Barbiturate toxicity

An uncommon presentation but you need to know that barbiturates can cause a profound coma mimicking brain death. Without good supportive care this overdose or mis-adventure can be lethal.

Toxic Mechanism:

Barbiturates cause CNS depression by enhancing GABA – they increase the opening of the chloride channel on the GABA complex. Barbiturates also block the excitatory neurotransmitter glutamate. This combined action results in the inhibition of the cardiorespiratory centres and the hypothalamic autonomic nuclei resulting in hypotension, hypothermia and respiratory arrest.

Toxicokinetics: 

  • Well absorbed orally, however there is rapid redistribution and high volumes of distribution resulting in only a few barbiturates having any medical benefit of given orally. Hence the use of the short acting barbiturates thiopentone and pentobarbitone via the IV route
  • Oral barbiturate use includes phenobarbitone and primidone which are less lipid soluble, distribute more slowly to the CNS and have slower redistribution away from the CNS. They have a slow onset of action and a small volume of distribution 0.9L/kg.
  • All are metabolised by saturable hepatic microsomal pathways.
  • Phenobarbitone undergoes both enterohepatic and enteroenteric recirculation and 25 – 50% is excreted unchanged in the urine
  • Phenobarbitone has a prolonged half-life ranging from 35 – 140 hours.

Resuscitation:

  • Reduced GCS: Intubate and ventilate early if there is a declining GCS.

Risk Assessment

  • >8 mg/kg of phenobarbitone is expected to produce toxic neurological symptoms in the non-tolerant individual. Multiples above this dose are expected to produce a profound coma.
  • Patients who have injected a large dose of thiopentone or pentobarbitone in a suicide attempt often have a fatal outcome with the onset of toxicity occurring within seconds to minutes. If they make it to hospital and receive supportive care the coma is expected to last 24 – 48 hours.
  • Oral ingestion of phenobarbitone or primidone takes 1 – 2 hours to reach clinical toxicity but the coma may persist for days or weeks.
  • Children: most toxicity is secondary to therapeutic error. >8 mg/kg of phenobarbital or >40 mg/kg of primidone would cause neurological symptoms requiring medical assessment.
  • Clinical features:
    • CNS: Ataxia, lethargy, slurred speech, drowsiness, vertigo and nystagmus followed by coma, hypotonia, hypothermia and respiratory arrest. In high doses the coma can mimic brain death with loss of brainstem reflexes, even an EEG can look like brain death with a barbiturate overdose.
    • CVS: Tachycardia, and hypotension in large overdose secondary to medullary depression, peripheral vasodilatation and direct myocardial depression.
    • Other: Hypothermia, reduced bowel sounds, skin bullae over pressure areas (Barbiturate blisters – however, not specific to barbiturates).

Supportive Care

Investigations

  • Screening: 12 lead ECG, BSL, Paracetamol level
  • Specific: 
    • Barbiturate levels: Phenobarbitone is the easiest to source but all levels correlate well with CNS depression. Serial levels are essential in those who are comatose to guide enhanced elimination. In patients that are alert they are not useful.
    • A phenobarbitone level >100 mg/L (>430 micromol/L) prompts consideration for haemodialysis.
    • [DDET + Correlation between phenobarbitone levels and clinical features] [table id=185 /] [/DDET]

Decontamination:

  • Activated charcoal 50 grams (1 g/kg in children) can be given only once the airway has been secured via a nasogastric tube.

Enhanced Elimination

  • Haemodialysis can be used to shorten the length of stay in ICU and expedite neurological review. Most commonly it is used in the long-acting barbiturates where prolonged coma is expected (phenobarbitone and primidone).
  • A phenobarbitone level >100 mg/L (>430 micromol/L) prompts consideration for haemodialysis or haemodynamic instability, evidence of end organ dysfunction, climbing/plateauing levels despite MDAC (if appropriate).
  • Multiple-dose activated charcoal (MDAC) can increase the rate of elimination in phenobarbitone.

Antidotes

  • None available

Disposition

  • All children who have ingested >8 mg/kg of phenobarbital or >40 mg/kg of primidone requiring medical assessment. They can be discharged if they remain asymptomatic for 6 hours post ingestion.
  • Adults as well can be monitored for 6 hours and if asymptomatic can be medically cleared.
  • Symptomatic patients require admission and if there is significant CNS depression, intubation and ICU.

References and Additional Resources

Additional Resources:

References:

  • Ebid A-HIM, Abdel-Rahman HM. Pharmacokinetics of phenobarbital during certain enhanced elimination modalities to evaluate their clinical efficacy in management of drug overdose. Therapeutic Drug Monitoring  2001; 23(3):209-216.
  • Frenia ML, Schauben JL, Wears RL et al. Multiple-dose activated charcoal compared to urinary alkalinization for the enhancement of phenobarbital elimination. Clinical Toxicology 1996; 34(2):169-175.
  • Murray L et al. Toxicology Handbook 3rd Edition. Elsevier Australia 2015. ISBN 9780729542241
  • Pond SM, Olson KR, Osteroloh JD et al.  Randomized study of the treatment of Phenobarbital overdose with repeated doses of activated charcoal.  Journal of the American Medical Association 1984; 251(23):3104-3108.
  • Roberts DM, Buckley NA. Enhanced elimination in acute barbiturate poisoning – a systematic review. Clinical Toxicology 2011; 49:2-12

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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

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