Original research
Ramosetron vs. ramosetron plus dexamethasone for the prevention of
postoperative nausea and vomiting (PONV) after laparoscopic
cholecystectomy: Prospective, randomized, and double-blind study
Jung-Hee Ryu
a
, Ji-Eun Chang
b
, Hye-Rim Kim
b
, Jung-Won Hwang
a
, Ah-Young Oh
a
, Sang-Hwan Do
a
,*
aDepartment of Anesthesiology & Pain Medicine, Seoul National University Bundang Hospital, 166 Kumi-ro, Bundang-gu, Seongnam-si, Kyonggi-do 463-707, Republic of Korea bDepartment of Anesthesiology & Pain Medicine, Seoul National University Hospital, Seoul, Republic of Korea
a r t i c l e i n f o
Article history:
Received 25 September 2012 Accepted 21 December 2012 Available online 11 January 2013
Keywords: Pain Postoperative Serotonin (5-hydroxytryptamine) Antagonism PONV Surgery Laparoscopy
a b s t r a c t
Introduction: Up to 75% of the patients undergoing laparoscopic cholecystectomy develop postoperative nausea and vomiting (PONV). Both ramosetron, a serotonin subtype 3 (5-HT3) antagonist, and
dex-amethasone are effective for PONV prophylaxis following laparoscopic cholecystectomy but their com-bined effect has not been investigated. We investigated the efficacy and tolerance of ramosetron alone and ramosetron with dexamethasone for PONV prophylaxis after laparoscopic cholecystectomy. Methods: Seventy six patients scheduled for laparoscopic cholecystectomy were randomized to receive either intravenous (i.v.) 0.3 mg ramosetron (group R), or 8 mg dexamethasone plus 0.3 mg ramosetron (group D). Standardized anesthesia with desflurane and remifentanil was used in all patients. Post-operative nausea, retching, vomiting, rescue antiemetics, pain scores, rescue analgesics and side effects were assessed at 0e2, 2e24 and 24e48 h postoperatively.
Results: Seventy two patients were randomized. The overall incidence of PONV did not differ (p¼ 0.31) but fewer patients needed rescue antiemetics in group D than in groups R (3 vs. 13 patients, respec-tively; p¼ 0.01) during 0e48 h postoperatively. Additionally, pain scores were significantly lower in group D during the study period (p< 0.01) and rescue analgesics were required less often in group D during 2e48 h postoperatively (p < 0.01).
Conclusions: In patients undergoing laparoscopic cholecystectomy, the combined use of ramosetron and dexamethasone was more effective than ramosetron alone for reducing the need for rescue antiemetics and pain control following the procedure.
Ó 2013 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.
1. Introduction
Laparoscopic cholecystectomy (LC) is frequently performed for
gallbladder stones or polyps. Postoperative nausea and vomiting
(PONV) is one of the most common adverse events after
laparo-scopic surgery with reported incidences of 40
e75%.
1This
unde-sirable side effect may delay postoperative recovery and discharge,
so the prophylactic use of antiemetics for high-risk patients is
required to reduce hospital costs and increase patient satisfaction.
2In numerous investigations, PONV in patients scheduled for LC
has been prevented and treated with a variety of antiemetics
including anticholinergics,
3antihistamines,
4butyrophenones,
5benzamide,
1,6dexamethasone,
7-9and 5-HT
3antagonists.
1,3,4,6,7Among the numerous antiemetic therapies, a combination of
a serotonin receptor antagonist (e.g. ondansetron, granisetron,
tropisetron, dolasetron, and ramosetron) with dexamethasone is
considered to be highly effective for preventing PONV after LC.
Ramosetron, a 5-HT
3receptor antagonist, has prophylactic
antie-metic effects after LC.
10Dexamethasone, alone or in combination
with other 5-HT
3antagonists, is effective for preventing PONV, pain
control and improving the recovery pro
file after LC.
7e9A Pubmed search using terms of
“ramosetron” and “
dex-amethason
” revealed no studies of the combined effects of
ramo-setron plus dexamethasone for preventing PONV. We hypothesized
that a combination of dexamethasone and ramosetron would be
more effective for PONV prophylaxis and pain control than
ramo-setron alone after LC. Therefore, we designed and conducted
a prospective, randomized, and double-blind study to compare the
ef
ficacy and tolerability of intravenous (i.v.) ramosetron plus
dex-amethasone and ramosetron alone for the prophylaxis of PONV in
patients undergoing LC.
