Research Report

Journal of International Medical Research

41(3) 654–663
Comparison of ramosetron ! The Author(s) 2013
Reprints and permissions:
with combined ramosetron sagepub.co.uk/journalsPermissions.nav
DOI: 10.1177/0300060513487627
and midazolam for imr.sagepub.com

preventing postoperative
nausea and vomiting in
patients at high risk following
laparoscopic gynaecological
surgery
Eun Young Park1, Soo Kyung Lee1,
Mae Hwa Kang1, Kyung Jee Lim1, Yi Seul Kim1,
Eunjoo Choi2 and Young-Han Park3

Abstract
Objectives: This randomized, double-blind study compared the antiemetic efficacy of ramosetron
with that of ramosetron combined with midazolam, and investigated whether the timing of
midazolam administration affected the incidence of postoperative nausea and vomiting (PONV).
Methods: Nonsmoking female patients undergoing laparoscopic gynaecological surgery were
randomized to three groups: group R received intravenous (i.v.) normal saline at induction of
anaesthesia and 30 min before the end of surgery; group RM1 received midazolam i.v. at induction
of anaesthesia and normal saline i.v. 30 min before the end of surgery; group RM2 received normal
saline i.v. at induction of anaesthesia and midazolam i.v. 30 min before the end of the surgery. All
patients received 0.3 mg ramosetron i.v. at the end of surgery. Incidence of PONV and need for
rescue antiemetics were assessed during the 48-h postoperative period.
Results: A total of 126 patients were included in the analyses. There was no significant difference
in the incidence of severe nausea, emetic episodes or use of antiemetics among the three groups.
The incidence of complete response (no PONV and no rescue antiemetics) was significantly higher

