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tox.neuroleptic-malignant-syndrome.core.v1PRODUCTION
tox.neuroleptic-malignant-syndrome.core.v1

Neuroleptic malignant syndrome

toxicologyacuteadultpediatric
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Care setting:

Encounter flow

12/12 authored

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

Current phase

Frame

Detailed

Recognize NMS as an idiosyncratic dopamine-blockade (or dopaminergic-withdrawal) hyperthermic emergency and triage the hyperthermic/rigidity-with-respiratory-compromise subset up front [Strawn 2007 NMS consensus; DSM-5]

Inputs
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Actions
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Advance rule
Set
Advance when

NMS pattern recognized; life-threatening hyperthermic/rigidity subset flagged

Patient inputs (18)

Young agitated males overrepresented for antipsychotic NMS; elderly Parkinson patients for withdrawal-type; weight-based dantrolene/benzodiazepine/fluid dosing

Identifying the precise causative neuroleptic / antiemetic (high-potency, parenteral, depot, rapidly titrated) is the cornerstone — it must be STOPPED [Strawn 2007]

Abrupt levodopa/amantadine/agonist withdrawal or malabsorption precipitates parkinsonism-hyperpyrexia syndrome — the agent must be RESTARTED, not stopped [critical-care tox review]

Serotonergic agents (SSRI/SNRI/MAOI/linezolid) raise the competing serotonin-syndrome diagnosis — the key sibling differential [Strawn 2007]

Prior NMS episode and pre-existing catatonia are major risk factors and shift treatment toward benzodiazepines/ECT (malignant-catatonia overlap)

Psychomotor agitation, dehydration, and physical restraint use are modifiable precipitants and worsen rhabdomyolysis

Markedly elevated CK (often >1000) supports NMS and drives rhabdomyolysis/AKI fluid management [DSM-5 criteria]

Myoglobinuric AKI from rhabdomyolysis; baseline renal function for fluid plan and RRT decision

Metabolic acidosis tracks severity and impending autonomic/cardiopulmonary collapse

Hyperthermia is a defining feature and the leading mortality driver — drives aggressive active cooling

Tachycardia is part of autonomic instability; tracks severity and dysautonomia

Labile BP / autonomic instability → autonomic collapse; guides ICU escalation

Tachypnea, chest-wall rigidity → respiratory failure / aspiration risk; airway watch

Generalized LEAD-PIPE rigidity (± tremor/dystonia) is the cardinal pivot vs serotonin-syndrome clonus/hyperreflexia and anticholinergic absence of rigidity

Stupor/coma/mutism severity; catatonic features signal malignant-catatonia overlap

Male sex is a recognized risk factor; alters pretest probability

Leukocytosis is characteristic and must be reconciled against an infectious differential (sepsis/CNS infection)

Low serum iron is a supportive associated finding in NMS

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

Severity triggers (6)

6 need judgement
  • informationallife_threateninghyperthermic_hypermetabolic_crisis
    Marked hyperthermia (often >40°C) with severe rigidity and hypermetabolism in NMS [Strawn 2007]
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationallife_threateningrigidity_with_respiratory_failure
    Severe generalized / chest-wall rigidity producing respiratory failure or aspiration [Strawn 2007]
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationallife_threateningrhabdomyolysis_aki_dic
    Markedly elevated CK with rising creatinine / myoglobinuric AKI and/or disseminated intravascular coagulation [Strawn 2007; DSM-5]
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationallife_threateningautonomic_collapse
    Severe autonomic instability — labile or refractory blood pressure, malignant arrhythmia, hemodynamic collapse [Strawn 2007]
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationallife_threateningparkinsonism_hyperpyrexia_dopaminergic_withdrawal
    NMS-like hyperthermia + rigidity + AMS precipitated by abrupt withdrawal / malabsorption of levodopa/amantadine/dopamine agonist in Parkinson disease [critical-care tox review]
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalsevererefractory_nms_malignant_catatonia_overlap
    NMS refractory to supportive care + dantrolene + dopaminergic agent, or diagnostic/therapeutic overlap with malignant catatonia [Strawn 2007]
    Trigger could not be auto-evaluated — needs clinician judgement.

