Toxicology and Overdose Management — Part 3: Cardiovascular Drug, Antidepressant & Psychotropic Poisonings
Complete management of TCA poisoning (sodium bicarbonate protocol), calcium channel blocker overdose (high-dose insulin), beta-blocker toxicity, digoxin poisoning (DigiFab), serotonin syndrome, neuroleptic malignant syndrome, lithium toxicity, and antipsychotic overdose.
1. Tricyclic Antidepressant (TCA) Poisoning
Tricyclic antidepressant overdose remains one of the most dangerous drug ingestions encountered in the emergency department. Despite declining prescribing rates, TCAs continue to cause significant mortality due to their narrow therapeutic index and multiple toxic mechanisms.1 2
1.1 Toxic Mechanisms
TCAs exert toxicity through at least four pharmacologic actions:
| Mechanism | Clinical Effect |
|---|---|
| Sodium channel blockade (fast cardiac Na+ channels) | QRS prolongation, wide-complex arrhythmias, Brugada-like pattern, hypotension (decreased contractility) |
| Alpha-1 adrenergic antagonism | Hypotension, vasodilation |
| Anticholinergic effects (muscarinic receptor blockade) | Tachycardia, mydriasis, dry skin, urinary retention, decreased bowel sounds, delirium, hyperthermia, seizures |
| GABA-A receptor antagonism | Seizures (lowered seizure threshold) |
| Norepinephrine and serotonin reuptake inhibition | Early hypertension and tachycardia |
1.2 Clinical Features
Time course: Patients can deteriorate rapidly — from awake and conversant to seizures, arrhythmias, and cardiac arrest within 30–60 minutes. The critical observation window is the first 6 hours after ingestion; most life-threatening events occur within this period.1
Cardiovascular toxicity markers on ECG:
| ECG Finding | Significance |
|---|---|
| QRS duration > 100 ms | Increased risk of seizures |
| QRS duration > 160 ms | Increased risk of ventricular arrhythmias |
| R wave in aVR > 3 mm | Suggestive of sodium channel blockade; associated with increased toxicity |
| R/S ratio > 0.7 in aVR | Highly suggestive of TCA poisoning |
| Right axis deviation of terminal 40 ms | Characteristic finding |
| Sinus tachycardia | Almost universal (anticholinergic effect) |
| Brugada-like pattern | Type 1 Brugada pattern in right precordial leads (V1-V3) |
| QTc prolongation | Variable; less clinically important than QRS |
1.3 Sodium Bicarbonate Protocol — Primary Antidote
Sodium bicarbonate is the first-line treatment for TCA cardiovascular toxicity. It works by: (1) increasing extracellular sodium concentration (competing with TCA for sodium channels), (2) increasing serum pH (reducing TCA binding to sodium channels), and (3) increasing protein binding of TCA in alkalemic conditions.1 2 3
Indications for Sodium Bicarbonate
- QRS duration > 100 ms
- Ventricular arrhythmias
- Hypotension refractory to IV fluids
- Seizures (as adjunct to benzodiazepines)
Dosing Protocol
| Step | Detail |
|---|---|
| Bolus | 1–2 mEq/kg IV push (typically 1–2 ampules of 8.4% NaHCO₃; each 50-mL ampule contains 50 mEq) |
| Repeat | May repeat every 3–5 minutes as needed for persistent QRS widening |
| Infusion | After bolus: 150 mEq NaHCO₃ in 1 liter D5W at 150–250 mL/hour |
| Target arterial pH | 7.50–7.55 (do NOT exceed 7.60) |
| Monitor | Continuous cardiac monitoring; repeat ECG after each bolus; serum pH, electrolytes (especially potassium and calcium) |
Key Management Principles
- QRS narrowing on the monitor is the immediate indicator of response
- Hypertonic saline (3%) can be used as an alternative or adjunct if sodium bicarbonate is not narrowing the QRS (provides sodium loading without further alkalinization)
- Maintain hyperventilation if intubated to support alkalemia
- Monitor and replace potassium aggressively (alkalemia drives K+ intracellularly)
- Monitor ionized calcium (alkalemia reduces ionized calcium)
1.4 Seizure Management in TCA Poisoning
| Priority | Agent | Notes |
|---|---|---|
| First-line | Benzodiazepines (lorazepam 4 mg IV or diazepam 10 mg IV) | Also treats agitation and may reduce arrhythmia risk |
| Second-line | Phenobarbital (15–20 mg/kg IV at 50–100 mg/min) | If seizures persist |
| Adjunct | Sodium bicarbonate bolus | Address the underlying sodium channel blockade |
