Antipyretic drugs for children
BMJ 2006; 333 doi: https://doi.org/10.1136/bmj.333.7557.4 (Published 29 June 2006) Cite this as: BMJ 2006;333:4
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The initial paper concerning the use of paraceetamol and ibuprofen in
children is a well thought out and balanced paper stating there is really
no
indication for simultaneous or alternate use of ibuprofen and paracetamol
in
children with fever. Whether fever needs to be treated is still debated,
and it
probably only needs to be treated when it becomes pathological. In the
recurrent desire to treat fever, there may be remnants of the times when
fever
in children often closely preceded death from infectious disease...
That being said, some of the responses to this topic concerning
relative risks
from paracetamol or ibuprofen (NSAIDs) are very strange: they rely on case
-
control studies, results of irrelevant usage (high-dose, long term risks
in
adults) and animal experiments to try to state that NSAIDs are more
dangerous than paracetamol (which may be true in the absolute, but not in
this specific case). For some strange reason I had always thought that the
double-blind randomised controlled trial was the referecne methodology to
answer medical questions. In this field there is a major clinical trial
that
shows equal tolerability of ibuprofen and paracetamol in children with
fever
(1), including in those below 2 years of age (2), but is somehow not
cited.
Concerning observational studies, since ibuprofen is generally more
effective
than paracetamol, it will be used when paracetamol fails, i.e., in more
severe
infections, often when high fever is a harbinger of complications which
may
then be attributed to ibuprofen (something called the protopathic bias:
blaming the messenger for the message) (3).
When protopathic bias is likely, good clinical trials will give answers.
Recent
history in many fields (eg, HRT) should help us not forget this.
That being said, of course, the first treatment of fever in children,
if needed,
is rehydration and cooling, which will reduce the risk of renal failure,
which
does exist with ibuprofen, even if it is rare (4). Reducing the use of
paracetamol will also reduce therisk of inadvertent overdosing, still the
first
cause of liver failure in small children (5).
1. Lesko SM, Mitchell AA. An assessment of the safety of pediatric
ibuprofen.
A practitioner-based randomized clinical trial. Jama 1995;273(12):929-33.
2. Lesko SM, Mitchell AA. The safety of acetaminophen and ibuprofen among
children younger than two years old. Pediatrics 1999;104(4):e39.
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(5):1108-15.
4. Lesko SM, Mitchell AA. Renal function after short-term ibuprofen use in
infants and children. Pediatrics 1997;100(6):954-7.
5. Mahadevan SB, McKiernan PJ, Davies P, Kelly DA. Paracetamol induced
hepatotoxicity. Arch Dis Child 2006;91(7):598-603.
Competing interests:
None declared
Competing interests: No competing interests
Editor - Hay et al (1) address in their editorial on antipyretics in
children a very important topic including the lack of evidence that two
drugs are more advantageous than monotherapy and absence of evidence of
effectiveness for drug therapies compared with physical methods in
reducing fever. I disagree though with their statement that given the
desire from parents and clinicians to do something when faced with febrile
children it is churlish to withhold combined drug treatment even when
lacking evidence. Benefits of mild to moderate fever have been well
described and in a very comprehensive review Walsh and Edwards (2)
describe the lack of parents’ knowledge about normal body temperature,
correct dosage or role of antipyretics. This has resulted in a nearly
trebling of overdosing in the last 20 years and increase in unnecessary
use of healthcare services.
The results of the randomised controlled trial Hay and colleagues are
currently conducting (http://www.controlled-
trials.com/isrctn/trial/|/0/26362730.html) into drugs therapy of fever are
desperately needed but clearly, fever management is more than assessing
drug effectiveness and should include education of parents and health care
professionals about the benefits of mild to moderate fever and the role
antipyretics may play.
1 Hay et al. Antipyretic drugs for children. BMJ 2006; 333:4-5
2 Walsh A, Edwards H. Management of childhood fever by parents:
literature review.
J Adv Nurs. 2006 Apr;54(2):217-27.
Competing interests:
None declared
Competing interests: No competing interests
I was also surprised to read the editorial on antipyretic drugs for
children that did not mention the causal relation of salicylate to Reye's
syndrome in human and higher mortality in infected animals treated with
non-steroidal anti-inflammatory drugs (NSAIDs) compared with vehicle
control.
I have collected nine papers which reported 15 animal experiments to
investigate the effects of NSAIDs on mortality in infected animals.
