Serotonin syndrome: Difference between revisions

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==Background==
==Background==
*Can be produced by any serotonergic medication
*Can be produced by any serotonergic medication
*Vast majority of cases occur with therapeutic dosages
*1 in 6 U.S. adults take at least one psychoactive medication<ref>Moore TJ and Mattison DR. Adult Utilization of Psychiatric Drugs and Differences by Sex, Age, and Race. JAMA Intern Med. Published online December 12, 2016. doi:10.1001/jamainternmed.2016.7507.</ref>
*Majority of cases occur within therapeutic drug dosages
*Most common cause is ingestion of foods high in L-Tryptophan while taking an MAOI. Second most common is ingestion of both SSRI and MAOI<ref>Stork CM. Serotonin Reuptake Inhibitors and Atypical Antidepressants. In: Flomenbaum N, Goldfrank L, Hoffman R, Howland MA, et al, eds. Goldfrank’s Toxicologic Emergencies. 8th Ed. New York, NY: McGraw-Hill; 2006: 1070-1082</ref>
*Most common cause of death is severe hyperthermia
*Most common cause of death is severe hyperthermia


===Causative Agents===
===Causative Agents<ref>Brown CH. Drug-induced Serotonin Syndrome. US Pharm. 2010;35(11):HS-16-HS-21.</ref>===
====Antidepressants====
*[[SSRIs]]
*[[SSRIs]]
*MAOIs
*[[SNRIs]]
*TCAs
*[[Bupropion]]<ref>Thorpe EL, Pizon AF, Lynch MJ, Boyer J. Bupropion induced serotonin syndrome: a case report. J Med Toxicol. 2010;6(2):168-171. doi:10.1007/s13181-010-0021-x</ref>
*Drugs of Abuse: Cocaine, Ecstasy, Marijuana, Meth
*[[Buspirone]]
*Analgesics: Demerol, fentanyl
*[[TCAs]]
*Antiemetics
*[[Lithium]]
*[[Mirtazapine]]
*[[Trazodone]]
*[[Valproic acid]]
*MAOIs (should have washout period of 2+ weeks prior to starting a SSRI)
**Phenelzine
**Selegiline
**Tranylcypromine
 
====Drugs of Abuse====
*[[Cocaine]]
*[[Ecstasy (MDMA)]]
*[[Methamphetamine]]
*[[LSD]]
 
====Analgesics====
*[[Fentanyl]]
*[[Meperidine]] (Demerol)
*[[Methadone]]
*[[Tramadol]]
 
====[[Antiemetics]]====
*[[Metoclopramide]]
*[[Ondansetron]]
 
====Over the counter Medications====
*[[Dextromethorphan]]
*Oral decongestants ([[Pseudoephedrine]])
 
====Herbal products====
*St John’s Wort, Ginseng, Nutmeg, Yohimbe
 
====Other Medications====
*Triptans
*Triptans
*Ergot alkaloids
*Bromocriptine
*Bromocriptine
*OTC: Cough meds like [[Dextromethorphan]], herbal products, St John’s Wort
*[[Linezolid]]
*[[Carbamazepine]]
*[[Cyclobenzaprine]]
*L-tryptophan, 5-hydroxytryptophan
*[[Methylene blue]]


==Clinical Features==
==Clinical Features==
*[[Altered mental status]]: Agitated delirium  
*[[Altered mental status]]: Agitated delirium.  Patients generally hyperactive.
*Autonomic Instability: Hyperthermia, Tachycardia, hypertension, diaphoresis <ref>Boyer, E. W. and Shannon, M. (2005) ‘The Serotonin Syndrome’, New England Journal of Medicine, 352(11), pp. 1112–1120. doi: 10.1056/nejmra041867</ref>
*Autonomic Instability: Hyperthermia, tachycardia, hypertension, diaphoresis, gastrointestinal illness <ref>Boyer, E. W. and Shannon, M. (2005) ‘The Serotonin Syndrome’, New England Journal of Medicine, 352(11), pp. 1112–1120. doi: 10.1056/nejmra041867</ref>
**Often labile blood pressure, HR
**Often labile blood pressure, HR
*Neuromuscular Abnormalities: Myoclonus, ocular clonus, rigidity, hyperreflexia, tremor
*Neuromuscular Abnormalities: Clonus, ocular clonus, myoclonus, rigidity, hyperreflexia, tremor, seizures
**More pronounced in the lower extremities
**More pronounced in the lower extremities
**Myoclonus: most common finding
**Clonus (inducible or spontaneous): most common finding<ref>Farkas, J. Serotonin Syndrome. The Internet Book of Critical Care. https://emcrit.org/ibcc/serotonin/. Published June 13th, 2019. Accessed December 31st, 2020.</ref>
***Important to identify because it does not occur in other conditions that mimic serotonin syndrome
***Important to identify because it does not occur in other conditions that mimic serotonin syndrome
**Hyperactivity as opposed to rigidity in [[neuroleptic malignant syndrome]]