| AVOID | Phenytoin | Worsens sodium channel blockade; contraindicated |
| AVOID | Physostigmine | Historically used for anticholinergic effects but can cause asystole, seizures, and cholinergic crisis; contraindicated in TCA poisoning |
1.5 Hypotension Management
| Step | Intervention |
|---|---|
| 1 | IV crystalloid boluses (20 mL/kg) |
| 2 | Sodium bicarbonate bolus (1–2 mEq/kg) |
| 3 | Norepinephrine infusion (first-line vasopressor) |
| 4 | Consider IV lipid emulsion (20% intralipid) for refractory cases |
| 5 | Avoid pure vasodilators; avoid phenytoin; avoid class IA and class IC antiarrhythmics |
1.6 Disposition
- All symptomatic patients or those with ECG abnormalities: ICU admission with continuous monitoring
- Asymptomatic patients with normal ECG at 6 hours post-ingestion may be medically cleared for psychiatric evaluation
- QRS < 100 ms for 12–24 hours before considering sodium bicarbonate discontinuation
2. Calcium Channel Blocker (CCB) Poisoning
Calcium channel blocker overdose is one of the most lethal cardiovascular drug ingestions. The two major subclasses (dihydropyridines and non-dihydropyridines) have overlapping but distinct toxicologic profiles.4 5
2.1 Classification and Toxic Profiles
| Subclass | Agents | Primary Toxic Effects |
|---|---|---|
| Dihydropyridines | Amlodipine, nifedipine, felodipine, nicardipine | Peripheral vasodilation → profound hypotension; reflex tachycardia initially, then bradycardia with severe toxicity |
| Non-dihydropyridines | Verapamil, diltiazem | Myocardial depression + vasodilation + AV nodal blockade → bradycardia, hypotension, conduction blocks; verapamil is the most lethal |
2.2 Clinical Presentation
- Bradycardia (non-dihydropyridines predominantly; can occur with all in severe toxicity)
- Hypotension (all agents; may be refractory)
- Hyperglycemia (inhibition of insulin release from pancreatic beta cells — a hallmark feature distinguishing CCB from beta-blocker toxicity)
- Metabolic acidosis (lactic acidosis from poor perfusion)
- Altered mental status (from hypoperfusion)
- Pulmonary edema (severe cases)
- Mesenteric ischemia (non-occlusive, from prolonged hypotension)
Note on sustained-release formulations: Amlodipine, extended-release verapamil, and extended-release diltiazem may have markedly delayed onset of toxicity (up to 12–24 hours). Patients ingesting SR formulations require prolonged observation even if initially asymptomatic.
2.3 Management Algorithm
2.3.1 Initial Resuscitation
| Intervention | Details |
|---|---|
| IV fluids | 20 mL/kg normal saline bolus; repeat as needed; avoid excessive fluids (risk of pulmonary edema) |
| Atropine | 0.5–1 mg IV for symptomatic bradycardia (often ineffective in severe CCB toxicity) |
| Calcium | See Section 2.3.2 |
| GI decontamination | Activated charcoal if within 1–2 hours; whole bowel irrigation for sustained-release formulations |
2.3.2 Calcium — First-Line Pharmacologic Agent
| Agent | Dose | Notes |
|---|---|---|
| Calcium chloride (10%, central line preferred) | 1–2 g (10–20 mL) IV over 5–10 minutes | Contains 3 times more elemental calcium than calcium gluconate per gram; vesicant — central line or large, well-functioning peripheral line only |
| Calcium gluconate (10%) | 3–6 g (30–60 mL) IV over 5–10 minutes | Safer for peripheral administration |
| Repeat | Every 10–20 minutes as needed, up to 3–4 doses | |
| Infusion | Calcium gluconate 0.6–1.5 mL/kg/hr of 10% solution | Monitor ionized calcium; target 2–3 times normal (up to ~2.0 mmol/L) |
2.3.3 High-Dose Insulin Euglycemia Therapy (HIET) — Cornerstone of Severe CCB Toxicity
HIET is the most effective intervention for severe CCB overdose. Insulin promotes myocardial carbohydrate utilization (the stressed myocardium preferentially uses glucose over fatty acids), improves cardiac contractility, and has vasodilatory effects that improve tissue perfusion.4 5 6
| Component | Protocol |
|---|---|
| Bolus | Regular insulin 1 unit/kg IV push |
| Infusion | Regular insulin 1 unit/kg/hour, titrate up to 10 units/kg/hour based on hemodynamic response |
| Dextrose bolus | D50W 25 g (50 mL) IV concurrently with insulin bolus |
| Dextrose infusion | D10W or D25W infusion to maintain blood glucose 100–250 mg/dL |
