Paech, Michael J. DM*; Rucklidge, Matthew W.M. FRCA*; Lain, Jennifer FANZCA*; Dodd, Philip H. FRCA*; Bennett, Emma-Jane MBBS*; Doherty, Dorota A. PhD†
Section Editor(s): Glass, Peter S. A.
Independent of a patient's baseline risk of postoperative nausea and vomiting (PONV), ondansetron and dexamethasone alone each reduce PONV with similar efficacy to total IV anesthesia with propofol (1). Multiple interventions, including prophylaxis using two or more antiemetic drugs, are recommended for patients at high risk of PONV (2,3). Dexamethasone with ondansetron is an attractive combination (3,4), because ondansetron is most effective against early vomiting (4), whereas dexamethasone is effective against both early and late (2–24 h) nausea and vomiting, its late efficacy being pronounced (5). Women having day-surgical gynecological laparoscopy are a surgical population at high risk of PONV, for whom multimodal strategies are most effective (6,7).
The optimum prophylactic dose of ondansetron alone appears to be 4–8 mg (4). Dexamethasone 8–10 mg is widely used (5) but smaller doses are effective for ambulatory laparoscopic surgery (8) and 2.5 mg may be the minimum effective dose after major gynecological surgery (9). The combination of ondansetron and dexamethasone is more effective than single drug prophylaxis for ambulatory gynecological surgery (10), but there is little information about dose combinations of these drugs (11). Authorities have recommended more studies to identify optimal combinations of dexamethasone combined with a 5-HT3 antagonist (5) and the minimum effective doses for this combination (12).
The aim of this study was to investigate dose combinations of ondansetron and dexamethasone for the prevention of PONV after gynecological laparoscopy in order to establish whether one or more of four different combinations were more effective. Our null hypothesis was that there was no difference in the efficacy of combinations of 2 or 4 mg of these two drugs.
This randomized, double-blind, study received institutional Ethics Committee approval and all participants gave written informed consent. We recruited women scheduled for day-surgical gynecological laparoscopy at our tertiary referral Women's Hospital. Exclusion criteria were use of drugs having antiemetic activity including steroids, opioid tolerance, hypertension, diabetes, or a contraindication to nonsteroidal antiinflammatory drugs.
Patient characteristics recorded preoperatively were age, weight, reproductive status and stage of menstrual cycle, and history of smoking, PONV or motion sickness. Other demographic data recorded were type of laparoscopic procedure, the duration of anesthesia, the requirement for reversal of neuromuscular block, and the requirement for and dose of postoperative opioid. A risk score (range 0–4) (13) was calculated according to the number of risk factors present (female gender, nonsmoker, history of PONV or motion sickness, and postoperative opioid requirement).
The anesthetic regimen was standardized, all patients receiving IV midazolam 2 mg and fentanyl 2 mcg/kg 2 min before induction. Anesthesia was induced using a target-controlled propofol infusion, starting at 6–8 mcg/mL and titrated downward during maintenance. Further boluses of fentanyl 1 mcg/kg were given as required. Airway management was achieved using either a laryngeal mask or orotracheal tube. All patients' lungs were ventilated with oxygen and air (inspired oxygen fraction 0.3–0.4) in the presence of a nondepolarizing neuromuscular blocking drug of the anesthesiologists' choice. This was later reversed, if required, by neostigmine with either atropine or glycopyrrolate. After the surgery, the gynecologist instilled 30 mL of ropivacaine 5 mg/mL into the pelvic peritoneal cavity and attempted to fully evacuate the carbon dioxide pneumoperitoneum. In the postanesthesia care unit (PACU), postoperative analgesia was achieved using rectal naproxen 500 mg and nurse-controlled IV fentanyl (25 mcg at a minimum interval of 5 min). In the day-surgical unit, a second liter of IV crystalloid was administered over 4 h and oral acetaminophen with codeine (1 g/60 mg), supplemented by oral tramadol 100 mg, was available if required. Supplemental oxygen was given until patients were ready for discharge from the PACU.
