4. Drug Overdoses (TCA, Salicylates, Acetaminophen, Beta-Blocker/CCB, Iatrogenic Intoxications)

Quick Recap

Toxicology System, Protocol 4/8. Covers the highest-yield ICU drug overdoses not already addressed in dedicated protocols: tricyclic antidepressants, salicylates, acetaminophen, beta-blocker/calcium channel blocker overdose, and common hospital-acquired (iatrogenic) intoxications.

1. Tricyclic Antidepressants (TCA)

Mechanism of toxicity: sodium channel blockade (quinidine-like/Class IA antiarrhythmic effect) plus anticholinergic and alpha-adrenergic blocking effects.

Presentation: anticholinergic toxidrome (see Organophosphate Poisoning protocol Section 2 for the full toxidrome table), confusion/coma, tachycardia, QRS prolongation, rightward axis deviation of the terminal 40ms of the QRS complex (a specific, distinctive ECG clue), QT prolongation. Seizures can occur, driving acidosis, which itself precipitates arrhythmia/hemodynamic collapse — a self-reinforcing deterioration loop, so prompt seizure treatment is also cardioprotective, not just neuroprotective. Seizures plus impaired sweating can also cause life-threatening hyperthermia.

Diagnosis: specific drug levels are NEITHER valuable NOR required for acute management — diagnose and treat based on the clinical/ECG picture; qualitative urine/serum screens only retrospectively support the diagnosis.

Treatment — sodium bicarbonate is the primary antidote:

• Indicated for: ventricular arrhythmias, QRS >100ms, OR hypotension with acidosis (pH <7.20)
• Dosing: 1-2 mEq/kg IV bolus every 3-5 minutes until ECG changes/hypotension resolve, target pH <=7.55, followed by an infusion of 150 mEq in 1L D5W at TWICE maintenance rate, adjusted to a target arterial pH of 7.45-7.50
• Mechanism benefit is multifactorial, including a favorable direct effect on myocardial sodium channels (not purely an acid-base correction)
• AVOID combining bicarbonate infusion with hyperventilation — risks inducing life-threatening alkalosis and hypokalemia
• Lidocaine (Class IB) may be considered for arrhythmias refractory to bicarbonate
• AVOID Class IA and IC antiarrhythmics (procainamide, flecainide) — these share the same sodium-channel-blocking mechanism as the TCA itself and will worsen toxicity
• Magnesium sulfate has shown effectiveness for TCA-induced wide-complex tachycardia unresponsive to other agents, despite limited evidence
• Benzodiazepines for seizures; propofol for refractory seizures
• Activated charcoal if presenting within 2 hours and no contraindication
• IV lipid emulsion (20%, 1.5mL/kg bolus then 0.25-0.5mL/kg/min infusion) for unstable patients refractory to standard treatment
• Hemodialysis and hemoperfusion are NOT beneficial in TCA overdose (highly protein-bound, large volume of distribution)
• Physostigmine should NOT be given — significant toxicity risk, unlike its role in pure anticholinergic toxidromes from other agents

2. Salicylates

Toxicity threshold: plasma level >40-50 mg/dL (therapeutic range 20-35 mg/dL).

Mechanism: direct GI corrosive injury plus multiple metabolic effects — direct respiratory center stimulation, uncoupling of mitochondrial oxidative phosphorylation, inhibition of the tricarboxylic acid cycle, enhanced lipolysis/ketone generation.

Presentation: tinnitus, vertigo, nausea/vomiting, GI bleeding, diaphoresis, hyperthermia, tachycardia, ventricular arrhythmias, acute lung injury/pulmonary edema, CNS symptoms (confusion, seizures, coma). Classic lab pattern: MIXED respiratory alkalosis (direct respiratory center stimulation) + anion gap metabolic acidosis — a distinctive dual acid-base disturbance. Also: deranged glucose regulation, prolonged PT, rhabdomyolysis, renal failure.

Critical severity marker: coincident CNS changes (confusion, seizures) WITH tachycardia and diaphoresis signals SEVERE toxicity and warrants immediate, aggressive action — do not wait for a specific level threshold if this clinical combination is present.

