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Three Part Question

[In adult patients presenting with severe serotonin syndrome], is [dantrolene better than placebo] at [reducing patient mortality]?

Clinical Scenario

A 30 year old male is brought to the emergency department following the ingestion of MDMA on a night out. He presents with a temperature of 41 degrees C, rigidity and severe agitation. He is diagnosed with serotonin syndrome and sedated with diazepam. Ice packing is used to attempt patient cooling, however his temperature continues to rise. You consider whether or not dantrolene would reduce the likelihood of patient mortality.

Search Strategy

04/07/17
Cochrane (three separate searches):
• “Serotonin syndrome”
• “Serotonin toxicity”
• “Dantrolene”

Ovid: Embase 1980 to 2017 Week 27
(Exp serotonin syndrome/ OR serotonin toxicity.mp. OR mdma.mp. OR exp 3,4 methylenedioxymethamphetamine/ OR ecstasy.mp. OR ssri overdose.mp.) AND (exp dantrolene/)
LIMIT human, English, abstracts

Ovid: MEDLINE(R) 1946 to June Week 4 2017
(Exp serotonin syndrome/ OR serotonin toxicity.mp. OR mdma.mp. OR exp 3,4 methylenedioxymethamphetamine/ OR ecstasy.mp. OR ssri overdose.mp.) AND (exp dantrolene/)

Search Outcome

Cochrane: 0 articles.
Embase: 10 articles, 2 relevant.
Medline: 1 articles, 0 relevant.
Total relevant papers found: 2.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
B.E. Grunau et al 2010 Canada	Patients aged 15 or older with known exposure to MDMA, documented hyperpyrexia (≥38˚C) and survived at least until time of initial assessment and management	Systematic Review	Patient survival in those with temperatures 38.0–39.9˚C.	3/3 given dantrolene survived. 7/8 not given dantrolene survived.	Review lacks evidence of a higher quality than case reports/series, such as random controlled trials. Patients that concomitantly consumed other substances, such as opiates and cannabis were also included. Data did not include amount of MDMA ingested. Formal statistical analysis was not conducted. Study unable to take into account cooling method and use of neuromuscular paralysis.
			Patient survival in those with temperatures 40–41.9˚C.	10/10 given dantrolene survived. 15/27 not given dantrolene survived.
			Patient survival in those with temperatures ≥42˚C.	8/13 given dantrolene survived. 0/4 not given dantrolene survived.
P. Armenian et al 2013 USA	Patients aged 19-35 years intoxicated with MDMA or other amphetamines.	Case Series	Patient fully recovered.	1/3 patients given dantrolene fully recovered. 3/7 patients not given dantrolene fully recovered.	As it is only a case series, this article is of low evidential quality. The management of two patients, of the 12 mentioned is not recorded in the article. Results do not take into account condition prior treatment. Confounding variables, such as other cooling methods used were not taken into account.
			Patient survival with sequelae.	1/3 given dantrolene survived with sequelae. 3/7 patients not given dantrolene survived with sequelae.
			Patient deceased.	1/3 patients given dantrolene died. 1/7 patients not given dantrolene survived.

Comment(s)

As an established treatment in malignant hyperthermia, dantrolene has already shown efficacy when treating one drug-induced hyperthermia. It is also suggested for use by the National Poisons Information Service in for muscle hyperactivity in serotonin syndrome.The above evidence supports the use of the substance in addressing serotonin syndrome as well, though the papers available rely solely on case reports to support its use. Consequently, caution should be applied when relying on dantrolene therapy in these patients.

Clinical Bottom Line

According to available evidence, dantrolene is both safe and effective in treating serotonin syndrome, regardless of patient temperature.

References

1. Grunau, B., Wiens, M. and Brubacher, J. Dantrolene in the treatment of MDMA-related hyperpyrexia: a systematic review CJEM 2010; 12(05), pp.435-442
2. ] Armenian, P., Mamantov, T., Tsutaoka, B., Gerona, R., Silman, E., Wu, A. and Olson, K. Multiple MDMA (Ecstasy) Overdoses at a Rave Event. Journal of Intensive Care Medicine 2013; 28(4), pp.252-258.