Indian J Pediatr (January 2018) 85(1):1–4
DOI 10.1007/s12098-017-2457-3
ORIGINAL ARTICLE
Comparison of Antipyretic Efficacy of Intravenous (IV)
Acetaminophen versus Oral (PO) Acetaminophen
in the Management of Fever in Children
Shuvendu Roy 1 & A. K. Simalti 1
Received: 29 March 2017 / Accepted: 9 August 2017 / Published online: 9 September 2017
# Dr. K C Chaudhuri Foundation 2017
Abstract
Objective To assess the dynamics of the onset of antipyretic
efficacy of intravenous (IV) acetaminophen vs. oral (PO) acet-
aminophen in the management of fever in children.
Methods This observational single-dose study was conducted
at Department of Pedriatrics, Army Hospital (Research and
Referral), a multispecialty tertiary care center in New Delhi in
fever patients to assess the antipyretic efficacy of IV acetamin-
ophen 15 mg/kg/dose vs. PO acetaminophen 15 mg/kg/dose
over 6 h. Subjects were randomly assigned to receive either
IV acetaminophen (n = 200) or PO acetaminophen (n = 200).
Results Demographics and baseline characteristics were sim-
ilar between the two groups and were normally distributed.
Allergic reaction was found in 7 (3.5%) patients in IV acet-
aminophen group and was absent in PO acetaminophen
group. Onset of constipation and dry mouth was found in 8
patients (4%) in IV acetaminophen group and was absent in
PO acetaminophen group. Additional dose was required in 6
patients (3%) in intravenous acetaminophen group and 10
patients (5%) in oral acetaminophen group respectively.
Statistically significant differences in the rate of fall in tem-
perature through 180 min were observed in favor of the IV
acetaminophen group when compared to those receiving PO
acetaminophen.
Conclusions A single dose of intravenous acetaminophen is safe
and effective in reducing fever where patients are unable to tol-
erate oral administration or when rapid reduction of temperature
is desirable.
* A. K. Simalti
ashishsimalti@rediffmail.com
1
Department of Pediatrics, Army Hospital (Research & Referral),
New Delhi 110010, India
Keywords Fever . Pediatrics . Acetaminophen .
Paracetamol . Intravenous . Oral
Introduction
Fever is one of the commonest presenting symptoms in clinical
medicine in all age group patients. It is defined as oral temper-
ature of >37.2 °C (>98.9 °F) in the morning or >37.7 °C
(>99.9 °F) in the evening [1]. Fever can be caused by a numer-
ous ailments ranging from potentially serious conditions to very
benign illness. Treatment with antipyretics not only reduces
fever but also improves the associated other symptoms (e.g., −
arthalgia, myalgia, headache, nausea, vomiting) [2, 3]. Both
pharmacologic and non-pharmacologic methods like tepid
sponging [4] have been used to reduce body temperature in
febrile patients. Extensive studies have been done in children
comparing the efficacy of various antipyretics including para-
cetamol, ibuprofen, nimesulide, ketoprofen, propacetamol, and
dipyrone.
Among these, acetaminophen is considered safest antipy-
retic as well as analgesic and is the most widely used antipy-
retic. Per oral (PO) acetaminophen was first approved by the
U.S. Food and Drug Administration (FDA) in the year 1951
and was marketed in 1953 in United States. Intravenous (IV)
acetaminophen was first approved in Europe in 2001. As of
now acetaminophen has received approval for short-term
management of fever as well as acute pain in about 80 coun-
tries besides United States [5, 6]. Most of the available studies
on acetaminophen were carried out in endotoxin-induced fe-
brile models [7, 8] and in intensive care patients [9]. There is
scarcity of literature on the effect of route of administration
(oral and intravenous) on antipyretic efficacy of paracetamol
in children. Therefore, the authors decided to compare the
2 Indian J Pediatr (January 2018) 85(1):1–4
antipyretic efficacy of oral and intravenous paracetamol in
febrile children.
Material and Methods
It was a prospective observational study of one and a half year
duration conducted in a tertiary care centre at New Delhi.
Sample size was determined to be 200 and all admitted or
out-patient department cases with fever more than 1030 F were
included in study. Children who had received medicines with
antipyretic effects within 48 h of admission were excluded from
the study. Similarly, children with known hypersensitivity to
acetaminophen or other NSAIDs, impaired liver function, ac-
tive hepatic disease, or evidence of clinically significant liver
and renal disease were also not included in the study.
Necessary approval to conduct the study from the
Institutional Ethics committee was taken. Informed consent of
the parents of children was taken prior to enrolment in the