Screening consideration: many salicylate overdoses are ACCIDENTAL (found in cold/GI remedies, highly concentrated in oil of wintergreen) — screen any patient with an uncertain diagnosis, nonspecific symptoms, and a significant anion gap acidosis for salicylate exposure, not just patients with a known aspirin ingestion history.

Treatment:

• Activated charcoal (+ MDAC if no contraindication)
• Serum AND urine alkalinization with IV sodium bicarbonate — converts salicylate to its ionized form, which is trapped in plasma (reducing CNS penetration) and more readily excreted renally; target serum pH 7.45-7.55, urine pH 7.5-8.0 (see the general Urine Alkalinization dosing/monitoring protocol referenced in the Organophosphate Poisoning protocol's general framework)
• If respiratory alkalosis is the PRIMARY disturbance (not yet significant metabolic acidosis), further alkalinization is NOT necessary — a nuance worth applying rather than reflexively alkalinizing every salicylate-exposed patient
• Hemodialysis should be CONSIDERED in ALL clinically significant salicylate toxicity and is INDICATED in severe intoxication (level >90 mg/dL, altered mental status, impaired renal function, new hypoxemia, clinical deterioration, severe acidemia pH<=7.20, or electrolyte disturbance despite standard therapy) — DELAYS in initiating indicated hemodialysis result in unnecessary morbidity/mortality, so do not defer this decision
• Check serum glucose and give empiric dextrose if confusion/seizures occur — cerebral glucose concentration may be LOW despite NORMAL serum glucose in salicylate toxicity, a distinctive neuroglycopenic phenomenon worth knowing
• Benzodiazepines for seizures; IV fluids for substantial vomiting/insensible losses

3. Acetaminophen

Toxic threshold: acute ingestion of 150 mg/kg (or 10g), or chronic ingestion >4g/day.

Mechanism: the toxic metabolite NAPQI (via CYP2E1) accumulates once hepatic glutathione stores are overwhelmed -> hepatic and renal injury. CYP2E1 induction (ethanol, rifampin, isoniazid, carbamazepine) or depleted glutathione stores (chronic alcoholism-related malnutrition) INCREASE toxicity risk at a given ingested dose.

Course: early asymptomatic or mild GI symptoms; liver injury typically manifests 24-36 hours post-ingestion (AST/ALT/coagulation derangement) — the delayed-onset nature is why treatment decisions rely on ingested dose/timing and serum level nomograms rather than early symptoms.

Treatment: N-acetylcysteine (NAC) — see the Acute Liver Failure protocol (GI & Hepatology System) for full NAC dosing/timing detail, including the key point that NAC still improves outcomes even when started late (10-36h post-overdose) and that route (PO vs IV) does not affect efficacy.

Severe toxicity progressing to fulminant hepatic failure: early hepatology consultation or transfer to a liver-transplant-capable center. King's College Hospital criteria predict transplant need: (a) pH <7.30 despite adequate fluid resuscitation, OR (b) grade III-IV hepatic encephalopathy + creatinine >3.4 mg/dL + PT >100 sec (INR >6.5). Serum lactate is an additional prognostic marker. A suspected suicide attempt or substance use history alone does NOT preclude transplant listing, though formal psychiatric assessment is typically required as part of the evaluation process.

4. Beta-Blocker and Calcium Channel Blocker Overdose

Shared clinical picture: bradyarrhythmias, hypotension, AV blockade, cardiogenic shock — particularly severe with underlying cardiovascular disease or co-ingestion of both classes together.

Key differentiating clue: serum glucose and CNS toxicity presence (see also the Severe Hypoglycemia protocol, Endocrine & Metabolic System, Section 5 for this same discriminator): beta-blockers can cause HYPOGLYCEMIA (inhibited gluconeogenesis/glycogenolysis); calcium channel blockers tend to cause HYPERGLYCEMIA (pancreatic Ca2+ channel blockade reduces insulin release). CCB overdose RARELY causes altered mentation in the absence of shock, while more lipid-soluble beta-blockers (propranolol, metoprolol, timolol) can cause direct CNS toxicity (confusion, seizures, coma) independent of hemodynamic status.

