International Journal of Clinical Medicine, 2013, 4, 409-416 Published Online September 2013 (
Intraoperative Glycaemia Following Paracetamol with and
without Glucose: A Randomized-Controlled Trial
Ricardo Mota Pereira1*, Fátima Gonçalves1, João Costa2,3,4, Filomena Couto5, Carolina Sá1,
Isabel Neves1, Lucindo Ormonde1,4
1Department of Anaesthesiology, Santa Maria University Hospital, Lisbon, Portugal; 2Laboratory of Clinical Pharmacology and
Therapeutics, Faculty of Medicine, University of Lisbon, Lisbon, Portugal; 3Evidence-Based Medicine Centre, Faculty of Medicine,
University of Lisbon, Lisbon, Portugal; 4Instituto de Medicina Molecular (IMM), Faculty of Medicine, University of Lisbon, Lisbon,
Portugal; 5Department of Gynaecology, Santa Maria University Hospital, Lisbon, Portugal.
Email: *
Received August 3rd, 2013; revised August 31st, 2013; accepted September 6th, 2013
Copyright © 2013 Ricardo Mota Pereira et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background: Hyperglycaemia is conversely a risk factor for perioperative complications. We are currently using a ge-
neric 3.3 g glucose containing formula of intravenous 1000 mg paracetamol for perioperative analgesia. Our main goal
was to compare the trends of glycaemic values after administration of a generic 3.3 g glucose containing formula with a
non-glucose containing branded formula of intravenous 1000 mg paracetamol. Methods: A exploratory proof-of-con-
cept randomized clinical trial was conducted with 150 patients scheduled for elective gynaecologic. Patients were ran-
domly assigned into three groups: control group (saline); active-control group: intraoperative administration of a
branded non-glucose containing 1000 mg paracetamol formula; experimental group: intraoperative administration of a
generic 3.3 g glucose containing 1000 mg paracetamol formula. The primary outcome was mean change from baseline
in glaucoma. In case significant differences were found, the following secondary outcomes were explored: the proportion
of patients with high glycaemia values (>150 mg/dL) and the proportion of patients with negative glycaemic variation.
Results: Mean glycaemia change was higher after generic 3.3 g glucose containing paracetamol formula both in
comparison to placebo (16.3 mg/dL [95% CI: 6.1 to 26.6]) and active-control (19.1 mg/dL [8.2 to 30.0] groups. Similar
results were found in the intention-to-treat analysis. In only the experimental group, patients had high glycaemic values
(11.3%). Conclusions: This study showed that in non-diabetic, under non-cardiac surgery, administration of a generic
glucose-containing formula of intravenous 1000 mg paracetamol was associated with poorer glycaemic control. These
results raise the question of a possible increased risk among these patients. Further studies using diabetic patients are
Keywords: Paracetamol; Hyperglycaemia; Gyneacologic Surgical Procedures; Randomized Controlled Trial
1. Introduction
It has been demonstrated that inadequate glycaemic con-
trol in surgical patients increases perioperative morbidity
and mortality [1]. While most studies focus on neurosur-
gical [2], cardiac [3-5] and critical care patients [6], and
therefore further investigation is required, some of the
outcome key findings are most probably applicable to
general surgical patients [5].
Acute hyperglycaemia is associated with several dele-
terious effects such as suppressed immune function, in-
creased systemic vascular resistance, dehydration, elec-
trolyte and acid-base imbalance and central nervous sys-
tem dysfunction [7]. Although patients with diabetes
mellitus (DM) are at higher risk for perioperative com-
plications [8], the occurrence of intraoperative acute hy-
perglycaemia in non-DM patients is also considered [9,
10] to be a strong and independent predictor of poorer
outcome (sepsis, pneumonia, surgical wound infection).
Furthermore, individuals with previous unknown hyper-
glycaemia are at even higher risk than those with pre-
diagnosed DM [2].