Various NSAIDs were used including ibuprofen, flurubiprofen, mefenamic
acid, indomethacin, salicylate and so on. Mantel-Haenztel pooled odds
ratio for NSAIDs use on mortality was 10.00 (95% confidence interval (CI):
6.12-30.06, p<_0.00000001 _1.="_1." p="p"/> Another evidence available is a case-controlled study reported in the
Japanese Task Force's case control study on factors related to onset
and severity of influenza-related encephalopathy [2]. Strong relation
between the NSAIDs use and fatal influenza-related encephalopathy was
observed: crude odd ratio was 47.4 (95%CI; 3.29-1458, p=0.0019)[1,2],
though the task force reported that the study could not demonstrate any
definite relation of NSAIDs to occurrence of influenza-related
encephalopathy. Odd ratio for paracetamol was not significant (OR 2.25;
95%CI; 0.19-58.6) [1,2].
After the warnings against and restriction on use of salicylates,
Reye's syndrome disappeared in the U.S [3]. Also, restriction on use of
NSAIDs as antipyretics in Japan in 2001 led to dramatic decrease not only
in proportion of NSAIDs users (about 30 % to less than 7 %) in treating
fever but also in proportion of fatal cases (about 30 % to about 10 %)
among Reye's syndrome and/or post-viral infection encephalopathy
(including influenza-related encephalopathy) [4].
Many cases of neurological complication in previously healthy
children with influenza were reported in the United States recently [5].
I am very much concerned that increasing use of ibuprofen not only in
the US but also in Europe might contribute to the complicated morbidity
and mortality in flu children instead of salicylates for Reye's syndrome
in 1960s to 1980s worldwide or other NSAIDs antipyretics as a cause of
epidemics of post-viral infection-encephalopathy (including influenza-related encephalopathy) before 2001 in Japan.
I am also concerned about the sudden deaths during sleep and
accidental deaths after abnormal behavior after taking oseltamivir.
Oseltamivir phosphate may decrease body temperature for it acts as central
nervous system suppressants like barbiturates [6].
These two drugs (ibuprofen and oseltamivir) should be closely
monitored but should not be confused in epidemiological studies because
the spectra of the adverse effects caused by each drug are different:
ibuprofen may exacerbate infection and inflammatory responses (indicated
by the study [7]: paracetamol-ibuprofen combination was less effective
from 10 hours to 24 hours), inducing multi-organ failure including brain,
liver and so on in worst cases because they enhance induction of
cytokines[8]; on the other hand oseltamivir phosphate could suppress
central nervous system leading to sudden deaths from respiratory
suppression during sleep or accidental deaths after abnormal behavior [6].
References
1.Hama R. The Informed Prescriber. 2005 ; 20(12); 147-151 (in
Japanese, preliminary report)
2.Japanese Task Force. A case control study on factors related to
onset and severity of influenza-related encephalopathy: Result: Report of
the 2002 study. March 2003 (in Japanese)
3.Belay ED, Bresee JS, Holman RC et al. Reye's syndrome in the United
States from 1981 through 1997. N Engl J Med. 1999 May 6;340(18):1377-82.
4.Hama R. unpublished data.
5.Shay D. Surveillance among U.S. Children for Influenza-Related
Mortality and Encephalopathy.
http://www.fda.gov/ohrms/dockets/ac/05/slides/2005-4180s_06_shay.ppt
6.Hama R. Limited benefit and potential harm of oseltamivir including
sudden death and death from abnormal behavior: Rapid response on 26
November 2005 http://bmj.bmjjournals.com/cgi/eletters/331/7526/1203-
b#122513
7.Lal A, Gomber S, Talukdar B. Antipyretic effects of nimesulide,
paracetamol and ibuprofen-paracetamol. Indian J Pediatr 2000;67: 865-
70.[Medline]
8.Larrick JW, Kunkel SL. Is Reye's syndrome caused by augmented
release of tumour necrosis factor? Lancet. 1986 Jul 19;2(8499):132-3.
Competing interests:
None declared
Competing interests: No competing interests
As a health visitor I read with interest and some confusion the
Editorial and responses to this subject. Gary Nicholls suggests tepid
sponging but research is conflicting on whether or not it is effective in
lowering temperatures. Also, according to other recent research giving
paracetamol and ibuprofen alternatively is the best method for lowering
children’s temperature (Sarrell E. Michael et al. Antipyretic Treatment in
Young Children With Fever: Acetaminophen, Ibuprofen, or Both Alternating
in a Randomised, Double blind Study. Pediatrics & Adolescent Medicine
2006; 160:197-202.)
In my experience many mothers become afraid when their young child
has a fever or a temperature and may not be susceptible to the advice
that it's OK for the child to be 'burning up' as some of them say. We must
remember too that NHS immunisations fact sheets advise parents to give
paracetamol or ibuprofen to treat a 'fever' if this occurs after babies
are given their primary immunisations, or MMR.
