Clinical Therapeutics/Volume 34, Number 7, 2012

Perspectives
Update of the 2009 Italian Pediatric Society Guidelines About
Management of Fever in Children
Elena Chiappini, PhD1; Elisabetta Venturini, MD1; Nicola Principi, MD2;
Riccardo Longhi, MD3; Pier-Angelo Tovo, MD4; Paolo Becherucci, MD5;
Francesca Bonsignori, MD1; Susanna Esposito, MD2; Filippo Festini, RN1;
Luisa Galli, MD1; Bice Lucchesi, RPh6; Alessandro Mugelli, MD7; and
Maurizio de Martino, MD1; Writing Committee of the Italian Pediatric
Society Panel for the Management of Fever in Children
1
Department of Sciences for Woman and Child’s Health, University of Florence, Anna Meyer Children’s
University Hospital, Florence, Italy; 2Department of Maternal and Pediatric Sciences, Fondazione IRCCS
Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, University of Milan, Milan, Italy; 3Pediatric
Unit, Sant’Anna Hospital, Como, Italy; 4Department of Pediatrics, University of Turin, Turin, Italy;
5
Primary Care Practice, Florence, Italy; 6Health Authority 1, Massa, Italy; 7Department of Preclinical and
Clinical Pharmacology, University of Florence, Florence, Italy

ABSTRACT Ther. 2012;34:1648–1653) © 2012 Elsevier HS Journals,

Background: In 2009, the Italian Pediatric Society de-
veloped national guidelines for management of fever in
children for health care providers and parents/caregivers;
an update of these guidelines was scheduled after 2 years.
Objective: This article summarizes the update of
Italian guidelines on managing fever in children, focus-
ing specifically on measuring body temperature and
using antipyretic agents.
Methods: Relevant publications in English and Italian
were identified through searches of MEDLINE and the
Cochrane Database of Systematic Reviews from January
1, 2008, to May 1, 2012. On the basis of consensus of a
multidisciplinary expert panel, evidence levels and
strength of recommendations were reviewed.
Results: Axillary temperature measurement using a
digital thermometer is recommended in children
younger than 4 weeks. In the hospital or ambulatory
care setting, axillary temperature measurement using a
digital or infrared thermometer (tympanic or skin con-
tact or nocontact) is recommended in children older
than 4 weeks. Paracetamol and ibuprofen are the only
antipyretic drugs recommended for use in children;
however, combined or alternating use of these agents is
not recommended.
Conclusions: Recent scientific evidence mainly sup-
ports previous recommendations. The aim of the present
article was to support pediatric knowledge and stimulate
application of guidelines in daily clinical practice. (Clin
Inc. All rights reserved.
Key words: Antipyretic, Children, Fever, Guidelines.
INTRODUCTION
Scientific evidence on the management of fever in children is
constantly changing. In 2009, the Italian Pediatric Society
developed national guidelines for managing fever in children
for health care providers and parents/caregivers.1 An update
of these guidelines was scheduled after 2 years. Herein is
presented a summary of the main results.
METHODS
Relevant publications in English and Italian were iden-
tified through searches of MEDLINE and the Co-
chrane Database of Systematic Reviews from January
1, 2008, to May 1, 2012. The search strategy used has
been described previously,1and is summarized in the
Supplemental Appendix available online at http://dx.
doi.org/10.1016/j.clinthera.2012.06.011. On the basis
of consensus of a multidisciplinary expert panel, evi-
dence levels and strength of recommendations were
reviewed. The full text of the guidelines and related
Accepted for publication June 8, 2012.
http://dx.doi.org/10.1016/j.clinthera.2012.06.011
0149-2918/$ - see front matter
© 2012 Elsevier HS Journals, Inc. All rights reserved.

1648 Volume 34 Number 7


documents are available at http://www.snlg-iss.it/cms/
files/LG_SIP_febbre_aggiornamento_2011.pdf.
RESULTS
Update on Body Temperature Measurement
in Children
Most of the previous recommendations for fever detec-
tion are supported by new data. In children older than 4
weeks of age, axillary measurement using a digital ther-
mometer is again recommended, although recent literature
is not available on this issue. The low evidence level and
strength of recommendations are related to the few studies
available and to their poor consistency.