Recent studies found that 21% to 34% of patients who
underwent surgery had uncontrolled blood glucose level
(Blood Glycaemia (BG) > 150 mg/dl), particularly in the
immediate postoperative period (< 72 hours) [11]. Many
of these patients may miss a DM diagnosis as only two
*Corresponding author.
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Intraoperative Glycaemia Following Paracetamol with and without Glucose: A Randomized-Controlled Trial
thirds of those have a pre-established DM diagnosis [12].
Paracetamol (acetaminophen) is one of the safest and
more cost-effective [13] non-opioid analgesic when ad-
ministered in analgesic doses. Paracetamol is considered
an atypical nonsteroidal anti-inflammatory drug (NSAID)
[14], given the nonspecific and weak inhibition of COX-
3 [15], with central and peripheral effects.
In our hospital, it is currently in use a 3 g glucose con-
taining formula of intravenous 1000 mg paracetamol for
perioperative analgesia. To evaluate what is the impact of
this glucose containing paracetamol formula in the in-
traoperative glycaemic control among non-diabetic gen-
eral surgical patients, we conducted an exploratory proof-
of-concept randomized clinical trial.
2. Methods
All patients provided their written informed consent for
participating in this study, which was approved by the
Ethics Committee of our Hospital (Santa Maria Univer-
sity Hospital, Lisbon). This was an academic trial with-
out any direct or indirect funding.
2.1. Study Population
This study was conducted in the gynaecologic surgery
department of Santa Maria University Hospital (Lisbon,
Portugal). Non-diabetic female patients scheduled for
elective gynaecologic procedure were consecutively re-
cruited. Inclusion criteria were: 1) written informed con-
sent; 2) age between 18 and 80 years-old; 3) body mass
index (BMI) < 30 Kg/m2; 4) fasting glycaemic values >
60 mg/dL and <126 mg/dL; 5) American Society of An-
aesthesiology (ASA) classification 2; and 6) 8-hour
fasting period. Patients with a diagnosis of DM or glu-
cose impairment were excluded.
2.2. Study Design
Patients were randomly assigned to one of three groups:
1) Placebo-control group (saline); 2) Paracetamol 1000
mg in a non-glucose containing formula (active-control
group), and; 3) Paracetamol 1000 mg in a 3 g glucose
containing formula (experimental group). All intervena-
tions were delivered in the last third of the surgical pro-
cedure (15 minutes infusion).
Random sequence generation was independently done
by the principal investigator (RMP) that did not partici-
pate in the patients’ recruitment or evaluation. Opaque
sealed envelopes in a closed box were used to retain the
random codes and successively replaced until 150 con-
secutive patients were obtained. Hence, each new patient
had an equal chance of being allocated to one of the three
treatment groups. Allocation concealment was achieved
by making patients and assessment investigator (FC)
blind to treatment assignment. The investigators (FG, FC)
who administered the treatment were the only subjects
that were not blind to treatment assignment, however
they didn’t participated further in the study.
Primary outcome was defined as the mean change
from baseline in blood glucose. If significant differences
were found between groups, the following secondary
outcomes were investigated: proportion of patients with
high glycaemia values (>150 mg/dL) in the second meas-
urement and proportion of patients with negative varia-
tion in glycaemia between the two measurements. The
same investigator (FC) assessed all patients and perform-
ed all measurements. Fingerprick capillary glucose was
determined at the beginning of the surgery (baseline gly-
caemia) and 10 minutes after treatment infusion ending
(post-interventional glycaemia), using the Precision
Xceed Pro point-of-care glucometer (Abbott), which was
calibrated daily. All test-trips used were taken from the
same lot. For the capillary glucose measurement, the se-
cond finger from the opposite arm in which the drug was
administrated, was chosen. In none of the glycemic
measurements was found an invalid value, making un-
necessary a second attempt.
