Research Report

Journal of International Medical Research

41(4) 1203–1213
Ramosetron, midazolam, and ! The Author(s) 2013
Reprints and permissions:
combination of ramosetron sagepub.co.uk/journalsPermissions.nav
DOI: 10.1177/0300060513485864
and midazolam for prevention imr.sagepub.com

of postoperative nausea and

vomiting: A prospective,
randomized, double-blind
study

Won Joong Kim, Hyun Kang, Hwa Yong Shin,

Chong Wha Baek, Yong Hun Jung,
Young Cheol Woo, Jin Yun Kim and Gil Hoi Koo

Abstract
Objective: To compare the efficacy of ramosetron, midazolam, and the combination of
ramosetron and midazolam in the prevention of postoperative nausea and vomiting (PONV) in
female patients undergoing thyroidectomy.
Methods: Patients were randomized to receive 0.3 mg ramosetron (Group R), 75 mg/kg
midazolam (Group M) or 0.3 mg ramosetron combined with 75 mg/kg midazolam (Group RM)
before the induction of anaesthesia. PONV, use of rescue antiemetics, pain severity and fentanyl
consumption were assessed for 24 h after thyroidectomy.
Results: A total of 100 patients were enrolled; 94 patients completed the study. The severity of
nausea was statistically significantly reduced at 0–2 h in Group RM compared with Groups R and M,
and at 2–6 h in Group RM compared with Group M. The incidence of retching and vomiting was
significantly lower at 0–2 h, 2–6 h, 6–12 h in Group RM than in Group M, and lower in Group R than
Group M at 6–12 h. The requirement for rescue antiemetics was significantly lower at 0–2 h in
group RM than in group M.
Conclusion: The combination therapy of ramosetron and midazolam provided superior
antiemetic efficacy compared with midazolam single therapy, but did not show any significant
additional benefits compared with ramosetron single therapy.

Corresponding author:
Dr Hyun Kang, Assistant Professor, Department of
Anaesthesiology and Pain Medicine, Chung-Ang University
Department of Anaesthesiology and Pain Medicine, College of Medicine, 224-1 Heukseok-dong, Dongjak-gu,
College of Medicine, Chung-Ang University, Seoul, Seoul 156-755, Republic of Korea.
Republic of Korea Email: roman00@cau.ac.kr
1204 Journal of International Medical Research 41(4)

Keywords
Midazolam, ramosetron, thyroidectomy, postoperative nausea and vomiting, PONV

