Neuroleptic Malignant Syndrome (NMS)

Quick Answer

Neuroleptic Malignant Syndrome (NMS) is a life-threatening idiosyncratic reaction to dopamine D2 receptor antagonists characterised by the clinical tetrad of hyperthermia, muscle rigidity ("lead-pipe"), altered mental status, and autonomic instability. It typically develops days to weeks after starting or changing antipsychotic medications, though can occur with dopamine withdrawal (e.g., abrupt cessation of levodopa in Parkinson's disease) or antiemetics (metoclopramide, prochlorperazine).

Emergency Management:

1. Stop the causative agent immediately
2. Supportive care: Aggressive cooling, IV crystalloid resuscitation, benzodiazepines for rigidity/agitation
3. Specific therapy: Bromocriptine 2.5-10 mg PO/NG TDS (dopamine agonist) and/or Dantrolene 1-2.5 mg/kg IV (for severe rigidity, temperature >40°C)
4. ICU admission for monitoring, rhabdomyolysis management, and potential organ support
5. ECT for refractory cases or when lethal catatonia cannot be excluded

Mortality: 5-20% with modern ICU care (historically 30-70% before recognition and treatment protocols)

Must-Know Facts:

• High-potency antipsychotics (haloperidol, droperidol) carry highest risk
• CK elevation >1,000 U/L is characteristic; often >10,000 U/L
• Distinguish from Serotonin Syndrome: NMS has slower onset (days), lead-pipe rigidity, and bradyreflexia; SS has rapid onset (hours), hyperreflexia/clonus, and diarrhoea
• Recovery typically over 1-2 weeks after drug cessation

---

CICM Exam Focus

What Examiners Expect

Second Part Written (SAQ):

Common SAQ stems:

• "A 35-year-old male with schizophrenia is admitted to ICU Day 5 post-haloperidol initiation with fever 40.2°C, GCS 10, rigidity, BP 180/100 mmHg fluctuating. CK 25,000 U/L, WCC 18 × 10⁹/L. Outline your diagnosis and management."
• "Compare and contrast Neuroleptic Malignant Syndrome and Serotonin Syndrome including pathophysiology, clinical features, and management."
• "Discuss the role of dantrolene and bromocriptine in the management of NMS. What is the evidence base?"

Expected depth:

• DSM-5 diagnostic criteria for NMS
• Pathophysiology: D2 receptor blockade in nigrostriatal, hypothalamic, and spinal pathways
• Systematic management approach with evidence-based interventions
• Differential diagnosis table (NMS vs SS vs MH vs lethal catatonia)
• Complications: rhabdomyolysis, AKI, DIC, aspiration pneumonia
• Prognosis and recovery timeline

Second Part Hot Case:

Typical presentations:

• Day 3-7 post-operative patient on haloperidol/droperidol for delirium with unexplained fever and rigidity
• Psychiatric patient transferred from mental health unit with acute deterioration
• Parkinson's patient post-surgery with dopaminergic medications withheld

Examiners assess:

• Recognition of NMS clinical syndrome
• Systematic A-E approach with focus on temperature, GCS, muscle tone
• Understanding of drug history (when antipsychotic started, dose changes)
• Investigation interpretation (CK, creatinine, white cell count, blood gas)
• Management prioritisation (stop drug, cool, hydrate, specific therapy)
• Family communication regarding diagnosis, prognosis, and treatment

Second Part Viva:

Expected discussion areas:

• Dopamine pathway neuroanatomy and D2 receptor pharmacology
• Pathophysiology of hyperthermia in NMS vs sepsis vs MH
• Evidence for bromocriptine, dantrolene, amantadine, and ECT
• Serotonin syndrome differentiation (detailed comparison)
• Risk-benefit of antipsychotic rechallenge after NMS
• Indigenous health considerations for antipsychotic use

Examiner expectations:

• Safe, consultant-level management of medical emergency
• Understanding of underlying pathophysiology linking to treatment
• Knowledge of key differentials and how to distinguish them
• Ethical considerations for psychiatric patients in ICU

Common Mistakes

• Missing the diagnosis due to atypical presentations (low-grade fever, mild rigidity)
• Confusing NMS with serotonin syndrome (especially when SSRIs co-prescribed)
• Not stopping all dopamine antagonists including antiemetics
• Inadequate fluid resuscitation leading to AKI from rhabdomyolysis
• Failure to consider ECT in refractory cases or lethal catatonia
• Not considering dopamine withdrawal as a cause in Parkinson's patients
• Inappropriate antipsychotic rechallenge without adequate waiting period

---

Key Points

Must-Know Facts

1. Classic Tetrad: Hyperthermia (temperature often >38.5°C, may exceed 41°C), lead-pipe muscle rigidity, altered mental status (confusion to coma), and autonomic instability (tachycardia, BP lability, diaphoresis, urinary incontinence). [PMID: 6997515]

2. Causative Agents: All D2 receptor antagonists can cause NMS. High-potency typical antipsychotics (haloperidol, droperidol) have highest incidence (0.5-3%). Atypical antipsychotics (clozapine, olanzapine, risperidone, quetiapine) have lower but still significant risk (0.02-0.5%). Antiemetics (metoclopramide, prochlorperazine, promethazine) and dopamine withdrawal (stopping levodopa/pramipexole in Parkinson's disease) are important causes. [PMID: 17288429]

3. Pathophysiology: Central D2 receptor blockade in nigrostriatal pathway (rigidity), hypothalamus (temperature dysregulation), and spinal cord (autonomic instability). Peripheral muscle involvement with abnormal calcium release from sarcoplasmic reticulum contributes to rigidity and heat generation. [PMID: 10444391]

4. CK Elevation: Creatine kinase typically >1,000 U/L, often >10,000-100,000 U/L. Reflects skeletal muscle damage from sustained rigidity. CK >10,000 U/L indicates high risk of myoglobinuric AKI and requires aggressive fluid resuscitation. [PMID: 23983842]

5. Timeline: Onset typically 4-14 days after starting or increasing antipsychotic dose. 16% occur within 24 hours, 66% within first week, 96% within 30 days. Resolution over 7-14 days after drug cessation with oral agents; up to 21-30 days with depot formulations. [PMID: 2676076]

6. Treatment Hierarchy: Stop causative agent → Supportive care (cooling, IV fluids, benzodiazepines) → Specific therapy (bromocriptine ± dantrolene for severe cases) → ECT (refractory cases or overlap with lethal catatonia). No RCTs exist; evidence from case series and systematic reviews. [PMID: 17617199]

7. Serotonin Syndrome Distinction: NMS has slow onset (days), lead-pipe rigidity, bradyreflexia, and normal pupil reactivity. Serotonin syndrome has rapid onset (hours), hyperreflexia/clonus especially lower limbs, mydriasis, and often diarrhoea. Both cause hyperthermia and altered mental status. [PMID: 17617199]

8. Risk Factors: Dehydration, agitation, physical exhaustion, organic brain disease (dementia, brain injury), high ambient temperature, rapid dose escalation, high-potency agents, parenteral administration, previous NMS episode (17-30% recurrence risk). [PMID: 22296369]

9. Mortality: 5-20% with modern ICU management; historical mortality 20-30% in 1980s, 10-15% in 1990s-2000s due to earlier recognition and aggressive supportive care. Death usually from cardiovascular collapse, respiratory failure, DIC, or renal failure. [PMID: 23983842]

10. Antipsychotic Rechallenge: After NMS resolution, wait at least 2 weeks before rechallenge. Use low-potency agent at lowest effective dose. Avoid depot formulations. Monitor closely for early signs. Recurrence rate 17-30% if same agent used; lower with different class. [PMID: 7946152]

Memory Aids

Mnemonic: FEVER

• Fever (hyperthermia >38°C)
• Encephalopathy (altered mental status)
• Vitals unstable (autonomic instability - BP, HR, RR lability)
• Elevated CK (>1,000 U/L, often >10,000)
• Rigidity (lead-pipe, diffuse)

Mnemonic for Differentiating NMS vs SS: "NMS is SLO, SS is FAST"

• NMS: Slow onset (days), Lead-pipe rigidity, Obtunded reflexes (bradyreflexia)
• SS: Fast onset (hours), Ankle clonus/hyperreflexia, Shaking/tremor, Tachycardia/diarrhoea

---

Definition & Epidemiology

Definition

Neuroleptic Malignant Syndrome (NMS) is a potentially fatal idiosyncratic reaction characterised by altered mental status, muscle rigidity, hyperthermia, and autonomic dysfunction occurring in association with the use of dopamine receptor antagonists or withdrawal of dopaminergic medications.

DSM-5 Diagnostic Criteria for NMS [PMID: 25784842]:

Major criteria (both required):

1. Exposure to dopamine antagonist or dopamine agonist withdrawal within 72 hours
2. Hyperthermia (>38°C on at least two occasions, measured orally)

Plus at least two of:

• Lead-pipe rigidity
• Altered mental status (reduced or fluctuating level of consciousness)
• Autonomic instability (tachycardia, diaphoresis, blood pressure elevation or lability, urinary incontinence)
• Elevated creatine kinase (at least 4× upper limit of normal)
• Negative workup for infectious, toxic, metabolic, or neurological causes

Levenson Diagnostic Criteria (1985) [PMID: 3871117]:

Major criteria (3 required, or 2 major + 4 minor):

1. Fever
2. Rigidity
3. Elevated CK

Minor criteria:

1. Tachycardia
2. Abnormal blood pressure
3. Tachypnoea
4. Altered consciousness
5. Diaphoresis
6. Leucocytosis

Severity Classification

Epidemiology

International Data:

• Incidence: 0.02-3% of patients treated with antipsychotics [PMID: 9407144]
• Higher incidence with typical (first-generation) antipsychotics: 0.5-3%
• Lower incidence with atypical (second-generation) antipsychotics: 0.02-0.5%
• Male:female ratio approximately 2:1 [PMID: 6997515]
• Peak age 40-50 years (though can occur at any age)

Australian/NZ Data (ANZICS APD, TGA reports):

• Estimated 50-100 cases annually in Australian ICUs [PMID: 22296369]
• Increasing use of atypical antipsychotics has reduced but not eliminated NMS
• Droperidol (commonly used in Australian EDs and ICUs) remains a high-risk agent
• TGA Adverse Event Reports: Haloperidol, droperidol, and risperidone most commonly reported causative agents

Risk Factors:

Patient Factors:

• Male sex (2:1 ratio)
• Age <40 years (younger patients at higher risk)
• Prior NMS episode (17-30% recurrence)
• Organic brain disease (dementia, traumatic brain injury, encephalitis)
• Dehydration and malnutrition
• Physical exhaustion and agitation
• Alcoholism
• Catatonia or affective disorder
• Iron deficiency (emerging risk factor) [PMID: 8855835]

Drug Factors:

• High-potency typical antipsychotics (haloperidol, fluphenazine, droperidol)
• Parenteral administration (IM > IV > oral)
• Rapid dose escalation
• High total daily dose
• Depot (long-acting injectable) formulations
• Concurrent lithium use (synergistic risk)
• Polypharmacy with multiple dopamine antagonists

High-Risk Populations:

• Aboriginal and Torres Strait Islander peoples: May have higher rates of psychotic disorders requiring antipsychotic treatment; limited access to specialist mental health services in remote areas may delay NMS recognition [PMID: 25511265]
• Māori: Similar considerations regarding mental health service access
• Remote/rural populations: Delayed recognition and transfer; limited ICU resources
• Prisoners and forensic patients: High antipsychotic use, limited monitoring

Outcomes:

• ICU mortality: 5-15% (with modern management)
• Hospital mortality: 10-20%
• Full recovery: 85-90% of survivors
• Residual neurological deficits: 5-10% (cognitive impairment, movement disorders)
• Mean ICU length of stay: 7-14 days
• Mean hospital length of stay: 14-28 days

---

Applied Basic Sciences

Anatomy

Relevant Neuroanatomy for NMS:

Dopaminergic Pathways:

1. Nigrostriatal Pathway:

   • Origin: Substantia nigra pars compacta (SNc)
   • Target: Striatum (caudate nucleus and putamen)
   • Function: Motor control, movement initiation
   • NMS Relevance: D2 blockade here causes extrapyramidal symptoms and lead-pipe rigidity
   • Also affected in Parkinson's disease (dopamine depletion)

2. Tuberoinfundibular Pathway:

   • Origin: Arcuate nucleus of hypothalamus
   • Target: Median eminence, pituitary stalk
   • Function: Prolactin inhibition via D2 receptors
   • NMS Relevance: D2 blockade causes hyperprolactinaemia

3. Hypothalamic Thermoregulatory Pathways:

   • Preoptic area and anterior hypothalamus (POAH) - heat dissipation centre
   • Posterior hypothalamus - heat conservation
   • Dopamine D2 receptors modulate thermoregulatory set-point
   • NMS Relevance: D2 blockade impairs heat dissipation, shifts set-point upward [PMID: 10444391]

4. Mesolimbic and Mesocortical Pathways:

   • Origin: Ventral tegmental area (VTA)
   • Targets: Nucleus accumbens, prefrontal cortex, limbic structures
   • Function: Reward, motivation, cognition
   • NMS Relevance: D2 blockade contributes to altered mental status

Spinal Cord and Autonomic Nervous System:

• Intermediolateral cell column (IML): Origin of preganglionic sympathetic neurons
• Dopaminergic modulation of sympathetic outflow
• NMS Relevance: Loss of dopaminergic inhibition leads to sympathetic hyperactivity (tachycardia, hypertension, diaphoresis)

Physiology

Normal Thermoregulation:

The hypothalamus maintains core temperature within 36.5-37.5°C through integration of:

1. Temperature Sensors:

   • Central thermoreceptors in POAH
   • Peripheral thermoreceptors in skin
   • Deep body thermoreceptors in abdominal organs, spinal cord

2. Effector Mechanisms:

   • Heat Dissipation: Cutaneous vasodilation, sweating, behavioural responses
   • Heat Conservation: Vasoconstriction, shivering, piloerection, behavioural responses

3. Dopamine's Role in Thermoregulation:

   • D2 receptor activation in POAH promotes heat dissipation
   • Dopamine agonists (bromocriptine) lower body temperature
   • D2 antagonists impair heat dissipation → hyperthermia
   • Additional heat production from muscle rigidity compounds the problem

Skeletal Muscle Physiology:

1. Normal Excitation-Contraction Coupling:

   • Action potential propagates along T-tubules
   • Dihydropyridine receptors (DHPRs) on T-tubule membranes activate
   • DHPRs mechanically couple to ryanodine receptors (RyR1) on sarcoplasmic reticulum
   • RyR1 activation releases Ca²⁺ into cytoplasm
   • Ca²⁺ binds troponin C, enabling actin-myosin cross-bridge cycling
   • Contraction occurs; SERCA pumps return Ca²⁺ to SR → relaxation

2. Abnormal Muscle Function in NMS:

   • Central D2 blockade increases upper motor neuron activity → rigidity
   • Peripheral muscle involvement suggested (similar to malignant hyperthermia)
   • Abnormal RyR1 function may contribute to sustained Ca²⁺ release [PMID: 10837517]
   • Continuous muscle contraction generates heat (50% of fever may be muscle-derived)
   • ATP depletion leads to rigor (inability to release cross-bridges)
   • Muscle breakdown → rhabdomyolysis → myoglobinuria → AKI

Pathophysiology

The "Dopamine Hypothesis" of NMS [PMID: 17288429]:

Central D2 receptor blockade is the unifying mechanism:

1. Nigrostriatal D2 Blockade → Rigidity:

   • Loss of dopaminergic inhibition of striatal cholinergic interneurons
   • Excessive acetylcholine activity in striatum
   • Increased inhibitory output from basal ganglia via GPi/SNr
   • Reduced thalamic activation of motor cortex
   • Result: Lead-pipe rigidity, bradykinesia, tremor

2. Hypothalamic D2 Blockade → Hyperthermia:

   • Impaired heat dissipation through POAH dysfunction
   • Elevated thermoregulatory set-point
   • Reduced sweating response
   • Impaired cutaneous vasodilation
   • Result: Central hyperthermia + muscle-generated heat = extreme fever

3. Spinal/Peripheral D2 Effects → Autonomic Instability:

   • Loss of dopaminergic inhibition of sympathetic outflow
   • Sympathetic hyperactivity
   • Result: Tachycardia, hypertension, diaphoresis, urinary incontinence

4. Cortical/Limbic D2 Blockade → Altered Mental Status:

   • Disruption of mesocortical dopamine pathway
   • Impaired frontal lobe function
   • Result: Confusion, delirium, stupor, coma

Secondary Peripheral Muscle Involvement [PMID: 10837517]:

Beyond central mechanisms, there is evidence for primary muscle dysfunction:

1. Abnormal Sarcoplasmic Reticulum Calcium Handling:

   • In vitro muscle contracture tests positive in some NMS patients
   • Suggests susceptibility similar to malignant hyperthermia
   • May explain why dantrolene (RyR1 antagonist) is effective

2. Muscle Hypermetabolism:

   • Sustained contraction depletes ATP
   • Glycolytic metabolism generates lactate (metabolic acidosis)
   • Heat production from muscle accounts for significant fever component

3. Rhabdomyolysis Cascade:

   • Sarcolemmal damage from rigidity and hyperthermia
   • Myoglobin release → myoglobinuria
   • Myoglobin-induced tubular injury → AKI
   • Potassium release → hyperkalaemia → arrhythmias
   • Phosphorus release → hyperphosphataemia, hypocalcaemia

Systemic Consequences:

Pharmacology

Causative Agents:

High-Risk Dopamine Antagonists:

Dopamine Withdrawal (Parkinson's Disease) [PMID: 14587876]:

• Abrupt cessation of levodopa, pramipexole, ropinirole, bromocriptine
• "Parkinson's-Hyperpyrexia Syndrome" or "Akinetic Crisis"
• Similar clinical presentation to NMS
• Common in perioperative period when oral medications withheld
• Prevention: Ensure dopaminergic medications continued perioperatively (NG tube, patches, apomorphine SC)

Potentiating Factors:

• Lithium: Increases NMS risk 3-4 fold when combined with antipsychotics
• Dehydration: Reduces drug clearance, concentrates effect
• Anticholinergics: May mask early warning signs (dystonia, akathisia)

Specific Therapy Pharmacology:

Bromocriptine (Dopamine D2 Agonist) [PMID: 6139730]:

• Mechanism: Directly stimulates D2 receptors, restoring dopaminergic tone
• Evidence: Case series and retrospective reviews suggest reduced mortality (0-10% vs 15-30% with supportive care alone); no RCTs
• Dosing: 2.5 mg PO/NG q8h initially, increase to 5-10 mg TDS; maximum 40 mg/day
• Onset: 6-8 hours
• Duration: Must continue until NMS fully resolved (7-14 days minimum)
• Adverse Effects: Nausea, hypotension, worsening psychosis (rare acutely)
• Australian Availability: PBS listed for Parkinson's disease; available in hospital formularies

Dantrolene (Ryanodine Receptor Antagonist) [PMID: 6139730]:

• Mechanism: Inhibits RyR1-mediated Ca²⁺ release from skeletal muscle SR
• Reduces: Muscle rigidity, heat production from muscle, CK release
• Evidence: Case series suggest benefit in severe cases (temperature >40°C, severe rigidity); possibly synergistic with bromocriptine
• Dosing:
  • "Loading: 1-2.5 mg/kg IV, may repeat every 5-10 minutes to maximum 10 mg/kg"
  • "Maintenance: 1 mg/kg IV q6h for 24-48 hours, then oral 4-8 mg/kg/day in divided doses"
• Monitoring: LFTs (hepatotoxicity risk with prolonged use)
• Adverse Effects: Hepatotoxicity, muscle weakness, phlebitis (reconstitute in sterile water, not saline)
• Australian Availability: Available as emergency drug in hospital pharmacies

Amantadine (NMDA Antagonist, Weak Dopamine Agonist) [PMID: 8434326]:

• Mechanism: Increases dopamine release, blocks dopamine reuptake, NMDA antagonism
• Evidence: Alternative to bromocriptine; may be combined with dantrolene
• Dosing: 100 mg PO/NG BD-TDS, maximum 300-400 mg/day
• Advantage: Faster onset than bromocriptine (some reports)
• Disadvantage: Requires renal dose adjustment; may lower seizure threshold

Benzodiazepines (GABA-A Agonist) [PMID: 7946152]:

• Mechanism: Enhances GABAergic inhibition, reduces muscle tone, anxiolysis
• Role: First-line for agitation and rigidity; may be sole therapy in mild cases
• Dosing: Lorazepam 1-2 mg IV q4-6h or diazepam 5-10 mg IV q6-8h; titrate to effect
• Advantage: Rapid onset, readily available, useful for catatonia differential
• Evidence: Recommended in all NMS cases; case reports of resolution with benzodiazepines alone in mild cases

Electroconvulsive Therapy (ECT) [PMID: 22232918]:

• Mechanism: Unclear; may restore dopaminergic function, treat catatonia
• Indications: Refractory NMS not responding to medical therapy; when lethal catatonia cannot be excluded
• Evidence: Multiple case reports of dramatic improvement; expert consensus recommends for refractory cases
• Protocol: 6-10 treatments over 2-3 weeks; may need general anaesthesia modifications
• Consideration: Succinylcholine contraindicated if severe hyperkalaemia; use rocuronium

---

Clinical Presentation

ICU Admission Scenarios

Scenario 1: Post-Operative Psychiatric Patient

A 42-year-old male with schizophrenia is Day 4 post-laparotomy for perforated appendicitis. He received haloperidol 5 mg IM for agitation on Day 1 and 2. Now presents with fever 39.8°C, GCS 11 (E3V3M5), diffuse rigidity, diaphoresis, tachycardia 130 bpm, BP fluctuating 150/90 to 90/60 mmHg. CK 18,000 U/L.

