Paracetamol plus ibuprofen for the treatment of fever in children (PITCH): randomised controlled trial
BMJ 2008; 337 doi: https://doi.org/10.1136/bmj.a1302 (Published 02 September 2008) Cite this as: BMJ 2008;337:a1302All rapid responses
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The authors don´t mention the range of temperatures they were
treating (we don´t know the initial media temperature in each group). I
think it would be adequate to mention that.
In addition, they don´t mention wich were the suspected causes of
fever. I consider this also important... as sometimes suspected initial
viral diseases modifies and complicates with bacterian diseases and also
it´s not the same treating rubella (mild fever) than flu (usually
higher)for example.
In my opinion the disconfort relief can be associated also to the
analgesic power of both ibuprofen and paracetamol, so i think this article
opens a way to investigate if the relief is associated to analgesic, or
antipiretic power or both.
By the way i find the article really interesting, and the discussion
rich, as i can see there are lots of ways of managing fever problems that
also modifies with the country we work in!
Competing interests:
None declared
Competing interests: No competing interests
In the rapid responses in relation to PITCH, I read words like 'surprised', 'misleading title', 'just an opinion' from Nicholas Moore, Director of Clinical Research/clinical pharmacology and the word 'astonished' from Anthony Harnden, University Lecturer in General Practice. (1,2) However, they did not use these words in relation to the PITCH study. On the topic of pharmacovigilance, Beasley's research article in the Lancet is not the first to bring up an association between paracetamol use and chronic non-communicable diseases. (3) Pharmacovigilance should be included in Dr Anthony Harnden's editorial message as pharmacovigilance is in the interest of the public. (4)
After the NICE guidance, it's actually astonishing to see a conclusion suggesting that "Parents, nurses, pharmacists, and doctors should use (anti-inflammatory) medicines to supplement physical
measures to maximise the time children spend without fever."
I read from a deputy editor that the BMJ looks out for 'error, weakness, or incompleteness in the original article. The senior research editor writes that the BMJ maintains the advice to the authors and "want it to be as scientifically accurate as possible." (5, 6)
Fickleness is the word that comes to mind: fickleness from academics that do not apply their appraisal skills to the PITCH studies but divert to other areas, conveniently overlooking the fact that PITCH
didn't use a placebo and as such can not conclude with advice on using anti-inflammatory drugs in feverish children. (7) Let alone the advice on maximising time without fever…
Hopefully people will now realise that fever phobia is iatrogenic. If academics want to contribute to the health of society and would follow their scientific line of thought properly they ought to reassess PITCH for the sake of children and not pitch for their own sake.
Furthermore the misleading and fever phobia seeding title on the front page of the BMJ "Which drug for feverish children?" and the picture on the index page of a sleeping child with a flannel on the
forehead with the title "Paracetamol plus ibuprofen for the treatment of fever in children.", need to be retracted as the message is not evidence based but is causing documented harm. Due to the high impact factor, publications in the BMJ carry a massive responsibility, in this case for the children in the world. Due to error, weakness and incompleteness" in the original article, appropriate action should be taken
by those involved and the BMJ should retract the printed conclusions of the PITCH studies.
Ibuprofen is a marker of soft tissue infection more than its cause. http://www.bmj.com/cgi/eletters/337/sep23_2/a1767#202402
Ibuprofen and soft tissue infections. http://www.bmj.com/cgi/eletters/337/sep23_2/a1767#202444
Kanabar D, Dale S, Rawat M. A review of ibuprofen and acetaminophen use in febrile children and the occurrence of asthma-related symptoms. Clin Ther. 2007 Dec;29(12):2716-23 http://www.ncbi.nlm.nih.gov/pubmed/18201589
Wouter Havinga. In the interest of the public. http://bmj.com/cgi/eletters/337/sep02_2/a1409#202312
Tony Delamothe, deputy editor, BMJ. Setting limits to infinite error http://www.bmj.com/cgi/content/full/337/sep25_1/a1823
Trish Groves, Deputy editor BMJ. No numbers in the abstract. http://www.bmj.com/cgi/eletters/337/sep02_2/a1302#202361
Wouter Havinga. PITCH: an indication of the level of emotion in relation to childhood fevers. http://bmj.com/cgi/eletters/337/sep02_2/a1302#201799
Competing interests: see http://www.bmj.com/cgi/eletters/337/sep02_2/a1409#202312
Competing interests: see http://www.bmj.com/cgi/eletters/337/sep02_2/a1409#202312
In adults, NSAIDs and Aspirin can cause 'allergic' side effects due
to intollerance of COX 1 inhibition and subsequent release of leukotreines
with resultant urticaria, angioedema, rhinitis, wheeze. This intollerance
may become more common in children if the NSAID Ibuprofen is used
frequently over the childhood years - and presumably this is more likely
to occur in 'fever phobic' parents. Admittedly, Ibuprofen is a relatively
weak nsaid, but it can still cause anaphylaxis in adults. Paracetamol can
also cause these COX 1 inhibitor intollerant reactions but only in highly
sensitised patients since it is a very weak inhibitor of COX.
