainide delivery reduces the negative inotropic burden while quickly achieving Cmax levels associated with conversion of AF.

Fast and furious: flecainide toxicity presenting as monomorphic ventricular tachycardia.

A 63-year-old woman on flecainide, furosemide, and triamterene-hydrochlorothiazide presented with weakness and diarrhoea. She had profound hyponatraemia, hypokalaemia and a pre-renal acute kidney injury (AKI). Her ECG showed a regular wide complex tachycardia concerning for monomorphic ventricular tachycardia. She was haemodynamically stable and treated with aggressive electrolyte repletion and amiodarone. Flecainide toxicity can present as a variety of arrhythmias and early recognition is crucial. This case focuses on flecainide toxicity from multiple concomitant insults: diuretic use, diarrhoea, hypokalaemia, hyponatraemia and pre-renal AKI. We emphasise the importance of close outpatient monitoring of electrolytes in a patient on diuretics and flecainide to prevent life-threatening arrhythmias. We discourage use of multiple diuretics in patients taking flecainide.

Flecainide toxicity: a presentation to the emergency department with literature review.

Flecainide toxicity can result in increased cardiovascular instability which can significantly alter patient outcome if not recognised early. In this case report, the management of a 68-year-old woman who took an unintentional overdose of flecainide is detailed. We look at the management she received in the emergency department and her successful recovery and follow-up since the admission. In addition, the case report outlines the ECG changes that are most commonly documented in flecainide overdose and reviews the frequently used treatment methods for the overdose as summarised in current literature.

Renal failure, shock, and loss of pacemaker capture: A case of flecainide intoxication.

Flecainide intoxication is a severe intoxication that can lead to cardiogenic shock. We report on a 68-year-old female patient, who presented with a flecainide intoxication in the setting of renal failure. She was managed with invasive supportive therapy at the ICU and infusion of sodium bicarbonate and intravenous lipid emulsion (ILE, intralipid 20%), after which she made a complete recovery.

Digitalis Promotes Ventricular Arrhythmias in Flecainide- and Ranolazine-Pretreated Hearts.

A post hoc analysis of the PALLAS trial suggested life-threatening interactions of digitalis and dronedarone. Thus, there is concern about an interplay between digitalis and other drugs that influence cardiac electrophysiology. We therefore investigated the interaction between digitalis and flecainide or ranolazine. Twenty-five rabbit hearts were Langendorff-perfused and treated with flecainide (2 µM, 12 hearts) or ranolazine (10 µM, 13 hearts). Infusion of flecainide prolonged mean action potential duration [APD90, from 153 ms (interquartile range (IQR): 29.7 ms) to 159 ms (IQR: 24.9 ms, p = 0.04)] and effective refractory period [ERP, 170 ms (IQR: 40 ms) vs. 200 ms (IQR: 32.5 ms, p < 0.01)]. Administration of ranolazine prolonged APD90 [144 ms (IQR: 34.3 ms)) vs. 157 ms (IQR: 31.2 ms, p < 0.01)] and ERP [180 ms (IQR: 40 ms) vs. 200 ms (IQR: 30 ms, p < 0.01)]. Additional infusion of the digitalis glycoside ouabain (0.2 µM) abbreviated APD90 and ERP in both groups (flecainide: APD90: to 128 ms (IQR: 19 ms), ERP: to 170 ms (IQR: 20 ms), p < 0.01 each; ranolazine: APD90: to 141 ms (IQR: 40 ms), ERP: to 160 ms (IQR: 30 ms), p < 0.01 each). Ventricular vulnerability was assessed by a pacing protocol employing premature extra stimuli and burst stimulation. No proarrhythmic effect was observed with flecainide (1 vs. 3 episodes at baseline) or ranolazine (3 vs. 11 episodes at baseline). However, further infusion of ouabain had a proarrhythmic effect for both drugs (flecainide: 15 episodes, p = 0.04; ranolazine: 21 episodes, p = 0.09). Concomitant treatment of the sodium channel blockers flecainide or ranolazine with digitalis seems to be proarrhythmic. Abbreviation of repolarization and refractoriness that can facilitate re-entry was found as underlying mechanism.

