Tricyclic Antidepressant (TCA) Overdose

Meet the patient

A 30-year-old woman is brought in unconscious an hour after taking a bottle of her mother's amitriptyline. She is hot and dry, her pupils are wide, her pulse is 130, and the monitor shows a broad-complex tachycardia with a QRS of 150 ms.^[5][2]

Two exam questions are now live: what single drug reverses the cardiotoxicity, and which drugs must you never give? The trap is that this patient looks anticholinergic but dies from sodium-channel blockade — the widened QRS is the emergency, the dry skin is the clue, and the antidote is sodium bicarbonate given before the arrhythmia, not after.^[5][7]

What TCA overdose is — one lethal ECG

Tricyclic antidepressant (TCA) overdose is the clinical syndrome produced by acute ingestion of a supra-therapeutic quantity of a tricyclic antidepressant. It is defined by a clinical and electrocardiographic triad: cardiovascular toxicity from fast sodium-channel blockade (QRS widening, conduction block, ventricular dysrhythmias, hypotension), an anticholinergic (antimuscarinic) picture, and central nervous system toxicity (depressed consciousness, seizures, coma).^[4][5][6]

TCAs are among the commonest causes of drug poisoning seen in emergency departments, and they are lethal: case-fatality data from England and Wales put TCAs at 13.8 (95% CI 13.0-14.7) versus 0.5 (95% CI 0.4-0.7) for the SSRIs — a roughly 28-fold difference in case fatality between TCAs and SSRIs.^[8] The clinical skill is to recognise cardiotoxicity early — the widened QRS — and give sodium bicarbonate: once cardiotoxicity is evident, serum alkalinisation, preferably by sodium bicarbonate therapy, is the treatment of choice, and the QRS interval (particularly over 100 ms) is among the most sensitive ECG screens for it.^[6]

The topic is high-yield because it tests three layers that examiners return to repeatedly: the pharmacology (TCAs as cardiac sodium-channel blockers whose toxicity responds to alkalinisation and sodium loading), the electrocardiographic recognition (the QRS thresholds and the aVR terminal R wave), and the antidote ladder (sodium bicarbonate, benzodiazepines for seizures, lipid emulsion for refractory collapse) — together with the equally important avoid list (class Ia/Ic antiarrhythmics, phenytoin, flumazenil).^[7][4][1]

The agents — which tricyclic kills most

TCAs are classified by chemical generation and by relative toxicity in overdose — both axes are examinable.^[8][9]

^{[8] [9] [1] [2] [3] [7] [4]}

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A small supra-therapeutic dose — why TCA overdose stays among the deadliest

TCA overdose remains one of the most lethal common pharmaceutical poisonings: an expert consensus panel determined that ingestion of an amount exceeding the usual maximum single therapeutic dose, or equal to or greater than the lowest reported toxic dose, warrants emergency-department referral — for most TCAs this is over 5 mg/kg; for desipramine, nortriptyline and trimipramine over 2.5 mg/kg; for protriptyline over 1 mg/kg.^[1] Within-class differences matter as much: compared with amitriptyline, dosulepin (relative toxicity index 2.7) and doxepin (2.6) are more toxic by case fatality, while lofepramine carries the lowest risk of death in overdose.^[8][9]

Risk factors for severity:^[1]

• Co-ingestants — ingestion of a TCA in combination with other drugs might warrant referral to an emergency department even when the TCA dose alone would not; other psychopharmaceutical agents are the classic companions.^[1]
• Underlying cardiovascular or neurological disease — the ingestion of a TCA by a patient with significant underlying cardiovascular or neurological disease should cause referral at a LOWER dose than for other individuals.^[1]
• Deliberate self-harm — patients with suspected self-harm should be referred to an emergency department immediately; overdose with TCAs is a recognised method of suicide.^[1][8]
• Young children — patients less than 6 years of age need further evaluation after any TCA ingestion, including history and determination of co-ingestants.^[1]

Drug-specific risk:^[8][9]

• Dothiepin (dosulepin) is more toxic than amitriptyline by case fatality (relative toxicity index 2.7), and dosulepin and amitriptyline have been identified as particularly toxic tricyclics whose use has been restricted.^[8][9]
• Desipramine appears somewhat more likely than other TCAs to lead to death in overdose.^[9]
• Lofepramine is the exception, with the lowest risk of death in overdose.^[9]

Paediatric lethality: a 20-month-old toddler who ingested a potentially lethal amount of dothiepin deteriorated despite standard paediatric treatment recommendations for TCA toxicity and survived only after intravenous lipid emulsion was added to standard therapy (including sodium bicarbonate) and direct-current cardioversion for ventricular arrhythmia. Accidental toddler ingestion of a grandparent's tricyclic is a real and preventable lethal exposure.^[10]