I think promoting ibuprofen use in children may lead to trouble with
intollerance in the long term.
In addition, there is the question of Reye's syndrome which we feel may be
precipitated by using Aspirin in childhood. Am I the only person who
thinks Ibuprofen may have more of an Aspirin like effect, even though the
molecules of aspirin and paracetamol look more alike?
Could it not be that in future studies of the use of Ibuprofen in febrile
children that we end up seeing more asthma developing?
Marise McQueen
Competing interests:
None declared
Competing interests: No competing interests
Nicholas Moore is right, and this paper's abstract should have stated the number of participants. Our advice at http://resources.bmj.com/bmj/authors/types-of-article/research
asks authors of RCTs - such as this one - to provide a CONSORT-style abstract with a "results" subheading that states the number of participants randomised to each group.
For other types of study our advice asks for this subsection:
participants (instead of patients or subjects) - numbers entering and completing the study, sex, and ethnic group if appropriate. Give clear definitions of how selected, entry and exclusion criteria
We're sorry we didn't get the abstract right this time, and we're grateful for this important reminder.
Competing interests:
I'm the BMJ's senior research editor and I maintain our advice to authors
Competing interests: No competing interests
Congratulations to the authors for the interesting paper.
Pyrexia is a sign of healthy body's response to insult. The conventional
medical wisdom is to look for the cause of pyrexia, rather than
suppressing it. I agree, it is different in young children, as the febrile
child becomes irritable and difficult to manage at home. Both
acetaminophen and ibuprofen are effective antipyretic agents. I am sure
properly administered combination is safe and more effective (as
demonstrated in this study) than a single agent. But we shouldn't ignore
the efficacy of sensible physical measures, in our enthusiasm for
advocating pharmacologic treatments. I would use caution and restrict the
combination therapy to cases where single agents have failed in
controlling symptoms. We need more evidence before recommending ibuprofen-
paracetamol combination to public.
Competing interests:
None declared
Competing interests: No competing interests
Family Physicians and Pediatricians in Brazil normally prescribe
Paracetamol plus Dipyrone (that has proved its safety here)or Ibuprofen
only when fever comes up before 6 hours since last dose of one of them.
But they're not used at the same time. We normally use only one, 3
hours each, IF fever comes up before the intervall between the doses of a
single one.
Fever is a normal reaction of the body and the main problem about it
is febrile seizure, that has been proved not to harm (febrile seizure is a
normal reaction of the body and does not impair cognition, neurological
development or any other neurological condition).
So, I agree with the colleagues when they use paracetamol as the
first choice and associate other drugs only in cases they are needed.
1. Febrile Seizures: Clinical Practice Guideline for the Long-term
Management of the Child With Simple Febrile Seizures. Pediatrics
2008;121;1281-1286. http://www.pediatrics.org/cgi/content/full/121/6/1281
2. Anthony Harnden. Editorial: Antipyretic treatment for feverish
young children in primary care. BMJ 2008; 337:a1409.
