Comparison of dexamethasone, metoclopramide and
their combination in the prevention of postoperative
nausea and vomiting after laparoscopic
cholecystectomy
Nesek-Adam Višnja1, MD, MS, Grizelj-Stojčić Elvira1, MD, Rašić Žarko2, MD, PhD,
Čala Zoran2, MD, PhD, Mršić Viviana1, MD, Smiljanić Aleksandra1, MD
1
Department of Anesthesiology, Resuscitation and Intensive Care, Sveti Duh General
Hospital, Zagreb, Croatia
2
University Department of Surgery, Sveti Duh General Hospital, Zagreb, Croatia
Grizelj-Stojčić Elvira – mladen.stojcic@zg.htnet.hr
Rašić Žarko - zarko.rasic@zg.htnet.hr
Zoran Čala - zoran.cala@bol-svduh.htnet.hr
Correspondence to:
Nesek-Adam Višnja, MD, MS
Žerjavićeva 12
HR-10000 Zagreb
Croatia
tihomir.adam@zg.htnet.hr
Phone: +385913712136
1
Abstract
Background: Postoperative nausea and vomiting (PONV) are one of the most common
complaints following anesthesia and surgery. This study was designed to evaluate the efficacy
of dexamethasone, metoclopramide and their combination to prevent PONV in patients
undergoing laparoscopic cholecystectomy.
Methods: One-hundred and sixty ASA physical status I and II patients were included in this
randomized, double blind, placebo-controlled study. Patients were randomly assigned to 4
groups (n=40 each): group 1 consisting of control patients administered 0.9% NaCl; group 2
patients received metoclopramide 10 mg just before the end of anesthesia; group 3 patients
received dexamethasone 8 mg after the induction of anesthesia; and group 4 patients received
dexamethasone 8 mg after the induction of anesthesia and metoclopramide 10 mg before the
end of anesthesia. The incidence of PONV, mean visual analogue pain scores at rest and on
movement, time to the first request for analgesia, side effects, and well-being score were
recorded during the first 24 h postoperatively.
Results: Data were analyzed using one-way analysis of variance (ANOVA) and χ2 test, with
p<0.05 considered statistically significant. The total incidence of PONV was 60% with
placebo, 45% with metoclopramide, 23% with dexamethasone, and 13% with the combination
of dexamethasone plus metoclopramide. None of the dexamethasone plus metoclopramide
group patients (p<0.05 vs groups 1 and 2) and one dexamethasone group patient (p<0.05 vs
group 1) required antiemetic rescue, as compared with four patients in the metoclopramide
group and six patients in the placebo group. Pain scores, the time to the first request for
analgesia, and side effects were similar across the study groups.
Conclusion: Dexamethasone and the combination of dexamethasone plus metoclopramide
were more effective in preventing PONV than metoclopramide and placebo.
Key
words:
laparoscopic
cholecystectomy,
postoperative
nausea
and
vomiting,
dexamethasone, metoclopramide
2
Introduction
Postoperative nausea and vomiting (PONV) are one of the most common complaints
following anesthesia and surgery. The overall incidence of PONV has been estimated to 30%
depending on surgical, patient and postoperative factors [33]. The patients undergoing
laparoscopic cholecystectomy are especially prone to PONV, with the reported incidence of
53%-72% [20,22,23,25]. In an attempt to decrease such a high incidence, many antiemetics
have been studied [9,10,22,]. However, because of the multifactorial origin of PONV, none of
the currently available antiemetics is fully effective in all patients. At present, when
antiemetics of different pharmacological classes are available, it is possible to combine them
and provide better control of PONV without producing additional side effects [17].
Dexamethasone has been used as an antiemetic for more than 20 years in patients receiving
chemotherapy [15], with limited side effects [1], and has also been reported to decrease
PONV when added to the antiemetic regimen. [4,6]. Recently, a combination of ondansetron
and dexamethasone has been shown to be a highly effective prophylactic measure in patients
undergoing laparoscopic cholecystectomy [6]. However, the higher cost of ondansetron has
been a significant factor limiting its routine prophylactic use [28]. Therefore, we used
metoclopramide, the most common and low-cost antiemetic agent, instead of ondansetron.