Three mechanisms, and why alkalinisation is the engine of rescue

The pharmacology is the most frequently examined concept in this topic. TCAs act as cardiac fast-sodium-channel blockers — a sodium-channel-blocker poisoning that, unlike some other sodium-channel blockers, responds well to sodium bicarbonate therapy.^[7]

Mechanism 1 — fast sodium-channel blockade (the cardiotoxic and CNS-toxic mechanism)

Blocking the fast sodium current slows intraventricular conduction. The ECG consequence is the cardinal sign of TCA cardiotoxicity: QRS widening, with ventricular dysrhythmias, hypotension, heart block, bradyarrhythmias and asystole as the classical cardiovascular manifestations; seizures and coma complete the syndrome.^[5][6] It is predominantly the cardiotoxic effects that cause mortality, and once cardiotoxicity is evident the treatment of choice is serum alkalinisation, preferably by sodium bicarbonate therapy.^[6] Importantly, most deaths in patients who reach hospital are cardiac in origin and caused by direct depression of myocardial function rather than cardiac arrhythmias — a subtlety examiners love.^[4]

Mechanism 2 — anticholinergic (antimuscarinic) effects

The major features of TCA overdose are neurological, cardiac, respiratory and anticholinergic — the anticholinergic component gives the classic dry-hot-flushed-delirious picture that is usually the first diagnostic clue.^[4]

Mechanism 3 — circulatory collapse

Hypotension is a principal life-threatening feature; coma, convulsions, respiratory depression and hypotension are treated with standard resuscitation techniques and drugs, while significant cardiotoxicity or cardiac arrest is treated with alkalinisation by sodium bicarbonate or hyperventilation, aiming for an arterial pH of 7.45-7.55.^[4]

Why alkalinisation and sodium loading work

Sodium bicarbonate achieves serum alkalinisation and reduces sodium-channel blockade; it works synergistically with hyperventilation (PCO2 of about 30-35 mmHg), which reduces the dose of bicarbonate needed to reach the target pH and avoids adverse effects from excessive hypertonic sodium bicarbonate.^[7] This is the mechanistic justification for controlling ventilation and perfusion alongside the antidote: the two interventions are deliberately paired.^[7]

Enlarge

Blind, hot, dry and mad — then wide, then fits

The presentation spans the anticholinergic picture (the early clue), cardiovascular toxicity (the lethal component), and CNS toxicity (the cause of secondary deterioration).^[4][5]

The anticholinergic toxidrome (early and diagnostic)

^[4]

Cardiovascular features (the lethal component)

• QRS widening — the cardinal sign of cardiotoxicity and the most sensitive ECG screen.^[6]
• Ventricular dysrhythmias, hypotension, heart block, bradyarrhythmias, or asystole — the classical cardiovascular manifestations.^[5]
• A terminal 40-ms frontal-plane axis over 120 degrees — with QRS prolongation over 100 ms, the most sensitive ECG criteria for first-generation TCA toxicity.^[6]
• Deaths are cardiac in origin, caused by direct depression of myocardial function rather than cardiac arrhythmias.^[4]

CNS features

• Seizures and coma — common, and seizures predict a stormier course: in the landmark cohort, 34% of patients with a QRS of 0.10 s or longer seized.^[5][2]
• Respiratory depression — a major feature category of overdose; it drives the acidosis that defeats alkalinisation and is why the bicarbonate strategy is paired with ventilation.^[4][7]

Temporal sequence (reproduce verbatim)

Life-threatening complications develop within six hours of overdose or not at all — that single sentence is the six-hour observation rule and the answer to "when can this patient go home".^[4]

Paediatric presentation

Accidental ingestion in a toddler: a 20-month-old girl who ingested a potentially lethal amount of dothiepin deteriorated despite standard paediatric treatment and required intravenous lipid emulsion plus cardioversion for ventricular arrhythmia. A high index of suspicion, an ECG, and a thorough pill count are essential — and any child under 6 needs formal evaluation after a TCA ingestion.^[10][1]

Co-ingestion

Ingestion of a TCA in combination with other drugs might warrant referral even when the TCA dose alone would not — determine the presence of co-ingestants (especially other psychopharmaceutical agents) and underlying exacerbating conditions such as convulsions or cardiac arrhythmias.^[1]

The mimics — and the bedside questions that end each

Cyclic antidepressants may cause changes in the electrocardiogram at therapeutic or toxic serum levels; the most serious complications of toxicity are dysrhythmias, hypotension and seizures, and it is predominantly the cardiotoxic effects that cause mortality.^[6]