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RISK_STRATIFICATIONoptionalDrives risk stratification
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Recommended regimen

NMS — stop dopamine antagonist / restart dopaminergic → supportive ICU + active cooling → fluids/rhabdo-AKI → benzodiazepine → moderate–severe dantrolene ± bromocriptine/amantadine → refractory ECT → severe sedation+intubation±paralysis → safe later antipsychotic rechallenge (Strawn 2007; DSM-5)
axis: nms_stop_trigger_supportive_tiered_bundlestep 1 - Step 1 — Remove the cause: STOP the offending dopamine antagonist OR RESTART the dopaminergic agent (cornerstone)
Selected step "Step 1 — Remove the cause: STOP the offending dopamine antagonist OR RESTART the dopaminergic agent (cornerstone)" — Any suspected NMS — applies before/with all other steps
  • discontinue_offending_dopamine_antagonist
    first line
    causative_agent_withdrawal
    Immediately STOP all dopamine-D2 antagonists — antipsychotics (typical/atypical, including depot) and dopamine-blocking antiemetics (metoclopramide, prochlorperazine, promethazine) • medication_discontinuation • immediate and sustained
    triggers: antipsychotic_or_antiemetic_precipitated_nms
    Strawn 2007 — removing the dopamine blockade is the single most important intervention; depot agents prolong the course and warrant a longer supportive window
  • restore_dopaminergic_therapy
    first line
    dopaminergic_replacement
    RESTART (do NOT further withhold) levodopa/carbidopa, amantadine, or dopamine agonist at the prior steady-state dose; use enteral/NG route if absorption compromised • PO/NG • resume scheduled dosing
    triggers: parkinsonism_hyperpyrexia_from_dopaminergic_withdrawal
    Critical-care tox review — withdrawal-type NMS (parkinsonism-hyperpyrexia syndrome) is treated by reinstating dopaminergic tone, NOT by stopping medication

ed playbook — drug actions (5)

  1. 1. STOP dopamine antagonist / RESTART dopaminergic agent
    Discontinue all antipsychotics + dopamine-blocking antiemetics; OR reinstate levodopa/amantadine/agonist at prior dose (NG if needed) • medication change • immediate
    trigger: NMS suspected (Strawn 2007)
    Cause removal is the cornerstone (Strawn 2007)
  2. 2. active external cooling
    Evaporative cooling + fans, ice packs to groin/axillae/neck, cold IV crystalloid • physical • continuous to normothermia
    trigger: Core temp >38.5°C (Strawn 2007)
    Hyperthermia is the leading mortality driver; antipyretics minimally effective (Strawn 2007)
  3. 3. isotonic crystalloid
    Forced isotonic fluids; resuscitate then maintain brisk UOP • IV • bolus + titrated
    trigger: Elevated CK / volume depletion / rhabdomyolysis (Strawn 2007)
    Rhabdomyolysis/AKI prevention + supports cooling (Strawn 2007)
  4. 4. lorazepam
    1–2 mg IV q4–6h titrated • IV/IM • q4–6h titrated
    trigger: Agitation / mild NMS / catatonic features (Strawn 2007)
    Controls agitation, may hasten recovery, treats catatonia overlap (Strawn 2007)
  5. 5. dantrolene ± bromocriptine
    Dantrolene 1–2.5 mg/kg IV PRN; bromocriptine 2.5 mg PO/NG q6–8h • IV / PO-NG • titrated
    trigger: Moderate–severe rigidity/hyperthermia (Strawn 2007)
    Reduce hypermetabolism + restore dopamine tone for moderate–severe NMS (Strawn 2007)

Auto-drafted A&P note

ed

Subjective

- Possible entry pathways: Recent start / dose increase of an antipsychotic or dopamine-blocking antiemetic (metoclopramide, prochlorperazine, promethazine) [Strawn 2007 NMS consensus]; Abrupt withdrawal / dose reduction / malabsorption of levodopa, amantadine, or a dopamine agonist in Parkinson disease (parkinsonism-hyperpyrexia syndrome) [DSM-5; critical-care tox review]; Lead-pipe rigidity + hyperthermia + autonomic instability + altered mental status evolving over 1–3 days [Strawn 2007; DSM-5 NMS criteria].