2.3. Anaesthesia Protocol
After an 8-hour preoperative fasting, all patients were
pre-medicated with midazolam 0.05 mg/kg. General an-
aesthesia was induced with single doses of fentanyl (5
ug/kg) and propofol (2 mg/kg) given slowly as bolus
injections. Traqueal intubation was facilitated with ro-
curonium (0.4 mg/kg) and anaesthesia maintained with
sevoflurane vaporized in air and oxygen mixture (FiO2
0.4) titrated to achieve stable hemodynamics.
2.4. Statistical Analysis and Data Synthesis
This was an exploratory trial and we planned to enrol 40
patients per treatment group. Assuming that the response
within each subject group is normally distributed with
standard deviation (SD) of 20 mg/dL, this sample size
will allow detecting a true difference in the mean re-
sponse of treatment groups (experimental, placebo-con-
trol and active-control) of 15 mg/dL with a probability
(power) of 82% (analysis of variance with Bonferroni
correction). We considered that such difference is of po-
tential clinical significance. The Type I error probability
associated with this test of the null hypothesis that the
population means of the experimental and controls
groups were equal was 0.05.
The mean change from baseline in glycaemia values
between groups (primary outcome: dependent variable)
was compared using a full factorial generalized linear
model (GLM) with treatment group as main effect and
including terms for age, fasting period (Nulla per os:
NTO), surgery duration and baseline glycaemia. Interac-
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Intraoperative Glycaemia Following Paracetamol with and without Glucose: A Randomized-Controlled Trial
Copyright © 2013 SciRes. IJCM
tion terms were then removed depending on their level of
non-significance. Type III estimator was used to perform
the analysis. In case significant differences were found,
Bonferroni post-hoc analysis corrected for multiple com-
parisons was conducted to explore the nature of such
150 consecutive patients were randomized between Janu-
ary and May 2011. Seventeen patients were excluded
from the per-protocol analysis because of missing data
from the second glycaemia evaluation (n = 12) and de-
viation of study protocol (the anaesthesiologist did not
administered the treatment according to the protocol; n =
5). As a result, a total of 133 patients were included in
the per-protocol analysis (primary analysis) and 145 pa-
tients in the ITT analysis. Figure 1 shows the study’s
flow diagram. The main characteristics of the patients are
shown in Table 1.
A per-protocol and an intention-to-treat (ITT) analysis
were performed. ITT population comprised all random-
ized subjects that received treatment. The baseline gly-
caemia value was used to impute the missing values from
patients lacking the second glycaemia measurement.
All statistical analyses were done using SPSS 20.0 for
Windows (Lisbon, Portugal). Random codes were broken
only after the final results of the statistical analysis.
As a result of the chosen randomization methodology,
different groups sizes were obtained (49, 42 and 59 pa-
tients, for placebo-control, active-control and experi-
mental groups, respectively) since each new patient had
the same probability chance to be included in the differ-
ent groups.
3. Results
Following our inclusion and exclusion criteria, a total of
Figure 1. Study flow diagram. Mismatch collecting data due to second glycaemia measurements (lacks of post-interventional
glycaemia). Therapeutic error due to intraoperative administration of saline enriched with dextrose.
Intraoperative Glycaemia Following Paracetamol with and without Glucose: A Randomized-Controlled Trial
Table 1. Characteristics of the patients.
Placebo (Saline)
-Control Group
Paracetamol 1 g in non-glucose formula
(Active - Control Group)
Paracetamol 1 g in 3 g glucose
formula p value
n (ITT population) 49 39 57
Age, (years) 40.3 ± 1.9
(18 to 68)
48.3 ± 2.1
(18 to 81)
45.7 ± 1.7
(23 to 78) 0.014
Surgery duration (min) 103 ± 7
(35 to 245)
99 ± 7
(20 to 230)
100 ± 8
(28 to 295) 0.926
NPO (hours) 11.4 ± 0.4
(8 to 18)
10.2 ± 0.4
(8 to 17)
11.1 ± 0.3
(8 to 15) 0.091
Baseline glycemia (C1)
83.9 ± 1.8
(73 to 125)
91.1 ± 2.0
(74 to 114)
85.9 ± 1.7
(68 to 128) 0.628
Legend: Data expressed as Mean ± Standard Error (SE). NPO = Nulla pe r os.
