Residency · Residency · Critical Care

Toxicology in the ICU

General Approach to the Poisoned Patient

Initial Assessment

The evaluation of a poisoned patient in the ICU begins with recognition that airway compromise is the leading cause of death in poisoning and demands a low threshold for endotracheal intubation in any patient with a declining level of consciousness. A focused history should attempt to establish the substance or substances ingested, the estimated dose, the time of ingestion, the presence of co-ingestants, and whether the ingestion was accidental or intentional. Physical examination should focus on identifying a toxidrome, which can guide empiric management before laboratory results are available.

Core laboratory studies include a basic metabolic panel with calculation of the anion gap and osmolal gap, arterial or venous blood gas, lactate, liver function tests, coagulation studies, and specific drug levels for acetaminophen, salicylate, and ethanol. Acetaminophen and salicylate levels should be obtained in every patient with intentional ingestion, as co-ingestion is common and both have specific antidotes with time-sensitive efficacy. An electrocardiogram is essential for identifying QRS prolongation (sodium channel blockade), QTc prolongation, and other specific toxicological patterns. The urine drug screen has limited clinical utility in the ICU setting due to frequent false positives and negatives and rarely changes management.

Toxidrome Comparison

Toxidromes

Recognition of toxidromes provides the most rapid pathway to directed management. The sympathomimetic toxidrome, caused by cocaine, amphetamines, and MDMA, manifests with tachycardia, hypertension, hyperthermia, mydriasis, diaphoresis, and agitation. The anticholinergic toxidrome, remembered by the mnemonic "mad as a hatter, blind as a bat, dry as a bone, red as a beet, hot as a hare," presents with tachycardia, hyperthermia, mydriasis, dry skin and mucous membranes, urinary retention, and delirium. The key distinguishing feature between sympathomimetic and anticholinergic toxidromes is the skin: sympathomimetic patients are diaphoretic (wet), while anticholinergic patients are dry.

The cholinergic toxidrome, caused by organophosphates, carbamates, and nerve agents, is characterized by the DUMBELS mnemonic: diarrhea, urination, miosis, bronchorrhea/bronchospasm, emesis, lacrimation, and salivation. The opioid toxidrome presents with the classic triad of miosis (pinpoint pupils), respiratory depression, and decreased level of consciousness. The sedative-hypnotic toxidrome produces CNS and respiratory depression with normal pupils and hypothermia. Serotonin syndrome, caused by serotonergic drug interactions, presents with tachycardia, hypertension, hyperthermia, clonus (especially lower extremity), hyperreflexia, agitation, and diaphoresis.

Decontamination

Gastrointestinal decontamination strategies have become increasingly refined, with activated charcoal remaining the most broadly applicable intervention. Administered at 1 g/kg orally (maximum 50 g), activated charcoal is most effective when given within 1 to 2 hours of ingestion and requires an intact, protected airway. Importantly, activated charcoal does not bind metals (iron, lithium, lead), alcohols (methanol, ethylene glycol), hydrocarbons, or caustic substances, and is contraindicated when the airway is unprotected, after caustic ingestion, or when there is significant risk of hydrocarbon aspiration.

Whole bowel irrigation with polyethylene glycol solution (GoLYTELY) at 1 to 2 L/hr via nasogastric tube is indicated for sustained-release preparations, body packers, and ingestions of substances not adsorbed by charcoal such as iron and lithium. Gastric lavage is rarely indicated in modern practice and should be considered only for very recent (less than 1 hour) massive life-threatening ingestions. Enhanced elimination strategies include multi-dose activated charcoal, urinary alkalinization, and hemodialysis.

<image>Toxidrome comparison chart showing five major toxidromes in columns: sympathomimetic, anticholinergic, cholinergic, opioid, and serotonin syndrome. For each toxidrome, show a human body outline with annotated clinical findings: pupil size (mydriasis vs. miosis), skin appearance (diaphoresis vs. dry), vital sign changes (HR, BP, temp, RR), mental status, bowel sounds, and unique distinguishing features. Below each toxidrome: list of causative agents and specific antidotes/treatments. Include a "distinguish from" row highlighting key differentiating features between commonly confused toxidromes (e.g., anticholinergic vs. sympathomimetic: dry skin vs. diaphoresis; serotonin syndrome vs. NMS: clonus/hyperreflexia vs. rigidity/bradyreflexia).</image>

Specific Poisonings

Acetaminophen (APAP)

Acetaminophen is the most common cause of acute liver failure in Western countries. Toxicity is dose-dependent, occurring with ingestion exceeding 150 mg/kg or 7.5 g in a single ingestion, with lower thresholds in patients with chronic alcohol use, malnutrition, or medications that induce CYP2E1. The mechanism of toxicity involves the accumulation of NAPQI, a toxic metabolite normally detoxified by glutathione conjugation. When glutathione stores are depleted by excessive NAPQI production, the unbound metabolite causes direct hepatocellular necrosis.