We conducted a prospective randomized, double-blind, placebo-controlled study to evaluate
the efficacy of dexamethasone plus metoclopramide in comparison with either antiemetic
alone to prevent PONV in patients undergoing laparoscopic cholecystectomy.
3
Methods
One-hundred and sixty ASA physical status I and II patients scheduled for elective
laparoscopic cholecystectomy under general anesthesia were enrolled in this randomized
double-blind placebo-controlled study. The Hospital Ethics Committee approved the study
and a written informed consent was obtained from each patient. Patients under the age of 18
years or patients with previous allergic reaction to any of the protocol medications, and those
who had vomited or had received any antiemetic within 24 hours prior to surgery were
excluded. Exclusion criteria also included gastrointestinal, renal or liver disease, pregnancy,
smoking, history of motion sickness, and conversion to open cholecystectomy. Patients were
allocated randomly to one of the four medication groups (n=40 each). Study medications were
prepared by a technician anesthetist in identical 5-mL syringes and administered in a doubleblind fashion. Each patient received two syringes, one just after the induction of anesthesia
and the other at the end of surgery. After tracheal intubation, group 1 patients received
placebo (0.9% saline) in two syringes; group 2 received placebo after the induction of
anesthesia and metoclopramide 10 mg at the end of surgery; group 3 received dexamethasone
8 mg after the induction of anesthesia and placebo at the end of surgery; and group 4 received
dexamethasone 8 mg after the induction of anesthesia and metoclopramide 10 mg at the end
of surgery.
The same standardized anesthestic technique was used in all patients. General anesthesia was
induced with thiopental (5 mg/kg) and fentanyl (2 μg/kg) In all groups’ rocuronium bromide
(0.6 mg/kg) was given to facilitate tracheal intubation. Anesthesia was maintained with 1.0%2.5% (inspired concentration) isoflurane in oxygen. Additional fentanyl and rocuronium
bromide were used if necessary. Ventilation was controlled mechanically and was adjusted to
keep end-tidal CO2 between 35 and 40 mm Hg. Laparoscopic cholecystectomy was performed
by European technique using three ports. During surgery the patients were placed in reverse
Trendelenburg position and the abdominal cavity was insufflated with carbon dioxide until
the intra-abdominal pressure reached 12-14 mm Hg. A temporary nasogastric tube was placed
to promote emptying of gastric contents. Prior to endotracheal extubation, the nasogastric tube
was suctioned again and then removed. At the end of surgery, atropine 0.01 mg/kg and
neostigmine 0.05 mg/kg were administered i.v. for reversal of muscle relaxation, and the
trachea was extubated. All patients received i.v. lactated Ringer’s solution at a rate of 10
ml/kg during anesthesia and 2 ml/kg/h after anesthesia until patients tolerated oral fluids.
4
Patients were monitored during anesthesia by continued ECG, noninvasive blood pressure,
pulse oximetry and capnometry. All patients received supplementation of O2 – 4 L/min by a
facemask for 2 h postoperatively.
After surgery, patients were observed for 24 h. The incidence of nausea and vomiting was
recorded during three assessment periods, at 0-4, 4-12 and 12-24 h, by nursing staff without
knowledge of which antiemetic the patients had received. Vomiting was defined as forceful
expulsion of gastric contents through the mouth, whereas nausea was defined as a subjectively
unpleasant sensation associated with awareness of the urge to vomit1,6. We made no
distinction between vomiting and retching. Patients were asked to indicate nausea, vomiting
or retching experienced during the three study periods by “yes” or “no”. If patients
experienced nausea for 30 min, more than one emetic episode in 15 min, or if specifically
demanded antiemetic, a rescue antiemetic (10 mg thiethylperazine) was given intravenously.
Complete response was defined as the absence of nausea and vomiting throughout the study
period.