No significant interactions existed between treatment,
surgery time, NPO and baseline glycaemia. Placebo con-
trol group patients were younger than in the other groups
(p = 0.014). Table 2 shows the main results for the per-
protocol and ITT analysis of the primary outcome (mean
change from baseline in blood glucose), as well as the
results of the exploratory secondary outcomes. Post-hoc
analysis for the primary outcome showed significant dif-
ferences between the experimental group and both pla-
cebo and active-control groups (p 0.001 for both per-
protocol and ITT data), without significant differences
between the placebo and the active-control group. For the
per-protocol population, the mean difference between the
experimental and the placebo and active-control groups
were 16.3 mg/dL (95% Confidence Interval [CI]: 6.1 to
26.6) and 19.1 md/dL (95% CI: 8.2 to 30.0), respectively.
For the ITT population, these differences were 15.0
md/dL (95% CI: 5.2 to 24.7) and 18.4 md/dL (95% CI:
7.9 to 28.8), respectively.
In only the experimental group, patients (11.3%) had
high glycaemia values (Figure 2). All glycaemic meas-
urements were above threshold for hypoglycaemia (mini-
mum glucose value was 65 mg/dL, 74 mg/dL and 66
mg/dL for placebo-control, active-control and experi-
mental groups, respectively).
4. Discussion
The most relevant findings of our study are: 1) intrave-
nous paracetamol formulation containing glucose is as-
sociated with a mean increase of glycaemia in female
non-diabetic patients submitted to elective gynaecologi-
cal surgery; Similar results were found considered both
per-protocol and ITT analysis, which strength this con-
clusions; 2) intravenous paracetamol formulation con-
taining glucose is associated with a higher proportion of
patients showing poor glycaemic control. In fact, only
patients randomised to the experimental group had abso-
lute glucose blood values above the so-called “hypergly-
caemic barrier” (>150 - 180 mg/dl).
As previously described, high glycaemic values might
increase the risk of occurrence of adverse effects and
poor outcomes after surgery. The clinical association
between hyperglycaemia and adverse clinical outcomes
was first reported in 1985 when Longstreth and Inui [4]
demonstrated a poorer neurologic recovery following
out-of-hospital cardiac arrest associated with hypergly-
cemia. Several mechanisms promote hyperglycaemia as a
response to the metabolic stress during surgery, namely
through the production and release of the counterregula-
tory hormones (glucagon, epinephrine and cortisol) [7],
peripheral insulin resistance throughout glucocorticoid
therapy [2] and glucose-stimulated insulin depression by
inhalatory anesthesic agents. Although patients with DM
have a higher incidence of perioperative complications
[16,17], development of acute hyperglycaemia perio-
peratively per se (i.e. even in those with previously nor-
mal glucose tolerance) is also recognized as a predictor
of adverse outcome. [7,18]
The goal of optimal glycaemic values has been the
subject of several studies. [19-21] Nevertheless, the gly-
caemic values considered as optimal for medical and
surgical patients have been controversial, both for the
intra- or perioperative periods and for critical or non-
critical patients. Van der Berghe et al. reported the first
major trial of intensive insulin therapy (IIT) in an adult
critical care unit. By targeting blood glucose < 110 mg/dl,
they reported a 32 % (95% CI: 2% - 55%) risk reduction
in mortality, particularly from multiple organ failure and
sepsis. [22] Unfortunately, several subsequent multi-
institutional studies have failed to replicate these results.
The NICE-SUGAR (Normoglycaemia in Intensive Care
Evaluation-Survival Using Glucose Algorithm Regula-
tion) reported an increase risk of death at 90 days (Odds
Ratio 1.14; 95% CI: 1.02 - 1.28) with IIT strategy to
achieve 81 - 108 mg/dl compared with a more relaxed
target (<180 mg/dl). According to the authors, this mor-
tality increase was related with the higher risk of hypo-
glycaemia episodes. [23]
Although there’s controver y between the benefits of s
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Intraoperative Glycaemia Following Paracetamol with and without Glucose: A Randomized-Controlled Trial 413
Table 2. Outcome results.