==Differential Diagnosis==
==Differential Diagnosis==
{{Movement disorder DDX}}
{{AMS and fever DDX}}
{{AMS and fever DDX}}


==Diagnosis==
==Evaluation==
===Hunter Toxicity Criteria Decision Rules===
===Hunter Toxicity Criteria Decision Rules===
Serotonergic agent plus 1 of the following<ref>Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM 2003;96:635-642</ref>:
Serotonergic agent plus 1 of the following<ref>Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM 2003;96:635-642</ref>:
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*Ocular Clonus AND (agitation or diaphoresis)
*Ocular Clonus AND (agitation or diaphoresis)
*Tremor AND hyperreflexia
*Tremor AND hyperreflexia
*Hypertonia AND temp >38 AND (ocular clonus or inducible clonus)
*Hypertonia AND temperature >38 AND (ocular clonus or inducible clonus)


''84% Sn, 97% Sp''
''84% Sn, 97% Sp''
{{Serotonin syndrome vs neuroleptic malignant syndrome}}


==Management==
==Management==
*Discontinue all serotonergic drugs
*Discontinue all serotonergic drugs
*Aggressive supportive care
*Aggressive supportive care
**If pressors required, direct acting (e.g. norepi, epi) preferred, MAO inhibition causes erratic response to dopamine
**If pressors required, direct acting (e.g. norepinephrine, epi) preferred, MAO inhibition causes erratic response to dopamine
*[[Benzos]]
*[[Benzos]]
**Goal is to eliminate agitation, neuromuscular abnormalities, elevations in HR/BP
**Goal is to eliminate agitation, neuromuscular abnormalities, elevations in HR/BP
**In severe cases, large doses are required (diazepam IV 10-20 mg, titrated with 10 mg increments)
*[[Cyproheptadine]]<ref>Graudins, A., Stearman, A. and Chan, B. (1998) ‘Treatment of the serotonin syndrome with cyproheptadine’, The Journal of Emergency Medicine, 16(4), pp. 615–619. doi: 10.1016/s0736-4679(98)00057-2</ref>
*[[Cyproheptadine]]<ref>Graudins, A., Stearman, A. and Chan, B. (1998) ‘Treatment of the serotonin syndrome with cyproheptadine’, The Journal of Emergency Medicine, 16(4), pp. 615–619. doi: 10.1016/s0736-4679(98)00057-2</ref>
**Give if benzos and supportive care fail to improve agitation and abnormal vitals
**Give if benzodiazepines and supportive care fail to improve agitation and abnormal vitals
**Serotonin antagonist
**Serotonin antagonist
***Also has antihistamine and anticholinergic properties that may exacerbate other mixed toxicology picture
**Give 12mg PO/NG; repeat with 2mg q2hr until clinical response is seen (max 32mg/d)
**Give 12mg PO/NG; repeat with 2mg q2hr until clinical response is seen (max 32mg/d)
**Give 4mg q6hr x48hr if pt is responsive to initial dose
**Give 4mg q6hr x48hr if patient is responsive to initial dose
*[[Chlorpromazine]]<ref>Gillman PK. The serotonin syndrome and its treatment. J Psychopharmacol 1999;13:100-109</ref>
*[[Chlorpromazine]]<ref>Gillman PK. The serotonin syndrome and its treatment. J Psychopharmacol 1999;13:100-109</ref>
**Phenothiazine with antiserotonergic effects
**Phenothiazine with antiserotonergic effects
**50mg to 100mg IM
**50mg to 100mg IM
**Can consider in severe cases
**Avoid in:
*[[Dexmedetomidine]]<ref>Rushton WF, Charlton NP. Dexmedetomidine in the treatment of serotonin syndrome. Ann Pharmacother. 2014; 48(12):1651-1654.</ref>
***Hemodynamically unstable patients as can cause serious hypotension<ref>Frank C. Recognition and treatment of serotonin syndrome. Can Fam Physician. 2008 Jul; 54(7): 988–992.</ref>
***Cases in which NMS may still be on the differential
*[[Dexmedetomidine]]<ref>Rushton WF, Charlton NP. Dexmedetomidine in the treatment of serotonin syndrome. Ann Pharmacother. 2014; 48(12):1651-1654.</ref><ref>Duggal HS, Fetchko J. Serotonin syndrome and atypical antipsychotics. Am J Psychiatry. 2002;159(4):672–3.</ref>
**Small case series found this helpful in adolescent cases refractory to benzos
**Small case series found this helpful in adolescent cases refractory to benzos
*Dantrolene generally not recommended as it can worsen serotonin toxicity<ref>Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005 Mar 17; 352(11):1112-20.</ref>
*Treat hyperthermia
*Treat hyperthermia
**Hyperthermia due to increase in muscular activity, not change in set point
**Hyperthermia due to increase in muscular activity, not change in set point
**[[Intubate]] and paralyze if temp > 41.1
**[[Intubate]] and paralyze if temperature > 41.1
**Standard [[cooling measures]]
**Standard [[cooling measures]]
***Fans, water sprays, ice packs, cooled crystalloids, cooling blankets


