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ABIM Critical Care Medicine

26.2 Critical Care Toxicology, Toxidromes & Specific Antidotes

Key Takeaways

Clinical toxidromes allow rapid empiric classification: Sympathomimetic toxicity presents with hyperthermia, mydriasis, hypertension, and prominent diaphoresis, whereas anticholinergic toxicity is distinguished by anhidrosis ('dry as a bone') and urinary retention.
Pure beta-blockers must be strictly avoided in severe sympathomimetic (cocaine/amphetamine) toxicity due to the risk of unopposed alpha-adrenergic vasoconstriction precipitating coronary vasospasm and hypertensive crisis.
Acetaminophen toxicity requires prompt treatment with N-acetylcysteine (NAC) guided by the Rumack-Matthew nomogram; NAC therapy should continue beyond 21 hours if transaminases remain elevated, coagulopathy persists, or acetaminophen remains detectable.
Salicylate toxicity causes mixed primary respiratory alkalosis and high anion gap metabolic acidosis; management relies on aggressive potassium repletion and intravenous sodium bicarbonate for urinary and systemic alkalinization, with emergent hemodialysis indicated for levels > 100 mg/dL, altered mental status, or pulmonary edema.
High-Dose Insulin-Euglycemia Therapy (HIET) is the premier metabolic inotropic rescue for severe beta-blocker and calcium channel blocker overdoses, providing direct carbohydrate substrate to failing myocytes while reversing shock.

Last updated: October 2026

Clinical Toxidrome Recognition in the ICU

When evaluating a patient with suspected acute poisoning or an undifferentiated altered mental status, identifying a characteristic toxidrome—a constellation of physical signs and symptoms associated with specific pharmacological classes—allows immediate, targeted resuscitation before definitive laboratory confirmation is available.

1. Sympathomimetic Toxidrome

Causative Agents: Cocaine, amphetamines, methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA / "ecstasy"), synthetic cathinones ("bath salts"), ephedrine, pseudoephedrine.
Pathophysiology: Massive central and peripheral release and reuptake inhibition of catecholamines (norepinephrine, epinephrine, dopamine, serotonin), stimulating alpha- and beta-adrenergic receptors.
Clinical Manifestations: Severe agitation, hypervigilance, delirium, hyperthermia, tachycardia, hypertension, mydriasis (dilated pupils), hyperactive bowel sounds, tremors, seizures, and profuse diaphoresis.
Critical Management Nuance: Diaphoresis is the key physical finding distinguishing sympathomimetic toxicity from anticholinergic toxicity. First-line therapy relies on aggressive intravenous benzodiazepines (lorazepam or diazepam) to blunt central sympathetic outflow, control seizures, and facilitate evaporative cooling. Direct-acting vasodilators (phentolamine, nicardipine, nitroglycerin, or nitroprusside) may be added for refractory hypertension.

Warning

Avoid Pure Beta-Blockers in Cocaine and Sympathomimetic Toxicity: The administration of pure beta-adrenergic antagonists (such as propranolol or metoprolol) in severe cocaine or amphetamine intoxication blocks beta-2 mediated peripheral vasodilation while leaving alpha-1 adrenergic receptors uninhibited. This "unopposed alpha-adrenergic stimulation" can precipitate catastrophic arterial vasoconstriction, severe hypertensive crisis, acute coronary vasospasm, and acute myocardial infarction.