study. Following receipt of consent, children were divided into
two groups, one group receiving oral acetaminophen (15 mg/
kg/dose) and the other group receiving IV acetaminophen
(15 mg/kg/dose) as antipyretic. Children were enrolled in each
group consecutively. Baseline vital parameters including mean
arterial pressure using non-invasive blood pressure monitor by
oscillometric technique were recorded. Following administra-
tion of the drug the child was monitored for the primary effi-
cacy outcome. Axillary temperature was recorded with mercu-
ry thermometer for 5 min every ½ hourly, till 6 h. Children
were monitored for any evidence of intolerance. All the data
including the primary and secondary outcomes were recorded.
All the statistical analysis was performed using SPSS ver-
sion 20. The clinical profile of patients was analyzed by
Student t test (quantitative variables) and chi-square test (qual-
itative variables). Five percent probability level was consid-
ered to be statistically significant i.e., p < 0.05.
Results
A total of 400 participants were enrolled, allocated groups and
subsequently received study intervention; 200 in intravenous
acetaminophen arm and 200 in the oral acetaminophen arm.
Baseline and demographics characteristics were similar in
both the groups and were normally distributed with mean
(±SD) age being 6.7 (±2.75) y. The mean weight was 23.3
(± 6.41) kg and the majority of subjects were boys (71%).
The sex distribution was similar in both the groups (Table 1).
Allergic reaction (rash,itching) was found in 7 patients in
Intravenous acetaminophen group and was absent in oral acet-
aminophen group. Onset of constipation and dry mouth was
found in 8 patients (4%) in intravenous acetaminophen group
and was absent in oral acetaminophen group. Additional dose
was required in 10 patients (5%) and in 6 patients (3%) in oral
acetaminophen group and intravenous acetaminophen group
respectively (Table 2).
The present study revealed that intravenous acetaminophen
brought a more rapid reduction of fever as compared to oral
acetaminophen (Fig. 1). Statistically significant difference in
the weighted sum of temperature differences (WSTD) in
180 min (p < 0.004) was noted in favor of the intravenous
acetaminophen group as against the group receiving oral acet-
aminophen. Beyond 4 h, no difference in WSTD was found in
both the groups (Fig. 1). Up to 4 h, the intravenous acetamin-
ophen receiving children had lower mean temperatures over-
all, and maximum mean temperature 1 °C less than those who
received oral acetaminophen between 0 to 180 min. It has
been observed that although the basal temperature was found
to be same in both the groups after 4 h of initiating the therapy,
IV acetaminophen group experienced a faster descent of tem-
perature in initial 2 h.
A difference which was statistically significant in the re-
duction of maximum temperature was achieved during the
duration T0 min to T240 min in the subjects who were given
intravenous acetaminophen as compared to subjects who were
given oral acetaminophen, while at point T240 and onwards,
temperature reduction achieved same pattern in both groups.
The faster decent in body temperature in IV group is presum-
ably due to the pharmacokinetic superiority of an intravenous
administration. However the temperature observed at the end
of study period of 6 h was mainly similar in both the groups,
suggesting the fact that IV acetaminophen brings down the
temperature faster than the oral one.
Discussion
Fever is not a primary illness but a physiologic mechanism
and has beneficial effects in fighting against infection. There is
no evidence that fever itself worsens the course of an illness or
that it causes long-term neurologic complications. Thus, the
primary goal of treating a febrile child should be to improve
the child’s overall comfort rather than focus on normalization
of body temperature. The most common indications for initi-
ating antipyretic therapy by pediatricians are a temperature
higher than 38.3 °C (101 °F) and improving the child’s overall
comfort [10]. Most pediatricians observe, with some
supporting data from research, that febrile children have al-
tered activity, sleep, and behavior in addition to decreased oral
intake [11]. Unfortunately, there is a paucity of clinical re-
search addressing the extent to which antipyretics improve
discomfort associated with fever or illness.
Acetaminophen is synthetic, non-opioid, centrally acting
antipyretic and analgesic agent [12]. It’s efficacy profile is
well-established along with a safe risk vs. benefit ratio.
Besides it is not associated with known harmful drug to drug
Indian J Pediatr (January 2018) 85(1):1–4 3

