Tricyclic Antidepressant Overdose

Quick Answer

Tricyclic antidepressant (TCA) overdose is a life-threatening poisoning characterised by a triad of anticholinergic effects, cardiac sodium channel blockade, and CNS toxicity. TCAs remain one of the most lethal classes of drugs in overdose, with mortality primarily from refractory arrhythmias and seizures. [1,2]

Toxidrome:

• Anticholinergic: Mydriasis, tachycardia, dry skin/mucous membranes, urinary retention, decreased bowel sounds, hyperthermia
• Sodium channel blockade: QRS widening greater than 100 ms (seizure risk), greater than 160 ms (arrhythmia risk), R wave in aVR greater than 3 mm
• Alpha-adrenergic blockade: Hypotension, vasodilation [3,4]

Key ECG findings:

• QRS duration greater than 100 ms: 33% risk of seizures
• QRS duration greater than 160 ms: 50% risk of ventricular arrhythmias
• R wave amplitude in aVR ≥3 mm: Highly predictive of toxicity
• Terminal 40 ms rightward axis deviation (R/S ratio in aVR ≥0.7) [5,6]

Treatment priorities:

1. Sodium bicarbonate 1-2 mmol/kg IV bolus for QRS greater than 100 ms or hypotension (target pH 7.50-7.55)
2. Benzodiazepines for seizures (diazepam 5-10 mg IV or midazolam 5-10 mg IV/IM)
3. Norepinephrine for refractory hypotension (direct-acting alpha-agonist)
4. Lipid emulsion rescue (20% intralipid 1.5 mL/kg bolus) for cardiac arrest or refractory shock
5. VA-ECMO for refractory cardiogenic shock or cardiac arrest [7,8]

Avoid:

• Flumazenil: Lowers seizure threshold; precipitates refractory seizures in mixed overdoses
• Physostigmine: Causes bradycardia, AV block, and asystole via vagal enhancement
• Class Ia/Ic antiarrhythmics: Worsen sodium channel blockade [9,10]

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CICM Exam Focus

Key High-Yield Points

1. ECG risk stratification: QRS greater than 100 ms = seizure risk (33%); QRS greater than 160 ms = arrhythmia risk (50%); R wave aVR ≥3 mm highly sensitive for toxicity [5,6]
2. Sodium bicarbonate mechanism: Dual action—sodium load overcomes channel blockade + alkalinisation reduces drug-receptor binding [11,12]
3. pH target: 7.50-7.55; monitor for hypokalemia (alkalosis drives K+ intracellularly) [13]
4. Seizure management: Benzodiazepines first-line; avoid phenytoin (ineffective, may worsen cardiac conduction) [14,15]
5. Vasopressor choice: Norepinephrine preferred over dopamine (TCA depletes endogenous catecholamine stores) [16,17]
6. Lipid emulsion rescue: 20% intralipid 1.5 mL/kg bolus + 0.25 mL/kg/min infusion; reserved for cardiac arrest or refractory shock [18,19]
7. Dialysis ineffective: Large volume of distribution (15-40 L/kg), high protein binding (greater than 90%) [20,21]
8. Observation period: Minimum 6 hours if asymptomatic; admit all symptomatic patients to ICU for continuous cardiac monitoring [22]

Common Viva Themes

• Systematic approach to TCA overdose with ECG interpretation
• Mechanism of sodium bicarbonate: sodium load vs alkalinisation debate
• Why flumazenil and physostigmine are contraindicated
• Management of refractory hypotension and arrhythmias
• Role and evidence for lipid emulsion therapy
• Indications for VA-ECMO in poisoning
• Comparison with other sodium channel blockers (local anaesthetics, antiarrhythmics)

Common Pitfalls

• Giving flumazenil for coma (precipitates intractable seizures if benzodiazepines co-ingested)
• Using phenytoin for seizures (ineffective, may worsen cardiac toxicity)
• Relying on serum TCA levels (poor correlation with toxicity; ECG is superior)
• Under-dosing sodium bicarbonate (may need repeated boluses or infusion)
• Forgetting to monitor potassium during bicarbonate therapy (alkalosis causes hypokalemia)
• Missing delayed absorption due to anticholinergic gastroparesis (observe for 6+ hours)
• Using dopamine instead of norepinephrine (dopamine requires intact catecholamine stores)

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Key Points

• TCA overdose toxidrome: Anticholinergic + sodium channel blockade + alpha blockade [3,4]
• ECG is the best predictor of toxicity: QRS greater than 100 ms = seizures; QRS greater than 160 ms = arrhythmias; R wave aVR ≥3 mm [5,6]
• Sodium bicarbonate 1-2 mmol/kg IV bolus is first-line treatment for QRS widening or hypotension [11,12]
• Target arterial pH 7.50-7.55; may require multiple boluses or infusion [13]
• Benzodiazepines for seizures; avoid phenytoin (Class I sodium channel blocker) [14,15]
• Norepinephrine is preferred vasopressor (direct-acting alpha-agonist) [16,17]
• Lipid emulsion for cardiac arrest or refractory shock (neutral recommendation; rescue therapy) [18,19]
• VA-ECMO achieves up to 86% survival in TCA-induced cardiac arrest (reversible toxin) [23,24]
• Dialysis and hemoperfusion are ineffective (high Vd, protein binding) [20,21]
• Flumazenil and physostigmine are absolutely contraindicated [9,10]

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Pharmacology and Toxicokinetics

Classification of Tricyclic Antidepressants

TCAs are classified by their chemical structure and relative potency of anticholinergic, antihistaminic, and sodium channel blocking effects.

