Electrical instability and sudden loss of pacemaker capture—A tale of flecainide toxicity

Key Teaching Points.

• •Flecainide is a potent antiarrhythmic drug, commonly used for treatment of atrial fibrillation. The drug has a narrow therapeutic window, and toxicity can lead to life-threatening cardiac events.
• •Typical cardiovascular findings of flecainide toxicity include sinus bradycardia, atrioventricular block, slowing of His-Purkinje conduction with widening QRS complex, and ventricular arrhythmias. Furthermore, pacing thresholds can become excessively high, leading to loss of capture, potentially lethal if no escape rhythm is present.
• •Early recognition of typical signs of toxicity are key. Treatment of flecainide toxicity is primarily supportive. Management of persistent cardiovascular instability and ventricular arrhythmias includes sodium bicarbonate infusion to reverse sodium channel blockade and intravenous lipid emulsions.

Introduction

Flecainide is a potent antiarrhythmic medication commonly used to manage various arrhythmias, mainly atrial fibrillation. Although effective, it possesses a narrow therapeutic window, and toxicity can lead to life-threatening cardiac events. This report details the case of a patient with an in-hospital bradycardic arrest despite a permanent pacemaker, discovered to be caused by severe flecainide toxicity.

Case report

An 81-year-old man presented with progressive exertional dyspnea and lower extremity edema caused by acute on chronic decompensated heart failure with preserved ejection fraction and concomitant acute kidney injury. His medical history was significant for acute pericarditis with effusion requiring a pericardial window, torrential tricuspid regurgitation, stage IIIb chronic kidney disease, paroxysmal atrial fibrillation, and sinus node dysfunction, for which a dual-chamber pacemaker with conduction system pacing had been implanted. Relevant home medications included amlodipine, apixaban, flecainide, and torsemide. The patient was hospitalized for intravenous diuresis and heart failure optimization. On day 7, he developed profound hypotension, widening QRS complexes, nonsustained ventricular tachycardia, atrioventricular block, and intermittent loss of ventricular capture, followed by slow idioventricular rhythm and bradycardic arrest requiring cardiopulmonary resuscitation, mechanical ventilation, and transfer to intensive care.

Immediately after brief resuscitation, vital signs were within normal limits. His heart rate was 60 beats/min, and blood pressure was 140/78 mm Hg. Physical examination demonstrated marked jugular venous distension with V waves, holosystolic murmur at the lower left sternal border, and bilateral pitting lower extremity edema. Echocardiogram post-arrest showed decline in left ventricular ejection fraction to 35% with known grade III diastolic dysfunction. Serum creatinine level had peaked at 2.2 mg/dL, with estimated glomerular filtration rate 27 mL/min/1.73 m² in the days before cardiac arrest. Three consecutive high-sensitivity troponins were low, ranging from 58 ng/L to 71 ng/L. Electrocardiogram (ECG) showed sinus rhythm with intermittent loss of ventricular capture (Figure 1). The captured ventricular beats had markedly widened QRS duration of 360 ms with a prolonged QTc interval of 720 ms (corresponding to 500 ms after correction for prolonged QRS duration). Pacemaker interrogation indicated underlying sinus rhythm with complete heart block and no escape rhythm. The atrial threshold was chronically elevated at 2.1 V/0.4 ms, whereas the ventricular threshold had risen to 4.5 V/0.4 ms in both unipolar and bipolar configurations (measured 1.6 V/0.4 ms a month prior).

Figure 1.

Electrocardiogram immediately after bradycardic arrest. Sinus rhythm with appropriate atrial sensing and unipolar ventricular pacing. There is intermittent failure to capture the ventricle. Captured QRS complexes are wide (360 ms), with a prolonged QTc interval of 720 ms (corresponding to 500 ms after correction for prolonged QRS duration).

Significant acidemia and electrolyte abnormalities that could potentially result in loss of pacemaker capture were ruled out (pH, 7.43; potassium level, 3.9 mmol/L; magnesium level, 2.2 mg/dL; and ionized calcium, 1.27 mmol/L). Pacemaker or lead malfunction was unlikely given unchanged pacing impedances, and CT imaging ruled out lead perforation and dislodgement. A septal myocardial infarction (thus leading to rising pacing thresholds) was deemed unlikely in the absence of significant troponin elevation. On careful review of medications, the patient was found to be on an unusually high dose of flecainide (200 mg 2 times daily). This exceeds the recommended maximum daily dose of 300 mg even among healthy patients with normal weight and kidney function. Furthermore, ECG performed a week before hospitalization showed widened QRS complex (238 ms) in the setting of declining renal function. This contrasted with an ECG recorded approximately 1 year ago with left anterior fascicular block and QRS duration of 110 ms.