http://www.bmj.com/cgi/content/extract/337
3. Martin Richardson, Monica Lakhanpaul and on behalf of the
Guideline. Assessment and initial management of feverish illness in
children younger than 5 years:summary of NICE guidance. BMJ 2007;334;1163-
1164. http://bmj.com/cgi/content/full/334/7604/1163
4. Brazilian Cochrane Centre. Dipyrone for acute primary headaches.
Cochrane Database Syst Rev. 2007 Apr 18;(2):CD004842
Competing interests:
None declared
Competing interests: No competing interests
The NICE guideline and development group already confirmed that thermometer results do not need treatment according to the treat discomfort with analgesics is still not verified with this study. Hay and colleagues have based their conclusion on speculation. This is outlined in their discussion under the heading "Implications of this research". The conclusion is not based on scientific results as the study did not include placebo but, as pointed out in the children with fever. The BMJ will make serious editorial mistakes if it decides to print the advice in the conclusion of this article - to consider treating fever with ibuprofen and to consider adding paracetamol - because it is based on speculation and furthermore, to have that conclusion promoted in the third sentence in the box which highlights "What this study adds". Thereby the BMJ adds weight to the hypnotic mantra The publication of that conclusion on the BMJ website has already had this seeding impact through reports in the press. (3) The conclusion that follows from this study, could such a way that they will be more confident to support the fever process in physiological patterns and benefits of childhood fevers. (4) Therefore, Hay and colleagues have conducted an important study that can contribute in opening up several lines of research, by people who are willing to think outside of the box.
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Competing interests:
None declared
Competing interests: Hay and colleagues state that ibuprofen and paracetamol can reduce temperature but these analgesics were not compared with placebo. Therefore it is also not clear if they provide additional statistical significant improvement in fever associated discomfort, or in activity levels in treated children as compared to placebo. 1
Recently, the BMJ published a clinical study according to which the
combination of ibuprofen and paracetamol is more effective in going
temperature down in children with fever (1). In turn, ibuprofen is more
effective as monotherapy than paracetanol in controlling this symptom;
that is why the authors conclude that for discomfort feverish children;
first it should be administrate ibuprofen and then consider adding
paracetamol for 24 hours in case of do not obtain the expected recovery.
However, there are a few reports that suggest an association between
the intake of ibuprofen or ibuprofen and paracetamol and an increased risk
to suffer from soft-tissue infections, some of them very serious such as
necrotizing fasciitis (2,3,4,5,6). Some of these studies shown an increase
of the risk arose from the intake of ibuprofen as monotherapy (2,3,5,6),
or the combination between ibuprofen and paracetamol (3,4); but at the
same time a few of them are very emphatic showing that there is not an
increase in the risk associated to the intake of paracetamol alone
(3,4,7).
The main risk factors for suffering from necrotizing fasciitis
associated to nonsteroideal anti-inflammatory drugs (NSAIDs) include age
(children) and a viral disease during the treatment. In fact, a French,
case (patients with soft tissue necrotizante infection)-control study,
published recently (6), documented that among 38 cases that were reported
to the National System of Pharmacovigilance between 2000 and 2004, 25
patients were exposed to ibuprofen and 24 patients had have chickenpox. In
the same study patients had a median age of 4 years old, and the adjusted
odds ratios for exposure to NSAIDs and for viral infection were 31,38 (IC
95% 6,40 – 153,84) and 17,55 (IC 95% 3,47 – 88,65) respectively.
It is quite interesting that in Hay´s et. al. study (1), 57 children
with viral diseases were included (36,5%), and although it says that five
children were hospitalized due to adverse serious events, it is not clear
how these events happened or none extra information besides the medication
taken is given.
To conclude, I think that is not possible to ignore the available
evidence, and although the combination of ibuprofen and paracetamol could
be more effective for treating fever in children, precautions have to be
taken when administrating this combination in children with viral
infections, especially in children with chickenpox, and in this population
the administration of paracetamol should be considered as monotherapy,
decreasing the risk of suffering from soft tissue infections such as
necrotizing fasciitis.
References
1. Hay A, Costelloe C, Redmond N, Montgomery A, Fletcher M,
Hollinghurst S, Peters T. Paracetamol plus ibuprofen for the treatment of
fever in children (PITCH): randomised controlled trial. BMJ. 2008; 337:
a1302.
2. Zerr DM, Alexander ER, Duchin JS, Koutsky LA, Rubens CE. A case-
control study of necrotizing fasciitis during primary varicella.
Pediatrics. 1999; 103: 783 - 790.