Effects of Na+ channel blockers on extrasystolic stimulation-evoked changes in ventricular conduction and repolarization.

Antiarrhythmic agents which belong to class Ia (quinidine) and Ic (flecainide) reportedly increase propensity to ventricular tachyarrhythmia, whereas class Ib agents (lidocaine and mexiletine) are recognized as safe antiarrhythmics. Clinically, tachyarrhythmia is often initiated by a premature ectopic beat, which increases spatial nonuniformities in ventricular conduction and repolarization thus facilitating reentry. This study examined if electrical derangements evoked by premature excitation may be accentuated by flecainide and quinidine, but unchanged by lidocaine and mexiletine, which would explain the difference in their safety profile. In perfused guinea pig hearts, a premature excitation evoked over late repolarization phase was associated with prolonged epicardial activation time, reduced monophasic action potential duration (APD), and increased transepicardial dispersion of the activation time and APD. Flecainide and quinidine increased conduction slowing evoked by extrasystolic stimulation, prolonged APD, and accentuated spatial heterogeneities in ventricular conduction and repolarization associated with premature excitation. Spontaneous episodes of nonsustained monomorphic ventricular tachycardia were observed in 50% of heart preparations exposed to drug infusion. In contrast, lidocaine and mexiletine had no effect on extrasystolic stimulation-evoked changes in ventricular conduction and repolarization or arrhythmic susceptibility. These findings suggest that flecainide and quinidine may promote arrhythmia by exaggerating electrophysiological abnormalities evoked by ectopic beats.

Hypertonic sodium bicarbonate versus intravenous lipid emulsion in a rabbit model of intravenous flecainide toxicity: no difference, no sink.

CONTEXT: The use of intravenous lipid emulsion (ILE) as an antidote in non-local, anaesthetic drug toxicity has generated considerable interest. Flecainide is a lipophilic anti-arrhythmic with a significant cardiotoxic profile, with blockade of sodium and potassium channels causing arrhythmias and shock in severe toxicity. ILE has been proposed as a treatment option in severe flecainide toxicity refractory to other modalities. OBJECTIVE: We compared the effects of ILE and hypertonic sodium bicarbonate in a rabbit model of flecainide toxicity. MATERIALS AND METHODS: Twenty sedated and ventilated New Zealand White Rabbits received flecainide infusion titrated to a mean arterial pressure (MAP) of 60% baseline, which was defined as toxicity. The rabbits then received either sodium bicarbonate or ILE, and the flecainide infusion was reduced in an attempt to model ongoing enteric absorption. MAP and heart rate were recorded every minute for 15 min and plasma flecainide concentration was measured at toxicity and 15 min. ECG QRS duration was recorded at baseline, toxicity and at 5, 10 and 15 min post-toxicity. RESULTS: No difference was observed in heart rate (p = 0.2804), MAP (p = 0.1802) or QRS duration (p = 0.7471) between groups. The immediate rate of rise in MAP was greatest in the bicarbonate group in the 5 min immediately post-toxicity. CONCLUSIONS: In this study, no differences were observed between an active control of hypertonic sodium bicarbonate and ILE for the primary endpoint of MAP at 15 min nor for QRS duration at any timepoint. There was a transient rapid increase in blood pressure seen in the sodium bicarbonate group that was not sustained. No increase was seen in blood concentration of flecainide in the ILE group, suggesting no 'lipid sink' for flecainide in this model. More research is warranted to define any role for ILE in flecainide toxicity.

Detecting drug-induced prolongation of the QRS complex: new insights for cardiac safety assessment.