In children older than 4 weeks, use of an infrared ther-
mometer (with or without skin contact or auricular) re-
mains controversial2–7; some authors support the use of
these devices.5–9 In particular, in a prospective study of
251 children, a significant correlation (P ⬍ 0.001) was
reported between axillary temperature measured using a
mercury-in-glass thermometer and mid-forehead temper-
ature measured using a noncontact infrared thermome-
ter. The noncontact infrared thermometer also has the
advantage of measuring body temperature in 2 seconds
and being comfortable for children.7 Temperatures ob-
tained via skin-contact infrared thermometers and rectal
thermometers were compared in a prospective cross-sec-
tional study of 42 children aged 1 to 4 years. That study
reported that the infrared thermometer predicts 83% of
fever detected via rectal temperature, and is an effective
screening tool for identifying fever in children in this age
group.5 Inaccuracy of infrared thermometers with or
without skin contact was found in 4 observational studies
in 100, 198, 200, and 474 children, respectively.2– 4,10
Fortuna et al3 and Holzhauer et al4 reported that the
infrared thermometer tended to overestimate tempera-
ture in children without fever and to underestimate tem-
perature in children with fever. A monotonic linear rela-
tionship between rectal temperature measurements and
infrared thermometry was found that was statistically
significant (P ⬍ 0.01). However, the slope of the regres-
sion line was far from unity (0.70 ⫾ 0.05; r2 ⫽ 0.48; P ⬍
0.01), and the 95% prediction band for an infrared mea-
surement using a rectal temperature was unacceptably
broad, approximately 4°F. An ideal agreement between
the 2 techniques should have a slope of 1 and an intercept
of zero. In addition to only moderate agreement between
the methods, there was also evidence that infrared ther-
mometry overestimated rectal temperature in patients
without fever and underestimated rectal temperature in
July 2012
E. Chiappini et al.
patients with fever (r2 ⫽ 0.15; P ⬍ 0.01).3 Infrared ther-
mometry with or without skin contact did not agree with
rectal thermometry sufficiently to indicate its routine
use.3,4
Recommendations
Axillary temperature measurement using a digital
thermometer is recommended in children younger than
4 weeks (evidence level III; strength of recommenda-
tion, B). In the hospital or ambulatory care setting,
axillary temperature measurement using a digital ther-
mometer or an infrared thermometer (tympanic or
with or without skin contact) is recommended in chil-
dren older than 4 weeks (evidence level II; strength of
recommendation, B).
Update Regarding Use of Antipyretic Drugs
Paracetamol and ibuprofen are the only antipyretic
drugs recommended for use in children, and only when
fever is associated with evident discomfort.11 How-
ever, the treatment regimen recommended in children
remains controversial insofar as combined or alternat-
ing use of paracetamol and ibuprofen.7,11–14 A ran-
domized controlled trial was performed to establish
the relative clinical efficacy and cost-effectiveness of
paracetamol plus ibuprofen compared with paraceta-
mol or ibuprofen alone in patients without fever. Dur-
ing the first 4 hours without fever, use of both agents
was superior to use of paracetamol alone (adjusted
difference, 55 minutes; 95% confidence interval [CI],
33–77 minutes; P ⬍ 0.001), and may have been as
effective as ibuprofen (adjusted difference, 16 minutes;
95% CI, ⫺6 to 39 minutes; P ⫽ 0.20). With combined
use of both drugs, fever resolved 23 minutes (95% CI,
2– 45 minutes; P ⫽ 0.02) sooner than with paraceta-
mol alone, but not sooner than with ibuprofen alone
(adjusted difference, ⫺3 minutes; 95% CI, 24 –18 min-
utes; P ⫽ 0.80). During the first 24 hours without fe-
ver, combined use of both drugs was superior to parac-
etamol alone (adjusted difference, 4.4 hours; 95% CI,
2.4 – 6.3 hours; P ⬍ 0.001) or ibuprofen alone (ad-
justed difference, 2.5 hours; 95% CI, 0.6 – 4.5 hours;
P ⫽ 0.008). However, that study also reported that the
recommended maximum number of doses of paraceta-
mol and ibuprofen in 24 hours was exceeded in 8%
and 11% of children, respectively. These data suggest
that the combination of paracetamol and ibuprofen
could be confusing and cause risk of toxicity.15
1649
 Clinical Therapeutics
A prospective, randomized, double-blind, placebo-
control study compared the efficacy of paracetamol
versus paracetamol alternated with ibuprofen in 38