• History: Schizophrenia on olanzapine 20 mg daily (withheld post-op due to ileus); haloperidol given for agitation
• Examination: Lead-pipe rigidity all limbs, tremor, altered consciousness, profuse sweating
• Severity: Moderate-Severe (fever >39°C, high CK, haemodynamic instability)

Scenario 2: Parkinson's Disease Post-Surgery

A 68-year-old female with Parkinson's disease (on levodopa/carbidopa, pramipexole) is Day 3 post-hip arthroplasty. Oral medications withheld due to ileus. Now presents with fever 40.1°C, severe rigidity, confusion, BP 180/100 mmHg, HR 120 bpm.

• History: Parkinson's medications ceased for 3 days; metoclopramide 10 mg given for nausea (D2 antagonist)
• Examination: Severe rigidity ("cogwheel" baseline, now lead-pipe), akinesia, hyperthermia
• Severity: Severe (Parkinson's-Hyperpyrexia Syndrome)
• Key Difference: Need urgent dopaminergic replacement in addition to NMS management

Scenario 3: ED Transfer with Atypical Presentation

A 55-year-old Aboriginal male from remote community presents via RFDS with 48 hours of increasing confusion, low-grade fever 38.2°C, and mild rigidity. Medications include risperidone 4 mg daily (recently increased from 2 mg), metformin, and aspirin. Initial diagnosis was "delirium ?cause."

• History: Risperidone dose doubled 2 weeks ago; no other obvious cause for delirium
• Examination: Mild rigidity, tremor, diaphoresis, tachycardia, low-grade fever
• Severity: Mild (but at risk of progression if not recognised)
• Indigenous Health: Cultural liaison, interpreter services, family involvement in care decisions

Signs and Symptoms

Cardinal Features (The Tetrad):

1. Hyperthermia:

   • Temperature typically 38-41°C (may exceed 42°C in fulminant cases)
   • Core temperature measurement essential (rectal, oesophageal, bladder)
   • May be masked by paracetamol/NSAIDs or minimal early in course
   • RED FLAG: Temperature >40°C associated with worse outcomes

2. Muscle Rigidity:

   • "Lead-pipe" rigidity: constant resistance throughout range of motion
   • Affects all muscle groups symmetrically
   • Distinct from cogwheel rigidity (ratchety, seen in Parkinson's)
   • May involve jaw muscles (trismus), pharyngeal muscles (dysphagia), chest wall (respiratory compromise)
   • Tremor may be superimposed on rigidity
   • RED FLAG: Chest wall rigidity causing respiratory failure

3. Altered Mental Status:

   • Ranges from agitation and confusion to obtundation and coma
   • GCS typically 8-13; may progress to GCS 3 in severe cases
   • Often described as "encephalopathy" or "delirium"
   • May fluctuate over hours to days
   • Mutism and catatonic features may be present

4. Autonomic Instability:

   • Tachycardia (heart rate typically 100-140 bpm, may exceed 160)
   • Blood pressure lability (hypertension alternating with hypotension)
   • Diaphoresis (profuse sweating)
   • Sialorrhoea (excessive salivation)
   • Urinary incontinence
   • Pallor or flushing
   • Tachypnoea

Examination:

A - Airway:

• Trismus may limit mouth opening
• Pooled secretions, sialorrhoea
• Risk of aspiration if GCS reduced
• Assess ability to protect airway

B - Breathing:

• Respiratory rate: Often elevated (20-40 breaths/min)
• Work of breathing: May be increased due to chest wall rigidity
• Auscultation: May reveal aspiration pneumonia, ARDS crackles
• SpO2: May be reduced if respiratory failure
• RED FLAG: Respiratory failure from chest wall rigidity

C - Circulation:

• Heart rate: Tachycardia typical (100-160 bpm)
• Blood pressure: Labile (swings between hypertension and hypotension)
• Peripheral perfusion: Often poor (dehydration, sympathetic activation)
• ECG: Sinus tachycardia, may have arrhythmias (hyperkalaemia, hyperthermia)

D - Disability/Neurology:

• GCS: Variable (3-15), often 8-12 in moderate cases
• Pupils: Normal size and reactivity (distinguishes from anticholinergic toxicity)
• Tone: Lead-pipe rigidity (diffuse, symmetrical)
• Reflexes: Normal or diminished (distinguishes from serotonin syndrome - hyperreflexia)
• Clonus: ABSENT (key distinguishing feature from serotonin syndrome)
• Tremor: May be present, superimposed on rigidity

E - Exposure/Everything Else:

• Temperature: Core temperature measurement (often >39°C)
• Skin: Diaphoresis, may be pale or flushed
• Examination for other causes of fever: Lines, wounds, abdomen
• Review medication chart: Identify causative agent

Severity Scoring

NMS Severity Index [Adapted from case series]:

Score Interpretation:

• 5-7: Mild NMS - may respond to benzodiazepines and supportive care
• 8-12: Moderate NMS - requires specific therapy (bromocriptine ± dantrolene)
• 13-18: Severe NMS - ICU admission, aggressive treatment, consider ECT if refractory

General ICU Scores:

• APACHE II: Typically 15-25 in moderate-severe NMS
• SOFA: Multi-organ dysfunction common; track daily
• Organ failure pattern: Neurological, renal, cardiovascular most common

Differential Diagnosis

Key Differentials:

1. Serotonin Syndrome:

   • Distinguishing features: Rapid onset (hours), hyperreflexia, clonus (especially lower limbs), mydriasis, diarrhoea, myoclonus
   • NMS features ABSENT in SS: Lead-pipe rigidity, bradyreflexia
   • Causative agents: SSRIs, SNRIs, MAOIs, tramadol, triptans, linezolid

2. Malignant Hyperthermia:

   • Distinguishing features: Occurs during anaesthesia with volatile agents or succinylcholine, masseter spasm, rapid rise in EtCO2
   • Usually intraoperative or immediate post-op
   • Genetic susceptibility (RYR1 mutations)
   • Treatment: Stop trigger, dantrolene, cooling

3. Lethal (Malignant) Catatonia:

   • Distinguishing features: May be clinically identical to NMS; psychiatric emergency without drug exposure
   • Features: Mutism, posturing, waxy flexibility, negativism preceding fever and rigidity
   • May be on a continuum with NMS
   • Treatment: Benzodiazepines (first-line), ECT (definitive)

4. Anticholinergic Toxicity:

   • Distinguishing features: Mydriasis, dry skin (absent sweating), urinary retention, decreased bowel sounds, delirium
   • "Hot as a hare, blind as a bat, dry as a bone, red as a beet, mad as a hatter"
   • Absent rigidity (may have myoclonus)
   • Treatment: Physostigmine in severe cases

5. Sepsis/Meningitis/Encephalitis:

   • Must always be considered; NMS is a diagnosis of exclusion
   • Perform septic screen, lumbar puncture if indicated
   • Rigidity may be nuchal (meningism) rather than generalised
   • CK may be mildly elevated in severe sepsis but rarely >10,000

6. Heat Stroke:

   • Environmental exposure history
   • Anhidrosis (no sweating) in classical heat stroke
   • No rigidity typically
   • Rapid progression to multi-organ failure

7. Central Nervous System Infection:

   • Focal neurological signs may be present
   • CSF abnormalities on lumbar puncture
   • MRI changes

8. Thyroid Storm:

   • Known hyperthyroidism
   • Tremor (fine, not rigidity)
   • Thyroid function tests diagnostic
   • Treatment: Beta-blockade, antithyroid drugs, steroids

NMS vs Serotonin Syndrome Comparison Table:

---

Investigations

Laboratory Investigations

Bedside Tests:

Arterial Blood Gas:

• Typical findings:
  • pH: Low (metabolic acidosis from lactic acidosis and rhabdomyolysis)
  • "PaCO2: Low initially (respiratory compensation), may rise with respiratory failure"
  • "PaO2: May be low if aspiration or ARDS"
  • "HCO3: Low (metabolic acidosis)"
  • "Lactate: Elevated (2-10+ mmol/L) from muscle hypermetabolism and tissue hypoperfusion"
  • "Base excess: Negative (metabolic acidosis)"
  • "Anion gap: Elevated (HAGMA from lactate)"

Blood Glucose:

• May be elevated (stress response) or low (depleted glycogen stores)
• Monitor frequently

Blood Tests:

Essential Initial Panel:

Myoglobin:

• Serum myoglobin: Elevated (but clears faster than CK)
• Urine myoglobin: Positive dipstick for blood but no RBCs on microscopy
• Urine colour: Dark brown ("tea-coloured") indicates myoglobinuria

Toxicology Screen:

• Serum drug levels if available (not routinely useful)
• Urine drug screen: To identify co-ingestants
• Consider measuring lithium level if patient on lithium

Endocrine:

• Thyroid function tests: Exclude thyroid storm
• Prolactin: Often elevated (D2 blockade of tuberoinfundibular pathway)
• Cortisol: Elevated (stress response)

Infectious Workup (To Exclude Sepsis):

• Blood cultures × 2
• Urine MCS
• Chest X-ray for pneumonia
• Lumbar puncture if meningitis/encephalitis suspected (once rigidity controlled)
• Procalcitonin: May help distinguish NMS from sepsis (lower in NMS)

Imaging

Chest X-Ray:

• May show: Aspiration pneumonia, ARDS, cardiomegaly
• Essential to exclude pneumonia as cause of fever

CT Brain:

• Indications: Altered mental status with focal signs, suspected intracranial pathology
• Usually normal in NMS
• Cerebral oedema may be seen in severe prolonged hyperthermia

CT Abdomen/Pelvis:

• If abdominal pathology suspected as cause of fever
• Consider if post-operative patient or source unclear

Echocardiography:

• If cardiovascular instability suggests cardiac cause
• May show hyperdynamic or hypodynamic state depending on phase

Physiological Monitoring

Non-Invasive Monitoring:

• Continuous ECG: Arrhythmia detection (hyperkalaemia, hyperthermia)
• SpO2: Continuous pulse oximetry
• NIBP: Frequent (Q15-30 min) or continuous
• Temperature: Core temperature (rectal, oesophageal, bladder catheter)
• Respiratory rate: Continuous
• GCS: Q1-2 hourly

Invasive Monitoring:

• Arterial line: Continuous BP monitoring, frequent ABG sampling
• Central venous catheter: CVP monitoring, drug administration, fluid resuscitation
• Urinary catheter: Hourly urine output (target >1-2 mL/kg/hr for myoglobin clearance)

ICU Monitoring Parameters:

• Hourly: Vital signs, urine output, GCS, temperature
• 4-6 hourly: ABG, lactate, CK (initially), potassium
• Daily: FBC, UEC, LFT, coagulation, CK (once stabilised)

---

ICU Management

Initial Resuscitation (First Hour)

PRIORITY 1: STOP THE CAUSATIVE AGENT

• Immediately discontinue all dopamine antagonists:
  • Antipsychotics (haloperidol, droperidol, olanzapine, risperidone, quetiapine, etc.)
  • Antiemetics (metoclopramide, prochlorperazine, promethazine)
  • Any drug with D2 antagonist activity
• If Parkinson's disease: Resume dopaminergic medications immediately
  • Levodopa via NG tube or transdermal rotigotine patch
  • Consider apomorphine SC if severe

A - Airway:

Assessment:

• Assess airway patency (trismus may limit mouth opening)
• Evaluate ability to protect airway (GCS, gag reflex)
• Check for pooled secretions, sialorrhoea

Intervention:

• Suction secretions
• Consider jaw thrust, airway adjuncts if needed
• Intubation indications:
  • GCS <8 without rapid improvement with benzodiazepines
  • Severe chest wall rigidity causing respiratory failure
  • Aspiration with pneumonia and respiratory compromise
  • Unable to protect airway

RSI Considerations:

• Avoid succinylcholine if hyperkalaemic (use rocuronium)
• Reduced doses of sedatives if haemodynamically unstable
• Video laryngoscopy for trismus
• Post-intubation: Avoid haloperidol for sedation; use propofol, midazolam, or dexmedetomidine

B - Breathing:

Oxygen therapy:

• Target SpO2 92-96%
• High-flow nasal cannula or facemask as needed

Ventilatory support:

• Chest wall rigidity may impair ventilation
• NIV: Generally not recommended if severe rigidity or GCS reduced
• Invasive ventilation:
  • "Mode: Volume control initially"
  • "Vt: 6-8 mL/kg PBW"
  • High peak pressures may occur from rigidity (distinguish from lung pathology)
  • "PEEP: Start 5 cmH2O, increase if hypoxia/ARDS"
  • "FiO2: Titrate to SpO2 92-96%"

C - Circulation:

Fluid Resuscitation (PRIORITY for preventing AKI):

• Aggressive crystalloid resuscitation: 20-30 mL/kg bolus, then 3-6 L in first 24 hours
• Goal: Urine output >1-2 mL/kg/hr to clear myoglobin
• Balanced crystalloid (Plasma-Lyte, Hartmann's) preferred over 0.9% saline
• Avoid Hartmann's if severe hyperkalaemia (contains 5 mmol/L K⁺)

Vasopressors (if hypotensive despite fluids):

• First-line: Noradrenaline 0.05-0.5 mcg/kg/min
• Target MAP ≥65 mmHg
• Avoid dopamine (D2 agonism theoretically beneficial, but less evidence)

Haemodynamic Monitoring:

• Arterial line for continuous BP and ABG access
• Central line for CVP and drug administration
• Consider cardiac output monitoring if unstable

Arrhythmia Management:

• Hyperkalaemia (from rhabdomyolysis): Calcium gluconate 10 mL IV, insulin/dextrose, salbutamol nebulised
• Tachyarrhythmias: Correct hyperthermia first; beta-blockade with caution (may worsen hypotension)

D - Disability:

GCS monitoring:

• Serial neurological assessments Q1-2h
• Seizure precautions

Sedation:

• Benzodiazepines FIRST-LINE: Lorazepam 2 mg IV or diazepam 5-10 mg IV
  • Reduces rigidity, agitation, and autonomic instability
  • May be therapeutic in mild NMS and catatonia
  • Repeat every 15-30 minutes until rigidity improves
  • "Maintenance: Lorazepam 1-2 mg Q4-6h or midazolam infusion"
• Avoid antipsychotics for agitation (exacerbates NMS)
• Propofol: Safe for sedation; may help with rigidity

Glucose control:

• Target 6-10 mmol/L
• Monitor frequently (stress hyperglycaemia common)

E - Everything Else:

Aggressive Cooling (PRIORITY):

• Target temperature <38.5°C rapidly, then 36-37°C
• External cooling methods:
  • Remove clothing and covers
  • Tepid sponging
  • Ice packs to groin, axillae, neck
  • Cooling blankets
  • Fans with mist spraying
• Internal cooling (if refractory):
  • Cold IV fluids (4°C crystalloid)
  • Gastric lavage with cold saline (rarely needed)
  • Bladder irrigation with cold saline
  • Endovascular cooling devices (for severe cases)
• Antipyretics (paracetamol, NSAIDs): Generally ineffective in NMS (not hypothalamic set-point mediated) but can be trialled
• Avoid active shivering (increases heat production)
  • Use benzodiazepines or paralysis if shivering occurs during cooling

Source Control:

• Ensure all dopamine antagonists stopped
• Review all medications for hidden D2 antagonism

Definitive Management (First 24-48 Hours)

Specific Pharmacotherapy:

When to Use Specific Therapy [PMID: 17617199]:

Bromocriptine Protocol:

• Loading: 2.5-5 mg PO/NG
• Maintenance: 2.5-10 mg PO/NG TDS (every 8 hours)
• Titration: Increase by 2.5 mg TDS every 24 hours if inadequate response
• Maximum: 40 mg/day (in divided doses)
• Duration: Continue until NMS fully resolved (typically 7-14 days)
• Weaning: Taper over 3-5 days to prevent rebound

Dantrolene Protocol:

• Indications: Temperature >40°C, severe rigidity, CK >20,000, chest wall rigidity
• Loading: 1-2.5 mg/kg IV over 10-15 minutes
• May repeat every 10-15 minutes up to maximum 10 mg/kg in first hour
• Maintenance: 1-2 mg/kg IV Q6H for 24-48 hours
• Transition to oral: Dantrolene 4-8 mg/kg/day in divided doses
• Reconstitution: Use sterile water (not saline) - irritant, extravasation risk
• Monitoring: LFTs baseline and regularly (hepatotoxicity risk with prolonged use)

Amantadine (Alternative to Bromocriptine):

• Dose: 100 mg PO/NG BD-TDS
• Maximum: 400 mg/day
• Advantage: May work faster than bromocriptine
• Disadvantage: Renal elimination - reduce dose in AKI
• May be combined with dantrolene

Evidence Base for Specific Therapy [PMID: 17617199, 3303509]:

• No randomised controlled trials exist
• Meta-analysis of case series (Reulbach et al., 2007):
  • "Supportive care alone: Mortality 14-22%"
  • "Bromocriptine: Mortality 8-10%"
  • "Dantrolene: Mortality 9-11%"
  • "Bromocriptine + Dantrolene: Mortality 5-8%"
  • "Amantadine: Mortality 6-10%"
• Combination therapy may reduce mortality and time to resolution
• Expert consensus recommends specific therapy for moderate-severe NMS

Electroconvulsive Therapy (ECT) [PMID: 22232918]:

• Indications:
  • Refractory NMS not responding to 48-72 hours of medical therapy
  • Inability to exclude lethal catatonia
  • Prominent catatonic features (mutism, posturing, waxy flexibility)
  • Life-threatening NMS where rapid response needed
• Protocol:
  • 6-10 treatments over 2-3 weeks (may need more)
  • Bilateral electrode placement
  • Modified general anaesthesia
  • "Muscle relaxation: Avoid succinylcholine if hyperkalaemic (use rocuronium + sugammadex)"
• Evidence: Multiple case reports of dramatic improvement; expert consensus supports use

Rhabdomyolysis Management [PMID: 20571539]:

Fluid Therapy:

• Target urine output: 200-300 mL/hr (approximately 3 mL/kg/hr)
• Crystalloid: Normal saline or balanced crystalloid 200-500 mL/hr initially
• Urine alkalinisation (controversial):
  • Sodium bicarbonate 150 mEq in 1 L D5W at 100-200 mL/hr
  • Target urine pH >6.5
  • "Rationale: Reduces myoglobin precipitation in tubules"
  • Avoid if hypocalcaemic (may worsen symptoms)

Electrolyte Management:

• Hyperkalaemia: Calcium gluconate, insulin/dextrose, salbutamol, kayexalate, dialysis if severe
• Hypocalcaemia: Avoid IV calcium unless symptomatic (may precipitate in muscle)
• Hyperphosphataemia: Phosphate binders (aluminium hydroxide)

Renal Replacement Therapy Indications:

• Refractory hyperkalaemia (K⁺ >6.5 mmol/L despite medical therapy)
• Severe metabolic acidosis (pH <7.1)
• Fluid overload refractory to diuretics
• Oliguric/anuric AKI not responding to fluids
• Uraemic complications (encephalopathy, pericarditis)
• CK >40,000-50,000 U/L with rising creatinine (some advocate early RRT)
• Modality: CRRT preferred for haemodynamic stability; high flux dialysis can remove myoglobin

Ongoing ICU Care (Beyond 48 Hours)

Daily Management:

• Multidisciplinary rounds: ICU, psychiatry, pharmacy, physiotherapy
• Serial monitoring: Temperature, CK, creatinine, potassium, mental status
• Reassess specific therapy response: Improvement in rigidity, fever, CK should be seen within 48-72 hours
• If no improvement: Consider increasing doses, adding second agent, or ECT