| Potassium monitoring | Check every 30–60 minutes initially; supplement to maintain K+ ≥ 3.5 mEq/L |
| Glucose monitoring | Point-of-care glucose every 15–30 minutes initially, then hourly once stable |
Key principles of HIET:
- Do NOT delay insulin therapy waiting for glucose results — hypoglycemia is easily treated; death from refractory shock is not
- Hyperglycemia is expected in severe CCB toxicity (insulin release inhibition) and may not require additional dextrose initially
- Onset of hemodynamic benefit: 15–60 minutes (slower than vasopressors)
- Titrate aggressively: if no improvement, escalate to 2, then 5, then 10 units/kg/hour
- Most patients will become hypoglycemic during or after the infusion — continue dextrose even after insulin is weaned
2.3.4 Vasopressors
| Agent | Role |
|---|---|
| Norepinephrine | First-line vasopressor for refractory hypotension |
| Epinephrine | Alternative; provides both vasopression and inotropic support |
| Vasopressin | Adjunct for refractory vasoplegia (0.03–0.04 units/min) |
| Dopamine | Alternative; less preferred |
| Phenylephrine | May worsen bradycardia (reflex); generally avoid |
2.3.5 Additional Therapies for Refractory CCB Toxicity
| Intervention | Protocol | Evidence Level |
|---|---|---|
| Intravenous lipid emulsion (ILE) | 20% lipid: 1.5 mL/kg bolus over 2–3 min, then 0.25 mL/kg/min for 30–60 min | Case reports; consider in cardiac arrest or peri-arrest |
| Methylene blue | 1–2 mg/kg IV over 5–10 min; may repeat in 1 hour | Emerging evidence for vasoplegia refractory to vasopressors; treats calcium channel blocker-induced vasoplegia |
| Glucagon | 3–5 mg IV bolus (see beta-blocker section) | May provide modest benefit; limited evidence in CCB toxicity |
| ECMO/mechanical circulatory support | VA-ECMO as bridge therapy | For cardiac arrest or refractory cardiogenic shock |
| Pacing | Transcutaneous or transvenous | For symptomatic bradycardia/conduction blocks unresponsive to atropine and calcium |
3. Beta-Blocker Poisoning
3.1 Clinical Presentation
The cardinal features of beta-blocker overdose are bradycardia and hypotension. Additional features vary by agent:7
| Feature | Details |
|---|---|
| Bradycardia | Sinus bradycardia, AV block (all degrees), junctional rhythms |
| Hypotension | Due to decreased contractility and decreased heart rate |
| Hypoglycemia | Particularly in children and with non-selective agents; beta-blockade inhibits glycogenolysis and gluconeogenesis |
| Bronchospasm | Non-selective agents (propranolol) |
| Seizures and QRS widening | Propranolol — due to membrane-stabilizing (sodium channel blocking) activity |
| QTc prolongation | Sotalol — also has class III antiarrhythmic (potassium channel blocking) properties; risk of torsades de pointes |
| CNS depression | Lipophilic agents (propranolol, metoprolol) cross the blood-brain barrier |
3.2 Distinguishing Beta-Blocker from CCB Toxicity
| Feature | Beta-Blocker | CCB |
|---|---|---|
| Blood glucose | Hypoglycemia (especially children) | Hyperglycemia (inhibits insulin secretion) |
| Mental status | Depression (lipophilic agents) | May be preserved until late |
| ECG | Sinus brady, AV block; QRS widening (propranolol) | Sinus brady, AV block; no QRS widening |
3.3 Management
3.3.1 Glucagon — Traditional First-Line (Beta-Blocker–Specific)
Glucagon activates adenylate cyclase via a non-beta-adrenergic receptor mechanism, bypassing the blocked beta-receptor to increase heart rate and contractility.7 8
| Component | Protocol |
|---|---|
| Bolus | 3–5 mg IV over 1 minute (in adults); pediatric: 0.05–0.15 mg/kg |
| Repeat | May repeat in 5 minutes if no response; up to 10 mg total |
| Infusion | Effective bolus dose per hour (e.g., if 5 mg worked, infuse 5 mg/hour) |
| Common side effects | Vomiting (almost universal at high doses — protect airway), hyperglycemia, hypokalemia |
| Preparation | Reconstitute lyophilized glucagon with sterile water (NOT the diluent provided, which contains phenol — toxic in high doses) |
3.3.2 High-Dose Insulin Euglycemia Therapy
HIET is increasingly recognized as the preferred intervention for severe beta-blocker toxicity, as with CCB toxicity.5 6 Protocol is identical to that described in Section 2.3.3.
