Amitriptyline is one of the most commonly used (and sometimes misused) tricyclic antidepressants. Amitriptyline is indicated for the treatment of major depression and as well as nocturnal enuresis (where organic pathology has been excluded). Their main therapeutic effect is thought to be due to inhibition of both noradrenaline and serotonin reuptake and is thought to lead to increased activity at their specific post-synaptic receptors. Amitriptyline is available in 10, 25 and 50mg tablets in Australia.

However, tricyclics also block inactivated fast sodium channels. Tricyclics are also similar in structure to phenothiazines and thus share many of their properties (serotonin and noradrenaline reuptake inhibition, alpha-2-adrenoreceptor blockade, muscarinic receptor blockade etc.).

These aspects of tricyclic pharmacology have significant implications with regards to their toxicology.

—

Return of the ADME:

• Absorption:
  — Rapidly absorbed following oral administration. Time to peak levels is 2 hours
• Distribution:
  — Large volume of distribution (5-20L/kg).
  — Highly bound to plasma and tissue proteins
• Metabolism:
  — Undergoes hepatic metabolism by oxidation via Cytochrome p450 to active metabolites such as nortriptyline
• Excretion:
  — Mainly in the urine as metabolites. Very little is excreted unchanged

—

As mentioned earlier, amitriptyline (like other tricyclic antidepressants) have multiple potential toxicological properties due to their structure, these are:

• CNS effects
  — Delirium/confusion/agitation, sedation, seizures, coma (often precedes cardiovascular signs)
• Cardiovascular effects
  — Sinus tachycardia, hypertension, hypotension (due to alpha2-adrenoreceptor blockade), broad complex tachycardia (can develop bradycardia pre-arrest)
• Anticholinergic effects
  — Can occur at time or presentation or be delayed and prolonged
  — Agitation, restlessness, delirium, mydriasis (big pupil), dry, warm skin, tachycardia, ileus, urinary retention
• Metabolic acidosis
  (remember she was tachypnoeic at presentation… trying to compensate for this!)

—

This patient has taken a life-threatening overdose and is predictably demonstrating many of the aforementioned clinical features associated with amitriptyline toxicity.

Murray et al (2011) states that ingestion of greater that 10mg/kg is thought to be considered potentially life-threatening and onset of severe toxicity often occurs within two hours of ingestion (how’s that for timing?). However the dose is less than 30 mg/kg, which is the dose expected to result in severe toxicity with pH-dependent cardiotoxicity and coma lasting >24 hours.

Nevertheless she is at significant risk of developing seizures, broad complex tachycardias, coma and ultimately cardiac arrest.

As always, co-ingestion should forever be sitting in the back of your mind as a possibility and management should be accompanied with appropriate investigations to exclude other potential toxins. Given her acute decrease in conscious state, drugs such as alcohol, opiates and other anti-depressants warrant consideration as possible co-ingestants.

—

Regardless of what you would do, this is what was actually done!

In this case, the patient was fortunately in the right place (resuscitation bay) and the decision was made to promptly sedate and intubate the patient with ongoing sedation via propafol infusion. Whilst the patient was initially given boluses of sodium bicarbonate along with crystalloid, this was later changed to a sodium bicarbonate infusion (100mmol in 1L N/Saline at 250ml/hr) that was continued during the patient’s ICU admission. Serial ECGs were utilised to monitor progress, looking for resolution of the ECG changes specific to amitriptyline toxicity.

