Bhansali S, Tan RBM, Spilios M, Cecchin F. Pacing Clin Electrophysiol. 2022 Dec;45(12):1385-1389. doi: 10.1111/pace.14565. PMID: 35903996.
Take Home Points:
- Phenytoin should be part of the cache of anti-arrhythmic medications for ventricular arrhythmias.
- A phenytoin therapeutic range for the management of arrhythmias has not been established. The 10-20 mcg/mL therapeutic range was developed for the treatment of seizures.
- Phenytoin serum levels between 10-40 mcg/mL may be necessary to achieve rhythm control, whilst monitoring for side effects.
Commentary from Dr. Robert Gallotti (Seattle, USA ), section editor of EP Journal Watch:
Phenytoin, as a clinical pharmacologic agent, has been described in over 100 diseases over the course of the past century. The paper by Bhansali et al. describes two cases where high dose phenytoin was used to control malignant ventricular arrhythmia, as well as a literature review of the medication.
The first case described was that of a full-term infant with a heterozygous SCN5A mutation (Q1474P) in the NaV1.5 inactivation gate, and a common polymorphism (K897T) in KCNH2 gene. Shortly after delivery for fetal bradycardia, the infant was noted to have 2:1 atrioventricular block with frequent episodes of torsades de pointes (TdP), and a baseline QTc of 680 milliseconds. Early pharmacologic therapies included isoproterenol, magnesium, propranolol and mexiletine. The infant underwent dual chamber implantable cardioverter defibrillator as well as a left cardiac sympathetic denervation (LCSD) at 1 month of age. On a combination of propranolol, ranolazine and mexiletine, partial rhythm control was achieved (+TdP, but no ICD shocks). This regimen sustained the patient until 1 year of age, at which time they began having appropriate ICD shocks. Mexiletine dosing was plagued by seizures at higher serum levels and breakthrough arrhythmic storms if a lower serum level was targeted.
Fosphenytoin was given as a last-ditch effort during an arrhythmic storm, which resulted in an abrupt termination of TdP. The patient was eventually transitioned to oral phenytoin with a trough serum level maintained between 20-30 mcg/mL. After 6 months of rhythm control, the medication regimen was simplified to propranolol and phenytoin, on which the patient has been successful managed for 6 years. Breakthrough arrhythmic events have occurred only in the setting of malabsorption secondary to viral gastroenteritis.
The second case described was that of an 11-year-old who initially presented with syncope and polymorphic ventricular tachycardia (VT). His genetic evaluation revealed a heterozygous VUS in the KCNH2 gene (A190T). Two years after his initial presentation, the patient began having repetitive polymorphic VT and ventricular fibrillation events resulting in appropriate ICD shocks. Lidocaine, amiodarone, esmolol, and procainamide were administered sequentially, with no significant effect on arrhythmia burden. The patient eventually developed VF refractory to defibrillation necessitating CPR. A fosphenytoin bolus was given which allowed them to be successfully defibrillated. Given poor hemodynamics, ECMO cannulation was performed. During this time, the patient was noted to have frequent PVC’s that would trigger non-sustained VT. He was taken to the electrophysiology lab, where PVCs were mapped and successfully ablated on the LV apex.
Following this procedure, the patient was able to be decannulated and eventually discharged on amiodarone, nadolol, and phenytoin. On a subsequent hospitalization for breakthrough arrhythmia, the patient’s anti-arrhythmic regimen was adjusted to flecainide and high dose phenytoin (serum level 25-40 mcg/mL). The patient has been successfully maintained on this regimen for 2 years.
Discussion:
The authors of this paper presented two cases of malignant ventricular arrhythmias of probable different etiologies (1 due to SCN5A gain-of-function mutation, 1 of unknown mechanism), where high dose phenytoin played a crucial role in gaining and maintaining rhythm control. The use of phenytoin in patients with long QT syndrome, is certainly not novel, dating back to 1984 when a case series described the inadvertent use of phenytoin in two families who had been misdiagnosed with epilepsy rather than long QT.
While phenytoin has been in use for many decades, and is available in oral, intravenous, and intramuscular forms, pediatric dosing is not well studied. The therapeutic range of 10-20 mcg/mL for serum blood levels, was developed for the management of seizures. The authors of this paper note that the therapeutic range for the management of arrhythmias has not been determined, and both cases presented required serum levels >25 mcg/mL to achieve and maintain rhythm control.
Side effects of phenytoin are typically dose related, and most commonly begin when serum levels are >20 mcg/mL, however, there have been case reports of a few patients showing no signs of toxicity even at serum levels >40 mcg/mL. Side effects include nystagmus, ataxia, lethargy, coma. Hypersensitivity or idiosyncratic reactions can occur within weeks of therapy and are not dose related. Long-term use leads to gingival hyperplasia in younger patients and can lead to calcium deficiency.
