What medications, such as bromocriptine, propranolol, baclofen, dantrolene, and amantadine, are used to treat central fever in patients with significant neurological impairment or critical illness?

Pharmacologic Management of Central Fever

First-Line Approach: Antipyretics

For patients with suspected central fever, antipyretics (particularly acetaminophen/paracetamol) should be used as first-line therapy for symptomatic relief, though they often provide inadequate temperature control in true central fever. 1, 2

• Acetaminophen 1000 mg orally every 4-6 hours (maximum 4 g/day) is recommended for patients capable of oral intake 2
• Antipyretics are primarily for patient comfort rather than temperature reduction itself in critically ill patients 1, 2
• Physical cooling methods cause discomfort and are not recommended as first-line therapy 2
• Central fever is a diagnosis of exclusion requiring thorough workup to rule out infectious causes before considering pharmacologic agents 1

Specific Pharmacologic Agents for Refractory Central Fever

When antipyretics fail to control central fever, several medications have demonstrated efficacy based on case reports and clinical experience, though high-quality evidence is limited 3, 4:

Bromocriptine (Dopamine Agonist)

Bromocriptine is the most commonly reported medication for treating refractory central fever, with evidence supporting its use in prolonged cases. 3, 5

• Mechanism: Acts as a dopamine agonist to restore hypothalamic thermoregulatory function 6, 3
• Dosing: Case reports describe variable dosing strategies; one successful case used bromocriptine to reduce baseline temperature from >39°C to 37°C within one week 5
• Evidence: Multiple case reports demonstrate effectiveness in restoring normothermia when antipyretics fail 3, 5
• Important caveat: Bromocriptine is also used to treat neuroleptic malignant syndrome (NMS), which can present similarly to central fever with hyperthermia and muscle rigidity 6, 7

Critical safety warning: Abrupt discontinuation of bromocriptine can precipitate withdrawal symptoms including apathy, anxiety, depression, fatigue, insomnia, sweating, and pain 7

Propranolol (Beta-Blocker)

Propranolol 20-30 mg every 6 hours has demonstrated effectiveness in controlling central fever associated with autonomic dysfunction, particularly in traumatic brain injury. 8

• Mechanism: Addresses both temperature dysregulation and autonomic dysfunction (tachycardia, profuse sweating) through central nervous system effects on blood pressure and temperature regulation 8
• Dosing: 20-30 mg every 6 hours reduced temperatures by at least 1.5°C within 48 hours in reported cases 8
• Clinical context: Most effective in patients with signs of autonomic dysfunction (tachycardia, diaphoresis) accompanying fever 8
• Duration: Continue until all signs of autonomic dysfunction resolve; premature discontinuation results in fever recurrence within 3 days 8

Baclofen (GABA-B Agonist)

Baclofen represents an alternative option for central fever management, though evidence is limited to case reports. 3

• Mechanism: GABA-B receptor agonist that may modulate central thermoregulation 3
• Evidence: Anecdotal case reports support its use, but dosing strategies and duration vary significantly 3
• Clinical utility: Consider when bromocriptine or propranolol are contraindicated or ineffective 3

Dantrolene (Muscle Relaxant)

Dantrolene is primarily indicated for malignant hyperthermia and neuroleptic malignant syndrome rather than central fever, but may be considered in severe refractory cases. 9, 6

• Primary indication: Malignant hyperthermia (calcium dysregulation in skeletal muscle) and NMS 9
• Mechanism: Reduces muscle contraction-generated heat by affecting calcium regulation 9
• Important distinction: Central fever differs mechanically from malignant hyperthermia—the initiator is central rather than peripheral muscle dysfunction 9
• Use in central fever: Not well-established; effectiveness has not been demonstrated in controlled studies even for NMS 6

Amantadine

Amantadine has limited evidence for central fever management and carries significant risks, particularly regarding abrupt discontinuation. 6

• Critical warning: Abrupt discontinuation can precipitate NMS-like syndrome with fever, muscle rigidity, altered consciousness, and autonomic dysfunction 6
• Withdrawal risks: May cause delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression, and slurred speech 6
• Clinical consideration: Given the risk profile and limited evidence for central fever, amantadine should be reserved for cases where other options have failed 6

Clinical Algorithm for Medication Selection

Step 1: Confirm central fever diagnosis by excluding infectious causes (chest radiograph, blood cultures, appropriate imaging) 9, 1, 10

Step 2: Initiate acetaminophen 1000 mg every 4-6 hours for symptomatic relief 2

Step 3: If fever persists and meets criteria for central fever (onset within 72 hours of neurologic injury, persistent pattern, negative infectious workup, diagnosis of subarachnoid hemorrhage/intraventricular hemorrhage/tumor), consider specific pharmacologic agents 10

Step 4: Select medication based on clinical presentation:

• Bromocriptine: First choice for prolonged central fever without prominent autonomic dysfunction 3, 5
• Propranolol: Preferred when autonomic dysfunction (tachycardia, diaphoresis) accompanies fever 8
• Baclofen: Alternative when first-line agents contraindicated 3
• Dantrolene: Reserve for suspected NMS or malignant hyperthermia rather than pure central fever 9, 6
• Amantadine: Last-line option due to withdrawal risks 6

Key Predictors of Central Fever

Central fever is more likely when the following combination is present (90% probability) 10:

• Negative cultures
• Absence of infiltrate on chest radiograph
• Diagnosis of subarachnoid hemorrhage, intraventricular hemorrhage, or tumor
• Onset of fever within 72 hours of admission

Critical Pitfalls to Avoid

Do not discontinue bromocriptine or amantadine abruptly: Both medications can precipitate serious withdrawal syndromes including NMS-like presentations with hyperthermia, muscle rigidity, and altered mental status 6, 7

Do not confuse central fever with NMS: NMS presents with muscle rigidity, elevated creatine phosphokinase, and is associated with antipsychotic medications (particularly haloperidol in ICU settings), whereas central fever lacks these features 9

Do not delay infectious workup: Central fever remains a diagnosis of exclusion; premature treatment with these agents while missing an infection can worsen outcomes 9, 1, 10

Monitor for medication-specific adverse effects: Bromocriptine can cause impulse control disorders, hallucinations, and psychotic symptoms; propranolol may cause bradycardia and hypotension 6, 7, 8

Monitoring and Duration

• Continue central temperature monitoring using pulmonary artery catheters, bladder catheters, or esophageal thermistors when available 1
• Maintain treatment until fever resolves and, for propranolol, until autonomic dysfunction completely abates 8
• Taper medications gradually rather than stopping abruptly to avoid withdrawal phenomena 6, 7
• Reassess for infectious causes if fever recurs after medication discontinuation 10