BACKGROUND: Drugs slowing the conduction of the cardiac action potential and prolonging QRS complex duration by blocking the sodium current (I(Na)) may carry pro-arrhythmic risks. Due to the frequency-dependent block of I(Na), this study assesses whether activity-related spontaneous increases in heart rate (HR) occurring during standard dog telemetry studies can be used to optimise the detection of class I antiarrhythmic-induced QRS prolongation. METHODS: Telemetered dogs were orally dosed with quinidine (class Ia), mexiletine (class Ib) or flecainide (class Ic). QRS duration was determined standardly (5 beats averaged at rest) but also prior to and at the plateau of each acute increase in HR (3 beats averaged at steady state), and averaged over 1h period from 1h pre-dose to 5h post-dose. RESULTS: Compared to time-matched vehicle, at rest, only quinidine and flecainide induced increases in QRS duration (E(max) 13% and 20% respectively, P<0.01-0.001) whereas mexiletine had no effect. Importantly, the increase in QRS duration was enhanced at peak HR with an additional effect of +0.7 ± 0.5 ms (quinidine, NS), +1.8 ± 0.8 ms (mexiletine, P<0.05) and +2.8 ± 0.8 ms (flecainide, P<0.01) (calculated as QRS at basal HR-QRS at high HR). CONCLUSION: Electrocardiogram recordings during elevated HR, not considered during routine analysis optimised for detecting QT prolongation, can be used to sensitise the detection of QRS prolongation. This could prove useful when borderline QRS effects are detected. Analysing during acute increases in HR could also be useful for detecting drug-induced effects on other aspects of cardiac function.

Pediatric flecainide toxicity from a double dose.

A 23-month-old boy was brought to the emergency department of an adult and pediatric tertiary care center 1 hour after an inadvertent "double dose" of 120 mg flecainide (9.2 mg/kg). His electrocardiogram revealed sinus rhythm with a terminal R wave in aVR greater than 7 mm, a bifascicular block, and prolonged QRS and QTc intervals. A dramatic improvement in the bifascicular block and terminal R wave occurred after the administration of sodium bicarbonate. He was discharged after 36 hours with no complications. This case demonstrates that flecainide can cause significant cardiac conduction disturbances in doses much lower than previously described. All supratherapeutic ingestions should be assessed in hospital.

Intoxicación por flecainida / Flecainide poisoning

La flecainida es un antiarrítmico que actúa bloqueando los canales de sodio durante la fase 0 del potencial de acción, retardando la conducción cardiaca y disminuyendo la contractilidad. La intoxicación por este fármaco es muy infrecuente, con un inicio de acción rápido en forma de hipotensión y arritmias cardiacas y una alta mortalidad. No existe antídoto y su tratamiento está basado en la experiencia de los escasos casos descritos. Tanto la insuficiencia renal como hepática pueden alterar el metabolismo de la flecainida, lo que ocasiona acúmulo de la misma. Es recomendable no utilizar flecainida en este tipo de casos a menos que los beneficios claramente superen los riesgos de su utilización. En tales casos es indispensable la vigilancia clínica, electrocardiográfica y hemodinámica, así como la monitorización de niveles plasmáticos. Presentamos un caso de intoxicación por flecainida para tratamiento de fibrilación auricular en un paciente con un cuadro séptico en resolución, que sufría afectación hepática y renal(AU)

Flecainide is an antiarrhythmic drug that blocks sodium channels during phase 0 of cardiac action potential, delaying conduction and reducing contractility. Intoxication by this drug is rare. Onset of effect, which is rapid, takes the form of hypotension and cardiac arrhythmias; mortality is high. No antidote is available and management is based on the few cases that have been reported. The metabolism of flecainide is affected by both kidney and liver failure, which lead to accumulation of the drug. Flecainide should not be used in patients with such failure unless the potential benefits clearly outweigh the risks. If flecainide is prescribed, diligent clinical, electrocardiographic, and hemodynamic vigilance is imperative and plasma levels of the drug should be monitored. We report a case of flecainide poisoning in which the drug was prescribed to treat atrial fibrillation in a man with resolving sepsis with renal and hepatic complications(AU)

Criteria for arrhythmogenicity in genetically-modified Langendorff-perfused murine hearts modelling the congenital long QT syndrome type 3 and the Brugada syndrome.

