Does the use of antipyretics in children prolong
febrile illness?
David King
Clinical Research Fellow
05/09/2013
Clinical scenario
• A 13 month old is admitted with a temperature of
39.6ᵒC with no obvious focus
• Currently sleeping
• Nurse asks for regular antipyretics to be
prescribed “to keep the child comfortable”.
• You wonder if there is any evidence that regular
antipyretics can be harmful in this situation
Clinical question
In children with an acute febrile illness (population)
does the use of antipyretics (intervention)
compared to no antipyretics (comparison) prolong
the time to resolution of the fever (outcome)?
Search strategy
• Pubmed
(http://www.ncbi.nlm.nih.gov/pubmed/)
searched with the terms “antipyretic AND prolong
AND illness”
– 5 results
– 1 systematic review
The Journal of Pediatrics, Volume 163, Issue 3, September
2013, Pages 822–827.e2
Background to the study
• Fever is an important part of the response to
infection
• Animal studies show that fever associated with an
increase in survival
• Fever is an evolutionarily conserved trait
?beneficial
• Some studies indicate illnesses can be prolonged
by antipyretics
“Fever phobia”
• Term coined in the 1980s
• Parents and healthcare professionals rush to
treat fever and are not satisfied until apyrexial
– “They can go home if their temperature stays down”
– “We’ll do bloods if they spike again”
– “Their temperature is still raised; can you prescribe
ibuprofen?”
– “When you go home give paracetamol and ibuprofen
regularly for a couple of days”
Studies eligible for inclusion
• Randomised or quasirandomised controlled trial in which
the authors compared one antipyretic drug with another
– Primary outcome method was time to resolution of fever
– Secondary outcomes were infection-specific indications of
disease resolution
Search strategy
• Medline/Embase/Google scholar searched
– Freetext and MeSH filter
• “freetext and MeSH term (ie, Medical Subject Headings;
where applicable): child, children; temperature, fever,
acetaminophen, antipyretic, ibuprofen, NSAID, paracetamol,
antibodies; and behavioral symptoms or symptoms, fever
clearance, healing, recovery
• RCT filter applied
• Reference lists checked by hand – no additional studies
found
Results
Details of the included studies
• Three studies in children with malaria
– Paracetamol compared with placebo
– Naproxen compared with placebo
– Ibuprofen compared with placebo
• One study in children with varicella
– Paracetamol compared to placebo
– Excluded as no information on time to fever resolution
• Two studies in children with presumed viral
illnesses/fever of unknown origin
– Paracetamol compared with placebo
Primary outcome
Slightly shorter duration of fever
with antipyretics
Did they use the right data...?
Secondary outcomes
No difference in any of the other
signs/symptoms of infection
Discussion
• No evidence that antipyretics prolong febrile illness in the
trials studied (in terms of time to fever resolution)
• Authors also state that data on other outcomes such as
malaria parasite clearance and time to symptom
resolution shows no effect of antipyretics
Critical analysis
Critical analysis (2)
Critical analysis (3)
• Was it reasonable to combine the results of the
studies?
–
–
–
–
Several illnesses studied
Malaria, varicella, viral illnesses
Different antipyretics
Although statistical heterogeneity low, still very
different illnesses and treatments – are they
equivalent?
– Quality of the studies variable
Critical analysis (4)
• What are the results of the review and how
precise are they?
– No difference in time to resolution of fever when
antipyretics used
– Some of the results look statistically suspect
Critical analysis (5)
• Can the results be applied to the local population?
– Majority of studies examined children with malaria
– Only two looked at children with viral illness or fever of
unknown origin
– Results may be applicable but different populations and
illnesses
– None of the studies examine combining antipyretics
Critical analysis (6)
• Were all important outcomes considered?
– No
– The results of two studies were not acknowledged in the
discussion
• Brandt et al – time to clearance of malaria parasites
significantly prolonged in patients taking paracetamol
• Doran et al – time to scabbing of varicella lesions significantly
prolonged in children taking paracetamol
• Discussed with authors via email
– Not felt to be “clinically significant” but discussion could be
clearer – writing follow-up letter to clarify
Summary
• Available evidence does not indicate that antipyretics
prolongs febrile illnesses
• However, majority of studies conducted in children
overseas with malaria
• Is this applicable to our population?
• Is this true when paracetamol/ibuprofen combined?
• Further research required