Tricyclic antidepressant toxicity

Background

• Tricyclic antidepressants (TCAs) remain a leading cause of death from prescription drug overdose
• Common TCAs: amitriptyline, nortriptyline, imipramine, desipramine, doxepin, clomipramine
• Narrow therapeutic index — lethal dose is only 3-5x therapeutic dose
• Multiple mechanisms of toxicity:
  • Sodium channel blockade → QRS widening → ventricular arrhythmias (most dangerous)
  • Anticholinergic effects → tachycardia, mydriasis, urinary retention, hyperthermia, AMS
  • Alpha-1 receptor blockade → hypotension
  • Norepinephrine/serotonin reuptake inhibition → initial hypertension, tachycardia
  • GABA-A antagonism → seizures
  • Potassium channel blockade → QT prolongation
• Rapidly absorbed; toxicity can progress from alert to cardiac arrest within 1 hour

Clinical Features

Anticholinergic Toxidrome

• Tachycardia, mydriasis, dry skin/mouth, urinary retention
• Altered mental status (agitation → delirium → coma)
• Decreased bowel sounds, ileus
• Hyperthermia

Cardiovascular

• Sinus tachycardia (most common cardiac finding)
• Wide-complex tachycardia (sodium channel blockade)
• Hypotension (alpha blockade, myocardial depression)
• Right axis deviation of terminal QRS
• Brugada-like pattern
• Ventricular tachycardia/fibrillation (leading cause of death)

Neurologic

• Seizures (occur in 10-20% of significant ingestions; usually brief but may be refractory)
• Myoclonus, tremor
• Coma

ECG Findings (Critical)

• QRS >100 ms: increased risk of seizures
• QRS >160 ms: increased risk of ventricular arrhythmias
• R wave >3 mm in aVR (sensitive marker of sodium channel blockade)
• R/S ratio >0.7 in aVR
• Right axis deviation of terminal 40 ms QRS
• Sinus tachycardia, QT prolongation

Differential Diagnosis

• Other sodium channel blocking agents: Class IA/IC antiarrhythmics, cocaine, diphenhydramine, carbamazepine
• Anticholinergic toxicity
• Other causes of wide-complex tachycardia
• Serotonin syndrome (if combined with serotonergic agents)
• Mixed overdose (coingestion is common)

Evaluation

• ECG (most important test — get immediately)
  • Repeat ECG every 15-30 minutes in first 2 hours
• BMP: monitor for metabolic acidosis (worsens sodium channel blockade)
• Blood gas: pH (acidosis worsens toxicity; alkalosis is protective)
• Acetaminophen and salicylate levels (coingestion screening)
• Urine drug screen: may detect TCA, but false positives common (diphenhydramine, cyclobenzaprine, carbamazepine, phenothiazines)
• TCA levels are NOT useful for acute management (do not correlate with toxicity)
• Lactate, glucose

Management

Immediate

• Continuous cardiac monitoring
• IV access, supplemental O2
• GI decontamination: activated charcoal 1 g/kg if presenting within 1-2 hours and patient is alert with protected airway
  • Anticholinergic effects delay gastric emptying → charcoal may be beneficial even at 2+ hours
• Do NOT induce emesis (rapid deterioration risk)

Sodium Bicarbonate (Cornerstone of Treatment)

• Indicated for:
  • QRS >100 ms
  • Ventricular arrhythmias
  • Hypotension refractory to fluids
• Bolus: 1-2 mEq/kg IV push (repeat every 3-5 minutes until QRS narrows)
• Infusion: 150 mEq NaHCO3 in 1L D5W at 150-250 mL/hr after initial bolus
• Goal serum pH: 7.50-7.55 (alkalosis overcomes sodium channel blockade)
• Mechanism: increases serum sodium (competes for channel) AND alkalosis favors protein-bound (non-toxic) TCA form
• Continue until QRS normalizes

Seizures

• Benzodiazepines first-line: lorazepam 2-4 mg IV, repeat q5min
• Do NOT use phenytoin (also blocks sodium channels; may worsen cardiac toxicity)
• If refractory: propofol, phenobarbital, or intubation with neuromuscular blockade
• Treat aggressively — prolonged seizures cause acidosis which worsens cardiac toxicity

Hypotension

• IV fluid bolus (NS 1-2L)
• Sodium bicarbonate bolus
• Norepinephrine (first-line vasopressor; alpha agonism counteracts TCA alpha blockade)
• Avoid pure beta-agonists
• Refractory: consider lipid emulsion therapy (ILE)

Refractory Ventricular Arrhythmias

• Sodium bicarbonate is first-line
• Lidocaine (Class IB — may be used)
• Avoid Class IA (procainamide) and Class IC (flecainide) antiarrhythmics
• Avoid amiodarone if possible (sodium channel blockade)
• Lipid emulsion therapy: 20% Intralipid 1.5 mL/kg IV bolus then 0.25 mL/kg/min for refractory arrest
• ECMO for refractory cardiac arrest

Monitoring

• Serial ECGs every 15-30 min initially
• Continuous telemetry for minimum 6 hours after last ECG abnormality resolves
• ABG/VBG to guide bicarbonate therapy
• Serum pH goal 7.50-7.55

Disposition

• ICU admission for: QRS widening, arrhythmias, seizures, hypotension, altered mental status
• Monitored bed for asymptomatic patients with normal ECG × 6 hours
• Psychiatric evaluation after medical clearance for all intentional ingestions
• Consider discharge only if:
  • Asymptomatic for 6 hours
  • Normal ECG with QRS <100 ms
  • Normal mental status
  • Psychiatric clearance obtained
• Poison control: 1-800-222-1222

See Also

• Anticholinergic toxicity
• Sodium channel blocker toxicity
• Serotonin syndrome
• Toxicology
• Cardiac arrest

References

• Kerr GW, et al. Tricyclic antidepressant overdose: a review. Emerg Med J. 2001;18(4):236-241. PMID 11435353
• Woolf AD, et al. Tricyclic antidepressant poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol. 2007;45(3):203-233. PMID 17453872
• Body R, et al. Guidelines in Emergency Medicine Network (GEMNet): guideline for the management of tricyclic antidepressant overdose. Emerg Med J. 2011;28(4):347-368. PMID 21436332