Objective

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

Assessment

**Neuroleptic malignant syndrome** (tox.neuroleptic-malignant-syndrome.core.v1).
Phenotype framing: Distinguish from SEROTONIN SYNDROME (serotonergic agent, onset <24h, clonus/HYPERreflexia/myoclonus, hyperactive bowel), malignant hyperthermia (anesthetic/succinylcholine, intra-operative), malignant catatonia (a continuum), anticholinergic toxidrome (dry, no rigidity), sympathomimetic toxidrome, severe acute dystonia, heat stroke, CNS infection / status epilepticus, thyroid storm, and drug-induced parkinsonism [Strawn 2007; DSM-5]
Scope: Recognize NMS as an idiosyncratic dopamine-blockade (or dopaminergic-withdrawal) hyperthermic emergency and triage the hyperthermic/rigidity-with-respiratory-compromise subset up front [Strawn 2007 NMS consensus; DSM-5]

No severity triggers fired against current inputs.

Plan

Regimen axis: **NMS — stop dopamine antagonist / restart dopaminergic → supportive ICU + active cooling → fluids/rhabdo-AKI → benzodiazepine → moderate–severe dantrolene ± bromocriptine/amantadine → refractory ECT → severe sedation+intubation±paralysis → safe later antipsychotic rechallenge (Strawn 2007; DSM-5)** — step "Step 1 — Remove the cause: STOP the offending dopamine antagonist OR RESTART the dopaminergic agent (cornerstone)".
1. discontinue_offending_dopamine_antagonist Immediately STOP all dopamine-D2 antagonists — antipsychotics (typical/atypical, including depot) and dopamine-blocking antiemetics (metoclopramide, prochlorperazine, promethazine) medication_discontinuation immediate and sustained (causative_agent_withdrawal, first line) — Strawn 2007 — removing the dopamine blockade is the single most important intervention; depot agents prolong the course and warrant a longer supportive window
2. restore_dopaminergic_therapy RESTART (do NOT further withhold) levodopa/carbidopa, amantadine, or dopamine agonist at the prior steady-state dose; use enteral/NG route if absorption compromised PO/NG resume scheduled dosing (dopaminergic_replacement, first line) — Critical-care tox review — withdrawal-type NMS (parkinsonism-hyperpyrexia syndrome) is treated by reinstating dopaminergic tone, NOT by stopping medication

Setting playbook (ed) — Recognize NMS, immediately STOP the offending dopamine antagonist (or RESTART dopaminergic therapy if withdrawal-type), start active cooling + fluids, exclude CNS infection / serotonin syndrome / heat stroke, and triage ICU disposition (Strawn 2007; DSM-5)
3. STOP dopamine antagonist / RESTART dopaminergic agent Discontinue all antipsychotics + dopamine-blocking antiemetics; OR reinstate levodopa/amantadine/agonist at prior dose (NG if needed) medication change immediate — NMS suspected (Strawn 2007) (Cause removal is the cornerstone (Strawn 2007))
4. active external cooling Evaporative cooling + fans, ice packs to groin/axillae/neck, cold IV crystalloid physical continuous to normothermia — Core temp >38.5°C (Strawn 2007) (Hyperthermia is the leading mortality driver; antipyretics minimally effective (Strawn 2007))
5. isotonic crystalloid Forced isotonic fluids; resuscitate then maintain brisk UOP IV bolus + titrated — Elevated CK / volume depletion / rhabdomyolysis (Strawn 2007) (Rhabdomyolysis/AKI prevention + supports cooling (Strawn 2007))
6. lorazepam 1–2 mg IV q4–6h titrated IV/IM q4–6h titrated — Agitation / mild NMS / catatonic features (Strawn 2007) (Controls agitation, may hasten recovery, treats catatonia overlap (Strawn 2007))
7. dantrolene ± bromocriptine Dantrolene 1–2.5 mg/kg IV PRN; bromocriptine 2.5 mg PO/NG q6–8h IV / PO-NG titrated — Moderate–severe rigidity/hyperthermia (Strawn 2007) (Reduce hypermetabolism + restore dopamine tone for moderate–severe NMS (Strawn 2007))