Based on a computer-generated random number sequence, stratified for history of motion sickness or PONV, patients were allocated using sealed opaque envelopes to one of four groups: dexamethasone 4 mg and ondansetron 4 mg (Group O4/D4), dexamethasone 4 mg and ondansetron 2 mg (Group D4/O2), dexamethasone 2 mg and ondansetron 4 mg (Group D2/O4), or dexamethasone 2 mg and ondansetron 2 mg (Group D2/O2). The study drugs were prepared by the hospital pharmacy, immediately before surgery, in a coded 5 mL syringe, and were administered immediately after induction of anesthesia. All observers and investigators were thus unaware of study group allocation.
Postoperatively, patients were monitored until discharge from hospital by nursing staff and then interviewed by telephone at 24 and 72 h by a research nurse. Treatment for PONV followed the hospital algorithm at that time, which prescribed prochlorperazine 12.5 mg IM initially, followed by droperidol 1 mg IV in the event of an inadequate response. The criteria for treatment were a single episode of vomiting or retching or a patient complaint of nausea. The incidence of vomiting and retching was assessed at discharge from the PACU, at hourly intervals until discharge from hospital and at 24 h. The presence and severity of nausea were assessed at similar times, using a 0–100 mm visual analog scale. The need for treatment of emesis or nausea, unplanned admission to hospital, the complete response (no vomiting and no antiemetic treatment at discharge) and time to readiness for discharge were recorded. Before discharge, patients completed a visual analog scale for satisfaction with their recovery. At 24 h postoperatively, they were asked about postdischarge episodes of vomiting, use of antiemetic medication, and provided a numerical 0–10 score for nausea and for satisfaction. A modified quality of recovery score (14), excluding questions about psychological support not applicable to day-surgical patients, and with a maximum possible score of 165, was recorded before, and at 24 and 72 h after, surgery.
The sample size calculation was based on the primary outcome, the incidence of vomiting up to discharge from hospital. In previous studies in this surgical population using prophylactic ondansetron, the incidence of vomiting was up to 33% (15). Assuming an incidence of 25% in the group receiving D2/O2, a sample size of 151 patients per group had 80% power to demonstrate a reduction in incidence from 25% to 15% in at least one of the other combinations of dexamethasone and ondansetron, at an overall significance level of 5% (χ2 test).
Descriptive statistics were median, interquartile range and range for continuous data. Categorical outcomes were summarized using frequency distributions. Nausea scores up to 6 h postoperatively were summarized using maximum and average scores to account for varying durations of hospital stay. Comparisons of continuous outcomes among groups were based on Kruskal-Wallis analysis of variance, a nonparametric analysis of variance necessary due to lack of normality. The χ2 test was used for comparisons of categorical outcomes among groups. Duration until first antiemetic treatment and first vomiting episode were estimated using Kaplan-Meier survival probabilities and log-rank test was for group comparisons. SAS version 8.2 (SAS Institute, Cary, NC) statistical software was used for data analysis. P values <0.05 were considered statistically significant.
To allow for withdrawals, we randomized 624 patients between March 2001 and December 2003. Ten of 624 patients were excluded, because of a change of surgical procedure to laparotomy (n = 6), failure to proceed with laparoscopy (n = 1), failure to collect data (n = 1) or withdrawal of consent (n = 2). There were six major protocol violations, involving failure to use the standardized anesthetic or postoperative analgesic technique, which were included in the intention-to-treat analysis of 614 patients.
Twenty-eight patients (4.5%) had unplanned hospital admission, for management of medical problems or pain management (n = 13), surgical complications (n = 11), administrative reasons (n = 3) and uncontrolled PONV (n = 1). The four groups did not differ with respect to demographic characteristics or preoperative PONV risk score, anesthetic and surgical details, or intraoperative, postoperative and total dose of fentanyl (Table 1).
The incidence of vomiting during the 24-h study period did not differ significantly among groups at any assessment (Fig. 1). The primary outcome (incidence of vomiting until discharge) was 5%, 4%, 9%, and 8% for Groups D4/O4, D4/O2, D2/O4, and D2/O2 respectively (P = 0.17).
