Effect of Intravenous Propacetamol on Blood Pressure in

Febrile Critically Ill Patients

Moshe Hersch, M.D., M.Sc., David Raveh, M.D., and Gabriel Izbicki, M.D.
Study Objectives. To investigate the effect of intravenous propacetamol, a
parenteral bioprecursor of acetaminophen, on systemic blood pressure in
critically ill patients with fever, and to establish the prevalence and clinical
significance of this effect.
Design. Prospective, observational study.
Setting. A six-bed medical-surgical intensive care unit (ICU) of a university-
affiliated tertiary care hospital in Israel.
Patients. Fourteen critically ill patients (aged 17–83 yrs) with sepsis and fever
(body temperature ≥ 38°C) who received an intravenous infusion of
propacetamol 2 g over 15–20 minutes every 6 hours as needed to reduce fever.
Measurements and Results. Demographic data, including degree of sepsis, were
collected at baseline (before propacetamol infusion). Blood pressure, heart rate,
body temperature, and need for fluid or vasopressor therapy were recorded at
baseline, at end of infusion, and at 15, 30, 45, 60, 90, and 120 minutes after
propacetamol administration. The drug was administered on 72 occasions in
the 14 patients. Mean ± SE systolic, diastolic, and mean arterial pressures
recorded 15 minutes after propacetamol administration were significantly lower
than baseline measurements: 123 ± 29 versus 148 ± 33, 62 ± 12 versus 70 ± 15,
and 83 ± 16 versus 97 ± 19 mm Hg, respectively (p<0.05). In 24 (33%) of the
72 infusions, systolic blood pressure decreased to below 90 mm Hg and
required intervention with fluid bolus administration on six occasions; a fluid
bolus was accompanied by a dosage increase or initiation of a norepinephrine
infusion on 18 occasions. No correlation, however, was noted between the
degree of decrease in mean arterial pressure and decrease in temperature
(r2=0.01), or the degree of decrease in mean arterial pressure and decrease in
heart rate (r2=0.23), at each data collection time point, as measured by linear
regression.
Conclusion. Intravenous propacetamol, given in antipyretic doses, caused a
significant decrease in blood pressure 15 minutes after administration in febrile
critically ill patients. This drug-induced hypotension was clinically relevant in
that interventions to control blood pressure were required. Thus, clinicians
should be aware of this potential deleterious effect, particularly in specific
populations such as critically ill patients.
Key Words: propacetamol, blood pressure, adverse drug reactions, drug
information, drug safety, septic shock, critical care.
(Pharmacotherapy 2008;28(10):1205–1210)