children aged 6 months to 6 years. There were no sig-
nificant differences in body temperature between the 2
groups at 0, 3, and 6 hours. The group that received
alternating drugs had significantly lower mean temper-
atures at both 4 hours (38.0°C vs 37.4°C; P ⫽ 0.05)
and 5 hours (37.8°C vs 37.9° C; P ⫽ 0.003). The re-
duction of fever in the 2 groups was not clinically rel-
evant, and parents did not perceive any difference in
fever control between the groups.12
Another study compared the antipyretic effect of 3
different treatment regimens in children over a single
6-hour observation period: ibuprofen alone, ibuprofen
combined with paracetamol, or ibuprofen followed by
paracetamol. Differences in temperature curves were
significant (P ⬍ 0.001); the combined and alternating
arms resulted in significantly better antipyresis com-
pared with the ibuprofen-only group at 4 to 6 hours
(hour 4, P ⬍ 0.005; hours 5 and 6, P ⬍ 0.001). All but
1 of the children in the combined and alternating
groups were afebrile at hours 4, 5, and 6. In contrast, in
children receiving ibuprofen alone, 30%, 40%, and
50% had temperatures ⬎38.0°C at hours 4, 5, and 6,
respectively (hour 4, P ⫽ 0.002; hours 5 and 6, P ⬍
0.001).16 However that study was performed in a small
sample of only 46 children, and the 6-hour observation
period allowed for evaluation of only a single cycle of
drug administration, and did not evaluate the effect of
multiple doses over a longer observation period or ad-
verse events that could occur from this pratice.16
Although the aforementioned studies provide some
evidence that combination therapy may be more effec-
tive for lowering temperature, questions remain about
the safety profile of this practice and its effectiveness in
improving discomfort, which is the primary treatment
end point. The possibility that parents will either not
receive or not understand dosing instructions, along
with the wide array of formulations of these drugs,
increases the potential for inaccurate dosing or over-
dosing. This practice may only provoke the fever pho-
bia that already exists.11,14
In addition, these studies did not include adequate
numbers of patients to fully evaluate the efficacy of this
practice. Therefore, there is insufficient evidence to
support or refute the routine use of combination ther-
apy using paracetamol and ibuprofen. Practitioners
who choose to follow this practice should counsel par-
1650
ents carefully about proper dosage and dosing inter-
vals, and focus on the child’s comfort rather than re-
ducing fever.11,14
Considering also the worldwide dosages of these
drugs, often in combination, and the incredibly rare
occurrence of toxicity from dual use, there are few data
about toxicity, and on the basis of findings of these
studies, no conclusion can be reached about the safety
of any treatments. Furthermore, these studies contain
no data for infants younger than 6 months.14 Both
paracetamol and ibuprofen are associated with possi-
ble toxicities such as hepatotoxicity, and gastric and
antiplatelet effects, respectively. There are a number of
concerns about combined therapy, in particular possi-
ble renal toxicity caused by the additive and possibly
synergistic effects of drug metabolites in children with
dehydration, misdosing, and increased parental con-
cern about fever.14 In 2009, the first case of acute kid-
ney and liver failure was reported in a child with dehy-
dration receiving treatment with both paracetamol and
ibuprofen administered at therapeutic antipyretic
dosages.13
Recommendations
Paracetamol and ibuprofen are the only anti-
pyretic drugs recommended for use in children (evi-
dence level I; strength of recommendation, A). Com-
bined or alternating use of ibuprofen and paracetamol
is not recommended (evidence level VI; strength of rec-
ommendation, D).
Paracetamol and Risk of Asthma
In the past 10 years, several studies have reported an
association between paracetamol and asthma or al-
lergy.17–27 Taking paracetamol could increase airway
inflammation in persons with asthma or a predisposi-
tion to asthma, contributing to more severe and more
frequent symptoms. Furthermore, there is the possibil-
ity that those exposed to paracetamol in utero or in the
first year of life might be more likely to develop asthma
later in childhood.28 It has also been noted that the
increased use of paracetamol during the past 5 decades
has coincided with an increased prevalence of allergy
and asthma.29 There are several possible mechanisms
to explain a link between paracetamol and asthma.