Outcome Population
Placebo (Saline)
-Control Group
Paracetamol 1g in
non-glucose formula
(Active - Control Group)
Paracetamol 1 g in 3 g
glucose formula p value
Per-Protocol analysis
(n = 133)
17.5 ± 3.1
(7 to 65)
14.7 ± 3.5
(10 to 50)
33.8 ± 2.8
(9 to 116)
F = 6.357;
p < 0.001
Primary outcome: Mean
change from baseline in
blood glucose (mg/dL) ITT analysis
(n = 145) 16.3 ± 3.0 13.0 ± 3.4 31.3 ± 2.7 F = 6.434;
p < 0.001
N (%) with high glycemia
(>150 mg/dL)
Per-Protocol analysis
(n = 133) 0 (0) 0 (0) 6 (11.3) 0.009*
N (%) with negative
glycaemia variation
Per-Protocol analysis
(n = 133) 5 (11.1) 5 (14.3) 2 (3.8) 0.198*
Legend: Data expressed as Mean ± Standard Error (SE). *Fisher exact test.
Figure 2. Baseline and post-intervention glycaemia for individual patients, according to treatment group. Values are ex-
pressed in mg/dL.
tight blood glucose control (<110 mg/dl) versus the
standard blood glucose management (<200 mg), there is
some data [24] suggesting that glycaemic values above
140 mg/dl are associated with post-operative complica-
tions and poorer outcome. In fact, randomized controlled
trials in medical [23], cardiac [25-27] and neurosurgical
[28] populations have found reduced rates of bacteraemia,
duration of antibiotic usage, infections rates [29], and
incidence of recurrent infections in patients with tight
glycaemic control (<150 mg/dl) [1]. Margarita Ramos et
al. further showed that every 40 mg/dL increase in post-
operative glucose above those values led to a 30% in-
creased risk of postoperative infections (pneumonia,
wound infections, urinary tracts infections and sepsis) in
the first 30 days after surgery [30].
Most of the research on glucose control has been con-
ducted in the critical care setting and the results obtained,
being later generalized to the non-critical and non-car-
diac surgery patients [1,31]. In 2010, the Society for
Ambulatory Anaesthesia (SAMBA) [32] published guide-
lines for perioperative management in diabetic patients
undergoing ambulatory surgery. According to this guide-
line, in patients with well-controlled diabetes the intra-
operative blood glucose levels should be maintained be-
low 180 mg/dl. Guidelines for non-critical and non-DM
patients are still lacking. Our results are a first contribu-
tion for an evidence-based discussion on this matter.
In addition, perioperative glycaemic control also de-
pends on hypoglycaemia prevention, namely due to po-
tential neurological injury. [33,34] A blood glucose level
below 70 mg/dl is generally considered an alert value for
hypoglycaemia. [35] This end point value allows time for
prevention of symptomatic hypoglycaemia, which usu-
ally occurs at blood glucose levels of 45 to 55 mg/dL.
[32] During our study, no patients showed hypoglycae-
It is predictable that any anaesthetic technique that
modifies the intra-operatively neuroendocrine stress re-
sponse could also modulate the subsequent metabolic
sequelae and mitigate perioperative hyperglycaemia. [7]
It is well known the benefit effect of blocking the sym-
pathetic neuroendocrine response through the spinal and
epidural anaesthesic techniques on the preventive strat-
egy of supressing the hyperglycaemic stimulus [36]. Dif-
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Intraoperative Glycaemia Following Paracetamol with and without Glucose: A Randomized-Controlled Trial
ferently, propofol and opioids do not have a major effect
on glucose metabolism. [2] In this study, all patients
were submitted to surgery under balanced general anaes-
thesia and with the same anaesthetic protocol, according
to patients’ weight. Therefore, our study is not likely
biased due to confounding anaesthesic variables.