Agent-specific nuances: sotalol and acebutolol have additional potassium-channel-blocking effects -> QT prolongation, torsades risk. Dihydropyridine CCBs (amlodipine) typically cause hypotension WITH reflex tachycardia at therapeutic-adjacent doses (lacking SA/AV nodal activity), but this selectivity is LOST at toxic doses, resulting in bradycardia like non-dihydropyridine agents.

Treatment (essentially identical for both classes given the shared final-common-pathway cardiotoxicity):

• Atropine 0.5mg IV q3-5min, max 3mg
• Calcium: calcium chloride 1g IV (or calcium gluconate 3g IV) q10-20min, max 3g calcium chloride (9g calcium gluconate)
• Glucagon 5-10mg IV bolus, then 1-10mg/h infusion — bypasses the blocked beta-receptor/calcium channel, directly stimulating cAMP production
• High-dose insulin euglycemic therapy (HIET): regular insulin 1 unit/kg IV bolus, then 0.5-10 units/kg/h infusion WITH concurrent dextrose — improves myocardial contractility via a mechanism distinct from glucagon/calcium, increasingly recognized as a particularly effective therapy for this specific toxidrome; requires close glucose AND potassium monitoring given the high insulin dose
• Vasopressors as needed
• IV lipid emulsion (Intralipid) 20%, 1.5mL/kg bolus then 0.25-0.5mL/kg/min for refractory cases
• Consider cardiac pacing and extracorporeal life support (ECMO) for refractory cardiogenic shock unresponsive to the above

5. Hospital-Acquired (Iatrogenic) Intoxications — A Distinct ICU-Specific Category

Propofol infusion syndrome (PRIS): history of propofol infusion presenting with hypertriglyceridemia, lactic acidosis, hyperkalemia, renal failure, rhabdomyolysis, cardiac arrhythmias, progressive cardiovascular collapse — mortality 30-50%. Management: discontinue propofol immediately; supportive care including RRT and ECMO as needed. (See Status Epilepticus protocol, Neurology System, for the parallel PRIS risk during high-dose propofol use for refractory status epilepticus.)

Gabapentin toxicity: confusion/lethargy, particularly with recent renal function decline (gabapentin is renally cleared and accumulates in renal impairment) — discontinue medication; hemodialysis if severe.

Propylene glycol intoxication: from PROLONGED infusion of propylene-glycol-containing medications (diazepam, phenytoin, lorazepam specifically implicated given common high-dose/prolonged ICU use) — anion gap (lactic) metabolic acidosis, renal failure, hypotension, increased osmolar gap — management: hemodialysis, supportive care, discontinue the offending infusion. (Cross-reference: this is the same mechanism flagged in the Severe Metabolic Acidosis protocol, Renal System, as an under-recognized cause of unexplained lactic acidosis with osmolar gap in patients on prolonged lorazepam infusion.)

Methemoglobinemia: multiple causes — local anesthetics (benzocaine spray), dapsone, sulfonamides (TMP-SMX), metoclopramide, rasburicase, nitrites/nitrates (nitroglycerin, nitroprusside, nitric oxide) — diagnose via CO-oximetry (same principle as the oxygen saturation gap concept in Smoke/Inhalational Injury protocol, Respiratory System); treat with methylene blue 1-2mg/kg IV over 5 minutes.

Linezolid-associated serotonin syndrome: a drug-interaction-driven cause of serotonin toxidrome when linezolid (a weak MAO inhibitor) is combined with serotonergic agents (SSRIs, SNRIs, other antidepressants) — relevant given linezolid's common ICU use for MRSA/resistant organism coverage; screen medication lists specifically for this interaction before starting linezolid in a patient on serotonergic medications.

6. Investigations

Serum drug levels where clinically useful (acetaminophen, salicylate — NOT TCA, per Section 1), ECG (QRS/QT assessment, arrhythmia screening), ABG (mixed acid-base pattern recognition, especially salicylates), glucose (beta-blocker vs CCB discriminator), electrolytes, renal/hepatic function, co-oximetry if methemoglobinemia suspected, osmolar gap if propylene glycol toxicity suspected.