Date received: 15 February 2013; accepted: 22 February 2013

Although several studies have reported

Introduction the combination therapy of 5-HT3 antagon-
Postoperative nausea and vomiting (PONV) ists and antiemetics with different mechan-
is a frequent and distressing outcome of isms of action,13,14 the prophylactic effect of
surgery that can adversely influence a a combination of ramosetron and midazo-
patient’s recovery.1 PONV is influenced by lam for PONV has not been assessed in
a variety of factors that include the charac- patients after thyroidectomy. It was
teristics of the patient, the surgery and the hypothesized that combination therapy
anaesthesia used.1,2 Moreover, female sex, with ramosetron and midazolam would be
nonsmoking, use of postoperative opioids more effective than single therapy with
and a prior history of motion sickness or either drug, in preventing PONV. Thus,
PONV are well-known risk factors for the present study compared the antiemetic
PONV.3 efficacy of ramosetron, midazolam, and the
Thyroidectomy is one of the most combination of ramosetron and midazolam,
common elective surgeries, and the inci- in women undergoing thyroidectomy.
dence of associated PONV is relatively
high, ranging between 60 and 84%.4,5 Patients and methods
Considering the multifactorial aetiology
of PONV and the current evidence suggest-
Study population
ing the limited efficacy of single antiemetic This prospective, randomized, double-
prophylaxis, combination therapies (invol- blinded study enrolled consecutive female
ving of antiemetics with different mechan- patients scheduled for thyroidectomy under
isms of actions) may offer a more effective general anaesthesia at Chung-ang
approach in preventing PONV, in patients University Hospital, Seoul, Republic of
at moderate to high risk of PONV.6,7 Korea, between January and September
The 5-hydroxytryptamine receptor 3 2012. Eligible patients were non-smoking
(5-HT3) antagonists are frequently used for females, aged 20–65 years, with American
the prevention of PONV.8 Among the 5-HT3 Society of Anesthesiologists physical status
antagonists, ramosetron (NaseaÕ ; Astellas of I or II (http://www.asahq.org/Home/
Pharma Korea Inc., Seoul, Republic of For-Members/Clinical-Information/ASA-
Korea) is a newly developed drug with Physical-Status-Classification-System),
higher 5-HT3 receptor affinity and longer where the need for opioids for postoperative
duration of action than its congeners such as pain management was anticipated. Patients
ondansetron and granisetron.9 Midazolam, with three or four risk factors of PONV were
which is a rapid and short-acting selected. Patients with diabetes mellitus or
benzodiazepine, has been widely used as a gastrointestinal disease, and those who were
premedicant: several investigators have smokers, menstruating or had taken an
demonstrated the antiemetic properties of antiemetic medication 72 h before surgery
midazolam, when administered as a bolus were excluded from the study. Decisions to
before or after induction of anaesthesia, or enrol or exclude patients were made by an
given postoperatively as a continuous investigator at the preoperative anaesthetic
infusion.10–12 evaluation who did not otherwise
Kim et al. 1205

participate in conducting the study and data appropriately prior to surgery. Patients
collection. arrived in the operating room without any
Study approval was obtained from the premedication. After recording noninvasive
Ethical Committee of Chung-ang blood pressure, heart rate and peripheral
University, Seoul, Republic of Korea, and oxygen saturation, the randomly selected
this study was carried out according to the experimental medication was injected intra-
principle of the Declaration of Helsinki venously as a bolus over 30 s, immediately
(2000 version). Written consent was before anaesthesia. Patients in Group R
obtained from all patients after they were received 0.3 mg ramosetron (NaseaÕ ,
given an explanation about the purpose of Astellas Pharma Korea Inc., Seoul,
the study, the side-effects that might occur, Republic of Korea); patients in Group M
and how to use the intravenous patient- received 75 mg/kg midazolam (Midazolam
controlled analgesia (IV–PCA) device. This InjectionÕ , Bukwang Pharm, Seoul,
trial is registered with Australia New Republic of Korea); patients in Group RM
Zealand Clinical trials Registry received 0.3 mg ramosetron combined with
(ANZCTR) (ACTRN12612000757819; 75 mg/kg midazolam, administered as for the
Web address: https://www.anzctr.org.au/ single medications.
Trial/Registration/TrialReview.aspx?id¼ Anaesthesia was induced with 2 mg/kg
362765). fentanyl i.v. and 5 mg/kg thiopental i.v.;
orotracheal intubation was facilitated with
0.8 mg/kg rocuronium bromide i.v.
Inhalation anaesthesia was maintained with
Study randomization 1.5–2.5% sevoflurane in 50% O2/N2O.
Patients were divided into three groups While maintaining anaesthesia, the tidal
based on the antiemetic treatment they volume was regulated to keep the end tidal
were to receive: ramosetron alone (Group CO2 pressure in the range of 30–35 mmHg.
R); midazolam alone (Group M); ramose- Lactated Ringer’s solution was given at a
tron combined with midazolam (Group rate of 5 ml/kg/h by i.v. infusion throughout
RM). The randomization was based on a surgery. Approximately 15 min before the
random table, generated using the R Project end of surgery, 0.5 mg/kg fentanyl was
for Statistical Computing (http://www. administered i.v. for postoperative pain con-
r-project.org/) Block randomization with a trol and the IV–PCA device was connected.
block size of four and equal allocation was The instrument used for IV–PCA was the
employed to prevent imbalances in treat- Basal/Bolus Infusor (Baxter Healthcare
ment assignments. The randomization Corporation, Deerfield, IL, USA) contain-
sequence was generated by a statistician ing 20 mg/kg fentanyl in a final solution
who was not involved with the study. volume of 100 ml. Continuous infusion was
Patient group allocation was revealed to set at 0.2 ml/h with a bolus of 1.2 ml and a
the anaesthetist immediately prior to induc- lockout time of 15 min. Muscle relaxation
tion of anaesthesia, by means of numbered was antagonized by a combination of 0.4 mg
and sealed envelopes. glycopyrrolate i.v. and 15 mg pyridostigmine
i.v. at the end of surgery. The patient was
extubated when fully awake. Anaesthesia
Antiemetic therapy and anaesthesia
duration was defined as the period from
procedures induction until the discontinuation of
Patients fasted for 8 h for solid food and nitrous oxide, and was recorded for all
2 h for clear fluids, and were hydrated patients.
1206 Journal of International Medical Research 41(4)