A diagnosis of life-threatening flecainide toxicity was made based on these findings. A serum flecainide level of 3.45 μg/mL was confirmatory (therapeutic range, 0.20–1.00 μg/mL and toxic level greater than 1.5 μg/mL). Based on the already abnormal ECG before admission, we suspect accumulation of toxic levels of flecainide over several days or even weeks up until the dramatic event.

Discussion

Flecainide is a lipophilic drug with oral bioavailability of 90%. Classified as a Class IC anti-arrhythmic agent in the Vaughan-Williams system, flecainide acts by inhibiting fast-acting sodium channels during phase 0 of the cardiac action potential. Approximately 27% of the drug is excreted unchanged in urine, whereas most is eliminated as inactive metabolites via urine, with only a minimal fraction (5%) eliminated via feces. Importantly, the plasma half-life can vary from approximately 12 hours in patients with normal renal function after a single dose to 17 hours in those with moderate renal disease, and up to 26 hours in patients with end-stage renal failure.¹

Our patient exhibited all the cardiovascular findings of flecainide toxicity (Figure 2)—sinus bradycardia, atrioventricular block, slowing of His-Purkinje conduction with widening QRS complex, and ventricular arrhythmias.^2,3 Potential extracardiac manifestations can include nausea, vomiting, dizziness, visual disturbances, and seizures, although severe neurological symptoms are rare.^3,4

Figure 2.

Electrocardiogram during peak flecainide intoxication. After reprogramming the pacemaker to high output, ventricular pacing reliably captured. Unipolar pacing spikes can be seen, followed by bizarrely widened QRS complexes of 348 ms, fusing with the T waves.

Flecainide’s negative inotropic effect was evident with decline in left ventricular ejection fraction to 35%. The drug was promptly discontinued, and the patient was monitored with serial ECGs and pacemaker interrogations. A conservative approach was deemed reasonable given reliable ventricular capture at high output pacing (6.0V/2.0ms), resolution of nonsustained ventricular arrhythmias, and stabilizing renal function. Figure 3 depicts progressive narrowing of QRS complexes in the first 3 days of recovery. By day 4, intrinsic conduction had resumed, QRS narrowed, and eventually, ECG at 2 weeks’ follow-up resembled the ECG from a year earlier with first-degree AV block and left anterior fascicular block.

Figure 3.

Follow-up electrocardiograms showing progressively decreasing toxic flecainide effects. These serial ECGs were taken over 4 days after the initial event, exhibiting progressive narrowing of QRS with weaning off flecainide effects, with eventual resumption of AV conduction with a first-degree AV block and narrower QRS complex with left anterior fascicular block (ultimately reaching a QRS duration of 108 ms, comparable to an ECG from a year prior).

Pacing thresholds also returned to baseline, and the device could be reprogrammed to its initial settings (ventricular output at 3.5 V/0.4 ms in DDD mode with AV hysteresis to favor intrinsic conduction). Furthermore, the left ventricular ejection fraction improved to 55%, and the patient did not require inotropes.

If cardiovascular instability and ventricular arrhythmias persist, sodium bicarbonate infusion can be used to reverse sodium channel blockade by elevating plasma sodium concentration and alkalinizing blood pH. Intravenous lipid emulsions, serving as a “lipid sink” for this lipophilic drug, also have been used^3,5,6 Because of its large distribution volume, dialysis is largely ineffective for flecainide elimination. Apart from these interventions, care is mainly supportive, such as hemodynamic support for hypotension or transvenous pacing for those with bradycardia. Beware that pacing thresholds may be excessively high with failure to capture, as occurred in our patient.

Conclusion

In conclusion, flecainide is a potent antiarrhythmic drug with a distinct therapeutic window. Inadvertent overdosing, particularly in the setting of renal dysfunction, can result in electrical and cardiovascular instability. Marked widening of the QRS complexes is an early sign of excessive sodium channel blockade. Recognition of this ECG finding can result in prompt intervention and help mitigate lethal consequences of flecainide toxicity.

Disclosures

The authors have no conflicts of interest to disclose.