^{[7] [8] [4]}

The decisive bedside questions are: is the QRS widened? (a sodium-channel blocker — and one that responds to bicarbonate), what does lead aVR show? (a terminal R wave 3 mm or more predicts seizures and arrhythmias), and what exactly was ingested, when, and with what co-ingestants?.^[2][3][1]

The bedside minute — glucose, the ECG, and the cardinal changes

Focused history:^[1][8][9]

• Drug name — which TCA? Dosulepin (2.7) and doxepin (2.6) are more toxic than amitriptyline by case fatality; desipramine appears somewhat more likely than other TCAs to lead to death in overdose.^[8][9]
• Dose and number of tablets — over 5 mg/kg (most TCAs), over 2.5 mg/kg (desipramine, nortriptyline, trimipramine) or over 1 mg/kg (protriptyline) exceeds the emergency-department referral threshold.^[1]
• Time of ingestion — drives the six-hour observation rule: life-threatening complications develop within six hours of overdose or not at all.^[4][1]
• Co-ingestants — especially other psychopharmaceutical agents; combination ingestions may warrant referral at a lower dose.^[1]
• Reason — suspected self-harm mandates immediate emergency-department referral.^[1]
• Underlying disease — significant cardiovascular or neurological disease lowers the referral threshold.^[1]

Focused examination:^[4][5]

• Vital signs — heart rate, blood pressure (hypotension is a cardinal severe feature), respiratory rate (respiratory depression is a major feature category), conscious level, temperature.
• Toxidrome-directed exam — pupils, mucosae, skin, bowel sounds, bladder, tone and reflexes, to map the neurological, cardiac, respiratory and anticholinergic features of overdose.^[4]
• Cardiovascular and neurological exam — to grade shock and coma.^[5]

ECG — obtain early and recognise the cardinal changes:^[6][2]

1. QRS widening — over 100 ms is among the most sensitive screens for first-generation TCA toxicity.^[6]
2. Terminal 40-ms frontal-plane axis over 120 degrees — the companion sensitive criterion.^[6]
3. Terminal R wave 3 mm or more in lead aVR — the only ECG variable that independently predicts seizures and arrhythmias.^[3]
4. Dysrhythmias — ventricular dysrhythmias, heart block, bradyarrhythmias, asystole.^[5]

Establish continuous cardiac monitoring and IV access. An ECG or rhythm strip should be checked during the prehospital assessment of a TCA overdose patient; a wide-complex arrhythmia with a QRS duration longer than 100 ms is an indicator that the patient should be immediately stabilised, given sodium bicarbonate, and transported.^[1] With repeated bicarbonate dosing it is imperative to monitor and correct potassium and sodium abnormalities and observe changes in serum pH and on the electrocardiogram.^[7]

The ECG predicts severity — the level does not

First-line investigations: a 12-lead ECG with continuous cardiac monitoring (the single most important investigation), and a venous/arterial blood gas — with repeated bicarbonate doses, monitor serum pH, potassium and sodium.^[1][7]

The QRS duration thresholds (Boehnert & Lovejoy, NEJM 1985 — reproduce verbatim)

The landmark 1985 prospective study of 49 patients established the QRS duration (not the serum drug level) as the predictor of seizures and ventricular arrhythmias:^[2]

The aVR terminal R wave (Liebelt 1995)

In a prospective cohort of 79 patients (seizures 20%, ventricular arrhythmias 6%), the terminal R wave in aVR was greater in patients who developed seizures or arrhythmias (4.4 versus 1.8 mm). An RaVR of 3 mm or more had 81% sensitivity (PPV 43%) versus 82% sensitivity for a QRS over 100 ms — and on multiple logistic regression, an RaVR of 3 mm or more was the ONLY ECG variable that significantly predicted seizures and arrhythmias (OR 6.9, 95% CI 1.2 to 40).^[3]

Target serum pH for alkalinisation

The alkalinisation end-point is arterial pH 7.45 to 7.55, achieved by sodium bicarbonate OR hyperventilation; hypertonic bicarbonate works synergistically with hyperventilation to a PCO2 of about 30-35 mmHg. Stop at the alkalinisation target — do not chase complete QRS correction: even when the QRS responds, it takes a few hours to return completely to normal, and excessive dosing beyond 6 mmol/kg risks harm.^[4][7]

Role of the serum TCA level

A serum TCA level is NOT useful for acute management — serum drug levels failed to predict the risk of seizures or ventricular arrhythmias accurately and are not of predictive value. Treatment is driven by the ECG and the patient.^[2] The QRS interval longer than 100 ms is a better predictor of serious complications than an elevated serum TCA level.^[5]