* Corresponding author. Tel.: þ82 31 787 7501; fax: þ82 31 787 4063. E-mail address:shdo@snu.ac.kr(S.-H. Do).
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International Journal of Surgery
j o u r n a l h o m e p a g e : w w w . t h e i j s . c o m
1743-9191/$e see front matter Ó 2013 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.
2. Methods
This prospective, randomized, and double-blind investigation was registered with the Clinical Research information Service (CRiS, registration number KCT0000267) and the study protocol was approved by the Institutional Review Board of Seoul National University Bundang Hospital (No. B-1109-135-301). After then, informed consent from each patient, a total of 76 American Society of Anesthesiol-ogist (ASA) physical status IeII subjects, aged 25e65 years, and scheduled for elective LC under general anesthesia from October 2011 to January 2012 were enrolled. Exclusion criteria included: gastrointestinal disease, obesity (more than 50% greater than their ideal body weight), pregnancy or menstruation, history of motion sickness and/or postoperative emesis, diabetes mellitus, use of steroids or antiemetics within 1 month of surgery and history of allergy to any study medication.
Patients were randomized to receive either intravenous ramosetron alone (group R, n¼ 38) or intravenous ramosetron plus dexamethasone (group D, n ¼ 38) using a computer-generated randomization code (Random Allocation Software Version 1.0) with block size 4. Randomization was performed before the induction of anesthesia by an independent anesthesiologist who is responsible for patient allo-cation and not otherwise involved in this study. Study mediallo-cations were prepared by an anesthetic nurse not involved in this study. Study medications consisted of (1) an identical syringe with 2 ml solution with normal saline for group R or 8 mg dex-amethasone (Dexdex-amethasoneÒ; Daewon Pharm., Seoul, Korea) for group D, administered immediately after the induction of anesthesia and (2) a syringe with 2 ml solution with 0.3 mg ramosetron (NaseaÒinjectable; Astellas Pharma Inc., Tokyo, Japan) which was injected at the end of surgery. Syringes were labeled with the patient’s inclusion number and passed to the anesthesiologist. Patients, anes-thesiologists, and outcome assessors were blinded to group assignment.
Patient received IV 0.03 mg/kg midazolam as a pre-anaesthestic medication. On arrival in the operating room, standard monitors with continuous electrocardio-gram, noninvasive blood pressure, pulse oximetry and capnography were applied to the patient. Anesthesia was induced with i.v. 2 mg kg1propofol and 3e4 ng ml1
remifentanil target-controlled infusion; 0.6 mg kg1rocuronium was administered prior to endotracheal intubation. Immediately after the induction of anesthesia, study medication (normal saline or dexamethasone) was administered to the pa-tient by the blinded anesthesiologist. Maintenance of anesthesia consisted of des-flurane 4.0e6.0% (inspired concentration), medical air in oxygen (FiO2¼ 0.5) and
IV remifentanil 2e3 ng ml1. Ventilation was mechanically controlled and an
end-tidal concentration of carbon dioxide was maintained between 4.5 and 5.0 kPa throughout the surgery. Muscle relaxation was achieved with rocuronium, as required. Nasopharyngeal temperature was monitored and maintained at 36e37C
throughout the surgery using a warming pad. Lactated Ringer’s solution was infused at the rate of approximately 10 ml kg1h1during the surgery. At the end of the procedure, desflurane and remifentanil administration were discontinued and 0.3 mg ramosetron was administered intravenously. Muscle relaxation was reversed with i.v. 0.01 mg kg1glycopyrrolate and 0.04 mg kg1neostigmine. Extubation was done after spontaneous ventilation of the patient became adequate.
Patients’ characteristics including age, gender, weight, height, non smoking status, Apfel simplified risk scores11
and information on surgery and anesthesia were collected. All patients were transferred to the post-anesthesia recovery unit (PACU) until they fulfill discharge criteria and then moved to the ward. Episodes of nausea, retching and vomiting and the requirement of rescue antiemetics were recorded at three assessment periods, 0e2 h, 2e24 h, and 24e48 h, by a nursing staff blinded to treatment assignment. Nausea was defined as a subjectively unpleasant inclination to vomit; retching was defined as an involuntary effort to vomit without expulsion of gastric contents; vomiting was defined as actual expulsion of gastric contents from the mouth.12The degree of nausea (NRS; numerical rating scale, with 0¼ none to
100¼ most severe) was assessed verbally in order to guide the need of rescue an-tiemetics and this data was not part of analysis. The rescue antiemetic was i.v. metoclopramide (10 mg), which was administered to patients with an NRS for nausea> 30 or more than one episode of vomiting.