The experiments investigated the applicability of two established criteria for arrhythmogenicity in Scn5a+/Delta and Scn5a+/- murine hearts modelling the congenital long QT syndrome type 3 (LQT3) and the Brugada syndrome (BrS). Monophasic action potentials (APs) recorded during extrasystolic stimulation procedures from Langendorff-perfused control hearts and hearts treated with flecainide (1 microM) or quinidine (1 or 10 microM) demonstrated that both agents were pro-arrhythmic in wild-type (WT) hearts, quinidine was pro-arrhythmic in Scn5a+/Delta hearts, and that flecainide was pro-arrhythmic whereas quinidine was anti-arrhythmic in Scn5a+/- hearts, confirming clinical findings. Statistical analysis confirmed a quadratic relationship between epicardial and endocardial AP durations (APDs) in WT control hearts. However, comparisons between plots of epicardial against endocardial APDs and this reference curve failed to correlate with arrhythmogenicity. Restitution curves, relating APD to diastolic interval (DI), were then constructed for the first time in a murine system and mono-exponential growth functions fitted to these curves. Significant (P<0.05) alterations in the DI at which slopes equalled unity, an established indicator of arrhythmogenicity, now successfully predicted the presence or absence of arrhythmogenicity in all cases. We thus associate changes in the slopes of restitution curves with arrhythmogenicity in models of LQT3 and BrS.

Actions of flecainide on susceptibility to phase-2 ventricular arrhythmias during infarct evolution in rat isolated perfused hearts.

The mechanism of flecainide-induced unexpected death remains uncertain. Phase-2 ventricular arrhythmias occur during infarct evolution. We examined whether flecainide (0.74 and 1.48 microM, representing the peak unbound plasma and total blood concentrations, respectively, at 'therapeutic' dosage) has proarrhythmic activity on phase-2 arrhythmia susceptibility during infarct evolution. To achieve this, we used the Langendorff-perfused rat heart preparation (n=8 per group) in which baseline phase-2 arrhythmia susceptibility is low. Left main coronary occlusion evoked phase-1 (acute ischaemia-induced) ventricular arrhythmias including fibrillation (VF) in all hearts. By 90 min, hearts were relatively arrhythmia-free. Randomized and blinded switch of perfusion to flecainide at 90 min caused no increase over baseline in the incidence of VF, tachycardia (VT) or premature beats (VPB) during the following 150 min of ischaemia, or during reperfusion (begun 240 min after the onset of ischaemia). In separate hearts, catecholamines (313 nM norepinephrine and 75 nM epinephrine) were co-perfused with flecainide from 90 min of ischaemia. Catecholamine perfusion increased heart rate, coronary flow and QT interval, and shortened PR interval (all P<0.05), actions that were not altered by flecainide. Catecholamine perfusion caused a weak nonsignificant increase in phase-2 VPB, VT and VF incidence, but there was no proarrhythmic interaction with flecainide. In conclusion, the present findings suggest that the increased risk of death associated with clinical use of flecainide is not due to facilitation of phase-2 ventricular arrhythmias.

Prevention by calcium antagonists of profibrillatory effects of class I antiarrhythmic drugs in acute myocardial ischemia: study in pig heart in situ.

Class I antiarrhythmic drugs do not decrease, but increase, the risk of ventricular fibrillation in the ischemic myocardium. On the contrary, vulnerability to fibrillation related to ischemia appears to be substantially reduced by calcium antagonists. We assessed whether the calcium antagonist diltiazem (0.50 mg/kg bolus plus 0.02 mg/kg/min infusion) could prevent the profibrillatory effect or even partially restore the antifibrillatory effect of a class I antiarrhythmic drug, flecainide (1 mg/kg bolus plus 0.04 mg/kg/min infusion) in the ischemic myocardium of anesthetized, open-chest pigs. Ischemia was obtained by completely occluding the left anterior descending coronary artery near its origin. Vulnerability to fibrillation was assessed by electrical fibrillation threshold (EFT), measured with diastolic impulses of 100 msec duration delivered at a rate of 180 beats/minute. Diltiazem did not oppose the rise in EFT induced by flecainide in the absence of ischemia (6.8 +/- 1.2 to 9.9 +/- 0.9 mA, p<0.001). It limited the fall in EFT observed under the dual influence of ischemia and flecainide (4.2 +/- 0.9 vs 1.3 +/- 0.6 mA, p<0.001). By reducing calcium entry into myocardial fibers, diltiazem delayed ischemic depolarization, as evidenced by reduced shortening of the monophasic action potential duration from 215 +/- 7 to 200 +/- 4 msec, instead of 178 +/- 6 (p<0.001), and reduced lengthening of intraventricular conduction time from 33 +/- 5 to 43 +/- 4 msec, instead of 53 +/- 4 (p<0.01). Therefore, diltiazem is likely to prevent the loss and even the reversal of the antifibrillatory properties of flecainide due to myocardial ischemia in dosages that do not adversely affect myocardial contractility or atrioventricular conduction to a large extent.