Assessment of efficacy Statistical analyses

The primary endpoint of this study was the In a pilot study involving 10 subjects who
severity of PONV. The severity of nausea, underwent thyroidectomy with ramosetron,
incidence of retching and vomiting together, the SD of the VNRS was 1.2 (unpublished
and the need for rescue antiemetics, were data). Hypothesizing that the SD would be
evaluated at 2 h in the postanaesthesia care equal for the three groups (midazolam,
unit (PACU) and from 2–6, 6–12, and 12– ramosetron, and ramosetron combined
24 h in the ward. Patients were questioned with midazolam), the results using the
by an anaesthetic nurse, who was unaware calculated value with an a-error of 5% and
of the group identities, as to the severity of a power of test of 80% to distinguish a
nausea and incidence of retching and vomit- difference in the VNRS of 1, showed that 30
ing. Nausea was defined as per the report of subjects were required for each group of
the patient when they felt nauseated, that is, patients. Considering patient refusal rate
‘I feel like vomiting or a have a sensation like and compliance rate as 5% and 90%,
motion sickness’. Retching was defined as respectively, 100 patients were required for
the laboured, spasmodic, rhythmic contrac- the present study.
tions of respiratory muscles without the For intergroup comparisons, the distri-
expulsion of gastric contents. Vomiting bution of the data was first evaluated for
was defined as the forceful expulsion of normality using the Shapiro–Wilk test.
gastric contents. Severity of nausea was Normally distributed data were presented
graded using an 11-point verbal numerical as the mean  SD or mean  SE. Groups
rating scale (VNRS), with 0 representing no were compared using analysis of variance
nausea and 10 representing worst possible and a post hoc Tukey test. The non-
nausea. When the patient had nausea (by normally distributed data were expressed
scoring at level 5 on the VNRS or requesting as medians (quartile 1–3) and were analysed
an antiemetic), the first-line rescue antie- using the Kruskal–Wallis test with
metic was given: 10 mg metoclopramide i.v.; Bonferroni’s correction.
5 mg dexamethasone i.v. was the second-line Descriptive variables were presented as n
antiemetic treatment. (%) and analysed using 2-test or Fisher’s
Postoperative pain intensity was assessed exact test, as appropriate. A P-value < 0.05
using a visual analogue scale (VAS) that was considered statistically significant. All
ranged between 0 mm (no pain) and 100 mm analyses were performed using SPSSÕ stat-
(worst pain imaginable). Patients received istical software, version 18.0 (SPSS Inc.,
30 mg of ketorolac i.v. if they complained of Chicago, IL, USA) for WindowsÕ .
pain (>40 mm on the VAS), and the total
amount of infused fentanyl from the IV–
PCA device over 24 h was recorded.
Results
A total of 100 patients were enrolled in the
Assessment of safety study; four patients were excluded because
The incidence of the most frequently of incomplete data collection and two
reported side-effects of the 5-HT3 antagon- patients were excluded because of with-
ists (including headache, dizziness, and drawal of consent. Thirty patients were
drowsiness) were also assessed.15 No other randomized to Group M and 32 patients
side-effects were recorded. These variables each to Groups R and RM. Patient charac-
were assessed by an anaesthetic nurse, who teristics and operative data were similar in
was unaware of the group identities. the three groups (Table 1).
Kim et al. 1207