==Disposition==
==Disposition==
*Severe cases may require [[intubation]] and [[ventilation]] in ICU
*24hr admission for [[altered mental status]] or abnormal [[vital signs]] requiring further supportive care
*Discharge mild cases with minimal intervention required after 6 hrs of observation


==See Also==
==See Also==
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<references/>
<references/>


[[Category:Tox]]
[[Category:Toxicology]]

Latest revision as of 20:10, 17 April 2024

Background

  • Can be produced by any serotonergic medication
  • 1 in 6 U.S. adults take at least one psychoactive medication[1]
  • Majority of cases occur within therapeutic drug dosages
  • Most common cause is ingestion of foods high in L-Tryptophan while taking an MAOI. Second most common is ingestion of both SSRI and MAOI[2]
  • Most common cause of death is severe hyperthermia

Causative Agents[3]

Antidepressants

Drugs of Abuse

Analgesics

Antiemetics

Over the counter Medications

Herbal products

  • St John’s Wort, Ginseng, Nutmeg, Yohimbe

Other Medications

Clinical Features

  • Altered mental status: Agitated delirium. Patients generally hyperactive.
  • Autonomic Instability: Hyperthermia, tachycardia, hypertension, diaphoresis, gastrointestinal illness [5]
    • Often labile blood pressure, HR
  • Neuromuscular Abnormalities: Clonus, ocular clonus, myoclonus, rigidity, hyperreflexia, tremor, seizures
    • More pronounced in the lower extremities
    • Clonus (inducible or spontaneous): most common finding[6]
      • Important to identify because it does not occur in other conditions that mimic serotonin syndrome
    • Hyperactivity as opposed to rigidity in neuroleptic malignant syndrome

Differential Diagnosis

Movement Disorders and Other Abnormal Contractions

Altered mental status and fever

Evaluation

Hunter Toxicity Criteria Decision Rules

Serotonergic agent plus 1 of the following[7]:

  • Spontaneous clonus
  • Inducible clonus AND (agitation or diaphoresis)
  • Ocular Clonus AND (agitation or diaphoresis)
  • Tremor AND hyperreflexia
  • Hypertonia AND temperature >38 AND (ocular clonus or inducible clonus)

84% Sn, 97% Sp

Serotonin syndrome vs Neuroleptic malignant syndrome

  • History of a new serotonergic drug or a dose increase of a serotonergic drug are helpful
  • Serotonin syndrome is usually much more acute in onset than NMS which may develop over days or weeks
  • Presence of ‘lead pipe’ rigidity is typical of NMS, while serotonin syndrome typically manifests with tremor and hyperreflexia
  • Elevations in CK, LFTs, and WBC, coupled with a low iron level, distinguishes NMS from serotonin syndrome among patients taking both neuroleptic and serotonin agonist medications simultaneously

