Phenytoin toxicity

Phenytoin intoxication can occur either with repeated supra therapeutic dosing or an acute overdose. Dose-dependent CNS depression occurs. Most presentations are benign and have good outcomes with supportive care. The main risk to patients is falling which can last days.

Toxic Mechanism:

Phenytoin is a sodium channel blocker, this is why you should never give it as an intravenous bolus. It would cause acute sodium channel blockade like a tricyclic antidepressant causing widening of the QRS with risk of dysrhythmias including VT. Specifically it suppresses membrane post-titanic potentiation and hyper excitability.

Toxicokinetics: 

  • Slow and erratic absorption orally.
  • Peak levels are delayed by 24 – 48 hours
  • Volume of distribution is 0.6 L/kg
  • Protein binding is high (90%)
  • It is metabolised in the liver, importantly this metabolism is saturable and plasma levels can rise dramatically with only a slight increase in daily dosing.
  • Elimination half-lives in a poisoned patient can vary between 24 to 230 hours.

Resuscitation:

  • Attention to ABC, if there is a reduced GCS or an unprotected airway or respiratory depression, intubation and ventilation will need to be performed.
  • Ventricular dysrhythmias (seen if phenytoin is given rapidly as an IV push, not with an oral overdose):
    • Sodium bicarbonate 2 mmol/kg IV repeated every 1-2 minutes to restore a perfusing rhythm, multiple doses maybe required.
    • It is unlikely that defibrillation will work.
    • Lignocaine 1.5 mg/kg IV is third line when the pH is >7.5
    • If the QRS persists in widening after boluses of sodium bicarbonate then the patient will require intubation and ventilation to maintain a pH>7.5
  • Seizures: IV benzodiazepines incrementally dosed every 5 minutes to effect.
    • Check the patient is not in a dysrhythmia
    • Can be managed with benzodiazepines (varying doses in the textbooks, easy method is 0.1mg/kg IV for lorazepam (max 4mg) / midazolam (max 10mg) / diazepam (max 10mg). Or…
    • Lorazepam 0.1mg/kg max 4mg
    • Diazepam 0.15mg/kg max 10mg
    • Midazolam 0.2mg/kg max 10mg

Risk Assessment

  • Dose-dependent CNS effects are seen. Mainly cerebellar features (ataxia, nystagmus, slurred speech, tremor, involuntary movements and ophthalmoplegia). These findings may be subtle in a patient with chronic toxicity, consider in anyone who has fallen on phenytoin.
    • 10 – 15 mg/kg = Standard therapeutic loading
    • >20 mg/kg = Ataxia, dysarthria and nystagmus
    • >100 mg/kg = Potential for coma and seizures
  • Coma and seizures are rare
  • Cardiovascular effects are only seen with rapid intravenous administration (hypotension, bradycardia, ventricular dysrhythmias and asystole)
  • Symptoms take hours to precipitate and 2 – 4 days to resolve as levels slowly fall.
  • Children: Ingestion of one to two 100 mg tablets is insufficient to cause symptoms.

Supportive Care

  • General supportive care
  • The main consideration is a falls risk secondary to the ataxia. Bed rails should be used along with assistance to mobilise.
  • If intubated consider FASTHUGSINBED Please

Investigations

  • Screening: 12 lead ECG, BSL, Paracetamol level
  • Specific:
    • EUC, VBG and serum osmolality  – hypernatraemia and hyperglycaemia can occur from a non-ketotic hyperosmolar coma in large overdoses.
    • Phenytoin levels – useful to confirm the diagnosis and levels correlate with toxicity:
      • Nystagmus >20 mg/L (80 micromol/L)
      • Severe ataxia 30 – 40 mg/L (120 -160 micromol/L)
      • Coma >50 mg/L (200 micromol/L)
    • ECG monitoring is not required for oral toxicity

Decontamination:

  • 50 g (1 g/kg in a child) of activated charcoal can be given within 4 hours of an acute oral overdose and may reduce the length of stay in hospital.

Enhanced Elimination

  • Both Multiple dose activated charcoal and charcoal haemoperfusion and plasmapheresis are all possible given the pharmacokinetics of phenytoin but are not routine choices. Consult a clinical toxicologist for advice as these can be utilised in massive overdoses.

Antidote

  • None available

Disposition

  • Children only require assessment and observation if they become symptomatic (ataxia or drowsiness) otherwise they can remain at home.
  • Patients who are asymptomatic 6 hours post ingestion (GCS 15, can heel-toe-walk) are medically fit for discharge. Discharge should not occur over night.
  • Those who develop symptoms will require the appropriate treatment and level of observation, usually on the ward. Most symptoms resolve within 2 – 4 days. Once asymptomatic and can walk they are medically fit for discharge.
  • Patients who require intubation and ventilation will require ICU.

Additional Resources and References:

Additional Resources:

Video: Sodium Channel Blockade and the ECG

References:


toxicology library antidote 700 1

Toxicology Library

DRUGS and TOXICANTS

Dr Neil Long BMBS FACEM FRCEM FRCPC. Emergency Physician at Burnaby Hospital in Vancouver Emergency. Loves the misery of alpine climbing and working in austere environments. Supporter of FOAMed, toxicology, tropical medicine, sim and ultrasound

Leave a Reply

This site uses Akismet to reduce spam. Learn how your comment data is processed.