Management of Fever

1. Definition and Normal Body Temperature

• Normal mean oral temperature: 36.6°C (99th percentile upper limit = 37.7°C / 99.9°F, which defines fever)
• Rectal temperatures are ~0.4°C higher than oral readings
• Hyperpyrexia: fever >41.5°C (>106.7°F)
• Diurnal variation: lowest at 8 AM, highest at 4 PM

2. Pathophysiology

• Pyrogens (exogenous or endogenous cytokines: IL-1, IL-6, TNF, IFN) signal the hypothalamic thermoregulatory center
• Hypothalamic set point rises
• Peripheral vasoconstriction reduces heat loss → patient feels cold
• Shivering and non-shivering thermogenesis increase heat production
• Behavioral adjustments (adding clothing)

• Once pyrogens are cleared (or antipyretics used), set point is reset downward
• Vasodilation and sweating dissipate excess heat → patient sweats and feels warm

3. Fever vs. Hyperthermia - Key Distinction

4. Causes of Fever (Disease Categories)

1. Infectious diseases - most common cause
2. Autoimmune and non-infectious inflammatory disorders (e.g., SLE, RA, vasculitis)
3. Malignancy (lymphoma, renal cell carcinoma - "B symptoms")
4. Drug fever (vaccines, medications - penicillins, sulfonamides, carbamazepine)
5. Endocrine disorders (hyperthyroidism, adrenal insufficiency)
6. Intrinsic hypothalamic malfunction

5. Evaluation of the Febrile Patient

History

• Duration, pattern (intermittent, remittent, hectic), height
• Associated symptoms, exposure history (sick contacts, travel, vectors)
• Medications, immunosuppression status
• Special populations: neonates, elderly, immunocompromised, patients on anticytokines may lack fever despite serious infection

Laboratory Workup

• CBC with differential (band forms, toxic granulations, Döhle bodies suggest bacterial infection; neutropenia may indicate viral illness)
• CRP and ESR - most valuable for detecting occult disease
• Blood cultures (before antibiotics when indicated)
• Site-directed cultures and imaging

Temperature Measurement

• Same site should be used consistently during monitoring
• Electronic devices for oral, tympanic, or rectal temperatures are reliable

6. Antipyretic (Pharmacological) Management

When to Treat Fever?

• Temperature is very high (hyperpyrexia >41°C)
• Patient is uncomfortable, tachycardic, or febrile seizures have occurred
• Patient has limited cardiac reserve where tachycardia is dangerous
• Fever compromises CNS function (brain injury patients - target ≤37°C)

A. Paracetamol (Acetaminophen) - FIRST LINE

• Mechanism: Weak COX-1 and COX-2 inhibitor peripherally; also interacts with endogenous opioid, cannabinoid, and serotonergic systems. Acts centrally on the hypothalamic thermoregulatory center.
• Antipyretic but NOT anti-inflammatory in clinical doses
• Dose (adults): 325-500 mg every 4-6 hours; max 4 g/day (note: even 4 g/day may cause LFT abnormalities)
• Pediatric: 10-15 mg/kg every 4-6 hours
• Route: Oral or IV

• Safe in peptic ulcer disease, hemophilia, aspirin-sensitive asthma
• Does not antagonize uricosuric agents
• No platelet inhibition

• Dose-dependent hepatotoxicity (centrilobular necrosis) - toxic at >10-15 g in adults
• Toxic metabolite: N-acetyl-p-benzoquinone imine (NAPQI)
• Antidote: N-acetylcysteine (NAC)
• Renal damage can occur even at usual doses

B. NSAIDs - Second Line / When Anti-inflammatory Effect Also Needed

• Peptic ulcer disease, renal impairment, bleeding disorders
• Dengue fever - avoid NSAIDs and aspirin (hemorrhagic risk); use only paracetamol
• Aspirin contraindicated in children with viral illness (Reye's syndrome)

C. Combining Antipyretics

• Alternating paracetamol and ibuprofen is practiced, particularly in children, for more sustained fever control
• Combining simultaneously can potentiate GI toxicity of NSAIDs
• Recent systematic review (PMID: 39779424) found parents/caregivers prefer ibuprofen for children due to longer duration of action and single-dose efficacy

7. Non-Pharmacological (Physical) Cooling

• Tepid sponging (lukewarm water, 29-32°C) - promotes evaporative cooling
• Removing excess clothing and bedding
• Adequate oral hydration
• Cooling fans (avoid cold water - may cause vasoconstriction and shivering, increasing core temp)
• Cooling blankets - reserved for hyperpyrexia; should always be used alongside antipyretics, not alone

8. Special Situations

Febrile Seizures (Children)

• Treat fever promptly with paracetamol/ibuprofen
• Diazepam (rectal/IV) for active seizure
• Recurrence prophylaxis with antipyretics during subsequent febrile illness

Fever in CNS Injury/Brain Trauma

• Even modest fever (>37°C) worsens neuronal injury
• Aggressively treat with antipyretics; cooling blankets if refractory
• Surface or intravascular temperature control devices for refractory fever

Fever in Pregnancy

• Paracetamol is the antipyretic of choice
• Avoid NSAIDs (especially after 20 weeks - premature closure of ductus arteriosus)
• Note: emerging data (PMID: 42500177) on prenatal paracetamol exposure and autism spectrum disorder risk requires cautious, judicious use

Fever in Neutropenic Patients

• Defined as single oral temperature >38.3°C (101°F) or ≥38°C (100.4°F) sustained for >1 hour
• Medical emergency - initiate empirical broad-spectrum antibiotics within 1 hour
• First-line monotherapy: cefepime, meropenem, piperacillin-tazobactam, or ceftazidime
• Add vancomycin if: sepsis, suspected MRSA, catheter-site infection, or severe mucositis

Fever in Dengue

• Paracetamol only - strict avoidance of aspirin and NSAIDs

Drug Fever

• Discontinue suspected causative agent; fever resolves within 24-72 hours

9. Summary Algorithm

Fever detected (>37.7°C oral)
       ↓
Fever or Hyperthermia?
       ↓                     ↓
    FEVER              HYPERTHERMIA
(set point raised)    (set point normal)
       ↓                     ↓
Treat underlying      Physical cooling
cause + antipyretics  (NOT antipyretics)
       ↓
Is treatment indicated?
• Temp >38.5°C with discomfort
• Hyperpyrexia (>41°C)
• High-risk patient (cardiac, CNS)
       ↓
FIRST LINE: Paracetamol 500-1000 mg q4-6h (max 4 g/day)
± NSAID (ibuprofen 400 mg q6h) if anti-inflammatory needed
+ Non-pharmacological: tepid sponging, fluids, rest
       ↓
Identify and treat the UNDERLYING CAUSE

• Harrison's Principles of Internal Medicine 22E (2025) - Chapter 20: Fever (Dinarello & Surana), p.177-180
• Katzung's Basic and Clinical Pharmacology 16E - Acetaminophen/Antipyretics, p.1027
• Rosen's Emergency Medicine - Fever vs. Hyperthermia, p.2788