1
Department of Anaesthesiology and Pain Medicine,
Hallym University Sacred Heart Hospital, College of
Medicine, Hallym University, Anyang, Republic of Korea
2
Department of Anaesthesiology and Pain Medicine, Seoul
National University Bundang Hospital, Seongnam, Republic
of Korea
3
Department of Obstetrics and Gynaecology, Hallym
University Sacred Heart Hospital, College of Medicine,
Hallym University, Anyang, Republic of Korea
Corresponding author:
Dr Soo Kyung Lee, Department of Anaesthesiology and
Pain Medicine, Hallym University Sacred Heart Hospital,
896 Pyeongchon-dong, Dongan-gu, Anyang 431-070,
Republic of Korea.
Email: agnetask@gmail.com
Park et al.
in the RM1 (30/41; 73%) and RM2 (30/42; 71%) groups compared with group R (19/43; 44%).
Conclusions: Midazolam given at induction of anaesthesia or at the end of the surgery, combined
with ramosetron, was more effective than ramosetron alone in reducing the incidence of PONV.
Keywords
Ramosetron, midazolam, postoperative nausea and vomiting (PONV)
Date received: 26 February 2013; accepted: 4 March 2013
Introduction
Postoperative nausea and vomiting (PONV)
is one of the most unpleasant complications
associated with anaesthesia and surgery,
causing not only patient discomfort but
also increased postoperative pain. The inci-
dence of PONV is nearly 80% in high-risk
patients.1 Many patients state that PONV is
an undesirable postoperative outcome with
a higher priority than incisional pain.2
Although antiemetic prophylaxis can sig-
nificantly reduce the incidence of PONV, its
incidence remains high for patients with
multiple risk factors. It has been reported
that the incidence of PONV is 66.7% in
patients given ondansetron after laparo-
scopic gynaecological surgery and a post-
operative opioid.3 Therefore, PONV
prophylaxis should be considered for
patients at moderate-to-high risk for
PONV.4 Furthermore, combining two or
more antiemetics with different mechanisms
of action has been shown to be more effective
than using a single agent, in high-risk
patients.4–7
The 5-hydroxytryptamine (5-HT3) recep-
tor antagonists are the recommended
first- and second-line pharmacological antie-
metics for PONV prophylaxis and they have
favourable side-effect profiles.4 Ramosetron
has a higher affinity for the serotonin 5-HT3
receptor than ondansetron, granisetron or
tropisetron, and its efficacy is well main-
tained during a 48-h period.8 The efficacy of
655
0.3 mg ramosetron to reduce the incidence of
PONV in female patients after gynaeco-
logical surgery was found to be similar to
that of 8 mg ondansetron.9
Midazolam is a commonly used drug for
sedation, premedication and co-induction of
anaesthesia. Besides its known anxiolytic
effects, it has been reported that midazolam
plays a role in the prevention10–14 and
treatment15,16 of PONV. Midazolam admin-
istered after the induction of anaesthesia,
with or without dexamethasone, reduced the
incidence of PONV in children following
strabismus repair.11 However, several stu-
dies have reported controversial findings
associated with the use of midazolam in
combination with antiemetics.17,18
Furthermore, it has been reported that
midazolam given 30 min before the end of
surgery was more effective than premedica-
tion with midazolam at decreasing the inci-
dence of PONV.12
We hypothesized that ramosetron com-
bined with midazolam would be more effect-
ive in reducing the incidence of PONV than
ramosetron administered alone, following
laparoscopic gynaecological surgery in
patients at high risk of PONV. The primary
purpose of this randomized, double-blind
study was to compare the antiemetic efficacy
of ramosetron alone with that of ramosetron
and midazolam in combination. This study
also investigated whether the timing of
midazolam administration affected the inci-
dence of PONV in patients at high risk of
656
PONV, who were undergoing laparoscopic
gynaecological surgery.
Patients and methods
Study population
This randomized, double-blind study
enrolled nonsmoking female patients who
were classified as American Society of
Anesthesiologists physical status I or II
(i.e. normal/ healthy or with mild systemic
disease; http://www.asahq.org), aged 19–64
years, and scheduled to undergo laparo-
scopic gynaecological surgery of <2 h in
duration under general anaesthesia at the
Department of Obstetrics and Gynaecology,
Hallym University Sacred Heart Hospital,
College of Medicine, Hallym University,
Anyang, Republic of Korea, between
August 2012 and January 2013. The
patients underwent laparoscopic ovarian
cystectomy, ovarian wedge resection, myo-
mectomy, salpingo-oophorectomy or hys-
terectomy. According to the simplified risk
scores for predicting PONV,1 there are four
predictors: female sex; history of motion
sickness or PONV; nonsmoking; use of
postoperative opioids. As all female patients
enrolled in the study were scheduled to use
postoperative opioid-based intravenous
(i.v.) patient-controlled analgesia (PCA)
and were nonsmokers, they all had at least
three risk factors for PONV. The minimum
anticipated incidence of PONV was 61% in
patients with at least three risk factors.1
Exclusion criteria included any of the fol-
lowing: pregnancy or breast-feeding; obesity
(body mass index >30 kg/m2), psychological
disease; use of nasogastric tube; administra-
tion of antiemetics or systemic steroids
within 24 h; vomiting within 24 h; alcohol
or drug abuse; allergy to drugs used in
the study.
This study was approved by the
Institutional Review Board of Hallym
University Sacred Heart Hospital (reference
numbers: IORG0004993, IRB00005964).
Journal of International Medical Research 41(3)
Written informed consent was obtained
from each patient.
Study design and anaesthesia protocol
Patients were premedicated with 0.004 mg/kg
glycopyrrolate, administered intramuscu-
larly. While in the operating room, all
patients were monitored by standard limb
lead electrocardiography and noninvasive
blood pressure measurement, pulse oxim-
etry (CARESCAPE Monitor B650; GE
Healthcare, Helsinki, Finland) and the bis-
pectral index (BIS VISTATM Monitoring
System; Aspect Medical Systems, Norwood,
MA, USA). General anaesthesia was
induced with 4–5 mg/kg of thiopental
sodium i.v. and 0.15–0.3 mg/kg per min of
remifentanil i.v.; endotracheal intubation
was facilitated with 0.6 mg/kg of rocuronium
bromide i.v; anaesthesia was maintained with
inhaled 1.5–2.5% sevoflurane, continuous i.v.
infusion of 0.05–0.2 mg/kg/min remifentanil
and air in oxygen (fraction of inspired
oxygen, 0.5). The infusion rate of remifen-
tanil and the concentration of sevoflurane
were adjusted to maintain blood pressure
and heart rate within a 20% deviation from
values measured before anaesthesia, and a
BIS between 40 and 60. Mechanical ventila-
tion was adjusted to maintain a partial
pressure of end-tidal carbon dioxide of
35–40 mmHg throughout the procedure.
Rocuronium bromide 0.1–0.15 mg/kg i.v.
was administered for muscle relaxation as
required, and all patients received 1 mg/kg
fentanyl i.v. 20 min before the end of
surgery.
Study drugs were prepared in 5-ml syr-
inges: normal saline 5 ml or 50 mg/kg mid-
azolam (maximum 5 mg) in a total volume of
5 ml normal saline. Patients were randomly
allocated into one of three groups (R, RM1,
RM2) by the sealed-envelope method.
Patients in group R received normal saline
i.v. at induction of anaesthesia and 30 min
before the end of surgery. Patients in group
Park et al.
RM1 received midazolam i.v. at induction of
anaesthesia and normal saline i.v. 30 min
before the end of surgery. Patients in group
RM2 received normal saline i.v. at induction
of anaesthesia and midazolam i.v. 30 min
before the end of surgery.
At the end of surgery, sevoflurane and
remifentanil administration were stopped
and 0.3 mg ramosetron i.v. was adminis-
tered. Antagonism of muscle relaxation
was achieved with i.v. administration of
0.04 mg/kg neostigmine and 0.008 mg/kg
glycopyrrolate. The endotracheal tube was
removed when adequate ventilation was
recovered and the patient was awake. For
postoperative pain control, a PCA device,
consisting of an i.v. infusion of 16–17 mg/kg
fentanyl in a total volume of 100 ml normal
saline, was initiated at the completion of
surgery; administration of PCA continued
for 48 h.
During the postoperative period, patients
received 30 mg ketorolac i.v. by their request
or when they reported a pain score >6 on an
11-point verbal rating scale (VRS; 0, no
pain; 10, worst imaginable pain).
Study assessments
Demographic data, duration of surgery,
duration of anaesthesia and history of
motion sickness or PONV were recorded
for each patient. All episodes of PONV
(nausea, retching and vomiting) were rec-
orded during three time periods: 0–2 h,
2–24 h, and 24–48 h after surgery. An inves-
tigator (Y. S. K.), who did not know which
drug was administered to which patient,
assessed all episodes of PONV.
The primary efficacy variable of this
study was the incidence of complete
response during the 48-h period after sur-
gery. The secondary efficacy variables were
the incidence of severe nausea, emetic epi-
sodes, and need for rescue antiemetics.
Nausea was defined as a subjectively
unpleasant sensation associated with an
657
inclination to vomit. Retching was defined
as an involuntary effort to vomit that does
not result in ejection of gastric contents.
Vomiting was defined as the forceful expul-
sion of gastrointestinal contents from the
stomach through the mouth. Retching and
vomiting were defined as emetic episodes.
The severity of nausea was evaluated on a
VRS (0, no nausea; 10, worst imaginable
nausea) divided into mild (1–3), moderate
(4–6) and severe (7–10) nausea. Complete
response was defined as the absence of
PONV with no need for rescue antiemetic
therapy during the 48-h period after surgery.
The rescue antiemetic, metoclopramide
(i.v.), was given as a 10-mg dose in cases of
severe nausea or two or more emetic epi-
sodes, or in response to a patient’s request.
If the first-line rescue therapy with metoclo-
pramide was ineffective, the second-line
rescue antiemetic, ondansetron (i.v.) was
given as a 4-mg dose. When both metoclo-
pramide and ondansetron treatments were
ineffective, PCA was stopped for 3 h.
Adverse events (including headache, dizzi-
ness, drowsiness and general weakness) were
also recorded.
Statistical analyses
In a preliminary study conducted in
10 patients who were given 0.3 mg ramose-
tron i.v. alone, five patients (50%) who
underwent laparoscopic gynaecological sur-
gery (using fentanyl-based PCA) showed a
complete response during the 48-h period
after surgery. The sample-size calculation
was made using power analysis (a ¼ 0.05,
b ¼ 0.8) to detect a 30% increase in the rate
of complete response (from 50% to 80%),
and was found to require 40 patients per
group. Assuming a potential dropout rate of
10%, the final sample size was set at 44
patients per group.
The data were presented as mean  SD or
n (%) of patients. All statistical analyses
were performed using the IBMÕ SPSSÕ
658 Journal of International Medical Research 41(3)