2. Anticholinergic (Antimuscarinic) Toxidrome

Causative Agents: First-generation antihistamines (diphenhydramine, hydroxyzine), tricyclic antidepressants (amitriptyline, nortriptyline), scopolamine, atropine, benztropine, antispasmodics (oxybutynin), and plants (Datura stramonium [Jimson weed], Atropa belladonna).
Pathophysiology: Competitive inhibition of acetylcholine at central and peripheral muscarinic ( $M_1 - M_5$ ) receptors.
Clinical Manifestations: The classic mnemonic details the syndrome:
- "Blind as a bat" (mydriasis with loss of visual accommodation / cycloplegia)
- "Mad as a hatter" (delirium, hallucinations, picking at non-existent objects, speech dyspraxia)
- "Red as a beet" (cutaneous flushing from compensatory peripheral vasodilation)
- "Hot as a hare" (hyperthermia from loss of thermoregulatory sweating)
- "Dry as a bone" (marked anhidrosis, parched oral mucosa, dry axillae)
- "Full as a flask" (urinary retention from detrusor relaxation and internal sphincter contraction)
- Additional features: Absent or hypoactive bowel sounds, sinus tachycardia.
Critical Management Nuance: Supportive therapy includes Foley catheterization to relieve bladder distension, active cooling, and benzodiazepines for psychomotor agitation. Physostigmine (a tertiary amine carbamate that inhibits acetylcholinesterase and crosses the blood-brain barrier; dose $0.5 - 2\text{ mg}$ slow IV over 5 minutes) can reverse central and peripheral delirium in pure anticholinergic poisoning. However, physostigmine is strictly contraindicated if tricyclic antidepressant (TCA) toxicity or cardiac conduction abnormalities (prolonged QRS $> 100\text{ ms}$ , terminal $R$ wave in aVR, PR prolongation) are present, as it can precipitate severe refractory bradyasystole and cardiac arrest.

3. Cholinergic Toxidrome

Causative Agents: Organophosphate and carbamate insecticides, chemical nerve agents (sarin, tabun, soman, VX), and acetylcholinesterase-inhibiting medications (neostigmine, pyridostigmine, donepezil).
Pathophysiology: Irreversible (organophosphates) or reversible (carbamates) inhibition of acetylcholinesterase, leading to toxic accumulation of acetylcholine at muscarinic, nicotinic, and central nervous system synapses.
Clinical Manifestations:
- Muscarinic Overstimulation: Remembered by the mnemonics SLUDGEM (Salivation, Lacrimation, Urination, Defecation, Gastrointestinal motility, Emesis, Miosis) or DUMBELS (Diarrhea, Urination, Miosis, Bronchorrhea / Bronchospasm / Bradycardia, Emesis, Lacrimation, Salivation). The "Killer B's"—profuse pulmonary bronchorrhea, severe bronchospasm, and bradycardia—represent the leading cause of lethal asphyxiation.
- Nicotinic Overstimulation: Fasciculations, muscle cramping, profound flaccid paralysis (including diaphragmatic arrest), hypertension, and initial tachycardia.
- Central Nervous System: Encephalopathy, coma, and intractable seizures.
Management Algorithm:
1. Personal Protective Equipment (PPE) & Decontamination: Healthcare workers must don chemical-resistant PPE. Remove all patient clothing and copiously wash skin with soap and water.
2. Atropine: Competitive antagonist at muscarinic receptors. Administer $2$ to $4\text{ mg}$ IV bolus, doubling the dose every 3 to 5 minutes until muscarinic toxicity resolves. The sole therapeutic endpoints for atropinization are cessation of bronchorrhea, clearance of lung crackles, and resolution of bronchospasm (with heart rate $> 80\text{ bpm}$ ). Pupil size and heart rate are not the primary endpoints for halting atropine.
3. Pralidoxime (2-PAM): A nucleophilic oxime that reactivates phosphorylated acetylcholinesterase at neuromuscular nicotinic junctions, treating muscle fasciculations and weakness. Administer a loading dose of $1$ to $2\text{ g}$ IV over 30 minutes followed by a continuous infusion of $500\text{ mg/h}$ . Pralidoxime must be initiated early, before the phosphorylated enzyme undergoes covalent "aging" (chemical dealkylation), rendering inhibition irreversible.

