Hyperthermia- thinking outside the box: Drug Fevers

Drug class / toxidrome	Representative agents	Heat-generation mechanism	Key clinical clues
Sympathomimetic stimulants	Cocaine / crack; amphetamine salts (dextro- / lisdexam-); methamphetamine; MDMA / ecstasy; synthetic cathinones (“bath salts”); PCP; ketamine	Massive catecholamine surge → agitation, intense muscle activity, ↑ metabolic rate	Profuse sweating, mydriasis, severe tachycardia / HTN; rhabdo common
Anticholinergic agents	Atropine, scopolamine; diphenhydramine / doxylamine; tricyclics (amitriptyline); benztropine, trihexyphenidyl; oxybutynin, tolterodine	Inhibits sweating → impaired heat dissipation while metabolic heat production continues	Hot dry skin, delirium, urinary retention, dry mucosa, mydriasis
Mitochondrial uncouplers	High-dose salicylates (aspirin, oil of wintergreen); 2,4-dinitrophenol (DNP); pentachlorophenol	Uncouples oxidative phosphorylation → 100 % of energy released as heat	Hyperpnea, mixed metabolic + resp alkalosis; temp can climb extremely fast
Excess thyroid hormone / thyroid storm	Levothyroxine OD (intentional / iatrogenic); decompensated Graves’ disease	Marked ↑ basal metabolic rate throughout body tissues	Hyperpyrexia with severe tachyarrhythmia, tremor, altered mental status
Methylxanthines & related CNS stimulants	Theophylline (toxic levels), aminophylline, concentrated caffeine powders / tablets	β-adrenergic stimulation, seizures, continuous muscle activity	Tremor, vomiting, SVT / VT, hyperthermia
“Drug-fever” (immune-mediated)	β-lactams, sulfonamides, vancomycin; phenytoin, carbamazepine; allopurinol; heparin	Cytokine-mediated reset of thermoregulatory set-point	Usually < 40 °C; may look well after antipyretic; rash or eosinophilia possible

Bedside Pearls

• Pattern recognition matters:
  • Dry, flushed skin → anticholinergic.
  • Sweaty, hypertensive, wildly agitated → sympathomimetic.
  • Hyperpnea + high anion-gap acidosis → salicylate.
• Active cooling is urgent: ice packs, mist-and-fan, cool IV fluids; consider internal cooling if T > 41 °C.
• Benzodiazepines early for any stimulant-driven hyperthermia—reduce muscle activity and catecholamine surge.
• Salicylate OD: serum/urine alkalinization, whole-bowel irrigation (enteric-coated), hemodialysis if level > 100 mg/dL, severe acidosis, or AMS.
• DNP toxicity: deteriorates in minutes; no specific antidote—maximize cooling; dantrolene or ECMO used experimentally.
• Thyroid storm: β-block (esmolol), thionamide (PTU / methimazole), iodide, hydrocortisone, aggressive cooling.