Non-pharmacologic actions:
- Continuous cardiac monitor + SpO2 + continuous core-temperature probe (Strawn 2007)
- Active cooling: evaporative mist + fans, ice packs to groin/axillae/neck, cold IV fluids (Strawn 2007)
- AVOID further dopamine antagonists including antiemetics (metoclopramide/prochlorperazine/promethazine) (Strawn 2007)
- Remove physical restraints once chemically sedated — restraint alone worsens hyperthermia/rhabdomyolysis (Strawn 2007)
- Foley for hourly UOP if rhabdomyolysis/hyperthermia (Strawn 2007)
- Protect airway if depressed consciousness / chest-wall rigidity / aspiration risk (Strawn 2007)
- Early toxicology / regional poison-center + psychiatry + neurology consult (Strawn 2007)

AVOID / contraindication checks:
- Do_not_re challenge_with_the_same_dopamine_antagonist_acutely (Strawn 2007 NMS consensus)
- Avoid_further_dopamine_antagonists_including_antiemetics_metoclopramide_prochlorperazine_promethazine_during_acute_NMS (Strawn 2007)
- Do_not_stop_dopaminergic_therapy_in_withdrawal type_parkinsonism hyperpyrexia_RESTART_it (critical care tox review)
- Avoid_succinylcholine_with_rhabdomyolysis_or_hyperkalemia_use_non depolarizing_paralytic_for_ECT_or_RSI (Strawn 2007)
- Physical_restraint_only_without_chemical_sedation_worsens_hyperthermia_rhabdomyolysis_and_autonomic_instability (Strawn 2007)
- Avoid_combining_dantrolene_with_calcium_channel_blockers_cardiovascular_collapse_risk (Strawn 2007)
- Antipyretics_are_ineffective_for_myogenic_NMS_hyperthermia_use_active_cooling (Strawn 2007)
- Taper_dantrolene_and_dopamine_agonist_slowly_abrupt_stop_causes_rebound (Strawn 2007)

Monitoring

Regimen monitoring:
- continuous core temperature and telemetry (Strawn 2007)
- q1h vitals during active cooling and dysautonomia (Strawn 2007)
- serial CK until trending down (Strawn 2007)
- renal function and electrolytes q6-12h for rhabdomyolysis AKI (Strawn 2007)
- coagulation panel for DIC surveillance (Strawn 2007)
- venous or arterial pH and lactate clearance (Strawn 2007)
- hourly urine output for rhabdomyolysis (Strawn 2007)
- daily rigidity and mental status resolution scoring (Strawn 2007)
- LFTs during dantrolene therapy (Strawn 2007)
- VTE surveillance during immobility (Strawn 2007)
- continuous capnography if intubated or paralyzed (Strawn 2007)

Setting (ed) monitoring:
- Vitals + core temp q15min during active cooling (Strawn 2007)
- CK, Cr, electrolytes, lactate, coagulation on arrival and serially (Strawn 2007)
- Mental-status / rigidity score q15–30min (Strawn 2007)
- Hourly UOP if rhabdomyolysis (Strawn 2007)
- Serial ECG for QTc / arrhythmia from dysautonomia (Strawn 2007)