One discussed mechanism is airway inflammation due
to paracetamol-induced decreased concentration of the
endogenous antioxidant glutathione, leading to a de-
crease in pulmonary antioxidant defence. Paracetamol
Volume 34 Number 7

is metabolized predominantly in the liver, where a mi-
nor fraction is converted to a highly reactive metabolite
that is inactivated by glutathione. Depletion of gluta-
thione increases the susceptibility to free radical dam-
age. In addition, in the human fetal liver, paracetamol
is oxidized to a metabolite that is conjugated with glu-
tathione. Furthermore, reduced levels of glutathione
may alter antigen presentation and recognition,
thereby favoring the type 2 T-cell (Th2) pathway. It has
been noted that paracetamol, in contrast to aspirin,
does not block the cyclooxygenase-2 pathway. Cyclo-
oxygenase-2 is activated during viral respiratory infec-
tions. Cyclooxygenase-2 increases the production of
prostaglandin E2. This inhibits the production of Th1
cytokines such as interferon-c and IL-2, but not IL-4,
thus shifting the Th1:Th2 balance toward Th2.26
The largest study to consider the correlation be-
tween asthma and paracetamol is ISAAC (Interna-
tional Study of Asthma and Allergy in Childhood)
Phase III, which included 205,487 children aged 6 to 7
years from 72 countries. That study demonstrated an
association between exposure to paracetamol given to
reduce fever in the first year of life and the risk of
asthma at age 6 to 7 years.23 Paracetamol use in in-
fancy was also associated with an increased risk of
symptoms of rhinoconjunctivitis and eczema.23 Two
years later, data for 320,000 adolescents aged 13 to 14
years were also available.17 Nearly 30% of all 13- to
14-year-old adolescents reported taking paracetamol
at least once a month. In both age groups, there was a
paracetamol dose-dependent increase in the prevalence
and severity of asthma. In 6- to 7-year-old children, the
risk of current asthma was increased 1.61-fold (95%
CI, 1.46 –1.77) in those who took paracetamol more
than once a year but less than once a month, and 3.23-
fold (95% CI. 2.91–3.60) in those who took paraceta-
mol at least once a month.23 In 13- to 14-year-old
adolescents, the risk in those who took paracetamol
more than once a year but less than once a month was
1.43 (95% CI, 1.33–1.53), and in those who took
paracetamol at least once a month was 2.51 (95% CI,
2.33–2.70).17 Although the study had many strengths,
including large sample size, use of standardized mea-
sures and methods, and generally consistent results
across multiple sites, interpretation was limited by fail-
ure to adjust to the potential confounding factor re-
lated to respiratory infections in early life.30 This is a
major methodologic weakness because paracetamol is
used to treat fever during episodes of respiratory infec-
July 2012
E. Chiappini et al.
tion, and early life respiratory infections have been re-
peatedly demonstrated to increase the risk of develop-
ing asthma. In addition, the ISAAC findings may have
been affected by recall bias because exposure data were
collected retrospectively. A recent systematic review
that included 19 studies confirmed an increased risk of
asthma and wheezing in both children and adults ex-
posed to paracetamol.31 However, the studies included
in the review were quite heterogeneous, and the au-
thors were unable to stratify the findings by study de-
sign quality because of too few studies. There remains
a possibility that confounding variables might explain
some or all of the association between paracetamol and
asthma; thus, further studies are needed to clarify this
correlation. At present, the clinical approach may ben-
efit from a balance between the likely risks and benefits
of paracetamol, in particular in children with a per-
sonal or family history of asthma.
DISCUSSION
Recent literature mainly supports previous recommen-
dations. The objective of the present article was to sup-
port pediatric knowledge and stimulate application of
guidelines in daily clinical practice.
ACKNOWLEDGMENTS
The authors represent the Writing Committee of the
Italian Pediatric Society Panel for Management of Fe-
ver in Children.
