Laparoscopic surgical procedures have the advantages of quick recovery, shorter hospital stay, and early return to regular activities, when compared with open surgical procedures. One of the most common causes of morbidity after laparoscopic surgery is postoperative nausea and vomiting (PONV) with reported incidences in the range of 40% to 80%.1 Studies have revealed multiple risk factors for PONV in laparoscopic surgery: exposure to opioids, female sex, history of previous PONV, type of surgical procedure, prolonged surgery, carbon dioxide retention, and peritoneal distension because of pneumoperitoneum.2–6 PONV may delay recovery and discharge,2 thus nullifying the primary advantages of laparoscopy; and excessive vomiting may result in dehydration and electrolyte imbalances. Therefore, it is imperative to reduce the incidence of these adverse events in the most effective manner possible.
Various classes of drugs have been studied as prophylaxis and treatment of PONV,4 including serotonin antagonists,2,3,7–9 anticholinergics,8 butyrophenones,10 benzamides,2,3 steroids,7,11,12 and antihistamines.9 5-Hydroxytryptamine type 3 (5-HT3) receptor antagonists are the most commonly used class of antiemetics in the perioperative setting. The 5-HT3 receptor antagonists block receptors in the chemoreceptor trigger zone (CTZ) as well as in the vagal nerve terminals. Dexamethasone enhances the antiemetic effect of 5-HT3 receptor antagonists, although the exact mechanism is not known.13
Because the cause of PONV is multifactorial, combinations of different classes of antiemetics are likely to be more effective than monotherapy.14,15 Several studies have compared combinations of dexamethasone with one of the 5-HT3 receptor antagonists with the latter alone in various types of gynecological, obstetric, pediatric, and general surgical procedures. A meta-analysis has reported outcomes in favor of the combination of dexamethasone with ondansetron in children undergoing strabismus surgery.16 No similar review could be found concerning patients undergoing laparoscopic procedures. Habib et al17 in 2004 found that the combination of ondansetron and dexamethasone was superior to ondansetron alone for PONV prophylaxis, but the studies included were composed of a heterogeneous surgical population. Hence, this systematic review and meta-analysis was designed to find out whether the combination of dexamethasone and 5-HT3 antagonist is superior to the latter alone as prophylaxis of PONV in laparoscopic surgical patients.
The reporting of this systematic review and meta-analysis follows the PRISMA recommendations.18 A protocol for this systematic review and meta-analysis has not been registered.
Bibliographical Search and Analysis
Prospective, randomized-controlled trials (RCTs) that compared the prophylactic effects of the combination of dexamethasone and a 5-HT3 receptor antagonist with that of the latter alone on PONV in adult patients undergoing laparoscopic procedures were included in the meta-analysis. Only those studies that clearly documented the anesthetic techniques and the protocols of administration of the drugs under study and clearly described the definition and evaluation of nausea and vomiting were included. We did not impose any language restriction or seek unpublished data or trials.
Two authors (A.S. and S.M.) independently searched PubMed, PubMed Central, Scopus, Central Register of Clinical Trials of the Cochrane Collaboration, and Google Scholar for eligible controlled trials using the following search words: laparoscopy, laparoscopic surgery, dexamethasone, ondansetron OR granisetron OR palonosetron OR ramosetron OR dolasetron OR tropisetron OR antiserotonin, postoperative, nausea, vomiting OR PONV until July 31, 2015. The detailed search strategy in PubMed is described in the Supplemental Digital Content 1 (http://links.lww.com/AA/B523). No non-English database was searched.
Two authors (A.S. and S.B.) independently searched for the potentially eligible trials and selected the trials to be included. Any disagreement arising between these 2 authors was settled by the third author (S.M.). A flow diagram showing study selection procedure is shown in Figure 1.
Prospective observational studies, retrospective analysis, trials conducted in pediatric populations, case reports, case series, animal studies, and studies not reporting on any one of the predefined outcomes were excluded from the analysis. Studies were excluded if the patients were undergoing nonlaparoscopic procedures, or the drugs under study were not administered intravenously.
We collected the required data from the full text of the trials. Initially, all data were tabulated in Microsoft ExcelTM spread sheet. One author (S.M.) initially extracted data from the eligible trials, and those data were cross-checked independently by 2 other authors (A.S. and D.K.B.). Statistical analyses were done by 2 authors (S.M. and A.S.) independently and cross-checked.
