Pediatr Drugs (2017) 19:479–486
DOI 10.1007/s40272-017-0237-1
ORIGINAL RESEARCH ARTICLE
Alternating Acetaminophen and Ibuprofen versus Monotherapies
in Improvements of Distress and Reducing Refractory Fever
in Febrile Children: A Randomized Controlled Trial
Shuanghong Luo1 • Mengdong Ran2 • Qiuhong Luo1 • Min Shu1 • Qin Guo1
Yu Zhu1 • Xiaoping Xie3 • Chongfan Zhang4 • Chaomin Wan1
Published online: 18 May 2017
Ó Springer International Publishing Switzerland 2017
Abstract
Background No evidence can be found in the medical
literature about the efficacy of alternating acetaminophen
and ibuprofen treatment in children with refractory fever.
Objective Our objective was to assess the effect of alter-
nating acetaminophen and ibuprofen therapy on distress
and refractory fever compared with acetaminophen or
ibuprofen as monotherapy in febrile children.
Methods A total of 474 febrile children with axillary tem-
perature C38.5 °C and fever history B3 days in a tertiary
hospital were randomly assigned to receive either (1) alter-
nating acetaminophen and ibuprofen (acetaminophen 10 mg/
kg per dose with shortest interval of 4 h and ibuprofen 10 mg/
kg per dose with shortest interval of 6 h and the shortest
interval between acetaminophen and ibuprofen C2 h;
n = 158), (2) acetaminophen monotherapy (10 mg/kg per
dose with shortest interval of 4 h; n = 158), or (3) ibuprofen
monotherapy (10 mg/kg per dose with shortest interval of
6 h; n = 158). The mean Non-Communicating Children’s
Pain Checklist (NCCPC) score was measured every 4 h, and
axillary temperatures were measured every 2 h.
& Chaomin Wan
wanchaomin@scu.edu.cn
1
Department of Pediatrics, West China Second University
Hospital, Sichuan University, No. 17 Section Three, Ren Min
Nan Lu Avenue, Chengdu 610041, Sichuan, China
2
Department of Epidemiology and Health Statistics, West
China School of Public Health, Sichuan University, Chengdu,
Sichuan, China
3
Department of Pediatrics, Dujiangyan Medical Center,
Chengdu, Sichuan, China
4
Department of Clinical Epidemiology, Children’s Hospital of
Fudan University, Shanghai, China
•
Results In total, 471 children were included in an intention-
to-treat analysis. No significant clinical or statistical differ-
ence was found in mean NCCPC score or temperature during
the 24-h treatment period in all febrile children across the
three groups. Although the proportion of children with
refractory fever for 4 h and 6 h was significantly lower in the
alternating group than in the monotherapy groups (4 h:
11.54% vs. 26.58% vs. 21.66%, respectively [p = 0.003]; 6
h: 3.85% vs. 10.13% vs. 17.83%, respectively [p \ 0.001]),
the mean NCCPC score of children with refractory fever for 4
or 6 h was not lower than those in either of the monotherapy
groups. The number of patients who developed persistent
high body temperature was consistent across all study groups.
Conclusions Alternating acetaminophen and ibuprofen can
reduce the proportion of children with refractory fever, but
if one cycle of alternating therapy cannot reduce febrile
distress as defined by NCCPC score, two or more cycles of
alternating therapy may have minimal to no clinical effi-
cacy in some cases.
The trial was registered with the Chinese Clinical Trial
Registry as ChiCTR-TRC-13003440 and the WHO Reg-
istry Network as U1111-1146-6714.
Key Points
Alternating acetaminophen and ibuprofen can reduce
the proportion of children with refractory fever
compared with monotherapies.
If one cycle of alternating therapy does not reduce
febrile distress, two or more cycles of alternating
therapy may have minimal to no clinical efficacy.
