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tox.serotonin-syndrome.core.v1PRODUCTION
tox.serotonin-syndrome.core.v1

Serotonin syndrome

toxicologyacuteadultpediatric
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12/12 authored

Canonical 12-phase frame with authored status for this dossier.

Current phase

Frame

Detailed

Recognize serotonin toxicity as a clinical diagnosis (Hunter criteria) on a serotonergic exposure, and triage the hyperthermic/rigid life-threatening subset up front [Boyer & Shannon NEJM 2005]

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Serotonin toxicity pattern recognized; severe hyperthermic/rigid subset flagged

Patient inputs (17)

Pediatric/adolescent serotonergic ingestion or accidental combination; weight-based benzodiazepine and fluid dosing

Weight-based benzodiazepine, fluid, cyproheptadine, and paralytic dosing

SSRI/SNRI, MAOI (incl linezolid, methylene blue), TCA, triptans, tramadol/meperidine/fentanyl, dextromethorphan, ondansetron, lithium, MDMA/amphetamines, St John’s wort — identifying the precipitant(s) confirms exposure and is the agent to STOP [Boyer & Shannon NEJM 2005]

Onset usually <24h of a dose change/addition/combination — the temporal link is a Hunter-criteria prerequisite and differentiates from NMS (slower) [Dunkley QJM 2003]

Recent antipsychotic / antiemetic dopamine antagonist (or abrupt dopaminergic withdrawal) reframes toward NMS — the key sibling pivot [Boyer & Shannon NEJM 2005]

Sustained clonus/rigidity + hyperthermia → rhabdomyolysis; CK trend drives aggressive fluids

Rhabdomyolysis-associated AKI; baseline renal function for fluid/correction decisions

Metabolic (lactic) acidosis from sustained muscular hyperactivity tracks severity and impending decompensation

Hypoglycemia is a universal AMS mimic; co-screen mandatory

Tachycardia, QT prolongation (TCA/citalopram/ondansetron co-ingestion), and dysrhythmia screen

CLONUS (spontaneous > inducible > ocular) and hyperreflexia are the diagnostic hallmark and the dominant Hunter-criteria discriminators; lower-limb predominance is characteristic

Lower-limb-predominant rigidity/hypertonia in severe disease can compromise ventilation and drive hyperthermia — gates sedation + paralysis

Hyperthermia (severe >38.5–41°C) is the leading mortality driver and gates aggressive active cooling + paralysis/intubation

Agitation/anxiety/confusion severity drives benzodiazepine dosing and Hunter-criteria scoring

DIAPHORESIS + hyperactive bowel sounds/diarrhea distinguish serotonin toxicity from the DRY skin / ileus of anticholinergic toxidrome

Tachycardia tracks autonomic instability severity; benzodiazepine titration target

Labile hypertension vs hypotension signals autonomic instability severity and shock risk

* = hard-required. Engine cannot meaningfully run until these are filled.

Severity triggers (6)

6 need judgement
  • informationallife_threateningsevere_hyperthermia_over_38_5C
    Core temperature >38.5–41°C in a serotonergic-toxic patient (severe serotonin toxicity hyperthermia) [Boyer & Shannon NEJM 2005]
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationallife_threateningrigidity_with_respiratory_compromise
    Severe (lower-limb-predominant) rigidity/hypertonia compromising ventilation or rapidly rising temperature [Boyer & Shannon NEJM 2005]
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalsevereserotonin_toxicity_seizure
    Seizure complicating serotonin toxicity [Boyer & Shannon NEJM 2005]
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalsevererhabdomyolysis_aki_dic
    Markedly elevated CK with rising creatinine / myoglobinuric AKI, or disseminated intravascular coagulation [ACMT serotonin toxicity guidance]
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalsevererapidly_rising_temperature
    Rapidly rising core temperature in serotonin toxicity even before the 38.5°C threshold (impending life-threatening hyperthermia) [Boyer & Shannon NEJM 2005]
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseveresevere_autonomic_instability
    Severe autonomic instability — labile/extreme hypertension or hypotension with tachycardia and diaphoresis in serotonin toxicity [Boyer & Shannon NEJM 2005]
    Trigger could not be auto-evaluated — needs clinician judgement.