The following data were collected from each of the studies: name of the first author, year of publication, incidence of nausea, vomiting, and PONV during the postoperative period at 6 and 24 hours, number of patients requiring a rescue antiemetic, pain intensity at 24 hours, and reported complications.
The quality of eligible trials was assessed using the tool of “risk of bias” according to Review Manager, version 5.2.3 software (RevMan; Cochrane Collaboration, Oxford, UK). Random sequence generation, allocation concealment, blinding, incomplete data, and selective reporting were assessed independently by 2 authors (S.M. and D.K.B.) based on the method of the trials, and each was graded “yes,” “no,” or “unclear,” which reflected a high risk of bias, low risk of bias, and uncertain bias, respectively. Publication bias was assessed by funnel plot and Egger regression test, which is furnished in the Supplemental Digital Content 2 (http://links.lww.com/AA/B524).
Primary outcome of this meta-analysis was the incidence of PONV during the initial 24 postoperative hours. The secondary outcomes were incidence of nausea and vomiting during the postoperative period at 6 and 24 hours, incidence of PONV during the initial 6 hours, number of patients requiring a rescue antiemetic, pain intensity at 24 hours, and reported complications. For continuous outcomes, means and SD values were extracted for both groups, a mean difference was computed at the study level, and a weighted mean difference was computed to pool the results across all studies. If the values were reported as median and an interquartile range or total range of values, the mean value was estimated using the median and the low and high end of the range for samples smaller than 25; for samples greater than 25, the median itself was used. The SD was estimated from the median and the low and high end of the range for samples smaller than 15, as range/4 for samples from 15 to 70, and as range/6 for samples more than 70. If only an interquartile range was available, SD was estimated as interquartile range/1.35.19 For binary outcomes, we calculated the following: (1) the odds ratio (OR) for each trial; (2) the pooled OR using the Mantel-Haenszel method; (3) the number needed to treat (NNT) where a statistical significance was found, that is, the number of patients who must be treated for 1 patient to benefit from the intervention.
Primary outcome was calculated with 95% confidence interval (95% CI), and secondary outcomes with 99% confidence interval (99% CI). The I2 statistic was used to analyze the heterogeneity of trials. As possibility of heterogeneity is high because of different anesthetic techniques used, inverse variance random-effects model was used for analysis even when I2 < 30%. A priori, it was decided that the primary outcome (incidence of PONV during the initial 24 postoperative hours) will be subanalyzed according to specific 5-HT3 antagonists studied, if possible. Pooled analysis was done in RevMan software (Review Manager [computer program]; version 5.3, 2014, The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen). Publication bias was tested by visual inspection of funnel plot, and Egger regression test was performed in Comprehensive Meta-analysis software (version 2.2.034, 2006, Biostat, Englewood, NJ).
The review methodology has been depicted in Figure 1 as per PRISMA guidelines.18 Finally, 17 randomized controlled trials7,11,12,14,20–32 met our inclusion criteria and a total of 1402 adult patients (702 patients in combination group and 700 patients in 5-HT3 receptor antagonist alone group) were included in the meta-analysis and have been summarized in Table 1. There was no disagreement among the authors regarding inclusion of studies.
Risk of Bias Within Studies
All the included studies were randomized. Summary of risk of bias for individual studies is shown in Figure 2.
Characteristics of Individual Studies
Summary of findings from individual studies is provided in Table 1. Nine RCTs11,12,14,21,23,26,28,30,32 studied ondansetron with dexamethasone, whereas granisetron22,29 and ramosetron20,24 were studied by 2 RCTs each. Three RCTs25,27,31 studied palonosetron, and 1 RCT7 studied dolasetron. All studies evaluated an 8-mg dose of dexamethasone, except 3: two7,30 used 4 mg and one21 used 10 mg.
