aka Toxicology Conundrum 046
A 41-year old man is brought to ED after becoming drowsy while in police custody. He states that he has taken an overdose of diazepam tablets prior to being arrested. On arrival to ED he is ataxic and mildly drowsy (GCS 14). He is admitted to the medical ward for observation. Around eight hours later a MET call is placed as he has become unmanageable on the ward…
When the MET team arrives, he is confused, restless and continually trying to climb out of bed. He appears to be hallucinating and is picking at imaginary objects in the air. His pupils are fixed and dilated. He has a marked sinus tachycardia (140bpm), with low BP (90/62). His skin is flushed and warm. Mucous membranes are dry. Temperature is 38 C. A catheter has been inserted for urinary retention after a bladder scan showed 850ml in his bladder. Attempts have been made to sedate him using antipsychotic agents, but this has only made him worse!
Q1. Is this presentation consistent with benzodiazepine overdose?
- Benzodiazepine overdose typically produces mild sedation, lethargy, slurred speech and ataxia.
- More significant CNS depression may be seen with ingestion of alprazolam or in the presence of co-ingestants (alcohol, opioids).
- Massive benzodiazepine ingestion may result in hypothermia, bradycardia and hypotension.
However… agitation, tachycardia, urinary retention and dilated pupils are not features of benzodiazepine overdose.
This presentation is not consistent with isolated benzodiazepine overdose.
Q2. What toxidrome is this patient experiencing?
This patient has developed a classic anticholinergic toxidrome.
The hallmark of this toxidrome is an agitated delirium accompanied by variable signs of central and peripheral muscarinic (acetylcholine) receptor blockade.
Signs of central muscarinic blockade:
Agitated delirium characterised by
- Fluctuating mental status
- Visual hallucinations
- Picking at objects in the air
- Mumbling slurred speech
- Disruptive behaviour
Tremor, myoclonus, coma, seizures (rare)
“A fumbling, mumbling mess”
Signs of peripheral muscarinic blockade:
- Dilated pupils
- Sinus tachycardia
- Dry mouth
- Hot, flushed, dry skin
- Increased temperature
- Urinary retention
Q3. What types of drug may produce this toxidrome?
There are numerous agents that may produce an anticholinergic toxidrome. The most important ones are summarised below.
- Antihistamines – promethazine, doxylamine, diphenhydramine, chlorpheniramine.
- Antipsychotics (phenothiazines and butyrophenones) – chlorpromazine, droperidol, haloperidol.
- Atypical antipsychotics – olanzapine, quetiapine.
- Anticonvulsants – carbamazepine.
- Antidepressants – tricyclic antidepressants.
- Antispasmodics – hyoscine butylbromide (Buscopan), oxybutynin.
- Antiemetics – hyoscine hydrobromide (Kwells).
- Antiparkinsonian agents – benztropine.
- Antimuscarinics – atropine, glycopyrrolate (usually only peripheral symptoms).
- Plants – Datura species (Jimsonweed), certain mushrooms.
Q4. How is this toxidrome managed?
These patients are very demanding and require scrupulous supportive care to manage the behavioural effects of delirium and prevent complications such as dehydration, injury and pulmonary aspiration:
- Sedation is usually required for behavioural control. Benzodiazepines are the first-line therapy, e.g. IV diazepam in 5mg-10mg increments, aiming for a patient that is sleepy but easily roused. Avoid over-sedating the patient as this will increase the risk of aspiration.
- One-to-one nursing is frequently necessary to maintain adequete supervision.
- Intravenous fluids should be prescribed as patients are typically unable to eat and drink and may be dehydrated at presentation.
- Insertion of a urinary catheter is usually required for management of urinary retention.
- Avoid using sedative drugs with anticholinergic properties (e.g. antipsychotics such as olanzapine) as this will exacerbate the delirium.
Q5. Is there an antidote?
Physostigmine is the specific antidote to anticholinergic delirium and may be used for behavioural control in carefully selected cases.
Mechanism of action
- Physostigmine is a reversible acetylcholinesterase inhibitor (similar to carbamate insecticides).
- It temporarily blocks the breakdown of acetylcholine, thus enhancing its effects at muscarinic and nicotinic receptors.
- This increased cholinergic activity overcomes muscarinic receptor blockade, transiently reversing the effects of the anticholinergic agents.
- Severe anticholinergic delirium unresponsive to benzodiazepine sedation.
- Poisoning with a pure anticholinergic agent (e.g. atropine).