statistical software package, version 20.0
(IBM Corporation, Somers, NY, USA).
Statistical analyses were undertaken using
the Student’s t-test, 2-test and Fisher’s
exact test. A P-value < 0.05 was considered
statistically significant.
Results
A total of 132 patients were enrolled in this
study. Six patients were withdrawn from the
study: pethidine was used as a rescue anal-
gesic (instead of ketorolac) in four patients
(one, two, and one in groups R, RM1, and
RM2, respectively); unexpected intraopera-
tive events occurred in one patient in group
RM1 (a large amount of intraoperative
bleeding associated with transfusion) and
one patient in group RM2 (conversion to
laparotomy). Demographic data (including
duration of surgery and incidence of patients
with histories of motion sickness or PONV),
and rescue analgesic use were similar among
the three groups (Table 1).
The proportion of patients without
nausea was significantly higher in groups
RM1 and RM2, compared with group R, at
2–24 h and 24–48 h (P < 0.05 for all com-
parisons; Table 2). The incidence of com-
plete response (no PONV and no use of
antiemetics during the 48-h period after
surgery) was significantly higher in groups
RM1 (73%) and RM2 (71%) compared
with group R (44%) (P < 0.05 for both
comparisons; Table 2), but there was no
significant difference between complete
response rates in groups RM1 and RM2.
Incidence of severe nausea, emetic episodes
and use of rescue antiemetics was lower in
groups RM1 and RM2 compared with
group R, but there were no significant
differences among the three groups
(Table 2). There were also no significant
differences in the incidence of adverse events
among the three groups (Table 3).
Discussion
This current randomized, double-blind
study compared the antiemetic efficacy of
ramosetron administered alone with that of
ramosetron administered in combination

