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Phenytoin Poisoning, Emergency Medicine

Basics

Description

- 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

- Level 40 " “90 Ž ¼g/mL: - Level >90 mg/mL: - Coma - Respiratory depression - Paradoxical seizures

- ABCs: - IV access - Cardiac monitor (with IV overdose)

  • 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 phenytoinChange in dosage formDrug interactionChange in serum albumin

Diagnosis

Signs and Symptoms

  • Level 20 " “40 Ž ¼g/mL (or mg/L):NystagmusDizzinessAtaxiaDrowsinessNausea/vomitingDiplopiaSlurred speech
  • Level 40 " “90 Ž ¼g/mL:
  • Level >90 mg/mL:ComaRespiratory depressionParadoxical seizures
  • Hypotension/bradycardia with rapid IV administration:Fosphenytoin injection does not contain propylene glycolHypotension/dysrhythmia unlikely with fosphenytoin
  • Hypersensitivity reaction following chronic use:RashFeverNeutropeniaAgranulocytosisHepatitisCholangitis

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 manufacturersRepeat 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 phenytoinMeasure 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 formulationDetermine 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 accessCardiac 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 charcoalAdminister 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)