Flecainide-Induced Torsade de Pointes Successfully Treated with Intensive Pharmacological Therapy

Flecainide is a class IC anti-arrhythmic drug that acts by blocking the fast inward sodium channels during phase 0 of action potential. It is used to treat both supraventricular and ventricular arrhythmias. However, flecainide is also a pro-arrhythmic agent, and overdose may cause nausea, vomiting, hypotension, bradycardia, varying degrees of atrioventricular block, tachyarrhythmias (such as torsades de pointes [TdP]), and sustained ventricular tachycardia. These symptoms may result in rapid-onset hypotension, with an associated mortality rate as high as 10%. The management of flecainide overdose includes supportive and pharmacological measures; however, difficult cases have been successfully treated with extracorporeal membrane oxygenation (ECMO) and intra-aortic balloon pumps. The authors present a case of a patient who visited their hospital with flecainide intoxication and life-threatening arrhythmias, including TdP, ventricular tachycardia, and ventricular fibrillation. The patient was successfully treated with intensive pharmacological therapy.


Introduction
Flecainide is a class IC anti-arrhythmic drug that acts by blocking the fast inward sodium channels during phase 0 of action potential.It is used to treat both supraventricular and ventricular arrhythmias.However, flecainide is also a pro-arrhythmic agent, and overdose may cause nausea, vomiting, hypotension, bradycardia, varying degrees of atrioventricular block, tachyarrhythmias (such as torsades de pointes [TdP]), and sustained ventricular tachycardia.These symptoms may result in rapid-onset hypotension, with an associated mortality rate as high as 10%.The management of flecainide overdose includes supportive and pharmacological measures; however, difficult cases have been successfully treated with extracorporeal membrane oxygenation (ECMO) and intra-aortic balloon pumps.The authors present a case of a patient who visited their hospital with flecainide intoxication and life-threatening arrhythmias, including TdP, ventricular tachycardia, and ventricular fibrillation.The patient was successfully treated with intensive pharmacological therapy.

Case
A 20-year-old man who attempted to commit suicide by ingesting approximately 5,000 mg of flecainide presented to the emergency department one hour after the ingestion.The patient had been taking flecainide as a "pill in the pocket" for the treatment of supraventricular tachycardia over the previous month.Before arrival at Ilsan Paik hospital, the patient had a bout of vomiting and grand mal seizure in the national 119-rescue services ambulance.Two generalized seizures were also noted during his transport to the hospital.Upon arrival at the emergency department, the patient was semi-comatose, with a Glasgow Coma Scale score of 4.
His blood pressure was 44/23 mmHg , and the electrocardiogram (ECG) showed an irregular, wide complex bradycardia with a heart rate of 40 to 55 BPM (Figure 1).The initial treatment included intravenous (IV) administration of normal saline and dopamine.Despite initial management, the patient had an episode of irregular, wide QRS tachycardia as well as consecutive pulseless ventricular fibrillations (Figure 2); hence, cardiopulmonary resuscitation (CPR) was started.The initial arterial blood gas showed a pH of 7.241; pCO2 was 32.2 mmHg, pO2 117.9 mmHg, and HCO3-13.5 mmol/L.Chemical screens revealed blood urine nitrogen (BUN) level of 12 mg/dL and a creatinine level of 1.43 mg/dL; however, serum electrolytes were within the normal range.Although serum flecainide levels were not analyzed, the history of flecainide ingestion together with the wide QRS complex on the ECG suggested flecainide-induced TdP.After IV administration of 80 mEq of an 8.4% solution of sodium bicarbonate, the patient regained spontaneous circulation and the femoral pulse was palpable; CPR was therefore terminated.
A jugular venous catheter and a left femoral arterial-line catheter were prepared; moreover, an L-tube and Foley catheter were inserted.Gastric lavage was performed, followed by the administration of 50 g of activated charcoal.The patient's blood pressure was 87/44 mmHg, heart rate 104 BPM, and SpO2 97%.
Continuous IV infusions of norepinephrine and heparin were started; sodium bicarbonate was also intravenously administered continuously at a rate of 45 mEq/h.Additionally, 2 g of IV MgSO4 was administered, and a continuous IV infusion of amiodarone was initiated.
The patient was then transferred to the medical intensive care unit for ongoing observation.Upon arrival, various cardiac arrhythmias, including ventricular fibrillation, were noted (Figure 3).
Unfortunately, there was no palpable spontaneous pulse.CPR was initiated together with an IV administration of 8 mg of epinephrine and 8 mg of atropine.After complete CPR, including three rounds of direct-current (DC) cardioversion for a total of 21 minutes, femoral pulsation became palpable and the CPR was terminated.Since ventricular arrhythmia was sustained after CPR, lidocaine was administered first as a 60 mg IV bolus and then as a continuous IV infusion at 3 mg/h.After stabilization, the ECG showed a normal ejection fraction (57%) with no segmental wall motion abnormalities.Fifty hours    post ingestion, the patient remained hemodynamically stable; the ECG displayed a sinus rhythm at a rate of 89 BPM and a prolonged QTc of 608 msec (Figure 4).He was then extubated and finally, made a full recovery.He was discharged 7 days post admission with no evidence of end organ damage.  2 In particular, the rate-dependent conduction slowing associated with the flecainide has been implicated as a potential mechanism for drug proarrhythmia.

