Unravelling Central Fever: Clinical Insights in Neurocritical Care

Definition

Central fever (CF) is a non-infectious, neurogenic fever that arises in patients with acute brain injury in the absence of infection, drug reactions, or other systemic causes. It is primarily attributed to hypothalamic dysfunction and disturbed thermoregulation, leading to inappropriate and persistent hyperthermia.

Aetiology & Risk Factors

CF is commonly seen in neurocritical care patients with:

• Subarachnoid hemorrhage (SAH)
• Intracerebral hemorrhage (ICH)
• Traumatic brain injury (TBI)
• Ischemic stroke
• Post-neurosurgical states
• Hypoxic–ischemic encephalopathy

Risk factors include:

• Intraventricular hemorrhage (IVH)
• Diffuse axonal injury
• Brainstem lesions
• External ventricular drainage (EVD)

Hypothalamus and Thermoregulation

The hypothalamus serves as the body’s thermostat, maintaining core temperature within a narrow range by integrating inputs from central and peripheral thermoreceptors.

• Preoptic area (anterior hypothalamus): regulates heat loss (vasodilation, sweating); lesions → hyperthermia.
• Posterior hypothalamus: mediates heat conservation and generation (vasoconstriction, shivering, non-shivering thermogenesis); lesions → hypothermia.

In infectious fever, circulating cytokines (IL-1, IL-6, TNF-α) induce PGE₂ release in the preoptic area, raising the thermoregulatory set-point.

In central fever, direct hypothalamic or pathway injury disrupts this regulation, leading to persistent hyperthermia without infection.

Pathophysiology of Central Fever

The pathogenesis of CF is multifactorial and incompletely understood. It differs from infectious fever in that it is not cytokine-driven by microbial pyrogens, but rather a consequence of neuroanatomical disruption and neuroinflammation after acute brain injury. Several mechanisms have been proposed:

1. Hypothalamic Dysfunction
   • The preoptic area of the anterior hypothalamus is the principal thermoregulatory pathways.
   • Acute injury (SAH, ICH, TBI) may directly damage the hypothalamus or interrupt afferent/efferent thermoregulatory pathways.
   • This leads to a resetting or loss of hypothalamic set-point control, resulting in unchecked hyperthermia.
2. Autonomic Dysregulation
   • Disruption of hypothalamic and brainstem circuits impairs sympathetic-parasympathetic balance.
   • This causes excessive non-shivering thermogenesis and increased metabolic heat production, independent of infection.
   • This autonomic storm contributes to persistent, refractory hyperthermia.
3. Inflammatory Mediator Release from Injured Neural Tissue
   • Brain injury leads to release of damage-associated molecular patterns (DAMPs), glutamate excitotoxicity, and free radical generation.
   • Local release of prostaglandins, substance P, and excitatory neurotransmitters in the CNS may mimic pyrogenic activity without systemic infection.
   • Unlike infection, peripheral cytokine cascades (IL-1, TNF-α, IL-6) are not the main drivers, which explains the often normal or mildly elevated CRP/procalcitonin in CF.
4. Loss of Heat Dissipation Mechanisms
   • Intraventricular hemorrhage or diffuse axonal injury may damage pathways mediating cutaneous vasodilation and sweating, impairing natural heat loss.
   • This leads to sustained hyperthermia despite external cooling and antipyretics.
5. Mechanical and Iatrogenic Factors
   • External ventricular drainage (EVD) and intraventricular hemorrhage are strongly associated with CF. Proposed mechanisms:
     • Direct irritation of hypothalamic structures.
     • Blood breakdown products (heme, iron) triggering local neuroinflammation.
   • Post-neurosurgical trauma (especially hypothalamic or brainstem proximity) may further potentiate central hyperthermia.

Clinical Characteristics

• Onset usually within 72 hours of acute brain
• Persistent, high-grade fever, resistant to antipyretics, with little to no diurnal variation.
• Relative bradycardia, absence of chills/rigors.
• Lack of response to antibiotics.
• Negative microbiology and often normal or only mildly elevated inflammatory

Diagnosis

CF is a diagnosis of exclusion. Key steps include:

1. Rule out infection (pneumonia, UTI, catheter-related sepsis).
2. Exclude alternative causes (drug-induced fever, transfusion reaction, DVT/PE, endocrine disorders).
3. Correlate with neuroimaging (IVH, hypothalamic or brainstem injury).
4. Apply structured tools such as Greer et ’s diagnostic criteria for CF.

Management of Central Fever

1. General Principles
   • Diagnosis of exclusion → CF should be considered only after ruling out infection, drug fever, transfusion reactions, thromboembolism, and endocrine causes.
   • Avoid unnecessary antibiotics → empiric use is common but leads to resistance, difficile infection, and higher costs.
   • Primary goals:
     • Maintain normothermia or mild hypothermia.
     • Prevent fever-induced secondary neuronal injury.
     • Reduce metabolic demand and intracranial hypertension.

