A comparative study of the antiemetic efficacy of dexamethasone, ondansetron, and metoclopramide in patients undergoing gynecological surgery

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1 Med Sci Monit, 2010; 16(7): CR PMID: Clinical Research Received: Accepted: Published: A comparative study of the antiemetic efficacy of dexamethasone, ondansetron, and metoclopramide in patients undergoing gynecological surgery Authors Contribution: A Study Design B Data Collection C Statistical Analysis D Data Interpretation E Manuscript Preparation F Literature Search G Funds Collection Tugsan Egemen Bilgin 1 ABDEF, Handan Birbicer 1 ABDEF, Zeliha Ozer 1 ADE, Nurcan Doruk 1 BDF, Ekrem Tok 2 ABC, Ugur Oral 1 G 1 Department of Anesthesiology and Reanimation, Mersin University School of Medicine, Mersin, Turkey 2 Department of Obstetric and Gynecology, Mersin University School of Medicine, Mersin, Turkey Source of support: Departmental sources Background: Material/Methods: Summary Postoperative nausea and vomiting (PONV) are some of the most-common and undesirable adverse effects after surgery performed under general anesthesia. We investigated the prophylactic value of dexamethasone as an alternate to ondansetron or metoclopramide to prevent PONV after gynecologic surgery. One hundred sixty ASA I-II patients scheduled for elective gynecologic surgery were enrolled. Before induction of anesthesia, patients were randomly allocated to receive intravenously dexamethasone (8 mg) in group D, ondansetron (4 mg) in group O, metoclopramide (10 mg) in group M, and saline (2 ml) in group P. Total incidence of nausea and vomiting, rescue antiemetic requirement, pain scores, and any adverse effects were recorded at 3 observational periods (0 2 hours, 2 12 hours, and hours). Results: Total rates of PON, POV, and PONV were significantly higher in group P at 0 2 hours and 2 12 hours compared with group D, O, and M (P<.05). There was no difference in PON, POV, and PONV among D, O, and M groups. None of the groups differed in PONV in the subsequent hours. Number of patients requiring rescue antiemetic was significantly higher in group P than the other groups at 0 2 hours (10%, 10%, 15%, and 45% in group D, O, M, and P) (P<.05). Conclusions: Prophylactic IV dexamethasone 8 mg significantly reduces the incidence of PONV in gynecologic surgery. At this dosage, dexamethasone is as effective as ondansetron 4 mg and metoclopramide 10 mg, and is more-effective than placebo. key words: gynecological surgery dexamethasone metoclopramide ondansetron postoperative nausea vomiting Full-text PDF: Word count: 2917 Tables: 3 Figures: References: 29 Author s address: Tugsan Egemen Bilgin, Mersin University School of Medicine, Department of Anesthesiology and Reanimation, Mersin, Turkey, tugsanb@yahoo.com CR336 Current Contents/Clinical Medicine IF(2009)=1.543 Index Medicus/MEDLINE EMBASE/Excerpta Medica Chemical Abstracts Index Copernicus

2 Med Sci Monit, 2010; 16(7): CR Bilgin TE et al Dexamethasone as first-line anti-emetic Background Postoperative nausea and vomiting (POVN) is a common and undesirable after effect after surgery performed under general anesthesia. The anesthetist is usually blamed, despite evidence that postoperative nausea and vomiting results from several factors, some related to anesthesia, others to surgery, and some to the patients themselves. The importance of POVN is generally underestimated because it is self-limiting. However, its impact on the cost of health care is not negligible. In an attempt to decrease the incidence of PONV in the ambulatory setting, several anti-emetics have been studied. Metoclopramide [which has a dose-dependent action on central dopaminergic D2 receptors, central and peripheral 5-HT3 receptors, and peripheral 5 HT4 receptors], has been one of the most popular antiemetic for decades [1]. It is still used widely in clinical practice for the prevention of postoperative nausea and vomiting, although conflicting results are present [2,3]. Ondansetron, which was thought to represent the first universally effective anti-emetic for postoperative nausea and vomiting, was shown to have a role in preventing of PONV. However, the high cost of ondansetron has been a major constraint in its routine prophylactic use [4]. Dexamethasone also was used as a stand alone drug in both pediatric and adult patients undergoing surgery [4 6]. Dexamethasone, which has been reported to be better in preventing nausea, [7] and which supposedly decreases 5-HT levels in the central nervous system [8,9], has recently been proposed to decrease the incidence of PONV [5,6,10,11]. Perhaps the most important nugget from these anti-emetic agents was that none of the drugs tested