The Rumack-Matthew nomogram guides treatment decisions by plotting the APAP serum level against time post-ingestion (applicable only for acute single ingestions at 4 to 24 hours post-ingestion). Treatment is indicated when the level falls above the treatment line, which begins at 150 mcg/mL at 4 hours in the US protocol.

N-acetylcysteine is the definitive antidote, serving as a glutathione precursor and direct antioxidant. The IV protocol consists of 150 mg/kg over 1 hour, followed by 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours. NAC should be continued beyond the standard 21-hour protocol if the INR is rising, AST/ALT is rising, or clinical deterioration is evident. While most effective within 8 hours of ingestion, NAC provides benefit at any time point. For staggered or chronic ingestions, the nomogram is not applicable, and treatment should be initiated if acetaminophen is detectable with elevated transaminases or if there is any clinical concern.

Salicylate Toxicity

Salicylate poisoning produces one of the most physiologically complex toxicological syndromes encountered in the ICU. Toxicity occurs at doses exceeding 150 mg/kg, with severe toxicity above 300 mg/kg. The pathophysiology involves uncoupling of oxidative phosphorylation, which produces a primary metabolic acidosis with an elevated anion gap, combined with direct central respiratory stimulation producing a primary respiratory alkalosis. This classic mixed acid-base disorder, with concurrent respiratory alkalosis and metabolic acidosis, is nearly pathognomonic for salicylate poisoning.

Symptoms progress from tinnitus, nausea, and tachypnea in mild toxicity to altered mental status, seizures, and pulmonary edema in severe toxicity. Salicylate levels above 40 mg/dL indicate toxicity, above 70 mg/dL indicate severe toxicity, and levels above 100 mg/dL are potentially lethal without treatment.

Treatment centers on IV sodium bicarbonate infusion to achieve a blood pH of 7.45 to 7.55 and a urine pH above 7.5. The mechanism is ion trapping: salicylate, a weak acid, becomes ionized in alkaline urine and cannot be reabsorbed across the renal tubular epithelium, dramatically enhancing renal excretion. One of the most critical clinical pearls in toxicology is that intubation should be avoided if at all possible in salicylate toxicity. The patient's compensatory hyperventilation is maintaining blood pH; the brief apneic period during rapid sequence intubation, combined with the inability to immediately match the pre-intubation minute ventilation, produces acute acidemia that drives salicylate into the central nervous system and can precipitate cardiovascular collapse. If intubation is absolutely necessary, the pre-intubation respiratory rate (often 20 to 30 breaths per minute) must be matched immediately, and bicarbonate infusion should be continued.

Hemodialysis is indicated for salicylate levels exceeding 90 mg/dL, renal failure, pulmonary edema, altered mental status, or clinical deterioration despite alkalization. Dextrose 50 percent should be administered if altered mental status is present, as brain glucose levels may be critically low even when serum glucose is normal. Hypokalemia must be corrected aggressively, as it prevents effective urine alkalinization through hydrogen-potassium exchange in the distal tubule.

Toxic Alcohols (Methanol, Ethylene Glycol)

Methanol and ethylene glycol are both metabolized by alcohol dehydrogenase to their respective toxic metabolites, providing the rationale for therapy targeting this enzyme. Methanol is converted to formic acid, which produces retinal toxicity and blindness, as well as basal ganglia necrosis. Ethylene glycol is converted to glycolic acid and then oxalic acid, which forms calcium oxalate crystals that deposit in the renal tubules causing acute kidney injury and can also produce cranial nerve palsies.

The diagnostic approach relies on two key laboratory findings that evolve over time as the parent alcohol is metabolized. Early after ingestion, an elevated osmolal gap (exceeding 10 mOsm/L) is present, reflecting the osmotically active parent compound in the serum. As metabolism progresses, the parent alcohol is converted to its organic acid metabolite, and the picture shifts to an elevated anion gap metabolic acidosis. This temporal conversion from osmolal gap to anion gap is a classic teaching point: a normal osmolal gap does not exclude toxic alcohol poisoning if sufficient time has elapsed for metabolism, as the anion gap will be elevated instead.