We’ll talk some more about whether this was optimal management or not below…

Learn more:

• LITFL ECG Library — Tricyclic antidepressant overdose

—

Use the Resusi-RSI-DEAD approach as all good toxicologists do…

Resuscitation

• Amitriptyline and other tricyclic overdoses are potentially life-threatening and should be managed accordingly in an area that is able to provide appropriate monitoring, resuscitation and ventilatory support (given the high likelihood of intubation in significant overdoses)
• Intubation and hyperventilation (aim for pH 7.50-7.55) are mainstays of treatment for severe overdoses (where there is a decline in GCS) in addition to sodium bicarbonate (discussed below)
• Ventricular arrhythmias caused by amitriptyline toxicity are unlikely to respond to cardioversion or defibrillation
  — First line treatment is sodium bicarbonate (100mmol or 2mmol/kg) should be given IV every 1-2 minutes until rhythm and perfusion are restored
  — Second line treatment is lignocaine (1.5mg/kg) IV once pH is greater than 7.5
• Serial ECGs and blood gases are vital to proper and effective management
• Treat hypotension with volume- crystalloid, sodium bicarbonate or failing this, vasopressor (noradrenaline or adrenaline) infusions
• Treat seizures with benzodiazepines as per usual
• Don’t stop resuscitation until patient has been intubated, has received sodium bicarbonate and has been hyperventilated to achieve a pH of 7.50-7.55. Good neurological outcome following even hours of prolonged CPR and arrest is still possible.

Supportive care and monitoring

• Supportive care will suffice for small ingestions so it is essential that it is done properly!
• Secure appropriate IV access
• Ensure adequate hydration with IV fluids- crystalloid will suffice with small (<10mg/kg) ingestions
• Remember FASTHUGS IN BED Please especially pressure care, bladder care and DVT prophylaxis
• Cardiac monitoring should continue until toxicity is reversed if ECG changes are present

Investigations

• The ECG is one of the most vital investigations in this scenario
  — Diagnostic features include prolongation of QRS, PR intervals, dominant R wave in aVR, and QT prolongation
  — QRS widening reflects the degree of fast sodium channel blockade
  — QRS > 100ms is predictive of seizures, QRS > 160ms is predictive of ventricular tachycardia
• Paracetamol and blood glucose levels should be performed as recommended for all intentional overdoses
• Use blood gases to monitor the adequacy of alkalinisation
• Consider possible co-ingestants

Decontamination

• Activated charcoal can be useful for large ingestions >10mg/kg but should not be given without a definitive airway (i.e. a tube) being established prior
• Charcoal not indicated for smaller ingestions as supportive care is often enough

Enhanced elimination

• Not useful

Antidotes

• Sodium Bicarbonate is a key treatment in amitriptyline and other tricyclic antidepressant toxicity.
• This is discussed in great detail in another case of amitriptyiline toxicity in Toxicology Conundrum 022.

Disposition

• As in this case, patients with severe ingestions require HDU/ICU support (or alternatively transport to a more appropriate centre if warranted) until medically stable
• Patients with non-life-threatening overdoses (<10mg/kg) can be managed in an appropriate ward setting until clinically well
• Psychiatric review is mandatory.

—

The retrospectoscope is an amazing tool but never around until after its too late… funny that.

A few thoughts:

• Following intubation and establishment of a secure airway the patient could have been administered activated charcoal. There are few downsides in this setting and the activated charcoal might decrease any ongoing drug absorption from the gut.
• Whilst an infusion of sodium bicarbonate was used due to ongoing prolongation of the patient’s QRS and for practical reasons, boluses of sodium bicarbonate are thought to be more effective as they lead to rapid shifts in concentration of free drug due to the effect on binding to plasma and tissue proteins. Also infusions may lead to renal compensation and thus reduce the effectiveness of the antidote… throwing the baby (bicarbonate) out with the bath water (well… you know).
• Hyperventilation of intubated patients is an effective means of alkalinisation and could have been used may have achieved the same aim as a sodium bicarbonate infusion

In any event, the patient went on to do well. She was extubated the following day following reversal of her ECG changes and once medically cleared was admitted to an inpatient psychiatric unit for further management.

—

Alprazolam is a short-acting benzodiazepine.