Table 1. Baseline characteristics of female patients who underwent thyroidectomy, given antiemetic therapy
with either 0.3 mg ramosetron (Group R), 75 mg/kg midazolam (Group M) or 0.3 mg ramosetron combined
with 75 mg/kg midazolam (Group RM) before induction of anaesthesia.
Group R Group M Group RM
Characteristic n ¼ 30 n ¼ 32 n ¼ 32

Age, years 47.5 (38.5–56.5) 47.0 (39.3–47.8) 48.5 (37.3–54.0)

Height, cm 159.3  8.4 160.9  9.8 160.5  8.2
Weight, kg 60.7  8.5 60.1  9.0 59.3  9.2
Anaesthesia time, min 138.5 (130.0–156.3) 150 (126.3–173.8) 145.0 (130.8–164.8)

Data presented as mean  SD or median (quartile 1–3).

Normally distributed data were analysed using analysis of variance and a post hoc Tukey test; non-normally distributed data
were analysed using the Kruskal–Wallis test.
No statistically significant between-group differences (P  0.05).

Severity of nausea, as measured on the retching and vomiting, and use of rescue
VNRS, was statistically significantly antiemetics, especially in the early post-
reduced at 0–2 h in Group RM compared operative period in the PACU. However,
with Groups R and M, and also at 2–6 h in our findings did not show any significant
Group RM compared with Group M additional benefits compared with ramose-
(P < 0.05 for between-group differences) tron alone, except for a reduction in the
(Figure 1). The incidence of retching and severity of nausea at 0–2 h.
vomiting was statistically significantly lower To the best of our knowledge, there are
at 0–2 h, 2–6 h, 6–12 h in Group RM than in no available reports evaluating the combin-
Group M, and was also lower in Group R ation therapy of ramosetron and midazolam
than in Group M at 6–12 h (P < 0.05 for as a bolus for adult patients for the prophy-
between-group differences) (Figure 2). The laxis of PONV. In paediatric patients (aged
requirement for rescue antiemetic medica- 4–12 years), who underwent strabismus
tion was statistically significantly lower only surgery, 6 mg/kg ramosetron or 6 mg/kg
at 0–2 h in Group RM compared with ramosetron and 0.1 mg/kg midazolam
Group M (P < 0.05 (Table 2). (administered prior to induction of anaes-
There were no significant differences in thesia) exhibited a similar incidence of
the severity of postoperative pain between nausea, retching and vomiting during the
the groups (data not shown). Additionally, first and second 24-h periods,14 which is
there were no significant between-group consistent with findings of the present study.
differences in cumulative fentanyl consump- Furthermore, studies of the combination
tion from the IV–PCA device, or rescue therapy of ramosetron and midazolam as a
analgesic requirement within the first 24 h continuous infusion have not been reported,
postsurgery (Table 3). but it has been documented that a continu-
ous infusion of ondansetron and midazolam
was more effective than ondansetron
Discussion continuous-infusion monotherapy.16 In this
In the present study, undertaken in female study, the incidence of PONV in the group
patients undergoing thyroidectomy, the receiving ondansetron and midazolam
combined administration of ramosetron added to a IV–PCA device containing
and midazolam provided superior anti- fentanyl was significantly lower than that
emetic efficacy than midazolam alone in observed in the group receiving ondansetron
terms of severity of nausea, incidence of added to the IV–PCA at PACU, 24 h
1208 Journal of International Medical Research 41(4)