The guideline was developed by a multidisci-
plinary panel of clinicians and experts in evidence-
based medicine and the methodology of guideline
development who were identified with the help of the
participating scientific societies. Specifically, the
panel included a referee from the NGLP National
Board, experts in the fields of general pediatrics,
emergency medicine, neonatology, epidemiology, in-
fectious diseases, nursing practice, pharmacology,
toxicology, research methodology; and a member of
the parents’ association Noi per Voi. Writing Com-
mittee of the Italian Pediatric Society Panel for the
Management of Fever in Children was constituted
when The Panel met for the first time on June 2007
and authors who should represent Writing Commit-
tee were identified. Both authors contributed equally
to the literature search, figure creation, study design,
data collection data interpretation and writing the
present article.
1651
 Clinical Therapeutics
CONFLICTS OF INTEREST
The authors have indicated that they have no conflicts
of interest regarding the content of this article.
SUPPLEMENTARY MATERIAL
A supplemental appendix accompanying this article can
be found in the online version at http://dx.doi.org/
10.1016/j.clinthera.2012.06.011.
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Address correspondence to: Maurizio de Martino, MD, Department of

Sciences for Woman and Child’s Health, University of Florence, Anna
Meyer Children’s University Hospital, Viale Pieraccini 24, I-50139, Flor-
ence, Italy. E-mail: maurizio.demartino@unifi.it

July 2012 1653

 Clinical Therapeutics
SUPPLEMENTAL APPENDIX
Research Strategies
Question 1. How should body temperature be mea-
sured in children?
Search Strategy: PUBMED search of articles in Eng-
lish or Italian, from January 1, 2008, to May 1, 2012,
using key words “children AND (fever OR body tem-
perature) AND (thermometry OR thermometer).”
Field: Title/abstract.
Summary of Evidence: Of 26 studies found, 8 stud-
ies were excluded because they were not inherent to the
question. Studies extracted: 18 (17 observational stud-
ies, 1 guideline). After review of the literature, another
2 observational studies were included.
Search Details: Children[Title/Abstract] AND
(fever[Title/Abstract] OR (body[Title/Abstract] AND
temperature[Title/Abstract])) AND (thermometry
[Title/Abstract] OR thermometer[Title/Abstract]) AND
(“2008/01/01”[PDAT]:“2012/05/01”[PDAT]).
Question 2. How should clinicians regard mea-
surements of a child’s temperature taken by
parents/caregivers?
Search Strategy: PUBMED search of articles in English
or Italian, from January 1, 2008, to May 1, 2012, using key
words “children AND fever AND (parents OR mother OR
management OR attitudes).” Field: Title/abstract. Limits:
Human, Meta-Analysis, Randomized Controlled Trial, Re-
view, English, Italian, All Child 0–18 years.
Summary of Evidence: Of 90 studies found, 89 were
excluded because they were not inherent to the ques-
tion. Studies extracted: 1 (meta-analysis). After review
of the literature, 3 observational studies were added.
Search Details: Children[Title/Abstract] AND
fever[Title/Abstract] AND (parents[Title/Abstract]
OR mother[Title/Abstract] OR management[Title/
Abstract] OR attitudes[Title/Abstract]) AND (“humans”
[MeSH Terms] AND (Meta-analysis[ptyp] OR Practice
Guideline[ptyp] OR Randomized Controlled Trial[p-
typ] OR Review[ptyp]) AND (English[lang] OR Ital-
ian[lang]) AND (“infant”[MeSH Terms] OR
“child”[MeSH Terms] OR “adolescent”[MeSH Terms])
AND (“2008/01/01”[PDAT]:“2012/05/01”[PDAT])).
Question 3. Is it appropriate to use physical meth-
ods to reduce a child’s body temperature?
Search Strategy: PUBMED search of articles in Eng-
lish or Italian, from January 1, 2008, to May 1, 2012,
1653.e1
using key words “fever AND (treatment OR physical
methods OR external cooling OR tepid sponging).”
Field: Title/abstract. Limits: Human, Meta-analysis,
Practice Guideline, Randomized Controlled Trial, Re-
view, English, Italian, All Children 0 –18 years.
Summary of Evidence: Of 173 studies found, 171
were excluded because they were not inherent to the
question. Studies extracted: 2 (randomized controlled
trials).