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Run this disease's risk and dosing calculators inline.

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Recommended regimen

Serotonin syndrome — STOP serotonergic agents → supportive + benzodiazepine sedation → active cooling for hyperthermia → cyproheptadine (moderate-severe) → SEVERE: deep sedation + non-depolarizing paralysis + intubation (definitive for hyperthermia/rigidity) → rhabdo/AKI management (Boyer & Shannon NEJM 2005; ACMT serotonin toxicity guidance)
axis: serotonin_syndrome_stop_and_sedate_bundlestep 1 - Step 1 — STOP ALL serotonergic agents (the cornerstone) + supportive care
Selected step "Step 1 — STOP ALL serotonergic agents (the cornerstone) + supportive care" — Any patient meeting Hunter criteria on a serotonergic exposure
  • discontinue_all_serotonergic_agents
    first line
    offending_agent_withdrawal
    Immediately stop SSRI/SNRI, MAOI (incl linezolid, methylene blue), TCA, triptans, tramadol/meperidine/fentanyl, dextromethorphan, ondansetron, lithium, MDMA/amphetamines, St John’s wort • medication_discontinuation • once, sustained
    triggers: serotonin_toxicity_confirmed, serotonergic_exposure_identified
    Boyer & Shannon NEJM 2005 — removing the offending serotonergic agent is the single most important intervention; most cases resolve within 24h after removal + supportive care
  • isotonic_crystalloid
    first line
    crystalloid
    Balanced crystalloid / NS — resuscitate then target generous UOP titrated to CK trend and volume status • IV • bolus + maintenance titrated
    triggers: volume_depletion, hyperthermia, CK_rising
    ACMT — IV fluids + brisk urine output support cooling and rhabdomyolysis/AKI prevention; core supportive measure alongside continuous monitoring

ed playbook — drug actions (6)

  1. 1. discontinue all serotonergic agents
    Immediate cessation of every serotonergic drug • medication_discontinuation • once, sustained
    trigger: Hunter criteria met on a serotonergic exposure (Boyer & Shannon NEJM 2005)
    Cornerstone — removal of the offending agent; most resolve within 24h (Boyer & Shannon NEJM 2005)
  2. 2. lorazepam (or diazepam/midazolam)
    Lorazepam 2–4 mg IV (or midazolam 5–10 mg IM if no IV) • IV/IM • q5–10min titrated, no fixed ceiling
    trigger: Agitation / tremor / myoclonus / autonomic features / seizure (Boyer & Shannon NEJM 2005)
    First-line — blunt agitation and the neuromuscular/autonomic drive (Boyer & Shannon NEJM 2005)
  3. 3. active external cooling
    Evaporative/ice-water cooling + cold IV crystalloid • physical • continuous to normothermia
    trigger: Core temp >38.5°C (urgent toward 41°C) (Boyer & Shannon NEJM 2005)
    Hyperthermia drives mortality; antipyretics ineffective — fever is muscular (Boyer & Shannon NEJM 2005)
  4. 4. isotonic crystalloid
    Resuscitate then maintain brisk UOP • IV • bolus + titrated
    trigger: Volume depletion / elevated CK / hyperthermia (ACMT serotonin toxicity guidance)
    Rhabdomyolysis/AKI prevention + supports cooling (ACMT serotonin toxicity guidance)
  5. 5. cyproheptadine
    12 mg PO/NG then 2 mg q2h (max 32 mg/day) • PO/NG • q2h then q6h
    trigger: Moderate-severe not responding to stop-agent + benzodiazepines + cooling (Boyer & Shannon NEJM 2005)
    5-HT2A antagonist antidote; adjunct, not a substitute for supportive care (Boyer & Shannon NEJM 2005)
  6. 6. RSI with non-depolarizing paralysis (rocuronium) + deep sedation
    Rocuronium RSI + deep sedation, continued cooling • IV • once, airway secured
    trigger: Severe hyperthermia / rigidity with respiratory compromise refractory to benzos + cooling (Boyer & Shannon NEJM 2005)
    Definitive treatment for life-threatening hyperthermia/rigidity; avoid succinylcholine if rhabdo/hyperK (Boyer & Shannon NEJM 2005)

Auto-drafted A&P note

ed

Subjective

- Possible entry pathways: Recent serotonergic dose change/addition + clonus / hyperreflexia / myoclonus / tremor (serotonin toxicity cluster) [Boyer & Shannon NEJM 2005]; Core temperature >38.5°C with inducible/spontaneous clonus or hypertonia after a serotonergic agent (severe serotonin toxicity) [Hunter criteria — Dunkley QJM 2003]; Agitation / anxiety / confusion + autonomic instability (tachycardia, diaphoresis, mydriasis) within 24h of a serotonergic medication [Boyer & Shannon NEJM 2005].