480
1 Introduction
Fever has long been a symptom of high concern to parents
and pediatricians because it is an early clinical manifesta-
tion of many acute infections. Refractory fever, defined as
a poor response to an antipyretic agent or fever recurrence
before the next pharmacological dose, often causes parental
panic and anxiety [1]. In practice, a regimen of alternating
acetaminophen and ibuprofen has been used to treat chil-
dren with refractory fever [2–5] at different dosages and
intervals [5–10] despite concerns about potential drug
toxicity and harmful interactions [10–14]. A Cochrane
review [15] and another systematic review [16] indicated
that combined or alternating acetaminophen and ibuprofen
may have some efficacy in reducing temperature in all
febrile children, but there is no evidence about efficacy in
reducing refractory fever, and improvement of distress
remains inconclusive. The safety of alternating antipyretic
therapy has also not yet been determined, and the possi-
bility that parents may not understand dosing instructions
increases the potential for incorrect and over-dosing
[15–18]. For these reasons, some guidelines stress that
alternating acetaminophen and ibuprofen may only be
considered if the distress persists or recurs before the next
dose is due [19], and some guidelines recommend com-
pletely avoiding the use of both antipyretics [20, 21]. Thus,
more evidence is needed to determine the value of alter-
nating antipyretic therapy. To further assess the effect of
alternating acetaminophen and ibuprofen therapy com-
pared with monotherapies in reducing refractory fever and
distress in febrile children, we conducted a randomized
open-labeled controlled trial.
2 Methods
2.1 Participants
This trial was approved by the Ethics Committee of West
China Second University Hospital of Sichuan University
and registered with the Chinese Clinical Trial Registry as
ChiCTR-TRC-13003440 and the World Health Organiza-
tion (WHO) Registry Network as U1111-1146-6714. It was
performed in a tertiary care facility in a city with a popu-
lation of approximately 800,000 people, where medical
services are provided to all local children directly.
We prospectively recruited febrile children who under-
went a pediatric emergency room observation or who were
hospitalized. Children aged 6 months to 5 years were eli-
gible if their axillary temperature was C38.5 °C and they
exhibited a fever history of B3 days. Children were
excluded if they had any of the following conditions:
S. Luo et al.
moderate to severe dehydration; known contraindication to
any antipyretic; any malignancy, chronic metabolic dis-
ease, immune system disease, critical illness or condition;
any medical or surgical condition that precludes the
absorption of an antipyretic (such as frequent vomiting);
use of any antipyretic or drug affecting temperature in the
preceding 6 h; or previous participation in this trial.
2.2 Procedure
A statistician created a randomization allocation sequence
using SPSS v19.0 and kept it and the intervention
instructions in serially numbered opaque sealed envelopes.
For eligible children, an investigator collected their
demographic information and completed a medical record.
One researcher then obtained informed consent from the
parents and enrolled and randomly assigned the participant
into either the alternating acetaminophen and ibuprofen
(AI) group, the acetaminophen monotherapy group, or the
ibuprofen monotherapy group according to the allocation
sequence. In total, 158 participants were allocated to each
group. Axillary temperature was taken at 0, 2, 4, 6, 8, 10,
12, 14, 16, 18, 20, 22, and 24 h, and distress was measured
at 0, 4, 8, 12, 16, 20, and 24 h after initial administration of
the antipyretic. A separate researcher administered the
antipyretics to the children according to the indication and
interval of their allocated intervention and recorded other
follow-up data.
2.3 Intervention
After enrollment, children received an initial antipyretic
administration immediately. The AI group received an
initial dose of acetaminophen 10 mg/kg. The second dose
administered to these participants was ibuprofen 10 mg/kg.
This sequence was repeated in this order for 24 h. After
initial antipyretic agent administration, the requirement for
intervention was temperature of C38.5 °C and reduction of
temperature by B0.5 °C compared with the temperature
measured 2 h before, with an interval of C4 h from the
previous dose of acetaminophen or C6 h from the previous
dose of ibuprofen at the same time.
The acetaminophen group received only acetaminophen
10 mg/kg per dose for 24 h. After an initial dose, the
requirement for intervention in this group was a tempera-
ture C38.5 °C with an interval of C4 h from the previous
dose of acetaminophen.
The ibuprofen group received only ibuprofen 10 mg/kg
per dose for 24 h. After an initial dose, the requirement for
intervention in this group was a temperature C38.5 °C with
an interval of C6 h from the previous dose of ibuprofen.