The incidence of nausea before discharge and between discharge and 24 h did not differ significantly among groups. The overall incidence of nausea until 24 h postoperatively was significantly higher among groups receiving only 2 mg of dexamethasone (P < 0.03, Table 2). Maximum nausea scores did not significantly differ among groups nor did average scores, which were low in all groups (Fig. 2).
There were no significant differences among groups before discharge in the incidence of no nausea or vomiting, a complete response (range 80%–83%), requirement for rescue treatment (range 17%–20%, with two or more treatments required by 75% of these patients) (Table 2). There were no significant differences in duration to first vomit or first antiemetic treatment.
Satisfaction scores were high and did not significantly differ among groups (Table 2). Of the 32% who did not record complete satisfaction, 9% expressed dissatisfied at discharge, 14% at 24 h postoperatively, and 6% on both occasions, with no significant differences among groups.
There were no significant differences among groups for time spent in PACU, time to discharge, or quality of recovery at 24 and 72 h (Table 3). The median change in the quality of recovery score was a small reduction in quality (range minus 2–4 across groups).
Subset analysis limited to patients with a history of PONV or motion sickness showed that the group comparisons were analogous to those performed on all patients.
In this study, we addressed a clinically relevant question about the efficacy of four different small dose combinations of two effective antiemetic drugs. We studied comparable groups based on a history of PONV or motion sickness and on a validated risk score, monitored both early and late symptoms and patient satisfaction, and used a realistic sample size. With the exception of a small difference among groups in the overall incidence of nausea, there were no other significant differences between each combination of dexamethasone 2 or 4 mg with ondansetron 2 or 4 mg when used as prophylaxis against pre- and postdischarge PONV. Approximately 80% of female patients, most at high risk of PONV and all undergoing day-case gynecological laparoscopic surgery, neither vomited nor required treatment for PONV.
The baseline risk for PONV among women having gynecological laparoscopy is high, given the strong influence of female gender. We used the simplified score suggested by Apfel et al. (13), based on four important risk factors (female gender, history of motion sickness or PONV, nonsmoking and use of postoperative opioids) and these were well matched across our groups. Although imperfect (16), risk assessment may be useful as a guide to group comparison in trials and when applied to estimate of individual risk can reduce the institutional incidence of PONV (17).
We attempted to minimize the influence of anesthetic technique on emetic events and maximize the quality of recovery by using propofol-based IV anesthesia and IV hydration, while avoiding nitrous oxide (1,2). Total IV anesthesia reduces the risk of PONV to a similar degree to each of the antiemetics we studied (1). We did not mandate avoidance of neostigmine, which does not significantly impact PONV (18). Our results appear similar to those of other studies that used either a multimodal strategy, or in which at least two antiemetic drugs were combined, to reduce PONV (6,7). For example, total IV anesthesia and prophylactic ondansetron and droperidol produced a similar response rate in male and female patients having laparoscopic cholecystectomy (6). Prophylactic droperidol, dexamethasone and ondansetron produced an 88% response rate for the absence of vomiting in outpatient gynecological laparoscopy (7), although the patient risk factors and various aspects of postdischarge PONV were not detailed.
For simplicity, we administered both drugs immediately postinduction. Ondansetron is more effective when administered at the end of anesthesia, whereas the reverse appears true for dexamethasone (19,20), so an alternative timing schedule may possibly have improved outcomes. The recommended dose of ondansetron alone for the prevention of PONV is 4 mg, although meta-analysis supports maximal efficacy with 8 mg (5) and only 1 mg effectively treats early PONV in a gynecological population (21). Active metabolites of dexamethasone are detectable for 72 h and efficacy against PONV is prolonged (5). Although prophylactic doses of 4–10 mg are popular, and 1.25 mg is no more effective than placebo, 2.5 mg is effective in some situations (10). Given that each additional antiemetic produces an independent risk reduction (1), we chose to investigate doses within the smaller therapeutic dose range of each drug. Lee et al. (22) combined droperidol with dexamethasone 2, 4, 8, or 12 mg for PONV prophylaxis among a mixed surgical female population and concluded that 8 mg was the minimum effective dose. Differences from our study included heterogenous surgical procedures, a smaller sample size and combination with droperidol. Elhakim et al. (12) recommended dexamethasone 8 mg (vs. 2, 4, or 16 mg) with ondansetron 4 mg, but the study involved a different surgical population and dose combinations. Thomas et al. (11) combined dexamethasone 8 mg with ondansetron 4 mg in an outpatient gynecological laparoscopy population and found no PONV in 65% of patients, a result similar to that found in our group receiving dexamethasone 4 mg and ondansetron 2 mg.