3.3.3 Additional Interventions
| Intervention | Details |
|---|---|
| Atropine | 0.5–1 mg IV for symptomatic bradycardia; often only partially effective |
| Calcium | 1–2 g calcium chloride IV (or 3–6 g calcium gluconate); less effective than in CCB toxicity |
| Vasopressors | Norepinephrine or epinephrine infusion for refractory hypotension |
| Sodium bicarbonate | 1–2 mEq/kg IV bolus for QRS widening (propranolol sodium channel blockade) |
| Magnesium sulfate | 2 g IV over 10 min for sotalol-induced QTc prolongation/torsades |
| Overdrive pacing | For sotalol-induced torsades; isoproterenol infusion as temporizing measure |
| IV lipid emulsion | Consider for lipophilic agents (propranolol) in refractory toxicity or cardiac arrest |
| Pacing | Transcutaneous or transvenous for refractory bradycardia |
4. Digoxin Poisoning
4.1 Mechanisms and Risk Factors
Digoxin inhibits the Na+/K+-ATPase pump, leading to increased intracellular sodium and, via the Na+/Ca2+ exchanger, increased intracellular calcium. This produces its therapeutic (positive inotropy) and toxic (arrhythmogenic, vagotonic) effects. Toxicity produces hyperkalemia due to impaired cellular potassium uptake.9 10
Factors increasing toxicity risk:
- Renal impairment (primary elimination route)
- Hypokalemia (K+ competes with digoxin at Na+/K+-ATPase; low K+ → increased digoxin binding)
- Hypomagnesemia
- Hypercalcemia
- Hypothyroidism
- Advanced age
- Drug interactions (amiodarone, verapamil, quinidine, clarithromycin increase digoxin levels)
4.2 Clinical Presentation
| System | Acute Toxicity (Single Large Ingestion) | Chronic Toxicity (Accumulation) |
|---|---|---|
| GI | Nausea, vomiting, abdominal pain (prominent and early) | Anorexia, nausea (may be subtle) |
| Cardiac | Almost any arrhythmia; bidirectional VT, accelerated junctional rhythm, ventricular ectopy with slow ventricular rate, high-degree AV block | Similar arrhythmia spectrum; may be more gradual |
| CNS | Drowsiness, confusion | Visual disturbances (xanthopsia — yellow-green halos), confusion, weakness |
| Metabolic | Hyperkalemia (potassium > 5.0 is a marker of severity; > 5.5 is life-threatening and predicts poor prognosis without antidote) | Hypokalemia may coexist (from diuretic use) |
Hallmark arrhythmias of digoxin toxicity:
- Paroxysmal atrial tachycardia (PAT) with AV block
- Bidirectional ventricular tachycardia (nearly pathognomonic)
- Accelerated junctional rhythm
- Regularization of atrial fibrillation (suggests complete heart block with junctional escape)
- Frequent PVCs, ventricular bigeminy
4.3 Digoxin-Specific Antibody Fragments (DigiFab) — The Antidote
DigiFab consists of antigen-binding (Fab) fragments of anti-digoxin antibodies. They bind free digoxin, rendering it pharmacologically inactive. DigiFab is highly effective and begins to work within 20–30 minutes of infusion.9 10
Indications for DigiFab
| Indication | Details |
|---|---|
| Life-threatening arrhythmias | Ventricular tachycardia, ventricular fibrillation, high-degree AV block with hemodynamic compromise |
| Potassium > 5.0 mEq/L in acute ingestion | Marker of severe poisoning; predictor of cardiac arrest |
| Hemodynamic instability | Symptomatic bradycardia or hypotension unresponsive to atropine |
| Acute ingestion > 10 mg in adults or > 4 mg in children | Empiric treatment before levels return |
| Chronic toxicity with significant arrhythmia or symptoms | Lower threshold for treatment |
DigiFab Dosing
Method 1 — Based on digoxin level (known steady-state level):
Number of vials = (Serum digoxin level in ng/mL) x (Weight in kg) / 100
Method 2 — Based on amount ingested (known acute ingestion):
Number of vials = (Amount ingested in mg) x 0.8 / 0.5
(0.8 = approximate bioavailability; 0.5 mg = amount of digoxin neutralized per vial)
Method 3 — Empiric dosing (unknown ingestion or emergent need):
| Scenario | Dose |
|---|---|
| Acute toxicity, life-threatening | 10–20 vials empirically |
| Chronic toxicity | 3–6 vials (lower total body burden) |
| Pediatric | 1–2 vials initially; may repeat |
Administration: Each vial is reconstituted in 4 mL sterile water and diluted in normal saline. Infuse over 30 minutes (may be given as IV push in cardiac arrest).
