Which medication overdoses can cause fever (hyperthermia)?

Medication Overdoses That Cause Fever

The most clinically significant medication overdoses causing hyperthermia include tricyclic antidepressants, antipsychotics (causing neuroleptic malignant syndrome), anticholinergics, sympathomimetics (including cocaine), salicylates, and serotonin syndrome-inducing agents. 1, 2, 3

Major Drug Classes and Mechanisms

Antipsychotics (Neuroleptic Malignant Syndrome)

• Antipsychotic medications including risperidone, amisulpride, and other dopamine antagonists cause hyperthermia through dopamine D2 receptor blockade in the hypothalamus and nigrostriatal pathways. 4, 5
• NMS presents with the classic tetrad: hyperthermia (often >102.5°F), "lead pipe" muscle rigidity, altered mental status, and autonomic instability (tachycardia, hypertension). 5
• Elevated creatine phosphokinase from rhabdomyolysis is characteristic. 4
• Mortality has decreased from 76% to <10-15% with prompt recognition, but delayed treatment remains life-threatening. 5
• Critical error: Adding metoclopramide (Reglan) to patients already on antipsychotics can precipitate or worsen NMS since it is also a dopamine antagonist. 5

Tricyclic Antidepressants

• Amitriptyline and other tricyclics cause hyperpyrexia along with cardiac dysrhythmias, seizures, and CNS depression. 2
• Overdose manifestations include QRS widening (≥0.10 seconds), prolonged QT interval, muscle rigidity, and altered mental status. 2
• Hyperpyrexia occurs as part of the anticholinergic effects and altered thermoregulation. 2

Sympathomimetics

• Cocaine overdose causes hyperthermia through hypermetabolism, and elevated temperature directly increases toxicity. 1
• Treat hyperthermia aggressively with external cooling as it worsens outcomes. 1
• Other sympathomimetics (amphetamines, MDMA) cause similar hyperthermic crises through increased metabolic activity and impaired heat dissipation. 3, 6

Anticholinergics

• Anticholinergic agents (including trihexyphenidyl, antihistamines, and many others) cause hyperthermia by blocking heat dissipation through sweating. 7, 3
• Classic presentation: hot/dry/erythematous skin, mydriasis, dry mucous membranes, hypoactive bowel sounds, tachycardia, and agitated delirium. 7
• Patients have increased susceptibility to heat stroke while taking these medications. 7

Salicylates

• Salicylate overdose causes hyperthermia through uncoupling of oxidative phosphorylation, leading to increased metabolic heat production. 6, 8

Serotonin Syndrome

• Excessive serotonergic activity from SSRIs, MAOIs, or drug combinations causes hyperthermia with hyperreflexia, clonus, mydriasis, and diarrhea. 3, 9, 8
• Distinguished from NMS by more rapid onset, hyperreflexia (vs. rigidity), and recent addition of serotonergic agents. 5

Critical Management Principles

Immediate Actions

• Discontinue all suspected offending medications immediately—this is the definitive treatment. 4, 5
• Initiate aggressive external cooling measures for any drug-induced hyperthermia, as antipyretics are ineffective. 3, 8
• Secure airway and establish IV access. 2
• Obtain ECG immediately for tricyclic or sympathomimetic overdose. 2

Specific Interventions

• For NMS: Benzodiazepines for agitation/muscle activity, external cooling, IV fluids for dehydration and elevated CK, and ICU-level monitoring. 4, 5
• For tricyclic overdose: Sodium bicarbonate to maintain pH 7.45-7.55 if QRS ≥0.10 seconds. 2
• For cocaine: Benzodiazepines, nitroglycerin for vasospasm, avoid beta-blockers (Class III recommendation). 1
• For severe anticholinergic toxicity: Consider physostigmine only for life-threatening symptoms unresponsive to other therapies. 2

Monitoring Requirements

• Minimum 6 hours of cardiac monitoring and observation, extended if any signs of toxicity develop. 2
• Monitor for complications: rhabdomyolysis, multi-organ failure, disseminated intravascular coagulation. 3
• ICU admission for severe cases with hemodynamic instability or altered mental status. 8

Key Diagnostic Pitfalls

• Drug-induced hyperthermia is unresponsive to antipyretics—this distinguishes it from infectious fever. 3
• Always rule out infection first, but don't assume all fever is infectious in patients on these medications. 4
• The lag time between starting a drug and fever development averages 21 days (median 8 days) for simple drug-induced fever. 4, 7
• Never rechallenge patients who experienced NMS with the same antipsychotic. 4
• Atypical presentations of classic syndromes are common in the ICU setting. 8