4. Opioid Toxidrome

Pathophysiology: Agonism at mu-, kappa-, and delta-opioid receptors within the central nervous system and gastrointestinal tract.
Clinical Manifestations: The classic triad consists of central nervous system depression (stupor/coma), miosis (pinpoint pupils), and severe respiratory depression (bradypnea, hypopnea, or apnea). Hypothermia, bradycardia, hypotension, and absent bowel sounds are frequent. Note that miosis may be absent in overdoses involving meperidine (anticholinergic properties), tramadol, co-ingested sympathomimetics, or profound cerebral anoxia.
Critical Management Nuance: The primary goal of Naloxone therapy in a non-cardiac arrest setting is not the complete restoration of full alertness, but the restoration of adequate spontaneous alveolar ventilation (respiratory rate $\ge 10 - 12\text{ breaths/min}$ ). Start with low-dose titrated intravenous naloxone ( $0.04 - 0.1\text{ mg}$ IV), doubling every 2 minutes. Administering large empiric boluses ( $2 - 4\text{ mg}$ ) in opioid-dependent individuals triggers severe acute withdrawal, violent delirium, and a massive catecholamine surge precipitating non-cardiogenic flash pulmonary edema. High initial doses ( $2 - 10\text{ mg}$ ) are indicated only in patients with synthetic ultra-potent opioid exposure (fentanyl analogs, carfentanil) or primary cardiac arrest.

5. Sedative-Hypnotic Toxidrome

Causative Agents: Benzodiazepines, barbiturates, gamma-hydroxybutyrate (GHB), z-drugs (zolpidem).
Pathophysiology: Enhanced GABA-mediated inhibitory neurotransmission.
Clinical Manifestations: Central nervous system depression, lethargy, slurred speech, ataxia, and stupor with relatively preserved vital signs in isolated benzodiazepine ingestion. Barbiturates cause marked hypothermia, hypotension, and respiratory depression.
Critical Management Nuance: Flumazenil (competitive GABA-A antagonist) is contraindicated in the routine management of undifferentiated coma, chronic benzodiazepine users, or suspected multi-substance ingestions (especially tricyclic antidepressants). Flumazenil precipitates sudden, refractory status epilepticus and lethal withdrawal that cannot be overcome with readministered benzodiazepines. Treatment is strictly supportive airway protection and mechanical ventilation.