Important Notes After DigiFab Administration
- Serum digoxin level will be falsely elevated after DigiFab (assay measures both free and Fab-bound digoxin) — levels are uninterpretable for 1–2 weeks
- Monitor for rebound toxicity (especially with massive ingestion, as Fab fragments may be cleared faster than total digoxin burden)
- Avoid calcium in digoxin toxicity (historically believed to worsen — “stone heart” theory). Recent evidence suggests calcium may be safer than previously thought, but DigiFab remains the definitive treatment.
- Potassium replacement in digoxin toxicity requires extreme caution: hyperkalemia worsens digoxin toxicity, but as DigiFab works, potassium shifts intracellularly, and hypokalemia may rapidly develop
5. Serotonin Syndrome
5.1 Definition and Mechanism
Serotonin syndrome is a potentially life-threatening drug reaction resulting from excessive serotonergic activity at central and peripheral serotonin receptors (primarily 5-HT2A). It typically occurs from drug interactions involving two or more serotonergic agents, or from overdose of a single serotonergic agent.11 12
5.2 Common Precipitating Drug Interactions
| Drug Class/Agent | Examples | Mechanism |
|---|---|---|
| SSRIs | Fluoxetine, sertraline, citalopram, escitalopram, paroxetine | Serotonin reuptake inhibition |
| SNRIs | Venlafaxine, duloxetine | Serotonin reuptake inhibition |
| MAOIs | Phenelzine, tranylcypromine, selegiline, moclobemide | Decreased serotonin metabolism (most dangerous combinations) |
| TCAs | Clomipramine (most serotonergic TCA) | Serotonin reuptake inhibition |
| Opioids | Meperidine, tramadol, fentanyl, methadone | Serotonin reuptake inhibition |
| Antibiotics | Linezolid (MAOI activity) | Inhibits MAO-A |
| Triptans | Sumatriptan, rizatriptan | 5-HT1B/1D agonism |
| Other | Lithium, dextromethorphan, St. John’s wort, MDMA, methylene blue (MAOI activity) | Various serotonergic mechanisms |
Most dangerous combination: MAOI + SSRI (or any serotonin-releasing agent, including meperidine, MDMA, dextromethorphan). This combination can produce fatal serotonin syndrome.
5.3 Hunter Serotonin Toxicity Criteria (Diagnostic Standard)
The Hunter criteria are the validated diagnostic standard for serotonin syndrome. They have a sensitivity of 84% and specificity of 97% for clinically significant serotonin toxicity.11 12
Prerequisite: Patient must have been exposed to a serotonergic agent.
Then, any ONE of the following:
| Criterion | Description |
|---|---|
| 1 | Spontaneous clonus |
| 2 | Inducible clonus AND (agitation OR diaphoresis) |
| 3 | Ocular clonus AND (agitation OR diaphoresis) |
| 4 | Tremor AND hyperreflexia |
| 5 | Hypertonia AND temperature > 38°C AND (ocular clonus OR inducible clonus) |
Key definitions:
- Spontaneous clonus: rhythmic, involuntary muscle contractions present without provocation
- Inducible clonus: clonus elicited by rapid dorsiflexion of the ankle (> 3 beats)
- Ocular clonus: spontaneous, slow, continuous, lateral eye movements (distinct from nystagmus)
5.4 Management
| Severity | Features | Management |
|---|---|---|
| Mild | Tremor, hyperreflexia, mild clonus, anxiety | Discontinue serotonergic agents; observation; benzodiazepines for agitation |
| Moderate | Significant clonus, agitation, tachycardia, hypertension, hyperthermia (< 40°C) | Discontinue agents; IV benzodiazepines; cyproheptadine; IV fluids; active cooling if temp > 39°C |
| Severe | Hyperthermia > 40°C, sustained clonus, delirium, autonomic instability, rhabdomyolysis | ICU admission; aggressive cooling; cyproheptadine; intubation and neuromuscular paralysis (non-depolarizing agent) if temperature > 41°C; avoid succinylcholine |
Cyproheptadine — Specific Serotonin Antagonist
| Component | Protocol |
|---|---|
| Loading dose | 12 mg orally (may be crushed and given via NG tube) |
| Maintenance | 4 mg every 2–4 hours as needed (some protocols: 2 mg every 2 hours) |
| Maximum daily dose | 32 mg |
| Onset | 1–2 hours (oral administration only) |
| Side effects | Sedation (may be therapeutic), anticholinergic effects |
Additional measures:
- External cooling for hyperthermia (ice packs, evaporative cooling, cooling blankets)
- IV benzodiazepines for agitation and muscle hyperactivity
- If temperature > 41°C: intubation + non-depolarizing neuromuscular blockade (succinylcholine contraindicated — risk of hyperkalemia from rhabdomyolysis) to abolish muscle hyperactivity, which is the source of heat generation
- Avoid antipyretics (acetaminophen, NSAIDs) — ineffective as the hyperthermia is from muscle activity, not a hypothalamic setpoint change
6. Neuroleptic Malignant Syndrome (NMS)
6.1 Etiology