Figure 1. Severity of nausea, graded using an 11-point verbal numerical rating scale (VNRS), over 24 h
postsurgery in female patients who underwent thyroidectomy. Patients received either 0.3 mg ramosetron
(Group R), 75 mg/kg midazolam (Group M) or 0.3 mg ramosetron combined with 75 mg/kg midazolam (Group
RM) before induction of anaesthesia. Values expressed as mean  SE. *P < 0.05 Group RM compared with
Group M; yP < 0.05 Group RM compared with Group R (analysis of variance).

after recovery.16 These differences between preventing PONV have not been reported,
bolus and continuous infusion are probably but publications have compared the
due to the short elimination half-life (1.7– antiemetic effects of ondansetron and
2.6 h) of midazolam. The present study midazolam. For example, treatment using
results also show that the combination ondansetron for antiemetic prophylaxis did
therapy of ramosetron and midazolam was not provide a superior benefit compared with
effective in reducing the severity of nausea midazolam in minor gynaecological or uro-
only in the early postoperative period. These logical procedures,18 and midazolam used in
drugs differ, however, in potency and effi- subhypnotic doses was as effective as ondan-
cacy with regard to the pharmacodynamic setron in patients undergoing abdominal or
actions, and the antiemetic effect of mid- gynaecological surgery without untoward
azolam last longer than the effects of sed- sedative or cardiovascular effects.17 These
ation.17 Thus, additional studies are needed findings17,18 correspond to the results pre-
to resolve the above differences. sented here, in that the incidence of nausea
Comparative studies of monotherapy between ramosetron alone and midazolam
with either ramosetron or midazolam for alone was not significantly different.
Kim et al. 1209

Figure 2. Incidence of retching and vomiting over 24 h postsurgery in female patients who underwent
thyroidectomy. Patients received either 0.3 mg ramosetron (Group R), 75 mg/kg midazolam (Group M) or
0.3 mg ramosetron combined with 75 mg/kg midazolam (Group RM) before induction of anaesthesia. Values
expressed as mean  SE. *P < 0.05 compared with Group M (analysis of variance).

Ramosetron was, however, more effective in resulting in haematomas in the neck, and
reducing the incidence of vomiting than can also increase the risk of airway
midazolam, in the present study. obstruction.21
The chemoreceptor trigger zone and the Ramosetron is a newly developed 5-HT3
emetic centre are associated with agonistic receptor antagonist with a more potent and
and antagonistic actions of various anaes- longer receptor antagonising effect com-
thetic-related agents and stimuli.1 Head and pared with previous-generation 5-HT3
neck surgeries (including thyroid surgery) receptor antagonists.22 It is a carbazalone
are associated with high rates of nausea and derivative that is structurally related to
vomiting; these symptoms are probably serotonin and possesses specific serotonin
related to vagal stimulation during surgical receptor antagonist properties without alter-
manipulation and the substantial levels of ing dopamine, histamine, adrenergic or cho-
inflammation and oedema that are found in linergic receptor activity. Metabolism of
neck tissues.19,20 As well as causing discom- inactive metabolites occurs predominantly
fort to patients undergoing thyroid surgery, in the liver and the elimination half-life of
PONV increases the risk of other adverse ramosetron is 4–5 h.23 In addition, the
consequences. For example, vomiting can elimination half-life of ramosetron (9 h) is
increase the risk of postoperative bleeding, longer than that of ondansetron (3.5 h) or
1210 Journal of International Medical Research 41(4)

Table 2. Requirements for rescue antiemetics over the first 24 h postoperation in female patients who
underwent thyroidectomy and received either 0.3 mg ramosetron (Group R), 75 mg/kg midazolam (Group M)
or 0.3 mg ramosetron combined with 75 mg/kg midazolam (Group RM) before induction of anaesthesia.