Search Details: Children[Title/Abstract] AND
fever[Title/Abstract] AND (treatment[Title/Abstract]
OR (physical[Title/Abstract] AND methods[Title/
Abstract]) OR (external[Title/Abstract] AND cooling-
[Title/Abstract]) OR (tepid[Title/Abstract] AND
sponging[Title/Abstract])) AND (“humans”[MeSH
Terms] AND (Meta-analysis[ptyp] OR Practice Guide-
line[ptyp] OR Randomized Controlled Trial[ptyp] OR
Review[ptyp]) AND (English[lang] OR Italian[lang])
AND (“infant”[MeSH Terms] OR “child”[MeSH
Terms] OR “adolescent”[MeSH Terms]) AND
(“2008/01/01”[PDAT]:“2012/05/01”[PDAT])).
Question 4. Is there a correlation between the de-
gree of fever and the severity of the underlying disease?
Search Strategy: PUBMED search of articles in Eng-
lish or Italian from January 1, 2008, to May 1, 2012,
using key words “children AND fever AND (predic-
tion rule OR prediction tool OR risk factors OR bac-
teremia OR severity of disease).” Field: Title/abstract.
Limits: Human, Meta-analysis, Randomized Con-
trolled Trial, Review, English, Italian, All Children
0 –18 years.
Summary of Evidence: Of 20 studies found, all were
excluded because they were not inherent to the ques-
tion. Studies extracted: 0.
Search Details: Children[Title/Abstract] AND
fever[Title/Abstract] AND ((prediction[Title/Abstract]
AND rule[Title/Abstract]) OR (prediction[Title/
Abstract] AND tool[Title/Abstract]) OR (risk[Title/
Abstract] AND factors[Title/Abstract]) OR bacteremia
[Title/Abstract] OR (severity[Title/Abstract] AND disease
[Title/Abstract])) AND (“humans”[MeSH Terms]
AND (Meta-analysis[ptyp] OR Practice Guide-
line[ptyp] OR Randomized Controlled Trial[ptyp] OR
Review[ptyp]) AND (English[lang] OR Italian[lang])
AND (“infant”[MeSH Terms] OR “child”[MeSH
Terms] OR “adolescent”[MeSH Terms]) AND
(“2008/01/01”[PDAT]:“2012/05/01”[PDAT])).
Volume 34 Number 7

Questions 5 and 6. Is use of antipyretic drugs advis-
able in children with fever? Which antipyretic drugs
and modes of administration should be used?
Search Strategy: PUBMED search of articles in English
or Italian from January 1, 2008 to May 1, 2012, using key
words “children AND fever AND (paracetamol OR ibu-
profen OR acetaminophen OR antipyretics).” Field: Title/
abstract. Limits: Human, Meta-analysis, Randomized
Controlled Trial, Review, Human, English, Italian.
Summary of Evidence: Of 34 studies found, 14 stud-
ies were excluded because they were not inherent to the
question. Studies extracted: 17 (10 randomized con-
trolled trials, 6 reviews, 1 meta-analysis). After review
of the literature, another 4 studies were added (1 re-
view,1 editorial, 1 observational study, 1 case report).
Search Details: Children[Title/Abstract] AND fever-
[Title/Abstract] AND (paracetamol[Title/Abstract] OR ibu-
profen[Title/Abstract] OR acetaminophen[Title/Abstract]
OR antipyretics[Title/Abstract]) AND (“humans”[MeSH
Terms] AND (Meta-Analysis[ptyp] OR Practice Guide-
line[ptyp] OR Randomized Controlled Trial[ptyp] OR
Review[ptyp]) AND (English[lang] OR Italian[lang]) AND
(“2008/01/01”[PDAT]:“2012/05/01”[PDAT])).
Question 7. Should paracetamol be administered
rectally or orally?
Search Strategy: PUBMED search of articles in Eng-
lish or Italian from January 2, 2008, to May 1, 2012,
using key words “Fever AND (acetaminophen OR parac-
etamol) AND (oral OR rectal).” Field: Title/abstract.
Limits: Meta-analysis, Randomized Controlled Trial, Re-
view, Human, English, Italian, All Children 0–18 years.
Summary of Evidence: Of 12 studies found, 11 stud-
ies were excluded because they were not inherent to the
question. Studies extracted: 1 (meta-analysis).