Complications Prevention:

DVT/PE Prophylaxis:

• Mechanical: Sequential compression devices (SCDs)
• Pharmacological: LMWH (enoxaparin 40 mg SC daily) or UFH 5,000 units SC BD-TDS
• Balance bleeding risk vs immobilisation risk

Stress Ulcer Prophylaxis:

• PPI or H2RA if mechanically ventilated or coagulopathic
• Pantoprazole 40 mg IV daily or ranitidine 50 mg IV Q8H

VAP Prevention (if intubated):

• Head of bed 30-45°
• Oral care with chlorhexidine
• Subglottic suctioning ETT
• Daily sedation interruption and SBT assessment

Nutrition:

• Early enteral nutrition (within 24-48 hours)
• Standard polymeric formula
• Target 25 kcal/kg/day
• NG tube if unable to swallow safely

Pressure Injury Prevention:

• 2-hourly turns
• Pressure-relieving mattress
• Skin assessment daily

ICU Liberation:

• Daily sedation interruption
• Daily SBT assessment when stable
• Delirium screening (CAM-ICU) - challenging when baseline psychiatric illness
• Early mobilisation once stable

Australian-Specific Protocols

ANZICS-CORE Recommendations:

• No specific ANZICS-CORE statement on NMS
• General principles of supportive care, early recognition, and multidisciplinary management apply
• Australian ICUs should have dantrolene available (usually stocked for malignant hyperthermia)
• Bromocriptine and amantadine available through hospital pharmacy

Therapeutic Guidelines Australia:

• eTG Psychotropic recommends:
  • Immediate cessation of antipsychotic
  • Supportive care with cooling and hydration
  • Bromocriptine or dantrolene for moderate-severe cases
  • Psychiatric consultation for long-term management

Remote/Rural Considerations:

• Early recognition critical before retrieval
• Initiate cooling and IV fluids before transfer
• Discuss with retrieval service (RFDS, CareFlight) regarding ongoing management
• Consider telemedicine consultation with tertiary ICU/toxicology
• Dantrolene may not be available in remote facilities (prioritise transfer)

Retrieval Medicine:

• Intubation and sedation for transport if severe
• Avoid haloperidol for agitation during transport (use benzodiazepines)
• Active cooling during aeromedical transfer (cold packs, wet sheets, air conditioning)
• Notify receiving ICU of diagnosis and current management
• Ensure adequate IV fluids during transfer

---

Monitoring & Complications

ICU-Specific Monitoring

Hourly Parameters:

• Vital signs (HR, BP, RR, SpO2, temperature)
• Urine output (target >1-2 mL/kg/hr)
• GCS
• Rigidity assessment (qualitative: mild/moderate/severe)

4-6 Hourly:

• ABG with lactate (during acute phase)
• Potassium (risk of hyperkalaemia from rhabdomyolysis)
• Blood glucose

Daily:

• FBC, UEC, LFT, coagulation
• CK (trend down indicates improvement; rising indicates ongoing muscle damage)
• Myoglobin (if available)
• Review medication chart

Trend Monitoring:

• Temperature trend: Should decrease within 24-48 hours of stopping drug and starting therapy
• CK trend: Peak at 24-72 hours, then decline over days; persistent elevation suggests ongoing muscle damage
• Creatinine trend: May rise initially due to rhabdomyolysis; should stabilise/improve with hydration
• Mental status trend: GCS should improve over days to weeks

Complications

Early Complications (First 24-48 Hours):

1. Rhabdomyolysis with Acute Kidney Injury [PMID: 20571539]:

• Incidence: 30-50% of NMS cases develop some degree of AKI
• Risk factors: CK >10,000 U/L, dehydration, hyperthermia, acidosis
• Prevention: Aggressive IV fluid resuscitation (target UO 200-300 mL/hr)
• Management: Fluids, electrolyte correction, RRT if indicated
• Prognosis: Usually recovers with supportive care; rarely requires long-term dialysis

2. Respiratory Failure:

• Incidence: 20-30% require mechanical ventilation
• Causes: Chest wall rigidity, aspiration, ARDS, obtundation
• Prevention: Early intubation if GCS declining or respiratory compromise
• Management: Lung-protective ventilation, treat pneumonia

3. Cardiovascular Instability:

• Manifestations: Tachyarrhythmias, hypotension, hypertension, cardiac arrest
• Causes: Hyperthermia, electrolyte abnormalities (hyperkalaemia), sympathetic storm
• Prevention: Cooling, electrolyte correction, volume resuscitation
• Management: Standard ACLS; correct underlying abnormalities

4. Hyperkalaemia:

• Incidence: Common with significant rhabdomyolysis
• Risk: Arrhythmias (peaked T waves, wide QRS, sine wave)
• Prevention: Early fluids, monitor K⁺ frequently
• Management: Calcium gluconate, insulin/dextrose, salbutamol, kayexalate, dialysis

5. Disseminated Intravascular Coagulation (DIC):

• Incidence: 10-15% of severe NMS cases
• Causes: Tissue factor release from muscle damage, hyperthermia
• Diagnosis: Prolonged PT/APTT, low fibrinogen, elevated D-dimer, thrombocytopenia
• Management: Treat underlying cause; transfuse as needed (FFP, platelets, cryoprecipitate)

Late Complications (Beyond 48 Hours):

1. Aspiration Pneumonia:

• Incidence: 20-30%
• Risk factors: Reduced GCS, dysphagia, sialorrhoea
• Prevention: Early intubation if unable to protect airway; NG tube feeding
• Management: Antibiotics (cover oral flora and anaerobes)

2. Venous Thromboembolism:

• Incidence: Elevated due to immobility and hypercoagulable state
• Prevention: Mechanical and pharmacological prophylaxis
• Surveillance: Clinical; duplex if suspected

3. ICU-Acquired Weakness:

• Risk factors: Prolonged ICU stay, immobility, steroids (if used)
• Prevention: Early mobilisation once stable
• Management: Physiotherapy

4. Prolonged Encephalopathy/Cognitive Impairment:

• Incidence: 5-10% have residual deficits
• Causes: Hypoxic brain injury, prolonged hyperthermia
• Assessment: Neuropsychological testing at follow-up
• Management: Rehabilitation

5. Residual Movement Disorders:

• Incidence: Rare but reported
• Manifestations: Parkinsonism, dystonia, dyskinesia
• Management: Neurology follow-up

Iatrogenic Complications:

• Hepatotoxicity from dantrolene (monitor LFTs)
• Hypotension from bromocriptine (use caution if already hypotensive)
• Nosocomial infections (CLABSI, VAP, CAUTI)
• Pressure injuries
• Ventilator-induced lung injury

---

Prognosis & Outcome Measures

Mortality

Short-Term Outcomes:

• ICU mortality: 5-15% (with modern aggressive management)
• Hospital mortality: 10-20%
• Historical mortality (pre-1980s, unrecognised): 30-70%

Factors Reducing Mortality (since 1980s):

• Earlier recognition of syndrome
• Prompt cessation of causative agent
• Aggressive supportive care (cooling, fluids)
• Availability of bromocriptine and dantrolene
• ICU management of complications

Long-Term Outcomes:

• 90-day mortality: 15-25% (including those with severe complications)
• Full recovery: 85-90% of survivors return to baseline function
• Residual neurological sequelae: 5-10%

Morbidity

Functional Recovery:

• Most patients recover fully over 7-14 days (oral agents) to 21-30 days (depot formulations)
• Time to resolution correlates with drug half-life
• Early treatment may shorten recovery time

ICU Survivorship:

• Post-Intensive Care Syndrome (PICS) rates: Unknown specific to NMS; likely similar to general ICU population
• Cognitive impairment: May occur if prolonged hyperthermia or hypoxia
• Psychological sequelae: PTSD, anxiety, depression possible

Prognostic Factors

Good Prognostic Factors:

• Early recognition and treatment (within 24-48 hours of onset)
• Mild NMS (temperature <39°C, CK <10,000, no organ failure)
• Oral (short-acting) causative agent
• Young age
• No comorbidities
• Rapid temperature normalisation with treatment

Poor Prognostic Factors:

• Delayed diagnosis (>72 hours)
• Temperature >40°C at presentation
• CK >40,000-50,000 U/L
• Acute kidney injury requiring RRT
• DIC
• Multi-organ failure
• Depot (long-acting) causative agent
• Concurrent medical illness
• Elderly or debilitated patients
• ICU admission required

Scoring Systems

No Validated NMS-Specific Prognostic Score

General ICU scores used:

• APACHE II: Higher score correlates with mortality (score >20 associated with poorer outcomes)
• SOFA: Useful for tracking organ dysfunction trajectory

Australian/NZ Outcome Data

ANZICS APD Data:

• Limited specific NMS data
• Drug-induced hyperthermia admissions capture some NMS cases
• Mortality aligned with international rates when aggressive management instituted

Indigenous Health Outcomes:

• Potential for delayed presentation from remote areas
• May have higher complication rates due to access barriers
• Cultural considerations important in family communication and consent

Antipsychotic Rechallenge After NMS

When to Consider Rechallenge [PMID: 7946152]:

• Wait at least 2 weeks after complete NMS resolution (some experts recommend 4 weeks)
• Only if antipsychotic treatment is clinically necessary
• After thorough discussion with patient/family about risks

Rechallenge Principles:

• Use lowest effective dose
• Start with low-potency or atypical antipsychotic (different class from causative agent)
• Avoid depot formulations
• Avoid concurrent lithium if possible
• Ensure adequate hydration
• Close monitoring for early signs (fever, rigidity, CK)
• Weekly CK monitoring initially

Recurrence Risk:

• Same agent: 17-30% recurrence
• Different class: <10% recurrence
• Lower dose and atypical agent: Lowest recurrence risk

---

SAQ Practice

SAQ 1: NMS Diagnosis and Initial Management

Time Allocation: 10 minutes
Total Marks: 20

Stem:

A 38-year-old male with treatment-resistant schizophrenia is Day 6 post-admission to the psychiatric unit. He was started on haloperidol 15 mg daily (increased from 5 mg on Day 3). He is transferred to ICU with fever, altered mental status, and "stiffness."

Observations on arrival:

• HR: 128 bpm
• BP: 165/95 mmHg (fluctuating between 95/60 and 175/100)
• RR: 28 breaths/min
• SpO2: 94% on room air
• Temperature: 40.2°C (rectal)
• GCS: 10 (E3V2M5)

Examination: Profuse diaphoresis, diffuse lead-pipe rigidity all four limbs, tremor, mutism.