Eleven trials were conducted on patients undergoing laparoscopic cholecystectomy,7,11,12,20,24–26,29–32 2 on laparoscopic bariatric surgery,22,23 1 each on diagnostic laparoscopy,14 laparoscopic tubal ligation,28 laparoscopy-assisted vaginal hysterectomy,21 and outpatient laparoscopic surgery.27
The follow-up period was 6 hours for 2 studies,23,24 24 hours for 10 studies,7,11,12,14,22,24,26,28–30 48 hours for another 4 RCTs,20,21,25,31 and 72 hours for 1 RCT.27
PONV at 24 Hours
Eleven trials7,11,20,22,24–26,28–31 reported the incidence of PONV together up to 24 hours; and the difference was statistically significant in favor of the combination group (OR 0.38, 95% CI 0.27–0.54; I2=0%; NNT = 6.6; n = 951; Figure 3). When the composite end point of PONV is considered, results for specific 5-HT3 antagonists were statistically significant for ondansetron (OR 0.29, 95% CI 0.16–0.53; I2 = 0%; NNT = 5.4; n = 335; 4 RCTs11,26,28,30) and palonosetron (OR 0.22, 95% CI 0.08–0.64; NNT = 6; n = 144; 2 RCTs25,31). Granisetron (OR 0.36, 95% CI 0.12–1.06; I2 = 0%; n = 180; 2 RCTs22,29) and ramosetron (OR 0.52, 95% CI 0.14–1.89; I2 = 61%; n = 152; 2 RCTs20,24) did not show statistically significant results, but the confidence intervals were wide suggesting that our data are insufficient to reach a conclusion regarding this outcome. Only 1 trial7 used dolasetron, results of which favored the combination. Visual inspection of funnel plot revealed asymmetry; however, Egger regression test did not suggest any publication bias (P = .16). Incidences of nausea and vomiting separately up to 24 hours postoperatively were reported by 9 RCTs7,11,14,20,22,25,26,29,31: their pooled analysis showed statistically significant improvement with the combination (nausea: OR 0.31, 99% CI 0.16–0.59; I2 = 0%; NNT = 8.5; n = 742; vomiting: OR 0.35, 99% CI 0.16–0.76; I2 = 0%; NNT = 11.3; n = 742). (Supplemental Digital Content 2, http://links.lww.com/AA/B524.)
PONV at 6 Hours
Five studies11,12,25,26,32 reported incidences of nausea and vomiting separately up to 6 hours in the postoperative period; and pooled analysis shows statistically significant benefit when dexamethasone has been combined with 5-HT3 antagonist rather than the latter alone in terms of prevention of nausea (OR 0.26, 99% CI 0.11–0.66; I2 = 0%; NNT = 8.8; n = 405); however, the pooled data were inconclusive with respect to prevention of vomiting, with a wide confidence interval (OR 0.37, 99% CI 0.12–1.15; I2 = 0%; n = 405). Pooled analysis from 6 trials,11,23,25–27,32 which reported incidence of PONV combined together, did not show statistically significant difference (OR 0.43, 99% CI 0.17–1.09; I2 = 33%; n = 475; Figure 4). Among these 6 trials, 4 studied ondansetron and the other 2 studied palonosetron. (Supplemental Digital Content 2, http://links.lww.com/AA/B524.)
Requirement for a Rescue Antiemetic
Pooled analysis from 6 RCTs11,20,26,29–31 showed the combination was more effective at reducing the requirement for a rescue antiemetic (OR 0.21, 99% CI 0.10–0.46; I2 = 0%; NNT = 6; n = 531), which was statistically significant. (Supplemental Digital Content 2, http://links.lww.com/AA/B524.)
Pain Intensity at 24 Hours
Pain score (reported in visual analog scale, 0–10 in 4 RCTs and in numerical rating scale, 0–100 in 1 RCT,20 which was converted to values in a 0–10 scale) documented at 24 hours, as reported in 5 RCTs,11,20,21,26,31 was lower in the combination group (weighted mean difference −0.67, 99% CI −1.27 to −0.08; I2 = 76%; n = 361) and the difference was statistically significant. (Supplemental Digital Content 2, http://links.lww.com/AA/B524.)
Common drug-related adverse effects that have been reported in the included RCTs are headache, dizziness, fatigue, diarrhea, transient chest pain, pruritus, and heartburn. Only headache and dizziness were reported in a sufficient number of studies so as to allow pooling of data. Their incidences (headache: OR 0.83, 99% CI 0.41 to 1.69; I2 = 0%; n = 762; 9 RCTs11,12,20,23,24,26,29–31 and dizziness: OR 1.10, 99% CI 0.33 to 3.71; I2 = 0%; n = 587; 7 RCTs11,20,23,24,26,29,30) showed no statistically significant difference between the groups, although confidence intervals are wide, suggesting insufficient data. (Supplemental Digital Content 2, http://links.lww.com/AA/B524.)
