What is the management of Neuroleptic Malignant Syndrome (NMS)?

Management of Neuroleptic Malignant Syndrome

Immediately discontinue all antipsychotic medications and initiate aggressive supportive care, which forms the cornerstone of NMS management and has reduced mortality from 76% to less than 10-15%. 1, 2

Immediate Actions

Discontinue the offending agent as the first and most critical step—this applies to all dopamine antagonists or recently withdrawn dopamine agonists. 2 Do not wait for diagnostic confirmation if clinical suspicion is high, as early recognition is crucial for survival. 1

Supportive Care Framework

Agitation Management

• Administer benzodiazepines as first-line agents for agitation rather than additional antipsychotics. 2, 3
• Avoid physical restraints entirely, as they exacerbate isometric muscle contractions, worsening hyperthermia and lactic acidosis, thereby increasing mortality. 2

Temperature Control

• Implement external cooling measures for hyperthermia, targeting temperatures that often exceed 40.4°F and can reach 41°C or higher. 1, 2, 3
• For extreme hyperthermia (>41.1°C), emergency sedation, neuromuscular paralysis, and intubation may be required. 2

Fluid and Metabolic Management

• Administer aggressive IV fluids to address dehydration, autonomic instability, and elevated creatine kinase with potential rhabdomyolysis. 2, 3
• Monitor for renal failure development—hemodialysis may become necessary if renal failure occurs, though recent data suggest this is rarely required. 1, 4

Pharmacologic Interventions for Severe Cases

Consider dopaminergic agents and muscle relaxants only in severe NMS, as evidence shows benefit specifically in this subset. 2, 5

Dopaminergic Therapy

• Bromocriptine may be used to address dopamine deficiency in severe cases. 2
• The evidence for bromocriptine shows lower mortality in severe NMS compared to supportive care alone. 5

Muscle Relaxants

• Dantrolene sodium may reduce muscle rigidity and hyperthermia in severe cases. 2
• However, the FDA label explicitly states that dantrolene is not indicated for NMS treatment, and patients may expire despite its use. 6, 7 This creates a clinical dilemma, but systematic analysis shows lower mortality with dantrolene in severe cases compared to supportive care alone. 5
• Be aware of dantrolene's adverse effects: hepatotoxicity (hours to days post-administration), pulmonary edema (possibly related to diluent volume), thrombophlebitis, and tissue necrosis from extravasation. 6, 7

Electroconvulsive Therapy (ECT)

• ECT showed the lowest mortality rate in severe NMS cases in systematic analysis, though it is typically reserved for refractory cases. 5

Critical Monitoring Requirements

Laboratory Surveillance

• Obtain complete blood count, electrolytes, renal function, liver function, creatine kinase, arterial blood gases, and coagulation studies. 2
• Monitor for leukocytosis (15,000-30,000 cells/mm³), electrolyte abnormalities consistent with dehydration, and CK elevation ≥4 times upper limit of normal. 1, 3

Complication Monitoring

• Watch for rhabdomyolysis with elevated creatine kinase, which can lead to acute kidney failure in nearly half of severe cases. 2, 4
• Monitor for metabolic acidosis, elevated liver enzymes, seizures, and disseminated intravascular coagulation. 2

ICU Admission

• Approximately 25% of NMS patients require intensive care unit admission, and 45% may require mechanical ventilation. 2, 4

Treatment Hierarchy Based on Severity

Mild to Moderate NMS:

• Discontinue antipsychotics and provide supportive care only (benzodiazepines, cooling, IV fluids). 2
• No statistically significant benefit from specific pharmacotherapy (dantrolene, bromocriptine, ECT) in this subset. 5

Severe NMS:

• Discontinue antipsychotics, provide aggressive supportive care, AND add specific pharmacotherapy (dantrolene and/or bromocriptine). 2, 5
• Consider ECT for refractory cases, as it demonstrated the lowest mortality in severe cases. 5
• Specific therapies showed statistically significant lower mortality (P = 0.018) compared to purely symptomatic therapy in severe cases. 5

Clinical Pitfalls

• Do not delay treatment waiting for diagnostic certainty—the diagnosis is clinical, with no pathognomonic laboratory findings. 1
• Do not use physical restraints, as they worsen outcomes through increased muscle contraction and heat generation. 2
• Do not rechallenge with antipsychotics for at least 2 weeks following complete resolution of symptoms. 8
• Be aware that most cases coded as NMS do not meet DSM-5 diagnostic criteria—apply stricter diagnostic standards using the point-based system (≥76 points indicates probable NMS). 1, 4