Specific Critical Care Ingestions & Protocols

Toxin / Drug Class	Clinical Manifestations & Pathophysiology	Key Diagnostic Workup & Thresholds	First-Line Antidote & ICU Dosing Protocol
Acetaminophen (APAP)	Hepatocellular necrosis due to CYP2E1 oxidation to NAPQI, exhausting glutathione stores ( $< 30\%$ ) with Zone 3 centrilobular necrosis.	Serum APAP level plotted on the Rumack-Matthew Nomogram between 4 and 24 hours post-ingestion. Action line starts at $150\text{ mcg/mL}$ at 4 hours.	N-Acetylcysteine (NAC): IV 21-hour protocol: $150\text{ mg/kg}$ in $200\text{ mL}$ D5W over $1\text{ h}$ , then $50\text{ mg/kg}$ in $500\text{ mL}$ D5W over $4\text{ h}$ , then $100\text{ mg/kg}$ in $1000\text{ mL}$ D5W over $16\text{ h}$ . Continue beyond 21 hours if APAP detectable, AST/ALT rising, or INR $> 1.5$ .
Salicylates (Aspirin)	Mitochondrial uncoupling of oxidative phosphorylation combined with direct medullary respiratory center stimulation. Mixed primary respiratory alkalosis and high anion gap metabolic acidosis.	Serial salicylate levels (toxic $> 30-40\text{ mg/dL}$ ; severe $> 80-100\text{ mg/dL}$ ), blood gas, urine pH, serum potassium.	Sodium Bicarbonate infusion ( $100-150\text{ mEq}$ in 1 L D5W at $1.5-2\times$ maintenance) targeting urine pH $7.5-8.0$ and blood pH $7.45-7.55$ for ion trapping. Replete potassium aggressively to $\ge 4.0-4.5\text{ mEq/L}$ . Hemodialysis (EXTRIP) if level $> 100\text{ mg/dL}$ ( $> 90$ with impaired kidney function), altered mental status, new hypoxemia requiring oxygen, or failure of standard therapy; suggested for pH $\le 7.20$ or a level above $90\text{ mg/dL}$ .
Ethylene Glycol	Metabolized by ADH to glycolic acid and oxalic acid. Oxalate complexes with calcium, forming calcium oxalate crystals, causing acute tubular necrosis, renal failure, and tetany/QTc prolongation.	Elevated osmolar gap early; severe high anion gap metabolic acidosis late. Urine microscopy demonstrates envelope- or needle-shaped calcium oxalate crystals.	Fomepizole: $15\text{ mg/kg}$ IV loading dose over $30\text{ min}$ , then $10\text{ mg/kg}$ every $12\text{ h}$ for 4 doses. Add Thiamine $100\text{ mg}$ IV and Pyridoxine $50\text{ mg}$ IV q6h. Hemodialysis (EXTRIP 2023) is recommended for an anion gap above $27\text{ mmol/L}$ , glycolate above $12\text{ mmol/L}$ , coma, seizures, or AKI (suggested for an anion gap of 23 to 27); with fomepizole, it is suggested for an EG concentration above $50\text{ mmol/L}$ (about $310\text{ mg/dL}$ ) or an osmolal gap above 50.
Methanol	Metabolized by ADH to formaldehyde and formic acid, which inhibits cytochrome c oxidase, causing retinal toxicity ("snowfield" blindness) and bilateral putaminal necrosis.	Elevated osmolar gap early, severe HAGMA late. Visual acuity deficit, optic disc hyperemia on fundoscopy, putaminal hypodensities on head CT/MRI.	Fomepizole: $15\text{ mg/kg}$ IV loading dose, then $10\text{ mg/kg}$ every $12\text{ h}$ . Add Folinic acid (or folic acid) $50\text{ mg}$ IV q4-6h to enhance formate clearance. Emergent Hemodialysis (EXTRIP 2015) for coma, seizures, new visual deficits, pH $\le 7.15$ , persistent acidosis, or an anion gap above 24; or a methanol level above $70\text{ mg/dL}$ on fomepizole, above $60\text{ mg/dL}$ on ethanol, or above $50\text{ mg/dL}$ without an alcohol dehydrogenase blocker.
Beta-Blockers & Calcium Channel Blockers	Profound bradycardia, high-grade AV block, myocardial depression, vasoplegic shock. CCBs cause marked hyperglycemia (inhibiting insulin release); beta-blockers (propranolol) cause seizures and wide QRS.	Point-of-care glucose, serial 12-lead ECGs, focused cardiac ultrasound for depressed left ventricular ejection fraction.	High-Dose Insulin-Euglycemia Therapy (HIET): Regular insulin $1\text{ unit/kg}$ IV bolus with $25-50\text{ g}$ D50W, followed by $1\text{ unit/kg/h}$ infusion (titrated up to $2-10\text{ U/kg/h}$ ) with concentrated dextrose and potassium maintenance. Adjuncts: Calcium chloride $1-2\text{ g}$ IV, Glucagon $5-10\text{ mg}$ IV, Intralipid 20% emulsion rescue, and VA-ECMO.
Digoxin	Inhibition of $\text{Na}^+/\text{K}^+$ -ATPase pump increases intracellular calcium (arrhythmogenicity) and increases vagal tone. Acute overdose causes severe hyperkalemia; chronic toxicity worsened by hypokalemia.	Serum digoxin level, serum potassium, ECG (frequent PVCs, bidirectional VT, atrial tachycardia with variable block).	Digoxin-Specific Fab (DigiFab): Empiric $10 - 20\text{ vials}$ IV for cardiac arrest or life-threatening instability. In non-arrest, calculate vials: $\text{Vials} = \frac{[\text{Digoxin } (\text{ng/mL})] \times \text{Weight } (\text{kg})}{100}$ . Treat hyperkalemia $> 5.0-5.5\text{ mEq/L}$ with Fab; IV calcium is no longer considered absolutely contraindicated, but Fab is the treatment of choice.

