12-phase flow (12)

1. 1FRAME
   Neuroleptic Malignant Syndrome (NMS) = drug-induced toxidrome from idiosyncratic reaction to antipsychotic (AP) D2 blockade — typical (haloperidol > fluphenazine) > atypical (olanzapine, risperidone, quetiapine, aripiprazole, paliperidone, lurasidone) > clozapine (rare); also anti-emetic D2 blockers (metoclopramide, prochlorperazine, droperidol); LAI depot AP; dopamine-agonist withdrawal (Parkinsonism-hyperpyrexia syndrome). Tetrad = severe rigidity + hyperthermia + autonomic instability + altered MS (stupor/mutism/catatonic). Diagnosis via DSM-5-TR 2022 + Levenson 1985 criteria. Pharmacology pivot: STOP all AP IMMEDIATELY; ICU + supportive (cooling + IV hydration); benzodiazepine (lorazepam) for agitation + neuromuscular control; dantrolene 1-2.5 mg/kg IV q6h for severe rigidity + hyperthermia + rhabdo; bromocriptine 2.5 mg PO TID titrate up to 7.5 mg TID for D2 agonism (opposes AP blockade); ECT rescue for refractory or catatonia-NMS continuum (Fink + Taylor). AVOID succinylcholine (rhabdo hyperK; use rocuronium), re-introduction of offending AP without 2-week wash-out (~ 30% recurrence per Pope 1991), abrupt clozapine discontinuation (withdrawal NMS), parenteral AP during NMS (extends syndrome), dopamine antagonist anti-emetics during acute NMS (extends syndrome — use ondansetron) (Strawn AJP 2007 PMID 17541055).
   inputs: temperature, heart_rate, sbp, current_meds_full_antipsychotic_review
   advance: NMS diagnosis confirmed by DSM-5-TR criteria + AP exposure within 72 h to 2 weeks documented (DSM-5-TR 2022; Strawn AJP 2007)
2. 2ENTRY
   Recognise tetrad (severe rigidity + hyperthermia + autonomic instability + AMS) + AP exposure within 72 h to 2 weeks; IV access + cardiac monitor + STOP all AP (mandatory first step per Strawn AJP 2007)
   inputs: age, temperature, current_meds_full_antipsychotic_review
   advance: All AP discontinued + IV access established + cooling initiated if T > 38.5°C + ICU consultation requested
3. 3CONTEXT
   Comprehensive medication reconciliation incl. typical AP (haloperidol, fluphenazine, chlorpromazine), atypical AP (olanzapine, risperidone, quetiapine, aripiprazole, paliperidone, lurasidone, ziprasidone, clozapine), LAI depot AP (washout impossible — supportive duration extended by weeks), anti-emetic D2 blockers (metoclopramide, prochlorperazine, droperidol, promethazine — frequent unrecognised trigger), VMAT2 inhibitors (tetrabenazine, deutetrabenazine, valbenazine), and recently discontinued dopamine agonists (levodopa, pramipexole, ropinirole) or clozapine (withdrawal NMS); duration of AP therapy + recent dose changes + parenteral/IM administration + co-morbidities (psychosis, bipolar, depression with adjunctive AP, Parkinson disease, Huntington disease); pregnancy status; prior NMS history (recurrence ~ 30% — chart-flag mandatory)
   inputs: age, sex_and_pregnancy_status, current_meds_full_antipsychotic_review
   advance: Complete med rec + DSM-5-TR criteria scored + trigger AP identified + LAI depot exposure assessed (Strawn AJP 2007; DSM-5-TR 2022)
4. 4RED_FLAGS
   Hyperthermia > 41°C → aggressive cooling + intubation + paralysis (rocuronium, AVOID succinylcholine) + benzo infusion (life-threatening; mortality 5-20% if untreated). Rhabdomyolysis-AKI → aggressive IV fluids + alkalinization + serial CK monitoring; CRRT if AKI severe. DIC (PT/PTT prolonged + thrombocytopenia + D-dimer elevated) → ICU + supportive. ARDS → mechanical ventilation + lung-protective settings. Cardiac arrhythmia from autonomic instability + electrolyte derangement → telemetry + treat reversible causes (do NOT use droperidol / haloperidol for arrhythmia). Concurrent serotonin syndrome differential if patient on AP + serotonergic agent — route via workup.hyperthermic_toxidromes. Catatonia-NMS continuum suspected (stupor + mutism + waxy flexibility + posturing) → benzo lorazepam challenge + ECT consideration
   inputs: temperature, sbp, creatine_kinase, creatinine
   actions: workup.hyperthermic_toxidromes, workup.severe_agitation
   advance: RED flags screened + life-threats addressed + diagnosis differentiated from serotonin syndrome / malignant catatonia / malignant hyperthermia / sepsis (Strawn AJP 2007; DSM-5-TR 2022)
5. 5INITIAL_WORKUP