Like other benzodiazepines, alprazolam binds to a specific site on the GABA-A receptor (gamma-amino-butyric acid) increasing the frequency of chloride channel opening. This is the basis for its anxiolysis, sedation, hypnosis, skeletal muscle relaxation, amnesia and anti-convulsant effects.

Alprazolam is typically used for the treatment of anxiety disorders including panic disorder, social anxiety disorder and generalised anxiety disorder. Alprazolam is available in Australia as a standard-release preparation ranging from 250micrograms to 2mg in dosage.

Alprazolam is considered to be more toxic in overdose than other benzodiazepines.

———

ADME again:

• Absorption
  — Rapid oral absorption ranging from 80 to virtually 100% complete. Peak levels in 1-2 hours.
  Distribution
  — Total body water (volume of distribution 0.8 to 1.3L/kg)
  — Highly protein-bound as observed with other benzodiazepines
• Metabolism
  — Metabolised into active alpha-hydroxy metabolites (less active than alprazolam itself) by hepatic microsomal oxidation.
• Excretion
  — Elimination half-life of 12 to 15 hours and clearance of 0.7 to 1.5ml/min/kg (reduced in the elderly and cirrhosis).
  — Metabolites excreted via urine.

———

Alprazolam, in particular, is associated with a greater degree of CNS depression compared with other benzodiazepines and there is increased need for intubation and ventilation.

Alprazolam overdose causes drowsiness, ataxia, and slurred speech 1-2 hours after ingestion (as reflected by the time to reach peak plasma levels). Conscious state can steadily decrease put the patient at risk of airway obstruction, hypoxia and aspiration. In very large ingestions, overdoses can produce cardiovascular compromise with bradycardia and hypotension in addition to hypothermia and rarely coma.

———

This patient has had a large alprazolam overdose with a predictable decrease on his level of consciousness.

As observed in most benzodiazepine overdoses, cardiovascular compromise is absent. Most benzodiazepine overdoses can be managed with supportive therapy — usually an overnight stay in an appropriate ward with psychiatric review once conscious state has improved.

This being said, despite the history of isolated alprazolam overdose, it is important to always consider the possibility of co-ingestion. This can have significant consequence both with regards to diagnosis and to appropriate toxicological management (such as consideration of the use of the benzodiazepine antagonist, flumazenil). Agents of note to consider are other CNS depressants such as alcohol, opiates and anti-depressants.

The use of flumazenil and whether it is appropriate to use in this scenario will be discussed later in the article.

———

As always with a tox case, we use the Resus-RSI-DEAD approach…

Supportive care is sufficient for most benzodiazepine overdoses in the absence of cardiovascular compromise, provided adequate toxicological work-up has been completed.

Resuscitation

• Patients should be managed in an appropriate environment with consideration to airway management in the event of obstruction secondary to decreased conscious state.
• Intensive resuscitation should be considered in the instance of very large ingestions of alprazolam alone or mixed polypharmacy overdose with significant compromise.
• Seek and treat potential life threats such as hypoxia due to respiratory depression, airway obstruction and/ or aspiration

Supportive care and monitoring

• Secure appropriate IV access
• Consider re-warming of patients in the event of hypothermia
• Remember FASTHUGS IN BED Please: especially pressure cares, bladder cares and DVT prophylaxis as required

Investigations

• Screening paracetamol level, blood glucose levels and 12-lead ECG
• Further investigations if complications, comorbidities or coingestions suspected

Decontamination

• As symptoms typically begin 1-2 hours after ingestion, there is no benefit in decontamination and administration of activated charcoal may lead to life-threatening aspiration in the sedated patient

Enhanced elimination

• Not clinically useful

Antidotes

• Flumazenil, a competitive benzodiazepine antagonist, can be considered in some instances of benzodiazepine overdose. This will be discussed in greater detail below.

