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Serotonin Syndrome (DRUG-INDUCED), Emergency Medicine

Basics

Description

- Constellation of signs and symptoms from excessive stimulation of central and peripheral serotonergic receptors - Spectrum of symptoms may range from mild and subtle findings to severe and sometimes fatal toxicity - Results from use of serotonergic agents, alone or in combination with other serotonergic agents (may be therapeutic, intentional overdose, recreational, drug interactions) - Classic triad: - Autonomic dysfunction: Hyperthermia, diaphoresis, tachycardia, and hypertension - Cognitive changes: Confusion, agitation, hallucinations, decreased responsiveness - Neuromuscular excitability: Hyperreflexia, myoclonus, tremors

- GI: - Hyperactive bowel sounds - Diarrhea

- Stabilize airway, establish IV access, continuous cardiac and temperature monitoring - Conscientious avoidance of additional serotonergic agents while in-hospital (e.g., caution with ondansetron, fentanyl, linezolid, meperidine, dextromethorphan) - Supportive care is cornerstone of treatment - Aggressive cooling measures particularly important if hyperthermia present - Fluid resuscitation

- Cyproheptadine: - Nonspecific antihistamine with 5-HT2A antagonist activity may be considered for severe cases, but benefit has not been definitively established - Only PO available (must be crushed and given through oro- or nasogastric tube)

  • Constellation of signs and symptoms from excessive stimulation of central and peripheral serotonergic receptors
  • Spectrum of symptoms may range from mild and subtle findings to severe and sometimes fatal toxicity
  • Results from use of serotonergic agents, alone or in combination with other serotonergic agents (may be therapeutic, intentional overdose, recreational, drug interactions)
  • Classic triad:Autonomic dysfunction: Hyperthermia, diaphoresis, tachycardia, and hypertensionCognitive changes: Confusion, agitation, hallucinations, decreased responsivenessNeuromuscular excitability: Hyperreflexia, myoclonus, tremors

Epidemiology

Incidence and Prevalence Estimates

  • SSRIs implicated most often, alone or in combination with other drugs
  • Incidence higher in females but fatalities greater in males
  • Highest incidence in ages 19 " 39
  • Most fatalities from drug/drug interactions or recreational abuse

Etiology

  • Serotonin produced by metabolism of L-tryptophan
  • Exerts action on 5-hydroxytryptophan (5-HT) receptors of which there are 7 types located in central and peripheral nervous systems:Influences sleep and temperature regulation, affective behavior, food intake, migraines, emesis, sexual behavior, nociception, motor tone, GI motility, and vascular tone
  • Extensive list of serotonergic agents, with psychiatric meds most common (SSRIs, SNRIs):Examples: Citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, trazodone, venlafaxine
  • Other serotonergic agents include (not exhaustive):Buspirone, cocaine, dextromethorphan, fentanyl, lithium, MAOIs, MDMA (ecstasy), meperidine, methadone, metoclopramide, ondansetron, selegiline, St. Johns wort, TCAs, tramadol, triptans (controversial)

Diagnosis

Signs and Symptoms

History

  • May be difficult to obtain:Family, friends, EMS personnel, may provide additional information
  • Patient medication list: Prescribed medications, over-the-counter medications, herbal supplements
  • Medical history:Seizures, migraines, attention deficit/hyperactivity disorder, Parkinson, recent illnesses
  • Psychiatric history
  • Illicit drug abuse history
  • Onset of symptoms:Mental status/behavioral changes, development of hyperthermia, muscular rigidity/clonus

Physical Exam

  • Vital signs:HyperthermiaTachycardiaHypertension or hypotension (may evolve into frank shock and cardiovascular collapse)
  • Dermatologic:Diaphoresis, normal color
  • GI:Hyperactive bowel soundsDiarrhea
  • Mental status/neurologic:AgitationAltered mental statusOcular clonusHallucinationsWaxing/waning delirium
  • Musculoskeletal:Clonus: Most helpful finding in diagnosis, greater in lower extremitiesHypertonicity and rigidity, greater in lower extremitiesHyperreflexia, greater in lower extremities

Essential Workup

  • Careful history and physical exam as it is a clinical diagnosis
  • Hunter criteria " most sensitive (84%) and specific (97%) criteria for diagnosis. Requires having taken/been on a serotonergic agent and 1 of the following:Spontaneous clonusInducible clonus plus agitation or diaphoresisOcular clonus plus agitation or diaphoresisTremors plus hyperreflexiaHypertonia plus temperature >38 °C plus ocular clonus or inducible clonus
  • Consider other etiologies (sepsis, CVA, etc.)

