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Acetaminophen has greater antipyretic
efficacy than aspirin in endotoxemia: A
randomized, double-blind, placebocontrolled trial
Objective: To compare the antipyretic efficacy of aspirin and acetaminophen (INN, paracetamol) in 30 male
volunteers with the use of endotoxin (lipopolysaccharide) to elicit a standardized febrile response.
Methods: A randomized, double-blind, placebo-controlled trial was conducted in parallel groups. Subjects
received an intravenous endotoxin bolus of 4 ng/kg after premedication with either placebo, 1000 mg
aspirin, or 1000 mg acetaminophen by mouth.
Results: Peak body temperatures were 38.5C 0.2C in the placebo group, 37.6C 0.2C in the acetaminophen group (P = .001 versus placebo), and 38.6C 0.2C in the subjects treated with aspirin (P =
.001 versus acetaminophen; P = .570 versus placebo) at 4 hours after lipopolysaccharide infusion. Subjective symptom scores for chills and perception of fever were higher in the placebo group than in the acetaminophen group (chills, 2.5 0.3 versus 1.0 0.2, P = .009 and fever, 2.5 0.2 versus 2.0 0.2, P =
.021). Tumor necrosis factor, interleukin-6, and interleukin-8 levels rose by several orders of magnitude (P < .001 versus baseline in all groups), without significant intergroup differences.
Conclusions: Acetaminophen was the superior antipyretic drug in endotoxemia compared with aspirin.
Treatment with acetaminophen ameliorates subjective symptoms induced by endotoxemia without compromising the humoral response of a subject to endotoxin. This observation has clinical interest and may
also help to improve the lipopolysaccharide model, which can be used to test anti-inflammatory and anticoagulatory drugs. (Clin Pharmacol Ther 1999;66:51-7.)
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52 Pernerstorfer et al
Although fever is often the first and leading symptom to suggest an infectious disease, the practice of
fever control in sepsis is still controversial.9 A recent
trial found that ibuprofen reduced fever and pulse rate
and lessened lactic acidosis in patients with sepsis,
despite unchanged mortality.10 A clue for this puzzling
discrepancy could be given by seminal experimental
studies that unequivocally showed ibuprofen to enhance
the release of TNF-, IL-6, and IL-8 in human volunteers infused with endotoxin.11,12 Thus it appears that
the potentially beneficial effects of ibuprofen on the
lipopolysaccharide-induced febrile response are outweighed by the enhanced systemic inflammatory reaction. Yet it is ill characterized whether other antipyretic
drugs, such as acetaminophen (INN, paracetamol) and
aspirin (the most commonly used antipyretics), may
have a more favorable anti-inflammatory profile in
endotoxemia. Although several comparisons on the
analgesic and antipyretic activity of ibuprofen and
ketorolac versus acetaminophen have been made,13-15
direct comparisons of the antipyretic activity of aspirin
and acetaminophen in adults are scarce. Furthermore,
direct comparisons of the antipyretic efficacy of aspirin
and acetaminophen have mainly been done in pediatric
patients,16-18 whereas to the best of our knowledge, no
controlled trial has yet compared the antipyretic efficacy in adults.
Infusion of endotoxin is an established model that has
previously been used to test antipyretic drugs.15,19 We
therefore planned to compare the antipyretic efficacy of
aspirin and acetaminophen in volunteers receiving
lipopolysaccharide intravenously, which produces clinical symptoms of a systemic inflammatory response.
METHODS
Study design and study subjects. The study was
approved by the Institutional Ethics Committee of the
Vienna University Medical School, and all participants
gave written informed consent before they enrolled in
the study. Block randomization (n = 3) was used
because one vial of endotoxin was used for every three
subjects in the study. The study was designed as a randomized, double-blind placebo-controlled trial in three
parallel groups (n = 10 per group) in 30 healthy male
subjects (mainly students) with body mass indices that
ranged from the 15th to the 85th percentile (because
different clearance rates for acetaminophen have been
reported in relation to weight and sex20).
Health status was determined by a battery of laboratory and clinical tests, including evaluation of medical
history, physical examination, and hematologic, biochemical, virologic, and drug screening as described
previously.21,22 Exclusion criteria were hypersensitivity to either aspirin or acetaminophen and regular or
recent (within 3 weeks) intake of any drugs, including
over-the-counter medication.
Study protocol. Volunteers reported to the study ward
at 8 AM in the morning after fasting overnight. Throughout the entire study period they had to stay in bed in the
supine position, and they fasted for 812 hours after endotoxin infusion. A glucose 5% infusion (Leopold Pharma,
Austria) was started at 8:30 AM and continued over an
812-hour period at 3 mL/kg/h to ascertain adequate blood
glucose levels and adequate urinary output.
