What antipyretic to give to a patient with persistent fever after administering paracetamol (acetaminophen)?

Management of Persistent Fever After Paracetamol

Add ibuprofen as the next-line antipyretic agent for persistent fever after paracetamol administration. 1, 2

Immediate Pharmacological Management

Ibuprofen is the recommended addition when fever persists after paracetamol, with evidence demonstrating superior antipyretic efficacy and longer duration of action compared to paracetamol alone. 3, 4

Dosing Recommendations

• Adults: Ibuprofen 400-600 mg orally or intravenously 5
• Children: Ibuprofen 10 mg/kg per dose, administered every 6-8 hours (maximum 3 doses in 24 hours) 1, 6
• Paracetamol's maximum antipyretic effect may take up to 4 hours to manifest, so consider waiting this duration before adding ibuprofen if the clinical situation permits 2

Evidence Supporting Ibuprofen Addition

The combination approach is supported by multiple lines of evidence:

• Combination therapy provides 4.4 additional hours without fever over 24 hours compared to paracetamol alone and 2.5 additional hours compared to ibuprofen alone 6
• In the first 4 hours, combined therapy provides 55 additional minutes without fever compared to paracetamol alone 6
• Ibuprofen demonstrates faster fever clearance and greater temperature reduction than paracetamol, particularly effective in bacterial fever where it shows superiority within the first hour 7, 4
• IV formulations of both drugs (1000 mg paracetamol vs 400 mg ibuprofen) show equivalent efficacy in adult emergency department patients 5

Important Safety Considerations and Contraindications

When to Avoid or Use Caution with Ibuprofen

• Reduce dose in patients with impaired renal function 3
• Avoid in patients taking aspirin for antiplatelet effects, as ibuprofen antagonizes aspirin's irreversible platelet inhibition 3
• Use with caution in patients >60 years or those with compromised fluid status or renal insufficiency due to gastrotoxicity and renal failure risk 1
• Absolutely avoid aspirin in children under 16 years due to Reye's syndrome risk 1
• Avoid NSAIDs in patients with history of severe cutaneous reactions (SJS/TEN, DRESS) 3

Dosing Safety Pitfalls

The maximum recommended doses of paracetamol and ibuprofen are exceeded in 8% and 11% of cases respectively when combination therapy is used. 6 To prevent this:

• Carefully record all dose times when using both medications 6
• Paracetamol: maximum 5 doses in 24 hours (every 4-6 hours) 1
• Ibuprofen: maximum 3 doses in 24 hours (every 6-8 hours) 1

Adjunctive Non-Pharmacological Measures

While adding ibuprofen, implement these supportive measures:

• Encourage adequate fluid intake up to 2 liters per day in adults to prevent dehydration 8, 3, 2
• Consider tepid sponging as adjunctive physical cooling for persistent high fever, though evidence from randomized trials is limited 3, 2
• Avoid having patients lie flat on their back, as upright positioning improves comfort 8

When to Escalate Care

If fever persists despite combined paracetamol and ibuprofen therapy, escalate care for:

• Signs of clinical deterioration or development of complications 2
• Concerning symptoms: altered mental status, severe headache, neck stiffness, or respiratory distress 2
• Conduct thorough evaluation for the source of fever and consider appropriate infectious workup and antibiotics as warranted 2

Special Clinical Context: COVID-19

For patients with COVID-19 specifically, paracetamol is preferred to NSAIDs until more evidence is available, though ibuprofen may still be considered if paracetamol fails and clinical benefit outweighs theoretical concerns. 8

Cost-Effectiveness Consideration

Combination therapy is actually the most cost-effective option for both the healthcare system and families due to reduced healthcare service utilization (£14 vs £20 for paracetamol alone vs £18 for ibuprofen alone), despite the additional medication cost. 6