Tertiary Amines (more anticholinergic, more sedating):

Secondary Amines (less anticholinergic, more noradrenergic):

Amitriptyline and imipramine are the most commonly encountered TCAs in overdose and have the highest cardiotoxicity due to potent sodium channel blockade. [1,2]

Mechanism of Toxicity

TCA toxicity results from blockade of multiple receptor systems:

1. Cardiac Sodium Channel Blockade (Fast Na+ Channels)

TCAs bind to and block voltage-gated fast sodium channels (Nav1.5) in the myocardium, similar to Class Ia antiarrhythmic drugs (quinidine-like effect). [25,26]

• Slows Phase 0 depolarisation of the cardiac action potential
• Prolongs QRS duration (intraventricular conduction delay)
• Creates a rightward axis deviation of the terminal 40 ms vector (R wave in aVR)
• In severe toxicity: wide-complex tachycardia, ventricular fibrillation, asystole

pH-Dependent Binding: TCA binding to sodium channels is enhanced in acidosis. In the ionised (protonated) state, TCAs bind more avidly to the sodium channel receptor. Alkalinisation (increasing pH to 7.50-7.55) shifts the equilibrium toward the non-ionised form, reducing drug-receptor affinity. [11,12]

2. Muscarinic (M1) Anticholinergic Blockade

Central and peripheral antimuscarinic effects cause the classic anticholinergic toxidrome: [3,4]

• Eyes: Mydriasis (dilated pupils), blurred vision
• Skin: Dry, flushed, hot ("red as a beet, dry as a bone, hot as a hare")
• Heart: Sinus tachycardia
• CNS: Agitation, delirium, hallucinations, seizures, coma
• GI: Decreased bowel sounds, ileus, delayed gastric emptying
• GU: Urinary retention

3. Alpha-1 Adrenergic Blockade

Peripheral alpha-1 receptor antagonism causes: [3,16]

• Vasodilation and hypotension
• Reflex tachycardia (additive with anticholinergic effect)
• Contributes to refractory shock in severe poisoning

4. Histamine (H1) Receptor Blockade

• Sedation and CNS depression
• Contributes to hyperthermia

5. GABA-A Receptor Antagonism

• Lowers seizure threshold
• TCA-induced seizures are typically brief (self-limiting) but may become refractory
• Seizures worsen acidosis, which increases cardiotoxicity (vicious cycle) [14,27]

6. Potassium Channel Blockade

• Blocks the delayed rectifier potassium current (IKr)
• Prolongs cardiac repolarisation (QTc prolongation)
• Risk of Torsades de Pointes (polymorphic VT) [28,29]

Toxicokinetics in Overdose

The pharmacokinetic parameters of TCAs change dramatically in overdose due to saturation of metabolic pathways and anticholinergic effects on absorption. [20,21,30]

Clinical Implications:

1. Delayed absorption: Anticholinergic gastroparesis delays peak toxicity; patients may deteriorate hours after ingestion
2. Large Vd: TCAs distribute extensively into tissues; hemodialysis and hemoperfusion are ineffective
3. Active metabolites: Desmethyl metabolites (nortriptyline, desipramine) are equally cardiotoxic
4. Protein binding: Changes in pH affect free drug fraction; acidosis increases free TCA levels
5. Prolonged elimination: Severe overdoses may require ICU monitoring for 48-72+ hours

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Clinical Presentation

Toxidrome Recognition

The classic TCA toxidrome combines features of anticholinergic syndrome, sodium channel blockade, and CNS depression. [3,4]

Early Features (1-6 hours):

• Sinus tachycardia (often first sign)
• Mydriasis (dilated pupils)
• Dry mouth and skin
• Decreased bowel sounds
• Urinary retention
• Agitation, confusion, delirium

Progressive Features (6-12 hours):

• QRS widening (greater than 100 ms)
• Hypotension
• Seizures (often brief, may be multiple)
• Coma

Severe Toxicity:

• QRS greater than 160 ms
• Ventricular arrhythmias (VT, VF, Torsades)
• Refractory hypotension
• Cardiovascular collapse
• Respiratory depression/arrest

ECG Manifestations

The ECG is the single most important tool for risk stratification and monitoring in TCA overdose. [5,6,31]

Classic Findings:

ECG Progression in Severe Toxicity:

Normal → Sinus tachycardia → QRS widening → Terminal R aVR →
Wide-complex tachycardia → VT/VF → Asystole

Boehnert and Lovejoy (1985) established the landmark prognostic thresholds: [5]

• QRS below 100 ms: Low risk of major toxicity
• QRS 100-160 ms: Moderate risk; sodium bicarbonate indicated
• QRS greater than 160 ms: High risk of arrhythmias; aggressive treatment required

Liebelt et al. (1995) demonstrated that R wave amplitude in aVR ≥3 mm may be more sensitive than QRS duration alone for predicting seizures and arrhythmias. [6]