Table 1 shows the sequence, shortest intervals, and the
maximum number of medication deliveries in the three
Alternating Acetaminophen and Ibuprofen versus Monotherapies in Febrile Children 481

groups during the study. The pharmacy department of the
study hospital provided all antipyretics. The oral acet-
aminophen was a 1.5 g/15 ml suspension (Tylenol,
Shanghai Johnson & Johnson Pharmaceuticals, Ltd), and
oral ibuprofen was a 0.6 g/15 ml suspension (Motrin,
Shanghai Johnson & Johnson Pharmaceuticals, Ltd). No-
one was blinded to the intervention or requirements in this
study.
2.4 Efficacy and Safety Assessment
The primary measured outcomes were mean Non-Commu-
nicating Children’s Pain Checklist (NCCPC) scores and
temperature throughout 24 h of observation. The NCCPC
score has been used in the assessment of febrile children in
previously published trials [22]. NCCPC scores are used to
assess a child’s behavior over the previous 2 h and have been
validated as a measure of pain in children who are unable to
speak about their pain because of cognitive impairments or
disabilities. Parents and caregivers can use it without training
to assess a specific child even if they do not know the child
well [23–25]. A total score of C7 on the NCCPC indicates a
child is exhibiting pain, while a total score of B6 indicates a
child is not exhibiting pain. The study researchers measured
all outcomes. Researchers on duty completed the NCCPC
according to their observation of the patient, along with the
parents’ descriptions of the child’s behavior over the previ-
ous 2 h. They also measured axillary temperatures using a
mercury thermometer over a total time of 5 min.
Secondary outcomes included the proportion of children
with refractory fever for C4 h; low body temperature;
antipyretic use; incidence of rash, asthma, gastrointestinal
symptoms, hepatic dysfunction, and renal dysfunction from
all causes.
We considered an axillary temperature C38.5 °C as an
indication to initiate an antipyretic. Given the time to peak
concentration of acetaminophen and ibuprofen, refractory
fever was defined as the exhibition of temperatures
C38.5 °C for C 4 h. The proportion of children with
refractory fever was calculated as the number of children
with persistent temperatures C38.5 °C for C4 h divided by
the total number of group 9100%. Low body temperature
was defined as any measured temperature \36.0 °C. The
proportion of children with low body temperature was
calculated as the number of children with low body tem-
perature divided by the total number of the group 9100%.
Hepatic dysfunction and renal dysfunction were deter-
mined by the attending doctor’s diagnosis. Researchers,
doctors, and nurses involved were trained on the protocol
of the trial before it was performed.
2.5 Sample Size
Our null hypothesis was that the effect of alternating
acetaminophen and ibuprofen in children with acute fever
does not result in greater improvement in distress than
acetaminophen monotherapy or ibuprofen monotherapy.
Referring to the difference in NCCPC score on day 1 of the
intervention, Sarrell et al. [22] found that, to detect a 1.5
difference in mean NCCPC score (with a of 0.05, b of 0.2,
in a one-sided test accounting for the proportion lost to
follow-up B20%), a sample size of 474 subjects was nee-
ded, with 158 participants in each group. This sample size
could also detect a 0.5 °C difference in temperature.
2.6 Statistical Methods
Data were collected and stored in a MicrosoftÒ Excel
workbook, and statistical analyses were performed using
SAS 9.4. Analysis of variance (ANOVA) was used for
mean NCCPC score and mean temperature during the 24 h.
A Chi-squared test was used to test for differences in the
proportion of persistent fever exhibited C4 h after inter-
vention and of poor antipyretic effect exhibited 4–8 h after
treatment. Additionally, Fisher’s exact test was used to test
for poor antipyretic effect between groups at C10 h after
intervention. A two-sided p-value of B0.05 was considered
statistically significant.
3 Results
3.1 Protocol Deviations
Ibuprofen was administered at a dose of 10 mg/kg per dose
because we determined this was a typical dose.

Table 1 The shortest intervals Groups Study time (h)

and the maximum number of
medication deliveries of 0 2 4 6 8 10 12 14 16 18 20 22 24
acetaminophen and/or ibuprofen
in the three groups during the AIG A I A NA I A NA I A NA I A NA
study AG A NA A NA A NA A NA A NA NA NA NA
IG I NA NA I NA NA I NA NA I NA NA NA
A acetaminophen, AG acetaminophen monotherapy group, AIG alternating acetaminophen and ibuprofen
group, I ibuprofen, IG ibuprofen monotherapy group, NA not administered
482
3.2 Patients
This study was undertaken from June 2013 to January 2014.