Group R Group M Group RM Statistical

Time postsurgery n ¼ 30 n ¼ 32 n ¼ 32 significancea

0–2 h 7 (23.3) 13 (40.6) 4 (12.5) P < 0.05*

2–6 h 4 (13.3) 8 (25.0) 3 (9.4) NS
6–12 h 0 (0) 2 (6.3) 0 (0) NS
12–24 h 0 (0) 0 (0) 0 (0) NA

Data presented as n (%).

a
Categorical data were analysed using Fisher’s exact test.
*Group RM compared with Group M.
NS, no statistically significant between-group differences (P  0.05); NA, not applicable.

Table 3. Quantity of intravenous patient-controlled analgesia (IV–PCA), and requirement for rescue
analgesia, over the first 24 h postoperation in female patients who underwent thyroidectomy, given either
0.3 mg ramosetron (Group R), 75 mg/kg midazolam (Group M) or 0.3 mg ramosetron combined with 75 mg/kg
midazolam (Group RM) before induction of anaesthesia.

Group R Group M Group RM

Time postsurgery n ¼ 30 n ¼ 32 n ¼ 32

0–2 h
PCA volume, ml 0.9  1.1 1.0  1.0 0.8  1.0
Rescue analgesia 2 (6.7) 3 (9.4) 3 (9.4)
2–6 h
PCA volume, ml 6.1  4.4 5.4  3.2 6.5  3.9
Rescue analgesia 0 (0) 0 (0) 1 (3.1)
6–12 h
PCA volume, ml 9.1  5.8 8.1  4.2 8.9  5.3
Rescue analgesia 0 (0) 1 (3.1) 0 (0)
12–24 h
PCA volume, ml 12.5  7.8 10.  9.2 13.5  7.6
Rescue analgesia 0 (0) 0 (0) 0 (0)

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

Continuous data analysed using an analysis of variance; categorical data analysed using Fisher’s exact test.
No statistically significant between-group differences (P  0.05).

granisetron (4.9 h).24,25 The dose of ramose- requirement for an anxiolytic effect) [has
tron used in the present study was based on been established. A midazolam dose of
previous findings, that a minimum of 0.3 mg 50–75 mg/kg has been recommended for
of ramosetron is required to prevent PONV prophylactic antiemetic use;10 another
during the first 48 h after thyroidectomy.26,27 study reported that 75 mg/kg of midazolam
The antiemetic effects of midazolam injected into patients who had undergone
(which is used as a premedicant or as an thyroidectomy was as effective as 4 mg of
auxiliary drug for the management of ondansetron in preventing PONV, without
sedation, amnesia or situations with a creating any delay in the recovery time.28
Kim et al. 1211