Objective

- No vitals, labs, or imaging entered for this encounter.

Assessment

**Serotonin syndrome** (tox.serotonin-syndrome.core.v1).
Phenotype framing: Distinguish from NMS (dopamine-blocker exposure, BRADYreflexia, lead-pipe rigidity, slow onset/resolution), anticholinergic toxidrome (DRY skin, normal reflexes, NO clonus, ileus), sympathomimetic toxidrome, malignant hyperthermia (anesthetic trigger), thyroid storm, meningoencephalitis, status epilepticus [Boyer & Shannon NEJM 2005]
Scope: Recognize serotonin toxicity as a clinical diagnosis (Hunter criteria) on a serotonergic exposure, and triage the hyperthermic/rigid life-threatening subset up front [Boyer & Shannon NEJM 2005]

No severity triggers fired against current inputs.

Plan

Regimen axis: **Serotonin syndrome — STOP serotonergic agents → supportive + benzodiazepine sedation → active cooling for hyperthermia → cyproheptadine (moderate-severe) → SEVERE: deep sedation + non-depolarizing paralysis + intubation (definitive for hyperthermia/rigidity) → rhabdo/AKI management (Boyer & Shannon NEJM 2005; ACMT serotonin toxicity guidance)** — step "Step 1 — STOP ALL serotonergic agents (the cornerstone) + supportive care".
1. discontinue_all_serotonergic_agents Immediately stop SSRI/SNRI, MAOI (incl linezolid, methylene blue), TCA, triptans, tramadol/meperidine/fentanyl, dextromethorphan, ondansetron, lithium, MDMA/amphetamines, St John’s wort medication_discontinuation once, sustained (offending_agent_withdrawal, first line) — Boyer & Shannon NEJM 2005 — removing the offending serotonergic agent is the single most important intervention; most cases resolve within 24h after removal + supportive care
2. isotonic_crystalloid Balanced crystalloid / NS — resuscitate then target generous UOP titrated to CK trend and volume status IV bolus + maintenance titrated (crystalloid, first line) — ACMT — IV fluids + brisk urine output support cooling and rhabdomyolysis/AKI prevention; core supportive measure alongside continuous monitoring

Setting playbook (ed) — Recognize serotonin toxicity via Hunter criteria, STOP all serotonergic agents, achieve benzodiazepine sedation + active cooling, exclude NMS/anticholinergic/other mimics, and triage ICU disposition (Boyer & Shannon NEJM 2005; ACMT serotonin toxicity guidance)
3. discontinue all serotonergic agents Immediate cessation of every serotonergic drug medication_discontinuation once, sustained — Hunter criteria met on a serotonergic exposure (Boyer & Shannon NEJM 2005) (Cornerstone — removal of the offending agent; most resolve within 24h (Boyer & Shannon NEJM 2005))
4. lorazepam (or diazepam/midazolam) Lorazepam 2–4 mg IV (or midazolam 5–10 mg IM if no IV) IV/IM q5–10min titrated, no fixed ceiling — Agitation / tremor / myoclonus / autonomic features / seizure (Boyer & Shannon NEJM 2005) (First-line — blunt agitation and the neuromuscular/autonomic drive (Boyer & Shannon NEJM 2005))
5. active external cooling Evaporative/ice-water cooling + cold IV crystalloid physical continuous to normothermia — Core temp >38.5°C (urgent toward 41°C) (Boyer & Shannon NEJM 2005) (Hyperthermia drives mortality; antipyretics ineffective — fever is muscular (Boyer & Shannon NEJM 2005))
6. isotonic crystalloid Resuscitate then maintain brisk UOP IV bolus + titrated — Volume depletion / elevated CK / hyperthermia (ACMT serotonin toxicity guidance) (Rhabdomyolysis/AKI prevention + supports cooling (ACMT serotonin toxicity guidance))
7. cyproheptadine 12 mg PO/NG then 2 mg q2h (max 32 mg/day) PO/NG q2h then q6h — Moderate-severe not responding to stop-agent + benzodiazepines + cooling (Boyer & Shannon NEJM 2005) (5-HT2A antagonist antidote; adjunct, not a substitute for supportive care (Boyer & Shannon NEJM 2005))
8. RSI with non-depolarizing paralysis (rocuronium) + deep sedation Rocuronium RSI + deep sedation, continued cooling IV once, airway secured — Severe hyperthermia / rigidity with respiratory compromise refractory to benzos + cooling (Boyer & Shannon NEJM 2005) (Definitive treatment for life-threatening hyperthermia/rigidity; avoid succinylcholine if rhabdo/hyperK (Boyer & Shannon NEJM 2005))