One of the most common events that delays recovery after laparoscopic surgeries is postoperative nausea and vomiting. Results from our meta-analysis showed that the combination of dexamethasone and a 5-HT3 receptor antagonist, when administered prophylactically, is more effective in preventing PONV than the 5-HT3 antagonist alone, with very little heterogeneity among studies. The need for rescue antiemetic is also decreased in patients receiving the combination, although data are insufficient to detect any significant difference in the incidence of adverse effects. In addition, patients in the combination group reported less pain after 24 hours. However, the benefit is statistically significant only when dexamethasone is used along with ondansetron or palonosetron; definitive conclusions cannot be drawn for granisetron, ramosetron, or dolasetron because the CIs are wide in the absence of adequate number of RCTs.
Numerous RCTs have studied the effects of prophylactic 5-HT3 antagonists on PONV in laparoscopic surgeries and beneficial effect has been confirmed by meta-analysis.33 No specific 5-HT3 antagonist has been found to be better than another until now.34 The effect of dexamethasone has also been studied, and a meta-analysis by Karanicolas et al35 showed that dexamethasone significantly decreases PONV compared with placebo in laparoscopic cholecystectomy with a relative risk (RR) of 0.55. This study also reported the effect of dexamethasone in potentially decreasing postoperative pain.
Shen et al16 compared the effects of ondansetron, dexamethasone, and their combination in pediatric strabismus surgery in a meta-analysis and reported that both drugs were better than placebo in preventing PONV. This meta-analysis also compared ondansetron versus ondansetron and dexamethasone combination from 2 studies and observed that the combination was significantly better than ondansetron alone with a RR of 3.11.
In a meta-analysis by Habib et al,17 the combination of a 5-HT3 antagonist and dexamethasone was found to be better than the 5-HT3 antagonist alone in preventing overall nausea (NNT = 8) and vomiting (NNT = 7). This review included both adult and pediatric populations, as well as different surgical techniques.
Our study corroborates these findings, including a certain analgesic efficacy of dexamethasone. 5-HT3 receptor antagonists exert their effect on 5-HT3 receptors present both peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone of the area postrema.36,37 In contrast, dexamethasone has a central mechanism of action through an activation of the glucocorticoid receptors in the bilateral nuclei tractus solitarii in the medulla38 as well as a noncompetitive direct inhibitory effect on 5-HT3 receptors that is additive to the effects of 5-HT3 antagonists.39 Although 5-HT3 antagonists are quite effective against vomiting, dexamethasone also decreases the incidence of vomiting, but seems to have a more specific effect against nausea.40 This may explain why the combination produces an additive effect.11
The included studies were heterogeneous in many aspects, including different narcotics having been used in different doses and at different timings along with different types of surgeries and induction techniques. But overall, the statistical heterogeneity for the primary as well as most of the secondary outcome measures was minimal.
Finally, although the funnel plot is asymmetric, Egger regression test did not suggest any publication bias (P = .16). So the asymmetry is unlikely to represent publication bias (Figure 5).
There are a few limitations to this study. First, most of the studies did not report the detailed method of allocation concealment, and some of the studies did not mention methods of blinding. Second, some of the RCTs were conducted on relatively small sample sizes. Third, all RCTs did not report the primary or secondary outcomes, thus limiting the statistical power of this study. Fourth, there were an inadequate number of RCTs evaluating specific 5-HT3 antagonists, which precluded any meaningful conclusions from the subgroup analyses. Fifth, some of the RCTs used propofol for induction, whereas others used thiopental. Sixth, although most of the RCTs recorded 5-HT3 antagonist-related common adverse effects, none of them reported steroid related side-effects, for example, wound healing/infection, glycemic control, presence of mania, etc. Since the safety profile of perioperative dexamethasone is still inconclusive,2 this issue should be addressed in future RCTs. Another limitation is that pooled analysis of postoperative analgesic consumption could not be done, because the studies used different rescue analgesics.
In conclusion, combination of a 5-HT3 receptor antagonist and dexamethasone is significantly more effective than a 5-HT3 antagonist alone in preventing PONV after laparoscopic surgeries, with possible improvement in postoperative analgesia.
Name: Anirban Som, MD.
Contribution: This author helped design the study, analyze the data, and write the manuscript.
Name: Sulagna Bhattacharjee, MD, DNB.
Contribution: This author helped design the study and analyze the data.
Name: Souvik Maitra, MD, DNB.
Contribution: This author helped design the study and write the manuscript.
Name: Mahesh K Arora, MD.
Contribution: This author helped conduct the study and write the manuscript.
Name: Dalim Kumar Baidya, MD.
Contribution: This author helped design the study and conduct the study.
This manuscript was handled by: Tong J. Gan, MD.
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