March 22, 2021: How Do You Treat Drug-induced Hyperthermia in Serotonin Syndrome?

Serotonin syndrome manifestations include tachycardia, diaphoresis, hypertonicity, myoclonus, and seizures. The increased muscle activity is considered the primary etiology of hyperthermia (>41oC), which can lead to serious morbidity or mortality.

Hyperthermia caused by drugs does not respond to typical antipyretics such as ibuprofen or Tylenol. The initial treatment is environmentally cooling the patient, best by the “wet and windy” method.   Benzodiazepines reduce muscle activity and help decrease the temperature. Cyproheptadine, a serotonin receptor antagonist, has been considered but it is only available for oral administration and consensus of efficacy is lacking.

If hyperthermia persists, consider the administration of dantrolene. Dantrolene is best known for its use in the management of malignant hyperthermia. The drug binds to the ryanodine receptor (sarcoplasmic reticulum) which blocks calcium release and prevents the calcium dependent excitation-contraction coupling. Muscle contractions are thereby inhibited.   Given this mechanism, there is theoretical benefit. A few case reports have indicated a therapeutic effect.

If a patient has refractory hyperthermia despite these measures, intubation and paralysis with a non-depolarizing agent to further reduce heat generation from muscle activity may be considered.


1.  Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005 Mar 17;352(11):1112-20. doi: 10.1056/NEJMra041867. Erratum in: N Engl J Med. 2007 Jun 7;356(23):2437. Erratum in: N Engl J Med. 2009 Oct 22;361(17):1714. PMID: 15784664.

2. Tormoehlen LM, Rusyniak DE. Neuroleptic malignant syndrome and serotonin syndrome. Handb Clin Neurol. 2018;157:663-675. doi: 10.1016/B978-0-444-64074-1.00039-2. PMID: 30459031.

3. Nisijima K, Yoshino T, Yui K, Katoh S. Potent serotonin (5-HT)(2A) receptor antagonists completely prevent the development of hyperthermia in an animal model of the 5-HT syndrome. Brain Res. 2001 Jan 26;890(1):23-31. doi: 10.1016/s0006-8993(00)03020-1. PMID: 11164765.

Question prepared by: Barron Frazier, MD, Pediatric Emergency Medicine Fellow

Monroe Carell Jr. Children's Hospital at Vanderbilt


This Question was generated by a discussion of drug-induced hyperthermia during the time Dr. Frazier rotated on the Toxicology Service.  The above are treatment considerations-not dogma.  Each patient is different and must be considered individually.  Classic teaching is that dantrolene will only be efficacious in treating the hyperthermia caused by malignant hyperthermia or neuroleptic malignant syndrome.  However, there are limited animal and human studies on its’ use in heat stroke. We don’t understand all the mechanisms of action-perhaps it has more effects than prevention of muscle contraction.  A few years ago, Nashville had an outbreak of dinitrophenol ((DNP)-an agricultural herbicide/insecticide used for weight loss or muscle building) overdoses. These patients had persistent hyperthermia unresponsive to usual measures. Dantrolene was administered several times, and anecdotally, there was a rapid decrease in temperature within about 20 minutes.  (A case report in the BMJ 2018 where dantrolene had no effect on DNP-induced hyperthermia caused the authors to conclude dantrolene should not be used in this setting.)  There is little downside in using Dantrolene in treatment resistant drug-induced hyperthermia as the hepatotoxicity it causes follows chronic administration.  One should not underestimate how important it is to decrease a markedly elevated temperature.  If untreated, the patient will die from DIC in about 36 hours. ds

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Donna Seger, MD

Executive Director

Tennessee Poison Center

Poison Help Hotline: 1-800-222-1222