could be regarded as a criterion standard, and none was good enough to be used on its own; at best, they needed several to treat to prevent postoperative nausea and vomiting of about 3 compared with placebo. In addition, no large-scale trials have been performed comparing dexamethasone, ondansetron, and metoclopramide. This placebo-controlled, randomized, double-blind study was conducted in search of an economic and effective trial of dexamethasone, ondansetron, and metoclopramide for regular clinical use in the prevention of PONV in routine gynecologic surgery. The hypothesis was that in patients who underwent gynecologic surgery, dexamethasone, administered after induction of anesthesia, would allow lower cost rate and similar incidence of PONV compared with giving ondansetron and metoclopramide. Material and Methods This study was approved by the Research Ethical Committee of the Faculty of Medicine of Mersin University, and written informed consent from 160 female patients was obtained. All patients were ASA class I-II, aged years, and scheduled for elective total abdominal hysterectomy with bilateral salpingo-oophorectomy under general anesthesia. Exclusion criteria were patients with a history of motion sickness, previous postoperative vomiting, gastroesophageal reflux or gastrointestinal disorders, taking medications with known antiemetic activity, those who were pregnant or breastfeeding, a previous adverse reaction to dexamethasone, ondansetron, metoclopramide any other anti-emetic, chronic opioid use, body weight more than 100% over ideal, history of alcohol or drug abuse, or receipt of an antiemetic agent within 24 hours or significant hepatic impairment and difficult endotracheal intubation. Patients were instructed preoperatively in the use of the verbal analog scale (VAS) for pain assessment. All were fasted for 8 hours preoperatively and were premedicated with intravenous midazolam 0.15 mg kg 1 30 minutes before induction of anesthesia. Standard intraoperative monitoring included pulse oximetry, automated blood pressure measurement, and electrocardiogram lead II. Lactated Ringer s solution in 5% dextrose was initiated as fluid therapy in all patients. Before induction of anesthesia, patients were allocated randomly to receive 1 of 4 study drugs. Randomization was done by random number table generated by a computer program. The drugs were prepared by an anesthetist, who was not one of the observers, in three 2-mL syringes, which contained either 8 mg dexamethasone, 4 mg ondansetron, 10 mg metoclopramide, or 0.9% saline per syringe. They were marked only with a coded label to maintain the double-blind nature of the study. Thus, before induction of anesthesia, patients in group D (n=40) received IV 8 mg dexamethasone, group O (n=40) received 4 mg ondansetron, group M (n=40) received 10 mg metoclopramide, and group P (n=40) received 0.9% saline before anesthesia induction. Anesthesia was induced in all patients by propofol (2 3 mg kg 1 ) and maintained with sevoflurane 2 2.5% in a mixture of 67% nitrous oxide in oxygen. Neuromuscular relaxation was induced by an intravenous bolus of vecuronium ( mg kg 1 ) and maintained (0.03 mg kg 1 ) by bolus administration at 30-minute intervals. After endotracheal intubation, ventilation of the lungs was controlled (tidal volume of 7 10 ml kg 1, respiratory rate of 10 breaths min 1 ) to produce an endtidal carbon dioxide partial pressure in the range of kpa. At the end of surgery, patients were extubated following antagonism of residual neuromuscular block with atropine (0.015 mg kg 1 ) and neostigmine (0.05 mg kg 1 ). The incision area was infiltrated with bupivacaine 0.5% 20 ml, and tramadol 1 mg kg 1 was given intramuscularly for postoperative pain relief. In the recovery room, if no pain relief was obtained, tramadol 1 mg kg 1 intravenously to maintain a pain score <5 on a verbal analogue scale of 0 10 were given. The rescue antiemetic was metoclopramide 10 mg IV, which was prescribed to be given for prolonged nausea (exceeding 10 min) or vomiting or at the patient s request. The treatment was repeated if necessary. No antiemetics were administered intraoperatively. Pain was assessed using a verbal analog scale (VAS) from 0 to 10 (0=no pain at all, 10=maximum imaginable pain) by an anesthetist blinded to the treatment group. Nausea was assessed using a linear numerical scale of 0-3 (0=none, 1=mild, 2=moderate, 3=severe). Total incidence of PONV (postoperative nausea (PON) and postoperative vomiting (POV)) and the number of patients requiring rescue antiemetic was recorded by an anesthetist CR337 CR

