The Use of Intravenous Lidocaine in the Setting of Chronic Dofetilide Overdose: A Case Report

Introduction

Dofetilide is a class III antiarrhythmic used for the treatment of atrial fibrillation or flutter. Although the risks of ventricular arrhythmias and cardiac arrest associated with routine use of dofetilide are well described, ¹ we found few cases describing the acute management of patients experiencing these adverse effects in the setting of overdose, drug-drug interactions, and/or drug-disease state interactions.

Here we present a case of cardiac arrest management using intravenous lidocaine following prolongation of the heart rate corrected QT (QTc) interval in chronic dofetilide overdose due to a presumed prescribing error. This case is also the first report of a dofetilide overdose that occurred after the United States Food and Drug Administration (FDA) risk evaluation and mitigation strategies (REMS) program was discontinued in 2016. ²

Case Description

A 49-year-old male with a past medical history of atrial fibrillation, hypercholesterolemia, hypertension, and alcohol dependence presented to the emergency department (ED) after feeling diaphoretic and weak at work. He reported nausea and vomiting prior to admission and was medically managed in the ED with intravenous famotidine 20 mg once, ondansetron 4 mg twice, and fluids over the course of several hours. Intravenous lorazepam 2 mg was also given for suspected alcohol withdrawal, and the patient was held in the ED for further evaluation and monitoring. Initial assessments indicated patient weight 81.8 kg, height 67 inches, temperature 97.2° F, respiratory rate 22 breaths/minute, blood pressure 175/89 mm Hg, and pulse oximetry at 97% on room air. An initial electrocardiogram (ECG) reading revealed atrial fibrillation at 100 beats/min with a QTc calculation (Bazett’s formula) of 616 msec. Labs were significant for a lactate level of 3.5 mmol/L, potassium level of 3.1 mmol/L, and calcium level of 8.5 mmol/L. Serum creatinine was 0.69 mg/dL with a calculated Cockcroft-Gault creatinine clearance (CrCl) of 150 mL/min using actual body weight.

While awaiting further work up, the patient was seen taking his own home medications and was found pulseless shortly afterward. Cardiopulmonary resuscitation (CPR) was started and medical personnel began advanced cardiac life support (ACLS) efforts per protocol. A review of the medications the patient had on his person revealed a vial containing dofetilide 500 mcg capsules prescribed, per vial label, at 1000 mcg twice daily. This dose was noted to be double the maximum manufacturer recommended dose though it is unknown whether this was due to prescribing or inaccurate pharmacy transcription. ³ The dofetilide prescription duration, as written, was confirmed with the patient’s pharmacy as being greater than 1 year. Additional home medications included ibuprofen, diltiazem CD, folic acid, furosemide, dabigatran, rosuvastatin and senna at appropriately prescribed frequencies and doses. It was unknown which home medications were ingested prior to cardiac arrest since no medical personnel were present in the room at the time. In addition, no activated charcoal or gastric suctioning was administered.

The patient’s presenting rhythm was ventricular fibrillation. Torsades de pointes (TdP) was not identified during resuscitation. Defibrillation was performed 3 times and the patient was emergently intubated. The patient was also given 2 doses of intravenous epinephrine 1 mg and 1 dose of lidocaine 100 mg. Amiodarone was held due to a potential interaction with dofetilide and return of spontaneous circulation was achieved after 9 minutes. A post code ECG was significant for sinus rhythm at 137 beats per minute, QTc (Bazett’s formula) 401 msec, ST elevations, right axis deviation, right bundle branch block and biphasic t waves. The patient was subsequently transferred to the intensive care unit where electrolyte repletion and further supportive care was initiated. Though the patient was stabilized after transfer he subsequently died over a month later due to complications from sepsis.