   DSM-5-TR criteria scoring + complete neuromuscular exam (lead-pipe rigidity, hyporeflexia, no clonus); ECG (QTc baseline); CK + Cr + lactate + BMP + Mg + glucose + CBC + LFT (dantrolene hepatotoxicity baseline); UA dipstick (myoglobinuria); CT head if focal deficit (exclude ICH from HTN sympathetic surge OR structural cause of AMS); UDS to rule out illicit co-ingestants (sympathomimetics, serotonergic agents); LP if febrile AMS differential includes meningoencephalitis (after CT head)
   inputs: ecg_12_lead, creatine_kinase, creatinine, severe_muscle_rigidity_lead_pipe, mental_status_stupor_mutism_catatonic, autonomic_instability_features
   actions: workup.encephalopathy
   advance: Workup documented + DSM-5-TR criteria scored + alternative diagnoses (serotonin syndrome, malignant catatonia, malignant hyperthermia, sepsis, encephalitis, drug toxicity) excluded (Strawn AJP 2007; Levenson AJP 1985)
6. 6BRANCHING_WORKUP
   Mild NMS (early — CK rising, mild rigidity, no hyperthermia): STOP AP + IV fluids + observation; may progress — close monitoring. Moderate NMS (T 38-40°C + rigidity + autonomic + AMS): STOP AP + ICU consultation + benzo + dantrolene (if severe rigidity / CK > 1000) + bromocriptine. Severe NMS (T > 41°C + rhabdo + multi-organ): ICU + intubation + paralysis (rocuronium) + active cooling + dantrolene + bromocriptine NG + supportive organ support. Catatonia-NMS continuum suspected: benzo lorazepam challenge (2 mg IV) + ECT consideration. LAI depot exposure: supportive duration extended by weeks (no washout). Clozapine withdrawal-related NMS: restart clozapine cautiously OR transition to ECT. Dopamine-agonist withdrawal NMS (Parkinsonism-hyperpyrexia): restart agonist + supportive
   advance: Severity stratified + parallel diagnostic workup obtained when triggered (Strawn AJP 2007)
7. 7DIFFERENTIAL
   NMS vs serotonin syndrome (serotonergic agent + hours onset + clonus + hyperreflexia + agitation + diarrhoea + mydriasis; treatment = benzo + cyproheptadine — bromocriptine WORSENS SS) vs malignant catatonia (catatonic features dominant; lorazepam challenge + ECT — continuum with NMS per Fink + Taylor 2003) vs malignant hyperthermia (volatile anaesthetic exposure + masseter rigidity + ↑↑↑ CK + ↑↑↑ EtCO2; treatment = dantrolene + discontinue trigger) vs anticholinergic toxidrome (mydriasis + dry skin + urinary retention + delirium WITHOUT severe rigidity) vs sympathomimetic (MDMA / cocaine / methamphetamine + mydriasis + tachycardia + HTN + agitation) vs sepsis-driven encephalopathy (procalcitonin + culture + lactate; AP exposure incidental) vs heat stroke (environmental / exertional history) vs thyroid storm (TSH suppressed + Burch-Wartofsky score) vs serotonin-norepinephrine reuptake inhibitor withdrawal (less severe, more SSRI-discontinuation-syndrome features)
   advance: Working diagnosis assigned + alternative diagnoses excluded (Strawn AJP 2007; DSM-5-TR 2022; Boyer NEJM 2005 PMID 15784664 for SS differential)
8. 8RISK_STRATIFICATION
   Severity tier: mild (early — CK rising, mild rigidity, no hyperthermia) → STOP AP + observation + supportive; moderate (T 38-40°C + rigidity + autonomic + AMS) → ED → ICU/inpatient with dantrolene + bromocriptine; severe (T > 41°C + rhabdo + multi-organ + DIC) → ICU + intubation + paralysis + dantrolene + bromocriptine + supportive organ support. DSM-5-TR criteria positive → NMS diagnosis confirmed. Recurrence-risk stratification: prior NMS history (~ 30% recurrence on re-challenge); high-potency AP / rapid titration / parenteral AP / dehydration / agitation requiring restraints / hyperthermic environment / organic brain disease / lithium augmentation / post-partum status
   inputs: temperature, creatine_kinase
   advance: Severity tier + safety level + treatment selection documented (Strawn AJP 2007)
9. 9TREATMENT
   STEP 1 — STOP ALL antipsychotics IMMEDIATELY (mandatory; for LAI depot, washout is not possible — supportive duration extended; for dopamine-agonist withdrawal NMS, RESTART agonist). STEP 2 — ICU admission for severe NMS + supportive foundation: aggressive IV crystalloid (NS or LR 500-1000 mL bolus then maintenance 100-150 mL/h with UOP target > 1 mL/kg/h for rhabdo prophylaxis); passive + active cooling for hyperthermia (cooling blankets, ice packs, evaporative, surface cooling, cold IV fluids); DVT prophylaxis (mechanical + LMWH); electrolyte management. STEP 3 — Benzodiazepine: lorazepam 1-2 mg IV q 4-6 h for agitation + neuromuscular control + serves as lorazepam