Step 1 · Recognize — Hunter Criteria
- Serotonergic agent + ≥1 of:
- Spontaneous clonus
- Inducible clonus + agitation OR diaphoresis
- Ocular clonus + agitation OR diaphoresis
- Tremor + hyperreflexia
- Hypertonia + temp > 38°C + ocular or inducible clonus
- Onset typically < 24 h after dose change / new agent
- Lower-extremity clonus & hyperreflexia > upper — distinguishes from NMS
Common offenders
SSRI/SNRI, MAOI, TCAs, tramadol, meperidine, fentanyl, methadone, linezolid, methylene blue, dextromethorphan, MDMA, LSD, St. John's wort, ondansetron, metoclopramide, triptans, lithium.
Step 2 · Stop & sedate
- Stop ALL serotonergic agents — review home meds, recent changes, OTC, supplements
- Lorazepam 1–2 mg IV q5–10 min OR Midazolam 2–5 mg IV q5 min until tremor / agitation / autonomic surge controlled
- Benzos blunt hyperthermia, tremor, and HR — don't under-dose
Step 3 · Cool & support
- Cooling for temp > 38.5°C — strip, ice packs, cooling blanket, cold IVF
- IV NS · monitor for rhabdo (CK), AKI (BMP), DIC (coags, fibrinogen)
- Continuous cardiac, SpO₂, temp probe
Step 4 · Cyproheptadine (5-HT2A antagonist)
- Cyproheptadine 12 mg PO/NG load → 2 mg q2h until response → maintenance 8 mg q6h
- Max 32 mg/24 h · only enteral form available
- Adjunct, not replacement for benzos + cooling
Step 5 · Severe / refractory
- Temp > 41°C OR rigidity preventing ventilation → RSI + non-depolarizing paralytic (Rocuronium 1.2 mg/kg IV) — paralytic stops muscle heat production
- AVOID succinylcholine if hyperK
- AVOID bromocriptine, dantrolene, antipsychotics (can worsen syndrome)
- AVOID physical restraints alone — increases isometric heat
Step 6 · Disposition
- Mild (afebrile, hyperreflexia only): observe 6 h, dc with Psych/PCP follow-up if resolving
- Moderate-severe (hyperthermia, autonomic instability, rigidity): ICU
- Most resolve < 24 h after agent discontinuation; document offending agent + counsel patient