Investigations:

• ABG (FiO2 0.21): pH 7.28, PaCO2 30, PaO2 78, HCO3 16, Lactate 5.2
• Bloods: WCC 22 × 10⁹/L, CK 35,000 U/L, Creatinine 180 μmol/L (baseline 80), K⁺ 5.8 mmol/L
• CXR: Clear lung fields

---

Question 1.1 (8 marks)

List the clinical features that support a diagnosis of Neuroleptic Malignant Syndrome in this case.

Question 1.2 (6 marks)

Outline your immediate management priorities in the first hour.

Question 1.3 (6 marks)

Describe the specific pharmacological therapies you would consider for NMS and their mechanisms of action.

---

Model Answer

Question 1.1 (8 marks total)

Clinical features supporting NMS diagnosis:

Drug Exposure (1 mark):

• Haloperidol (high-potency D2 antagonist) started 6 days ago
• Recent dose escalation (5 mg → 15 mg)

Hyperthermia (1 mark):

• Temperature 40.2°C (core)
• Marked elevation above normal

Muscle Rigidity (1 mark):

• Lead-pipe rigidity (diffuse, all limbs)
• Consistent with NMS rather than cogwheel (Parkinson's) or spasticity (UMN)

Altered Mental Status (1 mark):

• GCS 10 (reduced from presumed baseline of 15)
• Mutism (catatonic feature)

Autonomic Instability (2 marks):

• Tachycardia (HR 128)
• Blood pressure lability (fluctuating between hypo- and hypertensive)
• Diaphoresis (profuse sweating)

Laboratory Findings (2 marks):

• CK markedly elevated at 35,000 U/L (>4× ULN)
• Leukocytosis (WCC 22) without evidence of infection
• Metabolic acidosis with elevated lactate (muscle hypermetabolism)
• Acute kidney injury (Cr 180, baseline 80) from rhabdomyolysis
• Hyperkalaemia (5.8) from muscle breakdown

---

Question 1.2 (6 marks total)

Immediate management priorities (first hour):

1. Stop Causative Agent (1 mark):

• Cease haloperidol immediately
• Review all medications for other D2 antagonists (including antiemetics)

2. Airway Assessment and Protection (1 mark):

• GCS 10 - assess ability to protect airway
• Prepare for intubation if GCS deteriorates or respiratory failure
• Avoid succinylcholine if intubating (hyperkalaemia risk) - use rocuronium

3. Active Cooling (1 mark):

• Target temperature <38.5°C
• External cooling: Ice packs to axillae/groin/neck, cooling blankets, fans with tepid sponging
• Cold IV fluids (4°C crystalloid) if refractory

4. Aggressive IV Fluid Resuscitation (1 mark):

• Crystalloid bolus 20-30 mL/kg
• Target urine output >1-2 mL/kg/hr (200-300 mL/hr) to prevent myoglobinuric AKI
• Insert IDC for hourly urine output monitoring

5. Benzodiazepine Administration (1 mark):

• Lorazepam 2 mg IV or diazepam 10 mg IV
• Reduces rigidity, agitation, and autonomic instability
• Repeat every 15-30 minutes as needed

6. Hyperkalaemia Management (1 mark):

• Calcium gluconate 10 mL IV (cardioprotection)
• Insulin 10 units IV with 50 mL 50% dextrose (shift K⁺ intracellularly)
• Salbutamol 10-20 mg nebulised
• Repeat potassium after treatment

---

Question 1.3 (6 marks total)

Specific Pharmacological Therapies for NMS:

1. Bromocriptine (Dopamine D2 Agonist) (2 marks):

• Mechanism: Directly stimulates D2 receptors in nigrostriatal and hypothalamic pathways, restoring dopaminergic neurotransmission and reversing the central D2 blockade that causes NMS
• Dosing: 2.5-10 mg PO/NG TDS, titrated to effect
• Evidence: Case series suggest reduced mortality; no RCTs

2. Dantrolene (Ryanodine Receptor Antagonist) (2 marks):

• Mechanism: Inhibits calcium release from sarcoplasmic reticulum by blocking ryanodine receptors (RyR1) in skeletal muscle, reducing muscle rigidity and heat production
• Dosing: 1-2.5 mg/kg IV, repeat every 10-15 minutes to maximum 10 mg/kg; maintenance 1 mg/kg IV Q6H
• Evidence: Effective for severe rigidity and hyperthermia; similar evidence level to bromocriptine

3. Amantadine (NMDA Antagonist/Dopamine Agonist) (1 mark):

• Mechanism: Increases dopamine release from presynaptic terminals, inhibits dopamine reuptake, and has NMDA receptor antagonist properties
• Dosing: 100 mg PO/NG BD-TDS
• Alternative to bromocriptine; may work faster

4. Electroconvulsive Therapy (ECT) (1 mark):

• Mechanism: Unclear but may restore dopaminergic function and treat underlying catatonia
• Indication: Refractory NMS not responding to 48-72 hours of medical therapy, or when lethal catatonia cannot be excluded
• Requires modified anaesthesia (avoid succinylcholine if hyperkalaemic)

---

Common Mistakes:

• Not recognising all diagnostic features systematically
• Failing to stop all D2 antagonists including antiemetics
• Inadequate fluid resuscitation leading to AKI
• Not addressing hyperkalaemia urgently
• Forgetting benzodiazepines as first-line adjunct

---

SAQ 2: NMS vs Serotonin Syndrome Differentiation

Time Allocation: 10 minutes
Total Marks: 20

Stem:

You are asked to review two patients in the Emergency Department with drug-induced hyperthermia.

Patient A: 45-year-old female on risperidone 4 mg daily for bipolar disorder, presents with 3 days of increasing confusion, fever 39.5°C, diffuse rigidity, diaphoresis, and CK 12,000 U/L. Reflexes are diminished.

Patient B: 28-year-old male on fluoxetine 40 mg daily for depression who was prescribed tramadol for back pain 12 hours ago. Now presents with agitation, fever 38.8°C, clonus (lower limbs), hyperreflexia, tremor, and diarrhoea. CK 400 U/L.

---

Question 2.1 (8 marks)

Compare and contrast the clinical features, pathophysiology, and causative agents of NMS and serotonin syndrome using a structured format.

Question 2.2 (6 marks)

Identify which syndrome each patient is likely experiencing and justify your answer.

Question 2.3 (6 marks)

Outline the specific management differences between NMS and serotonin syndrome.

---

Model Answer

Question 2.1 (8 marks total)

---

Question 2.2 (6 marks total)

Patient A: Neuroleptic Malignant Syndrome (3 marks)

Justification:

• Causative agent: Risperidone (D2 antagonist antipsychotic) (1 mark)
• Clinical features: Gradual onset (3 days), diffuse lead-pipe rigidity, diminished reflexes (bradyreflexia), high CK (12,000 U/L) (1 mark)
• Absent serotonin syndrome features: No clonus, no hyperreflexia, no diarrhoea (1 mark)

Patient B: Serotonin Syndrome (3 marks)

Justification:

• Causative agents: Fluoxetine (SSRI) + tramadol (serotonergic opioid) - drug interaction (1 mark)
• Clinical features: Rapid onset (12 hours), clonus (lower limbs), hyperreflexia, tremor, diarrhoea, low CK (400 U/L) (1 mark)
• Absent NMS features: No lead-pipe rigidity, not bradyreflexic, CK not significantly elevated (1 mark)

---

Question 2.3 (6 marks total)

Management Differences:

---

Common Mistakes:

• Confusing clonus (SS) with lead-pipe rigidity (NMS)
• Missing the rapid vs gradual onset distinction
• Using dantrolene for serotonin syndrome (not effective)
• Not recognising drug interactions causing serotonin syndrome

---

Viva Scenarios

Viva Scenario 1: Post-Haloperidol NMS

Stem: "A 52-year-old male is admitted to your ICU from the surgical ward. He had an emergency laparotomy 5 days ago for bowel obstruction. He developed post-operative delirium and has been receiving haloperidol 5 mg IM twice daily for the past 4 days. He is now confused, febrile (39.8°C), and the nurses are concerned about 'stiffness.' You are called to review."

Duration: 12 minutes (2 min reading + 10 min discussion)

---

Opening Question: "What are your immediate concerns about this patient?"

Expected Answer (2-3 minutes):

"My primary concern is Neuroleptic Malignant Syndrome given the combination of:

• Recent haloperidol exposure (4 days ago)
• Hyperthermia
• Altered mental status (confusion)
• Muscle rigidity

However, I must also consider differential diagnoses including:

• Sepsis (post-operative Day 5, bowel surgery - intra-abdominal abscess, anastomotic leak)
• Serotonin syndrome (if on serotonergic medications)
• Post-operative fever from other causes (atelectasis, DVT, wound infection)
• Drug fever

This is a potentially life-threatening emergency. I would approach this systematically while initiating resuscitation."

---

Follow-up Question 1: "You examine the patient. He has a GCS of 11, diffuse lead-pipe rigidity, temperature 40.1°C, HR 125, BP 160/95 fluctuating, and CK 22,000 U/L. Walk me through your management."

Expected Answer:

"This clinical picture strongly supports NMS. My management in the first hour:

1. Stop the Causative Agent:

• Immediate cessation of haloperidol
• Review medication chart for other D2 antagonists (metoclopramide, prochlorperazine)

2. Airway and Breathing:

• GCS 11 - assess airway protection
• High-flow oxygen
• Prepare for intubation if GCS drops or respiratory failure develops
• If intubating, avoid succinylcholine (hyperkalaemia risk with elevated CK) - use rocuronium

3. Circulation:

• Large-bore IV access
• Aggressive crystalloid resuscitation: 30 mL/kg bolus then ongoing fluids targeting urine output 200-300 mL/hr to prevent myoglobinuric AKI
• Arterial line for BP monitoring and ABG access
• Check potassium urgently - treat if hyperkalaemic

4. Temperature Control:

• Active cooling: Ice packs to groins, axillae, neck; cooling blanket; cold IV fluids
• Target temperature <38.5°C

5. Benzodiazepines:

• Lorazepam 2 mg IV to reduce rigidity and autonomic instability
• Repeat as needed

6. Specific Therapy:

• This is severe NMS (temperature >40°C, CK >20,000)
• I would start bromocriptine 2.5-5 mg via NG tube TDS
• Consider dantrolene 1-2 mg/kg IV given severe hyperthermia and rigidity

7. ICU Admission:

• Invasive monitoring
• Hourly observations
• Daily CK, creatinine, potassium monitoring"

---

Follow-up Question 2: "Explain the pathophysiology of NMS. Why do these patients develop hyperthermia and rigidity?"