Non-pharmacologic actions:
- Continuous cardiac monitor + SpO2 + continuous core-temperature probe (Boyer & Shannon NEJM 2005)
- Active cooling: evaporative mist + fans or ice-water immersion, ice packs to groin/axillae/neck, cold IV fluids (Boyer & Shannon NEJM 2005)
- AVOID prolonged physical restraint without chemical sedation — worsens hyperthermia/rhabdomyolysis/lactic acidosis (ACMT serotonin toxicity guidance)
- Foley for hourly UOP if rhabdomyolysis/hyperthermia (ACMT serotonin toxicity guidance)
- If severe hyperthermia/rigidity refractory: RSI with rocuronium + deep sedation, continue cooling (Boyer & Shannon NEJM 2005)
- Early toxicology / regional poison-center consult (ACMT serotonin toxicity guidance)

AVOID / contraindication checks:
- Antipyretics_ineffective_for_serotonin_toxicity_hyperthermia_is_muscular_use_active_cooling_and_benzodiazepines (Boyer & Shannon NEJM 2005)
- Avoid_succinylcholine_in_rhabdomyolysis_or_hyperkalemia_use_non_depolarizing_rocuronium (Boyer & Shannon NEJM 2005)
- Physical_restraint_only_without_chemical_sedation_worsens_hyperthermia_rhabdomyolysis_lactic_acidosis (ACMT serotonin toxicity guidance)
- Avoid_further_serotonergic_agents_including_some_antiemetics_ondansetron_metoclopramide_and_dextromethorphan (Boyer & Shannon NEJM 2005)
- Cyproheptadine_is_oral_NG_only_no_parenteral_form_do_not_delay_supportive_care_awaiting_it (ACMT serotonin toxicity guidance)
- Do_not_restart_offending_serotonergic_combination_durable_interaction_flag_required (ACMT serotonin toxicity guidance)

Monitoring

Regimen monitoring:
- continuous core temperature and telemetry (Boyer & Shannon NEJM 2005)
- RASS or agitation score and sedation depth (ACMT serotonin toxicity guidance)
- serial clonus and deep tendon reflex exam for resolution (Dunkley QJM 2003)
- CK and renal function q4-6h until trending down (ACMT serotonin toxicity guidance)
- coagulation studies if DIC concern (Boyer & Shannon NEJM 2005)
- lactate and bicarbonate clearance (Boyer & Shannon NEJM 2005)
- hourly urine output for rhabdomyolysis (ACMT serotonin toxicity guidance)
- continuous capnography if intubated or paralyzed (Boyer & Shannon NEJM 2005)

Setting (ed) monitoring:
- Vitals + core temp q15min during active cooling/sedation (Boyer & Shannon NEJM 2005)
- Serial clonus/reflex exam for resolution (Dunkley QJM 2003)
- Glucose, CK, creatinine, lactate on arrival and serially (ACMT serotonin toxicity guidance)
- Agitation/sedation score q15–30min (ACMT serotonin toxicity guidance)
- Hourly UOP if rhabdomyolysis (ACMT serotonin toxicity guidance)

