Is Treatment With Phenytoin for Digoxin-Induced Arrhythmias Feasible?

Digoxin (Lanoxin; Covis Pharmaceuticals), a cardiac glycoside derived from the Digitalis plant, has been used for more than a century to treat various cardiovascular conditions, including atrial fibrillation and heart failure. It reversibly inhibits the sodium-potassium ATPase pump in cardiac myocytes, thereby increasing intracellular sodium levels. The accumulation of sodium leads to an influx of calcium through the sodium-calcium exchange pump, enhancing myocardial contraction. Digoxin has a second mechanism of action: It stimulates the vagus nerve and prolongs conduction of the sinoatrial and atrioventricular (AV) nodes, slowing the heart rate.¹

The use of digoxin has fallen out of favor with new medications on the market, primarily due to its safety profile. Digoxin has a narrow therapeutic window (digoxin blood level: 0.5-1.2 ng/mL, indication-specific), which creates a higher likelihood of toxicity with its use, particularly in patients with renal impairment and specific drug interactions.¹ Between 2005 and 2010, there were estimated to be more than 5000 cases of digoxin toxicity annually, and in approximately 75% of these cases, individuals were hospitalized.²

Digoxin Toxicity and Primary Treatment

Digoxin toxicity can be difficult to identify because adverse effects can occur at levels that may not be traditionally considered toxic. Historically, digoxin toxicity was thought to be correlated with blood levels greater than 2 ng/mL. More recently, digoxin blood concentrations of 1.2 ng/mL or greater have been associated with an increased risk of toxicity, including mortality, in both atrial fibrillation and heart failure. Toxicity can present as nausea and vomiting, visual disturbances, lethargy, and life-threatening arrhythmias. Arrhythmias may include atrial tachycardia, all types of AV block, ventricular premature contractions, and—rarely—ventricular tachycardia or fibrillation.

The antidote for digoxin toxicity is digoxin immune Fab (DigiFab; BTG International). DigiFab is an antibody that binds to the digoxin molecules in the body and is then excreted by the kidneys. This antidote is effective in treating digoxin toxicity; however, it is a costly medication and may not be available in small community hospitals. In 2023, the average wholesale price of DigiFab was approximately $4599 per vial.³ For treatment, patients may require more than 10 vials, depending on the amount of digoxin ingested.²

Additionally, patients may not respond to DigiFab. A report published by the American Heart Association noted that approximately 10% of the 150 patients who were treated with DigiFab for life-threatening digitalis intoxication did not respond. According to the report, among the 56 patients who suffered cardiac arrest, 46% did not survive their hospital stay despite receiving treatment.⁴ For these reasons, alternative agents need to be available if a patient does not respond appropriately or if the hospital does not carry DigiFab due to its high cost.

Phenytoin for Digoxin-Induced Arrhythmias

Phenytoin (Dilantin; Viatris Specialty, LLC), a readily available medication in many emergency departments (EDs), shows promise as an alternative agent to treat arrhythmia suppression in patients presenting with digoxin toxicity. Phenytoin is well known and widely used for its antiepileptic properties; however, its mechanism of action suggests it may be a last-line option for digoxin-induced arrhythmias. Phenytoin is a class 1B antiarrhythmic that weakly blocks sodium channels. This channel interaction inhibits digoxin from binding to the sodium-potassium ATPase pumps in the heart.⁵ Phenytoin may be used to treat digoxin-induced arrhythmias when DigiFab is not readily available or if the arrhythmia does not resolve after treatment with this antidote.^5,6

The reported dose of phenytoin for cardiac arrhythmia treatment is 250 mg intravenous (IV) administered over 10 minutes, followed by a 100-mg bolus every 5 minutes, up to a total of 1000 mg. The recommended infusion rate is 10 to 25 mg/min in patients with a history of atherosclerotic cardiovascular disease (eg, hypertension, coronary artery ischemia, or congestive heart failure) or those aged 50 and older, and 30 to 40 mg/min in patients without atherosclerotic cardiovascular disease and younger than 50 years. To reduce the risk of hypotension, phenytoin must be infused at a maximum rate of 50 mg/min IV and administered with caution in patients with existing hypotension.^6,7