Postoperative analgesia was provided with a combination of metamizol 1.25 g and tramadol
hydrochloride 100 mg in 100 mL 0.9% NaCl over 20 min iv. Postoperative pain was also
recorded by nursing staff during three assessment periods: 0-4, 4-12 and 12-24 h. The severity
of postoperative pain with and without active movement was measured with the visual analog
scale (VAS), and analgesia was given upon request or when patients experienced pain of VAS
>3. If no relief was obtained or if the VAS exceeded score 5, an additional dose of tramadol
hydrochloride 25 mg was administered i.v. Time interval to the first administration of the
combination of tramadol hydrochloride and metamizol, and number of patients who needed
rescue analgesic were also recorded. The occurrence of side effects accompanying
dexamethasone and metoclopramide usage was recorded concomitantly with PONV
assessment. Patients were also asked to assess their postoperative state 24 h after surgery
using well-being score with regard to the incidence of nausea, vomiting, pain and side effects.
Well-being score was assessed on a 5-grade scale: 1 – very good; 2 – good; 3 – alternating; 4
– poor; 5 – very poor.
Results were calculated as mean  standard deviation (SD). Statistical analysis was performed
using STATISTICA 6.0 software. Parametric data were analyzed with one-way analysis of
variance (ANOVA) and for non-parametric variables we used 2-test. The level of
significance was set at p<0.05.
Sample size was predetermined by power analysis based on the expectation that the total
incidence of PONV in the placebo group would be 60%, with a 40% reduction in the
5
incidence of PONV in the treatment group. The α error was set at 0.05 and β error at 0.2;
according to power analysis, any group size of 37 patients was considered adequate. We
decided to enroll 40 patients per group to allow dropout.
6
Results
All 160 patients enrolled in the study had their surgical procedures completed. There was no
statistically significant difference among the four groups according to patient age, body
weight and height, duration of anesthesia, surgery and CO2 insufflation, and total fentanyl
consumption (Table 1).
The incidence of nausea and vomiting in each treatment group during the three assessment
periods are shown in Table 2. As expected, the incidence of vomiting was less frequent than
nausea in all periods, because some patients experienced nausea without vomiting.
Total incidence of PONV during 24 h was 60% in placebo group, 45% in metoclopramide
group, 23% in dexamethasone group, and 13% in dexamethasone plus metoclopramide group.
Thus, patients receiving 8 mg dexamethasone had significantly less PONV than those
administered placebo (p=0.0007) or 10 mg metoclopramide (p=0.0333). Those receiving the
combination of 8 mg dexamethasone and 10 mg metoclopramide also had a significantly
lower incidence of PONV as compared to placebo (p<0.0001) and 10 mg metoclopramide
(p=0.0013).
During the 24-h study period there was no difference in the incidence in PONV between the
dexamethasone and dexamethasone plus metoclopramide groups (p=0.2392), or between the
placebo and metoclopramide groups (p =0.1792)
In addition, the rate of complete response (no PONV) was 40% in placebo group, 55% in
metoclopramide group (p=0.1792 vs group 1), 78% in dexamethasone group (p=0.0007 vs
group 1, p=0.0333 vs group 2), and 88% in dexamethasone plus metoclopramide group
(p<0.0001 vs group 1, p=0.0013 vs group 2).
At 24 h after surgery, only one patient from dexamethasone group required antiemetic rescue
compared to six patients from placebo group (p=0.0479) and four patients from
metoclopramide group (p=0.1659). None of the patients from dexamethasone plus
metoclopramide group required antiemetic rescue, which was significantly lower compared to
placebo (p=0.0109) and metoclopramide groups (p=0.0402).
Postoperative analgesia with the combination of tramadol hydrochloride and metamizol
showed no significant difference among the four groups in terms of pain intensity at rest and
on movement, number of patients receiving postoperative analgesia, and time to first
analgesic request (Table 3). The intensity of postoperative pain was relatively minor; at 24 h
7
after surgery all four patients groups reported a similar low VAS pain score (median at rest;
group 1, 2.0; group 2, 2.1, and 1.9 in groups 3 and 4 and median with moment; group 1, 2.3;
group 2, 2.4; and 2.2 in groups 3 and 4). Analgesic supplementation with tramadol
hydrochloride 25 mg intravenously was only requested by two group 1 patients and one group
2 patient, and none of group 3 and 4 patients.
