Can phenytoin cause cardiac arrhythmias, particularly with rapid intravenous administration?

Can Phenytoin Cause Arrhythmia?

Yes, phenytoin can cause serious cardiac arrhythmias, particularly with rapid intravenous administration, including bradycardia, heart block, ventricular tachycardia, ventricular fibrillation, asystole, and cardiac arrest. 1

Mechanism and Risk Factors

The cardiovascular toxicity of IV phenytoin is primarily related to:

• Rapid infusion rate exceeding 50 mg/min in adults or 1-3 mg/kg/min in pediatric patients 1, 2
• Formulation components: IV phenytoin contains propylene glycol (40%) and ethanol (10%) at pH 12, which contribute significantly to cardiac toxicity 3, 2
• High-risk populations: Critically ill patients, elderly patients, those with pre-existing cardiac disease, hypotension, or severe myocardial insufficiency 1

Critical caveat: Cardiac arrhythmias have been documented even at recommended doses and infusion rates in patients without underlying cardiac disease 1. This means adherence to infusion guidelines does not eliminate risk entirely.

Specific Arrhythmias Documented

The FDA label explicitly identifies these life-threatening arrhythmias associated with IV phenytoin 1:

• Bradycardia (including junctional bradycardia) 2, 4
• Heart block (various degrees) 2, 1
• Ventricular tachycardia 1
• Ventricular fibrillation 1
• Asystole and cardiac arrest 1, 5

Route-Specific Risk Profile

Intravenous administration carries the highest arrhythmia risk, with multiple case reports of cardiopulmonary arrest even with appropriate dosing and monitoring 5, 6. A systematic review found that rapid infusion (>50 mg/min) was the major cause of increased mortality in case reports, while clinical trials using recommended rates showed no deaths 7.

Oral phenytoin rarely causes cardiac toxicity. One retrospective study of 44 patients with oral overdose (peak levels up to 75 mcg/mL) found no clinically significant arrhythmias 8. However, one case report documented life-threatening junctional bradycardia with chronic oral overdose reaching 91 mcg/mL in a patient with hypoalbuminemia and hyperbilirubinemia 4.

Mandatory Safety Measures

When administering IV phenytoin, the following monitoring is non-negotiable 1, 2:

• Continuous ECG monitoring during and after infusion 2, 9
• Continuous blood pressure monitoring 2, 9
• Reduce infusion rate immediately if heart rate decreases by ≥10 beats per minute 3, 2, 9
• Maximum infusion rate: Never exceed 50 mg/min in adults or 1-3 mg/kg/min (whichever is slower) in pediatric patients 1, 9

Safer Alternative: Fosphenytoin

Fosphenytoin is strongly preferred over IV phenytoin when available because it has significantly fewer cardiovascular adverse events 3, 2. Key advantages include:

• Can be infused at up to 150 mg PE/min (three times faster than phenytoin) 2, 9
• Water-soluble formulation without propylene glycol or ethanol 3
• Lower risk of hypotension, bradycardia, and arrhythmias 3, 2
• Can be administered intramuscularly if needed 9

The American Academy of Pediatrics specifically recommends fosphenytoin when available due to lower cardiac toxicity risk 2.

Clinical Decision Algorithm

For status epilepticus or acute seizures requiring urgent anticonvulsant loading:

1. First choice: Use fosphenytoin if available (18-20 mg PE/kg IV at ≤150 mg PE/min) 2, 9
2. If only IV phenytoin available:
   • Assess cardiac risk factors (elderly, cardiac disease, hypotension, critical illness) 1
   • Ensure continuous cardiac/respiratory monitoring 1
   • Infuse at ≤50 mg/min in adults, ≤1-3 mg/kg/min in children 1, 9
   • Dilute only in normal saline, never dextrose 3, 9
3. Consider oral loading (20 mg/kg divided in 400 mg doses every 2 hours) for stable patients without active seizures, as this achieves therapeutic levels in 3-8 hours with minimal cardiac risk 3, 2