What is the management of serotonin syndrome?

Management of Serotonin Syndrome

Immediately discontinue all serotonergic agents and administer benzodiazepines as first-line treatment for agitation and neuromuscular symptoms, while providing aggressive supportive care including IV fluids and external cooling measures. 1, 2

Diagnosis and Recognition

Use the Hunter Criteria for diagnosis, which requires the presence of a serotonergic agent plus one of the following: spontaneous clonus, inducible clonus with agitation or diaphoresis, ocular clonus with agitation or diaphoresis, tremor and hyperreflexia, or hypertonia with temperature above 38°C and ocular or inducible clonus. 1, 2

• The clinical triad consists of mental status changes (agitation, confusion, delirium), autonomic hyperactivity (hyperthermia up to 41.1°C, tachycardia, hypertension, diaphoresis, mydriasis), and neuromuscular abnormalities (myoclonus, hyperreflexia, clonus, muscle rigidity, tremor). 3, 1, 4

• Clonus and hyperreflexia are highly diagnostic when occurring with serotonergic drug use and should prompt immediate action. 1, 4, 2

• Symptoms typically develop within 6-24 hours after starting or increasing the dose of a serotonergic medication. 1, 4

• The mortality rate is approximately 11%, and one-quarter of patients require intubation and ICU admission. 1, 2

Immediate Management Algorithm

Step 1: Discontinue All Serotonergic Agents

• Stop all serotonergic medications immediately—this is the cornerstone of treatment. 1, 2

Step 2: Supportive Care (All Cases)

• Administer benzodiazepines as first-line treatment for agitation, neuromuscular symptoms, and tremor. 1, 2

• Provide IV fluids for dehydration and autonomic instability. 1, 2

• Implement external cooling measures (cooling blankets) for hyperthermia—avoid antipyretics as they are ineffective since fever results from muscular hyperactivity rather than hypothalamic dysregulation. 1, 4

• Avoid physical restraints as they exacerbate isometric contractions, worsening hyperthermia and lactic acidosis. 1, 2

Step 3: Severity-Based Treatment

For Mild to Moderate Cases:

• Continue supportive care with benzodiazepines and monitoring. 1
• Most cases resolve within 24-48 hours after discontinuing serotonergic agents. 1

For Severe Cases (hyperthermia >41.1°C, severe muscle rigidity, autonomic instability):

• Administer cyproheptadine: 12 mg orally initially, then 2 mg every 2 hours until symptom improvement, followed by maintenance of 8 mg every 6 hours. 1, 4

• For pediatric patients: 0.25 mg/kg per day. 4, 5

• Admit to ICU with continuous cardiac monitoring. 1, 2

• Consider intubation and paralysis with non-depolarizing agents only (avoid succinylcholine due to risks of hyperkalemia and rhabdomyolysis). 4

• For hemodynamic instability, use direct-acting sympathomimetic amines (phenylephrine, norepinephrine) rather than indirect agents like dopamine. 4

Cyproheptadine Use

Cyproheptadine is a serotonin antagonist at 5-HT2A receptors and is recommended by the American Academy of Pediatrics as the antidote of choice for severe serotonin syndrome. 4, 5

• Continue cyproheptadine until the clinical triad resolves: mental status changes, neuromuscular hyperactivity, and autonomic instability. 1

• Side effects include sedation and hypotension, which require monitoring. 1, 4

• The FDA-approved dosing for adults is 4-20 mg daily for standard indications, but for serotonin syndrome specifically, higher doses (12-24 mg over 24 hours) are used based on guideline recommendations. 5, 4

Monitoring Parameters

• Watch for resolution of clonus and hyperreflexia, normalization of vital signs, return to baseline mental status, and cessation of diaphoresis and tremor. 1

• Monitor for complications including rhabdomyolysis (elevated creatine kinase), metabolic acidosis, elevated serum aminotransferase, renal failure, seizures, and disseminated intravascular coagulopathy. 1, 4

Critical Pitfalls to Avoid

• Do not confuse with neuroleptic malignant syndrome (NMS), which presents with lead pipe rigidity, delirium, and history of antipsychotic use rather than serotonergic agents—serotonin syndrome characteristically shows hyperreflexia and clonus. 4, 2

• Do not confuse with malignant hyperthermia, anticholinergic syndrome, or withdrawal syndromes—myoclonus (present in 57% of cases) and hyperreflexia help differentiate serotonin syndrome. 1, 2

• The presentation is extremely variable, and mild cases may be easily missed—maintain high clinical suspicion with any serotonergic drug use. 4

• Patients can deteriorate rapidly—close observation and preparation for rapid intervention is essential. 4