Disposition

• Patients presenting with isolated alprazolam overdose without cardiovascular compromise should be managed as inpatients until clinically well (alert and able to eat, drink and ambulate safely).
• An observation ward environment with appropriately trained nursing staff is usually adequate and no intensive monitoring is required.
• Profound coma, cardiovascular compromise or ECG changes may suggest a co-ingestant and may contra-indicate ward management.
• Patients requiring intubation or flumazenil infusion require admission and management in an HDU/ICU environment until medically stable.

———

Flumazenil is a competitive benzodiazepine antagonist that is structurally similar to midazolam, and binds to the benzodiazepine receptor sites on the GABA-A receptor.

Binding inhibits benzodiazepine activity and reverses their effects on the CNS. Flumazenil is given intravenously (0.1-0.2mg IV) and doses repeated every minute until reversal of benzodiazepine effects achieved. Infusions can also be used but are rarely required.

———

Indications for flumazenil administration

• Benzodiazepine overdose
  — Accidental paediatric ingestion with compromised airway and breathing
  — Deliberate self-poisoning with compromised airway and breathing where equiptment/skills for intubation and/or ventilation not available
• Confirming the diagnosis of benzodiazepine overdose
• Reversal of benzodiazepine conscious sedation (iatrogenic overdose)

Contraindications

• Known seizure disorder
• Known or suspected co-ingestions of drugs with pro-convulstant properties
• Known benzodiazepine dependence
• QRS prolongation of ECG (i.e. suggestion of TCA co-ingestion)

———

There are three important considerations with regards to the use of flumazenil that can present challenges to the emergency physician.

• re-sedation is common after flumazenil administration and repeated doses or even an infusion may be required until the patient’s clinical state improves.
• flumazenil can precipitate withdrawal in patients with dependence on benzodiazepines (e.g. agitation, tachycardia and seizures)
• flumacan also cause seizures in patients with an underlying predisposition (e.g. pro-convulsant medication, epilepsy).

Recommended management of these symptoms is titrated doses of benzodiazepines but the use of the initial toxin to treat the side-effects of the antidote is a highly undesirable situation! Benzodiazepines will not be as effective in treating seizures secondary to flumazenil administration given the existing antagonism at the benzodiazepine receptors. Other agents (e.g. barbiturates, propofol) may be needed to control seizures and the patietn may require intubation and ventilation.

In this case, the patient was assessed in a hospital with sufficient resources to intubate and ventilate if airway and breathing became compromised. This patient was regularly using alprazolam for the past year thus dependence is likely. It is also worth noting that none of the indications for the administration of flumazenil were present. The risk-benefit balance does not favour the use of flumazenil in this setting.

Fortunately, the patient suffered no ill effects but no further flumazenil doses were administered after consultation with a toxicologist.  The patient was discharged the following day following psychiatric review.

———

Lithium is a small monovalent cation. It is primarily used as lithium carbonate in the treatment for bipolar affective disorder but its actual mechanism of action is not clearly understood. It is thought to modulate intracellular second messengers (such as inositol triphosphate) as well as affect neurotransmitter production and release.

Lithium carbonate is available as a standard release (250mg) or a slow-release (450mg) presentation.

———

Remember ADME:

• Absorption
  — With standard release preparations, absorption is virtually complete within 6-8 hours with peak plasma levels occurring within 4 hours.
  — Slow release preparations reach peak levels up to 12 hours
• Distribution
  — Total body water (Vd=0.7-0.9L/g) with slow entry into tissue compartments including the central nervous system.
  — No plasma protein binding.
• Metabolism
  — None
• Excretion
  — Almost entirely renally excreted (some sequestration in bone).
  — Excretion is dependent on creatinine clearance (about 20% equals lithium clearance) so is reduced in states such as hypovolemia, renal impairment and hyponatremia.
  — Elimination half-life is 24 hours

———

These do:

• Drugs
  — e.g. NSAIDs, ACE inhibitors, SSRIs, thiazide diuretics, topiramate
• Dehydration
• Hyponatremia
• Hyperthyroidism
• Renal impairment (acute or chronic)

———

Yes, it is relevant.

