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
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:
- Hyperthermia
- Tachycardia
- Hypertension or hypotension (may evolve into frank shock and cardiovascular collapse)
- Dermatologic:
- Diaphoresis, normal color
- GI:
- Hyperactive bowel sounds
- Diarrhea
- Mental status/neurologic:
- Agitation
- Altered mental status
- Ocular clonus
- Hallucinations
- Waxing/waning delirium
- Musculoskeletal:
- Clonus: Most helpful finding in diagnosis, greater in lower extremities
- Hypertonicity and rigidity, greater in lower extremities
- Hyperreflexia, 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 clonus
- Inducible clonus plus agitation or diaphoresis
- Ocular clonus plus agitation or diaphoresis
- Tremors plus hyperreflexia
- Hypertonia 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 syndrome
- Sympathomimetic toxicity
- Malignant hyperthermia
- Anticholinergic toxicity
- Infectious 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 treatment
- Aggressive cooling measures particularly important if hyperthermia present
- Fluid resuscitation
Ed Treatment/Procedures
- Benzodiazepines are 1st-line medications:
- Aggressive cooling measures for hyperthermia:
- Ice packs, cooling blanket, cool mists/fans
- Hyperthermia 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 established
- Only 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)