Case Reports

A case report described the use of phenytoin for amiodarone-induced torsades de pointes, with a regimen of 100 mg IV over 5 minutes for 3 doses and then continued at 300 mg/day in the hospital. The patient was discharged home on 300 mg/day of oral therapy.⁸ The patient remained asymptomatic at their 2-month follow-up and was successfully treated with phenytoin.⁸

There are reports of phenytoin use in digoxin overdoses that date to the 1970s. A recent case report from 2022 used phenytoin as the treatment for a patient with digoxin-induced bidirectional ventricular tachycardia in Mexico.⁵ The patient was a man, aged 68 years, who initially presented to the ED after suffering a cardiac arrest. During his admission, he developed atrial fibrillation and started on digoxin for rate control. After 72 hours of digoxin therapy, he developed bidirectional ventricular tachycardia. A digoxin level was obtained, yielding 2 ng/mL. The patient was also found to have renal insufficiency that could have contributed to this elevated level. To treat the toxicity, phenytoin was chosen because DigiFab was unavailable at the site. The patient received 250 mg of IV phenytoin over 5 minutes every 6 hours with successful resolution of the arrhythmia.⁵ Due to phenytoin being readily available, it was chosen for this patient, and he responded well without recurrence of arrhythmia.

Another case report from 2010, whose findings were published in the Kansas Journal of Medicine, describes the use of fosphenytoin (Cerebyx; Pfizer) for digoxin-induced ventricular arrhythmias. Fosphenytoin is a water-soluble prodrug of phenytoin, converted by esterases in plasma. The phenytoin half-life is about 15 minutes when given IV. Due to this conversion to phenytoin, cases have used fosphenytoin to suppress cardiac arrhythmias. The use of fosphenytoin to treat cardiac arrhythmias allows for faster administration and reduced injection-site reactions due to its greater water solubility compared with phenytoin.⁹ Fosphenytoin is a more hemodynamically stable medication vs phenytoin because its formulation lacks propylene glycol, decreasing the incidence of hypotension and cardiac arrhythmias.¹⁰ 

This patient was a White man, aged 78 years, presenting for digoxin toxicity. The patient, with ischemic cardiomyopathy (ejection fraction, 10%) on digoxin 0.125 mg daily, presented with a blood pressure level of 105/45 mm Hg and bradycardia. Laboratory results showed decreased renal function and elevated electrolyte levels, including potassium at 8 mEq/L, magnesium at 2.9 mg/dL, and digoxin at 4.5 ng/mL. DigiFab was administered at a dose calculated using the formula: (serum digoxin level [ng/mL] × body weight [kg]) ÷ 100. Despite administration of DigiFab, the patient developed ventricular arrhythmias, including premature ventricular contractions (PVCs), followed by ventricular trigeminy, runs of wide-complex bradycardia, and a 6-beat run of ventricular tachycardia.

Fosphenytoin was chosen as the next line of treatment for this patient because IV phenytoin was not readily available at the institution. The patient received a bolus dose of 20 mg/kg of IV fosphenytoin, equivalent to 20 mg/kg of phenytoin. Within an hour of the loading dose, there was a significant decrease in PVCs, bigeminy, and ectopy. The DigiFab treatment was repeated, and fosphenytoin was continued every 12 hours throughout hospitalization. The patient died on hospital day 3 from renal complications; however, his arrhythmia was well controlled once the fosphenytoin was initiated. The patient did not have any known, direct complications from the fosphenytoin infusions.⁶

Conclusion

The current literature on the use of phenytoin for digoxin-induced arrhythmias is limited; however, available case reports have shown arrhythmia resolution. Further investigation is needed into the exact phenytoin dosing used. Phenytoin is a more cost-effective option than DigiFab and may be the most appropriate option in hospitals with limited resources without the traditional antidote, and for patients for whom DigiFab has been unsuccessful.

REFERENCES

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