Lithium toxicity can present as two distinct entities, either:

• an acute poisoning (almost always a deliberate ingestion), or
• a chronic poisoning (usually where lithium excretion is altered by extraneous factors such as dehydration or renal impairment)

The context in which the patient presents determines how useful a lithium level is. In this case, the patient has acute lithium toxicity.

In acute ingestions, the plasma level allows confirmation of ingestion and allows monitoring of ongoing lithium excretion (important especially with regards to neurotoxicity caused by lithium), the latter also assisting in determining disposition.

In chronic poisoning, lithium levels help confirm the diagnosis but do not correlate well with the severity of toxicity (they do not reflect levels in tissue compartments well, most importantly in the central nervous system). As in acute poisoning, levels can also be used for monitoring in those receiving treatment.

———

Acute lithium toxicity mainly affects the GI tract as lithium (like other metal salts) is a direct irritant. It causes nausea, vomiting, abdominal pain and diarrhoea.

25 grams is the magic number for risk assessment

• Ingestions of less than 25 g are usually benign, causing the aforementioned symptoms.
• Ingestions greater than 25 g produce more severe GI symptoms but in rare cases can lead to the neurotoxicity seen in chronic lithium toxicity if clearance of lithium is impaired. Reduced ability to excrete lithium promotes entry of lithium into the central nervous system and can lead to subsequent neurotoxicity.

———

This patient has taken a large amount of lithium (much greater than 25 g) and has the classic GI symptoms of acute lithium ingestion. Of note, he has mild renal impairment, which, if it should worsen, could lead to neurotoxicity without appropriate supportive treatment.

The danger for this patient lies in the timing of treatment —  lithium clearance can become further impaired from the hypovolemia secondary to GI losses and consequently the risk of lithium neurotoxicity increases.

The patient’s alteration in heart rate may be related to lithium as it settled following treatment, but as he was not haemodynamically compromised it was of little further clinical relevance.

———

As lithium excretion is ultimately dependent on renal function, supportive therapy is paramount in both acute and chronic toxicity.

Resuscitation

• Patients should be managed in an appropriately equipped and staffed resuscitation area until potentially toxic coingestants are excluded.
• There are no immediate life threats in this patient.

Supportive care and monitoring

• Correction of water deficits and ongoing hydration with intravenous fluid to prevent renal impairment (e.g. normal saline). Monitor urine output, >1 ml/kg/hr is recommended
• Correction of sodium deficits is also important as this too can affect lithium clearance
• Avoidance and cessation of any drugs that impair lithium clearance
• Remember FASTHUGS IN BED Please as required

Investigations

• Screening paracetamol level, blood glucose and 12-lead ECG
• Lithium level
• Urea, electrolytes and creatine

Decontamination

• Whole bowel irrigation has been advocated for overdose with sustained-release preparations, however there is no proven benefit compared to supportive therapy alone.
• As with other metals, activated charcoal does not adsorb lithium effectively and is not recommended.

Antidotes

• There are no antidotes for either acute or chronic lithium toxicity

Enhanced Elimination

• As lithium is not protein bound and has a small volume of distribution, it is potentially amenable to haemodialysis.
• In acute toxicity, haemodialysis is reserved for patients with established renal failure and those presenting with features of neurotoxicity.
• There is no lithium level cut-off for hemodialysis in acute lithium toxicity, unlike chronic lithium toxicity where hemodialysis is usually advised if serum lithium levels are >2.5mmol/L.

Disposition

• Patients with renal impairment or signs of neurotoxicity should be managed in an HDU/ICU environment until medically stable.
• Acutely poisoned patients without these concerning features can be admitted for observation and supportive care until resolution of GI symptoms, and may need ongoing monitoring of renal function and lithium levels (until <2.5 mmol/L and falling).