Thus, it was decided that a dose of 75 mg/kg Although a low incidence of PONV was
of midazolam should be used in the present expected >24 h postsurgery, patients
study. The antiemetic mechanism of mid- remained under close observation during
azolam has not been fully elucidated, but this period, and received antiemetic rescue
postulated mechanisms include: i) glycine medications immediately if they began
mimetic inhibitory effects; ii) enhancement vomiting or requested rescue medication
of the inhibitory effects of gamma amino >24 h postoperatively. Finally, the study
butyric acid; iii) augmentation of adenosi- population included patients with three or
nergic effects; iv) inhibition of dopamine more risk factors for PONV, and could
release; v) augmentation of adenosine- therefore be considered a biased, selective,
mediated inhibition of dopamine in the population. Thus, our findings should be
chemoreceptor trigger zone.10 Clinicians interpreted cautiously and cannot be applied
may hesitate to use hypnotic agents for to patients with a potentially lower risk of
antiemetic purposes because of the dangers PONV without further investigation.
of sedation. Doses used in the present study In conclusion, in female patients
were, however, lower than those recom- undergoing thyroidectomy, combination
mended for sedation, and the antiemetic therapy involving ramosetron and midazo-
effect of midazolam has already been lam provided superior antiemetic efficacy
shown to last longer than the effects of compared with midazolam monotherapy, in
sedation.17 The incidence of drowsiness was terms of reducing the incidence of nausea
observed to be similar among the groups, and vomiting, severity of nausea and use of
and no significant difference with respect to rescue antiemetics. These findings were espe-
recovery time was found between the differ- cially evident in the early postoperative
ent groups in this study. period. No significant additional benefits
Since midazolam has been found to act of the combination therapy regimen were
synergistically with fentanyl for the induc- observed when it was compared with ramo-
tion of anaesthesia, the dose of fentanyl can setron single therapy, except for the reduc-
be reduced, compared with the level used for tion in the severity of nausea at 0–2 h.
fentanyl monotherapy.29 Thus, this study
investigated not only the effectiveness of
midazolam for PONV but also its effective- Declaration of conflicting interest
ness for pain reduction after surgery. Our The authors declare that there are no conflict of
findings showed, however, show that VAS interest.
scores and the amount of infused fentanyl
among the groups were not significantly Funding
different within the first 24 h after surgery.
There were some limitations to the pre- This research was supported by Basic Science
sent study. First, there was no control group Research Program through the National
because of anticipated ethical problems of Research Foundation of Korea (NRF) funded
including a control group who would not by the Ministry of Education, Science and
receive any antiemetic therapy postsurgery. Technology (2012R1A1A1003700).
Secondly, there are certain inconsistencies
between the duration of action of ramose- References
tron and the time-period of postoperative 1. Watcha MF and White PF. Postoperative
fentanyl use. The duration of action of a nausea and vomiting. Its etiology, treatment,
single bolus of ramosetron is 24 h, but IV– and prevention. Anesthesiology 1992; 77:
PCA was infused for 48 h in this study. 162–184.
1212 Journal of International Medical Research 41(4)