Table 1. Demographic and clinical data for patients undergoing laparoscopic gynaecological surgery, who
received ramosetron alone (group R) or combined with midazolam, given intravenously (i.v.) at induction of
anaesthesia (group RM1) or 30 min before the end of the surgery (group RM2); normal saline 5 ml was given as
a control.

Characteristic Group R n ¼ 43 Group RM1 n ¼ 41 Group RM2 n ¼ 42

Age, years 37.7  10.4 39.1  11.2 38.9  9.8

Height, cm 160.6  5.2 160.1  6.6 159.8  5.5
Weight, kg 58.8  9.4 61.0  11.3 60.2  8.7
PONV/motion sickness history 15 (35) 14 (34) 16 (38)
Duration of surgery, min 71.7  24.8 74.5  24.0 73.1  26.9
Duration of anaesthesia, min 103.5  25.4 106.2  22.7 104.3  27.7
Rescue analgesic use 14 (33) 12 (29) 13 (31)

Data presented as mean  SD or n (%) of patients.

No statistically significant between-group differences (P  0.05); Student’s t-test and Fisher’s exact test.
All patients received ramosetron 0.3. mg i.v. at the end of surgery.
Group R, patients received normal saline at induction of anaesthesia and 30 min before the end of the surgery; group RM1,
patients received midazolam 50 mg/kg i.v. at induction of anaesthesia and normal saline 30 min before the end of the surgery;
Group RM2, patients received normal saline at induction of anaesthesia and midazolam 30 min before the end of the
surgery; PONV, postoperative nausea and vomiting.
Park et al. 659

Table 2. Incidence of postoperative nausea and vomiting, use of rescue antiemetics and complete response
in patients undergoing laparoscopic gynaecological surgery who received ramosetron alone (group R) or
ramosetron combined with midazolam, given intravenously (i.v.) at induction of anaesthesia (group RM1) or
30 min before the end of the surgery (group RM2).