Discussion

This case describes a medication dosing error that resulted in chronic dofetilide overdose. The Naranjo Adverse Drug Reaction Probability scale indicated a “probable” adverse reaction with a score of 6. ⁴ Several case reports have demonstrated dofetilide’s ability to prolong the QTc during unintentional overdose, ⁵ intentional overdose, ⁶ or through interactions with other QTc-prolonging medications.^7,8 It is important to point out that most of these cases were managed with early overdose recognition, activated charcoal as appropriate, aggressive magnesium and potassium repletion, and cardiac monitoring. Additional management strategies include isoproterenol infusion, cardiac pacing, and defibrillation.^2,9 Similar to our case, there are several reports of successful termination of dofetilide-induced ventricular arrhythmias with defibrillation.^6,10

Per prescription, the patient may have been receiving dofetilide 1000 mcg twice daily for over a year. In healthy volunteers, increases in QTc interval were linearly related to dofetilide dose and small clinical populations receiving greater than 500 mcg twice daily had a ventricular arrhythmia incidence rate as high as 15.8%. ³ The prolonged QTc observed in this patient was likely exacerbated by alcohol withdrawal, several drug-drug interactions and marked hypokalemia. Alcohol withdrawal is linked to ECG abnormalities through mechanisms such as acute electrolyte disturbances, increased catecholamine release, and cardiac remodeling.^11-15 Several patient home medications as well as 2 medications administered in the ED (ondansetron and famotidine) were QT-prolonging agents. In addition, diltiazem, a CYP3A4 inhibitor, may have increased serum concentrations of dofetilide even further. According to the Tisdale risk score for QT prolongation, the patient had several risk factors that include exposure to ≥ 2 QT-prolonging drugs (dofetilide, furosemide, ondansetron, and famotidine), loop diuretic use (furosemide), serum K⁺ < 3.5 mEq/L and admitting QTc >450 ms.^16,17 In retrospect, early medication reconciliation, overdose recognition, continuous cardiac monitoring, avoidance of additional drug-drug interactions, and electrolyte repletion may have been prudent in this case. ¹⁸

This case demonstrates the successful management of dofetilide overdose induced ventricular fibrillation with CPR, defibrillation, epinephrine, and lidocaine. While past ACLS guidelines prefer amiodarone, current updates recommend either amiodarone or lidocaine to treat shock-refractory ventricular fibrillation and pulseless ventricular tachycardia cardiac arrest.^19,20 Unlike amiodarone, lidocaine may diminish prolongation of the QTc ²¹ and has shown limited efficacy in animal models of TdP and clinical case reports.^22-25 In a prospective clinical trial of 22 healthy subjects, lidocaine significantly shortened the QTc prolonging effects of dofetilide by 20 ms. ²⁶ These authors suggest that QT prolonging agents such as dofetilide do so via blockade of the hERG potassium channel but also by increasing late sodium currents via inhibition of phosphoinositide 3-kinase.^26,27 As such, it is hypothesized that in the setting of a dofetilide overdose, a late sodium blocking agent such as lidocaine can shorten drug induced QTc prolongation. ²⁶ Though amiodarone may also have some effects on late sodium currents, it is primarily a class III antiarrhythmic and works by blocking potassium currents responsible for repolarization during phase 3 of the cardiac action potential.^26,28,29 Dofetilide’s package insert recommends avoiding concomitant use with other class III antiarrythmics and suggest that these agents should be withheld for at least 3 half-lives (3 months if using amiodarone) prior to initiation of dofetilide. ³

Conclusion

This report describes a probable case of QTc prolongation and cardiac arrest induced by dofetilide overdose. Our experience suggests lidocaine may be used as the preferred antiarrhythmic for ACLS in the setting of a suspected dofetilide overdose and highlights the role of pharmacists in cardiac emergencies. Although the dofetilide REMS program is no longer active, we emphasize the need for continual risk mitigation through periodic reassessments of appropriateness, dosing, and QTc due to evolving risk factors such as drug-drug interactions and/or drug-disease state interactions.