When a patient was deemed eligible for the study, the child’s
parents were recruited. In total, parents of 1515 children
declined to participate in this study because of the prolonged
inpatient time and a fear of adverse reactions, and parents of
474 participants provided informed consent to participate in
the study; 158 were assigned to each treatment group
thereafter. Three children were excluded from final analysis
because they did not receive any intervention after enroll-
ment. Ultimately, data from 471 children were included in
the intention-to-treat analysis (Fig. 1).
During the study, parents of seven children did not allow
their child’s temperature to be measured, and parents of
two children removed them from the hospital at 4 and 12 h,
respectively. We imputed their missing data with the last
temperature recorded and the last recorded NCCPC score
(Fig. 1).
3.3 Baseline Data
No significant differences were found in baseline demo-
graphic and clinical characteristics across the three groups
Fig. 1 Flow diagram of the patient selection and allocation process and the numbers followed-up and analyzed
S. Luo et al.
except for the proportion of non-compliance (Table 2). In
total, 31 children did not strictly receive their allocated
intervention (Fig. 1). Non-compliance was higher in the
monotherapy groups than in the AI group (7.59% with
acetaminophen vs. 10.83% with ibuprofen vs. 1.28% with
AI; p = 0.003) (Table 2).
3.4 Efficacy
No significant clinical or statistical differences were found
in mean NCCPC score or temperature during the 24 h
across the three groups (Table 3). However, the proportion
of children with refractory fever for 4 or 6 h was clinically
and statistically lower in the AI group than in either of the
monotherapy groups (refractory fever for 4 h: 26.58% with
acetaminophen, 21.66% with ibuprofen, 11.54% with AI;
p = 0.003; refractory fever for 6 h: 10.13% with acet-
aminophen, 17.83% with ibuprofen, 3.85% with AI;
p \ 0.001). No obvious toxicities were observed (Table 3).
3.5 Other Results
During the study, two patients developed persistent high
body temperature for [4 h (defined as axillary
Alternating Acetaminophen and Ibuprofen versus Monotherapies in Febrile Children 483

Table 2 Demographic and clinical characteristics in the three groups

Demographic and clinical characteristics AIG (n = 156) AG (n = 158) IG (n = 157) p-Value

At admission
Age, months 31.79 ± 17.11 30.22 ± 18.14 29.22 ± 16.48 0.177
Male sexa 59.62 (93/156) 61.39 (97/158) 57.96 (91/157) 0.825
Weight, kg 13.63 ± 3.78 13.59 ± 4.22 13.32 ± 3.87 0.760
Fever history, h 20.97 ± 21.57 20.54 ± 20.82 19.04 ± 20.73 0.696
Antibiotic usea 24.36 (38/156) 27.22 (43/158) 31.21 (49/157) 0.401
Febrile convulsion historyb 1.92 (3/156) 2.53 (4/158) 1.27 (2/157) 0.847
Axillary temperature 39.00 ± 0.42 38.98 ± 0.41 38.99 ± 0.42 0.415
NCCPC-R score 13.38 ± 5.79 13.49 ± 6.37 12.77 ± 6.26 0.538
During study
Intravenous fluid volume, ml 287.18 ± 249.51 394.94 ± 263.28 361.91 ± 252.05 0.487
Intravenous infusion duration, h 5.55 ± 3.45 5.57 ± 3.64 5.26 ± 3.73 0.698
Antibiotic usea 69.23 (108/156) 58.86 (93/158) 67.52 (106/157) 0.120
Glucocorticoid usea 2.56 (4/156) 1.27 (2/158) 1.27 (2/157) 0.610
Non-compliancea 1.28 (2/156) 7.59 (12/158) 10.83 (17/157) 0.003*
Follow-up
Total fever days 2.87 ± 1.23 2.91 ± 1.22 2.73 ± 1.19 0.419
Hospitalization days 4.83 ± 2.19 4.76 ± 2.45 4.68 ± 2.41 0.861
Discharge diagnosisa
Suppurative tonsillitis 41.03 (64/156) 31.01 (49/158) 31.21 (49/157) 0.338
Acute upper respiratory tract infection 18.59 (29/156) 29.75 (47/158) 22.29 (35/157)
Acute bronchitis 15.38 (24/156) 16.46 (26/158) 17.83 (28/157)
Pneumonia 7.05 (11/156) 6.33 (10/158) 11.46 (18/157)
Herpangina 4.49 (7/156) 3.16 (5/158) 3.82 (6/157)
Hand, foot, and mouth disease 3.85 (6/156) 3.16 (5/158) 2.55 (4/157)
Exanthema subitum 1.92 (3/156) 0.00 (0/158) 2.55 (4/157)
Other 7.69 (12/156) 10.13 (16/158) 8.28 (13/157)