Proarrhythmic actions of flecainide in an isolated tissue model of ischemia and reperfusion.

Flecainide may increase the incidence of cardiac arrhythmias in acute ischemia. The objective of this study was to determine the cellular actions underlying this effect in an isolated tissue model of acute ischemia and reperfusion. Transmembrane electrical activity was recorded with conventional microelectrode techniques from epi- and endocardial surfaces of right ventricular free walls from guinea pig hearts. Endocardium was stimulated. Tissues were equilibrated in Tyrode's solution for 60 min, then exposed to simulated ischemia (hypoxia, acidosis, lactate, hyperkalemia, no glucose) for 15 min and reperfused with normal Tyrode's solution for 30 min. In the absence of flecainide, sustained and nonsustained ventricular tachycardia occurred in 78% of hearts during ischemic conditions and 78% in early reperfusion (n = 14). Premature beats occurred in 14% of hearts in early reperfusion. Ventricular tachycardia was associated with abbreviation of endocardial effective refractory period and action potential duration, plus prolongation of transmural conduction time. Flecainide abolished premature beats at a concentration of 1 mumol/l or higher. However, an increase in the incidence of ventricular tachycardia occurred in both ischemia and reperfusion at all concentrations of flecainide (0.03-10.0 mumol/l). Proarrhythmic effects of flecainide were associated with selective prolongation of transmural conduction time in ischemia and early reperfusion. In epicardial slices flecainide lengthened conduction time transverse, but not parallel to fiber orientation. Our results suggest that proarrhythmic effects of flecainide in acute ischemia and reperfusion are mediated by potentiation of the arrhythmogenic effects of ischemia on anisotropic properties of the myocardium.

Lack of selectivity for ventricular and ischaemic tissue limits the antiarrhythmic actions of lidocaine, quinidine and flecainide against ischaemia-induced arrhythmias.

The antiarrhythmic effectiveness, electrocardiographic and haemodynamic properties of three representative class I antiarrhythmics have been investigated in anaesthetized rats. Quinidine, lidocaine and flecainide were chosen as representatives of class Ia, Ib and Ic, respectively. Lidocaine showed the greatest frequency and 'ischaemia' dependency and a high dose provided complete protection against ischaemic arrhythmias induced by coronary artery occlusion. Flecainide showed the least frequency and ischaemia dependency and the least antiarrhythmic effectiveness. Quinidine was only slightly more effective than flecainide. The three drugs were approximately equi-potent in lowering blood pressure which limited the maximum dose that could be tested. The highest dose of lidocaine also caused convulsions in conscious animals. Thus, while lidocaine had selectivity for ischaemic tissue, and for high frequencies, the central nervous system and cardiovascular toxicity limited its usefulness against ischaemia-induced arrhythmias. Quinidine and flecainide's lack of selectivity for ischaemia, and/or high frequencies, probably accounted for their limited antiarrhythmic actions against ischaemia-induced arrhythmias. This study emphasizes that class I drugs can only provide useful protection against ischaemia-induced arrhythmias if they have marked cardiac selectivity as well as selectivity for ischaemic cardiac tissue.

Determinants and mechanisms of flecainide-induced promotion of ventricular tachycardia in anesthetized dogs.

