Flecainide toxicity late after liver transplantation

Abstract

Flecainide is an antiarrhythmic agent indicated for patients with supraventricular arrhythmias without ischemic or structural heart disease. Flecainide toxicity is a rare condition in which patients may present with bradycardia, widening of QRS, PR prolongation, ventricular tachycardia, syncope, malaise, dizziness, visual disturbance, nausea, vomiting, and/or lethargy. It carries an associated mortality rate of approximately 10%. Herein, we describe the course of a patient who experienced flecainide toxicity in the setting of renal and liver failure.

Flecainide is an effective antiarrhythmic drug that carries a risk of cardiac arrhythmia, particularly at toxic drug levels. Described herein is a patient who was stable on flecainide for 7 years, yet presented with syncope secondary to flecainide toxicity.

CASE DESCRIPTION

A 50-year-old woman with a history of liver cirrhosis post-liver transplant and a history of supraventricular tachycardia, managed with flecainide 50 mg twice daily for 7 years, presented with syncope. She had dizziness, malaise, fever, nausea, vomiting, and sudden visual disturbance. On presentation, her blood pressure was 90/50 mm Hg and her heart rate was 35 beats/min. The electrocardiogram showed junctional rhythm with a QRS duration of 150 msec with a 3-second sinus pause on telemetry (Figure 1). The sodium level was 125 mEq/L; serum creatinine, 8.79 mg/dL (baseline 1.5); aspartate transaminase, 951 U/L; alanine transaminase, 846 U/L; alkaline phosphatase, 469 U/L; and total bilirubin, 1.4 mg/dL. The flecainide level was 2.2 μg/mL (therapeutic 0.2–1.0 μg/mL; toxic >1.5 μg/mL).

Figure 1.

Electrocardiogram on presentation.

The patient was diagnosed with flecainide toxicity precipitated by acute renal and liver failure. Flecainide was discontinued and she was treated with a sodium bicarbonate intravenous solution. During hospitalization, she converted to normal sinus rhythm. Her PR interval was initially 450 msec and later normalized (Table 1). The QRS duration narrowed, and nausea and dizziness resolved. She required continuous renal replacement therapy that was eventually switched to regular hemodialysis. She had a few bursts of atrial tachycardia and atrial fibrillation prior to discharge, which were controlled with metoprolol tartrate. After returning to baseline, she was discharged and underwent a successful outpatient supraventricular tachycardia/atrial tachycardia ablation. Kidney function recovered and the patient was taken off hemodialysis.

Table 1.

Cardiac characteristics of patient with flecainide toxicity

Variable	Prepresentation	On presentation		1 day postpresentation	On discharge
	NSR	Junctional rhythm	Sinus bradycardia	NSR with first-degree AV block	Sinus tachycardia
Rate (bpm)	71	35	45	67	105
PR duration (ms)	122	–	450	214	116
QRS duration (ms)	80	150	140	116	60
QTc duration (ms)	419	530	520	560	433

AV indicates atrioventricular; NSR, normal sinus rhythm.

DISCUSSION

Flecainide is a Vaughn-Williams class IC antiarrhythmic agent indicated for patients with supraventricular arrhythmias without ischemic or structural heart disease. It exerts its action through blocking open-state sodium channels and delaying phase 0 depolarization, slowing conduction in the atrium, His-Purkinje system, and ventricles. This can result in suppressing sinoatrial node automaticity and slowing the conduction. It can increase the refractory period in ventricular tissue.¹ Flecainide is primarily metabolized by the hepatic cytochrome P450 CYP2D6 system; 30% is excreted in urine unchanged. The elimination half-life ranges from 7 to 23 hours, but may take 58 hours, with a 40% drop in total clearance of the drug in renally impaired patients.^2,3 Flecainide toxicity is rare and carries a mortality rate of 10%. It can be precipitated by renal and liver failure; hyponatremia may contribute to cardiac toxicity by increasing the competitive inhibition of flecainide on sodium channels.^4,5

The diagnosis can be challenging given the nonspecific extracardiac symptoms, most frequently dizziness and visual disturbance.⁶ Cardiac manifestations include bradycardia, widening of QRS, PR prolongation, ventricular tachycardia, and syncope. The etiology of ventricular tachycardia is not well understood, but is hypothesized to be from reentrant circuits as a result of the heterogeneous increase of the refractory period in ventricular tissue.⁷

Flecainide’s high bioavailability and slow body clearance render management challenging. The drug is not effectively dialyzed. The most effective therapy to mitigate cardiac toxicity is a solution of high-dose sodium bicarbonate. The high sodium decreases sodium channel availability to flecainide through competitive inhibition. Additionally, serum alkalization, through electrostatic repulsion, limits binding of flecainide to sodium channels and can facilitate flecainide dissociation.⁸ Other treatments are fat emulsion (to sequester the lipolytic drug), amiodarone or lidocaine (for arrhythmia), transcutaneous pacing (for arrhythmia), or providing mechanical support through extracorporeal membrane oxygenation (for severe cases).^9,10

This patient presented with acute flecainide toxicity from decreased drug metabolization and clearance due to liver failure and renal failure, respectively. Cardiac toxicity was aggravated by hyponatremia. Treatment with sodium bicarbonate and hemodialysis was successful. The supraventricular tachycardia was eventually treated with an ablation, not antiarrhythmic drugs.

In conclusion, flecainide toxicity is rare, but can be lethal. As in this case study, cardiac manifestations include bradycardia, widening of QRS, PR prolongation, ventricular tachycardia, and syncope; symptoms may be nonspecific extracardiac. Flecainide toxicity should be suspected in patients with acute renal failure and hyponatremia. High-dose sodium bicarbonate is the mainstay medical treatment.

Funding Statement

This work was funded in part by the Baylor Health Care System Foundation.