Follow-up plan: Medication reconciliation to remove/avoid the offending serotonergic combination (durable allergy/interaction flag), pharmacist review of MAOI/linezolid/methylene-blue washout intervals, psychiatry safety plan if intentional, nephrology if AKI, return precautions for re-exposure [ACMT serotonin toxicity guidance]
- Close-out criterion: Medication reconciliation + interaction flag + psych/SUD follow-up documented

Monitoring phase: Continuous core-temperature + telemetry, RASS/agitation score, serial clonus/reflex exam for resolution, q4–6h CK + renal until trending down, coags if DIC concern, lactate/bicarbonate clearance, UOP, capnography if intubated/paralyzed [Boyer & Shannon NEJM 2005]

Disposition

Current setting: ed — Recognize serotonin toxicity via Hunter criteria, STOP all serotonergic agents, achieve benzodiazepine sedation + active cooling, exclude NMS/anticholinergic/other mimics, and triage ICU disposition (Boyer & Shannon NEJM 2005; ACMT serotonin toxicity guidance)

Disposition criteria:
- Discharge after observation: mild toxicity, afebrile, asymptomatic off offending agent, normal labs/ECG, reliable follow-up, psych cleared if intentional (ACMT serotonin toxicity guidance)
- Admit ward/observation: moderate toxicity needing monitoring, on cyproheptadine, mild rhabdomyolysis without AKI (ACMT serotonin toxicity guidance)
- Admit ICU: hyperthermia, severe rigidity/respiratory compromise, autonomic instability, seizures, rhabdo/AKI/DIC, or need for paralysis (Boyer & Shannon NEJM 2005)

Escalation triggers (move to higher acuity):
- Core temp >38.5–41°C or not falling with cooling + benzodiazepines → ICU + paralysis/intubation (Boyer & Shannon NEJM 2005)
- Rigidity with respiratory compromise → ICU + deep sedation + non-depolarizing paralysis + intubation (Boyer & Shannon NEJM 2005)
- Seizures → benzodiazepine escalation + ICU; exclude hypoglycemia/hyponatremia (Boyer & Shannon NEJM 2005)
- Rhabdomyolysis with rising creatinine / DIC / refractory autonomic instability → ICU (ACMT serotonin toxicity guidance)

Earlier-Return Triggers

Return-precaution thresholds (watch for):
- [LIFE_THREATENING] Core temperature >38.5–41°C in a serotonergic-toxic patient (severe serotonin toxicity hyperthermia) [Boyer & Shannon NEJM 2005]
- [LIFE_THREATENING] Severe (lower-limb-predominant) rigidity/hypertonia compromising ventilation or rapidly rising temperature [Boyer & Shannon NEJM 2005]
- [SEVERE] Seizure complicating serotonin toxicity [Boyer & Shannon NEJM 2005]

Citations

- Hunter Serotonin Toxicity Criteria (Dunkley QJM 2003); Boyer & Shannon, The Serotonin Syndrome, NEJM 2005; 2024-2025 critical-care toxicology reviews of serotonin toxicity and ACMT serotonin toxicity guidance [PMID:12925718](https://pubmed.ncbi.nlm.nih.gov/12925718/)
- Cited evidence (PMID 15784664) [PMID:15784664](https://pubmed.ncbi.nlm.nih.gov/15784664/)
- Cited evidence (PMID 16828120) [PMID:16828120](https://pubmed.ncbi.nlm.nih.gov/16828120/)
- Cited evidence (PMID 24973380) [PMID:24973380](https://pubmed.ncbi.nlm.nih.gov/24973380/)
- Cited evidence (PMID 29669141) [PMID:29669141](https://pubmed.ncbi.nlm.nih.gov/29669141/)

Last reconciled with current guidelines: 2026-05-16.
References
  • Hunter Serotonin Toxicity Criteria (Dunkley QJM 2003); Boyer & Shannon, The Serotonin Syndrome, NEJM 2005; 2024-2025 critical-care toxicology reviews of serotonin toxicity and ACMT serotonin toxicity guidance — PMID:12925718
  • Cited evidence (PMID 15784664) — PMID:15784664
  • Cited evidence (PMID 16828120) — PMID:16828120
  • Cited evidence (PMID 24973380) — PMID:24973380
  • Cited evidence (PMID 29669141) — PMID:29669141