Pyrexia in critically ill patients is very common.1 responses to the invading microorganism.
Most of these patients have an infection, with fever Although there is a debate about the role of this
being one of the most recognized systemic host physiopathologic response in fighting the
1206 PHARMACOTHERAPY Volume 28, Number 10, 2008
infection, 2 most practitioners in the intensive
care unit will try to reduce the fever, as every
increase in body temperature of 1°C above 37°C
increases oxygen consumption by 6–10%.3
Many of our critically ill patients with fever
have problems absorbing enterally administered
drugs, or at least, absorption is unpredictable.
Therefore, when we want to lower body temper-
ature in these patients, we prefer an intravenous
preparation with a good safety profile to circum-
vent this questionable enteric absorption. The
relatively well-known intravenous antipyretic and
analgesic drug dypirone is not an option in most
countries because of its rare but potentially lethal
adverse effect on bone marrow.4 Propacetamol, a
parenteral bioprecursor of acetaminophen, was
recently introduced for use in intensive care units
(ICUs) for the treatment of fever in critically ill
patients. Because acetaminophen is poorly
soluble and unstable in aqueous solution, it has
been administered parenterally as the water-
soluble prodrug, propacetamol hydrochloride,
which is readily cleaved in the blood by esterases
into acetaminophen and pharmacologically
inactive diethylglycine.5, 6 Thus, the pharmacologic
and pharmacokinetic profile of propacetamol is
identical to that of acetaminophen. A dose of 2 g
of intravenous propacetamol is bioequivalent to 1
g of intravenous acetaminophen.7 The maximum
plasma concentration after intravenous infusion
of acetaminophen 1 g is about 30 mg/L,
occurring at 15 minutes (i.e., end of infusion).8
It is our ICU’s practice to attempt to reduce a
patient’s body temperature when it reaches 38°C.
Preliminary observations by our staff have noted
that when defervescence started, approximately
15 minutes after propacetamol administration,
many patients demonstrated a significant
decrease in blood pressure that sometimes
necessitated an intervention (i.e., fluid bolus
administration and/or initiation or increase of
vasopressor therapy). Published data regarding
acetaminophen’s or its precursor’s effects on
blood pressure are limited and controversial.
Some studies showed no decrease in blood
pressure, and others demonstrated significant
From the Critical Care Unit (Drs. Hersch and Izbicki),
Infectious Disease Unit (Dr. Raveh), and Pulmonary Unit
(Dr. Izbicki), Shaare Zedek Medical Center, Jerusalem,
Israel.
Manuscript received December 6, 2007. Accepted
pending revisions March 13, 2008. Accepted for
publication in final form May 19, 2008.
Address reprint requests to Moshe Hersch, M.D., M.Sc.,
Critical Care Unit, Shaare Zedek Medical Center, Jerusalem,
Israel 91301; e-mail: hersch@szmc.org.il.
decreases in blood pressure, although mostly on
an anecdotal basis and usually after oral
administration.9–12 Thus, we sought to validate
prospectively our preliminary observation that
propacetamol therapy reduces blood pressure in
febrile patients in the ICU and to establish the
prevalence and clinical significance of this
phenomenon.
Methods
This prospective, observational study was
conducted from January 1, 2005–June 30, 2005.
The study was performed in a multidisciplinary
mixed (medical-surgical) six-bed ICU of a
university-affiliated tertiary care hospital in
Israel. The study was approved by the local
ethics committee. Written informed consent was
waived as propacetamol is routinely administered
in our ICU, and all the measurements performed
were part of routine ICU protocols. Oral consent
was obtained from patients’ next of kin.
Study Population
The study population consisted of critically ill
patients in the ICU who were febrile (body
temperature ≥ 38°C), ventilated, sedated, and
experiencing sepsis according to American
College of Chest Physicians–Society of Critical
Medicine consensus criteria. 13 In our ICU,
patients requiring ventilation are sedated to a
Ramsay Sedation Scale 14 score of 2–3 with an
intravenous infusion of midazolam and morphine.
Patients were excluded from the study if they
were receiving a hypotensive drug within 1 hour
before administration of propacetamol, had a
known allergy to acetaminophen, had acute liver
failure, or required an ICU-related procedure that
might affect their blood pressure. In addition, to
avoid a possible effect of sedation on blood
pressure, patients whose sedation protocol was
changed within 2 hours before or after adminis-
tration of propacetamol were excluded.
Drug Administration
Propacetamol (Prodafalgan; Laboratoires
UPSA, Rueil-Malmaison, France) 2 g was infused
intravenously over 15–20 minutes, every 6 hours
as needed, according to our ICU’s standard
practice and the manufacturer’s instructions, to
reduce fever. Normal saline (100 ml) was used as
the solvent and vehicle for drug administration.
When hypotension, defined as systolic blood
pressure below 90 mm Hg, was noted, we
 PROPACETAMOL-INDUCED HYPOTENSION IN CRITICALLY ILL PATIENTS Hersch et al 1207

followed our standard ICU protocol: repeated Table 1. Demographic and Clinical Data for the 14 Patients
boluses of colloids (250–500 ml) were administered Sex/
as needed and/or norepinephrine infusion was Age (yrs) Diagnosis on Admission to Intensive Care Unit
started or the dosage increased until systolic M/83 Pneumonia
M/63 Total colectomy
blood pressure rose above 90 mm Hg. F/70 Exploratory laparotomy, ileostomy
M/58 Gastrectomy, ileostomy
Data Collection F/81 Pancreatitis
F/52 Necrotizing fasciitis
Invasive intraarterial blood pressure (systolic, F/37 Appendectomy, ileostomy
diastolic, and mean arterial pressure), heart rate, M/75 Pneumonia
rectal temperature, and any fluid or vasopressor F/77 Perforated appendicitis
M/73 Acute respiratory failure, Legionella pneumonia
therapy were recorded before and 15, 30, 45, 60, F/17 Crohn’s disease, small-bowel obstruction
90, and 120 minutes after propacetamol admin- F/50 Wegener’s granulomatosis, encephalitis
istration. Body temperature was continuously M/55 Exacerbation of chronic obstructive
monitored in all patients by using a rectally pulmonary disease, mechanical ventilation
introduced temperature sensor probe (Datex- M/67 Exacerbation of chronic obstructive
pulmonary disease, mechanical ventilation
Ohmeda Corp., Helsinki, Finland).
Any adverse or allergic-type reaction during
and up to 120 minutes after propacetamol
administration was recorded. In addition, the years for women and 67.7 ± 9.9 years for men
number of occasions on which patients previously (p=0.2). Mean ± SD Acute Physiology and
treated with norepinephrine required an increase Chronic Health Evaluation (APACHE) II score
in dosage, as well as the number of occasions on for all patients was 24 ± 7. At start of propacetamol
which norepinephrine had to be started de novo, infusion, septic shock (patients receiving
were recorded. concomitant norepinephrine) was present during
19 infusions, whereas during the other 53
Statistical Analysis infusions, the patients had sepsis but did not
Statistical analysis was performed with require norepinephrine. No patients were
SigmaPlot 9.01 (Systat Software Inc., San Jose, receiving corticosteroids because of adrenal
CA). Blood pressure, heart rate, and rectal insufficiency during the study.
temperature readings from the six data-collection Mean ± SE systolic, diastolic, and mean arterial
time points after drug administration were pressures recorded 15 minutes after propacetamol
compared with baseline (before drug adminis- administration were significantly lower than
tration) by using a 2-tailed, paired t test. Linear baseline measurements: 123 ± 29 versus 148 ±
regression was used to determine if a correlation
was noted between the degree of decrease in
mean arterial pressure and decrease in rectal
temperature, as well as between decrease in mean 160
Systolic
arterial pressure and decrease in heart rate at 150