Vital parameters (electrocardiography, heart rate, and
oxygen saturation continuously; blood pressure at 20minute intervals) were monitored on a Care View System (Hewlett-Packard, Bblingen, Germany), and tympanic temperature was recorded hourly with an electronic thermometer (Thermoscan, San Diego, Calif).
Temperature measurements were performed by a single operator who calculated the mean values of measurements from both ears.23 For safety reasons, subjects in the study had to stay at the research ward
overnight until 24 hours after endotoxin infusion.
After the glucose infusion was started, placebo
(Genericon Pharma, Lannach, Austria), 1000 mg acetaminophen (Paracetamol Genericon Pharma, Lannach,
Austria), or 1000 mg acetylsalicylic acid (ASS Genericon Pharma), which is bioequivalent to aspirin from
Bayer, was administered orally. Aspirin, acetaminophen, and placebo tablets were not identical in
shape; to ensure adherence to the double-blind study
design, the tablets were therefore dissolved by a study
nurse who was otherwise not involved in the conduct
of the trial. At 9 AM the subjects received 4 ng/kg
lipopolysaccharide (National Reference Endotoxin,
Escherichia coli; United States Pharmacopeial Convention Inc, Rockville, Md) as an intravenous infusion over
a 1- to 2-minute period. For each randomization block
one vial of lipopolysaccharide was dissolved in sterile
physiologic saline solution less than 5 days before use
to achieve a final concentration of 20 ng/mL (ie, stock
solution). Aliquots of this stock solution (10 mL each)
were kept frozen at 20C and were thawed only once
to prevent repeated freezing-thawing cycles. After
thawing, lipopolysaccharide was filtrated through a 0.2
m filter (Syringe filters, Nalge, Nunc International,
Rochester, NY).
Sampling and analysis. Venous blood was drawn into
citrated Vacutainer tubes before any drug was administered and thereafter as indicated in the figures from an
indwelling venous line. Blood samples were centrifuged
at 2000g for 15 minutes at 4C and stored at 80C until
Pernerstorfer et al
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54 Pernerstorfer et al
Table I. Demographic variables and baseline values for body temperature and hemodynamics
Placebo (n = 10)
Age (y)
Height (cm)
Weight (kg)
Body mass index
Body temperature (C)
Heart rate (beats/min)
Systolic blood pressure (mm Hg)
Diastolic blood pressure (mm Hg)
Acetaminophen (n = 10)
Aspirin (n = 10)
Mean
Range
Mean
Range
Mean
Range
25.7
179
71.7
22.4
36.3
66
119
61
20.1-37.8
165-189
63-87
20.3-24.8
35.5-37.3
56-74
109-131
53-72
26.9
181
79.5
24.2
36.2
66
125
68
20.4-37
174-190
64-98
21.1-27.2
34.7-37.2
46-92
113-134
56-76
29.8
177
77.2
24.7
36.0
69
124
70
21-37.8
168-184
69-90
22.2-27.1
35.2-36.8
59-86
109-139
57-84
Furthermore it has been estimated that fever in children is caused by bacteria in approximately 30% of all
cases.33 The heterogenous cause in these patients may
therefore at least partially explain the discrepancy from
our findings. In some of these studies patients were concomitantly treated with antibiotics, which may present
an additional confounding effect.14,37
Finally, both drugs were introduced into clinical routine for adults before controlled trials became the gold
standard of clinical pharmacology of clinical drug evaluation, which may account for the lack of placebocontrolled trials that directly compared the two drugs.38
Cardiovascular response. The differences in temperature were closely mirrored by a blunted increase in
heart rate in the acetaminophen group (Fig 1). There
may be two determinants of heart rate increases during
endotoxemia. The early upstroke in pulse rate could be
the result of the increases in body temperature because
aspirin and acetaminophen suppressed both fever and
heart rate at 2 hours after lipopolysaccharide administration. It is conceivable that vasodilation, as indicated
by the decreased diastolic blood pressure, may be an
additional determinant of heart rate during endotoxemia.
Accordingly, mean arterial pressure in the subjects
in this study declined by less than 10% throughout the
entire study period, suggesting fairly unchanged cardiovascular function. Although this minor decline in
arterial blood pressure occurred equally in all groups,
a blunted increase in heart rate was noted only in the
subjects treated with acetaminophen who also showed
an attenuated febrile response. Because we did not measure cardiac output, we cannot answer whether effective antipyretic therapy could have influenced cardiac
output by changes in stroke volume. Still, we assume
that acetaminophen not only reduced the extent of the
febrile response but also blunted the cardiovascular
response. Our data are in general agreement with a
well-established rule of thumb that for every lC
Pernerstorfer et al
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56 Pernerstorfer et al
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