The first hour — stabilise, then sodium bicarbonate

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Begin with ABCDE, with the specific TCA modifications:^[4][1]

• AIRWAY and BREATHING — coma, convulsions, respiratory depression and hypotension are treated with standard resuscitation techniques and drugs; symptomatic patients may require intravenous fluids, cardiovascular agents and respiratory support in accordance with standard ACLS guidelines.^[4][1]
• VENTILATE with the antidote in mind — hypertonic sodium bicarbonate is recommended to be administered in conjunction with mechanical ventilation and hyperventilation to a PCO2 of about 30-35 mmHg and a pH of about 7.45-7.55; hyperventilation itself alkalinises and reduces the bicarbonate dose needed.^[7]
• CIRCULATION — hypotension unresponsive to fluids and dopamine may respond to a norepinephrine infusion (it succeeded in two TCA-overdose cases unresponsive to fluid challenge and dopamine).^[12]
• ECG EARLY — a wide-complex arrhythmia with a QRS longer than 100 ms mandates immediate stabilisation and sodium bicarbonate.^[1]

IV sodium bicarbonate — the specific antidote

^{[5] [7]}

Indications for hypertonic sodium bicarbonate:^[7][5]

• Clinically significant toxicity: seizures, shock (systolic blood pressure under 90 mmHg or mean arterial pressure under 65 mmHg), or ventricular dysrhythmia^[7]
• QRS duration over 100 ms, or terminal right-axis deviation over 120 degrees^[5]
• Sodium bicarbonate is still the treatment of choice for severe TCA toxicity, with hypertonic saline a promising alternative.^[5]

Rationale (the exam answer):^[7]

1. Alkalinisation and sodium loading reduce sodium-channel blockade — TCA poisoning is a sodium-channel-blocker poisoning that responds well to bicarbonate.^[7]
2. Synergy with hyperventilation — bicarbonate plus a PCO2 of about 30-35 mmHg achieves serum alkalinisation (pH about 7.45-7.55) at a lower bicarbonate dose, avoiding adverse effects of excessive hypertonic dosing.^[7]
3. Stop at the alkalinisation target — no further doses after achieving pH 7.45-7.55; a prolonged QRS takes a few hours to normalise even when responding.^[7]

Seizures — benzodiazepines, AVOID phenytoin

• First-line: a BENZODIAZEPINE — for TCA-associated convulsions, benzodiazepines are the recommended treatment.^[1]
• AVOID PHENYTOIN — in TCA poisoning it is of no benefit.^[4]
• Seizures are themselves an indication for hypertonic sodium bicarbonate (clinically significant toxicity), and with repeated boluses potassium and sodium must be monitored and corrected.^[7]

Refractory ventricular arrhythmia

For ventricular arrhythmias, lignocaine (lidocaine) is the antiarrhythmic that has been used; other antiarrhythmic drugs are contraindicated (class Ia, class Ic), potentially lethal (class II), of no benefit (phenytoin) or of unproven efficacy (classes III and IV).^[4]

Sodium, alkali, benzo — and the drugs to never give

The stepwise ladder, with escalation triggers, is the most frequently examined aspect of this topic.^[4][7][1]

1. ABCDE resuscitation — coma, convulsions, respiratory depression and hypotension with standard resuscitation techniques and drugs; intravenous fluids, cardiovascular agents and respiratory support per standard ACLS.^[4][1]
2. IV SODIUM BICARBONATE — the antidote for significant cardiotoxicity or cardiac arrest: bolus 1-2 mmol/kg, repeated if unstable, to a maximum of 6 mmol/kg, with hyperventilation to pH 7.45-7.55.^[4][7]
3. HYPERTONIC SALINE — appears to be a promising alternative when bicarbonate is insufficient.^[5]
4. SEIZURE control — benzodiazepines (phenytoin of no benefit).^[1][4]
5. VASOPRESSORS — hypotension unresponsive to fluids and dopamine may respond to norepinephrine.^[12]
6. INTRAVENOUS LIPID EMULSION — for cardiovascular failure that deteriorates despite standard therapy including sodium bicarbonate.^[10][11]

Decontamination

• Activated charcoal binds tricyclic antidepressants — give 30 to 50 g orally or by nasogastric tube; all patients with TCA overdose should receive activated charcoal.^[5][4]
• Do NOT induce emesis.^[1]
• Prehospital charcoal, if available, should only be carried out by health professionals, only if no contraindications are present, and must not delay transportation to hospital.^[1]