each time point. Values are expressed and 140

Blood Pressure (mm Hg)

plotted as mean ± SE. A p value of 0.05 or less 130 a

was considered to indicate a statistically signifi- 120

cant difference. 110

100 Mean arterial

90
Results b
80
Diastolic
During the study period, propacetamol was 70
b
given on 90 occasions to 20 patients with sepsis. 60
Six patients were excluded: four had sedation 50
protocol changes and two received ␤-blockers Baseline End of
Infusion
15 30 45 60 90 120

around the time of propacetamol infusion.

Therefore, 14 patients who received 72 propacetamol
infusions were included in the final analysis. The
patients’ demographic and clinical data are
shown in Table 1. Mean ± SD age was 54.8 ± 23
Time (minutes)
Figure 1. Mean ± SE systolic, diastolic, and mean arterial
pressures before, at end of, and after intravenous
propacetamol infusion in febrile patients in the intensive
care unit. ap<0.001, bp<0.05, both versus baseline values.
 1208 PHARMACOTHERAPY Volume 28, Number 10, 2008

33, 62 ± 12 versus 70 ± 15, and 83 ± 16 versus 97 lower body temperature16 (our study used a 2-g
± 19 mm Hg, respectively (p<0.05). These blood dose).
pressure decreases lasted 45 minutes after After we began to use propacetamol in our
propacetamol administration and then gradually ICU, we noted that many patients experienced a
increased, although they did not reach decrease in blood pressure after the drug was
preinfusion (baseline) values at 120 minutes infused, when temperature started to decline.
(Figure 1). Compared with baseline values, body This was surprising, as when hypothermic
temperature and heart rate also decreased patients (e.g., after undergoing coronary bypass
significantly 15 minutes after propacetamol surgery) warm up, their blood pressure usually
administration (Figure 2). During 24 (33%) of decreases due to vasodilatation, and these
the 72 infusions, systolic blood pressure patients often require fluid therapy. On the other
decreased to below 90 mm Hg, and interventions hand, a decrease in temperature (e.g., after
were necessary: on six occasions, only a fluid propacetamol administration in febrile patients)
bolus was required, and on 18 occasions, a fluid should provoke vasoconstriction and therefore
bolus was accompanied by a dosage increase (13 cause an increase in blood pressure, rather than a
times) or initiation (5 times) of a norepinephrine decrease. Our study validated our preliminary
infusion. No correlation was noted between the observation and showed a significant decrease in
degree of decrease in mean arterial pressure and blood pressure occurring 15 minutes after 24
decrease in temperature (r2=0.01) or between the (33%) of the 72 propacetamol infusions in febrile
degree of decrease in mean arterial pressure and critically ill patients. Interventions to increase
decrease in heart rate (r 2=0.23) at each time blood pressure were necessary with intravenous
point, as measured by linear regression. fluid bolus administration and, in some patients,
vasopressor therapy.
Discussion The observed decrease in blood pressure was
Of the studies regarding acetaminophen’s or its accompanied by significant decreases in heart
precursor’s effects on blood pressure,9–12 only one rate and temperature compared with baseline
was a prospective study that found that oral values. However, we found no statistically
acetaminophen administered 37 times to febrile, significant association between the degree of
intensive-care patients caused hypotension.10 In decrease in mean arterial pressure and decrease in
other studies, however, no decrease in blood temperature, or the degree of decrease in mean
pressure was documented after administration of arterial pressure and decrease in heart rate.
propacetamol. One study showed a trend toward Therefore, the mechanism of the blood pressure
a decrease in blood pressure, but it lacked decrease is not clear and is most likely multi-
statistical significance; this could be attributed to factorial. Nevertheless, we believe that in febrile
the fact that the drug was administered only 10 patients with sepsis, a small decrease in heart rate
times. 15 Another study found no decrease in and temperature could result in a reduction of
blood pressure after administration of cardiac output (the combination of reduction in
intravenous propacetamol; however, the frequency and intensity of myocardial
investigators used only a 1-g dose, which did not contractions). This, in itself, may induce a