2. Rabey PG and Smith G. Anaesthetic fac- 13. Jo YY, Lee JW, Shim JK, et al. Ramosetron,
tors contributing to postoperative nausea dexamethasone, and their combination for
and vomiting. Br J Anaesth 1992; 69: the prevention of postoperative nausea and
40S–45S. vomiting in women undergoing laparoscopic
3. Apfel CC, Läärä E, Koivuranta M, et al. A cholecystectomy. Surg Endosc 2012; 26:
simplified risk score for predicting post- 2306–2311.
operative nausea and vomiting: conclusions 14. Byon HJ, Lee SJ, Kim JT, et al. Comparison
from cross-validations between two centers. of the anti-emetic effect of ramosetron and
Anesthesiology 1999; 91: 693–700. combined ramosetron and midazolam in
4. Dejonckheere M, Deloof T, Dustin N, et al. children: a double-blind, randomised clinical
Alizapride in the prevention of post- trial. Eur J Anaesthesiol 2012; 29: 192–196.
thyroidectomy emetic sequelae. Eur J 15. Apfel CC, Roewer N and Korttila K. How to
Anaesth 1990; 7: 417–421. study postoperative nausea and vomiting.
5. Ewalenko P, Janny S, Dejonckheere M, et al. Acta Anaesthesiol Scand 2002; 46: 921–928.
Anti-emetic effects of subhypnotic doses of 16. Kim DS, Koo GH, Kang H, et al. The anti-
propofol after thyroidectomy. Br J Anaesth emetic effect of midazolam or/and ondanse-
1996; 77: 463–467. tron added to intravenous patient controlled
6. Gan TJ, Meyer TA, Apfel CC, et al. Society analgesia in patients of pelviscopic surgery.
for Ambulatory Anesthesia guidelines for Korean J Anesthesiol 2012; 62: 343–349.
the management of postoperative nausea 17. Unlugenc H, Guler T, Gunes Y, et al.
and vomiting. Anesth Analg 2007; 105: Comparative study of the anti-emetic effi-
1615–1628. cacy of ondansetron, propofol and midazo-
7. Apfel CC, Korttila K, Abdalla M, et al. A lam in the early postoperative period. Eur J
factorial trial of six interventions for the Anaesthesiol 2004; 21: 60–65.
prevention of postoperative nausea and 18. Lee Y, Wang JJ, Yang YL, et al. Midazolam
vomiting. N Engl J Med 2004; 350: vs ondansetron for preventing postoperative
2441–2451. nausea and vomiting: a randomised con-
8. Metaxari M, Papaioannou A, Petrou A, trolled trial. Anesthesia 2007; 62: 18–22.
et al. Antiemetic prophylaxis in thyroid 19. Fukuda H and Koga T. Stimulation of
surgery: a randomized, double-blind com- glossopharyngeal and laryngeal nerve affer-
parison of three 5-HT3 agents. J Anesth ents induces expulsion only when it is applied
2011; 25: 356–362. during retching in paralyzed decerebrate
9. Ryu J, So YM, Hwang J, et al. Ramosetron dogs. Neurosci Lett 1995; 193: 117–120.
versus ondansetron for the prevention of 20. Grélot L, Barillot JC and Bianchi AL.
postoperative nausea and vomiting after Activity of respiratory-related oropharyn-
laparoscopic cholecystectomy. Surg Endosc geal and laryngeal motoneurones during
2010; 24: 812–817. fictive vomiting in the decerebrate cat. Brain
10. Splinter WM, MacNeill HB, Menard EA, Res 1990; 513: 101–105.
et al. Midazolam reduces vomiting after 21. Lee HS, Lee BJ, Kim SW, et al. Patterns of
tonsillectomy in children. Can J Anaesth post-thyroidectomy hemorrhage. Clin Exp
1995; 42: 201–203. Otorhinolaryngol 2009; 2: 72–77.
11. Heidari SM, Saryazdi H and Saghaei M. 22. Kang YK, Park YH, Ryoo BY, et al.
Effect of intravenous midazolam pre- Ramosetron for the prevention of cisplatin-
medication on postoperative nausea and induced acute emesis: a prospective rando-
vomiting after cholecystectomy. Acta mized comparison with granisetron. J Int
Anaesthesiol Taiwan 2004; 42: 77–80. Med Res 2002; 30: 220–229.
12. Unlugenc H, Guler T, Gunes Y, et al. 23. Fujii Y. Current review of ramosetron in the
Comparative study of the anti-emetic effi- prevention of postoperative nausea and
cacy of ondansetron, propofol and midazo- vomiting. Curr Drug Saf 2011; 6: 122–127.
lam in the early postoperative period. Eur J 24. Rabasseda X. Ramosetron, a 5-HT3 recep-
Anaesthesiol 2003; 20: 668–673. tor antagonist for the control of nausea and
Kim et al. 1213

vomiting. Drugs Today (Barc) 2002; 38: study of the anti-emetic effects and toler-
75–89. ability of ramosetron in adults undergoing
25. Gan TJ. Selective serotonin 5-HT3 receptor middle ear surgery. Clin Ther 2003; 25:
antagonists for postoperative nausea and 3100–31008.
vomiting: are they all the same? CNS Drugs 28. Ha JH, Kwak KH, Seo JW, et al.
2005; 19: 225–238. Effectiveness of ondansetron and midazolam
26. Fujii Y and Tanaka H. Double-blind, pla- in the prevention of PONV after thyroidect-
cebo-controlled, dose-ranging study of omy. Korean J Anesthesiol 2007; 53: 344–349.
ramosetron for the prevention of nausea and 29. Ben-Shlomo I, abd-el-Khalim H, Ezry J,
vomiting after thyroidectomy. Clin Ther et al. Midazolam acts synergistically with
2002; 24: 1148–1153. fentanyl for induction of anesthesia. Br J
27. Fujii Y and Tanaka H. Randomized, double- Anaesth 1990; 64: 45–47.
blind, placebo-controlled, dosed-finding