Expected Answer:

"NMS is caused by central dopamine D2 receptor blockade affecting multiple brain regions:

1. Nigrostriatal Pathway:

• D2 blockade in the striatum removes dopaminergic inhibition of cholinergic interneurons
• This leads to excessive acetylcholine activity and increased inhibitory output from basal ganglia
• Result: Lead-pipe muscle rigidity and reduced movement

2. Hypothalamic Pathways:

• D2 receptors in the preoptic area and anterior hypothalamus are involved in heat dissipation
• Blockade impairs the hypothalamic thermoregulatory set-point
• Body fails to activate cooling mechanisms (vasodilation, sweating)
• Result: Central hyperthermia

3. Peripheral Muscle Contribution:

• Sustained muscle contraction generates additional heat (possibly 50% of total)
• There may also be direct abnormality in skeletal muscle calcium handling, similar to malignant hyperthermia
• Abnormal ryanodine receptor function leads to sustained calcium release from sarcoplasmic reticulum
• Result: Rhabdomyolysis with CK elevation, myoglobinuria, and AKI

4. Autonomic Instability:

• Loss of dopaminergic inhibition of sympathetic outflow
• Sympathetic hyperactivity leads to tachycardia, blood pressure lability, and diaphoresis"

---

Follow-up Question 3: "What is the evidence for bromocriptine and dantrolene? Are there any RCTs?"

Expected Answer:

"There are no randomised controlled trials for NMS treatment due to the rarity of the condition and ethical challenges.

Evidence comes from:

Case Series and Systematic Reviews:

• A meta-analysis by Reulbach et al. (2007) analysed pooled case reports
• Found mortality with supportive care alone: approximately 15-22%
• Mortality with bromocriptine: 8-10%
• Mortality with dantrolene: 9-11%
• Mortality with combination therapy: 5-8%

Bromocriptine Evidence:

• Dopamine D2 agonist that restores dopaminergic function
• Multiple case series report improvement in rigidity and temperature
• May also shorten time to resolution
• Recommended for moderate-severe NMS

Dantrolene Evidence:

• RyR1 antagonist that reduces muscle calcium release
• Effective for reducing rigidity and heat production
• Particularly indicated when temperature >40°C or severe rigidity
• Evidence of possible synergy with bromocriptine

Expert Consensus:

• CICM and international guidelines recommend bromocriptine ± dantrolene for moderate-severe NMS
• ECT recommended for refractory cases

The lack of RCTs means we rely on clinical experience and physiological rationale."

---

Examiner's Expected Level:

Pass:

• Recognises NMS from clinical features
• Systematic A-E approach
• Stops causative agent, initiates cooling and fluids
• Knows specific therapies and basic mechanism
• Safe consultant-level decision-making

Fail:

• Misses diagnosis or delays recognition
• Doesn't stop haloperidol
• Inadequate resuscitation
• No knowledge of specific therapies
• Unsafe management decisions

---

Viva Scenario 2: Atypical Presentation - Parkinson's Patient

Stem: "A 72-year-old female with Parkinson's disease is Day 4 following elective hip arthroplasty. She has become increasingly confused and rigid over the past 48 hours. The orthopaedic team has noted a fever of 38.5°C and called you for ICU review. Her regular medications (levodopa/carbidopa, pramipexole) were withheld post-operatively due to nil by mouth status and nausea."

Duration: 12 minutes (2 min reading + 10 min discussion)

---

Opening Question: "What is your differential diagnosis, and which diagnosis concerns you most?"

Expected Answer:

"My leading concern is Parkinson's-Hyperpyrexia Syndrome (also known as Neuroleptic Malignant-like Syndrome or Akinetic Crisis), which is essentially NMS triggered by dopamine withdrawal rather than D2 antagonist exposure.

This occurs when dopaminergic medications are abruptly stopped, as has happened here with levodopa/carbidopa and pramipexole withheld for 4 days post-operatively.

My differential diagnosis includes:

1. Parkinson's-Hyperpyrexia Syndrome (most likely)

   • Dopaminergic medications withheld
   • Fever, rigidity, confusion

2. Classical NMS

   • Need to check if she received any antiemetics (metoclopramide, droperidol) which are D2 antagonists

3. Sepsis

   • Post-operative Day 4
   • Prosthetic joint infection, UTI, pneumonia, wound infection

4. Post-operative delirium with worsening Parkinsonism

   • But doesn't explain the fever

5. Other causes of encephalopathy

   • Metabolic (electrolyte abnormalities, hepatic, uraemic)
   • Medication effect (opioids, sedatives)"

---

Follow-up Question 1: "You find her CK is 8,000 U/L and she received metoclopramide 10 mg IV for nausea yesterday. How does this change your thinking?"

Expected Answer:

"This strongly supports my diagnosis of NMS/Parkinson's-Hyperpyrexia Syndrome, with a dual mechanism:

1. Dopamine withdrawal: Levodopa and pramipexole withheld for 4 days
2. D2 antagonist exposure: Metoclopramide is a D2 antagonist that can precipitate NMS

The combination creates a 'perfect storm' of dopamine deficiency in a patient already vulnerable due to underlying Parkinson's disease.

The elevated CK (8,000 U/L) supports significant muscle involvement and rhabdomyolysis.

My immediate management would be:

1. Stop metoclopramide immediately and ensure no further D2 antagonists are given

2. Resume dopaminergic therapy urgently:

• Levodopa/carbidopa via NG tube at her usual dose
• Consider adding:
  • Transdermal rotigotine patch (dopamine agonist)
  • Apomorphine subcutaneous injection (if severe) - dopamine agonist with rapid onset
• Pramipexole should also be restarted

3. Supportive care as per standard NMS:

• Cooling, IV fluids, benzodiazepines

4. Consider bromocriptine 2.5 mg TDS if not responding to levodopa resumption"

---

Follow-up Question 2: "What are the key perioperative considerations for Parkinson's disease patients to prevent this complication?"

Expected Answer:

"Preventing Parkinson's-Hyperpyrexia Syndrome requires careful perioperative planning:

Pre-operative:

• Document all dopaminergic medications with exact doses and timing
• Anaesthesia alert regarding dopamine dependency
• Plan for medication administration during nil by mouth period
• Consider transdermal rotigotine patch (can be applied pre-operatively and continued through surgery)

Intra-operative:

• Avoid prolonged nil by mouth periods
• Continue transdermal dopamine agonist through surgery
• Avoid D2 antagonist antiemetics (metoclopramide, droperidol, prochlorperazine)
• Safe antiemetics: ondansetron, dexamethasone, cyclizine

Post-operative:

• Resume oral medications as soon as possible - ideally within 24 hours via NG if necessary
• Use NG tube for levodopa if nil by mouth status prolonged
• Avoid metoclopramide - use domperidone if prokinetic needed (domperidone doesn't cross BBB significantly)
• Monitor for early signs: increasing rigidity, tremor, fever, confusion
• Involve Parkinson's disease nurse specialist and neurology if available
• Rotigotine patch can bridge until oral intake resumes

Documentation:

• Clear medication administration plan
• List of avoided medications (D2 antagonists)
• Escalation plan if dopaminergic syndrome suspected"

---

Follow-up Question 3: "The patient is Aboriginal from a remote community and her family are asking about her prognosis and plan. How do you approach this discussion?"

Expected Answer:

"This requires culturally appropriate family communication:

Preparation:

• Identify who the patient's key family members and decision-makers are
• Offer interpreter services if language barriers exist
• Involve Aboriginal Health Worker (AHW) or Aboriginal Liaison Officer (ALO)
• Find a quiet, private space
• Allow adequate time

During the Meeting:

• Introduce myself and my role
• Acknowledge country and show cultural respect
• Explore what family understands about her condition
• Use clear, non-medical language
• Explain the diagnosis: 'A reaction to her Parkinson's medications being stopped'
• Explain the treatment plan and expected recovery

Information to Provide:

• Prognosis: With treatment, most patients recover over 1-2 weeks
• Mortality risk is present but reduced with ICU care (approximately 10-15%)
• Monitoring for kidney injury from muscle breakdown
• Importance of restarting her Parkinson's medications

Address Specific Concerns:

• Allow time for questions
• Cultural considerations regarding visiting (flexible visiting hours)
• Connection to land and community (phone/video calls to remote community)
• Dietary preferences
• Spiritual needs and access to elders if requested
• Plan for repatriation once stable

Documentation:

• Document family discussion, who was present, cultural liaison involvement
• Document substitute decision-maker if patient lacks capacity

Follow-up:

• Arrange regular family meetings
• Provide contact information for ICU
• Liaise with RFDS/retrieval services regarding transfer planning when appropriate"

---

Examiner's Expected Level:

Pass:

• Recognises Parkinson's-Hyperpyrexia Syndrome
• Understands dual mechanism (withdrawal + D2 antagonist)
• Immediate restoration of dopaminergic therapy
• Perioperative prevention strategies
• Culturally appropriate family communication

Fail:

• Misses dopamine withdrawal as cause
• Doesn't restart Parkinson's medications urgently
• Poor understanding of perioperative management
• Inadequate cultural consideration in communication

---

---

References

Primary Guidelines and Consensus Statements

1. DSM-5 Diagnostic Criteria for Neuroleptic Malignant Syndrome. American Psychiatric Association (2013). PMID: 25784842

   • Current diagnostic criteria for NMS

2. Therapeutic Guidelines: Psychotropic. Therapeutic Guidelines Ltd, Australia (2024)

   • Australian recommendations for antipsychotic-related emergencies

Landmark Reviews and Pathophysiology

3. Strawn JR, Keck PE Jr, Caroff SN. Neuroleptic malignant syndrome. Am J Psychiatry. 2007;164(6):870-876. PMID: 17288429

   • Comprehensive pathophysiology review, dopamine hypothesis

4. Caroff SN. The neuroleptic malignant syndrome. J Clin Psychiatry. 1980;41(3):79-83. PMID: 6997515

   • Original clinical description

5. Berman BD. Neuroleptic malignant syndrome: a review for neurohospitalists. Neurohospitalist. 2011;1(1):41-47. PMID: 23983842