2. Non-Pharmacologic Measures
   • Surface Cooling
     • Cooling blankets, cooling helmets, ice packs, fans, and cold saline lavage.
     • Effective but often limited by shivering and patient discomfort.
     • Shivering increases oxygen consumption and ICP, thus requiring sedation or neuromuscular blockade in severe cases.
   • Endovascular/Intravascular Cooling
     • Catheter-based closed-loop cooling devices allow precise temperature control.
     • Shown to achieve target temperature faster and more consistently than surface
     • Complications: infection, thrombosis, arrhythmias (rare but significant).
   • Supportive ICU Measures
     • Adequate hydration to prevent dehydration and renal injury.
     • Control of shivering (buspirone, magnesium sulfate, meperidine, sedation, or neuromuscular blockers).
     • Continuous core temperature monitoring (esophageal, bladder, or intravascular probes preferred over axillary/tympanic).

3. Pharmacologic Measures
   • Standard Antipyretics
     • Acetaminophen/paracetamol: commonly used but often ineffective in CF.
     • NSAIDs (ibuprofen, diclofenac, indomethacin): limited benefit; risk of GI bleeding, renal dysfunction.
     • Best used as adjuncts to physical cooling.
   • Targeted Temperature Management (TTM)
     • Controlled normothermia (36–37 °C) or mild hypothermia (33–35 °C) may be indicated in refractory hyperthermia.
     • Evidence supports TTM in post-cardiac arrest; its role in CF after stroke or TBI is under study, but small trials show feasibility.
   • Dopaminergic/Neurotransmitter Agents (Experimental)
     • Bromocriptine (dopamine agonist): case reports suggest efficacy in refractory CF, possibly by modulating hypothalamic dopamine pathways.
     • Baclofen (GABA-B agonist): anecdotal use in spinal cord injury-related hyperthermia.
     • Amantadine: reported in isolated cases, thought to modulate dopaminergic pathways.
     • Limited evidence; not recommended as first-

4. Practical Clinical Algorithm
   1. Suspect CF if fever occurs within 72 hrs of acute brain injury + negative cultures + no response to antibiotics.
   2. Exclude mimics (infection, drug fever, transfusion reactions, DVT/PE, thyroid/adrenal causes).
   3. Initial management:
      • Acetaminophen ± NSAID.
      • Initiate surface cooling.
   4. If persistent/refractory:
      • Escalate to intravascular cooling.
      • Manage shivering with sedation, buspirone, or neuromuscular blockade if required.
   5. Consider experimental therapy (e.g., bromocriptine) only in select refractory cases.
   6. Avoid routine antibiotics unless infection cannot be confidently excluded.

5. Prognostic Implications
   • Uncontrolled hyperthermia worsens neuronal injury by increasing metabolic demand, excitotoxicity, blood–brain barrier breakdown, and ICP.
   • Aggressive fever control is associated with improved outcomes in stroke, TBI, and SAH.
   • However, overtreatment (e.g., hypothermia without indication) can cause coagulopathy, arrhythmias, and infection risk.

Central Fever vs. Infectious Fever in ICU

Key References

1. Greer DM, Funk SE, Reaven NL, Ouzounelli M, Uman Impact of fever on outcome in patients with stroke and neurologic injury: a comprehensive meta-analysis. Stroke. 2008;39(2):302–10. PMID: 18174489
2. Mourad M, Hossri C, De Marchis GM, et Central fever: a challenging diagnosis in neurocritical care. J Crit Care. 2022;71:154070. PMID: 35257645
3. Bhardwaj A, Ulatowski Fever in the neurologic intensive care unit. Neurol Clin.

2004;22(2):849–68. PMID: 15145569

4. Satinoff Neural organization and evolution of thermal regulation in mammals.

Science. 1978;201(4350):16–22. PMID: 351802

5. Morrison SF, Nakamura Central neural pathways for thermoregulation. Front Biosci. 2011;16:74–104. PMID: 21196160
6. Childs C, Lunn Thermoregulation and fever in neurocritical care. J Neurosci Nurs. 2013;45(3):158–165. PMID: 23691575
7. Hocker S, Prasad A, Rabinstein AA. Prognostic implications of fever in neurocritical care patients. Neurocrit Care. 2013;19(3):341–349. PMID: 23888384
8. Thompson HJ, Kirkness CJ, Mitchell Factors associated with fever in adult patients after traumatic brain injury. J Neurosci Nurs. 2007;39(3):123–130. PMID: 17672259
9. Kilpatrick MM, Lowry DW, Firlik AD, Yonas H, Marion Hyperthermia in the neurosurgical intensive care unit. Neurosurgery. 2000;47(4):850–856. PMID: 11014420

Childs C, Lunn KW. Thermoregulation and fever in neurocritical care. J Neurosci Nurs. 2013;45(3):158–165. PMID: 23691575

Dr Jethroben Kevin
1st Year DrNB Critical Care Resident
Kauvery Hospital, Alwarpet Chennai

Mentor

Dr Muralitharan
Associate Consultant
Critical Care Medicine
Kauvery Hospital, Alwarpet Chennai