Differential Diagnosis

Other Sodium Channel Blockers:

• Class Ia antiarrhythmics (quinidine, procainamide, disopyramide)
• Class Ic antiarrhythmics (flecainide, propafenone)
• Local anaesthetics (lidocaine, bupivacaine)
• Cocaine
• Carbamazepine
• Propranolol (high dose)
• Diphenhydramine (high dose)

Anticholinergic Agents:

• Antihistamines (diphenhydramine, cyproheptadine)
• Antiparkinson drugs (benztropine, trihexyphenidyl)
• Antipsychotics (phenothiazines)
• Atropine
• Cyclopentolate
• Jimsonweed (Datura stramonium)

Mixed Overdose Considerations:

• Co-ingestion with benzodiazepines, opioids, alcohol is common
• Serotonin syndrome if combined with SSRIs/SNRIs
• Consider paracetamol co-ingestion (always check level)

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Investigations

Initial Assessment

Blood Gas Analysis:

• Respiratory acidosis (hypoventilation)
• Metabolic acidosis (seizures, hypoperfusion)
• Mixed acidosis common in severe toxicity
• Lactate elevation indicates tissue hypoperfusion

Electrolytes:

• Potassium: Monitor closely during bicarbonate therapy (alkalosis → hypokalemia)
• Sodium: May become hypernatraemic with aggressive bicarbonate
• Ionised calcium: Important for cardiac function
• Magnesium: Correct if low (risk of Torsades)

Renal Function:

• Baseline creatinine
• Monitor for rhabdomyolysis (prolonged seizures, immobilisation)

Hepatic Function:

• LFTs may be elevated due to hypoperfusion
• TCAs are hepatically metabolised

Serum TCA Levels:

• Not routinely recommended for acute management
• Poor correlation with clinical toxicity
• ECG changes are better predictors of outcome
• May be useful for confirming diagnosis if uncertain [22,32]

Co-ingestion Screening:

• Paracetamol level (always)
• Salicylate level
• Blood glucose
• Ethanol level
• Urine drug screen (benzodiazepines, opioids, cocaine)

ECG Monitoring

Continuous cardiac monitoring is essential for all TCA overdose patients.

Specific ECG Analysis:

1. Calculate QRS duration in limb leads (II or aVR)
2. Measure R wave amplitude in aVR
3. Calculate R/S ratio in aVR
4. Measure QTc interval
5. Assess for terminal R wave in V1
6. Monitor for arrhythmias

Serial ECGs:

• Every 15-30 minutes during active treatment
• Every 1-2 hours once stable
• Before discontinuing monitoring

Imaging

Chest X-ray:

• Aspiration pneumonitis (if decreased GCS)
• Pulmonary oedema (cardiogenic or ARDS)

CT Brain:

• If prolonged coma, focal neurological signs, or suspected trauma
• Exclude alternative diagnoses

Abdominal X-ray:

• May show radio-opaque tablets (rarely helpful)
• Assess for ileus

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Management

Resuscitation Priorities

ABCDE Approach:

A - Airway:

• Anticipate rapid deterioration
• Early intubation if GCS ≤8, seizures, or respiratory depression
• RSI with ketamine or propofol (avoid sodium channel blocking agents)
• Use succinylcholine with caution if prolonged seizures (hyperkalaemia risk) [33]

B - Breathing:

• Hyperventilate to target pH 7.50-7.55 (respiratory compensation)
• Hyperventilation can help while preparing sodium bicarbonate
• Avoid hypoxia and hypercapnia (worsen acidosis → increase cardiotoxicity)

C - Circulation:

• IV access (large bore, two sites)
• Continuous cardiac monitoring
• 12-lead ECG immediately
• Fluid resuscitation (cautious; avoid overload in cardiac dysfunction)
• Prepare sodium bicarbonate before deterioration

D - Disability:

• Blood glucose (treat hypoglycaemia)
• GCS assessment
• Pupil examination (anticholinergic mydriasis)
• Prepare benzodiazepines for seizures

E - Exposure:

• Temperature monitoring (hyperthermia)
• Assess for co-ingestions
• Examine for trauma

Decontamination

Activated Charcoal (1 g/kg, max 50-100 g): [34,35]

• Most effective within 1-2 hours of ingestion
• May consider up to 4 hours due to anticholinergic gastroparesis
• Contraindications: Unprotected airway, decreased GCS, active seizures
• Intubate first if airway is not protected
• Single dose only; multi-dose activated charcoal (MDAC) not recommended

Gastric Lavage:

• Rarely indicated
• Only consider if massive ingestion within 60 minutes
• Requires protected airway (intubation)
• Risk of aspiration, perforation, vagal stimulation

Whole Bowel Irrigation:

• Not recommended for TCA overdose
• TCAs are not sustained-release preparations
• Anticholinergic ileus is a contraindication

Sodium Bicarbonate Therapy

Sodium bicarbonate is the cornerstone of TCA cardiotoxicity management. [11,12,13]

Indications:

• QRS duration greater than 100 ms
• Ventricular arrhythmias
• Hypotension unresponsive to fluid resuscitation
• Prophylactically in severe ingestions before ECG changes

Mechanism of Action:

1. Sodium Load: Increases extracellular Na+ concentration, overcoming competitive sodium channel blockade by creating a larger electrochemical gradient
2. Alkalinisation: Increases pH, shifting TCA from ionised (active) to non-ionised form, reducing receptor binding affinity
3. Increased Protein Binding: Alkalosis may increase TCA binding to α1-acid glycoprotein, reducing free drug fraction

Dosing Protocol:

Administration:

1. Give 8.4% sodium bicarbonate (1 mL = 1 mmol) as IV bolus over 1-2 minutes
2. Repeat every 3-5 minutes until QRS narrows
3. If multiple boluses required, start infusion: 150 mmol (150 mL 8.4%) in 1L D5W at 150-250 mL/hour

Monitoring:

• Arterial blood gas every 15-30 minutes during active treatment
• Target arterial pH 7.50-7.55 (maximum 7.55)
• Monitor serum potassium (alkalosis causes hypokalemia)
• Monitor serum sodium (risk of hypernatraemia)
• Continuous ECG monitoring

Endpoints:

• QRS duration below 100 ms
• Haemodynamic stability
• Resolution of arrhythmias

Duration:

• Continue infusion for 12-24 hours after QRS normalisation
• Wean gradually to avoid rebound widening

Hypertonic Saline as Alternative

If pH already greater than 7.55 or significant metabolic alkalosis, hypertonic saline (3% NaCl) can provide sodium load without further alkalinisation. [36,37]

Dosing:

• 100-150 mL 3% saline IV bolus
• Monitor sodium levels (risk of hypernatraemia)

Evidence:

• McCabe et al. (1998) demonstrated equivalent efficacy of 3% saline and sodium bicarbonate in swine model [36]
• Reserved for patients with severe alkalosis who still have wide QRS

Seizure Management

TCA-induced seizures require immediate treatment to prevent metabolic acidosis and subsequent worsening of cardiotoxicity. [14,15,27]

First-Line: Benzodiazepines

• Diazepam 5-10 mg IV (repeat every 5 minutes as needed)
• Lorazepam 2-4 mg IV (repeat every 5 minutes as needed)
• Midazolam 5-10 mg IV/IM (if no IV access)

Second-Line: Refractory Seizures

• Propofol infusion: 1-2 mg/kg bolus, then 2-4 mg/kg/hour
• Phenobarbital: 15-20 mg/kg IV (loading dose)

AVOID:

• Phenytoin: Class Ib sodium channel blocker; may worsen cardiac conduction delays; ineffective for toxin-induced seizures [14]
• Carbamazepine: Also a sodium channel blocker

Post-Seizure Management:

• Check blood gas (seizures cause lactic acidosis)
• Bolus sodium bicarbonate if pH drops (acidosis worsens cardiotoxicity)
• Protect airway; intubate if GCS decreased
• EEG monitoring if prolonged coma

Hypotension Management

Algorithm:

Hypotension (SBP below 90 mmHg)
           ↓
Fluid resuscitation (500-1000 mL crystalloid)
           ↓
     Persists? → Sodium bicarbonate 1-2 mmol/kg IV
           ↓
     Persists? → Norepinephrine infusion
           ↓
     Persists? → Add vasopressin
           ↓
     Persists? → Consider lipid emulsion
           ↓
     Persists? → Consider VA-ECMO

Vasopressor Choice: [16,17]

AVOID:

• Dopamine: Indirect-acting; requires intact norepinephrine stores (depleted by TCAs)
• Dobutamine alone: May worsen hypotension (beta-2 vasodilation)

Arrhythmia Management

Sinus Tachycardia:

• No specific treatment required (anticholinergic effect)
• Will resolve with drug elimination
• Avoid beta-blockers (may worsen hypotension)

Wide-Complex Tachycardia (QRS greater than 160 ms):

• Sodium bicarbonate 2 mmol/kg IV bolus
• Repeat every 3-5 minutes until QRS narrows
• If refractory → consider lidocaine (Class Ib, less Na+ channel blockade) [38]

Ventricular Fibrillation/Pulseless VT:

• CPR and defibrillation per standard ACLS
• Sodium bicarbonate 2 mmol/kg IV bolus
• Lipid emulsion if refractory
• Consider VA-ECMO (ECPR)

Torsades de Pointes: [28,29]

• Magnesium sulfate 2 g IV over 2-5 minutes (first-line)
• Avoid Class Ia/Ic/III antiarrhythmics
• Overdrive pacing if refractory
• Correct hypokalaemia

Bradycardia/Heart Block:

• Uncommon with TCAs (usually tachycardia)
• If present, consider co-ingestion (beta-blocker, calcium channel blocker)
• External pacing if haemodynamically unstable
• Avoid atropine (will not overcome anticholinergic-induced block)

Lipid Emulsion Therapy

Intravenous lipid emulsion (ILE) is a rescue therapy for severe TCA toxicity. [18,19,39,40]

Indications (Expert Consensus 2016): [18]

• Cardiac arrest unresponsive to standard resuscitation
• Refractory shock despite maximal vasopressors and bicarbonate
• Neutral recommendation (use as last resort, not routine)

Mechanism:

• "Lipid sink": Lipophilic TCAs partition into the lipid phase, reducing free drug concentration
• Direct cardiac effects: May improve mitochondrial function
• Exact mechanism remains unclear

Dosing Protocol:

Practical Considerations:

• Use 20% Intralipid or SMOFlipid
• May interfere with laboratory assays (lipemic sample)
• Caution if planning VA-ECMO (may affect oxygenator function)

Evidence:

• Sirianni et al. (2008): First reported human case of successful ILE rescue in TCA overdose [39]
• French et al. (2011): Case of amitriptyline overdose with prolonged QRS responding to ILE [40]
• No RCTs; evidence from case reports and animal studies

VA-ECMO (Extracorporeal Life Support)

VA-ECMO is an emerging rescue therapy for refractory TCA-induced cardiogenic shock and cardiac arrest. [23,24,41]

Indications:

• Refractory cardiogenic shock despite maximal medical therapy
• Cardiac arrest (ECPR) with ongoing CPR
• Bridge to recovery (TCA toxicity is reversible)

Evidence:

Key Points:

• TCA toxicity is highly reversible; ECMO serves as "bridge to recovery"
• Better outcomes than ECMO for primary cardiac disease or sepsis
• Early activation is critical; do not wait for prolonged arrest
• Requires specialised ECMO centre
• May be combined with ILE (caution: lipid may affect oxygenator)

Enhanced Elimination

Haemodialysis:

• NOT effective for TCA removal
• Large volume of distribution (15-40 L/kg)
• High protein binding (greater than 90%)
• Only removes tiny fraction of total body drug burden

Haemoperfusion:

• NOT effective for same reasons
• Historically attempted but abandoned

Multi-dose Activated Charcoal (MDAC):

• NOT recommended for TCA overdose
• No evidence of improved outcomes
• Risk of aspiration in patients with decreased GCS

Exception:

• Supportive dialysis for acidosis or fluid overload remains appropriate

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Contraindicated Treatments

Flumazenil

Flumazenil is a benzodiazepine antagonist that is absolutely contraindicated in suspected TCA overdose. [9,42]

Mechanism of Harm:

• TCAs lower the seizure threshold
• Co-ingested benzodiazepines provide anticonvulsant protection
• Flumazenil reverses this protection, unmasking TCA-induced seizures
• These seizures are often refractory and difficult to control

Evidence:

• PMID 1593901: Cases of seizures and arrhythmias following flumazenil in TCA overdose
• PMID 2261066: Precipitation of seizures in TCA-BZD mixed overdose

Clinical Pearl: Never give flumazenil to a patient with unknown overdose or suspected TCA ingestion, even if benzodiazepines are confirmed.

Physostigmine

Physostigmine is an acetylcholinesterase inhibitor historically used for anticholinergic delirium. It is absolutely contraindicated in TCA overdose. [10,43]

Mechanism of Harm:

• Increases vagal tone
• Exacerbates TCA-induced cardiac conduction delays
• May cause severe bradycardia, AV block, and asystole

Evidence:

• PMID 7433407: Two cases of asystole following physostigmine in TCA overdose
• PMID 10842245: Review emphasising avoidance of physostigmine when TCA suspected

Clinical Pearl: If anticholinergic syndrome is suspected, use supportive care and benzodiazepines for agitation rather than physostigmine unless TCA has been definitively excluded.

Class I Antiarrhythmics

Class Ia and Ic antiarrhythmics should be avoided: [38]

Exception:

• Lidocaine (Class Ib) may be considered for refractory VT as it has less sodium channel blocking effect and faster unbinding kinetics

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Monitoring and Disposition

ICU Admission Criteria

All of the following require ICU admission:

• QRS greater than 100 ms
• Any arrhythmia
• Hypotension
• Seizures
• Altered mental status (GCS below 15)
• Requirement for intubation
• Any patient receiving sodium bicarbonate therapy

Monitoring Requirements

Duration of Monitoring

Asymptomatic Patient (No ECG changes, Normal GCS):

• Minimum 6 hours observation from time of ingestion
• May be cleared if remains asymptomatic with normal ECG at 6 hours

Symptomatic Patient:

• ICU monitoring for minimum 24-48 hours
• Continue until QRS below 100 ms for 12+ hours off bicarbonate
• Continue until haemodynamically stable off vasopressors
• Psychiatric evaluation before discharge if intentional overdose

Delayed Complications

Neurological:

• Hypoxic brain injury (prolonged arrest, hypotension)
• Aspiration pneumonitis
• Critical illness myopathy/neuropathy

Cardiac:

• Late arrhythmias (rare if QRS normalises)
• Cardiomyopathy (unusual)

Other:

• Rhabdomyolysis (prolonged seizures, immobilisation)
• Acute kidney injury
• Paralytic ileus

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Prognosis

Mortality

TCA overdose has significant mortality, though outcomes have improved with modern critical care. [1,2,22]

Predictors of Poor Outcome:

• QRS greater than 160 ms on presentation
• Cardiac arrest before hospital arrival
• Prolonged hypotension
• Delayed presentation
• Massive ingestion (greater than 50 mg/kg)
• Acidosis (pH below 7.2)
• Refractory arrhythmias

Recovery

Most patients who survive the initial 24-48 hours make a complete recovery.