- AV block
- Interventricular conduction abnormality (QRS >100ms)
Excessive dosing may produce side-effects due to excess cholinergic activity, resulting in a clinical picture similar to organophosphate poisoning.
- Bronchospasm, Bronchorrhoea and Bradycardia (the “killer bees”)
- “SLUDGE syndrome” with excess Salivation, Lacrimation, Urinary incontinence, Diarrhoea, Gastrointestinal upset and Emesis.
- Seizures may occur with rapid IV administration due to central cholinergic hyperactivity.
- Muscle weakness due to excess acetylcholine at the neuromuscular junction (suxamethonium-like effect).
Dosage and Administration
- Must be given in a monitored setting with appropriate staff and resources to manage adverse effects such as seizures, bradyarrhythmias and respiratory distress.
- Ensure there is no bradycardia / AV block / broad QRS on the 12-lead ECG.
- Give IV physostigmine 0.5 – 1mg as a slow push over 5 mins; repeat every 10 mins up to a maximum of 4mg.
- The clinical end-point of therapy is resolution of delirium.
- Delirium may reoccur in 1-4 hours as the effects of physostigmine wear off, at which time the dose may be cautiously repeated.
The response to therapy may be very dramatic (“end of the needle” response), with patients converted from a “fumbling, mumbling mess” into well-behaved, coherent individuals within seconds.
In this case, physostigmine was avoided as the patient had a history of seizures. He ultimately required intubation for florid delirium unresponsive to benzodiazepine sedation. Subsequently it emerged that he had been admitted under Toxicology earlier in the year for a large olanzapine overdose.
Q6. Is this presentation consistent with olanzapine overdose?
Yes and no.
- Olanzapine overdose may produce drowsiness and anticholinergic delirium.
- However, like other atypical antipsychotic drugs (quetiapine, clozapine), olanzapine causes paradoxically small pupils (due to peripheral alpha blockade) rather than the dilated pupils seen in this case.
The following day he is extubated in ICU. He tells you that he took an overdose of his girlfriend’s epileptic medications. He cannot remember the name of the medication but states that they were 400mg tablets that came in a yellow-and-white box; he took around 25 tablets in total.
Q7. Which drug is likely to be responsible for his clinical presentation?
- The history of anticonvulsant ingestion causing gradual onset of progressive drowsiness and anticholinergic delirium with deterioration over an 8-hour period is consistent with an extended-release carbamazepine preparation.
- He had taken 25 x 400mg Tegretol CR tablets (= 10g carbamazepine or ~140mg/kg)
- Carbamazepine level added onto his admission bloods confirmed ingestion, with a serum level of 39 mg/L.
Q8. Describe the toxicokinetics of this drug.
- Absorption: Carbamazepine is slowly and erratically absorbed. Peak plasma concentrations are typically delayed for 8-12 hours following ingestion. In overdose, ileus secondary to anticholinergic effects may result in ongoing absorption over several days. There are reports of peak levels being delayed by up to 96 hours following massive overdose with controlled-release tablets.
- Bioavailability is approximately 100% for the standard release preparation and 85% for the controlled release preparation.
- Distribution: Small volume of distribution (0.8 – 1.2 L/kg), hence may be cleared by dialysis.
- Protein Binding: 70-80% protein bound.
- Metabolism: Metabolised in the liver by cytochrome P450 3A4 to an active metabolite, carbamazepine 10,11 epoxide. This is further metabolised to inactive metabolites that are excreted in the urine.
- Excretion: Approximately 70% of an ingested dose is excreted in the urine as epoxidated, hydroxylated or conjugated metabolites; the remaining 30% is excreted in the faeces.
Q9. What are the usual toxic effects in overdose?
Carbamazepine causes gradual onset (over 8-12 hours) of the following symptoms:
- CNS effects – Cerebellar signs (ataxia, dysarthria, nystagmus, ophthalmoplegia), myoclonus, drowsiness, coma.
- Anticholinergic effects – See above.
- Sodium-channel blockade – Carbamazepine is structurally similar to the TCA imipramine and exerts similar (albeit less pronounced) sodium-channel blocking effects in overdose. Massive overdoses (>>50mg/kg) may be complicated by paradoxical seizures, hypotension and cardiac conduction abnormalities (1st degree AV block, QRS prolongation) with potential for ventricular dysrhythmias (rare).
Some example ECGs of carbamazepine cardiotoxicity can be found here.