Treatment begins with fomepizole, a specific alcohol dehydrogenase inhibitor, administered as a 15 mg/kg IV loading dose followed by 10 mg/kg every 12 hours for 4 doses, then 15 mg/kg every 12 hours. IV ethanol (10 percent solution targeting a serum ethanol of 100 to 150 mg/dL) is an alternative but is more difficult to titrate and has more adverse effects. Hemodialysis is indicated for toxic alcohol levels exceeding 50 mg/dL, renal failure, visual changes (methanol), severe acidosis (pH below 7.15), or clinical deterioration. Cofactor therapy enhances the metabolism of toxic metabolites: folic acid 50 mg IV every 6 hours for methanol (enhances formate metabolism to CO2 and water) and thiamine plus pyridoxine for ethylene glycol. When fomepizole is administered during hemodialysis, the dosing frequency must be increased to every 4 hours because fomepizole itself is dialyzable.

Sodium Channel Blocker Toxicity (TCA, Cocaine, Local Anesthetics)

Sodium channel blocker toxicity produces characteristic ECG findings including QRS widening beyond 100 ms, right axis deviation, and a terminal R wave in lead aVR exceeding 3 mm. Clinical manifestations include seizures, hypotension, and cardiac arrhythmias ranging from wide-complex tachycardia to ventricular fibrillation.

The cornerstone of treatment is sodium bicarbonate, administered as 1 to 2 mEq/kg IV bolus and repeated until the QRS narrows, targeting a serum pH of 7.45 to 7.55. The mechanism involves both sodium loading (which competes with the drug for sodium channels) and alkalinization (which increases protein binding of the drug). If bicarbonate alone is insufficient, hypertonic saline (3 percent) provides an additional sodium load. Intralipid (20 percent lipid emulsion) at 1.5 mL/kg IV bolus followed by 0.25 mL/kg/min infusion is the specific antidote for local anesthetic systemic toxicity (LAST) and may also benefit overdoses of other lipophilic drugs. Class IA and IC antiarrhythmics such as procainamide and flecainide are absolutely contraindicated as they worsen sodium channel blockade. Seizures should be treated with benzodiazepines; phenytoin must be avoided as it is itself a sodium channel blocker.

Beta-Blocker and Calcium Channel Blocker Overdose

Overdoses of beta-blockers and calcium channel blockers produce profound bradycardia and hypotension and carry high mortality. Beta-blocker toxicity is treated with glucagon (3 to 10 mg IV bolus followed by 3 to 5 mg/hr infusion), which bypasses the beta-receptor entirely and activates adenylyl cyclase through the glucagon receptor, increasing intracellular cAMP and restoring cardiac contractility. High-dose insulin euglycemic therapy (HIET), administered as regular insulin 1 unit/kg IV bolus followed by 1 to 10 units/kg/hr with concurrent dextrose (D10W to D50W) infusion and glucose monitoring every 30 minutes, has become a critical treatment for both beta-blocker and calcium channel blocker overdose. Vasopressors (norepinephrine, epinephrine) and lipid emulsion for lipophilic agents (such as propranolol) complete the therapeutic armamentarium.

Calcium channel blocker toxicity requires a slightly different approach. Calcium replacement (calcium chloride 1 to 3 g IV via central line or calcium gluconate 3 to 9 g IV) is the initial intervention. HIET is the primary treatment for severe CCB overdose, working by improving myocardial glucose utilization in the face of calcium channel blockade that impairs normal cardiac metabolism. Vasopressors including norepinephrine and vasopressin, methylene blue at 1 to 2 mg/kg IV for the vasoplegic component, and VA-ECMO as salvage therapy for refractory cardiogenic shock round out the management options.

Serotonin Syndrome

Serotonin syndrome results from excessive serotonergic activity, most commonly arising from drug interactions such as SSRI combined with MAOI, SSRI with linezolid, SSRI with tramadol, or MDMA use. The Hunter criteria provide the diagnostic framework: a serotonergic agent plus clonus (spontaneous, inducible, or ocular) OR agitation with hyperreflexia OR temperature above 38 degrees Celsius with clonus or hypertonicity.

The critical clinical distinction between serotonin syndrome and neuroleptic malignant syndrome (NMS) rests on the neuromuscular findings: serotonin syndrome produces clonus and hyperreflexia, while NMS produces lead-pipe rigidity and bradyreflexia. Treatment begins with discontinuation of all serotonergic agents. Cyproheptadine, a serotonin antagonist, is given as a 12 mg initial dose by mouth or nasogastric tube followed by 4 to 8 mg every 6 hours. Benzodiazepines are administered for agitation and muscle hyperactivity. Active cooling is required for hyperthermia exceeding 40 degrees Celsius; antipyretics are ineffective because the hyperthermia results from muscle hyperactivity rather than hypothalamic set-point elevation. If hyperthermia is refractory, neuromuscular blockade with non-depolarizing agents may be necessary, with succinylcholine specifically avoided due to the risk of hyperkalemia from concurrent rhabdomyolysis.