During the 0e48 h postoperative study period, patients were asked to evaluate their level of postoperative pain verbally, using NRS (0¼ none to 100 ¼ most severe). An i.v. bolus dose of 30 mg ketorolac was administered to the patient with an NRS >30. In addition, possible adverse effects related with ramosetron and dex-amethasone, such as QTc interval prolongation, headache, dizziness, wound infec-tion, stomach pain and increased appetite were also recorded.
In a preliminary study, 10 patients (with the same inclusion and exclusion cri-teria) undergoing LC were administered IV ramosetron at the end of surgery and the PONV incidence at postoperative 0e48 h was 40%. Reduction the incidence of PONV from 40% to 10% was considered to be clinically important. The analysis using sample size software (PASS 2005Ò, NCSS, USA) showed that 36 patients per group (power of 80% and type I error of 5%) would be sufficient to detect the antiemetic effect of ramosetron plus dexamethasone. Assuming a 5% dropout rate, thefinal sample size was set at 38 patients per group.
Analysis was performed using SPSS version 15.0 for Windows (SPSS, Chicago, IL, USA). Student’s t-test (two-sided) was used to compare continuous variables (age, weight, height, anesthesia time, operation time, dose rate of remifentanil, and pain NRS). The Chi-square test was used to analyze categorical variables (gender, ASA class, nonsmoking status, Apfel score, nausea, retching, vomiting, rescue antiemetics,
rescue analgesics and adverse effects). Data are presented as mean (SD) or as count (n). Two-sided P-values of<0.05 were considered statistically significant.
3. Results
Of the 76 patients enrolled in this study, 4 patients were
excluded for conversion to open cholecystectomy (2 patients in
group R, 1 patient in group D) and protocol violations (1 patient in
group D, ondansetron as rescue antiemetic instead of
metoclopra-mide). A total of 72 patients were randomized to 1 of 2 study groups
(
Fig. 1
). Patient characteristics including age, weight, height,
gen-der, non smoking status, ASA class, Apfel scores and information on
surgery and anesthesia are presented in
Table 1
.
Cumulative results for the 0
e48 h study period showed that
there was no difference in the overall incidence of PONV (p
¼ 0.31)
but the requirements for rescue antiemetics were lower in group D
than in groups R (13 patients for group R vs. 3 patients for group D;
p
¼ 0.01,
Table 2
).
The incidence of nausea of group D was comparable with that of
group R during the
first 24 h. However, the degree of nausea was
less severe and therefore rescue antiemetics were less required in
group D than in group R (8% [n
¼ 3] in group D vs. 33% [n ¼ 12] in
group R during the
first 2 h postoperatively [p ¼ 0.02], and 3%
[n
¼ 1] group D vs. 22% [n ¼ 8] in group R during the postoperative
2
e24 h [p ¼ 0.03]). No inter-group difference was observed during
24
e48 h postoperatively in the incidence of nausea and the need
for rescue antiemetics (p
¼ 1.0) (
Table 2
). Retching, vomiting, and
overall incidence of PONV were not different between the two
groups during 0
e2, 2e24 and 24e48 h postoperatively (
Table 2
).
Pain scores during 0
e2, 2e24 and 24e48 h were significantly
lower in group D than in group R (p
< 0.01,
Table 3
) and rescue
analgesics were required less frequently in group D than group
R during 2
e24 (p < 0.01) and 24e48 h (p < 0.01,
Table 3
)
postoperatively.
No difference was observed in common adverse events related
to ramosetron or dexamethasone treatment between the two
groups. Headache (2 patients in group R and 1 patient in group D)
and dizziness (3 patients in group R and 1 patient in group D) were
the most common adverse effects (
Table 3
).
4. Discussion
The
findings of this prospective, randomized, double-blind trial
revealed that a combination of ramosetron and dexamethasone
reduced the requirement for rescue aniemetics and postoperative
pain compared with ramosetron alone and caused no adverse effects
during the
first 48 postoperative hours in patients undergoing LC.