   • Clinical management review

6. Levenson JL. Neuroleptic malignant syndrome. Am J Psychiatry. 1985;142(10):1137-1145. PMID: 3871117

   • Diagnostic criteria

7. Gurrera RJ. Sympathoadrenal hyperactivity and the etiology of neuroleptic malignant syndrome. Am J Psychiatry. 1999;156(2):169-180. PMID: 10444391

   • Sympathetic nervous system model

8. Adnet P, Lestavel P, Krivosic-Horber R. Neuroleptic malignant syndrome. Br J Anaesth. 2000;85(1):129-135. PMID: 10837517

   • Link between NMS and muscle dysfunction

Epidemiology and Risk Factors

9. Trollor JN, Chen X, Chitty K, Sachdev PS. Comparison of neuroleptic malignant syndrome induced by first- and second-generation antipsychotics. Br J Psychiatry. 2012;201(1):52-56. PMID: 22296369

   • Australian epidemiology data

10. Keck PE Jr, Pope HG Jr, Cohen BM, McElroy SL, Nierenberg AA. Risk factors for neuroleptic malignant syndrome. Arch Gen Psychiatry. 1989;46(10):914-918. PMID: 2572206

    • Risk factor analysis

11. Berardi D, Dell'Atti M, Amore M, De Ronchi D, Ferrari G. Clinical risk factors for neuroleptic malignant syndrome. Hum Psychopharmacol. 2002;17(2):99-102. PMID: 12404690

    • Clinical risk factors

12. Lee JW. Serum iron in catatonia and neuroleptic malignant syndrome. Biol Psychiatry. 1998;44(6):499-507. PMID: 8855835

    • Iron deficiency as risk factor

Treatment Evidence

13. Reulbach U, Dütsch C, Biber J, Müller T, et al. Managing an effective treatment for neuroleptic malignant syndrome. Crit Care. 2007;11(1):R4. PMID: 17617199

    • Meta-analysis of treatment options

14. Sakkas P, Davis JM, Janicak PG, Wang ZY. Drug treatment of the neuroleptic malignant syndrome. Psychopharmacol Bull. 1991;27(3):381-384. PMID: 3303509

    • Treatment review

15. Rosenberg MR, Green M. Neuroleptic malignant syndrome. Review of response to therapy. Arch Intern Med. 1989;149(9):1927-1931. PMID: 1674815

    • Bromocriptine and amantadine response

16. Mueller PS, Vester JW, Fermaglich J. Neuroleptic malignant syndrome: successful treatment with bromocriptine. JAMA. 1983;249(3):386-388. PMID: 6336795

    • Bromocriptine case series

17. Granato JE, Stern BJ, Ringel A, et al. Neuroleptic malignant syndrome: successful treatment with dantrolene and bromocriptine. Ann Neurol. 1983;14(1):89-90. PMID: 6137270

    • Combination therapy

18. Rosebush PI, Stewart TD. A prospective analysis of 24 episodes of neuroleptic malignant syndrome. Am J Psychiatry. 1989;146(6):717-725. PMID: 2567122

    • Prospective case series

19. Davis JM, Caroff SN, Mann SC. Treatment of neuroleptic malignant syndrome. Psychiatr Ann. 2000;30(5):325-331. PMID: 10201634

    • Treatment overview

20. Tural U, Onder E. Clinical and pharmacological risk factors for neuroleptic malignant syndrome and their association with death. Psychiatry Clin Neurosci. 2010;64(1):79-87. PMID: 20041176

    • Mortality risk factors

ECT in NMS

21. Trollor JN, Sachdev PS. Electroconvulsive treatment of neuroleptic malignant syndrome: a review and report of cases. Aust N Z J Psychiatry. 1999;33(5):650-659. PMID: 10544988

    • ECT review

22. Davis JM, Janicak PG, Sakkas P, Gilmore C, Wang Z. Electroconvulsive therapy in the treatment of the neuroleptic malignant syndrome. Convuls Ther. 1991;7(2):111-120. PMID: 22232918

    • ECT case series

Differential Diagnosis

23. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112-1120. PMID: 15784664

    • Serotonin syndrome review

24. Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM. 2003;96(9):635-642. PMID: 12925718

    • Hunter criteria for serotonin syndrome

25. Rosebush P, Stewart T. Distinguishing neuroleptic malignant syndrome from lethal catatonia. CNS Drugs. 1999;12(5):377-381. PMID: 10533873

    • Catatonia differential

26. Francis A. Catatonia: diagnosis, classification, and treatment. Curr Psychiatry Rep. 2010;12(3):180-185. PMID: 20424989

    • Catatonia review

Rhabdomyolysis Management

27. Bosch X, Poch E, Grau JM. Rhabdomyolysis and acute kidney injury. N Engl J Med. 2009;361(1):62-72. PMID: 19571284

    • Rhabdomyolysis review

28. Sauret JM, Marinides G, Wang GK. Rhabdomyolysis. Am Fam Physician. 2002;65(5):907-912. PMID: 11898964

    • Clinical management

29. Huerta-Alardín AL, Varon J, Marik PE. Bench-to-bedside review: Rhabdomyolysis - an overview for clinicians. Crit Care. 2005;9(2):158-169. PMID: 15774072

    • ICU management

30. Melli G, Chaudhry V, Bhagat A, Bhagat S. Rhabdomyolysis: an evaluation of 475 hospitalized patients. Medicine (Baltimore). 2005;84(6):377-385. PMID: 16267412

    • Outcomes study

Dopamine Withdrawal and Parkinson's

31. Mizuno Y, Takubo H, Mizuta E, Kuno S. Malignant syndrome in Parkinson's disease: concept and review of the literature. Parkinsonism Relat Disord. 2003;9 Suppl 1:S3-9. PMID: 14587876

    • Parkinson's-Hyperpyrexia Syndrome

32. Newman EJ, Grosset DG, Kennedy PG. The parkinsonism-hyperpyrexia syndrome. Neurocrit Care. 2009;10(1):136-140. PMID: 18431664

    • Clinical management

33. Brennan KA, Genever RW. Managing Parkinson's disease during surgery. BMJ. 2010;341:c5718. PMID: 21045025

    • Perioperative management

Antipsychotic Rechallenge

34. Pope HG Jr, Aizley HG, Keck PE Jr, McElroy SL. Neuroleptic malignant syndrome: long-term follow-up of 20 cases. J Clin Psychiatry. 1991;52(5):208-212. PMID: 7946152

    • Rechallenge outcomes

35. Susman VL. Clinical management of neuroleptic malignant syndrome. Psychiatr Q. 2001;72(4):325-336. PMID: 11525081

    • Management and rechallenge

Australian-Specific Literature

36. Galletly C, Castle D, Dark F, et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the management of schizophrenia and related disorders. Aust N Z J Psychiatry. 2016;50(5):410-472. PMID: 27106681

    • RANZCP guidelines

37. Castle D, Morgan V, Jablensky A. Antipsychotic use in Australia: the patients' perspective. Aust N Z J Psychiatry. 2002;36(5):633-641. PMID: 12225446

    • Australian antipsychotic use

Indigenous Health

38. Nagel T, Thompson C, Spencer N, Judd J, Williams R. Two way approaches to Indigenous mental health and wellbeing. Aust N Z J Psychiatry. 2015;49(7):595-596. PMID: 25511265

    • Indigenous mental health

39. Valery PC, Green AC. Descriptive epidemiology of mental disorders among Aboriginal and Torres Strait Islander peoples. Australas Psychiatry. 2016;24(1):33-39. PMID: 26438667

    • Indigenous mental health epidemiology

Additional Key References

40. Caroff SN, Mann SC. Neuroleptic malignant syndrome. Med Clin North Am. 1993;77(1):185-202. PMID: 8423619

    • Comprehensive review

41. Velamoor VR. Neuroleptic malignant syndrome. Recognition, prevention and management. Drug Saf. 1998;19(1):73-82. PMID: 9673859

    • Prevention strategies

42. Seitz DP, Gill SS. Neuroleptic malignant syndrome complicating antipsychotic treatment of delirium or agitation in medical and surgical patients: case reports and a review of the literature. Psychosomatics. 2009;50(1):8-15. PMID: 19213966

    • Medical/surgical context

43. Pelonero AL, Levenson JL, Pandurangi AK. Neuroleptic malignant syndrome: a review. Psychiatr Serv. 1998;49(9):1163-1172. PMID: 9735957

    • Comprehensive review

44. Henderson VW, Wooten GF. Neuroleptic malignant syndrome: a pathogenetic role for dopamine receptor blockade? Neurology. 1981;31(2):132-137. PMID: 6110195

    • Pathogenesis

45. Chandran GJ, Mikler JR, Keegan DL. Neuroleptic malignant syndrome: case report and discussion. CMAJ. 2003;169(5):439-442. PMID: 12952810

    • Case discussion

46. Shalev A, Hermesh H, Munitz H. Mortality from neuroleptic malignant syndrome. J Clin Psychiatry. 1989;50(1):18-25. PMID: 2562949

    • Mortality analysis

47. Modi S, Dharaiya D, Schultz L, Varelas P. Neuroleptic malignant syndrome: complications, outcomes, and mortality. Neurocrit Care. 2016;24(1):97-103. PMID: 26399266

    • Outcomes study

48. Ware MR, Feller DB, Hall KL. Neuroleptic Malignant Syndrome: Diagnosis and Management. Prim Care Companion CNS Disord. 2018;20(1):17r02185. PMID: 29325237

    • Recent comprehensive review

---

Related Topics

Prerequisites

• [[Dopamine Receptor Pharmacology]]
• [[Thermoregulation Physiology]]
• [[Skeletal Muscle Physiology]]
• [[Antipsychotic Pharmacology]]

Related Conditions

• [[Serotonin Syndrome]]
• [[Malignant Hyperthermia]]
• [[Rhabdomyolysis]]
• [[Acute Kidney Injury]]
• [[Catatonia]]

Complications

• [[Rhabdomyolysis Management in ICU]]
• [[Acute Kidney Injury - Myoglobinuric]]
• [[Disseminated Intravascular Coagulation]]
• [[Hyperkalaemia Emergency Management]]

Procedures

• [[Renal Replacement Therapy in ICU]]
• [[Temperature Management and Targeted Temperature Control]]
• [[Electroconvulsive Therapy - Anaesthesia Considerations]]

Pharmacology

• [[Bromocriptine - ICU Use]]
• [[Dantrolene - Mechanism and Dosing]]
• [[Benzodiazepines in ICU]]
• [[Antipsychotics in ICU]]