Search Details: Fever[Title/Abstract] AND (acetamino-
phen[Title/Abstract] OR paracetamol[Title/Abstract])
AND (oral[Title/Abstract] OR rectal[Title/Abstract]) AND
(“humans”[MeSH Terms] AND (Meta-Analysis[ptyp] OR
Practice Guideline[ptyp] OR Randomized Controlled Trial
[ptyp] OR Review[ptyp]) AND (English[lang] OR Italian-
[lang]) AND (“infant”[MeSH Terms] OR “child”[MeSH
Terms] OR “adolescent”[MeSH Terms]) AND (“2008/
01/01”[PDAT]:“2012/05/01”[PDAT])).
Question 8. Are antipyretics well tolerated in children?
Search Strategy: PUBMED search of articles in Eng-
lish or Italian from January 1, 2008, to May 1, 2012,
using key words “Children AND fever AND (anti-
July 2012
E. Chiappini et al.
pyretics OR paracetamol OR ibuprofen) AND (side
effects OR toxicity OR tolerability OR interactions
OR safety).” Field: Title/abstract. Limits: Meta-analy-
sis, Randomized Controlled Trial, Review, Human.
Summary of Evidence: Of 10 studies found, 2 stud-
ies were excluded because they were not inherent to the
question. Studies extracted: 8 (6 reviews, 2 randomized
controlled trials).
Search Details: Children[Title/Abstract] AND fe-
ver[Title/Abstract] AND (antipyretics[Title/Abstract]
OR paracetamol[Title/Abstract] OR ibuprofen[Title/
Abstract]) AND ((side[Title/Abstract] AND effects[Title/
Abstract]) OR toxicity[Title/Abstract] OR tolerability-
[Title/Abstract] OR interactions[Title/Abstract] OR
safety[Title/Abstract]) AND (“humans”[MeSH Terms]
AND (Meta-Analysis[ptyp] OR Practice Guideline[ptyp]
OR Randomized Controlled Trial[ptyp] OR Review
[ptyp]) AND (English[lang] OR Italian[lang]) AND
(“2008/01/01”[PDAT]:“2012/05/01”[PDAT])).
Question 9. What precautions should be taken to
prevent antipyretic toxicity in children?
Search Strategy: PUBMED search of articles in Eng-
lish or Italian from January 1, 2008, to May 1, 2012,
using key words “Children AND (acetaminophen OR
paracetamol OR ibuprofen) AND (poisoning OR
overdose).” Field: Title/abstract. Limits: Human,
Meta-analysis, Practice Guideline, Randomized Con-
trolled Trial, Review, English, Italian.
Summary of Evidence: Of 3 studies found, 2 studies
were excluded because they were not inherent to the
question. Studies extracted: 1 (editorial).
Search Details: Children[Title/Abstract] AND (ac-
etaminophen[Title/Abstract] OR paracetamol[Title/
Abstract] OR ibuprofen[Title/Abstract]) AND (poi-
soning[Title/Abstract] OR overdose[Title/Abstract] OR
precautions[Title/Abstract]) AND (“humans”[MeSH
Terms] AND (Meta-Analysis[ptyp] OR Practice Guide-
line[ptyp] OR Randomized Controlled Trial[ptyp] OR
Review[ptyp]) AND (English[lang] OR Italian[lang])
AND (“2008/01/01”[PDAT]:“2012/05/01”[PDAT])).
Question 10. Can antipyretics be used in children
with chronic conditions?
Search Strategy: PUBMED search of articles in Eng-
lish or Italian from January 1, 2008, to May 1, 2012,
using key words “Children AND (acetaminophen OR
paracetamol OR ibuprofen OR antipyretic) AND (cys-
tic fibrosis OR diabetes OR chronic liver disease OR
1653.e2
 Clinical Therapeutics
malnutrition, OR asthma OR chronic disease).” Field:
Title/abstract. Limits: Human, Meta-analysis, Ran-
domized Controlled Trial, Review, English, Italian.
Summary of Evidence: Of 11 studies found, all were
excluded because they were not inherent to the ques-
tion. Studies extracted: 0.