No control group was included in this study because patients
undergoing LC are at high risk of PONV with reported incidences
ranging from 75 to 83%
8and withholding prophylactic antiemetics
from these patients would be unethical. Besides the general risk
factors of PONV such as female gender, a history of motion sickness
or PONV, nonsmoking status and the use of postoperative opioid,
11prolonged carbon dioxide insuf
flations and increased intracranial
pressure by cerebral vasodilation may contribute to the high
inci-dence of PONV after LC.
13The 5-HT
3
antagonists ramosetron has
been administered as an antiemetic after LC
10and combined
antiemetic agents targeting different receptors are recommended
for prophylactic use in groups at high risk of PONV.
2The
gluco-corticoid, dexamethasone produces an antiemetic effect, possibly
via the release of endorphin and inhibition of prostaglandin and
serotonin production.
14In this study, the incidence of PONV for 48 h
postoperatively was 39% with ramosetron alone and 28% with
ramosetron plus dexamethasone. The addition of dexamethasone
to ramosetron did not reduce the overall incidence of PONV
J.-H. Ryu et al. / International Journal of Surgery 11 (2013) 183e187 184
signi
ficantly but it did reduce the severity of nausea significantly
and consequently reduced the need for recue analgesics compared
with ramosetron alone 0
e24 h postoperatively. This result is not in
line with the results of previous studies, in which dexamethasone
Table 1
Patients’ characteristics and information on surgery and anaesthesia. Group R; i.v. ramosetron 0.3 mg alone group. Group D; IV dexamethasone 8 mg combined with ramosetron 0.3 mg group. ASA; American Society of Anesthesiologists. Values are expressed as mean (SD) or number of the patients (%). Data were analyzed using t-test (continuous variables) or Chi-square t-test (incidence variables).
Group R (n¼ 36) Group D (n¼ 36) Age (yr) 44 (20e65) 45 (24e64) Weight (kg) 70 (12) 66 (11) Height (cm) 165 (10) 164 (8) Male/Female (%) 16/20 19/17 Non smoking status, n, (%) 30 (83) 29 (81) Apfel Score, n, (%) 0 6 (17) 7 (19) 1 10 (28) 12 (33) 2 20 (56) 17 (47) Preoperative diagnosis, n, (%) Gallbladder stone 18 (50) 20 (56) Gallbladder polyp 6 (17) 10 (28) Acute cholecystitis 9 (25) 4 (11) Chronic cholecystitis 3 (8) 2 (6) Operation time (min) 48 (22) 48 (18) Anaesthesia time (min) 80 (24) 82 (21) Remifentanil (mg kg1min1) 0.14 (0.1) 0.11(0.02) ASA physical status I/II, n, (%) 23 (64)/13 (36) 22 (61)/14 (39)
Fig. 1. Flow diagram of patients. Seventy six patients were randomized. Three patients (2 patients from R group and 1 patient from D group) were eliminated due to conversion to open cholecytectomy and 1 patient was excluded from the analysis due to protocol violation (ondansetron administration instead of metoclopramide as a rescue antiemetic). R group; ramosetron alone group. D group: dexamethasone plus ramosetron group.
Table 2
Incidences of PONV and rescue analgesic. Group R; i.v. ramosetron 0.3 mg alone group. Group D; i.v. dexamethasone 8 mg combined with ramosetron 0.3 mg group. N/A; not applicable. Values are expressed as number of the patients (%). Data were analyzed using Chi-square test.
Group R (n¼ 36) Group D (n¼ 36) P value Postoperative 0e48 h Nausea 14 (39) 9 (25) 0.31 Retching 2 (6) 1 (3) >0.99 Vomiting 2 (6) 0 (0) 0.25 Rescue antiemetic 13 (36) 3 (8) 0.01 PONV 14 (39) 9 (25) 0.31 Postoperative 0e2 h Nausea 13 (36) 9(25) 0.44 Retching 1 (3) 0 (0) >0.99 Vomiting 0 (0) 0 (0) N/A Rescue antiemetic 12 (33) 3 (8) 0.02 PONV 13 (36) 9 (25) 0.44 Postoperative 2e24 h Nausea 10 (28) 3 (8) 0.06 Retching 1 (3) 1 (3) 1> 0.99 Vomiting 2 (6) 0 (0) 0.49 Rescue antiemetic 8 (22) 1 (3) 0.03 PONV 10 (28) 3 (8) 0.06 Postoperative 24e48 h Nausea 1 (3) 1 (3) >0.99 Retching 0 (0) 0 (0) N/A Vomiting 0 (0) 0 (0) N/A Rescue antiemetic 1 (3) 0 (0) >0.99 PONV 1 (3) 1 (3) >0.99
combined with a 5-HT
3antagonist decreased the incidence of
PONV in patients undergoing thyroidectomy
15or laparoscopic
surgery.