• Neurological recovery depends on duration of hypoxia/hypotension
• Cardiac function typically normalises as drug is metabolised
• No long-term cardiac sequelae in most survivors
• Psychiatric follow-up essential for intentional overdose

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Algorithm: TCA Overdose Management

SUSPECTED TCA OVERDOSE
        ↓
┌───────────────────────────────────────┐
│ IMMEDIATE ASSESSMENT                   │
│ • Airway, Breathing, Circulation       │
│ • 12-lead ECG                          │
│ • Continuous cardiac monitoring        │
│ • IV access x 2                        │
│ • Blood glucose, paracetamol level     │
└───────────────────────────────────────┘
        ↓
┌───────────────────────────────────────┐
│ ECG INTERPRETATION                     │
│ • QRS duration                         │
│ • R wave in aVR                        │
│ • QTc interval                         │
└───────────────────────────────────────┘
        ↓
   ┌────────────────────────────────────┐
   │        QRS below 100 ms                 │
   │    (Low risk)                      │
   │ • Observe 6 hours minimum          │
   │ • Serial ECGs                      │
   │ • Consider charcoal if below 2 hours    │
   └────────────────────────────────────┘
        ↓
   ┌────────────────────────────────────┐
   │      QRS 100-160 ms                │
   │    (Moderate risk)                 │
   │ • Sodium bicarbonate               │
   │   1-2 mmol/kg IV bolus             │
   │ • Target pH 7.50-7.55              │
   │ • ICU admission                    │
   └────────────────────────────────────┘
        ↓
   ┌────────────────────────────────────┐
   │       QRS greater than 160 ms                  │
   │     (High risk)                    │
   │ • Sodium bicarbonate               │
   │   2 mmol/kg IV bolus               │
   │ • Repeat every 3-5 min             │
   │ • Start infusion                   │
   │ • Prepare vasopressors             │
   │ • Alert ECMO team                  │
   └────────────────────────────────────┘
        ↓
┌───────────────────────────────────────┐
│ COMPLICATIONS MANAGEMENT              │
│                                       │
│ SEIZURES:                             │
│ • Benzodiazepines first-line          │
│ • Propofol/phenobarbital if refractory│
│ • AVOID phenytoin                     │
│                                       │
│ HYPOTENSION:                          │
│ • Fluids → Bicarbonate → Norepinephrine│
│ • Add vasopressin if refractory       │
│ • Consider lipid emulsion             │
│                                       │
│ ARRHYTHMIAS:                          │
│ • VT: Sodium bicarbonate, defibrillate│
│ • TdP: Magnesium sulfate 2g IV        │
│ • Consider lidocaine for refractory VT│
│                                       │
│ CARDIAC ARREST:                       │
│ • Standard ACLS + Bicarbonate         │
│ • Lipid emulsion rescue               │
│ • Early ECMO/ECPR                     │
└───────────────────────────────────────┘

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Formulary: Quick Reference Dosing

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Special Considerations

Pregnancy

• TCAs are teratogenic in first trimester
• Sodium bicarbonate is safe in pregnancy
• Lipid emulsion is safe if indicated
• Fetal monitoring in third trimester
• Consider delivery if maternal instability and viable fetus
• Neonatal monitoring for TCA toxicity

Paediatrics

• Children may be more susceptible to cardiotoxicity
• Lower threshold for bicarbonate administration
• Weight-based dosing critical
• Smaller margin of safety (10-20 mg/kg may be lethal)
• Early toxicology/PICU consultation

Elderly

• Prolonged elimination due to decreased hepatic/renal function
• More susceptible to anticholinergic effects
• Pre-existing cardiac disease increases arrhythmia risk
• Lower threshold for ICU admission
• Longer monitoring required

Australian Context

Poisons Information Centres:

• Australia: 13 11 26 (24 hours)
• New Zealand: 0800 764 766

Common TCAs in Australia:

• Amitriptyline (Endep, generic)
• Nortriptyline (Allegron)
• Doxepin (Deptran, Sinequan)
• Imipramine (Tofranil)

PBS Listings:

• Most TCAs available on PBS for depression, neuropathic pain
• Low cost contributes to availability for overdose

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SAQ Practice Questions

SAQ 1: Sodium Bicarbonate Mechanism

A 32-year-old female presents to the Emergency Department 2 hours after ingesting 50 tablets of amitriptyline 25 mg. Her ECG shows a QRS duration of 145 ms, sinus tachycardia 130/min, and an R wave in aVR of 5 mm. Blood pressure is 85/55 mmHg. She is confused but protecting her airway.

