Drug-Induced Hyperthermia Syndromes — Comprehensive Differential and Management

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Red flags

• MH: rise in ETCO2 despite increased minute ventilation is the EARLY diagnostic clue (Rosenberg 2015) → stop the volatile and succinylcholine, hyperventilate, cool actively and give DANTROLENE 2.5 mg/kg IV, repeated as needed — after dantrolene was introduced, MH mortality fell from 80% in the 1960s to under 10% (Krause 2004)
• Serotonin syndrome: CLONUS (inducible or spontaneous) + hyperreflexia + agitation + diaphoresis in a patient on a serotonergic drug are the features that actually predict toxicity (Hunter criteria, Dunkley 2003) — diagnose POSITIVELY, not by exclusion; hypertonicity and temperature over 38 degrees C mark life-threatening cases
• NMS vs serotonin syndrome: NMS is dopamine-antagonist exposure with RIGIDITY, hyperthermia, mental status change and sympathetic lability plus CK elevation (Gurrera consensus 2011); serotonin syndrome is clonus and hyperreflexia — they are opposite in tone and reflexes (Perry 2012)
• Do not rely on antipyretics — response to conventional antipyretics in NMS is poor (Horseman 2022); severe serotonin toxicity with hyperthermia and rigidity needs benzodiazepines, intubation, paralysis and ACTIVE COOLING (Chiew and Isbister 2025)
• Dantrolene reconstitution is SLOW — poor water solubility makes rapid intravenous preparation difficult in an emergency (Krause 2004) — order early and get pharmacy mixing while you cool
• Severe serotonin toxicity with hyperthermia and rigidity is an airway-and-paralysis emergency: intubate, paralyse with a NON-depolarising agent, cool — never succinylcholine, which is itself an MH trigger (Rosenberg 2015)
• MDMA can cause SIADH with symptomatic hyponatraemia even after isolated use — check the sodium in every ecstasy patient (Farah 2008)
• Physostigmine for anticholinergic delirium: titrate 0.5 to 1 mg with at least 10 to 15 minutes before re-dosing — higher doses tip into cholinergic toxicity and seizures are reported in up to 2.5 percent (Dawson and Buckley 2016)