8,16The ramosetron plus dexamethasone group had lower pain
scores during the study period (0
e48 h postoperatively) and
required less rescue analgesics for 2
e48 h postoperatively than the
ramosetron alone group. Although the groups did not differ in the
need of rescue analgesic during early postoperative period (0
e2 h),
the ramosetron plus dexamethasone group scored signi
ficantly
lower for pain than the ramosetron alone group during this period.
Several randomized controlled studies and meta-analyses have
found that single-dose dexamethasone is effective in postoperative
pain control after various surgeries including laparoscopic, breast
and thyroid surgeries.
9,15,17e20Possible mechanisms for this are its
anti-in
flammatory action and modulation of the systemic
physio-logical responses.
14In this study, dexamethasone was administered
immediately after induction of anesthesia and was effective in
reducing the pain scores at 48 h postoperatively. After LC, patients
frequently complain of severe early postoperative pain due to
car-bon dioxide pneumoperitoneum and stretching of the abdominal
wall.
21However, opioid-based analgesia administered via bolus
in-jection or patient
econtrolled analgesia may carry a greater risk of
PONV in these high-risk patients. Therefore, dexamethasone
treat-ment may be bene
ficial for patients without patientecontrolled
analgesia after LC in that it provides pain relief and reduced the
need for analgesics.
We monitored the patients for major adverse effects related to
ramosetron and dexamethasone such as headache, dizziness,
wound infection, stomach pain and increased appetite and QTc
prolongation for 48 h postoperatively. Both drugs were well
tol-erated during the study period: three cases of headache and four
cases of dizziness and the addition of dexamethasone to
ramose-tron did not affect the incidence of adverse events. Although
pro-longed glucocorticoid use may cause infection, delayed wound
healing, glucose intolerance, and adrenal suppression, a single dose
of dexamethasone is rarely associated with theses these serious
side effects.
14Patients with diabetes mellitus were excluded from
this study because of concerns regarding hyperglycemia.
The timing of the administration and dose (8 mg) of
dex-amethasone were based on previous studies
20,22that reported
a perioperative antiemetic effect. A meta-analysis of perioprative
single-dose dexamethasone for postoperative pain also found that
intermediate-dose dexamethasone (0.11
e0.2 mg/kg) had
opioid-sparing effects.
18Dexamethasone is most effective for PONV and
analgesia when administered at the time anesthesia
induc-tion
7,8,15,19,20,22considering its onset of action and the duration of
anesthesia.
This study had some limitations. First, preoperative
dex-amethasone administration was reported to enhance the recovery
from surgery
7,23and reduce PONV and postoperative pain.
How-ever, we did not assess the discharge time from PACU or hospital
stay, nor did we evaluate quality of recovery (such as patients
’
satisfaction, shivering, fatigue, or sense of well-being). Second, we
only observed patients for 48 h postoperatively and long-term
complications of glucocorticoid including wound infection and
impaired wound healing may be underestimated in this period.
Third, patients with diabetes mellitus were excluded from this
study as previous studies reported that i.v. dexamethasone 8 mg
administered at the beginning of surgery resulted in signi
ficantly
increased postoperative blood glucose concentrations.
24,255. Conclusion
In conclusion, combined i.v. 0.3 mg ramosetron and 8 mg
dex-amethasone was more effective than 0.3 mg i.v. ramosetron alone
for the relief of nausea and pain during the
first 48 postoperative
hours in patients with LC without increasing adverse effects. No
clinically signi
ficant adverse effects were observed in this study and
i.v. dexamethasone and ramosetron appear to be well tolerated in
these patients.
Ethical approval
Institutional Review Board of Seoul National University
Bun-dang Hospital (No.B-1109-135-301).
Role of funding source
This work was not supported by any institute.
Author contribution
Jung-Hee Ryu-study design, data collection, data analysis,
writing.
Ji-Eun Chang-Data colleciton, data analysis.
Hye-Rim Kim-Data collection.
Jung-Won Hwang-Study design, data collection.
Ah-Young Oh-Data collection.
Sang-Hwan Do-Study design, writing.
Con
flicts of interests
Authors have no con
flicts of interest or financial ties to disclose.
Acknowledgments
None.
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