Parameter Group R n ¼ 43 Group RM1 n ¼ 41 Group RM2 n ¼ 42

0–2 h
Nausea (0/1/2/3) 30/4/5/4 31/4/4/2 37/2/2/1
Emetic episode 4 (9) 2 (5) 1 (2)
Rescue antiemetics 4 (9) 3 (7) 1 (2)
2–24 h
Nausea (0/1/2/3) 21/7/7/8 31a/3/4/3 31a/4/3/4
Emetic episode 3 (7) 1 (2) 2 (5)
Rescue antiemetics 8 (19) 3 (7) 5 (12)
24–48 h
Nausea (0/1/2/3) 23/10/7/3 33a/5/2/1 34a/3/3/2
Emetic episode 3 (7) 1 (2) 0 (0)
Rescue antiemetics 5 (12) 1 (2) 2 (5)
0–48 h
Severe nausea 14 (33) 5 (12) 6 (14)
Emetic episode 10 (23) 4 (10) 3 (7)
Rescue antiemetics 12 (28) 5 (12) 8 (19)
a a
Complete response 19 (44) 30 (73) 30 (71)

Data presented as n (%) of patients.

aP < 0.05 compared with group R; 2-test.
All patients received 0.3 mg ramosetron i.v. at the end of surgery.
Group R, patients received normal saline at induction of anaesthesia and 30 min before the end of the surgery; group RM1,
patients received midazolam 50 mg/kg i.v. at induction of anaesthesia and normal saline 30 min before the end of the surgery;
Group RM2, patients received normal saline at induction of anaesthesia and midazolam 30 min before the end of the
surgery.
Nausea: 0, none; 1, mild; 2, moderate; 3, severe.
Emetic episode: retching and vomiting.
Complete response: absence of postoperative nausea and vomiting and no need for rescue antiemetic therapy during the
48-h period after surgery.

Table 3. Incidence of adverse events in patients undergoing laparoscopic gynaecological surgery who
received ramosetron alone (group R) or ramosetron combined with midazolam given intravenously (i.v.) at
induction of anaesthesia (group RM1) or 30 min before the end of surgery (group RM2).

Adverse event Group R n ¼ 43 Group RM1 n ¼ 41 Group RM2 n ¼ 42

Headache 3 2 2
Dizziness 4 3 3
Drowsiness and general weakness 1 1 1

Data presented as n patients.

