Main Cardiovascular Adverse Effects of Phenytoin
The primary cardiovascular adverse effects of phenytoin include severe hypotension, cardiac arrhythmias (bradycardia, heart block, ventricular tachycardia, and ventricular fibrillation), which can progress to asystole, cardiac arrest, and death. 1
Critical Cardiovascular Complications
The FDA explicitly warns that rapid intravenous administration of phenytoin increases the risk of severe cardiovascular reactions, with cardiac arrhythmias documented to include: 1
- Bradycardia and heart block - can occur even at recommended doses and infusion rates 1
- Ventricular tachycardia and ventricular fibrillation - have resulted in asystole and cardiac arrest 1
- Severe hypotension - particularly in critically ill, elderly, or patients with pre-existing cardiac disease 1
High-Risk Patient Populations
Severe cardiovascular complications are most commonly encountered in: 1
- Critically ill patients
- Elderly patients
- Patients with hypotension and severe myocardial insufficiency
- However, cardiac events have also been reported in adults and children without underlying cardiac disease or comorbidities at recommended doses and infusion rates 1
Rate-Dependent Toxicity
The infusion rate is the most critical modifiable risk factor: 1, 2, 3
- Intravenous administration should not exceed 50 mg per minute in adults 1
- In pediatric patients, administer at a rate not exceeding 1 to 3 mg/kg/min or 50 mg per minute, whichever is slower 1
- Although cardiovascular toxicity risk increases with infusion rates above 50 mg/min, these events have been reported at or below the recommended infusion rate 1
- For patients older than 50 years or with atherosclerotic cardiovascular disease, infusion rates should not exceed 25 mg/min 3
Clinical Evidence from Studies
A review of clinical trials from 1946-2014 found that rapid infusion rate (>50 mg/min) was the major cause of increased mortality in case reports, while no serious cardiovascular adverse effects leading to death occurred in clinical trials that applied recommended infusion rates and dosages 2. A prospective study demonstrated that patients with atherosclerotic cardiovascular disease had significantly more cardiovascular side effects (hypotension and bradycardia) compared to younger patients without cardiac disease 3.
Oral Phenytoin Cardiovascular Effects
Cardiovascular adverse effects from oral phenytoin are exceedingly rare: 2, 4
- No cardiovascular adverse effects were reported in oral phenytoin overdoses except one case with extremely high serum phenytoin level (91 mcg/mL) and hypoalbuminemia, which resulted in life-threatening junctional bradycardia 4
- This patient required temporary transvenous pacemaker implantation 4
Essential Monitoring Requirements
Because adverse cardiovascular reactions have occurred during and after infusions, careful cardiac and respiratory monitoring is needed during and after the administration of intravenous phenytoin. 1
- Monitor vital signs closely, especially blood pressure and heart rate via continuous ECG 5
- Reduce infusion rate or discontinue if heart rate decreases by 10 beats per minute 5
- Reduction in rate of administration or discontinuation of dosing may be needed based on patient response 1
Mechanism of Cardiovascular Toxicity
IV phenytoin contains propylene glycol (40%) and ethanol (10%) with pH of 12, which contributes to adverse cardiovascular effects 5. This formulation explains why fosphenytoin (a water-soluble prodrug) has fewer adverse events compared to IV phenytoin loading 5, 6.
Clinical Pitfalls to Avoid
- Never assume young patients without cardiac disease are immune to cardiovascular complications - cardiac events have been documented in this population at recommended doses 1
- Do not rely solely on infusion rate control - cardiovascular toxicity can occur even at recommended rates 1
- Use oral phenytoin whenever possible due to the risks of cardiac and local toxicity associated with intravenous administration 1