I always try to make a point of advising parents that at some time
their baby is bound to be unwell and to advise them if he has a
temperature not to wrap the baby up as is often the instinct of some
parents but to undress the baby and keep him cool. Also to offer extra
clear fluids or extra breastfeeds. Perhaps in future however,rather than
advise that a child with a fever is also given paracetamol or ibuprofen if
necessary I should simply tell parents to check with their GP first!
June Thompson
Health visitor, London
Competing interests:
None declared
Competing interests: No competing interests
Children with fevers are often miserable and appear unwell, worrying
doctor and parent, especially if the focus is not immediately obvious.
When the fever is controlled, the kid usually perks up dramatically.
In a more seriously ill child, this probably wouldnt happen. So response
to antipyretics is a useful way of triaging serious causes of fever from
non-serious. A response is reassuring to parents and doctor and the child
feels better. If I have a fever, I feel lousy. A couple of ibuprofen
later, I feel better.
Having spent 6 months in childrens A+E, I cant imagine not treating
febrile children.
Competing interests:
None declared
Competing interests: No competing interests
Some of my thoughts for you... Most importantly, no child should have
to endure 'Pain' and if pain is being treated, then paracetamol should be
used first, but Ibuprofen can be added in.
Paracetamol is always first line treatment for kids that need to be
treated - BUT there is no evidence base that giving antipyretic drugs
'prevents' febrile convulsions - only benzodiazepines have been shown to
perhaps do this.
Studies done comparing Ibuprofen and Paracetamol used a smaller dose of
paracetamol than is normally given and so the results are skewed.
Fevers of below 38.5 centigrade are helpful in the body's immune response
- and thus treating them is actually not beneficial.
Simple regimens are best for parents and prevent confusion. The use of one
agent - a single bottle with one syringe/measuring spoon prevents the
wrong dose being given, and telling them to get the child reviewed if
concerned, and in any case within 24 hours unless they are well again -
allows for appropriate review.
The use of alternate doses of drugs can cause error.
Recommend tepid sponging, and offer an icy-block or ice-lolly/icecream -
it usually helps at least build some rappor with the child!
Competing interests:
None declared
Competing interests: No competing interests
Antipyretic drugs for children
I was surprised to read an editorial on antipyretic drugs for
children that expressed no reservations regaring the need for such
medication.1 Thomas Sydenham, the famous seventeenth century physician
wrote:. “Fever is nature’s engine which she brings into the field to
remove her enemy.”2 How is it that, more than 300 years later, physicians
are still treating fever as a disorder rather than a defence mechanism?
Do we still believe that Molly Malone ‘died of a fever’, rather than from
the typhoid bugs in her cockles and musssels?!
The authors end their review with a warning that by prescribing two
drugs instead of one for the treatment of pyrexia, we may be encouraging
fever phobia. This is ironic. By prescribing drugs instead of recommending
equally effective environmental measures to prevent hyperpyrexia, the
medical profession is increasing fever phobia and failing to educate the
public on the significance of fever.3
1.Hay AD, Redmond N, Fletcher M. Antipyretic drugs for children. BMJ
2006;333:4-5
2. Sydenham T. Methodus curandi fibres 1666
3. Fowler AW. Fever-friend or foe, in Modern Medicine and the Bible,
Ortho Books, 2003
Alan W Fowler FRCS
High View, Litchard Rise,
Bridgend, CF31 1QJ
Competing interests:
None declared
Competing interests: No competing interests
Further to the issues raised by Hay et al1 regarding combination
antipyretic therapy, there appear to be growing concerns about first line
treatment of pyrexia and pain in children.
The All Wales Prescribing Advisory Group2 recently discussed the
observation that both parents and doctors may be using ibuprofen not only
in combination, but increasingly as the first line antipyretic/analgesic.
Prescribing data3 suggests that the number of prescribed items of
paracetamol 120mg/5mls have stayed constant between 2004 and 2006 (based
on January-April Welsh data) whereas ibuprofen 100mg/5mls items have
increased by approximately 30% over the same period.
Dr Hay1 notes that “Evidence on safety is also limited [paracetamol
and ibuprofen in combination]. Renal failure is associated with the use of
ibuprofen in dehydrated children …” The cBNF states that “in children
gastro-intestinal symptoms are rare in those taking NSAIDs for short
periods.”
However the adverse effect profile of non-steroidals in adults is
well documented: Adverse drug reactions have been shown to account for 6%
of hospital admissions and nonsteroidal anti-inflammatory drugs were
amongst the drugs most commonly implicated 4. Doctors have been advised
that paracetamol is a suitable first choice simple analgesic for most
patients with mild to moderate pain, as it is generally well tolerated and
effective.5
Both primary and secondary care physicians appear to have concerns
regarding the current treatment of pain and pyrexia in children.