challenge for catatonia-NMS continuum (Fink + Taylor 2003). STEP 4 — Dantrolene 1-2.5 mg/kg IV q 6 h (max 10 mg/kg/day) for severe rigidity + hyperthermia + rhabdo (Strawn AJP 2007); LFT baseline + serial monitoring (hepatotoxicity black box warning); taper after symptom resolution. STEP 5 — Bromocriptine 2.5 mg PO/NG TID, titrate up to 7.5 mg TID (max 45 mg/day) for D2 agonism opposing AP blockade — effective for autonomic instability + AMS; continue 10 days after resolution then taper to prevent rebound (Strawn AJP 2007). STEP 6 — Amantadine 100 mg PO BID as alternative or adjunct to bromocriptine — indirect dopaminergic + NMDA antagonist; useful when bromocriptine not tolerated. STEP 7 — ECT (electroconvulsive therapy) rescue for refractory NMS after 7-10 days of dantrolene + bromocriptine OR catatonia-NMS continuum (Fink + Taylor 2003) OR ongoing AP required + recurrence prevention; 6-10 bilateral sessions; effective in 60-80% of refractory cases. AVOID succinylcholine (rhabdo hyperK — use rocuronium; sugammadex available for reversal); AVOID re-introduction of offending AP without 2-week wash-out + alternative AP class + low dose + slow titration (recurrence ~ 30% per Pope 1991); AVOID abrupt clozapine discontinuation (withdrawal NMS — restart cautiously OR transition to ECT); AVOID dopamine antagonist anti-emetics (metoclopramide / prochlorperazine / droperidol) during acute NMS — use ondansetron.
   inputs: temperature, heart_rate, sbp, dbp, creatine_kinase
   advance: All AP stopped + ICU admitted (if severe) + IV fluids running + cooling initiated + benzo + dantrolene + bromocriptine started + CK trending down + temp < 38.5°C (Strawn AJP 2007)
10. 10DISPOSITION
    ICU for severe NMS (T > 41°C, rhabdo with CK > 5000, multi-organ involvement, intubation, paralysis, dantrolene IV, bromocriptine NG). Inpatient med-psych for moderate NMS resolving with dantrolene + bromocriptine + medication reconciliation + psych consult for alternative AP regimen + chart-flag in EHR. ED observation 24-48 h for mild NMS resolving with STOP AP + supportive — not typical disposition (most NMS requires admission). Outpatient follow-up at 1 week with primary psychiatry / PCP for medication review + alternative AP regimen counselling + chart-flag in EHR allergy/ADR list permanent
    advance: Level of care set + chart-flag in EHR for recurrence prevention (Strawn AJP 2007; Pope 1991)
11. 11MONITORING
    Continuous ECG + telemetry (autonomic instability arrhythmia risk); q 15-30 min BP + temp until stable; serial neuromuscular exam q 2-4 h (rigidity resolution); CK q 6 h until trending down; UOP target > 1 mL/kg/h if rhabdo; Cr q 12 h (AKI monitoring during dantrolene); mental status reassessment q 1 h initially; LFT q 24 h during dantrolene course (hepatotoxicity); CBC + electrolytes + acid-base q 6-12 h until stable; sedation level + airway protection assessment q 2 h if intubated. Resolution criteria: T < 38°C + rigidity resolved + autonomic features resolved + AMS resolved + CK trending down to baseline (Strawn AJP 2007; typically 1-2 weeks)
    inputs: temperature, heart_rate, creatine_kinase
    advance: BP at target + temp normal + rigidity resolved + CK trending down + mental status improving (Strawn AJP 2007)
12. 12FOLLOWUP
    Comprehensive medication review at discharge + alternative AP regimen counselling (atypical preferred if typical was trigger; low-potency preferred if high-potency was trigger; clozapine sometimes used as the lowest-NMS-risk agent for required AP; 2-week wash-out + low starting dose + slow titration); psychiatry consult for AP regimen continuation if psychosis / bipolar / treatment-resistant depression with adjunctive AP; pharmacy MTM for NMS-prevention education; document NMS in EHR allergy/ADR list + chart-flag permanent (recurrence ~ 30%); pain medicine consult NOT required (NMS is not chronic pain); if Parkinson disease, restart dopamine agonist post-resolution; outpatient PCP / psychiatry follow-up at 1 week + 1 month + q 1-3 months; patient + caregiver education on NMS recognition + 24-h ED return precaution; recurrence-prevention counselling (alternative AP regimen, slow titration, chart-flag at every visit) (Strawn AJP 2007; Pope 1991)
    advance: Alternative AP regimen documented + ADR documented + chart-flag in EHR + follow-up booked + patient/caregiver education completed (Strawn AJP 2007)