(a) Describe the mechanisms by which sodium bicarbonate improves TCA cardiotoxicity. (4 marks)

(b) Outline your initial management of this patient. (6 marks)

Model Answer

(a) Mechanisms of Sodium Bicarbonate (4 marks)

Sodium bicarbonate improves TCA cardiotoxicity through dual mechanisms:

1. Sodium Load (2 marks)

• TCAs competitively block fast voltage-gated sodium channels (Nav1.5)
• Sodium bicarbonate increases extracellular sodium concentration
• This increases the electrochemical gradient favouring sodium entry
• Effectively "outcompetes" the TCA for channel access
• Results in QRS narrowing by improving Phase 0 depolarisation

2. Alkalinisation (2 marks)

• TCAs are weak bases (pKa ~9)
• In acidosis, more TCA exists in the ionised (protonated) form
• The ionised form has higher affinity for the sodium channel receptor
• Alkalinisation (target pH 7.50-7.55) shifts equilibrium to non-ionised form
• Reduces drug-receptor binding affinity
• Also may increase TCA binding to plasma proteins, reducing free drug fraction

(b) Initial Management (6 marks)

Immediate Actions (2 marks)

• High-flow oxygen
• IV access x 2 (large bore)
• Continuous cardiac monitoring
• Prepare for intubation (deteriorating GCS, aspiration risk)
• Measure blood glucose, paracetamol level

Sodium Bicarbonate (2 marks)

• 8.4% sodium bicarbonate 1-2 mmol/kg IV bolus (approximately 100-150 mL for 70 kg patient)
• Repeat every 3-5 minutes until QRS below 100 ms
• Start bicarbonate infusion (150 mmol in 1L D5W)
• Target arterial pH 7.50-7.55
• Monitor potassium (correct hypokalemia)

Decontamination (1 mark)

• Activated charcoal 50 g via NG tube after intubation
• Within 2 hours of ingestion; may still be effective due to gastroparesis

Hypotension Management (1 mark)

• Fluid resuscitation (500-1000 mL crystalloid)
• If persists after bicarbonate: norepinephrine infusion
• Avoid dopamine (indirect-acting, ineffective with depleted catecholamine stores)

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SAQ 2: ECG Interpretation and Risk Stratification

A previously well 25-year-old male is brought to the Emergency Department after a witnessed intentional ingestion of an unknown antidepressant 90 minutes ago. He is drowsy (GCS 12: E3V4M5) but haemodynamically stable. The ECG is shown below [not included]:

12-lead ECG interpretation: Sinus tachycardia 115/min, QRS duration 165 ms, prominent R wave in aVR 7 mm, QTc 510 ms.

(a) What ECG features suggest tricyclic antidepressant toxicity? (3 marks)

(b) What complications would you anticipate based on the ECG findings? (3 marks)

(c) Outline your approach if this patient develops refractory ventricular tachycardia. (4 marks)

Model Answer

(a) ECG Features Suggesting TCA Toxicity (3 marks)

1. Sinus tachycardia (115/min) - anticholinergic effect
2. Prolonged QRS duration (165 ms) - sodium channel blockade slowing ventricular depolarisation
3. Prominent R wave in aVR (7 mm, greater than 3 mm threshold) - terminal 40 ms rightward axis deviation due to delayed right ventricular conduction
4. Prolonged QTc (510 ms) - potassium channel blockade (IKr inhibition)

Additional features that may be present:

• R/S ratio in aVR ≥0.7
• Terminal R wave in V1
• Deep S wave in leads I and aVL

(b) Anticipated Complications (3 marks)

Based on Boehnert and Lovejoy criteria:

1. Seizures - QRS greater than 100 ms associated with 33% seizure risk
2. Ventricular arrhythmias - QRS greater than 160 ms associated with 50% risk of VT/VF
3. Torsades de Pointes - QTc 510 ms places patient at risk for polymorphic VT
4. Hypotension - may develop due to alpha-blockade and myocardial depression
5. Respiratory arrest - CNS depression, possible rapid deterioration

(c) Approach to Refractory Ventricular Tachycardia (4 marks)

Immediate Actions (1 mark)

• Assess haemodynamic stability
• If pulseless or unstable → synchronised DC cardioversion 200J biphasic
• Continue CPR if pulseless

First-Line Treatment (1 mark)

• Sodium bicarbonate 2 mmol/kg IV bolus
• Repeat every 3-5 minutes
• May narrow QRS and terminate VT
• Hyperventilate to augment alkalinisation

Refractory VT (1 mark)

• Continue sodium bicarbonate (target pH 7.50-7.55)
• Consider lidocaine 1-1.5 mg/kg IV (Class Ib, faster unbinding kinetics)
• Avoid amiodarone (worsens QT), procainamide, flecainide (worsen Na+ blockade)
• If Torsades de Pointes: magnesium sulfate 2 g IV

Rescue Therapies (1 mark)

• Lipid emulsion 20%: 1.5 mL/kg bolus, then 0.25 mL/kg/min infusion
• Activate ECMO team for VA-ECMO consideration
• Continue resuscitation; TCA toxicity is reversible

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Viva Scenarios

Viva 1: Initial Presentation

Examiner: A 45-year-old woman is brought to ED by ambulance. Her husband says she took "a handful of her mother's antidepressant tablets" approximately 1 hour ago. On arrival, she is agitated, her pupils are dilated, her skin is dry and flushed, and her heart rate is 130/min. The paramedics have obtained IV access and she has received 500 mL normal saline. How would you approach this patient?

Candidate Response:

"This presentation is concerning for tricyclic antidepressant overdose given the anticholinergic features: dilated pupils, dry flushed skin, tachycardia, and altered mental status.

