What are the first-line antipyretics (fever reducers) for a patient presenting with fever, considering factors such as medical history, age, and weight?

First-Line Antipyretics for Fever Management

Paracetamol (acetaminophen) 1000 mg orally every 4-6 hours (maximum 4 g/day) is the first-line antipyretic for all patients capable of oral intake, regardless of age, weight, or medical history. 1, 2

Dosing by Population

Adults

• Oral paracetamol 1000 mg every 4-6 hours is the standard first-line therapy (maximum 4 g/day) 1
• Paracetamol demonstrates superior cardiovascular safety compared to NSAIDs, with no reports of cardiovascular harm 1
• Gastrointestinal complications are equivalent to placebo (RR 0.80,95% CI 0.27-2.37) 1
• Dose reduction is required in hepatic insufficiency or history of alcohol abuse; contraindicated in acute liver failure 1

Pediatric Patients

• Paracetamol 15 mg/kg per dose is the recommended pediatric dose for both fever and pain management 3
• This dose is significantly more effective than placebo and at least as effective as NSAIDs when used appropriately 3
• Older studies using subtherapeutic doses ≤10 mg/kg showed inferior efficacy, which led to historical misconceptions about paracetamol's effectiveness 3
• Paracetamol is indicated for children of all ages, unlike NSAIDs which have age restrictions 3
• Tolerability profile is similar to placebo for short-term use, with lower risk of adverse events than NSAIDs for consecutive-day dosing 3

Route of Administration Hierarchy

The oral route should always be prioritized when feasible 1:

1. Oral paracetamol: First choice for all patients capable of oral intake 1
2. IV paracetamol: Reserved for patients unable to take oral medications due to persistent vomiting, altered mental status, or NPO status for surgical procedures (only when IV access exists) 1
3. IM paracetamol: Avoid due to injection site pain, tissue trauma, and risk of intramuscular hematoma (especially in anticoagulated patients) 1

When Paracetamol Alone Is Insufficient

If fever persists above 101°F (38.3°C) after paracetamol administration:

• Consider adding ibuprofen as second-line therapy 4
• Allow 4 hours for paracetamol to reach maximum antipyretic effect before adding additional agents 4
• Paracetamol may be less effective for temperatures exceeding 38°C (100.4°F) 4
• A combination of paracetamol 500 mg/ibuprofen 150 mg shows superior efficacy in bacterial fever at 1 hour compared to paracetamol alone (48.6% vs 33.6%, p=0.040) 5

Critical Clinical Context: When Antipyretics Don't Matter

Antipyretics are for symptomatic relief and patient comfort only—they do not improve mortality or clinical outcomes in critically ill patients 1, 6:

• Meta-analysis of 13 RCTs (n=1,963) showed no improvement in 28-day mortality (RR 1.03; 95% CI 0.79-1.35), hospital mortality, or shock reversal 1
• Routine use of antipyretics solely to reduce temperature is not recommended in ICU patients 1
• The median time to defervescence is 5 days in critically ill patients with hematologic malignancies and 2 days in solid tumors after appropriate antibiotics—persistent fever alone does not indicate treatment failure 6

Special Population Considerations

Febrile Seizures in Children

• Antipyretics do not prevent recurrence of febrile seizures, even when given regularly every 4 hours versus contingent on temperature elevation 7, 1
• Neither acetaminophen nor ibuprofen reduces febrile seizure recurrence risk 7
• Antipyretics may be used for comfort, but families should be counseled that seizure prevention is not an achievable goal 7

Stroke Patients

• Insufficient evidence exists to support aggressive antipyretic therapy for improved functional outcomes or survival in acute ischemic stroke 7, 1
• Treatment for comfort remains reasonable, but no recommendation can be made for treating hyperthermia to improve functional outcome (Quality of evidence: Low) 7
• Preventive antipyretics in normothermic stroke patients show no benefit for functional outcome (RR 1.02,95% CI 0.94-1.10) or mortality (RR 0.96,95% CI 0.74-1.23) 7

COVID-19

• Paracetamol is preferred over NSAIDs in COVID-19 patients until more evidence is available 1, 6
• NSAIDs should be stopped in severe COVID-19 with kidney, cardiac, or gastrointestinal injury 1

Septic Shock

• Normothermia targeting with antipyretics is suggested in septic shock 7
• One well-conducted trial showed reduced vasopressor support and duration of shock with temperature management, though no difference in ICU or hospital discharge mortality 7

Physical Cooling Methods: Not Recommended

Physical cooling methods (tepid sponging, fanning) cause discomfort and are not recommended 1:

• These methods increase patient discomfort without improving outcomes 1
• Cooling devices should only be considered for refractory fevers unresponsive to antipyretics 1
• Nursing measures such as reducing environmental stimuli, uncovering patients in hot weather, and lowering ambient temperature are preferred over active physical cooling 1

Common Pitfalls to Avoid

• Do not use subtherapeutic pediatric doses (≤10 mg/kg)—these are ineffective and perpetuate the myth that paracetamol is inferior to NSAIDs 3
• Do not escalate antipyretics or add agents solely because fever persists—focus on identifying the underlying cause through appropriate diagnostic workup (chest X-ray, blood cultures, CT imaging if post-surgical) 6
• Do not choose IM route when oral or IV options are available—IM administration causes unnecessary pain and bleeding risk 1
• Do not expect antipyretics to prevent febrile seizures in children—counsel families appropriately to avoid false expectations 7