IV sodium bicarbonate — the protocol verbatim

• Bolus: 1-2 mmol/kg (1-2 mEq/kg) IV, repeated as needed — and if the patient remains unstable, up to a maximum of 6 mmol/kg.^[5][7]
• End-point: serum alkalinisation to pH about 7.45-7.55 — NOT complete correction of QRS prolongation; no further doses after achieving the target.^[7]
• Adjunct: administer in conjunction with mechanical ventilation and hyperventilation (PCO2 about 30-35 mmHg).^[7]
• Monitor: with repeated boluses, monitor and correct potassium and sodium abnormalities and observe changes in serum pH and on the ECG.^[7]
• Alkalinisation may also be achieved by hyperventilation alone, aiming for an arterial pH of 7.45-7.55.^[4]

Hypertonic saline (refractory)

Hypertonic saline appears to be a promising alternative to sodium bicarbonate for severe TCA toxicity — and regardless of which sodium load is used, the same maximum-dose discipline applies: exceeding 6 mmol/kg is likely to cause hypernatraemia, fluid overload, metabolic alkalosis and cerebral oedema.^[5][7]

Vasopressors (refractory hypotension)

Hypotension in TCA overdose is first treated with standard resuscitation including fluids. In two cases of TCA overdose with hypotension unresponsive to fluid challenge and dopamine, a norepinephrine infusion was subsequently successful — dopamine's effect may be blunted because TCAs compromise endogenous norepinephrine stores.^[12]

Intravenous lipid emulsion (ILE) — refractory collapse

• Intravenous lipid emulsion has emerged as a rescue antidote for refractory toxicities including cyclic antidepressants — used when the patient continues to deteriorate despite standard treatment.^[11]
• A 20-month-old toddler with a potentially lethal dothiepin ingestion deteriorated despite standard paediatric TCA therapy; lipid emulsion in addition to standard therapy (including sodium bicarbonate) and direct-current cardioversion for ventricular arrhythmia led to a successful outcome.^[10]
• A 13-year-old girl developed delayed seizures and cardiac arrest after amitriptyline ingestion and was treated with ILE as part of the rescue — delayed toxicity is real, and lipid rescue can come late in the course.^[11]

Escalation triggers

Clinically significant toxicity — seizures, shock (systolic under 90 mmHg or MAP under 65 mmHg), or ventricular dysrhythmia — drives escalation of hypertonic sodium bicarbonate (boluses to the 6 mmol/kg maximum, with ventilation), and deterioration despite standard therapy drives intravenous lipid emulsion.^[7][10]

Scenarios you will actually meet

^{[8] [9] [10] [11] [1]}

How the patient comes to harm — the preventable list

Cardiovascular complications: ventricular dysrhythmias, hypotension, heart block, bradyarrhythmias and asystole are the classical manifestations — and most deaths in patients who reach hospital are cardiac in origin, caused by direct depression of myocardial function rather than cardiac arrhythmias.^[5][4]

CNS and respiratory complications: seizures and coma, with respiratory depression; neurological, cardiac, respiratory and anticholinergic features define the overdose syndrome.^[4] In severe ingestions, delayed seizures and cardiac arrest can still occur — a 13-year-old developed both after amitriptyline ingestion.^[11]

Treatment-related harm (the preventable part): excessive hypertonic sodium bicarbonate — dosing until the QRS completely normalises, or exceeding 6 mmol/kg — risks hypernatraemia, fluid overload, metabolic alkalosis and cerebral oedema, potentially lethally; bicarbonate also causes hypokalaemia and hypocalcaemia (which can prolong the QT and cause torsade de pointes).^[7]

The classic pitfalls (high-yield — the AVOID list revisited)

Test yourself: which treatments must you AVOID in TCA overdose, and why?ShowHide

1. Class Ia and class Ic antiarrhythmics — contraindicated in TCA poisoning.^[4]
2. Phenytoin — of no benefit in TCA poisoning; benzodiazepines are the recommended anticonvulsant.^[4][1]
3. Flumazenil — not recommended for patients with TCA poisoning.^[1]
4. Inducing emesis — do not induce emesis after a TCA ingestion.^[1]
5. Physostigmine — has no role at all in TCA poisoning.^[4] Also avoid haemodialysis and haemoperfusion — of no benefit in TCA poisoning — and do not dose bicarbonate to complete QRS correction or beyond 6 mmol/kg.^[4][7]

Lipid-emulsion pitfalls: the patient's laboratories may be uninterpretable for several hours after lipid emulsion, and pancreatitis can follow ILE therapy — recorded in the paediatric amitriptyline case treated with lipid emulsion.^[11]