———

• The Ramones
• As Leon said in Tox Tunes #35: “Not bad for a group that knew only 3 or 4 chords and whose entire play list contains few works much longer than 2 minutes.”
• Don’t believe it was the 144th greatest song of all time? Here’s the proof.

http://www.youtube.com/watch?v=lQeo3OfuEDM

• Doctor Robert
• The song by The Beatles is based on “a New York doctor who habituated his socialite clients to narcotics by mixing methedrine with vitamin shots”.
• Leon featured this track in Tox Tunes #6.

http://www.youtube.com/watch?v=hCpGy3pwkKM

• The Sonics
• They featured in Tox Tunes #24, where Leon notes that, among others, they were a big influence on the White Stripes. They hailed from Tacoma, WA, a stones throw from what would become the epicentre of the Grunge explosion many years later.
• Now might be a good time to check out our Strychnine Tox Conundrum too…

http://www.youtube.com/watch?v=f7Nffq0bOgE

• Cocaine
• As Leon tells us in Tox Tunes #10: “This Cole Porter song was introduced by Ethel Merman in the 1934 musical Anything Goes. At that time, apparently, no one had problems with the second verse”:

“Some they may go for cocaine,
I’m sure that if I took even one sniff
That would bore me terrifically too,
Yet I get a kick out of you.”

• The line was changed for the movie version to: “Some like the perfume from Spain”…

http://www.youtube.com/watch?v=FtwO2tKZmwQ

• aka Jake Walk or Jake paralysis, the term refers to an organophosphate-induced delayed paralysis caused by consumption of Jamaican Ginger aka Jake.
• Jake leg affected thousands in the American South and Midwest during prohibiton due to the adulteration of bootlegged Jamaican Ginger (~80% ethanol) with tri-ortho cresyl phosphate.
• Leon mentions Jake Leg here, in the context of the recent phenomenon of levamisole-adultered cocaine.

http://www.youtube.com/watch?v=P9UZct0EEH4

No.

• Quetiapine overdose characteristically causes brisk sinus tachycardia (e.g. 120-150 bpm) and QTc prolongation.
• Sinus bradycardia with a normal QTc is not consistent with quetiapine poisoning as the cause of coma.
• Fixed dilated pupils and loss of brainstem reflexes are also not consistent with quetiapine — despite having antimuscarinic effects, quetiapine normally causes paradoxically small pupils.

See an example ECG of a patient with quetiapine toxicity.

Baclofen

Baclofen is a synthetic derivative of GABA, used primarily for management of painful muscle spasms in conditions such as spinal cord injury, cerebral palsy and multiple sclerosis. It is closely related to the recreational drug, Gamma-Hydroxybutyrate (GHB).

In overdose, it causes a picture similar to barbiturate coma:

• Profound CNS depression with loss of brainstem reflexes.
• Flaccid tone with absent deep tendon reflexes.
• Bradycardia.
• Respiratory depression.
• Need for intubation and mechanical ventilation.
• Hypothermia.

Other effects seen with baclofen overdose:

• Hypertension or hypotension (the former is more commonly reported — the mechanism of this is unknown).
• Paradoxical seizures.
• Pupil abnormalitites — miosis or mydriasis.
• Agitated delirium.
• 1st degree AV block and QT prolongation are rarely reported.

The duration of coma is usually 24 to 48 hours but may be prolonged (i.e. several days) with massive doses or in patients with renal failure. 

• Baclofen acts as an agonist at pre- and postsynaptic GABA-B receptors in the brain and spinal cord.
• Therapeutic (antispasmodic) effects occur primarily at the spinal cord level; in overdose there is also increased GABA activity within the brain.
• Activation of presynaptic GABA-B receptors causes inhibition of excitatory neurotransmitter release within the CNS.
• The mechanism is thought to involve hyperpolarisation of the presynaptic membrane and reduced calcium influx into the nerve terminal with resultant impairment of calcium-dependent exocytosis of excitatory neurotransmitters.
• The net result is a generalised CNS depression similar to that seen with barbiturates, propofol and other general anaesthetics.
• Paradoxical seizures occur due to presynaptic inhibition of inhibitory neurons (i.e. disinhibition).