Q10. What is the dose-related risk assessment for this agent?
The dose-related risk assessment for carbamazepine is summarised below:
- 20-50mg/kg - Mild-moderate CNS and anticholinergic effects.
- > 50mg/kg - Fluctuating mental status with intermittent agitation and risk of progression to coma within the first 12 hours. Risk of hypotension and cardiotoxicity with massive doses.
Hence 140mg/kg is a sigificant carbamazepine overdose.
Our patient did have some initial hypotension that responded to fluids and ECG changes suggestive of cardiotoxicity (QRS broadening to 120ms, R’ wave in aVR of 2-3mm), but never became cardiovascularly unstable.
Q11. How do serum levels correlate with toxicity?
- 8-12 mg/L = Normal therapeutic range
- >12mg/L - Nystagmus and ataxia
- >20mg/L - Drowsiness and anticholinergic delirium
- >40mg/L - Coma, seizures and cardiac conduction abnormalities
The level of 39 mg/L is consistent with his symptoms.
Q12. How is poisoning with this agent usually managed?
- Intubation and ventilation may be required for coma with loss of airway reflexes or for florid combative delirium not responsive to other measures.
- Paradoxical seizures are managed with titrated doses of benzodiazepines (e.g. diazepam 5-10mg IV). Barbiturates are second-line agents for refractory toxicological seizures (e.g. RSI with thiopentone 3-5 mg/kg).
- Ventricular dysrhythmias due to sodium-channel blockade are treated with boluses of IV sodium bicarbonate.
- Paracetamol level, 12-lead ECG, blood sugar (= routine toxicological screening tests).
- Serum carbamazepine level (repeat every 6 hours in comatose patients).
- Serial ECGs to assess for cardiotoxicity.
- Oral activated charcoal (50g) may be given to patients who present early and asymptomatic with ingestions <50mg/kg.
- In patients with established CNS toxicity, charcoal is only given once the patient has been intubated and nasogastric tube position has been confirmed on chest x-ray.
Enhanced elimination techniques are used with aim of reducing the duration of mechanical ventilation and ICU stay.
- Carbamazepine coma is the most common indication for multiple-dose activated charcoal (MDAC). This treatment works by interrupting enterohepatic circulation and reducing ongoing absorption from the gut. Doses of nasogastric charcoal (25g) are given every 2-4 hours until levels are falling, the patient is improving or bowel sounds disappear (e.g. due to anticholinergic ileus). There is a potential risk of bowel obstruction from charcoal concretions.
- Carbamazepine and its active metabolite (10,11 epoxide) can be removed by haemodialysis / CVVHD. Indications for extracorporeal elimination are not clear but it may be considered in comatose patients with large ingestions and evidence of haemodynamic instability or rising serum levels after 48 hours.
- For a light-hearted spot of revision, check out this clever little ditty by Ed Schaefer.
- Anonymous. Position statement and practice guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. J Toxicol Clin Toxicol. 1999;37(6):731-51 [abstract].
- Graudins A, Peden G, Dowsett RP. Massive overdose with controlled-release carbamazepine resulting in delayed peak serum concentrations and life-threatening toxicity. Emerg Med (Fremantle). 2002 Mar;14(1):89-94 [abstract].
- Harder JL, Heung M, Vilay AM, Mueller BA, Segal JH. Carbamazepine and the active epoxide metabolite are effectively cleared by hemodialysis followed by continuous venovenous hemodialysis in an acute overdose.
Hemodial Int. 2011 Jul;15(3):412-5 [abstract].
- Olsen KR. Poisoning and Drug Overdose (5th edition), McGraw-Hill, USA 2007.
- MICROMEDEX 2.0 (database). Accessed 06/12/2011.
- MIMS Online (database). Available at https://www.mimsonline.com.au. Accessed 06/12/2011.
- Murray L, Daly FFS, Little M, and Cadogan M. Toxicology Handbook (2nd edition), Elsevier Australia 2011. [Google Books Preview].
- Ram Prabahar M, Raja Karthik K, Singh M, Singh RB, Singh S, Dhamodharan J. Successful treatment of carbamazepine poisoning with hemodialysis: a case report and review of the literature. Hemodial Int. 2011 Jul;15(3):407-11 [abstract].
- Soderstrom J, Murray L, Little M, Daly FF. Toxicology case of the month:
Carbamazepine overdose. Emerg Med J. 2006 Nov;23(11):869-71 [full text].