<image>ECG interpretation guide for toxicological emergencies showing six ECG strips with annotations. Strip 1: Wide QRS >120 ms with right axis deviation and terminal R in aVR — sodium channel blocker toxicity (TCA). Strip 2: QTc prolongation >500 ms with U waves — drug-induced long QT (antipsychotics, fluoroquinolones, methadone). Strip 3: Peaked T waves with shortened QT — hyperkalemia (could be from digitalis toxicity or rhabdomyolysis). Strip 4: Regularized atrial fibrillation with slow ventricular rate — digoxin toxicity. Strip 5: Sinus bradycardia with AV block — beta-blocker or calcium channel blocker overdose. Strip 6: Sinus tachycardia with ST depression — sympathomimetic toxicity. Each strip includes the specific antidote and treatment approach in a box below.</image>

Enhanced Elimination Techniques

Key Antidotes Reference

Hemodialysis for Poisoning (EXTRIP Guidelines)

The effectiveness of hemodialysis for toxin removal depends on the physicochemical properties of the toxin. Characteristics that favor dialytic removal include small molecular weight, low protein binding, small volume of distribution, and water solubility. The EXTRIP (Extracorporeal Treatments in Poisoning) workgroup has provided systematic reviews and consensus recommendations for specific toxins.

Hemodialysis is strongly recommended for severe poisoning with methanol, ethylene glycol, lithium, salicylates, and metformin (in the setting of severe lactic acidosis). It is suggested for life-threatening valproic acid, theophylline, and carbamazepine toxicity. Hemodialysis is not effective for toxins with large volumes of distribution or high protein binding, including digoxin (which requires specific Fab fragment antibody therapy), benzodiazepines, and opioids. Intermittent hemodialysis is preferred over CRRT for acute toxin removal due to higher clearance rates, though CRRT may be necessary in hemodynamically unstable patients.

Multi-Dose Activated Charcoal (MDAC)

Multi-dose activated charcoal enhances elimination by interrupting enterohepatic and enteroenteric circulation of toxins that are actively secreted into the gut lumen or undergo biliary excretion. Administered as 25 to 50 g every 2 to 4 hours, MDAC is effective for theophylline, carbamazepine, dapsone, phenobarbital, and quinine. Contraindications include ileus, bowel obstruction, and an unprotected airway.

Urinary Alkalinization

Urinary alkalinization achieves enhanced elimination through ion trapping of weak acids in alkalinized urine. A sodium bicarbonate infusion (150 mEq in 1 L D5W at 200 to 250 mL/hr) targets a urine pH above 7.5. This technique is effective for salicylates, phenobarbital, methotrexate, and chlorpropamide. Effective alkalinization requires correction of hypokalemia, as potassium depletion drives hydrogen-potassium exchange in the collecting duct, preventing urine alkalinization despite systemic bicarbonate loading.

Key Clinical Pearls

• Always check acetaminophen and salicylate levels in any intentional ingestion — co-ingestion is common and both have specific antidotes with time-sensitive efficacy
• In salicylate toxicity, do NOT intubate unless absolutely necessary — loss of compensatory hyperventilation causes rapid clinical deterioration; if intubation required, match the pre-intubation RR
• QRS >100 ms in suspected overdose: give sodium bicarbonate empirically — do not wait for drug identification
• In toxic alcohol poisoning, an elevated osmolal gap CONVERTS to an elevated anion gap as the parent alcohol is metabolized — a normal osmolal gap does not exclude toxicity if anion gap is elevated
• Fomepizole is the preferred ADH inhibitor over ethanol — easier to titrate, fewer adverse effects; remember to increase dosing frequency during hemodialysis
• High-dose insulin euglycemic therapy (HIET) is the primary treatment for severe calcium channel blocker overdose — do not rely on calcium alone
• Serotonin syndrome has CLONUS; NMS has RIGIDITY — this is the key distinguishing feature
• Intralipid (20% lipid emulsion) is the antidote for local anesthetic systemic toxicity (LAST) and may be beneficial in overdoses of other lipophilic drugs

References

1. Heard K. Acetylcysteine for acetaminophen poisoning. N Engl J Med. 2008;359(3):285-292.
2. Juurlink DN, Gosselin S, Kielstein JT, et al. Extracorporeal treatment for salicylate poisoning: systematic review and recommendations from the EXTRIP workgroup. Ann Emerg Med. 2015;66(2):165-181.
3. Levine M, Brent J, Burkhart K. Pocket guide to critical care pharmacotherapy. Springer. 2022.
4. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112-1120.
5. Gosselin S, Juurlink DN, Kielstein JT, et al. Extracorporeal treatment for acetaminophen poisoning: recommendations from the EXTRIP workgroup. Clin Toxicol. 2014;52(8):856-867.

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