BACKGROUND: Class IC antiarrhythmic agents such as flecainide are known to have potentially significant ventricular proarrhythmic actions, but the underlying mechanisms are incompletely understood. While some studies have reported proarrhythmia in both healthy dogs and dogs that previously have had a myocardial infarction (MI), there are no published, controlled studies comparing proarrhythmia in healthy dogs vs in dogs with MI. In addition, the concentration dependence of proarrhythmia is unknown and the electrophysiological changes associated with proarrhythmia are not well established. METHODS: We administered successive loading and maintenance infusions of flecainide until ventricular tachyarrhythmia or death occurred in 13 healthy dogs and 19 dogs with 72-hour-old MIs (MI dogs). Ventricular proarrhythmia, defined as reproducible ventricular tachycardia absent under control conditions and occurring in the presence of flecainide, was observed in 4 of 13 healthy dogs (31%) and 15 of 19 MI dogs (79%, P = .02), and drug-induced spontaneous ventricular tachycardia occurred in 8 of 19 MI dogs but in no healthy dogs (P = .007). Activation data at the time of proarrhythmia were available for 11 MI dogs and provided evidence for reentry in 9, with a complete epicardial reentry circuit identified in 4 dogs and a partial circuit in 5. While flecainide slowed ventricular conduction in both the longitudinal and transverse directions, there were no significant differences between overall drug-induced conduction changes in MI dogs compared with healthy dogs. However, in 7 MI dogs for whom activation data were available during ventricular pacing at concentrations comparable to those causing proarrhythmia, flecainide induced a new arc of block in 6 of 7, whereas an arc of block was never observed in the absence of proarrhythmia. Conduction block was induced transverse to fiber orientation in a rate-dependent fashion and was caused by a regionally-specific effect of the drug. No differences were noted between refractory periods proximal and distal to the site of block. CONCLUSIONS: Prior MI strongly predisposes dogs to flecainide proarrhythmia, which occurs in the majority of such dogs in a concentration-related way. In most cases, activation data suggest that anisotropic reentry around a localized arc of rate-dependent transverse conduction block underlies proarrhythmia. These results provide insights into the conditions and mechanisms underlying the ability of flecainide to promote the occurrence of ventricular tachycardia.

Prolongation of intraventricular conduction time associated with fatal [correction of fetal] impairment of defibrillation efficiency during treatment with class I antiarrhythmic agents.

To test whether fatal deterioration of defibrillation efficiency during antiarrhythmic therapy can be prevented by avoiding extreme decrease in ventricular prevented by avoiding extreme decrease in ventricular conduction or toxic plasma drug levels, we determined the defibrillation threshold (DFT) before and during infusion of incremental doses of disopyramide (n = 8), mexiletine (n = 9), or flecainide (n = 9) in anesthetized dogs. Disopyramide did not alter DFT [from 4.4 +/- 1.5 to 4.4 +/- 1.6 J (3.1 +/- 1.2 micrograms/ml)]. Mexiletine tended to increase DFT [from 4.6 +/- 1.2 to 6.1 +/- 2.0 J (1.8 +/- 0.6 micrograms/ml); p < 0.05], and defibrillation eventually was unsuccessful in 3 of the 9 dogs. Although the plasma mexiletine level before refractory fibrillation was far beyond the human therapeutic range, prolongation of intraventricular conduction time (CT) was moderate (16 +/- 3%). Flecainide increased DFT from 4.2 +/- 1.3 to 6.1 +/- 1.5 J at a plasma level of 1.04 +/- 0.37 micrograms/ml (p < 0.0005). In 3 of 5 dogs that developed refractory fibrillation, plasma flecainide level before terminal ventricular fibrillation (VF) was not toxic, but prolongation of CT in the 5 dogs was remarkable (30 +/- 9%). Thus, VF resistant to defibrillation is not necessarily associated with both toxic plasma drug level and remarkably decreased conduction. Reliability of these valuables as indicators of fatally deteriorated defibrillation efficiency may vary among antiarrhythmic agents.