A
B
0.2 10
a
b
0.0
Temperature Change (°C)

Change in Heart Rate

0
-0.2
(beats/minute)

-0.4
-16
-0.6

-0.8
-20
-1.0

-1.2
-30
Baseline End of 15 30 45 60 90 120 Baseline End of 15 30 45 60 90 120
Infusion Infusion
Time (minutes) Time (minutes)

Figure 2. Mean ± SE changes in temperature (A) and heart rate (B) in febrile patients in the intensive care unit in relation to
time of receipt of intravenous propacetamol. ap<0.0001, bp<0.0005, both versus baseline values.
 PROPACETAMOL-INDUCED HYPOTENSION IN CRITICALLY ILL PATIENTS Hersch et al
decrease in blood pressure, as critically ill, febrile
patients are well known to experience vasoplegia17
and therefore are unable to maintain their blood
pressure by compensatory vasoconstriction.
Indeed, this theory is indirectly supported by the
fact that the hypotensive effect of propacetamol
was much more prevalent in patients with more
advanced sepsis (septic shock), who actually
received norepinephrine before propacetamol
administration (13 [68%] of 19 infusions),
compared with a much lower prevalence in
patients who were in an earlier stage of sepsis (5
[9%] of 53 infusions). To confirm our hypoth-
esis, cardiac output should have been measured
before, during, and after propacetamol
administration, a measurement that was not
performed in our study. Nonetheless, our
hypothesis is supported by the fact that the
cardiac index was already shown to be reduced
by 10% after administration of intravenous
propacetamol to postoperative patients.18, 19
Theoretically, the decrease in blood pressure
could have been related to propacetamol’s
analgesic effect; however, all of our patients were
treated with morphine and midazolam, using a
standard analgesia and sedation protocol,
routinely maintained by the nurses in order to
achieve a Ramsay score of 2–3.14 No changes in
sedation drug dosages were made around the
time of administration of intravenous propacetamol
in all patients, so that there was no influence of
sedation or analgesia on the decrease in blood
pressure around the time of drug administration.
As propacetamol was dissolved only in normal
saline, the observed phenomenon cannot be
attributed to the propacetamol vehicle. Moreover,
as propacetamol is hydrolyzed in the blood by
esterases into acetaminophen and pharmacologically
inactive diethylglycine, the observed pharmaco-
logic effects can only be attributed to acetaminophen
itself. Because the hypotensive effect was not
accompanied by any phenomena suggesting
hypersensitivity (e.g., rash, bronchospasm), this
also cannot be considered an allergic effect.
There are some limitations to our study. First,
as this was an observational study, it does not
have a control group. Nevertheless, a Spanish
study showed that the hypotensive effect is not
limited to acetaminophen only, as a minimal,
clinically nonrelevant decrease in arterial blood
pressure was observed with other analgesics or
nonsteroidal antiinflammatory drugs such as
metamizol or ketorolac.18, 19 Thus, the hypotensive
effect of propacetamol is most probably not
specific to this drug, but rather might be
1209
common to other antipyretic, analgesic drugs.
However, this drug-induced hypotension
becomes clinically relevant in critically ill, febrile
patients, as we observed in our study, as inter-
ventions to control blood pressure were required
for one third of the infusions administered.
A second limitation is that as cardiac output
was not measured in the study, the reason for
blood pressure decrease in these patients is
mainly hypothetical; therefore, further studies are
needed to assess the mechanism. Third, the drug
was administrated to only 14 patients, but the
analysis included 72 infusions. Therefore, this
study is, to the best of our knowledge, the largest
prospective analysis documenting a poorly
characterized adverse effect of intravenous
propacetamol.
Conclusion
This study showed that administration of
intravenous propacetamol can cause a significant
decrease in blood pressure in febrile critically ill
patients. This decrease in blood pressure
necessitated intervention with fluid bolus or
norepinephrine administration in 33% of the
infusions. Thus, when administering propacetamol
as an antipyretic to a febrile critically ill
population, clinicians should be aware of this
potential deleterious effect.
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