Bicarbonate pitfalls: hypokalaemia and hypocalcaemia (QT prolongation, torsade de pointes with mixed-channel drugs), hypernatraemia, fluid overload, metabolic alkalosis and cerebral oedema when exceeding 6 mmol/kg — monitor and correct potassium and sodium with repeated boluses, and stop once serum alkalinisation (pH about 7.45-7.55) is achieved.^[7]

Expect a lagging QRS: even when the QRS responds to alkalinisation, it takes a few hours for the duration to return completely to normal — a widening that persists at the target pH is not by itself a reason to keep dosing.^[7]

The six-hour rule — and what happens to the patient

Overall outcome: the death rate of those who reach hospital is 2-3%; most of these deaths are cardiac in origin and are caused by direct depression of myocardial function rather than cardiac arrhythmias.^[4] For contrast across antidepressant classes, case fatality is 13.8 for TCAs versus 0.5 for SSRIs — TCAs remain in a lethality league of their own.^[8]

Predictors of severity and poor outcome: the maximal limb-lead QRS duration (under 100 ms — no seizures or ventricular arrhythmias in the landmark cohort; 100 ms or longer — 34% seizures and 14% ventricular arrhythmias; 0.16 s or longer — ventricular arrhythmias only at or above this width), the aVR terminal R wave 3 mm or more (the only independent ECG predictor), an ingested dose over the referral threshold (over 5 mg/kg for most TCAs), co-ingestants, and underlying cardiovascular or neurological disease. The serum drug level is NOT predictive.^[2][3][1]

Disposition — the six-hour rule:^[4][1]

• Life-threatening complications develop within six hours of overdose or not at all — that is the rule itself.^[4]
• Unintentional poisonings: asymptomatic patients are unlikely to develop symptoms if more than 6 hours have passed since ingestion — they do not need emergency-department referral.^[1]
• Any symptom (weak, drowsy, dizzy, tremulous, palpitations) after TCA ingestion warrants emergency-department referral.^[1]
• A wide-complex arrhythmia with QRS longer than 100 ms on the ECG mandates immediate stabilisation and sodium bicarbonate.^[1]

Prevention/psychiatric strategy: patients with suspected self-harm should be referred to an emergency department immediately; the wide differences in toxicity between antidepressants are relevant to prescribing decisions, especially in individuals at risk.^[1][8]

Special populations — children, elimination, and the referral thresholds

• Paediatrics: accidental ingestion is typical in toddlers — a 20-month-old ingested a potentially lethal amount of dothiepin and deteriorated despite standard paediatric treatment; intravenous lipid emulsion in addition to standard therapy (including sodium bicarbonate) and direct-current cardioversion for ventricular arrhythmia led to a successful outcome. Children under 6 need formal evaluation after any TCA ingestion, including history and determination of co-ingestants.^[10][1]
• Elimination: haemodialysis and haemoperfusion are of no benefit in TCA poisoning — never reach for extracorporeal removal.^[4]
• Underlying cardiovascular or neurological disease: lowers the emergency-department referral threshold — the same ingestion is riskier in these patients.^[1]
• Massive or mixed overdoses: delayed seizures and cardiac arrest occurred after amitriptyline ingestion in a 13-year-old treated with lipid emulsion — the tempo can be longer than the classic six-hour window in severe cases, which is why symptomatic patients are never discharged on the clock alone.^[11]