Data are presented as mean ± standard deviation or % (n/N) unless otherwise indicated. ANOVA was used unless otherwise indicated
AG acetaminophen monotherapy group, AIG alternating acetaminophen and ibuprofen group, ANOVA analysis of variance, IG ibuprofen
monotherapy group, NCCPC-R Non-Communicating Children’s Pain Checklist – Revised
* p \ 0.05
a
Chi-squared test
b
Fisher’s exact test

temperatures C39.0 °C for C4 h), and both patients had
febrile convulsions at admission. AI in 2-h intervals failed
to reduce their persistent high body temperature
effectively.
4 Discussion
Our results showed that the ability of AI to reduce distress or
the body temperature of febrile children during the 24-h
period was no greater than that of acetaminophen or
ibuprofen monotherapy (Table 3). The results described
herein differ from those described in previously published
studies [22, 26–29]. These studies showed statistical differ-
ences in temperature or distress between AI and
monotherapy groups, but the clinical value was limited. This
may be related to differences in intervention administration.
We considered giving children in the AI group the other
antipyretic only when their temperature remained C38.5 °C
and their temperature decreased by B0.5 °C compared with
the temperature measured 2 h before, because it is not nec-
essary to administer alternating therapy to children who are
responding well to monotherapy. Previous studies adminis-
tered one or more cycles of alternating acetaminophen and
ibuprofen to all children in the alternating therapy group
regardless of their body temperature or whether or not they
were exhibiting fever, which may have resulted in an
overoptimistic estimate of the efficacy of alternating therapy.
Our study indicated that AI was more effective than
monotherapy at decreasing the proportion of children with
484 S. Luo et al.

Table 3 Mean Non- Outcomes AIG (n = 156) AG (n = 158) IG (n = 157) p-Value

Communicating Children’s Pain
Checklist score and mean Mean NCCPC score over 24 h 6.20 ± 5.85 5.72 ± 5.80 6.60 ± 6.30 0.424
temperature over 24 h,
Mean temperature over 24 h 37.33 ± 0.85 37.37 ± 0.86 37.42 ± 0.86 0.659
proportion of children with
refractory fever for C4 h, and PRF for 4 ha 11.54 (18/156) 26.58 (42/158) 21.66 (34/157) 0.003*
incidence of low body PRF for 6 ha 3.85 (6/156) 10.13 (16/158) 17.83 (28/157) \0.001*
temperature, rash, asthma, PRF for 8 ha 1.92 (3/156) 6.33 (10/158) 5.10 (8/157) 0.149
gastrointestinal symptoms, and b
hepatic or renal dysfunction PRF for 10 h 1.92 (3/156) 2.53 (4/158) 1.91 (3/157) 1.000
from all causes in the three PRF for 12 hb 1.28 (2/156) 0.63 (1/158) 0.64 (1/157) 0.701
groups PRF for 14 hb 1.28 (2/156) 0.63 (1/158) 0.64 (1/157) 0.701
PRF for 16 hb 1.28 (2/156) 0.63 (1/158) 0.64 (1/157) 0.701
PRF for 18 hb 1.28 (2/156) 0.63 (1/158) 0.64 (1/157) 0.701
b
PRF for 20 h 1.28 (2/156) 0.63 (1/158) 0.00 (0/157) 0.329
PRF for 22 hb 0.64 (1/156) 0.63 (1/158) 0.00 (0/157) 0.776
PRF for 24 hb 0.64 (1/156) 0.63 (1/158) 0.00 (0/157) 0.776
Number of antipyretic doses 3.24 ± 1.49 3.24 ± 1.38 2.78 ± 1.16 0.002*
Low body temperatureb 1.92 (3/156) 2.53 (4/158) 1.91 (3/157) 0.909
Rasha 8.33 (13/156) 8.86 (14/158) 8.28 (13/157) 0.979
Asthmab 0.00 (0/156) 0.00 (0/158) 1.27 (2/157) 0.221
Gastrointestinal symptomsa 84.62 (132/156) 84.18 (133/158) 85.35 (134/157) 0.958
Hepatic dysfunction from all causes 0.00 (0/156) 0.00 (0/158) 0.00 (0/157) –
Renal dysfunction from all causes 0.00 (0/156) 0.00 (0/158) 0.00 (0/157) –
Data are presented as mean ± standard deviation or % (n/N) unless otherwise indicated. ANOVA was used
unless otherwise indicated
AG acetaminophen monotherapy group, AIG alternating acetaminophen and ibuprofen group, ANOVA
analysis of variance, IG ibuprofen monotherapy group, NCCPC-R Non-Communicating Children’s Pain
Checklist – Revised, PRF proportion of children with refractory fever