Follow-up plan: Document the offending agent as an allergy/adverse-reaction; defer ANY antipsychotic rechallenge ≥2 weeks after full recovery, then use a lower-potency / different-class agent with slow titration and close monitoring; restore steady-state dopaminergic therapy for Parkinson patients; psychiatry/neurology continuity, nephrology if AKI, patient/family NMS education and return precautions [Strawn 2007]
- Close-out criterion: Adverse-reaction documented + safe rechallenge / dopaminergic plan and specialty follow-up arranged

Monitoring phase: Continuous core-temperature + telemetry, q1h vitals during cooling, serial CK + renal function + electrolytes + coagulation (DIC) until trending down, lactate clearance, hourly UOP for rhabdomyolysis, daily rigidity / mental-status resolution scoring, VTE surveillance, capnography if intubated/paralyzed [Strawn 2007]

Disposition

Current setting: ed — Recognize NMS, immediately STOP the offending dopamine antagonist (or RESTART dopaminergic therapy if withdrawal-type), start active cooling + fluids, exclude CNS infection / serotonin syndrome / heat stroke, and triage ICU disposition (Strawn 2007; DSM-5)

Disposition criteria:
- Admit ICU: any hyperthermia, autonomic instability, rhabdomyolysis/AKI, respiratory compromise, or depressed consciousness (Strawn 2007)
- Admit ward (monitored): mild NMS, normothermic, stable autonomics, mild CK elevation without AKI, cause removed (Strawn 2007)
- Do NOT discharge acutely — NMS evolves over 1–3 days and can deteriorate (Strawn 2007)

Escalation triggers (move to higher acuity):
- Hyperthermia / hypermetabolic crisis or temp not falling with cooling → ICU + dantrolene ± sedation/paralysis (Strawn 2007)
- Rigidity with respiratory failure / aspiration → ICU + airway control (Strawn 2007)
- Rhabdomyolysis with AKI or DIC → ICU + forced fluids ± RRT (Strawn 2007)
- Autonomic collapse (labile/refractory BP, arrhythmia) → ICU + titratable hemodynamic support (Strawn 2007)
- Parkinsonism-hyperpyrexia from dopaminergic withdrawal → ICU + reinstate dopaminergic therapy (critical-care tox review)

Earlier-Return Triggers

Return-precaution thresholds (watch for):
- [LIFE_THREATENING] Marked hyperthermia (often >40°C) with severe rigidity and hypermetabolism in NMS [Strawn 2007]
- [LIFE_THREATENING] Severe generalized / chest-wall rigidity producing respiratory failure or aspiration [Strawn 2007]
- [LIFE_THREATENING] Markedly elevated CK with rising creatinine / myoglobinuric AKI and/or disseminated intravascular coagulation [Strawn 2007; DSM-5]

Citations

- Strawn et al. Am J Psychiatry 2007 NMS consensus + 2024-2025 critical-care toxicology / psychiatry reviews of NMS and parkinsonism-hyperpyrexia syndrome; DSM-5 NMS diagnostic criteria [PMID:17541044](https://pubmed.ncbi.nlm.nih.gov/17541044/)
- Cited evidence (PMID 18540211) [PMID:18540211](https://pubmed.ncbi.nlm.nih.gov/18540211/)
- Cited evidence (PMID 20381122) [PMID:20381122](https://pubmed.ncbi.nlm.nih.gov/20381122/)
- Cited evidence (PMID 34662957) [PMID:34662957](https://pubmed.ncbi.nlm.nih.gov/34662957/)
- Cited evidence (PMID 30801893) [PMID:30801893](https://pubmed.ncbi.nlm.nih.gov/30801893/)

Last reconciled with current guidelines: 2026-05-16.
References
  • Strawn et al. Am J Psychiatry 2007 NMS consensus + 2024-2025 critical-care toxicology / psychiatry reviews of NMS and parkinsonism-hyperpyrexia syndrome; DSM-5 NMS diagnostic criteria — PMID:17541044
  • Cited evidence (PMID 18540211) — PMID:18540211
  • Cited evidence (PMID 20381122) — PMID:20381122
  • Cited evidence (PMID 34662957) — PMID:34662957
  • Cited evidence (PMID 30801893) — PMID:30801893