NMS is caused by dopamine receptor (D2) antagonism or abrupt withdrawal of dopaminergic agents:13
Causative agents:
- Typical antipsychotics: haloperidol, droperidol, chlorpromazine, fluphenazine
- Atypical antipsychotics: risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, clozapine
- Antiemetics: metoclopramide, prochlorperazine, promethazine
- Withdrawal of dopamine agonists: levodopa/carbidopa, bromocriptine, amantadine
6.2 Clinical Features
| Feature | Description |
|---|---|
| Hyperthermia | Often severe (> 40°C/104°F), may exceed 42°C |
| Lead-pipe rigidity | Generalized, severe, does NOT improve with benzodiazepines alone |
| Altered mental status | Confusion → obtundation → coma; catatonia |
| Autonomic instability | Tachycardia, labile blood pressure (hypertension or hypotension), tachypnea, diaphoresis |
| Laboratory abnormalities | CK markedly elevated (typically > 1,000, often > 10,000 U/L), leukocytosis, metabolic acidosis, elevated LDH, myoglobinuria |
6.3 Management
| Intervention | Protocol |
|---|---|
| Discontinue causative agent | Immediate; restart dopaminergic agent if NMS is from withdrawal |
| Aggressive cooling | External cooling measures; target normothermia |
| IV fluids | Aggressive crystalloid resuscitation for rhabdomyolysis prevention (target UOP 1–2 mL/kg/hr) |
| Dantrolene | 1–2.5 mg/kg IV every 6–12 hours (max 10 mg/kg/day); continue until CK is trending down and rigidity improves |
| Bromocriptine | 2.5 mg orally/NG every 8 hours; may increase to 5 mg every 8 hours; continue for 10 days after resolution then taper |
| Amantadine | Alternative to bromocriptine: 100 mg orally/NG every 12 hours |
| Benzodiazepines | Lorazepam 1–2 mg IV for agitation and as adjunct for rigidity |
| Avoid | Succinylcholine (hyperkalemia risk); antipyretics (ineffective); anticholinergic agents |
Monitoring: CK, renal function, electrolytes, urine myoglobin every 6–12 hours. ICU admission is standard.
7. Lithium Toxicity
7.1 Pharmacokinetics and Risk Factors
Lithium has a narrow therapeutic index (therapeutic level: 0.6–1.2 mEq/L). It is renally eliminated (no hepatic metabolism, no protein binding), and toxicity is strongly influenced by renal function and volume status.14
| Type | Description | Key Features |
|---|---|---|
| Acute ingestion | Single large ingestion in lithium-naive patient | GI symptoms predominate early; neurologic effects delayed; levels poorly correlate with toxicity initially (before tissue distribution) |
| Acute-on-chronic | Single large ingestion in patient already on lithium | Moderate GI + neurologic symptoms; higher risk because tissue stores already present |
| Chronic toxicity | Gradual accumulation (most dangerous) | Neurologic symptoms predominate; can occur at “therapeutic” levels; levels may only be mildly elevated (1.5–2.5); precipitated by dehydration, renal impairment, NSAIDs, ACE inhibitors, diuretics |
7.2 Clinical Manifestations by Severity
| Level (mEq/L) | Symptoms |
|---|---|
| 1.5–2.5 (mild-moderate) | Nausea, vomiting, diarrhea, tremor, lethargy, confusion |
| 2.5–3.5 (moderate-severe) | Marked confusion, ataxia, myoclonus, hyperreflexia, dysarthria, nystagmus |
| > 3.5 (severe) | Seizures, coma, renal failure, cardiovascular collapse, SILHA (syndrome of irreversible lithium-associated neurotoxicity) |
7.3 Management
| Intervention | Details |
|---|---|
| IV fluids | Aggressive normal saline resuscitation (restore volume and renal perfusion) |
| Avoid | NSAIDs, ACE inhibitors/ARBs, thiazide diuretics (all decrease lithium clearance) |
| Activated charcoal | NOT effective (lithium is not adsorbed) |
| Whole bowel irrigation | Consider for acute large ingestions or sustained-release lithium |
| Sodium polystyrene sulfonate (SPS) | NOT recommended (unreliable, risk of GI necrosis) |
| Hemodialysis | See Section 7.4 |
7.4 Hemodialysis Criteria for Lithium
Hemodialysis is the most effective method for rapidly reducing serum lithium levels. Recommendations from the extracorporeal treatments workgroup:15
| Indication | Recommendation |
|---|---|
| Level > 4.0 mEq/L regardless of symptoms | Hemodialysis recommended |
| Level > 2.5 mEq/L with impaired renal function (inability to excrete lithium) | Hemodialysis recommended |
| Significant neurologic symptoms (seizures, decreased consciousness) at any level | Hemodialysis recommended |
| Level > 5.0 mEq/L in acute ingestion | Hemodialysis recommended |
| Expected time for lithium to fall to < 1.0 mEq/L exceeds 36 hours | Hemodialysis suggested |
Important: Lithium has a slow intercompartmental redistribution; serum levels may rebound after hemodialysis. Continue monitoring levels for 6–8 hours after dialysis and repeat if rebound > 1.0 mEq/L.