• Rapidly and completely absorbed following oral administration.
• Peak serum levels occur at ~ 2 hours post ingestion.
• Lipophilic so readily crosses the blood-brain barrier.
• Relatively small Vd (0.7 L/kg).
• Primarily excreted unchanged in the urine.
• 15% metabolised by the liver.
• The mean elimination half-life is 3.5 hours, although this may be prolonged in overdose (15-35 hours in some case reports).

• Acute ingestion of > 200 mg is expected to produce significant CNS toxicity, with delirium, coma and paradoxical seizures.
• This amounts to only 8 x 25 mg tablets or 20 x 10 mg tablets.
• Smaller doses may cause mild drowsiness and delirium.

Our patient had ingested an enormous overdose of 2,500 mg of baclofen (a entire bottle of 100 x 25 mg tablets)!

Other agents that may cause coma with transient loss of brainstem reflexes:

• Barbiturates (e.g. phenobarbitone, primidone)
• Carbamazepine

Barbiturate and carbamazepine levels — readily available in most big centres — are useful in ruling out poisoning with these agents. Baclofen levels are less widely available, hence this diagnosis is usually a clinical one (often made retrospectively once collateral history becomes available).

Carbamazepine overdose was discussed in Toxicology Conundrum 046.

Resuscitation

• Early intubation and ventilation is indicated for patients with coma or respiratory depression.
• Paradoxical seizures are treated with benzodiazepines.
• Hypotension usually responds to fluid resuscitation.

Decontamination

• Nasogastric activated charcoal (50g) given following intubation may reduce the total dose of baclofen absorbed. It is given with the intention of reducing the duration of coma and length of ICU stay. Due to the rapid absorption kinetics of baclofen, charcoal is only likely to be useful if given within the first few hours.
• Conversely, activated charcoal is not recommended in the patient with an unprotected airway due to rapid onset of coma and seizures with the potential for charcoal pulmonary aspiration.

Enhanced Elimination

• Enhanced elimination is not normally necessary as patients do well with supportive care alone.
• However, a recent case report has suggested that there may be some benefit from haemodialysis (HD) in reducing duration of coma in large baclofen overdose — the authors reported an elimination half life of 15.7 hours before and 3.1 hours after instigation of HD in a 420 mg baclofen ingestion.

No!

• 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. 

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
• Confusion
• Restlessness
• Fidgeting
• 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
• Ileus

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.

With difficulty!

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.

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.

Toxicological Indications

• Severe anticholinergic delirium unresponsive to benzodiazepine sedation.
• Poisoning with a pure anticholinergic agent (e.g. atropine).

Contraindications

• Bradycardia
• AV block
• Interventricular conduction abnormality (QRS >100ms)
• Bronchospasm

Adverse Effects

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.

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.

Carbamazepine

• 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.

Carbamazepine (Tegretol) CR 400mg tablets

• 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.

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. 

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.

• 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.

Resuscitation

• 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.

Investigations

• 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.

Decontamination

• 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

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.

• The 10-hour level of 182mg/L is well above the treatment line, so the NAC infusion should continue for a full course of treatment (minimum of 20 hours), with repeat ALT testing at the end of the infusion.
• If the ALT remains abnormal at the end of the 20-hour infusion, NAC is continued at a rate of 100mg/kg every 16 hours.
• ALT is checked every 12-24 hours until it begins to normalise.
• NAC infusion must continue until the ALT is stable or falling.
• As the ALT is abnormal, bloods should also be sent for coagulation profile, renal function and platelet count to monitor for impending liver failure. These additional markers should also be repeated every 12-24 hours during treatment.

