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
*[[Buspirone]]
*Drugs of Abuse: Cocaine, Ecstasy, Marijuana, Meth
*[[TCAs]]
*Analgesics: Demerol, fentanyl
*[[Lithium]]
*Antiemetics
*[[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: Myoclonus, ocular clonus, rigidity, hyperreflexia, tremor, seizures
**More pronounced in the lower extremities
**More pronounced in the lower extremities
**Myoclonus: most common finding
**Myoclonus (inducible or spontaneous): most common finding
***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==
{{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]]


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


==See Also==
==See Also==
*[[Toxidromes]]
*[[Toxidromes]]
==Video==
{{#widget:YouTube|id=nicowGCfm30}}


==References==
==References==
<references/>
<references/>


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

Revision as of 21:07, 27 November 2019

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 [4]
    • Often labile blood pressure, HR
  • Neuromuscular Abnormalities: Myoclonus, ocular clonus, rigidity, hyperreflexia, tremor, seizures
    • More pronounced in the lower extremities
    • Myoclonus (inducible or spontaneous): most common finding
      • 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

Altered mental status and fever

Evaluation

Hunter Toxicity Criteria Decision Rules

Serotonergic agent plus 1 of the following[5]:

  • 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[6]
    • 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[7]
    • Phenothiazine with antiserotonergic effects
    • 50mg to 100mg IM
    • Avoid in:
      • Hemodynamically unstable patients as can cause serious hypotension[8]
      • Cases in which NMS may still be on the differential
  • Dexmedetomidine[9][10]
    • Small case series found this helpful in adolescent cases refractory to benzos
  • Dantrolene generally not recommended as it can worsen serotonin toxicity[11]
  • Treat hyperthermia
    • Hyperthermia due to increase in muscular activity, not change in set point
    • Intubate and paralyze if temperature > 41.1
    • Standard cooling measures

Disposition

See Also

Video

{{#widget:YouTube|id=nicowGCfm30}}

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. Boyer, E. W. and Shannon, M. (2005) ‘The Serotonin Syndrome’, New England Journal of Medicine, 352(11), pp. 1112–1120. doi: 10.1056/nejmra041867
  5. 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
  6. 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
  7. Gillman PK. The serotonin syndrome and its treatment. J Psychopharmacol 1999;13:100-109
  8. Frank C. Recognition and treatment of serotonin syndrome. Can Fam Physician. 2008 Jul; 54(7): 988–992.
  9. Rushton WF, Charlton NP. Dexmedetomidine in the treatment of serotonin syndrome. Ann Pharmacother. 2014; 48(12):1651-1654.
  10. Duggal HS, Fetchko J. Serotonin syndrome and atypical antipsychotics. Am J Psychiatry. 2002;159(4):672–3.
  11. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005 Mar 17; 352(11):1112-20.