Diagnosis Tests & Interpretation

Lab

  • Blood chemistry/electrolytes, renal function
  • Urine and serum tox screens may detect coingestants
  • Lactate, pH
  • Total CK
  • Cell count, blood/urine cultures if infectious process suspected

Imaging

  • Consider CT head if appropriate (trauma, infectious)
  • EKG:Evaluate QRS/QT intervals, dysrhythmias

Differential Diagnosis

  • Other intoxications (cocaine, amphetamines, anticholinergic agents, ecstasy, PCP):Neuroleptic malignant syndromeSympathomimetic toxicityMalignant hyperthermiaAnticholinergic toxicityInfectious process (meningitis, encephalitis)

Treatment

Pre-Hospital

  • Stabilize airway
  • Vital signs
  • IV access
  • Fingerstick glucose
  • Oxygen administration if needed

Initial Stabilization/Therapy

  • Stabilize airway, establish IV access, continuous cardiac and temperature monitoring
  • Conscientious avoidance of additional serotonergic agents while in-hospital (e.g., caution with ondansetron, fentanyl, linezolid, meperidine, dextromethorphan)
  • Supportive care is cornerstone of treatmentAggressive cooling measures particularly important if hyperthermia presentFluid resuscitation

Ed Treatment/Procedures

  • Benzodiazepines are 1st-line medications:
  • Aggressive cooling measures for hyperthermia:Ice packs, cooling blanket, cool mists/fansHyperthermia derives from muscular rigidity and is not usually responsive to antipyretic medications
  • Severe symptoms (e.g., uncontrollable hyperthermia) may necessitate intubation:Paralytics may be required to control muscular rigidity and hyperthermia
  • Cyproheptadine:Nonspecific antihistamine with 5-HT2A antagonist activity may be considered for severe cases, but benefit has not been definitively establishedOnly PO available (must be crushed and given through oro- or nasogastric tube)
  • Poison Control Center/Toxicology guidance (1-800-222-1222)

Follow-Up

Disposition

Admission Criteria

  • All patients suspected to have serotonin toxicity, even mild-appearing cases, should be admitted for monitoring and treatment
  • Severe symptoms including uncontrollable hypertension, altered mental status, cardiovascular instability, hyperthermia require ICU monitoring

Discharge Criteria

  • Discharge may be considered when all symptoms have resolved
  • Careful evaluation of discharge medications and patient education is essential
  • Poison Control Center guidance is recommended

Followup Recommendations

Follow up with primary care after discharge

Pearls and Pitfalls

  • Serotonin syndrome may be mild to severe in presentation; diagnosis in mild cases often elusive/missed
  • Mental status changes, hyperthermia, muscular clonus in lower extremities are important findings
  • Hyperthermia is due to muscular rigidity, should be aggressively controlled, and is not responsive to antipyretics
  • Cyproheptadine has not been shown definitively to be beneficial but may be considered in severe cases
  • Attentive supportive care and avoidance of serotonergic agents is the mainstay of care

Additional Reading

  • Ables AZ, Nagubilli R. Prevention, recognition, and management of serotonin syndrome. Am Fam Physician. 2010;81:1139 " 1142.
  • Boyer EW, Shannon M. The Serotonin syndrome. N Engl J Med. 2005;352(11):1112 " 1120.
  • Kant S, Liebelt E. Recognizing serotonin toxicity in the pediatric emergency department. Pediatr Emerg Care. 2012;28(8):817 " 824.
  • Sun-Edelstein C, Tepper SJ, Shapiro RE. Drug-induced serotonin syndrome: A review. Expert Opin Drug Saf. 2008;7(5):587 " 596.
  • Torre LE, Menon R, Power BM. Prolonged serotonin toxicity with proserotonergic drugs in the intensive care unit. Crit Care Resusc. 2009;11:272 " 275.

Codes

ICD9

333.99 Other extrapyramidal diseases and abnormal movement disorders

ICD10

G25.89 Other specified extrapyramidal and movement disorders

SNOMED

  • 371089000 Serotonin syndrome (disorder)