Discussion
The risk of pro-arrhythmia was reported in patients with myocardial infarction, who were taking flecainide.Although flecainide suppresses conductivity, it may perpetuate reentry in patients with structural heart disease.Flecainide-induced proarrhythmia has rarely been reported in patients with no structural heart disease.Instead, it is most often found in patients taking other anti-arrhythmic drugs, having electrolyte disorders, or an atrial flutter with a 1:1 ventricular conduction. 3Since we did not analyze flecainide blood levels, we could not confirm if this was a case of flecainide toxicity.However, since toxicity is suggested when there is a 50% increase in the duration of QRS or 30% increase in the prolongation of the PR interval, it is likely. 4re, we report a patient with flecainide-associated bradycardia-dependent TdP.In this patient, the onset of TdP showed a marked QT prolongation beyond 600 msec, and ectopic beats of the identical right bundle branch block on both occasions.Flecainide may lengthen the QT interval, mainly causing QRS broadening, as it lacks any significant effect on repolarization.Therefore, it is not believed to induce TdP alone or polymorphic ventricular tachycardia by lengthening QT.Indeed, cases of flecainide-induced TdP are rare and generally associated with other anti-arrhythmic drugs and/or electrolyte disorders.
There are only a few published studies in which tachyarrhythmia is directly linked with flecainide in the absence of other associated triggering factors. 5ecainide toxicity induce sinus node dysfunction, atrioventricular block, and QT prolongation.QT prolongation in flecainide toxicity is thought to be because of IKr channels in the ventricular myocytes.

