What is the management of serotonin syndrome?

Management of Serotonin Syndrome

The management of serotonin syndrome requires immediate discontinuation of all serotonergic agents, supportive care, benzodiazepines for agitation control, and cyproheptadine administration for moderate to severe cases. 1

Diagnosis

Before initiating treatment, confirm diagnosis using Hunter criteria, which require:

• Patient has taken a serotonergic drug within past 5 weeks
• Presence of one or more of the following:
  • Spontaneous clonus
  • Inducible clonus with agitation or diaphoresis
  • Ocular clonus with agitation or diaphoresis
  • Tremor and hyperreflexia
  • Hypertonia, temperature >38°C, and ocular or inducible clonus

These criteria have high sensitivity (84%) and specificity (97%) 1

Treatment Algorithm

Step 1: Discontinue Offending Agents

• Immediately stop all serotonergic medications 1, 2
• Common culprits include SSRIs, SNRIs, TCAs, MAOIs, opioids, antimigraine drugs, and certain antibiotics 1

Step 2: Provide Supportive Care

• Administer IV fluids 1
• Monitor vital signs closely
• Manage hyperthermia with cooling measures 3
• Avoid physical restraints as they may worsen hyperthermia and lactic acidosis 1

Step 3: Control Agitation and Neuromuscular Symptoms

• Administer benzodiazepines as first-line agents for agitation control 1, 2
• Benzodiazepines also help manage tremor 2

Step 4: Administer Serotonin Antagonist for Moderate to Severe Cases

• Cyproheptadine is the recommended antiserotonergic agent 1, 2, 4
• Dosing for adults: Initial dose of 12 mg orally, with maximum daily dose of 32 mg 1, 5
• Pediatric dosing (based on FDA label):
  • Ages 2-6 years: 0.25 mg/kg/day or 8 mg/m², typically 2 mg two or three times daily (not exceeding 12 mg/day) 5
  • Ages 7-14 years: 4 mg two or three times daily (not exceeding 16 mg/day) 5
  • Adults: 4-20 mg/day (most require 12-16 mg/day), not exceeding 0.5 mg/kg/day 5
• Chlorpromazine may be considered as an alternative, but use cautiously due to potential side effects 1

Step 5: Critical Care Management for Severe Cases

• For temperatures above 41°C, consider neuromuscular paralysis with non-depolarizing agents 1
• Approximately 25% of severe cases require intubation and mechanical ventilation 1
• Monitor for complications including rhabdomyolysis, metabolic acidosis, elevated liver enzymes, renal failure, seizures, and DIC 1

Expected Course and Prognosis

• Fever typically resolves within 1-3 days after removing the offending agent(s), but may take up to 7 days 1
• With prompt recognition and appropriate management, prognosis is favorable 2, 3
• Without proper treatment, mortality rate is approximately 11%, emphasizing the importance of aggressive treatment 1

Common Pitfalls and Caveats

• Serotonin syndrome is often misdiagnosed due to its diverse and nonspecific clinical manifestations 3, 4
• Distinguish from similar conditions such as neuroleptic malignant syndrome, sepsis, and decompensated hyperthyroidism 6
• All three classic features (altered mental status, neuromuscular abnormalities, and autonomic hyperactivity) may not occur simultaneously 3
• Prevention is key: avoid combining MAOIs with other serotonergic medications, and exercise caution when combining two or more non-MAOI serotonergic drugs 1
• Be vigilant when prescribing opioids with serotonergic effects alongside antidepressants 1
• Regular medication review is essential, as many commonly prescribed medications can contribute to serotonin syndrome 4