Evidence and the names that score marks

• Woolf AD et al, Clin Toxicol 2007 (PMID 17453872): the AACT/EAPCCT evidence-based consensus guideline for out-of-hospital management — dose-based referral thresholds (over 5 mg/kg for most TCAs), the six-hour asymptomatic rule, benzodiazepines for convulsions, flumazenil not recommended, ECG-based triage with sodium bicarbonate for QRS longer than 100 ms.^[1]
• Boehnert MT & Lovejoy FH Jr, N Engl J Med 1985 (PMID 4022081): the landmark prospective study (49 patients) establishing the QRS duration — not the serum level — as the predictor of seizures and ventricular arrhythmias.^[2]
• Liebelt EL et al, Ann Emerg Med 1995 (PMID 7618783): the prospective cohort (79 patients) showing the aVR terminal R wave of 3 mm or more is the only ECG variable that independently predicts seizures and arrhythmias (OR 6.9).^[3]
• Dziukas LJ & Vohra J, Med J Aust 1991 (PMID 2017063): the classic review — six-hour rule, charcoal for all, alkalinisation to pH 7.45-7.55 by bicarbonate or hyperventilation, lignocaine for ventricular arrhythmias, class Ia/Ic contraindicated, phenytoin of no benefit, physostigmine no role, dialysis no benefit, death rate 2-3% of those reaching hospital.^[4]
• Glauser J, Cleve Clin J Med 2000 (PMID 11060957): sodium bicarbonate as the treatment of choice, indicated for QRS over 100 ms or terminal right-axis deviation over 120 degrees, dosed 1-2 mEq/kg repeated as needed; charcoal 30-50 g; hypertonic saline a promising alternative.^[5]
• Groleau G et al, J Emerg Med 1990 (PMID 2254609): the ECG-manifestations review — QRS prolongation over 100 ms and terminal 40-ms axis over 120 degrees as the most sensitive screens; alkalinisation the treatment of choice once cardiotoxicity is evident.^[6]
• Chan BS & Buckley NA, Clin Toxicol 2024 (PMID 38597366): the modern dosing discipline — 1-2 mmol/kg boluses to a 6 mmol/kg maximum, pH 7.45-7.55 target with hyperventilation (PCO2 30-35 mmHg), stop at alkalinisation not QRS correction, monitor potassium and sodium.^[7]
• Hawton K et al, Br J Psychiatry 2010 (PMID 20435959): the case-fatality indices — TCAs 13.8 versus SSRIs 0.5; dosulepin 2.7 and doxepin 2.6 versus amitriptyline; citalopram 1.1 versus other SSRIs 0.3.^[8]
• Taylor D et al, Ther Adv Psychopharmacol 2024 (PMID 38827015): the systematic review of individual-TCA overdose toxicity — desipramine most lethal, lofepramine lowest risk, dosulepin and amitriptyline restricted.^[9]
• Hendron D et al, Pediatrics 2011 (PMID 22065274) and Levine M et al, Pediatrics 2012 (PMID 22753554): the paediatric lipid-emulsion rescue case reports — toddler dothiepin refractory to standard therapy, and delayed seizure/arrest after amitriptyline with pancreatitis and assay interference after ILE.^[10][11]
• Teba L et al, Am J Emerg Med 1988 (PMID 3178947): norepinephrine rescuing TCA-overdose hypotension unresponsive to fluids and dopamine.^[12]

^{[1] [7] [9]}

The mantra, and the memory devices

The mantra: read the QRS, give the bicarbonate to the pH target, control the seizures with a benzodiazepine, and keep class Ia/Ic, phenytoin and flumazenil out of the syringe.^[4][7]

• One-liner: TCA overdose = anticholinergic picture + WIDE QRS + seizures + hypotension; antidote = IV SODIUM BICARBONATE.^[4][5]
• ECG thresholds (reproduce verbatim): QRS under 100 ms — no seizures or ventricular arrhythmias recorded; 100 ms or longer — 34% seizures, 14% ventricular arrhythmias; ventricular arrhythmias ONLY at 0.16 s or longer; aVR terminal R wave 3 mm or more — the only independent predictor (OR 6.9).^[2][3]
• Antidote verbatim: SODIUM BICARBONATE 1-2 mmol/kg (1-2 mEq/kg) IV bolus, repeated as needed, maximum 6 mmol/kg, with hyperventilation (PCO2 30-35 mmHg) to pH 7.45-7.55.^[5][7]
• Why bicarbonate works: alkalinisation plus sodium loading reduces sodium-channel blockade, and it works synergistically with hyperventilation — TCAs are the sodium-channel-blocker poisoning that responds well.^[7]
• AVOID list: class Ia and class Ic antiarrhythmics (contraindicated), phenytoin (no benefit), flumazenil (not recommended), induced emesis, physostigmine (no role), haemodialysis/haemoperfusion (no benefit).^[4][1]
• Seizure treatment verbatim: a BENZODIAZEPINE for TCA-associated convulsions — never phenytoin.^[1][4]
• Hypotension verbatim: standard resuscitation with fluids first; norepinephrine infusion rescued cases unresponsive to fluid challenge and dopamine.^[12]
• Observation rule: life-threatening complications develop within six hours of overdose or not at all; asymptomatic unintentional ingestions beyond 6 hours do not need referral.^[4][1]
• Mortality facts: death rate 2-3% of those reaching hospital, mostly cardiac from direct myocardial depression; case fatality 13.8 for TCAs versus 0.5 for SSRIs; dosulepin and doxepin more toxic than amitriptyline.^[4][8]
• Dose thresholds: over 5 mg/kg (most TCAs), over 2.5 mg/kg (desipramine, nortriptyline, trimipramine), over 1 mg/kg (protriptyline) — the emergency-department referral thresholds.^[1]
• Discriminator one-liner: COMA + WIDE QRS + ANTICHOLINERGIC picture = TCA until proven otherwise. ^[4][5]