The potential side effects include headache, dizziness, anxiety, sleep disturbances, sedation
and perineal itching. In our study, the most frequently reported side effects were sleep
disturbances, sedation and headache, with no significant between-group differences (Table 4).
Perineal itching was not observed in any of our patients.
The patient postoperative state is summarized in Table 5. Two patients from the placebo
group and none of the patients from other groups described their postoperative state as poor
and very poor. The patients administered dexamethasone and dexamethasone plus
metoclopramide reported a significantly higher rate (p<0.005) of very good postoperative
state than those receiving placebo. Also, the patients administered placebo reported a
significantly higher rate of alternating postoperative state than those receiving dexamethasone
(p=0.0231) and the combination of dexamethasone plus metoclopramide (p=0.0068).
8
Discussion
This study compared the efficacy of the combination of dexamethasone and metoclopramide
with either antiemetic alone in patients undergoing laparoscopic cholecystectomy. Although
laparoscopic cholecystectomy decreased surgical morbidity and has become an accepted
procedure for the treatment of cholelithiasis [24], the high incidence of PONV remains a
major clinical problem.
The etiology of PONV after laparoscopic surgery performed under general anesthesia is not
fully understood, but is probably multifactorial [33]. Several factors, including age, sex,
smoking, history of motion sickness, intraoperative use of fentanyl and isoflurane, residual
pneumoperitoneum after CO2 insufflation [7], peritoneum distension, diaphragm irritation and
visceral organ irritation and manipulation [16], have been considered to influence the
incidence of PONV. In this study, however, treatment groups were similar with respect to
demographic data and duration of anesthesia, surgery and CO2 insufflation, whereas those
with a history of motion sickness and smoking were excluded from the study. Therefore, the
difference in the incidence of PONV among the groups could be attributed to the variation in
the antiemetic drugs administered.
As mentioned before, dexamethasone is a corticostereoid with an anti-inflammatory effect
that provides postoperative analgesia [8], prevents nausea and vomiting in patients receiving
highly emetogenic cancer chemotherapy [1,15], and reduces postoperative nausea and
vomiting [8,27,30]. The recommended dose in the prevention of PONV is 8-10 mg.
Therefore, in our study a dose of 8 mg dexamethasone was chosen. The mechanism of the
antiemetic action of dexamethasone and the precise site of action remain unclear. A previous
study has suggested that dexamethasone may antagonize prostangladin [2] or release
endorphins [11], resulting in mood elevation, a sense of well-being, and stimulate appetite.
Dexamethasone was found to be effective when used alone in the prevention of PONV in
several studies [31,32]. Henzi et al. [13] analyzed 17 trials involving 1946 patients, which
compared prophylactic dexamethasone with placebo to prevent PONV, and found it to be
superior to placebo without evidence of any clinically relevant toxicity. In our study, we also
found the total incidence of PONV to be 60% when no antiemetic was given prophylactically,
to be significantly reduced to 23% upon the pretreatment with dexamethasone.
Metoclopramide is a central dopaminergic D2 receptor antagonist and a prokinetic drug,
increasing gastric emptying and shortening bowel transit time. The meta-analysis by Domino
9
et al. [5] has shown that metoclopramide is not as effective as ondansetron and droperidol in
preventing postoperative vomiting. Henzi et al. [12] also performed a meta-analysis of
metoclopramide and found the dose of 10 mg to have no significant anti-nausea effect. Our
results with metoclopramide are in agreement with the study results of Hanzi et al. [12]. In
our study metoclopramide proved to be a poor antiemetic agent in a dose of 10 mg, associated
with a high incidence of PONV (45%). We found no significant reduction of PONV on
comparing metoclopramide with placebo.
Several studies compared a single dose of dexamethasone with a single dose of
metoclopramide in the prophylaxis and treatment of PONV, and found dexamethasone to be
superior in the control of nausea and vomiting [14,29]. Our study confirmed this observation
in terms of better antiemetic effects of dexamethasone vs metoclopramide, with an incidence
of complete response of 78%.