Flecainide-Induced Torsade de Pointes
Absorption from the gastrointestinal tract is reasonably rapid, with maximum concentration occurring after 3-4 hours post drug ingestion. 4Flecainide is eliminated, largely unchanged, by the kidney, and is metabolized to some degree by the hepatic cytochrome P450 2D6.It also has a long elimination half-life (7 to 24 hours), which makes the treatment of a severe overdose more difficult. 6e primary treatment of an acute flecainide overdose should be aimed at reducing gastrointestinal absorption via gastric lavage and activated charcoal administration.Other available measures of detoxification include forced diuresis, hemofiltration, and hemoperfusion.However, these procedures have limitations: forced diuresis may exacerbate flecainide-induced cardiac insufficiency; hemofiltration may not remove flecainide effectively as the drug is tightly bound to proteins; and finally, hemoperfusion may result in hypocalcaemia, which would further prolong the QTc interval. 7ministration of a hypertonic sodium bicarbonate solution appears to improve the hemodynamic instability resulting from flecainide toxicity.As illustrated in this case, the benefits can be dramatic and occur within minutes, despite the fact that the mechanism of action is complex and involves the combination of an increase of intracellular sodium and pH, resulting in the displacement of flecainide from the sodium channels. 8However, there is no recommended dose of sodium bicarbonate.One common practice is to use a bolus of 50 to 100 mEq of hypertonic sodium bicarbonate solution, targeting a pH value of 7.5 to 7.55.
There are several case reports demonstrating that intensive sodium bicarbonate therapy improves survival without resorting to ECMO. 9 In the case reported herein, the total dose of bicarbonate used was above 500 mEq.
There are case reports showing that anti-arrhythmic agents have been used to terminate flecainide-induced arrhythmias; moreover, in several case reports, sinus rhythm was restored soon after the administration of lidocaine.Although lidocaine is also a sodium channel blocker, it is postulated that its fast-on/fast-off kinetics allow it to compete for the sodium channel, hence reversing the toxicity of other more potent sodium channel blockers (such as the class IC agents). 10Other case reports have identified IV amiodarone or MgSO4 as the principle agent responsible for terminating flecainide-induced ventricular arrhythmias. 11,12cause hypotension can develop rapidly after a flecainide overdose, hepatic and renal blood flow is reduced.Measures to maintain vital organ perfusion will enhance flecainide clearance and its redistribution to other body tissues.One method to provide the hemodynamic support necessary to allow flecainide clearance and redistribution is ECMO.Yasui, et al. 13 showed that this technique allowed flecainide clearance and redistribution to continue in one patient with flecainide overdose, reducing the half-life of the drug to six hours.Since the use of ECMO is accompanied by complications including coagulopathies (requiring blood product support), hemorrhage at the cannulation point, and femoral nerve palsy, it should be used cautiously.
Although there is no standard treatment for flecainide overdose, the case reported here demonstrates that an intensive pharmacological therapy, including the administration of sodium bicarbonate, amiodarone, MgSO 4, and lidocaine, can rescue patients from flecainide toxicity with no recourse to extracorporeal therapy.

Figure 1 .
Figure 1.Initial twelve-lead electrocardiogram (ECG) upon arrival in the emergency department.The ECG showed marked QRS widening and an irregular rhythm, with a rate of 40 to 55 beats/min.The QRS duration is 168 msec and corrected QT interval is 602 msec.

Figure 2 .
Figure 2. Electrocardiogram in the emergency department during cardiopulmonary resuscitation.The rhythm strip recording showed irregular, wide-complex tachycardia.

Figure 3 .
Figure 3. Electrocardiogram (ECG) after intensive care unit admission during cardiopulmonary resuscitation.The ECG showed ventricular fibrillation.

Figure 4 .
Figure 4. Electrocardiogram (ECG) during the 3rd day of hospitalization.The ECG showed a normal sinus rhythm.The QRS duration is 106 msec and corrected QT interval is 608 msec.

Flecainide
acetate is a Vaughan Williams class IC antiarrhythmic agent used to treat supraventricular and ventricular arrhythmias.It acts by blocking the fast inward sodium channel during phase 0 of the action potential, resulting in a marked depression of all major conduction pathways.Overdose symptoms include nausea, vomiting, hypotension, bradycardia, varying degrees of atrioventricular block, and tachyarrhythmia.Compared with other acute drug intoxications, class IC drugs overdoses are associated with a high mortality rate. 1 Drugs that interact with their receptors more at faster heart rates are said to display use dependence.Class I antiarrhythmic drugs have frequency dependent effects on cardiac sodium channels, leading to greater reductions in Vmax of ventricular tissue at faster stimulation rates.CAST (Cardiac Arrhythmia Suppression Trial) reports have emphasized the potential deleterious or proarrhythmic risks of type I antiarrhythmic drug therapy.

Figure 5 .
Figure 5. Timeline representation of events.After the administration of sodium bicarbonate, amiodarone, magnesium sulfate, and lidocaine, the wide and irregular heart rhythm was restored to a sinus rhythm.CPR.cardiopulmonary resuscitation, DC. direct current; ER, emergency room; G/W, general ward; ICU, intensive care unit; PEA, pulseless electrical activity; ROSC, return of spontaneous circulation; SBP, systolic blood pressure; VF, ventricular fibrillation; VT, ventricular tachycardia.