By 56 hours post-ingestion, ALT has risen to 9000, with an INR of 2.5 and a platelet count of 200.  She has some RUQ tenderness and nausea. You start to wonder whether you should consider aeromedical retrieval to a tertiary hospital.

Paracetamol-induced hepatotoxicity is defined as a peak elevation in hepatic transaminases (ALT or AST) > 1000 IU/L in the context of paracetamol overdose.

This patient clearly has paracetamol-induced hepatotoxicity, along with evidence of impaired liver synthetic function (abnormal INR).

High-risk features mandating admission to a liver transplant centre are:

• INR >3.0 at 48 hours or >4.5 at any time.
• Oliguria or creatinine > 200 micromol/L
• Acidosis with pH < 7.3 after resuscitation
• Systolic hypotension with BP < 80mmHg
• Hypoglycaemia
• Severe thrombocytopenia
• Encephalopathy of any degree

Our patient has an INR <3.0 with normal renal function, pH, blood pressure, blood sugar and platelet count and no evidence of encephalopathy – so she does not meet criteria for transfer at this stage.

However, given that transfer to a tertiary centre may take several hours to organise, it would be useful to be able to predict whether this patient is likely to develop fulminant hepatic failure.

The risk of hepatic encephalopathy can be predicted by calculating the Schiodt score.

This scoring system uses three main factors to predict the risk of hepatic encephalopathy:

• Time interval between paracetamol ingestion and commencement of NAC
• INR
• Platelet count

Each of these risk factors is converted to a points score as follows:

[NB. In-between values are interpolated to give an intermediate risk score, e.g. time to NAC of 3 hours gives a point score (A) of 18]

INR	Point score (B)
8.0	96
6.0	85
4.3	73
3.1	60
2.5	51
2.1	44
1.9	38
1.6	29
1.4	22
1.3	16
1.2	11
1.0	0
0.9	-11

Hours post ingestion	≤1	12	24	48	72	96
	Point score (C)
Platelet count (109/L)
10	0	0	-1	-1	-2	-3
50	0	-2	-3	-6	-10	-13
100	0	-3	-6	-13	-19	-26
150	0	-5	-10	-19	-29	-38
200	-1	-6	-13	-26	-38	-51
300	-1	-10	-19	-38	-58	-77
400	-1	-13	-26	-51	-77	-103
500	-1	-16	-32	-64	-96	-128

The Schiodt score is calculated by the following equation:

 Overall score = (A + B + C – 99) / 10

This score is then converted to a probability of developing hepatic encephalopathy:

Overall score	Probability
≤ -6.00	0%
-5.00	1%
-4.00	2%
-3.00	5%
-2.50	8%
-2.00	12%
-1.50	18%
-1.00	27%
-0.50	38%
0.00	50%
0.50	62%
1.00	73%
1.50	82%
2.00	88%
2.50	92%
3.00	95%
4.00	98%
5.00	99%
≥ 6.00	100%

For our patient, the point scores are as follows:

•  Time to NAC of 10 hours gives (A) = 40
• INR of 2.5 gives (B) = 51
• Platelet count of 200 at 56 hours gives (C) = –30

Hence:

Overall score = (40 + 51 – 30 – 99) / 10 =  –3.8

This gives our patient an approximately 2-3% probability of developing hepatic encephalopathy.

Given that our patient is still relatively low risk, it is probably safe to leave them in the rural hospital for the time being. Serial blood tests and NAC infusion will need to continue until transaminases are falling and coagulopathy is improving.

•  The patient remained in the rural hospital on a NAC infusion.
• By 72 hours, ALT had fallen to 6000 and INR to 1.9
• By 84 hours, ALT had fallen to 3600, INR to 1.1 and she was feeling much better, with resolution of her RUQ tenderness and nausea.
• Following a further period of observation she was subsequently discharged to the care of psychiatry with no long term sequelae; ALT normalised over the following few days.