8. SSRI and SNRI Overdose
8.1 General Features
Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) have a wide therapeutic index and are generally safe in overdose. The primary concerns are serotonin syndrome (especially with co-ingestants) and seizures.16
Toxicity by agent:
| Agent | Unique Toxicity Concerns |
|---|---|
| Citalopram/escitalopram | QTc prolongation (dose-dependent); seizures more common than other SSRIs; ingestion > 600 mg citalopram warrants cardiac monitoring |
| Fluoxetine | Long half-life (active metabolite norfluoxetine: 4–16 days); drug interactions persist for weeks |
| Sertraline | Relatively benign in overdose |
| Paroxetine | Short half-life; withdrawal syndrome if abruptly stopped |
| Venlafaxine | Seizures (dose-dependent); tachycardia; hypertension; serotonin syndrome; QRS widening at very high doses (weak sodium channel blockade) |
| Duloxetine | Serotonin syndrome; hepatotoxicity (rare) |
| Bupropion (NDRI) | Seizures (hallmark toxicity, dose-dependent); tachycardia; agitation; delayed seizures (up to 24 hours with sustained-release) |
8.2 Management
- Supportive care for most patients
- Cardiac monitoring for citalopram/escitalopram (≥ 8 hours for QTc monitoring)
- Benzodiazepines for seizures
- Sodium bicarbonate for QRS prolongation (venlafaxine in massive overdose)
- Cyproheptadine if serotonin syndrome develops
- Observation period: 6 hours for immediate-release; 24 hours for sustained-release bupropion/venlafaxine
9. Antipsychotic Overdose
9.1 First-Generation (Typical) Antipsychotics
Toxicity features: anticholinergic effects, QTc prolongation, extrapyramidal symptoms (acute dystonia), lowered seizure threshold, hypotension (alpha blockade), NMS.17
9.2 Second-Generation (Atypical) Antipsychotics
| Agent | Key Toxicity Features |
|---|---|
| Quetiapine | Most common atypical in overdose; sedation, tachycardia, hypotension, QTc prolongation; generally survivable even in large ingestion |
| Olanzapine | Sedation, anticholinergic effects, hyperglycemia, tachycardia |
| Risperidone | QTc prolongation, extrapyramidal symptoms, orthostatic hypotension |
| Ziprasidone | QTc prolongation (most pronounced among atypicals) |
| Clozapine | Sedation, anticholinergic effects, seizures (dose-dependent), sialorrhea (paradoxically), agranulocytosis (chronic) |
| Aripiprazole | Generally benign; mild sedation; minimal hemodynamic effects |
9.3 Management
- Supportive care is the cornerstone
- Activated charcoal if within 1–2 hours
- Continuous cardiac monitoring (QTc); at least 6 hours
- IV fluids and vasopressors (norepinephrine preferred) for hypotension
- Benzodiazepines for seizures and agitation
- Magnesium sulfate 2 g IV for QTc prolongation > 500 ms
- Diphenhydramine 25–50 mg IV or benztropine 1–2 mg IV for acute dystonia
- Avoid all class IA and class III antiarrhythmics (further QTc prolongation)
Liebelt EL, Francis PD, Woolf AD. “ECG Lead aVR Versus QRS Interval in Predicting Seizures and Arrhythmias in Acute Tricyclic Antidepressant Toxicity.” Annals of Emergency Medicine. 1995;26(2):195-201. DOI: 10.1016/S0196-0644(95)70151-5 ↩︎ ↩︎ ↩︎