3. Lesko SM, O'Brien KL, Schwartz B, Vezina R,
Mitchell AA. Invasive group A streptococcal infection and nonsteroidal
antiinflammatory drug use among children with primary varicella.
Pediatrics. 2001; 107:1108 -1115.
4. Lesko SM. The safety of ibuprofen suspension in children. Int J
Clin Pract Suppl. 2003; 135: 50 - 53.
5. Leroy S, Mosca A, Landre-Peigne C, Cosson MA, Pons G. Ibuprofen in
childhood: evidence-based review of efficacy and safety. Arch Pediatr.
2007; 14: 477 - 484.
6. Souyri C, Olivier P, Grolleau S, Lapeyre-Mestre M; French Network
of Pharmacovigilance Centres. Severe necrotizing soft-tissue infections
and nonsteroidal anti-inflammatory drugs. Clin Exp Dermatol. 2008; 33: 249
-255.
7. Mikaeloff Y, Kezouh A, Suissa S. Nonsteroidal anti-inflammatory
drug use and the risk of severe skin and soft tissue complications in
patients with varicella or zoster disease. Br J Clin Pharmacol. 2008; 65:
203 - 209.
Competing interests:
None declared
Competing interests: No competing interests
Congratulations on a very interesting paper, that shows that adding
paracetamol to ibuprofen may have some benefit, but only after the first
four
hours, when the mean temperature is already under 37. Within the first
four
hours, which is probably what parents look for, ibuprofen acts better and
faster than paracetamol, as has already been demonstrated many times for
fever in children and for pain in adults. In this period, ibu+para is
marginally
better than ibu alone. Maybe the best might be to use ibu+para for the
first
dose, then continue on ibu alone (or para alone) - this might be another
interesting study, possibly avoiding the complex dosing schedule shown
here.
Two points that surprised me, however:
- Nowhere in the abstract is the number of patients included in the study
mentioned. Considering the importance of sample size in study evaluation,
this is very surprising. Or I missed it, but I read the abstract through
word by
word 3 times (at least). In the text, there is a long paragraph on
recruitment
difficulties, but it is nowhere written: "in the end 156 patients were
included
or randomized or analyzed, 52 in each group", though of course this
information can be found in tables or figures.
- The authors cite an ancillary result of sam Lesko's study, concerning
excess
asthma in children on paracetamol, but not the main study paper, which
might have been appropriate, since this study in 84000 patients
established
the equivalent safety of ibuprofen and paracetamol used to treat fever in
children. (Lesko SM, Mitchell AA.
An assessment of the safety of pediatric ibuprofen. A practitioner-based
randomized clinical trial. JAMA. 1995 Mar 22-29;273(12):929-33.)
Otherwise a very nice paper
Competing interests:
None declared
Competing interests: No competing interests
A missed opportunity.
This study by Hay et al used the maximum recommended dose of
ibuprofen and a 'standard' dose of paracetamol and so was not comparing
like with like - a missed opportunity funded by the HTA. Ibuprofen has
already been shown by a number of other studies (some cited in Hay's
paper) to be superior to paracetamol in terms of temperature reduction and
duration of action, however all of these studies were either of poor
methodological quality and/or used small doses of paracetamol vs maximum
doses of ibuprofen. The question of 'superiority' of the two drugs
therefore still unfortunately remains unanswered.
I totally agree with Purssel's response and that educating healthcare
professionals and parents that having a temperature is not a dangerous
thing in itself and is actually part of the body’s defence system to fight
infection. There is no need to treat it unless the child is very
uncomfortable or distressed by it, and if so we should treat these
symptoms NOT a thermometer reading. Evidence available shows that the use
of anti-pyretics does not prevent febrile convulsions.
Hay's study also showed that 6-13% of parents made errors in drug
administration & exceeded the maximum recommended daily dose of one or
both drugs when asked to give the two preparations even under these
clinical trial conditions. Surely this supports NOT recommending combining
the two drugs by parents at home given the lack of firm evidence that
combination is superior in terms of valid outcomes i.e. patient
distress/discomfort.
Sharon Conroy
Competing interests:
I was a member of the NICE guideline development group for the management of feverish illness in children.
Competing interests: No competing interests