3 Clinical Research Med Sci Monit, 2010; 16(7): CR Table 1. Patients characteristics and duration of surgery and anesthesia (Mean ±SD). Group D (n=40) Group O (n=40) Group M (n=40) Group P (n=40) Age (y) 39.55± ± ± ±7.18 Weight (kg) 67.36± ± ± ±9.35 Duration of surgery (min) 80.00± ± ± ±24.06 Duration of anesthesia (min) 93.64± ± ± ±24.61 Tramadol consumption* (n,%) 18 (45.0%) 22 (55.0%) 25 (62.5%) 19 (47.5%) * The number and percentage of patients requiring tramadol supplementation. during 3 periods within the first 24 hours after the operation: 0 2 hours in the recovery room, and 2 12 hours, and hours on the ward. This anesthetist, blinded to the study group, performed continuous observation of the patients in the recovery room. Nausea was defined as the subjectively unpleasant sensation associated with awareness of the urge to vomit, whereas vomiting was defined as the forceful expulsion of gastric contents from the mouth [12]. Pain scores and hemodynamic variables (systolic and diastolic blood pressure (SBP-DBP), heart rate (HR) and peripheral oxygen saturation (S P O 2 ) were recorded by the same anesthetist blinded to the treatment group at 3 observation periods (0 2 hours, 2 12 hours, and hours). The duration of anesthesia and surgery, the number of patients requiring tramadol supplementation was recorded. Any adverse effects (eg, deep sedation, hypotension, headache, or constipation) associated with study drugs also were recorded. Patients remained in postanesthesia care unit (PACU) electively for the first 2 hours and were then transferred to the ward when fully awake (as judged by response to commands and ability to verbal contact). Statistical analyses In the literature [6,13], a 30% reduction in the incidence of PONV was to be regarded as a clinically significant result. A power of 0.8 using a significance level of 0.05, the sample size required was 40 subjects per study group. The primary endpoint was defined as a reduction in the incidence of PONV at 24 hours. Statistical analyses were performed using SPSS software for Windows (Statistical Product and Service Solutions, version 9.05, SSPS Inc, Chicago, IL, USA). One-way ANOVA was used to compare differences in baseline characteristics among the 4 groups. Categoric variables were analyzed by using a series of 4 2 chi-square tests to determine differences among the 4 groups, followed by 2 2 chi-square tests or Fisher exact tests, as appropriate, for intergroup differences. The mean pain scores among the 4 groups were compared by Kruskal-Wallis test, followed by Mann-Whitney sum rank test for intergroup differences. Values for P less than.05 were considered significant. Data are shown as mean ±SD or n (%). Results There was no difference between groups in demographic data, duration of surgery, and anesthesia (Table 1). There was no statistically significant difference between groups in hemodynamic variables or S P O 2. Both remained within the normal range throughout the 0 2 hours, 2 12 hours, and hours observation. The total incidence of PON, POV, and PONV during the first 24 hours postoperatively is presented in Table 2. Statistically significant differences were found among the groups regarding with PON, POV, and PONV rates. Total rates of PON, POV, and PONV were significantly higher in group P at 0 2 hours and 2 12 hours compared with group D, O, and M (P<.05; Table 2). However, there were no significant differences in the incidence of PON, POV, and PONV at 3 observation periods between groups D, O, and M (Table 2). The rates of PON, POV, and PONV did not differ between the 4 groups at hours (Table 2). In the first 2 hours after surgery, 8 patients (20%) in the dexamethasone group (n=40), 8 patients (20%) in the ondansetron group (n=40), 10 patients (25%) in the metoclopramide group (n=40), and 26 patients (65%) in the placebo group (n=40) experienced PONV, whereas at 2 12 hours, this decreased to 4 patients (10%), 4 patients (10%), 4 patients (10%) and 18 patients (45%) in group D, O, M, and P groups. The total incidence of PONV was 5%, 0%, 5%, and 5% in group D, O, M, and P in the subsequent hours. The number of patients requiring rescue antiemetic was significantly higher in group P than the other groups at 0 2 hours (10%, 10%, 15%, and 45% in group D, O, M, and P) (P<.05). However, there was no significant difference in the number of patients requiring rescue anti-emetic between group D, O and M (P>.05) (Table 2). At 2 12 hours and hour observations, there was no significant difference in the number of patients requiring rescue antiemetic between groups (Table 2). Within the 24-hour observation period, 84 patients (52.5%) complained of pain despite bupivacaine 0.5% 20 ml infiltration to the incision area and tramadol (1 mg kg 1 ) intramuscularly: 18 in group D (45%), 22 in group O (55%), 25 in group M (62.5%), and 19 in group P (47.5%). These patients were given boluses of tramadol (1 mg kg 1 ) intravenously to keep pain scores below 5 on a verbal analogue scale of Pain scores were found to be similar between groups at any study period (mean pain scores; 1.8±0.02 in the dexamethasone group, 2.4±0.1 in the ondansetron group, 2.6±0.08 in the metoclopramide group, and 2.0±0.07 in placebo group within 24 hours), and there was no significant difference CR338

