Tricyclic antidepressant toxicity: Difference between revisions

(Major update: bicarb protocol with pH goal, QRS/aVR thresholds, lipid emulsion, avoid phenytoin, charcoal timing, NE as first-line pressor, ECMO for refractory arrest, references with PMIDs)
(Strip excess bold)
 
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*[[Tricyclic antidepressants]] (TCAs) remain a '''leading cause of death from prescription drug overdose'''
*[[Tricyclic antidepressants]] (TCAs) remain a '''leading cause of death from prescription drug overdose'''
*Common TCAs: amitriptyline, nortriptyline, imipramine, desipramine, doxepin, clomipramine
*Common TCAs: amitriptyline, nortriptyline, imipramine, desipramine, doxepin, clomipramine
*'''Narrow therapeutic index''' — '''lethal dose is only 3-5x therapeutic dose'''
*Narrow therapeutic index — lethal dose is only 3-5x therapeutic dose
*Multiple mechanisms of toxicity:
*Multiple mechanisms of toxicity:
**'''Sodium channel blockade''' → QRS widening → ventricular arrhythmias ('''most dangerous''')
**Sodium channel blockade → QRS widening → ventricular arrhythmias (most dangerous)
**'''Anticholinergic effects''' → tachycardia, mydriasis, urinary retention, hyperthermia, AMS
**Anticholinergic effects → tachycardia, mydriasis, urinary retention, hyperthermia, AMS
**'''Alpha-1 receptor blockade''' → hypotension
**Alpha-1 receptor blockade → hypotension
**'''Norepinephrine/serotonin reuptake inhibition''' → initial hypertension, tachycardia
**Norepinephrine/serotonin reuptake inhibition → initial hypertension, tachycardia
**'''GABA-A antagonism''' → seizures
**GABA-A antagonism → seizures
**'''Potassium channel blockade''' → QT prolongation
**Potassium channel blockade → QT prolongation
*Rapidly absorbed; '''toxicity can progress from alert to cardiac arrest within 1 hour'''
*Rapidly absorbed; toxicity can progress from alert to cardiac arrest within 1 hour


==Clinical Features==
==Clinical Features==
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*Altered mental status (agitation → delirium → coma)
*Altered mental status (agitation → delirium → coma)
*Decreased bowel sounds, ileus
*Decreased bowel sounds, ileus
*'''Hyperthermia'''
*Hyperthermia


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


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


===ECG Findings (Critical)===
===ECG Findings (Critical)===
*'''QRS >100 ms''': increased risk of seizures
*QRS >100 ms: increased risk of seizures
*'''QRS >160 ms''': increased risk of '''ventricular arrhythmias'''
*QRS >160 ms: increased risk of ventricular arrhythmias
*'''R wave >3 mm in aVR''' (sensitive marker of sodium channel blockade)<ref>Liebelt EL, et al. ECG lead aVR versus QRS interval in predicting seizures and arrhythmias in acute tricyclic antidepressant toxicity. ''Ann Emerg Med''. 1995;26(2):195-201. PMID 7618784</ref>
*R wave >3 mm in aVR (sensitive marker of sodium channel blockade)<ref>Liebelt EL, et al. ECG lead aVR versus QRS interval in predicting seizures and arrhythmias in acute tricyclic antidepressant toxicity. ''Ann Emerg Med''. 1995;26(2):195-201. PMID 7618784</ref>
*'''R/S ratio >0.7 in aVR'''
*R/S ratio >0.7 in aVR
*Right axis deviation of terminal 40 ms QRS
*Right axis deviation of terminal 40 ms QRS
*Sinus tachycardia, QT prolongation
*Sinus tachycardia, QT prolongation


