Basics
Description
- Phenytoin follows zero-order pharmacokinetics:
- Small incremental increase in dose can result in a large increase in plasma concentration.
- Half-life in overdose prolonged; may be up to 70 hr
- Cardiovascular toxicity from IV administration likely due to the diluent propylene glycol
- Fosphenytoin, a prodrug for parenteral administration, is metabolized to phenytoin, its active moiety.
Etiology
- Phenytoin intoxication results from acute, chronic, or acute-on-chronic administration.
- If the cause of the intoxication is unclear in a patient receiving chronic phenytoin therapy, consider that there may have been a:
- Change in the brand of phenytoin
- Change in dosage form
- Drug interaction
- Change in serum albumin
Diagnosis
Signs and Symptoms
- Level 20 " “40 Ž ¼g/mL (or mg/L):
- Nystagmus
- Dizziness
- Ataxia
- Drowsiness
- Nausea/vomiting
- Diplopia
- Slurred speech
- Level 40 " “90 Ž ¼g/mL:
- Level >90 mg/mL:
- Coma
- Respiratory depression
- Paradoxical seizures
- Hypotension/bradycardia with rapid IV administration:
- Fosphenytoin injection does not contain propylene glycol
- Hypotension/dysrhythmia unlikely with fosphenytoin
- Hypersensitivity reaction following chronic use:
- Rash
- Fever
- Neutropenia
- Agranulocytosis
- Hepatitis
- Cholangitis
Essential Workup
- Determine the time, route, and amount of ingestion.
- Phenytoin level:
- After oral overdose, the peak plasma concentration may not be reached until 24 hr or more post acute ingestion.
- Absorption differs with various oral preparations and manufacturers
- Repeat levels every 4 hr until levels have peaked and continue to steadily decline.
- Once levels begin declining, check every 24 hr until <30 Ž ¼g/mL.
- Free phenytoin level may be required in patients who are hypoalbuminemic or patients who are poor metabolizers.
Diagnosis Tests & Interpretation
Lab
- Fosphenytoin level:
- Measured as phenytoin
- Measure fosphenytoin after conversion to phenytoin is complete (2 hr post IV infusion or 4 hr post IM injection).
- Prior to complete conversion to phenytoin, immunoanalytic techniques may overestimate plasma phenytoin concentrations due to cross-reactivity with fosphenytoin.
- Electrolytes, BUN, creatinine, glucose:
- Check for anion gap metabolic acidosis due to coingestant, seizure activity, from propylene glycol in the IV formulation
- Determine glucose with altered mental status.
Differential Diagnosis
- Intoxication with other CNS depressants
- Guillain " “Barre syndrome
- Botulism
- Posterior fossa tumor
- Acute cerebellitis
Treatment
Pre-Hospital
- Differentiate phenytoin-induced altered mental status from other potentially serious causes:
- Head trauma common in seizure population
- Collect/transport prescription bottles and medications to aid in identification and quantification of ingestion
Initial Stabilization/Therapy
- ABCs:
- IV access
- Cardiac monitor (with IV overdose)
- For altered mental status:
- Accu-Chek.
- Administer naloxone, dextrose, and thiamine as indicated.
- Treat hypotension with IV fluids and Trendelenburg position:
- Dopamine for refractory hypotension
- Treat paradoxical seizures with diazepam.
Ed Treatment/Procedures
- Provide supportive care
- Activated charcoal
- Administer single dose.
- Multiple-dose activated charcoal may increase the clearance of phenytoin; does not correlate with clinical improvement in patients with phenytoin toxicity.
Medication
- Activated charcoal slurry: 1 " “2 g/kg up to 90 g PO
- Dextrose: D50W 1 amp: 50 mL or 25 g (peds: D25W 2 " “4 mL/kg) IV
- Dopamine: 2 " “20 Ž ¼g/kg/min IV titrated to desired BP
- Naloxone (Narcan): 2 mg (peds: 0.1 mg/kg) IV or IM initial dose
- Thiamine (vitamin B1): 100 mg (peds: 50 mg) IV or IM
Follow-Up
Disposition
Admission Criteria
- Altered mental status, severe ataxia, increasing phenytoin level
- Level >25 Ž ¼g/mL
- ICU admission with intoxication from IV phenytoin
- Fall precautions
Discharge Criteria
- Level ≤25 Ž ¼g/mL
- Ambulatory without ataxia
Follow-Up Recommendations
- Psychiatric referral for intentional ingestions/suicide attempts.
- Close primary care follow-up to check phenytoin levels.
- Anticipate altered pharmacokinetics and phenytoin levels with any change in manufacturer or dosage formulation
Pearls and Pitfalls
- Small incremental increases in dose of phenytoin can result in toxicity since phenytoin follows zero-order kinetics.
- Repeat phenytoin levels every 4 hr until declining.
Additional Reading
- McCluggage ‚ LK, Voils ‚ SA, Bullock ‚ MR. Phenytoin toxicity due to genetic polymorphism. Neurocrit Care. 2009;10:222 " “224.
- Skinner ‚ CG, Chang ‚ AS, Matthews ‚ AR, et al. Randomized controlled study on the use of multiple-dose activated charcoal in patients with supratherapeutic phenytoin levels. Clin Toxicol (Phila). 2012;50:764 " “769.
- Von Winckelmann ‚ SL, Spriet ‚ I, Willems ‚ L. Therapeutic drug monitoring of phenytoin in critically ill patients. Pharmacotherapy. 2008;28:1391 " “1400.
Codes
ICD9
966.1 Poisoning by hydantoin derivatives ‚
ICD10
T42.0X1A Poisoning by hydantoin derivatives, accidental, init ‚
SNOMED
- 74882009 Poisoning by phenytoin (disorder)
- 290968007 Accidental phenytoin poisoning (disorder)