No statistically significant between-group differences (P  0.05); 2-test.
All patients received 0.3 mg ramosetron intravenously at the end of surgery.
Group R, patients received normal saline at induction of anaesthesia and 30 min before the end of the surgery; group RM1,
patients received midazolam 50 mg/kg i.v. at induction of anaesthesia and normal saline 30 min before the end of the surgery;
Group RM2, patients received normal saline at induction of anaesthesia and midazolam 30 min before the end of the
surgery.
660
with midazolam, in female nonsmoking
patients at high risk for PONV undergoing
laparoscopic gynaecological surgery. This
current study found that the combination of
ramosetron and midazolam was more effect-
ive than ramosetron alone in reducing the
incidence of postoperative PONV. In add-
ition, the incidence of postoperative adverse
events was not significantly different among
the three treatment groups. In the present
study, midazolam was equally effective at
reducing PONV when given either at induc-
tion of anaesthesia or 30 min before the end
of the surgery.
The efficacy of ramosetron is maintained
in terms of nausea and vomiting 6–48 h after
treatment.8 Ramosetron was as effective as
ondansetron in reducing the incidence of
PONV in female patients after gynaeco-
logical surgery9 and more effective than
ondansetron in preventing vomiting and
reducing the severity of nausea related to
opioid-based i.v. PCA, in highly susceptible
patients.19
It has been reported that midazolam has
an effect on the prevention10–14 and treat-
ment15,16 of PONV. A continuous infusion
of midazolam was reported to be a more
effective antiemetic than ondansetron for
the prevention of PONV after cardiac sur-
gery,10 and low-dose midazolam infusion is
an effective treatment for patients with
PONV resistant to standard antiemetics.15
Midazolam administered after the induction
of anaesthesia, with or without dexametha-
sone, reduced the incidence of PONV in
children undergoing strabismus repair.11
However, several studies reported contro-
versial results associated with the use of
midazolam in combination with antiemetics.
The combination of dexamethasone and
midazolam reduced the incidence of vomit-
ing and the rescue antiemetic requirements,
but did not decrease the total incidence of
nausea and vomiting, compared with the use
of dexamethasone alone, in female patients
undergoing middle-ear surgery.17 Combined
Journal of International Medical Research 41(3)
midazolam and ramosetron had no advan-
tages compared with ramosetron alone in
reducing the incidence of PONV in children
undergoing strabismus surgery.18 Several
important risk factors associated with
PONV are female sex, nonsmoking status,
history of PONV or motion sickness, age,
duration of anaesthesia and use of post-
operative opioids.20,21 Longer procedures
(which are associated with longer exposure
to volatile anaesthetics) are associated with
an increased incidence of PONV.22
Intraoperative use of opioids23 and laparo-
scopic, strabismus, and middle-ear surgery21
may increase the risk of PONV. Patients
who participated in this current study had a
relatively high risk for PONV because of the
presence of several of these known risk
factors (including female sex, nonsmoking
status, laparoscopy, and intra- and post-
operative opioid use). Other risk factors
(such as a history of PONV or motion
sickness, age and duration of anaesthesia)
did not differ among the three groups.
Although the combination of ramosetron
and midazolam did not significantly
decrease the incidence of severe nausea,
emetic episodes or the use of rescue antie-
metics, the overall incidence of complete
responses was higher in patients given
the combination therapy compared with
ramosetron alone, demonstrating the
prophylactic efficacy of the combination
therapy.
Midazolam has been shown to be an
effective antiemetic when administered con-
tinuously,10,15 before14,18,24 and after17
induction of anaesthesia, or before the end
of the surgery.25 It was reported that mid-
azolam administered 30 min before the end
of surgery was more effective in decreasing
the incidence of PONV than midazolam
given 15 min before induction of anaesthe-
sia, in patients who had undergone lower
abdominal surgery lasting 1–2 h.12 In previ-
ous studies, doses of midazolam for pre-
venting PONV were 35–75 mg/kg.11,12,17,24
Park et al.
Watcha and White21 recommended the use
of minimally effective doses of antiemetic
drugs to reduce the incidence of sedation
and other deleterious side-effects, and potent
nonopioid analgesics such as ketorolac can
be used to avoid some opioid-related
adverse effects. The present study used
50 mg/kg of midazolam and (as a rescue
analgesic) ketorolac; the incidence of
adverse events did not differ significantly
among the three treatment groups.
Furthermore, midazolam given at anaesthe-
sia induction or 30 min before the end of the
surgery was effective for preventing PONV,
regardless of the time of administration in
this current study. However, this result may
not apply to other types of surgery, such as
those with durations longer than those of
procedures in the present study.
Although the precise mechanism of action
of the antiemetic effect of midazolam has not
been fully elucidated, it has been suggested
that benzodiazepines reduce the psychic
input to the vomiting centre; blocking the
re-uptake of adenosine may result in an
adenosine-mediated inhibition of dopamine
synthesis, release and action in the chemo-
receptor trigger zone.26 Adenosine receptor
agonists have been shown to inhibit nigros-
triatal release of dopamine,27 and benzodi-
azepines have been shown to inhibit the
uptake of adenosine into rat brain cortical
synaptosomes.28 Midazolam may also affect
striatal dopamine release29 and the anaes-
thetic actions of midazolam are partially
related to inhibition of dopamine neuron A1
activity.30 In our opinion, these studies sup-
port the hypothesis of Di Florio,26 and
demonstrate that midazolam combined
with ramosetron could reduce PONV more
effectively than ramosetron alone.
This current study had several limita-
tions. First, the concentrations of sevoflur-
ane and the infusion rates of remifentanil
were adjusted according to BIS and vital
signs, but the amounts were not measured
exactly. However, the amount of anaesthetic
661
used was probably a minor factor in terms of
causing PONV, because the durations of
anaesthesia did not differ significantly
among the three treatment groups.
Secondly, it was difficult to determine
which time of midazolam administration
was more effective in reducing PONV,
because the present study was not suffi-
ciently powered to compare such differences.
Further studies are required to determine
the appropriate dose and administration
time of midazolam in different types and
durations of surgery.
In conclusion, midazolam given at induc-
tion of anaesthesia or 30 min before the end
of the surgery combined with ramosetron
was more effective for the prevention of
PONV than ramosetron alone in patients at
high risk for PONV following laparoscopic
gynaecological surgery.
Declaration of conflicting interest
The authors declare that there are no conflicts of
interest.
Funding
This research received no specific grant from any
funding agency in the public, commercial, or not-
for-profit sectors.
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