* p \ 0.05
a
Chi-squared test
b
Fisher’s exact test

refractory fever for 4 or 6 h after initial treatment but did
not significantly decrease the proportion with refractory
fever for C8 h (Table 3). Three children receiving AI, four
receiving acetaminophen, and three receiving ibuprofen
had refractory fever for C10 h, which was consistent across
all study groups. Two children were diagnosed with an
acute upper respiratory tract infection and had febrile sei-
zures at admission then developed a persistent high body
temperature for more than 24 h. In these patients, two or
more cycles of AI in 2-h intervals failed to reduce the
persistent high body temperature. The proportion of chil-
dren with refractory fever for 4 h in either of the
monotherapy groups was similar to the caregivers’ reported
proportion of poor or lack of response to monotherapy in
other studies [2, 3, 5]. Additionally, our retrospective
analysis found the mean NCCPC score of children with
refractory fever for 4 (n = 18) or 6 (n = 6) h in the AI
group was not lower than in either of the monotherapy
groups [4 h: 8.98 ± 3.33 with AI vs. 10.10 ± 3.11 with
acetaminophen vs. 8.32 ± 2.84 with ibuprofen (p = 0.12);
6 h: 9.83 ± 1.49 with AI vs. 10.73 ± 3.73 with
acetaminophen vs. 8.72 ± 2.65 with ibuprofen
(p = 0.10)]. The development of persistent high body
temperatures was consistent across all study groups. These
results mean that two or more cycles of AI may have little
to no clinical benefit if children do not respond to one cycle
of alternating therapy. In other words, if changing the
antipyretic cannot reduce febrile children’s distress or
temperature, more antipyretics may have little to no clini-
cal benefit while also increasing the danger of an overdose.
One issue requiring attention is that there is no evidence
that reducing fever decreases morbidity or mortality from
febrile illness, nor does it reduce the recurrence of febrile
seizures [30, 31]. The primary goal of administering an
antipyretic in febrile children should be to reduce overall
distress not to simply lower body temperature. AI is not a
simple regimen in clinical practice [10]. Alternating the
two agents at different dosages and intervals may easily
cause confusion and result in an accidental overdose. In
this study, trained researchers with an appreciation of the
complexities of the practices were responsible for admin-
istering the antipyretics, thus providing a safer environment
Alternating Acetaminophen and Ibuprofen versus Monotherapies in Febrile Children
for the delivery of an alternating therapy for children with
refractory fever.
The open-label design and the lack of blinding due to
difficulties in recruiting participants are a limitation of this
study. Non-compliance is another study limitation. During
the study, 31 children did not receive their allocated
intervention strictly as required; 29 of these 31 (93.55%)
were from monotherapy groups (Table 2). In the AI group,
non-compliance was because administration of the next
drug to the child was delayed because parents were worried
that the short interval may increase an adverse effect. In
monotherapy groups, non-compliance was because the
other antipyretic was added temporarily, an antipyretic was
administered ahead of time because of poor response to the
allocated antipyretic, or an antipyretic was administered to
prevent the body temperature from rising although it had
not reached 38.5 °C (Fig. 1). This suggests that most par-
ents still have ‘‘fever phobia,’’ though the aim of using an
antipyretic in febrile children should be to relieve their
distress rather than simply decrease their body temperature
[21, 32]. To explore whether non-compliance affected our
results, we repeated an ANOVA in which we imputed data
for these patients after non-compliance with the last tem-
perature detected before non-compliance. The result
revealed stability in this analysis.