References
1 Hay A et al, Antipyretic drugs for children. BMJ 2006;333:4-5
2
http://www.wales.nhs.uk/sites3/docmetadata.cfm?orgid=371&id=57962&pid=14033
3. Prescribing Services NHS Wales
4 Pirmohamed M et al. Adverse drug reactions as cause of admission to
hospital: prospective analysis of 18 820 patients. BMJ 2004; 329: 15-19
5 MeReC bulletin vol16 no4
http://www.npc.co.uk/MeReC_Bulletins/2006Volumes/Vol16_No4.pdf
Competing interests:
None declared
Competing interests: No competing interests
I do agree with the authors regarding the weakness in the studies
they looked at. I was interested in the duration of action ( antipyretic
time ) of either paracetamol or brufen. I would like to share a personal
experience which could be an idea for further research. I wonder if using
paracetamol and brufen at alternative time could lead to better control of
child's pyrexia. From my experience as a parent,it does work. My son,who
is now 12 years old,used to suffer from pyrexia very often in the fist 2
years of his life including one episode of febrile convulsion .His GP
advice was to alternate paracetamol with brufen every three hours and it
did work. Needless to say that was before we came to UK
Competing interests:
None declared
Competing interests: No competing interests
Could "desires" be evidence of higher level than a case-control study?
One of the reasons why I thought the editorial's conclusion [1] was
strange is that it did not deny the rationale of the combined treatment
based on the desires among parents and clinicians to do something when
faced with febrile children in the absence of evidence from controlled
trials.
Could desires be evidence in evidence-based medicine (EBM)? If ever
so, are they of higher levels than a case-control study with outcome of
mortality and/or systematic review of animal experiments with outcome of
mortality when RCT with outcome of mortality or sever morbidity has never
been available?
ISDB manual [2] stresses the importance of evidence level ranked by
the strength of endpoints. The manual was written by modifying a hierarchy
introduced by the US National Cancer Institute [3]: overall survival is
the strongest endpoint.
A large scale randomized controlled trial (RCT) comparing three arms
(paracetamol and two different doses of ibuprofen but without placebo-only
arm) was conducted [4]. It was a non-placebo-controlled trial and still
not large enough for comparison of mortality risks: mortality was not
included in the main outcome and no death case was observed. However low
white blood cell count was significantly more common and acute
gastrointestinal bleeding was more common but not significant in ibuprofen
groups than paracetamol group. The reason may be short of power to detect
significant difference in acute gastrointestinal bleeding, Reye's
syndrome or death.
I found another RCT comparing ibuprofen with placebo for severe
sepsis [5]. No difference was reported in mortality (40 % with placebo and
37% with ibuprofen) at 30 days, but baseline renal failure was
significantly more prevalent in placebo group than ibuprofen group (67 %
vs. 53 %).
The on-going randomised controlled trial by Hay and colleagues [6]
surprisingly does not have placebo-only arm though they say that there is
absence of evidence of effectiveness for mono-therapies compared with
physical methods of reducing fever or placebo [1].
I would like to add an excellent decision making by Meune et al on
the use of NSAIDs for the treatment of viral myocarditis[7]. In view of
animal studies and in the absence of controlled studies of aspirin and
NSAIDs they did not recommend indiscriminate treatment with NSAIDs or high
-dose aspirin in patients with myocarditis where there is no or minimal
associated pericarditis. Is there any difference for other viral
infections?
References
1.Hay AD, Redmond N, Fletcher M. Antipyretic drugs for children. BMJ
2006;333:4-5
2.International Society of Drug Bulletin(ISDB):
http://66.71.191.169/isdbweb/pag/documents/12reviewing.pdf)
3. US National Cancer Institute. A hierarchy of strength of
endpoints: http://www.cancer.gov/cancertopics/pdq/levels-evidence-adult-
treatment/)
4. 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.
5. Bernard GR, Wheeler AP et al. The effects of ibuprofen on the
physiology and survival of patients with sepsis. The Ibuprofen in Sepsis
Study Group. N Engl J Med. 1997 Mar 27; 336(13):912-8.
6. Hay AD et al. http://www.controlled-
trials.com/isrctn/trial/|/0/26362730.html
7. Meune C, Spaulding C. et al. Risks versus benefits of NSAIDs
including aspirin in myocarditis: a review of the evidence from animal
studies. Drug Saf. 2003;26(13):975-81.
Competing interests:
None declared
Competing interests: No competing interests