^[4]

Ward-round test — three stems, a minute each

Stem 1 — the monitor shows a QRS of 150 ms (answer)ShowHide

The woman from the vignette has an anticholinergic picture and a QRS of 150 ms. What is the antidote, the dose, and the end-point? Model: Intravenous sodium bicarbonate — 1 to 2 mmol/kg (1 to 2 mEq/kg) as a bolus, repeated as needed and if she remains unstable, to a maximum of 6 mmol/kg, administered in conjunction with mechanical ventilation and hyperventilation to a PCO2 of about 30 to 35 mmHg. The end-point is SERUM ALKALINISATION — pH about 7.45 to 7.55 — not complete QRS correction: even when the QRS responds it takes a few hours to normalise, and dosing beyond the alkalinisation target risks hypernatraemia, fluid overload, metabolic alkalosis and cerebral oedema. Monitor and correct potassium and sodium, and drive every decision off the ECG — the serum TCA level does not predict severity.^[5][7][2]

Stem 2 — she fits, and someone reaches for phenytoin (answer)ShowHide

Minutes after the bicarbonate the patient has a generalised tonic-clonic seizure, and a junior asks for intravenous phenytoin. What do you do, and why does the choice matter so much here? Model: Stop them. For TCA-associated convulsions, benzodiazepines are the recommended treatment — phenytoin is of NO benefit in TCA poisoning. The antiarrhythmic context matters even more here: class Ia and class Ic drugs are contraindicated, class II agents are potentially lethal, and classes III and IV are of unproven efficacy — lignocaine is the antiarrhythmic that has been used. And remember that a seizure is itself clinically significant toxicity: it is an indication for hypertonic sodium bicarbonate within the dosing discipline above.^[1][4][7]

Stem 3 — collapse despite bicarbonate, and who goes home (answer)ShowHide

Despite bicarbonate, fluids and vasopressors the patient's blood pressure collapses. What is the rescue therapy, and separately, when is a TCA-overdose patient safe to discharge? Model: The rescue therapy for refractory cardiovascular failure is INTRAVENOUS LIPID EMULSION — it salvaged a toddler whose dothiepin toxicity deteriorated despite standard paediatric therapy (including sodium bicarbonate), with direct-current cardioversion for ventricular arrhythmia, and it was used in a 13-year-old with delayed seizures and cardiac arrest after amitriptyline; anticipate its own harms (pancreatitis, uninterpretable laboratories for hours). For refractory hypotension before that, a norepinephrine infusion rescued two cases unresponsive to fluid challenge and dopamine. Separately, the discharge rule is the six-hour rule: life-threatening complications develop within six hours of overdose or not at all, and asymptomatic unintentional ingestions beyond 6 hours do not need referral — but any symptom, or a wide-complex rhythm with a QRS longer than 100 ms, means admission and treatment.^{[10][11][12][4][1]}

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References12ShowHide

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2. [2]Boehnert MT, Lovejoy FH Jr. Value of the QRS duration versus the serum drug level in predicting seizures and ventricular arrhythmias after an acute overdose of tricyclic antidepressants N Engl J Med, 1985.PMID 4022081
3. [3]Liebelt EL, Francis PD, Woolf AD. ECG lead aVR versus QRS interval in predicting seizures and arrhythmias in acute tricyclic antidepressant toxicity Ann Emerg Med, 1995.PMID 7618783
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7. [7]Chan BS, Buckley NA. Common pitfalls in the use of hypertonic sodium bicarbonate for cardiac toxic drug poisonings Clin Toxicol (Phila), 2024.PMID 38597366
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9. [9]Taylor D, Poulou S, Clark I. The cardiovascular safety of tricyclic antidepressants in overdose and in clinical use Ther Adv Psychopharmacol, 2024.PMID 38827015
10. [10]Hendron D, Menagh G, Sandilands EA, Scullion D. Tricyclic antidepressant overdose in a toddler treated with intravenous lipid emulsion Pediatrics, 2011.PMID 22065274
11. [11]Levine M, Brooks DE, Franken A, Graham R. Delayed-onset seizure and cardiac arrest after amitriptyline overdose, treated with intravenous lipid emulsion therapy Pediatrics, 2012.PMID 22753554
12. [12]Teba L, Schiebel F, Dedhia HV, Lazzell VA. Beneficial effect of norepinephrine in the treatment of circulatory shock caused by tricyclic antidepressant overdose Am J Emerg Med, 1988.PMID 3178947