My immediate priorities are:

Assessment:

• Confirm ABC stability and apply continuous cardiac monitoring
• Obtain a 12-lead ECG immediately - this is the most important investigation
• Establish the timing and quantity of ingestion if possible
• Identify the specific medication (contact husband, check medication bottles)

ECG Interpretation: I would specifically look for:

• QRS duration (greater than 100 ms indicates significant toxicity)
• R wave amplitude in aVR (≥3 mm highly suggestive)
• QTc prolongation
• Any arrhythmias

Investigations:

• Arterial blood gas
• Electrolytes including potassium, magnesium
• Blood glucose
• Paracetamol level (always exclude co-ingestion)
• Renal function

Initial Management:

• If QRS below 100 ms: observe closely with serial ECGs
• If QRS ≥100 ms: sodium bicarbonate 1-2 mmol/kg IV bolus
• Prepare activated charcoal if below 2 hours and airway is protected
• Given her agitation, I would have a low threshold for intubation before giving charcoal

Disposition: Any patient with ECG changes, seizures, or altered mental status requires ICU admission for continuous monitoring."

Examiner Follow-up: The ECG shows QRS of 140 ms and R wave in aVR of 6 mm. What is your next step?

"The QRS of 140 ms with prominent R wave in aVR confirms significant TCA cardiotoxicity. I would immediately:

1. Administer sodium bicarbonate 1-2 mmol/kg IV bolus (approximately 100-150 mL of 8.4% solution)
2. Repeat the ECG in 5-10 minutes
3. If QRS does not narrow, repeat the bolus
4. If multiple boluses required, start an infusion of 150 mmol in 1L D5W
5. Check arterial blood gas - target pH 7.50-7.55
6. Monitor potassium and correct if low

I would also alert the ICU for admission and prepare for potential deterioration including seizures and arrhythmias."

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Viva 2: Refractory Hypotension

Examiner: You have been managing a patient with confirmed amitriptyline overdose in ICU. Despite 3 boluses of sodium bicarbonate totalling 300 mmol, the QRS has narrowed from 180 ms to 120 ms, but the blood pressure remains 75/45 mmHg. What are your next steps?

Candidate Response:

"Although the QRS has improved, the persistent hypotension indicates ongoing alpha-adrenergic blockade and possible myocardial depression. My approach would be:

Immediate Assessment:

• Confirm adequate intravascular volume (consider ECHO to assess filling)
• Check lactate and arterial blood gas
• Ensure pH is at target (7.50-7.55)
• Review potassium (hypokalemia from alkalosis may contribute)

Vasopressor Therapy:

• Start norepinephrine infusion at 0.1 mcg/kg/min
• Norepinephrine is preferred because it is a direct-acting alpha-agonist
• Dopamine is relatively contraindicated as it relies on intact norepinephrine stores, which are depleted by TCAs
• Titrate to MAP greater than 65 mmHg

Escalation if Norepinephrine Insufficient:

• Add vasopressin 0.01-0.04 units/min as an adjunct
• Consider adrenaline as alternative
• Ensure adequate calcium and magnesium levels

Rescue Therapies: If hypotension remains refractory despite maximal vasopressors:

1. Lipid Emulsion Therapy:

   • 20% Intralipid 1.5 mL/kg IV bolus over 1 minute
   • Follow with infusion 0.25 mL/kg/min
   • May repeat bolus every 3-5 minutes up to 3 times
   • Evidence is limited but may be beneficial in refractory cases

2. Consider VA-ECMO:

   • If hypotension is truly refractory
   • Early consultation with ECMO team
   • TCA toxicity is reversible, so ECMO can serve as a bridge to recovery
   • Literature shows up to 86% survival with timely VA-ECMO in toxicological causes"

Examiner Follow-up: What if the patient develops cardiac arrest?

"I would initiate standard ACLS with:

• High-quality CPR
• Defibrillation if shockable rhythm
• Sodium bicarbonate 2 mmol/kg IV bolus (may repeat)
• Lipid emulsion 1.5 mL/kg IV bolus
• Avoid dopamine and amiodarone
• Early ECMO/ECPR activation - TCA-induced cardiac arrest has better outcomes with ECMO than many other causes due to the reversible nature of the toxin
• Continue resuscitation for extended period; recovery possible after prolonged arrest if ECMO available"

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Key Clinical Pearls

1. ECG is the best risk stratifier - QRS duration and R wave in aVR are more predictive than serum drug levels

2. Sodium bicarbonate is life-saving - Do not delay; give empirically if TCA overdose suspected with ECG changes

3. Target pH 7.50-7.55 - Higher pH reduces drug-receptor binding; monitor potassium closely

4. Never give flumazenil - Risk of precipitating refractory seizures in mixed overdose

5. Norepinephrine, not dopamine - Direct-acting alpha-agonist is essential; dopamine is ineffective

6. Anticipate delayed absorption - Anticholinergic gastroparesis means toxicity may worsen hours after ingestion

7. Observe minimum 6 hours - Asymptomatic patients with normal ECG can be cleared after 6 hours

8. Phenytoin is contraindicated for seizures - Use benzodiazepines; phenytoin is ineffective and may worsen cardiac conduction

9. ECMO can be life-saving - TCA toxicity is reversible; early ECMO activation for refractory shock or arrest

10. Charcoal requires protected airway - Never give activated charcoal to a drowsy patient without intubation

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