However, current opinion questions the role of monotherapy, and combinations of
dexamethasone with some other antiemetics have been found to be more effective than any
drug alone [4,18,21]. Biswas et al. [4] demonstrated that granisetron plus dexamethasone
reduced the incidence of PONV after laparoscopic cholecystectomy more effectively than
granisetron alone. McKenzie et al. [21] studied ondansetron and ondansetron plus
dexamethasone in women undergoing general anesthesia for major gynecologic surgery, and
the results showed the combination to be more effective than ondansetron alone.
Because of the high cost of these agents, we decided to use the less expensive
metoclopramide in our study. Although some studies describe the combination of
metoclopramide and dexamethasone as an inefficient combination for the prevention of
PONV [8,19], our study found this combination to be effective when compared to placebo.
The total incidence of PONV after laparoscopy was only 13% in patients administered the
combination of dexamethasone plus metoclopramide. The more so, none of the patients from
the dexamethasone and metoclopramide group required rescue antiemetic, pointing to the
high efficacy of this antiemetic combination in the prevention of PONV. One of the potential
reasons why previous studies failed to show the beneficial effects of the combination of
dexamethasone and metoclopramide on the incidence of PONV as compared to placebo may
lie in the timing of metoclopramide administration. It has been recently confirmed that
metoclopramide, because of the short duration of its antiemetic effect, is more efficacious
when administered at the end of anesthesia than when given at its induction [26].
So, we believe that the favorable results recorded in our study could be attributed to the
administration of metoclopramide at the end of anesthesia.
10
Pain after laparoscopic cholecystectomy is relatively minor and most intense during the first 4
hours following surgery [3]. In our study, all the four patient groups experienced sufficient
pain relief upon administration of the combination of tramadol hydrochloride and metamizol,
and reported low VAS pain score (0-4) at rest and on movement.
The most common side effects observed in this study were headache, sedation and sleep
disturbances. These were relatively mild, and there were no differences in the incidence of
side effects among the treatment groups. To avoid perineal itching with dexamethasone, we
administered it after the induction of anesthesia.
In conclusion, the present study demonstrated the combination of dexamethasone plus
metoclopramide and dexamethasone alone to be superior to metoclopramide and placebo in
preventing PONV after laparoscopic cholecystectomy.
11
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14
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15
Table 1. Patient characteristics
Group 1
Placebo
Group 2
Metoclopramide
Group 3
Dexamethasone
Group 4
Dexamethasone
plus
metoclopramide
ASA I/II
24/16
26/14
25/15
22/18
Age (yrs)
54.9±15.5
49.4±13.9
49.6±11.7
50.9±14.5
Sex (M/F)
13/27
8/32
10/30
14/26
Weight (kg)
71.8±11.7
74.2±14.3
70.0 ±12.4
68.6±10.9
Height (cm)
172.0±12.4
173.7±12.7
170.0±11.2
171.3±12.2
Duration of
anesthesia
(min)
68±19
67±28
65±17
66±16
Duration of
surgery (min)
51±20
49±25
47±18
47±17
Duration of
PNP (min)
44±18
42±23
39±16
39±15
199±52
188±61
199±58
187±52
Fentanyl
administered
(μg)
Data presented as mean ± standard deviation (SD); no significant between-group differences
(PNP – pneumoperitoneum
16
Table 2. Incidence of nausea and vomiting during 24 h postoperatively according to
medication groups
Group 1
Group 2
Group 3
Group 4
Placebo
Metoclopramide
Dexamethasone
Dexametasone
plus
metoclopramide
0–4
nausea
9 (23)
7(18)
4 (10)
2 (5)*
vomiting
7 (18)
5 (13)
2 (5)
2 (5)
total PONV
16 (40)
12 (30)
6 (15) *
4 (10) *†
3 (8)
3 (8)
1 (3)
0 (0)
nausea
13 (33)
10 (25)
6 (15)
3 (8) *†
vomiting
10 (25)
7 (18)
3 (8) *
2 (5) *
total PONV
23 (58)
17 (43)
9 (23) *
5 (13) *†
5 (13)
4 (10)
1 (3)
0 (0) *†
nausea
14 (35)
11 (28)
6 (15) *
3 (8) *†
vomiting
10 (25)
7 (18)
3 (8) *
2 (5) *
total PONV
24 (60)
18 (45)
9 (23) *†
5 (13) *†
6 (15)
4 (10)
1 (3) *
0 (0) *†
rescue antiemetics
4 – 12
rescue antiemetics
12 –24
rescue antiemetics
Complete response
16 (40)
22 (55)
31 (78) *†
35 (88) *†
Number of patients (%) with nausea and vomiting during three-assessment period.
