Carbamazepine toxicity

Carbamazepine overdose has a predictable dose-dependent CNS depression and anticholinergic effects. Carbamazepine if unique in the anticonvulsants that is also has sodium channel blocking effects and can act similarly in overdose to a tricyclic antidepressant and the role of sodium bicarbonate should be remembered.

Toxic Mechanism

Structurally similar to imipramine (TCA) and therefore acts as a sodium channel blocker. It also blocks noradrenaline re-uptake and is a muscarinic, nicotinic and NMDA central adenosine receptor antagonist.

Toxicokinetics: 

• Slow and erratic absorption, this is important in a large overdose due to the inevitable ileus that will form due to the anticholinergic effects. The patient then has a large tablet bezoar that has continued erratic absorption potentially resulting in a fluctuating GCS/recovery. Absorption can last for several days.
• Small volume of distribution 0.8 – 1.2L/kg
• Hepatic metabolism to the active metabolite carbamazepine 10,11 epoxide which is then metabolised to an inactive form and  excreted in the urine.

Resuscitation:

• Attention to ABC, if there is a reduced GCS or an unprotected airway intubation and ventilation will need to be performed.
• Ventricular dysrhythmias will require a bolus of sodium bicarbonate, 1 – 2 mmol/kg boluses aiming for resolution of the QRS to baseline or <100ms.
• 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
  • 20 – 50 mg/kg = Mild to moderate CNS and anticholinergic effects
  • >50 mg/kg = Fluctuating GCS with intermittent agitation with progression to a coma within 12 hours.
  • Higher doses increase the risk of hypotension and cardiac toxicity.
• Whether the preparation is standard release or slow-release dictates the timing of symptoms (4 -8 hour onset vs 12 hours)
• Large overdoses may have a greater anticholinergic prodrome prior to coma
• If a coma develops it should be predicted to last for several days as explained in the toxokinetic section.
• Pregnancy: Teratogenic, overdoses in the first trimester should warrant further antenatal assessment.
• Children: Ingestion of one 400mg tablet is enough to cause significant intoxication in a toddler and warrants 8 hours of observation in hospital.
• Clinical features:
  • Mild to moderate CNS effects = nystagmus, dysarthria, ataxia, sedation, delirium, mydriasis, ophthalmoplegia and myoclonus
  • Fluctuating mental status with intermittent agitation leading to coma
  • Anticholinergic effects:

Supportive Care

• General supportive care
• Monitor for urinary retention
• If patient becomes agitated titrated doses of a benzodiazepine can be used for example 2.5 mg increments of intravenous diazepam until the patient is mildly sedated. This strategy may result in intubation and ventilation should absorption increase or high doses of benzodiazepines result in a reduced GCS.
• If intubated consider FASTHUGSINBEDPlease

Investigations

• Screening: 12 lead ECG, BSL, Paracetamol level
• Specific:
  • Carbamazepine levels:
    • 8 – 12 mg/L (34 – 51 micromol/L) = Therapeutic range
    • > 12 mg/L (51 micromol/L) = Nystagmus and ataxia
    • >20 mg/L (85 micromol/L) = CNS and anticholinergic effects
    • >40 mg/L (170 micromol/L) = Coma, seizures and cardiac conduction abnormalities
  • Serial 12 lead ECGs if the overdose is >50 mg/kg due to the sodium channel blocking effects. This should be performed every 12 hours unless there is an abnormality then more frequently. Typical findings are a 1st degree heart block and widening of the QRS.

Decontamination:

• Activated charcoal is considered in ingestions <50 mg/kg or larger ingestions of controlled-release if it is early post ingestion and the patient is asymptomatic.
• All other ingestions should receive activated charcoal once the airway is secured and via a nasogastric tube.

Enhanced Elimination

• Still remains controversial as their effect on outcome has not been studied in controlled trials
  • Multiple-dose activated charcoal is indicated in the intubated patient. Ceased immediately if bowel sounds stop. After the first 50 g of activated charcoal (1g/kg in children) repeat this at half dose (25g or 0.5g/kg in children)  every 2 hours if there is minimal aspirates from the nasogastric tube and bowel sounds are present. Treatment should rarely continue beyond 6 hours and needs re-evaluation with a toxicologist.
  • Haemodialysis and haemofiltration removes carbamazepine effectively. Indications include a prolonged coma with serum levels >40 mg/L (170 micromol/L) after 48 hours or haemodynamic instability.

Antidote

• None available

Disposition

• Children suspected of ingesting >20 mg/kg should be observed in hospital for at least 8 hours and not discharged overnight. (If a carbamazepine level is done after 1 hour and is negative this excludes ingestion and the child can be discharged).
• All patients who are clinically well at 8 hours with no anticholinergic features or sedation can be medically cleared.
• Patients with nystagmus, ataxia, drowsiness and anticholinergic effects are managed supportively in the ward environment after an 8 hour period of observation in the emergency department or HDU
• Patients with a reduced GCS or not protecting their airway require intubation and ICU admission. Patients who seize or are haemodynamically unstable also require ICU admission.
• Those admitted to ICU should be discussed with a toxicologist when extubation is being considered due to the risk of re-sedation with ongoing absorption. Practise varies but levels should be consistently low (<20 mg/L for at least 8 hours with no ongoing enhanced elimination)

Additional Resources and References

Additional Resources:

• ECG library – Carbamazepine toxicity
• CCC – Sodium channel blockade
• Tox Flashcard – Anticholinergic Toxidrome
• Tox conundrum 046 – A Fumbling, Mumbling Mess!

Video

References:

• Apfelbaum JD, Carabati EM, & Kerns WP II. Cardiovascular effects of carbamazepine toxicity.  Annals of Emergency Medicine 1995; 25: 631-635.
• Hojer J, Malmlund HO, Berg A. Clinical features in 28 consecutive cases of laboratory confirmed massive poisoning with carbamazepine alone. Journal of Toxicology-Clinical Toxicology 1993; 31:449-458
• Jones AL, Proudfoot AT. Features and management of poisoning with modern drugs used to treat epilepsy. Quartery Journal of Medicine 1998; 91:325-332
• Murray L et al. Toxicology Handbook 3rd Edition. Elsevier Australia 2015. ISBN 9780729542241
• Spiller HA. Management of carbamazepine overdose. Pediatric Emergency Care 2001; 17(6):452-456.
• Tapolyai M et al. Hemodialysis is as effective as hemoperfusion for drug removal in carbamazepine poisoning. Nephron 2002; 90(2): 213-215