==Differential Diagnosis==
==Differential Diagnosis==
*Other '''sodium channel blocking''' agents: Class IA/IC antiarrhythmics, cocaine, diphenhydramine, carbamazepine
*Other sodium channel blocking agents: Class IA/IC antiarrhythmics, cocaine, diphenhydramine, carbamazepine
*[[Anticholinergic toxicity]]
*[[Anticholinergic toxicity]]
*Other causes of wide-complex tachycardia
*Other causes of wide-complex tachycardia
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*'''ECG''' ('''most important test — get immediately''')
*'''ECG''' ('''most important test — get immediately''')
**Repeat ECG every 15-30 minutes in first 2 hours
**Repeat ECG every 15-30 minutes in first 2 hours
*'''BMP''': monitor for metabolic acidosis (worsens sodium channel blockade)
*BMP: monitor for metabolic acidosis (worsens sodium channel blockade)
*'''Blood gas''': pH (acidosis worsens toxicity; alkalosis is protective)
*Blood gas: pH (acidosis worsens toxicity; alkalosis is protective)
*'''Acetaminophen and salicylate levels''' (coingestion screening)
*Acetaminophen and salicylate levels (coingestion screening)
*'''Urine drug screen''': may detect TCA, but false positives common (diphenhydramine, cyclobenzaprine, carbamazepine, phenothiazines)
*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)
*'''TCA levels''' are NOT useful for acute management (do not correlate with toxicity)
*'''Lactate, glucose'''
*Lactate, glucose


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


===Sodium Bicarbonate (Cornerstone of Treatment)===
===Sodium Bicarbonate (Cornerstone of Treatment)===
*'''Indicated for''':
*Indicated for:
**'''QRS >100 ms'''
**QRS >100 ms
**Ventricular arrhythmias
**Ventricular arrhythmias
**Hypotension refractory to fluids
**Hypotension refractory to fluids
*'''Bolus: 1-2 mEq/kg IV push''' (repeat every 3-5 minutes until QRS narrows)
*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
*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)
*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
*Mechanism: increases serum sodium (competes for channel) AND alkalosis favors protein-bound (non-toxic) TCA form
*'''Continue until QRS normalizes'''
*Continue until QRS normalizes


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


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


===Refractory Ventricular Arrhythmias===
===Refractory Ventricular Arrhythmias===
*'''Sodium bicarbonate''' is first-line
*Sodium bicarbonate is first-line
*'''Lidocaine''' (Class IB — may be used)
*Lidocaine (Class IB — may be used)
*'''Avoid''' Class IA (procainamide) and Class IC (flecainide) antiarrhythmics
*Avoid Class IA (procainamide) and Class IC (flecainide) antiarrhythmics
*'''Avoid amiodarone''' if possible (sodium channel blockade)
*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
*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
*ECMO for refractory cardiac arrest


===Monitoring===
===Monitoring===
*'''Serial ECGs''' every 15-30 min initially
*Serial ECGs every 15-30 min initially
*Continuous telemetry for '''minimum 6 hours''' after last ECG abnormality resolves
*Continuous telemetry for minimum 6 hours after last ECG abnormality resolves
*ABG/VBG to guide bicarbonate therapy
*ABG/VBG to guide bicarbonate therapy
*Serum pH goal 7.50-7.55
*Serum pH goal 7.50-7.55
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==Disposition==
==Disposition==
*'''ICU admission''' for: QRS widening, arrhythmias, seizures, hypotension, altered mental status
*'''ICU admission''' for: QRS widening, arrhythmias, seizures, hypotension, altered mental status
*'''Monitored bed''' for asymptomatic patients with normal ECG × 6 hours
*Monitored bed for asymptomatic patients with normal ECG × 6 hours
*'''Psychiatric evaluation''' after medical clearance for all intentional ingestions
*Psychiatric evaluation after medical clearance for all intentional ingestions
*'''Consider discharge''' only if:
*Consider discharge only if:
**Asymptomatic for 6 hours
**Asymptomatic for 6 hours
**Normal ECG with QRS <100 ms
**Normal ECG with QRS <100 ms
**Normal mental status
**Normal mental status
**Psychiatric clearance obtained
**Psychiatric clearance obtained
*'''Poison control: 1-800-222-1222'''
*Poison control: 1-800-222-1222


==See Also==
==See Also==

Latest revision as of 09:28, 22 March 2026

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)[1]
  • 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

References

  1. ↑ Liebelt EL, et al. ECG lead aVR versus QRS interval in predicting seizures and arrhythmias in acute tricyclic antidepressant toxicity. Ann Emerg Med. 1995;26(2):195-201. PMID 7618784
  • 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
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