4 Med Sci Monit, 2010; 16(7): CR Bilgin TE et al Dexamethasone as first-line anti-emetic Table 2. Evaluation of postoperative nausea and vomiting (PONV) and the number of patients requiring rescue antiemetic after abdominal hysterectomy at different periods [n (%)]. Incidence of PON Incidence of POV Total incidence of PONV Number of patients requiring rescue antiemetic 0 2 hours (n=40) n (%) 2 12 hours (n=40) n (%) hours (n=40) n (%) Group D 6 (15) 2 (5) 2 (5) Group O 6 (15) 4 (10) 0 (0) Group M 8 (20) 4 (10) 2 (5) Group P 14 (35)* 12 (30)* 2 (5) Group D 2 (5) 2 (5) 0 (0) Group O 2 (5) 0 (0) 0 (0) Group M 2 (5) 0 (0) 0 (0) Group P 12 (30)* 6 (15)* 0 (0) Group D 8 (20) 4 (10) 2 (5) Group O 8 (20) 4 (10) 0 (0) Group M 10 (25) 4 (10) 2 (5) Group P 26 (65)* 18 (45)* 2 (5) Group D 4 (10) 2 (5) 1 (2.5) Group O 4 (10) 1 (2.5) 0 (0) Group M 6 (15) 2 (5) 0 (0) Group P 18 (45)* 10 (25)* 1 (2.5) * P<.05, between group P and group D, O, and M by chi-square test. PONV Postoperative nausea and vomiting; PON Postoperative nausea; POV Postoperative vomiting. CR Table 3. Adverse effects (the numbers of patient). Group D (n=40) Group O (n=40) Group M (n=40) Group P (n=40) Headache Dizziness 1 2 Constipation 1 1 Pruritus 2 Sedation 1 2 Apfel CC, Korttila K, Abdalla M et al: A factorial trial of six interventions for the prevention of postoperative nausea and vomiting. N Engl J Med, 2004; 350: between groups. There was also no significant difference between groups with respect to the number of patients requiring tramadol supplementation (Table 1). The most-common minor complication reported was headache (5 10%). No major complication was observed. The numbers of the adverse effects of the drugs are summarized in Table 3. Discussion Efficient prevention and management of postoperative nausea and vomiting [PONV] continues to be a concern that must be addressed [12]. The incidence of PONV in patients undergoing gynecologic procedures is estimated to be in the range of 25±93% [14 16]. In our study, we found that the total incidence of PONV was 65% at 0- to 2-hour period, 45% at 2- to 12-hour period and 5% at 12- to 24-hour period after gynecologic procedures when saline was given prophylactically. After pretreatment with dexamethasone 8 mg, the incidence of PONV was significantly reduced to 20% at 0- to 2-hour period, 10% at 2- to 12-hour period, and 5% at 12- to 24-hour period. We also found that the prophylactic administration of ondansetron and metoclopramide did significantly reduce the incidence of PONV CR339

5 Clinical Research Med Sci Monit, 2010; 16(7): CR after gynecologic surgery, and these drugs were equally effective in preventing PONV. The fact that 18 patients of group P requested rescue antiemetic at 0- to 2-hour period as compared with 4 of the group D, 4 in group O, and 6 in group M suggests that these drugs can effectively reduce the incidence of postoperative nausea and vomiting, at a dose of 8 mg, 4 mg, and 10 mg in group D, O, and M. Patients at high-risk of PONV should receive special considerations with respect to the prophylactic use of antiemetic drugs [12]. The practice of administering antiemetics before the induction of anesthesia was based on the hypothesis that block of specific receptors in the chemoreceptor trigger zone before the arrival of emetic stimuli would be associated with greater antiemetic efficacy. There is both direct and indirect evidence supporting the practice of administering prophylactic antiemetic drugs after induction of anesthesia or near the end of the operation. Dexamethasone appears to be most-effective when administered before induction of anesthesia rather than at the end [6]. This was the reason for using dexamethasone before surgery. The mechanism by which dexamethasone exerts its antiemetic action may be via the blockage of the corticoreceptors in the nucleus tractus solitarius of the central nervous system [6]. Dexamethasone may also exert its antiemetic action through some peripheral mechanism [2]. Additionally, dexamethasone may significantly reduce tissue inflammation around the surgical area and thus, reduce the ascending parasympathetic impulses to the vomiting center and reduce PONV [17]. A dose-response relation for dexamethasone could not be established. This