Significant
differences
(p<0.05)
compared
with:
*
group
placebo;
†
group
metoclopramide;
17
Table 3. Postoperative visual analog scale (VAS) pain score at rest and with activity,
first tramadol request, and analgesic rescue
VAS
Patients receiving
Rescue
Time to first
(mean range)
postoperative
analgesic
tramadol
analgesia
At rest
With
N (%)
administration
N (%)
(min)
2 (5)
70.3±17.1
1 (3)
68.9±21.4
0 (0)
71.8±23.5
0 (0)
68.6±23.0
activity
Group 1
0–4
3.6 (1.9-4.9)
3.9 (2.3-5.3)
30 (75)
4 – 12
2.7 (1.8-5.4)
3.1 (2.0-6.0)
5 (13)
12 – 24
2.0 (1.5-2.7)
2.3 (1.8-3.0)
0 (0)
35 (88)
Total 0 - 24
Group 2
0–4
3.5 (1.8-4.9)
3.8 (2.0-5.3)
28 (70)
4 – 12
2.6 (1.6-5.6)
2.9 (1.9-6.1)
6 (15)
12 – 24
2.1 (1.6-2.9)
2.4 (1.9-3.1)
0 (0)
34 (85)
Total 0 - 24
Group 3
0–4
3.4 (1.7-4.9)
3.7 (1.9-5.3)
28 (70)
4 – 12
2.5 (1.6-4.2)
2.8 (1.9-4.5)
5 (13)
12 – 24
1.9 (1.5-2.7)
2.2 (1.8-2.9)
0 (0)
33 (83)
Total 0 - 24
Group 4
0–4
3.4 (1.8-4.8)
3.7 (2.1-5.2)
29 (73)
4 – 12
2.6 (1.8-4.1)
2.8 (2.0-4.3)
4 (10)
12 – 24
1.9 (1.6-2.7)
2.2 (1.9-3.1)
0 (0)
Total 0 – 24
33 (83)
There were no significant between – group differences.
18
Table 4. Incidence of side effects
Group 1
Placebo
Group 2
Metoclopramide
Group 3
Dexamethasone
Group 4
Dexamethasone
plus
metoclopramide
Headache
4 (10)
3 (8)
2 (5)
3 (8)
Dizziness
1 (3)
0 (0)
0 (0)
1 (3)
Anxiety
3 (8)
4 (10)
2 (5)
2 (5)
Perineal itching
0 (0)
0 (0)
0 (0)
0 (0)
Sedation
3 (8)
3 (8)
4 (10)
3 (8)
Sleep disturbance
6 (15)
5 (13)
3 (8)
4 (10)
Values are number (%) of patients.
19
Table 5. Postoperative well-being scores
Very good
1
Good
2
Alternating
3
Poor
4
Very poor
5
Placebo
9 (23)
20 (50)
9 (23)
1 (3)
1 (3)
Metoclopramide
15 (38)
22 (55)
3 (8)
0 (0)
0 (0)
Dexamethasone
20 (50)*
19 (48)
1 (3) *
0 (0)
0 (0)
Dexamethasone plus
23 (58) *
15 (38)
2 (5) *
0 (0)
0 (0)
metoclopramide
Values are number (%) of patients.
Significant differences from placebo: * p<0.05
20