Body R, Bartram T, Azam F, Mackway-Jones K. “Guidelines in Emergency Medicine Network (GEMNet): Guideline for the Management of Tricyclic Antidepressant Overdose.” Emergency Medicine Journal. 2011;28(4):347-368. DOI: 10.1136/emj.2010.091553 ↩︎ ↩︎
Bruccoleri RE, Burns MM. “A Literature Review of the Use of Sodium Bicarbonate for the Treatment of QRS Widening.” Journal of Medical Toxicology. 2016;12(1):121-129. DOI: 10.1007/s13181-015-0483-y ↩︎
St-Onge M, Anseeuw K, Cantrell FL, et al. “Experts Consensus Recommendations for the Management of Calcium Channel Blocker Poisoning in Adults.” Critical Care Medicine. 2017;45(3):e306-e315. DOI: 10.1097/CCM.0000000000002087 ↩︎ ↩︎
Engebretsen KM, Kaczmarek KM, Morgan J, Holger JS. “High-Dose Insulin Therapy in Beta-Blocker and Calcium Channel-Blocker Poisoning.” Clinical Toxicology. 2011;49(4):277-283. DOI: 10.3109/15563650.2011.582471 ↩︎ ↩︎ ↩︎
Holger JS, Engebretsen KM, Fritzlar SJ, et al. “Insulin Versus Vasopressin and Epinephrine to Treat Beta-Blocker Toxicity.” Clinical Toxicology. 2007;45(4):396-401. DOI: 10.1080/15563650701285412 ↩︎ ↩︎
Love JN, Howell JM, Litovitz TL, Klein-Schwartz W. “Acute Beta Blocker Overdose: Factors Associated with the Development of Cardiovascular Morbidity.” Journal of Toxicology: Clinical Toxicology. 2000;38(3):275-281. DOI: 10.1081/CLT-100100131 ↩︎ ↩︎
Bailey B. “Glucagon in Beta-Blocker and Calcium Channel Blocker Overdoses: A Systematic Review.” Journal of Toxicology: Clinical Toxicology. 2003;41(5):595-602. DOI: 10.1081/CLT-120023761 ↩︎
Hauptman PJ, Kelly RA. “Digitalis.” Circulation. 1999;99(9):1265-1270. DOI: 10.1161/01.CIR.99.9.1265 ↩︎ ↩︎
Lapostolle F, Borron SW, Verdier C, et al. “Digoxin-Specific Fab Fragments as Single First-Line Therapy in Digitalis Poisoning.” Critical Care Medicine. 2008;36(11):3014-3018. DOI: 10.1097/CCM.0b013e31818b341c ↩︎ ↩︎
Boyer EW, Shannon M. “The Serotonin Syndrome.” New England Journal of Medicine. 2005;352(11):1112-1120. DOI: 10.1056/NEJMra041867 ↩︎ ↩︎
Dunkley EJC, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. “The Hunter Serotonin Toxicity Criteria: Simple and Accurate Diagnostic Decision Rules for Serotonin Toxicity.” QJM. 2003;96(9):635-642. DOI: 10.1093/qjmed/hcg109 ↩︎ ↩︎
Strawn JR, Keck PE, Caroff SN. “Neuroleptic Malignant Syndrome.” American Journal of Psychiatry. 2007;164(6):870-876. DOI: 10.1176/ajp.2007.164.6.870 ↩︎
Baird-Gunning J, Lea-Henry T, Hoegberg LCG, Gosselin S, Roberts DM. “Lithium Poisoning.” Journal of Intensive Care Medicine. 2017;32(4):249-263. DOI: 10.1177/0885066616651582 ↩︎
Decker BS, Goldfarb DS, Dargan PI, et al. “Extracorporeal Treatment for Lithium Poisoning: Systematic Review and Recommendations from the EXTRIP Workgroup.” Clinical Journal of the American Society of Nephrology. 2015;10(5):875-887. DOI: 10.2215/CJN.10021014 ↩︎
Isbister GK, Bowe SJ, Dawson A, Whyte IM. “Relative Toxicity of Selective Serotonin Reuptake Inhibitors (SSRIs) in Overdose.” Journal of Toxicology: Clinical Toxicology. 2004;42(3):277-285. DOI: 10.1081/CLT-120037428 ↩︎
Burns MJ. “The Pharmacology and Toxicology of Atypical Antipsychotic Agents.” Journal of Toxicology: Clinical Toxicology. 2001;39(1):1-14. DOI: 10.1081/CLT-100102873 ↩︎