The greatest risk with acetaminophen is acute liver
failure and death caused by overdose. Doses of \75 mg/kg
per day are viewed as safe for children aged \6 years [33].
The greatest risk with ibuprofen is gastrointestinal adverse
effects and hypersensitivity [34]. In our study, we admin-
istered acetaminophen 10 mg/kg rather than the maximum
recommended dose of 15 mg/kg in consideration of the
potential for increased hepatotoxicity from acetaminophen
when combined with ibuprofen [13]. The dose of 10 mg/kg
is clinically effective, and acetaminophen 7–15 mg/kg and
ibuprofen 4–10 mg/kg show comparable efficacy in treat-
ing children’s pain or fever [35, 36]. Nevertheless, using a
lower dose (10 mg/kg) rather than a maximum dose
(15 mg/kg) may have increased the use of the antipyretic in
the AI group; however, we do not believe this would
overestimate the efficacy of alternating therapy compared
with ibuprofen monotherapy. The mean number of anti-
pyretic uses in the AI group was not more than that in the
acetaminophen monotherapy group. It is important to note
that our study is almost certainly underpowered to assess
the safety of AI, but we did not observe any obvious
toxicities.
In addition, the distress score was measured at 4-h
intervals and body temperature was measured at 2-h
intervals, which was considered acceptable to parents and
children but does mean that not every measurement coin-
cided with the highest point of efficacy for each dose of
acetaminophen or ibuprofen. Our outcomes were used to
485
evaluate distress and temperature over a whole day because
results from the separated time points would be difficult to
generalize in clinical practice. The acetaminophen or
ibuprofen administration time was random because chil-
dren’s responses to antipyretic agents and fever recurrences
in each group were random and the requirement for inter-
vention in each group was a temperature C38.5 °C with a
minimal pharmacological interval from previous anti-
pyretic administration rather than a fixed administration
regardless of the presence of fever. As a result, the 4-hourly
distress score measurements and the 2-hourly body tem-
perature measurements should collect all information about
distress and temperature over a whole day.
Lastly, the rectal route has been widely viewed as the
gold standard for routine clinical measurement of body
temperature and is the common site for body temperature
measurement in many areas of the world [37, 38], but
taking rectal temperature measurements multiple times in
1 day are impractical and objectionable. Axillary temper-
ature measurements are preferred over rectal and oral
temperature measurements in the pediatric setting in the
city in which this study was performed. To ensure the most
accurate axillary temperature measurement possible, the
same trained researchers were responsible for measuring
the axillary temperature in all children.
5 Conclusions
Alternating acetaminophen and ibuprofen can reduce the
proportion of children with refractory fever compared with
monotherapies, but if one cycle of alternating therapy does
not reduce febrile distress, two or more cycles of alter-
nating therapy may have minimal to no clinical efficacy in
some cases.
Acknowledgements The authors thank all the children and parents
who agreed to participate in our study.
Compliance with Ethical Standards
Conflict of interest Luo SH, Ran MD, Luo QH, Shu M, Guo Q, Zhu
Y, Xie XP, Zhang CF, and Wan CM have no conflicts of interest.
Ethics approval and informed consent This trial was approved by
the Ethics Committee of West China Second University Hospital of
Sichuan University. All procedures performed in studies involving
human participants were in accordance with the ethical standards of
the institutional and/or national research committee and with the 1964
Helsinki declaration and its later amendments or comparable ethical
standards. Informed consent to participate in the study was obtained
from participants’ parents.
Funding The study was supported by the Program for Changjiang
Scholars and the Innovative Research Team at the University Min-
istry of Education of China (IRT0935) and the Applied Basic
Research Project of Sichuan Province (No. 2012JY0008).
486
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