Test Your Knowledge

A 22-year-old college student is brought to the intensive care unit by emergency medical services after being found agitated and disoriented at a music festival. On arrival, he is delirious and hallucinating. Vital signs: blood pressure 186/108 mmHg, heart rate 138 beats/min, respiratory rate 26 breaths/min, and core body temperature 39.4°C (102.9°F). Physical examination reveals widely dilated pupils (8 mm bilaterally) that are reactive, dry axillae, dry oral mucous membranes, flushed skin without perspiration, absent bowel sounds, and a palpably distended bladder. An ECG shows sinus tachycardia with a QRS duration of 84 ms and a QTc of 420 ms. What is the most appropriate initial management step?

Administer intravenous propranolol 1 mg every 5 minutes to control blood pressure and heart rate

Administer intravenous physostigmine 2 mg as a rapid intravenous push

Perform immediate endotracheal intubation, initiate an esmolol infusion, and administer activated charcoal via nasogastric tube

Place a urinary catheter, initiate evaporative external cooling, and administer titrated intravenous lorazepam

Test Your Knowledge

A 34-year-old man presents to the intensive care unit 16 hours after intentionally swallowing approximately 60 tablets of regular-strength aspirin (325 mg per tablet). He complains of severe nausea, persistent vomiting, and ringing in both ears. On examination, he is tachypneic and restless. Vital signs: blood pressure 118/72 mmHg, heart rate 116 beats/min, respiratory rate 34 breaths/min, and temperature 38.3°C (100.9°F). Arterial blood gas on room air reveals pH 7.48, PaCO2 20 mmHg, PaO2 96 mmHg, and HCO3- 14 mEq/L. Serum electrolytes demonstrate sodium 140 mEq/L, potassium 3.2 mEq/L, chloride 102 mEq/L, and an anion gap of 24 mEq/L. The serum salicylate level is 72 mg/dL. Which therapeutic intervention is the most critical immediate component of his medical resuscitation?

Perform endotracheal intubation and place on mechanical ventilation with a set respiratory rate of 14 breaths/min

Administer intravenous sodium bicarbonate with concurrent aggressive potassium chloride repletion to achieve urinary alkalinization

Administer intravenous acetazolamide to accelerate bicarbonate excretion into the renal tubules

Initiate broad-spectrum intravenous antibiotics and hydrocortisone for presumed septic shock with elevated lactic acid

Test Your Knowledge

A 52-year-old woman is admitted to the intensive care unit following an intentional overdose of sustained-release diltiazem and metoprolol succinate. On arrival, she is somnolent with cool, mottled extremities. Vital signs: blood pressure 64/38 mmHg, heart rate 34 beats/min, respiratory rate 14 breaths/min, and oxygen saturation 96% on room air. Bedside echocardiogram reveals severe global left ventricular hypokinesis with an estimated ejection fraction of 20%. Her point-of-care blood glucose is 342 mg/dL. Despite receiving 2 liters of intravenous crystalloids, 2 grams of intravenous calcium chloride, and a 10 mg bolus of glucagon, her mean arterial pressure remains 44 mmHg with persistent sinus bradycardia. What is the most appropriate next pharmacological intervention?

Initiate a high-dose norepinephrine infusion titrated up to 2 mcg/kg/min as the definitive therapy for the shock

Administer a 150 mEq intravenous sodium bicarbonate bolus to overcome membrane-depressant myocardial toxicity and narrow the QRS

Initiate High-Dose Insulin-Euglycemia Therapy (HIET) with a 1 unit/kg regular insulin bolus and a 1 unit/kg/h continuous infusion accompanied by concentrated dextrose

Administer intravenous physostigmine 2 mg by slow push to reverse anticholinergic tone and restore sinus node automaticity and conduction

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