1. Re:Please correct me if I am wrong ...

    Thank you for taking the time to respond to the paper. What we need to be quite clear about is the purpose and safety of this therapy. Antipyresis is not a necessary outcome, we know that many parents worry a lot about fever and this is a fear that is shared by quite a lot of parents. We also know that we have two very good drugs, which are generally very safe.

    By combining drugs we are saying to parents firstly that they should worry (we are after all giving multiple drugs to treat it); and secondly using a regimen for which the safety has not been established or which might confuse parents leading to misdosage. In order to justify such an approach the benefit would have to be large, and these data do not show a significantly large benefit, bearing in mind that we are aiming for an unnecessary outcome.

    The last part is of course, my interpretation of the data.

    Conflict of Interest:

    Author of the paper

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  2. anecdotal evidence should provisionally inform clinical practice

    Notwithstanding the statement made in the recommendation made by the Italian Pediatric Society Guidelines that "paracetamol and ibuprofen are generally well tolerated[as antipyretics]...when used at the recommended dosage"(1), and also notwithstanding the fact that "there are few data regarding toxicity[of either ibuprofen or paracetamol]..." and that "no conclusions can be reached regarding safety of any treatments"(2), there is ample scope for "rules of thumb" to be derived from anecdotal reports so as to inform safe clinical practice. Two such reports stand out, one giving an account of renal toxicity attributable to the sole use of nonsteroidal anti-inflammatory drugs(NSAIDs)(including ibuprofen 11.5-32 mg/kg/day in 6 instances, and ketoprofen in one instance)(3), and another dealing with hepatorenal toxicity following the combined use of ibuprofen and paracetamol(4). In the report of renal failure solely attributable to NSAIDs seven children aged, 4,5,9,13,14,and 15 were implicated, and only one had previous renal disease. Four presented with gastroenteritis and fever, one with vomiting associated with varicella, one with pneumonia, and another with fracture. The median(range) treatment duration was 3(1-5) days. During the course of renal failure serum creatinine peaked at 171, 208, 240, 280, 331, 384, and 648 mcmol/l, respectively, the latter in a 9 year old girl with gastroenetritis and no previous renal disease. She had taken NSAIDs for only 2 days. The median(range) delay until normalisation of serum creatinine was 7(3-8) days after discovery of renal failure. In their discussion of the report, the authors highlighted the potential danger of NSAIDs in volume depleted patients given the fact that, despite the requirement for prostaglandins to be mobilised in such situations, so as to safeguard the integrity of renal function, NSAIDs undermine renoprotection by inhibiting prostaglandin synthesis(3). The account of hepatorenal toxicity relates to the combined use of ibuprofen and paracetamol in a 5 year old girl admitted to hospital for treatemet of febrile convulsions associated with vomiting. During her hospital stay ibuprofen was admnistered as 5mg/kg/dose every 8 hours for a total of 3 doses alternating with paracetamol 11 mg/kg/dose for a total of 2 doses. On the fifth hospital day her serum creatinine had increased from its admission level of 0.60 mg/dl to 6.34 mg/dl with concurrent aspartate transaminase and gammaglutamyl transaminase levels of 144 iu/l, and 1394 iu/l, respectively, both of the latter parameters having been within the normal range on admission. By day 60 all abnormal parameters had reverted to the normal range. The "take away" message here was that "the combined ibuprofen and acetaminophen treatment, even if administerd at therapeutic dosages and in a reduced number of doses, may be dangerous in conditions of volume depletion"(4) References (1) Chiappini E., Principi N., Longhi R et al Management of fever in children: Summary of the Italian Pediatric Society Guidelines Clinical Therapeutics 2009;31:1826-1843 (2) Purssell E Systematic review of studies comparing combined treatment with paracetamol and ibuprofen, with either drug alone Arch Dis Child 2011;96:1175-79 (3) Ulinski T., Guigonis V., Dunan O., Bensman A Acute renal failure after treatment with non-steroidal anti-inflammatory drugs Eur J Pediatr 2004;163:148-150 (4)Zaffanello M., Brugnara M., Angeli S., Cuzzolin L Acute non-oliguric kidney failure and cholestatic hepatitis induced by ibuprofen and acetoaminophen: a case report Acta Paediatrica 2009;98:901-9

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    None declared

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  3. Please correct me if I am wrong ...

    I'm a busy paediatrician and commonly commit the sin of reading an article's conclusions and ignoring the data presented. In that context I was amazed to see the dissonance between the conclusions of both the editorial and the paper "Systemic review of studies comparing combined treatment with paracetamol and ibuprofen, with either drug alone" with the actual data presented. The conclusions of both seem to have been clearly written in the minds of both authors well in advance of thinking what the data say. I read the following conclusions. "There is little evidence of benefit or harm from combined treatment compared with the use of each drug alone." "Most studies showed some additional reduction in temperature . . . this rarely reached clinically or statistically significant levels." Considering the need for further research, ". . . resources should be targetted elsewhere."

    Compare these comments to the data. Temperature differences as large as 0.6, 1.1 and 1.2 degrees centigrade with significance levels p = 0.002 and p<0.001. Nearly half more of the combined group afebrile at 7 and 8 hours compared to single treatment groups! Explain that as of no importance to the parents involved and consider their incredulous expressions! Similarly try explaining this to the families of the 27% of children that were still pyrexial at 2 hours and at 4 hours that wouldn't have been if a combined treatment had been given. Or perhaps try minimising the superiority of a treatment that reduced reduced a symptom by 4 and a half hours per 24 hours more than the standard treatment with a statistical significance level of 0.001.

    Both the editorial and the article make the important point that the temperature is a potentially misleading surrogate for the real treatment aim of promoting patient comfort during illness. It is a non-sequitur however to present all this evidence on temperature with lack of evidence on comfort and conclude that combination therapy should be avoided and not further studied. These latter conclusions are simply not supported by the evidence presented in any way whatsoever.

    While Purssell may well be proved right in time I can think of a number examples of strong opinions presented in discussion and conclusion parts of papers which represent the author's beliefs rather than a dispassionate induction from the data or argument presented. (MMR scandal, delay in routine use of antenatal steroids with threatenned pre-term birth) Could our editors please point these out when they occur rather than simply echoing them?

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