Another TCA overdose!

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…

See also: 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. If reaching doses of greater than 6mmol/kg then consult a clinical toxicologist as you may cause iatrogenic death. See our antidote page for more information.
  — 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 and our antidote page.

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.

• Toxicology Conundrum 022: Tricyclic antidepressant overdose
• ECG Exigency 006: Seizures, Somnolence and a Scary ECG
• ECG Library: Tricyclic overdose (Sodium channel blockade)
• Katzung B, Masters S and Trevor, A. Basic and Clinical Pharmacology (11th Edition), McGraw-Hill, San Francisco, 2009