Tricyclic Antidepressant Poisoning

Tricyclic antidepressants (amitriptyline, nortriptyline, imipramine, dosulepin, clomipramine, doxepin) remain a leading cause of fatal drug overdose. Ingestion of 10 mg/kg is serious, and 15 to 20 mg/kg is potentially lethal. Toxicity develops within 1 to 2 hours and can deteriorate abruptly from alertness to coma, seizures and arrhythmia.

Mechanisms

• Fast sodium channel blockade in the His-Purkinje system and myocardium, which widens the QRS and depresses contractility
• Muscarinic blockade, which causes the anticholinergic syndrome
• Peripheral alpha-1 blockade, which causes vasodilatory hypotension
• GABA-A antagonism, which lowers the seizure threshold
• Norepinephrine and serotonin reuptake inhibition

The drugs are highly lipophilic and protein bound, with a large volume of distribution (10 to 50 L/kg), so dialysis does not remove them. Complications: ventricular tachycardia, refractory shock, status epilepticus, rhabdomyolysis, aspiration and hyperthermia. Most deaths occur before hospital arrival.

• Anticholinergic signs: dry mouth and skin, mydriasis, sinus tachycardia, urinary retention, ileus, agitated delirium, hyperthermia
• Then central nervous system depression progressing to coma, with myoclonus, hyperreflexia and seizures (often within 2 hours)
• Cardiovascular: QRS over 100 ms (seizure risk), QRS over 160 ms (ventricular arrhythmia risk), a terminal R wave in aVR over 3 mm, right axis deviation of the terminal 40 ms of the QRS, hypotension and ventricular tachycardia
• Red flags: QRS widening, seizure, coma, hypotension, and ingestion of more than 10 mg/kg

1. 12-lead ECG on arrival and repeated hourly: QRS duration, terminal R in aVR, R/S ratio in aVR over 0.7, and QT interval.
2. Venous or arterial blood gas (acidosis worsens sodium channel blockade), glucose, electrolytes, creatinine, creatine kinase and lactate.
3. Paracetamol and salicylate levels in every intentional overdose.
4. Serum tricyclic levels do not guide treatment. Urine immunoassays give false positives (cyclobenzaprine, quetiapine, diphenhydramine).
5. Continuous cardiac monitoring for at least 6 hours after ingestion. Discharge to psychiatric assessment only if the patient is asymptomatic with a normal ECG at 6 hours.

Differentials: other anticholinergic poisoning, sodium channel blocker toxicity (cocaine, carbamazepine, flecainide), serotonin syndrome, sympathomimetic toxicity.

1. Airway and monitoring: intubate for falling consciousness. Cooling for hyperthermia.
2. Gut decontamination: activated charcoal 50 g orally (children 1 g/kg, maximum 50 g) within 1 to 2 hours if the airway is protected.
3. Sodium bicarbonate for QRS over 100 ms, ventricular arrhythmia or hypotension:
   • 1 to 2 mmol/kg IV (1 to 2 mL/kg of 8.4%) by bolus over 1 to 2 minutes, repeated every 3 to 5 minutes until QRS narrows below 100 ms and blood pressure improves.
   • Then infusion of 150 mmol (150 mL of 8.4%) in 1 L of 5% dextrose at 200 to 250 mL/h.
   • Target arterial pH 7.50 to 7.55 and do not exceed 7.55. Monitor potassium (replace to above 4.0 mmol/L) and ionized calcium.
   • If intubated, hyperventilate to a PaCO2 of 30 to 35 mmHg.
4. Hypertonic saline 3% 1 to 2 mL/kg IV over 10 minutes is an alternative sodium load.
5. Seizures: lorazepam 4 mg IV (children 0.1 mg/kg, maximum 4 mg), repeated once, or diazepam 10 mg IV (children 0.2 mg/kg). Avoid phenytoin and flumazenil.
6. Hypotension: IV crystalloid 20 mL/kg, then norepinephrine 0.05 to 0.5 micrograms/kg/min.
7. Ventricular arrhythmia not responding to bicarbonate: lidocaine 1 to 1.5 mg/kg IV. Avoid class Ia, Ic and III drugs (including amiodarone), and beta blockers. Magnesium sulfate 2 g IV over 10 minutes for torsades.
8. Refractory shock or arrest: lipid emulsion 20% 1.5 mL/kg IV bolus then 0.25 mL/kg/min for 30 to 60 minutes, and venoarterial ECMO.
9. Avoid physostigmine (asystole and seizures).

Follow-up: cardiac monitoring until the ECG is normal and the patient is symptom free for 12 hours. Psychiatric assessment, and means restriction counseling before discharge.