7. Organ Support

Sodium bicarbonate for TCA cardiotoxicity; alkalinization + hemodialysis for salicylates; NAC for acetaminophen; atropine/calcium/glucagon/HIET/lipid emulsion for beta-blocker/CCB overdose; ECMO for refractory cardiotoxicity across multiple agent classes; RRT for propylene glycol/gabapentin toxicity; standard ICU supportive care.

8. Consultation Matrix

9. Monitoring Framework

Serial ECG (TCA, beta-blocker/CCB), serial ABG/pH (TCA bicarbonate titration, salicylate alkalinization), serial drug levels (acetaminophen, salicylate), glucose/potassium monitoring (HIET therapy), LFTs/coagulation (acetaminophen), triglycerides/CK/potassium (PRIS surveillance if on propofol).

10. Complications

Refractory arrhythmia/cardiac arrest, fulminant hepatic failure (acetaminophen), seizures, hyperthermia, PRIS, propylene glycol-associated renal failure, methemoglobinemia-related tissue hypoxia. Prevention: prompt agent-specific antidotal therapy, avoiding Class IA/IC antiarrhythmics in TCA overdose, not delaying indicated hemodialysis in salicylate toxicity, medication reconciliation to prevent linezolid-serotonergic interactions and prolonged propylene-glycol-containing infusions. Rescue: ECMO for refractory cardiotoxicity, liver transplantation for acetaminophen-induced fulminant hepatic failure meeting criteria, hemodialysis for salicylate/propylene glycol/gabapentin toxicity.

11. Escalation & De-escalation

Escalate: TCA arrhythmia refractory to bicarbonate -> lidocaine, magnesium, lipid emulsion; salicylate toxicity meeting hemodialysis criteria -> initiate without delay; beta-blocker/CCB shock refractory to atropine/calcium/glucagon -> HIET, lipid emulsion, ECMO.

De-escalate: ECG normalizing (TCA), pH/level trending favorably (salicylate), NAC course completing with resolving LFTs (acetaminophen), hemodynamics stabilizing off high-dose interventions (beta-blocker/CCB) -> wean support, transition to standard monitoring.

12. ICU Discharge Criteria

ECG normalized (TCA), salicylate level and acid-base status normalized, acetaminophen NAC course completed with resolving/normal LFTs and no transplant criteria met, hemodynamically stable off vasopressor/HIET support (beta-blocker/CCB), psychiatric evaluation completed for intentional ingestions.

13. Documentation & Medicolegal Checklist

14. Key Guidelines

American Academy of Clinical Toxicology / European Association of Poisons Centres position statements on gastric decontamination and specific antidotal therapies.

15. Controversies

Optimal HIET dosing ceiling and duration for beta-blocker/CCB overdose continues to be refined as clinical experience accumulates, given the wide cited range (0.5-10 units/kg/h). Lipid emulsion's efficacy across various lipophilic drug overdoses beyond local anesthetic toxicity (its clearest indication) remains based on emerging/limited evidence rather than robust RCT data. The precise threshold for psychiatric assessment sufficiency (vs an absolute exclusion) in transplant candidacy after intentional acetaminophen overdose involves genuine ethical and clinical judgment beyond a fixed protocol.

16. References

1. Toxicology (TCA, Salicylates, Acetaminophen, Beta-blocker/CCB, Hospital-Acquired Intoxications sections). Washington Manual of Critical Care, 4th ed, 2025 (Ch. 36).
2. Chyka PA, Erdman AR, Christianson G, et al. Salicylate poisoning: an evidence-based consensus guideline. Clin Toxicol. 2007;45(2):95-131.
3. Wax PM, Erdman AR, Chyka PA, et al. Beta-blocker ingestion: an evidence-based consensus guideline. Clin Toxicol. 2005;43(3):131-146.

See also: Organophosphate Poisoning (Toxicology System) for the shared general poisoned-patient framework; Acute Liver Failure (GI & Hepatology System) for full acetaminophen/NAC protocol detail; Severe Metabolic Acidosis (Renal System) for the propylene glycol-associated osmolar gap discussion.