Benzodiazepine toxicity

We discuss the management of benzodiazepine overdose including zopiclone and zolpidem as which carefully selected cases to use flumazenil. Benzodiazepines are a frequent presentation either as a single ingesting or in combination. With good supportive care prognosis is excellent.

Toxic Mechanism

Simple mechanism, they enhance the inhibitory neurotransmitter GABA by increasing the opening frequency of chlorine.

Toxicokinetics: 

• Rapid oral absorption
• Highly protein bound
• Varied Volume of distribution 0.4 – 4L/kg
• Hepatic metabolism to active metabolites
• Duration of effect depends on CNS tolerance and redistribution, rather than rate of elimination.

Resuscitation:

• Standard ABCDE approach 
• If patient is not protecting their airway or has an aspiration risk intubation is recommended.

Risk Assessment

• Usually isolated benzodiazepine overdose causes only mild sedation and can be managed with simple supportive care. The addition of other agents or ethanol will change your risk assessment and increase length of stay and mortality.
• Alprazolam causes greater CNS depression and is more likely to require intubation and ventilation.
• Zolpidem and zopiclone rarely cause severe CNS or respiratory depression
• Patients with a cardiac or respiratory history are at risk of greater complications
• Children: Ingestion of 1 -2 tablets manifests as mild sedation and ataxia within 2 hours.
• Clinical features: correlate poorly to benzodiazepine levels
  • Onset within 1 -2 hours
  • Ataxia, lethargy, slurred speech and reduced GCS. Profound coma is rare except with alprazolam or in mixed ingestions.
  • Apnoea indicated airway obstruction
  • Large ingestions can rarely cause hypothermia, bradycardia and hypotension.
  • Resolution of CNS depression occurs within 12 hours (unless elderly or co-morbidities), ataxia will persist for longer and your patient may be a falls risk.

Supportive Care

• General supportive care
• Monitor for urinary retention

Investigations

• Screening: 12 lead ECG, BSL, Paracetamol level

Decontamination:

• Activated charcoal is not recommended due to early onset of sedation and good outcomes are ensured by good supportive care.

Enhanced Elimination

• Not clinically useful.

Antidote

• Controversial – should be used with caution.
• Flumazenil is a competitive benzodiazepine antagonist. Indications include:
  • Reversal of conscious sedation (i.e. Iatrogenic over sedation)
  • Accidental paediatric ingestion
  • Diagnostic tool to avoid further investigation
  • Management of airway and breathing when resources are not available to safely intubate and ventilate the patient.
• The downside to giving flumazenil is the risk or precipitating a toxidrome or a seizure in someone who has either taken a mixed overdose or has a history of epilepsy or chronic benzodiazepine use. If the patient has a seizure you are now unable to give a benzodiazepine to terminate the seizure.

Disposition

• Most children can be observed at home unless there is significant ataxia or drowsiness.
• Patients with mild sedation can be managed supportively on the ward and discharged when clinically well (not at night)
• Patients who have significant CNS depression, intubation or a flumazenil infusion are admitted to intensive care or HDU.

Additional Resources and References

Additional Resources:

• CCC – Flumazenil
• CCC – Sedative toxidrome
• Tox conundrum 049 – Alprazoslammed

References:

• Buckley NA, Dawson AH, Whyte IM: Relative toxicity of benzodiazepines in overdose. British Medical Journal 1995; 310:219-221.
• Garnier R, Guerault E, Muzard D, et al. Acute zolpidem poisoning – analysis of 344 cases.  Journal of Toxicology-Clinical Toxicology 1994; 32(4):391-394.
• Isbister GK, O’Regan L, Sibbritt D et al. Alprazolam is relatively more toxic than other benzodiazepines in overdose. British Journal of Clinical Pharmacology 2004; 58(1): 88-95.