Table 1 Baseline statistics of all

cases Age (in years) Weight (in kg) HR (per min) RR (per min)

Mean 6.7742 23.2975 118.4400 23.9200

Std. Error of Mean 0.19361 0.45287 0.65604 0.19637
Median 6.2500 22.0000 122.0000 24.0000
Mode 5.00 20.00 124.00 24.00
Std. Deviation 2.73807 6.40452 9.27776 2.77708
Percentiles 25 5.0000 18.0000 112.0000 22.0000
50 6.2500 22.0000 122.0000 24.0000
75 9.0000 28.0000 126.0000 26.0000

HR Heart rate; RR Respiratory rate

interaction [13]. The present study revealed that intravenous
acetaminophen brought a faster reduction of temperature as
compared to oral acetaminophen. Statistically significant dif-
ferences in the weighted sum of temperature difference
(WSTD) through 180 min (p < 0.004) was seen in favor of
the intravenous acetaminophen group as against the group
receiving oral acetaminophen. However after 4 h, there
seemed to be no difference in the WSTD between both the
groups. Overall mean temperatures were lower in intravenous
acetaminophen receiving group for four hours, with a maxi-
mum mean temperature 1 °C lower than the oral acetamino-
phen receiving group. It has been observed that although the
basal temperature was found to be the same in both groups
after 4 h of initiating the therapy, IV acetaminophen group
experienced a faster decent of temperature in initial 2 h. The
faster decent in body temperature in IV group is presumably
due to the pharmacokinetic superiority of an intravenous ad-
ministration. However the temperature observed at the end of
study period of 6 h was mainly similar in both the groups –
suggesting the fact that IV acetaminophen brings down the
temperature faster than the oral one.
Having the choice of an intravenous preparation of acet-
aminophen for management of fever can be particularly advan-
tageous for children, where oral delivery may not be possible or
feasible due to numerous practical pediatric issues (e.g., irrita-
bility, refusing to take medicine etc.) and in some morbid clin-
ical conditions (e.g., oral intake is temporarily withheld as in
post op scenarios). Acetaminophen can also be administered
through rectal route. Although widely used, it is known to
factors which may include erratic placement of the suppository,
variability in absorption from different preparations of suppos-
itories, lipophilicity of rectal formulation, and the rectal pH at
the time of administration. Thus, absorption from acetamino-
phen suppositories tends to be highly variable and gradual
[16–18]. Higher doses given through this route may increase
the risk of drug accumulation along with toxicity in children
who absorb efficiently through rectal mucosa. Rectal adminis-
tration of drugs may not be socially feasible in some scenarios
(e.g., adolescent children, grown up girls).
Central nervous system is an active site for the antipyretic
effect of acetaminophen. Hence, cerebrospinal fluid (CSF)
concentration would be more relevant as compared to plasma
levels. The acetaminophen concentration– time curve of CSF
correlates better than that of plasma. Both of these curves are
similar except for the time lag to achieve CSF penetration
[19]. In an earlier study comparing both of these routes of
acetaminophen administration, the mean CSF concentration
was observed to be almost 70% higher with IV route when
compared to equivalent oral administration of acetaminophen
[20]. Kumpulainen and colleagues [19] observed that while
both, oral as well as rectal routes of acetaminophen adminis-
tration were effective, IV acetaminophen led to faster achieve-
ment of peak plasma and CSF levels resulting in faster onset
of action. Similar findings were observed in index study also.
The faster antipyretic effect by IV administration leads to
105 Intravenous acetaminophen
104.5
Oral acetaminophen
104
103.5
Mean Temperature (°F)

result in erratic and slow absorption [14, 15] because of several 103
102.5
102
101.5
Table 2 Comparison of adverse effects and need for additional dose 101
100.5
Adverse effects Oral group IV group P value 100
99.5
(n = 200) (n = 200) 99
98.5
98
Rash, itching 0 7 0.0076 97.5
Constipation 0 8 0.0043 97

Dry mouth 0 8 0.0043

Time post dose (min)
Additional dose requirement 10 6 0.3074
Fig. 1 Time post dose mean temperature variation in the study groups
4 Indian J Pediatr (January 2018) 85(1):1–4
faster correction of fever related symptoms, like nausea and
vomiting. This may also help in absorption of orally adminis-
tered medications. It has also been observed in this study that
adverse drug reactions were also very minimal in the study
groups. In view of these observations, faster reduction of tem-
perature by intravenous acetaminophen administration, it
might be considered superior in children, especially in some
specific pediatric ailments (e.g., febrile seizure, febrile en-
cephalopathy, high fever with feed refusal) where faster reduc-
tion of fever is considered essential to prevent a scary convul-
sive attack or alarming metabolic compromise.
Conclusions
From the results of the present study, it may be concluded that
a single dose of intravenous acetaminophen is safe and effec-
tive in reducing fever. Intravenous acetaminophen may be
useful where patients are unable to tolerate oral administration
or when rapid reduction of temperature is desirable.
Contributions SR: Concept, conducting study, manuscript preparation
and revision; AKS: Data collection and manuscript preparation. SR will
act as guarantor for the paper.
Compliance with Ethical Standards
Conflict of Interest None.
Source of Funding None.
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