Search Details: Children[Title/Abstract] AND (ac-
etaminophen[Title/Abstract] OR paracetamol[Title/
Abstract] OR ibuprofen[Title/Abstract] OR antipyretic
[Title/Abstract]) AND ((cystic[Title/Abstract] AND
fibrosis[Title/Abstract]) OR diabetes[Title/Abstract]
OR (chronic[Title/Abstract] AND liver[Title/Abstract]
AND disease[Title/Abstract]) OR malnutrition[Title/
Abstract] OR asthma[Title/Abstract] OR (chronic[Title/
Abstract] AND disease[Title/Abstract])) AND (“humans”
[MeSH Terms] AND (Meta-analysis[ptyp] OR Prac-
tice Guideline[ptyp] OR Randomized Controlled Tri-
al[ptyp] OR Review[ptyp]) AND (English[lang] OR
Italian[lang]) AND (“2008/01/01”[PDAT]:“2012/
05/01”[PDAT])).
Question 11. How should fever be managed in chil-
dren younger than 28 days?
Search Strategy: PUBMED search of articles in Eng-
lish or Italian from January 1, 2008, to May 1, 2012,
using key words “Newborn AND (acetaminophen OR
paracetamol),” Field: Title/abstract. Limits: Human,
Meta-analysis, Randomized Controlled Trial, Review,
English, Italian.
Summary of Evidence: One study was found. Stud-
ies extracted: 1 (review).
Search Details: Newborn[Title/Abstract] AND (ac-
etaminophen[Title/Abstract] OR paracetamol[Title/
Abstract]) AND (“humans”[MeSH Terms] AND
(Meta-analysis[ptyp] OR Practice Guideline[ptyp] OR
Randomized Controlled Trial[ptyp] OR Review
[ptyp]) AND (English[lang] OR Italian[lang]) AND
(“2008/01/01”[PDAT]:“2012/05/01”[PDAT])).
Question 12. Should antipyretics be used to prevent
adverse events associated with childhood vaccinations?
Search Strategy: PUBMED search of articles in Eng-
lish or Italianfrom January 1, 2008, to May 1, 2012,
1653.e3
using key words “Children AND (acetaminophen OR
paracetamol OR ibuprofen OR antipyretic) AND (im-
munization OR vaccine).” Field: Title/abstract. Limits:
Human, Meta-analysis, Randomized Controlled Trial,
Review, English, Italian.
Summary of Evidence: Of 4 studies found, 2 studies
were excluded because they were not inherent of the
question. Studies extracted: 2 (randomized controlled
trials).
Search Details: Children[Title/Abstract] AND (acet-
aminophen[Title/Abstract] OR paracetamol[Title/
Abstract] OR ibuprofen[Title/Abstract] OR antipyretic-
[Title/Abstract]) AND (immunization[Title/Abstract]
OR vaccine[Title/Abstract]) AND (“humans”[MeSH
Terms] AND (Meta-Analysis[ptyp] OR Practice Guide-
line[ptyp] OR Randomized Controlled Trial[ptyp] OR
Review[ptyp]) AND (English[lang] OR Italian[lang])
AND (“2008/01/01”[PDAT]:“2012/05/01”[PDAT])).
Question 13. Should antipyretics be used to prevent
febrile convulsions in children?
Search Strategy: PUBMED search of articles in Eng-
lish or Italian from January 1, 2008, to May 1, 2012,
using key words “Children AND (febrile seizures OR
febrile convulsion) AND (acetaminophen OR parac-
etamol OR ibuprofen OR antipyretics).” Field: Title/
abstract. Limits: Meta-analysis, Randomized Con-
trolled Trial, Review, English, Italian.
Summary of Evidence: Of 4 studies found, 1 study
was excluded because not inherent to the question.
Studies extracted: 3 (1 randomized controlled trial, 1
review, 1 guideline).
Search Details: Children[Title/Abstract] AND ((febrile
[Title/Abstract] AND seizures[Title/Abstract]) OR (febri-
le[Title/Abstract] AND convulsion[Title/Abstract]))
AND (acetaminophen[Title/Abstract] OR paracetamol-
[Title/Abstract] OR ibuprofen[Title/Abstract] OR anti-
pyretics[Title/Abstract]) AND (“humans”[MeSH Terms]
AND (Meta-Analysis[ptyp] OR Practice Guideline[ptyp]
OR Randomized Controlled Trial[ptyp] OR Review
[ptyp]) AND (English[lang] OR Italian[lang]) AND
(“2008/01/01”[PDAT]:“2012/05/01”[PDAT])).
Volume 34 Number 7