1. Does the use of antipyretics in children prolong febrile illness? David King Clinical Research Fellow 05/09/2013

2. Clinical scenario A 13 month old is admitted with a temperature of 39.6C 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

3. 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)?

4. Search strategy Pubmed (http://www.ncbi.nlm.nih.gov/pubmed/)http://www.ncbi.nlm.nih.gov/pubmed/ searched with the terms “antipyretic AND prolong AND illness” –5 results –1 systematic review

5. The Journal of Pediatrics, Volume 163, Issue 3, September 2013, Pages 822–827.e2

6. 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

7. “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”

8. 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

9. 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

11. Results

12. 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

13. Primary outcome Slightly shorter duration of fever with antipyretics

14. Did they use the right data...?

15. Secondary outcomes No difference in any of the other signs/symptoms of infection

16. 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

17. Critical analysis

18. Critical analysis (2)

19. 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

20. 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

21. 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

22. 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

23. 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