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:

• Tox conundrum 023 – Toxic seizures
• CCC – Sodium channel blockers

References:

• Anonymous. Position statement and Practice Guidelines on the use of Multi-Dose Activated Charcoal in the Treatment of Acute Poisoning. Journal of Toxicology-Clinical Toxicology 1999; 37(6):731-751.
• Craig S. Phenytoin poisoning Neurocritical Care 2005; 3(2):161-70.
• Curtis DL et al. Phenytoin toxicity: A review of 94 cases. Veterinary and Human Toxicology 1989; 31(92):164-165.
• Jones AL, Proudfoot AT. Features and management of poisoning with modern drugs used to treat epilepsy. Quarterly Journal of Medicine 1998; 91:325-332.
• Skinner CG et al. Randomised controlled study on the use of multiple-dose activated charcoal in patients with supra therapeutic phenytoin levels. Clinical Toxicology 2012; 50:764-769
• Wyte CD, Berk WA. Severe oral Phenytoin Overdose does not cause cardiovascular morbidity. Annals of Emergency Medicine 1991; 20(5) 510-512.