A variety of measurement techniques are currently in
use. Arterial samples are considered more accurate [37].
It is known that capillary testing should be avoided in
patients with haematocrit levels <25% or >60%, in shock,
with severe dehydration and when vasoactive agents such
as norepinephrine are given [38-40]. However, for most
surgical patients, phlebotomy or arterial access is not
routine [41]. In hemodynamically stable patients the cap-
illary glucose meter correlates well with laboratory ref-
erence values [7] and is strongly correlated with arterial
samples [41]. Also, the laboratory plasma values gener-
ally provide little additional information for non-ICU
patients and typically lower the mean glucose [42]. In
this study, all patients were hemodynamically stable and
non-critically ill, submitted to minor/moderate gynaeco-
logic procedures. Therefore, we think that the glycaemia
measurement technique used in our study does not rep-
resent a major limitation. Furthermore, to minimize bias,
the same investigator using the same capillary glucose
meter and technique, performed all measurements.
In our hospital, paracetamol is included in the analge-
sic strategy for all patients (medical and surgical). Sev-
eral peripheral and central mechanisms of action have
been suggested to explain the paracetamol analgesic
properties including selective inhibition of cyclooxy-
genase activity in the CNS, spinal interaction with 5-HT3
receptors [14], inhibition of neurons excited by substance
P and activation of suprasegmental descending inhibitory
pathways [15]. Due to the analgesic properties, parace-
tamol plays a key role in suppressing the surgery-induced
pain adrenergic stimulation, and this suppression could,
in theory, blunt the adrenergic hyperglycaemic response.
In our opinion, this is the most plausible explanation for
the findings in the paracetamol (without glucose) group,
which had the lowest increase in glycaemia.
Finally, as with most studies, this also presented some
limitations. First, this was an exploratory trial, which
aimed to address the question if paracetamol with glu-
cose is associated with an increased risk of poorer gly-
caemic control. We have not evaluated the clinical con-
sequences of this poorer glycaemic control. Second,
sample size was relatively small and we included only
female patients undergoing minor to moderate gynaeco-
logic procedures. This precludes the external validity of
the findings to other non-diabetic populations and gender.
Third, female patients underwent different types of sur-
geries. We have not performed post-hoc subgroup analy-
sis because of low power. The possibility exists that the
results could also differ according to the type of surgery.
Fourth, the paracetamol brand used in the experimental
(Paracetamol-APS®) and active-control (Perfalgan®) groups
were different. Although these are thought to be equiva-
lent, we cannot rule out bias emerging from this differ-
5. Conclusion
In conclusion, our results strongly suggest that admini-
stration of a glucose containing formula of paracetamol
may increase the risk of perioperative hyperglycemia in
non-diabetic patients submitted to non-cardiac surgery.
However, this was an exploratory “proof-of-concept”
trial and, although the results were robust, conclusions
and implications for practice should be thought with cau-
tion. Future clinical research should address the postop-
erative outcomes and potential consequences of this
poorer glycaemic control.
6. Acknowledgements
Specific author contributions: RMP contributed to the
concept and design, data analysis, and interpretation of
the data; wrote the first draft of the manuscript; critically
revised the manuscript; and gave final approval of the
submitted manuscript. FG contributed to the concept,
design, and data acquisition; critically revised the manu-
script; and gave final approval of the submitted manu-
script. JC contributed to data analysis, and interpretation
of the data; critically revised the manuscript; and gave
final approval of the submitted manuscript. IN made con-
tribution in the concept and design; and gave final ap-
proval of the submitted manuscript. FC contributed to
data acquisition. LO gave final approval of the submitted
Financial support and sponsorship: This was an
academic project without any direct or indirect funding.
Conflicts of interest: The authors do not have any
potential conflict of interest to declare.
Acknowledgement: Cochrane Coordinating Centre in
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