We found few differences in efficacy among the four dose combinations studied, although it is possible that smaller dose combinations than we assessed might be as effective as the combination of dexamethasone 4 mg and ondansetron 4 mg. Although there was no difference in the incidence of vomiting, nausea and vomiting, need for antiemetic treatment or patient satisfaction, the overall incidence of nausea differed, with the most frequent incidence found in patients receiving only 2 mg of dexamethasone. However, this isolated finding appears clinically unimportant, because average nausea scores in all groups were very low.
We did not observe any incidents or adverse events attributable to either drug, nor did groups differ in the time taken for discharge or in the quality of recovery. Both ondansetron and dexamethasone have very favorable side effect profiles after single-dose administration (2). There is speculation as to whether dexamethasone suppresses adrenal function, but wound infection rates were not increased in a high-risk surgical population exposed to dexamethasone 4 mg intraoperatively (23). Patient satisfaction is an important outcome of quality of care, and severe PONV is strongly related to dissatisfaction (24). The subjective symptom of nausea and the medullary-mediated reflex of vomiting or retching are significantly associated, but risk factors for each differ slightly, as does the efficacy of antiemetic drugs with different mechanisms and sites of action. The administration of multiple antiemetic drugs has been advocated for patients at high risk (2). We found no evidence that comparative responses were different among patients with a history of motion sickness or PONV, which is consistent with ondansetron being more effective than placebo regardless of whether or not patients have a history of PONV (25).
The attempt to identify minimum effective doses of these antiemetic drugs is important in view of controversy surrounding alternative, cost-effective prophylactic antiemetics, such as droperidol (2). Our study suggests minor differences in the clinical efficacy of 2 and 4 mg dose combinations of dexamethasone and ondansetron in a high-risk patient group. In the absence of a placebo control group, we do not know the baseline risk of PONV without prophylaxis in our study population, which had predictive risk factor scores of ∼3. Apfel et al. (13) predicted such a score would be associated with an incidence of PONV of about 60% after inhaled anesthesia without prophylactic antiemetic therapy. The observed incidence of PONV of 47% in the D4/O4 group was higher than might be expected on the basis of a 25% relative risk reduction for each intervention (in this case 3 interventions) predicted by Apfel et al. (1). We believe this was probably due to our frequent assessment of nausea and our classification of any score above zero (on a 0–100 scale) as positive for the presence of nausea. We acknowledge that the lack of a placebo group is a limitation of the study, but the use a placebo in this high-risk population conflicts with evidence-based practice. PONV outcomes are improved if a prophylactic antiemetic is used in addition to total IV anesthesia (1,26). Our previous study (26) found that the risk of early vomiting in a similar patient population having IV anesthesia without antiemetic was 50%, and that this was significantly reduced by the addition of dolasetron.
Another limitation of our study was that our sample size estimate was based on an estimated incidence of vomiting higher than that observed. This study was consequently under-powered for the primary outcome of early vomiting. Given the low incidence of vomiting in all groups (<10%), we consider that differences of clinical importance for this outcome are unlikely, even if a larger study were to show statistically significant differences among these dose combinations. In addition, there were no significant differences among groups in the overall incidence of both nausea and vomiting, or the incidence of vomiting and need for antiemetic treatment.
In this trial, with the exception of one secondary end point, the efficacy of the smallest dose combination (dexamethasone 2 mg with ondansetron 2 mg) did not significantly differ from that of larger dose combinations.
We gratefully acknowledge the work and cooperation of our research nurses, Desiree Cavill and Tracy Bingham, who coordinated the trial, Patrick Yapp, Margaret Finlayson and colleagues from the Pharmacy Department, and anesthetic, PACU and day-surgical unit nursing colleagues.
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