may mainly be because of the narrow ranges of doses used in adults. Thus, we do not know if smaller doses would still be effective, or if it was worthwhile to test larger doses. This may be regarded as a further argument for reducing the dose of dexamethasone. Ondansetron is a 5-hydroxytyriptamine (serotonin) subtype 3 receptor (5HT 3 ) antagonist found effective in the prevention of PONV in female outpatients undergoing gynecologic surgery [14,18]. The effectiveness of IV ondansetron in the prevention of PONV was evaluated by McKenzie and coworkers in a dose ranging study [14], and it was demonstrated that a single 4-mg IV appeared to be the lowest acceptable dose of ondansetron to prevent PONV. In this study, ondansetron 4 mg IV was used for the prevention of PONV. In addition to the previously mentioned studies involving dexamethasone and ondansetron, Monagle and associates have reported that 0.4 mg/kg of metoclopramide IV administered immediately before induction of anesthesia is effective in preventing PONV after minor gynecologic surgery [19]. Similarly, Chen and associates have stated that 10 mg of metoclopramide is effective as much as 4 mg of ondansetron for the prevention of vomiting in patients undergoing major gynecologic surgery [20]. However, Morris and associates failed to demonstrate any antiemetic activity with 10 mg of metoclopramide IV immediately before induction of anesthesia [3]. Although its antiemetic efficacy is under debate, some controlled trials performed during gynecologic and obstetric procedures, as well as our own data, showed that metoclopramide 10 mg is effective and safe [20,21]. Controversy also surrounds the recommended dose of the 5-HT3 antagonist ondansetron for antiemetic prophylaxis. In their meta-analysis, Tramer and associates concluded that the minimally effective dose of ondansetron for the prophylaxis of PONV was 8 mg [22]. In our study, this conclusion was based on comparisons of the efficacy of this dose with dexamethasone, metoclopramide, and placebo. The cause of PONV after gynecologic surgery is not fully understood. Risk factors such as age, surgical procedure, anesthetic care (intraoperative use of sevoflurane and neostigmine), postoperative pain management, and concurrent drugs may contribute to these episodes [23]. Because these risk factors may interfere with the interpretation of the study data, in this study, we standardized some of these factors (sex, type of surgery, anesthetic technique, premeditation drugs, induction of anesthesia, type of anesthetics used for the maintenance of anesthesia) within the study design. In addition, after random allocation, postoperative pain scores among groups were similar. Therefore, the differences in the occurrence of PONV among groups can be attributed to the study drugs. Postoperative pain is one of the etiologic factors of PONV. There is a positive correlation between postoperative pain and PONV. Effective management of pain may reduce the incidence of PONV [24]. In our study, there were no statistically significant differences in pain scores and rescue analgesic requirement between groups. As regards the safety study, the incidence of adverse effects due to the drug administration was negligible in our patients and did not significantly differ among the 4 groups. The treatment did not significantly alter the vital signs (blood pressure, heart rate, respiratory rate) compared with the basal values in the 4 groups. The major reported adverse effect was headache for ondansetron and constipation for metoclopramide [12], but there was no statistically significant difference in adverse effects between ondansetron, dexamethasone, metoclopramide, and placebo. Cost is an ever-increasing concern in today s health care system. Prophylactic antiemetic with dexamethasone is relatively inexpensive. Dexamethasone at a dosage of 8 mg costs US$ 2.50, and metoclopramide at a dose of 10 mg costs US$ 2.45, which is remarkably less expensive than a similar effective dosage of ondansetron 4 mg, which costs US$ Therefore, dexamethasone 8 mg or metoclopramide 10 mg is a more-reasonable choice than ondansetron 4 mg for the prevention of PONV. Conclusions Prophylactic IV dexamethasone 8 mg significantly reduces the incidence of PONV in patients undergoing gynecologic surgery. At this dosage, dexamethasone is as effective as ondansetron 4 mg, and metoclopramide 10 mg, and is more effective than placebo. The current techniques of intravenous anesthesia warrants antiemetic use nearly in all kinds of surgery. The development of new anesthetic techniques [25] may reduce the need of antiemetics, and thereby the cost of surgery. CR340

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