Management

  • Discontinue all serotonergic drugs
  • Aggressive supportive care
    • If pressors required, direct acting (e.g. norepinephrine, epi) preferred, MAO inhibition causes erratic response to dopamine
  • Benzos
    • Goal is to eliminate agitation, neuromuscular abnormalities, elevations in HR/BP
    • In severe cases, large doses are required (diazepam IV 10-20 mg, titrated with 10 mg increments)
  • Cyproheptadine[8]
    • Give if benzodiazepines and supportive care fail to improve agitation and abnormal vitals
    • Serotonin antagonist
      • Also has antihistamine and anticholinergic properties that may exacerbate other mixed toxicology picture
    • Give 12mg PO/NG; repeat with 2mg q2hr until clinical response is seen (max 32mg/d)
    • Give 4mg q6hr x48hr if patient is responsive to initial dose
  • Chlorpromazine[9]
    • Phenothiazine with antiserotonergic effects
    • 50mg to 100mg IM
    • Avoid in:
      • Hemodynamically unstable patients as can cause serious hypotension[10]
      • Cases in which NMS may still be on the differential
  • Dexmedetomidine[11][12]
    • Small case series found this helpful in adolescent cases refractory to benzos
  • Dantrolene generally not recommended as it can worsen serotonin toxicity[13]
  • Treat hyperthermia
    • Hyperthermia due to increase in muscular activity, not change in set point
    • Intubate and paralyze if temperature > 41.1
    • Standard cooling measures
      • Fans, water sprays, ice packs, cooled crystalloids, cooling blankets

Disposition

See Also

References

  1. ↑ Moore TJ and Mattison DR. Adult Utilization of Psychiatric Drugs and Differences by Sex, Age, and Race. JAMA Intern Med. Published online December 12, 2016. doi:10.1001/jamainternmed.2016.7507.
  2. ↑ Stork CM. Serotonin Reuptake Inhibitors and Atypical Antidepressants. In: Flomenbaum N, Goldfrank L, Hoffman R, Howland MA, et al, eds. Goldfrank’s Toxicologic Emergencies. 8th Ed. New York, NY: McGraw-Hill; 2006: 1070-1082
  3. ↑ Brown CH. Drug-induced Serotonin Syndrome. US Pharm. 2010;35(11):HS-16-HS-21.
  4. ↑ Thorpe EL, Pizon AF, Lynch MJ, Boyer J. Bupropion induced serotonin syndrome: a case report. J Med Toxicol. 2010;6(2):168-171. doi:10.1007/s13181-010-0021-x
  5. ↑ Boyer, E. W. and Shannon, M. (2005) ‘The Serotonin Syndrome’, New England Journal of Medicine, 352(11), pp. 1112–1120. doi: 10.1056/nejmra041867
  6. ↑ Farkas, J. Serotonin Syndrome. The Internet Book of Critical Care. https://emcrit.org/ibcc/serotonin/. Published June 13th, 2019. Accessed December 31st, 2020.
  7. ↑ Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM 2003;96:635-642
  8. ↑ Graudins, A., Stearman, A. and Chan, B. (1998) ‘Treatment of the serotonin syndrome with cyproheptadine’, The Journal of Emergency Medicine, 16(4), pp. 615–619. doi: 10.1016/s0736-4679(98)00057-2
  9. ↑ Gillman PK. The serotonin syndrome and its treatment. J Psychopharmacol 1999;13:100-109
  10. ↑ Frank C. Recognition and treatment of serotonin syndrome. Can Fam Physician. 2008 Jul; 54(7): 988–992.
  11. ↑ Rushton WF, Charlton NP. Dexmedetomidine in the treatment of serotonin syndrome. Ann Pharmacother. 2014; 48(12):1651-1654.
  12. ↑ Duggal HS, Fetchko J. Serotonin syndrome and atypical antipsychotics. Am J Psychiatry. 2002;159(4):672–3.
  13. ↑ Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005 Mar 17; 352(11):1112-20.
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