Dexamethasone Reduces Nausea and Vomiting but not Pain after Thyroid Surgery: A Meta-Analysis of Randomized Controlled Trials

Background

Thyroidectomies are one of the most common elective surgical procedures all over the world [1]. After thyroidectomy the incidence of postoperative nausea and vomiting (PONV), which is less than 30% in other surgical interventions [2], is 70–80% when no prophylactic antiemetic therapy is given [3,4]. PONV might be the main source of discomfort after thyroidectomy, and repeated or vigorous vomiting can lead to postoperative bleeding with subsequent airway obstruction and potential need for reparative surgery [5]. Apfel et al. found that patients were more afraid of PONV than postoperative pain, which substantiated the importance of avoiding PONV events [6]. Numerous antiemetics have been studied for the prevention and treatment of PONV following thyroidectomy, including tropisetron and dexamethasone [7,8]. Most published trials indicated improved prophylaxis against PONV by using effective antiemetic therapy in patients scheduled for thyroid surgery [1].

Postoperative pain and PONV are separate outcomes; however, it is well-recognized that pain can result in anxiety, which can be associated with nausea [9]. Interestingly, several studies have also shown that preoperative administration of steroids reduced postoperative pain after oral, orthopedic, spinal, and laparoscopic surgery [10–12].

Dexamethasone, an adrenocortical steroid, is effective in preventing the nausea and vomiting associated with cancer chemotherapy [13,14] and has shown efficacy against postoperative nausea in several studies [15–20]. Previous meta-analyses concluded that dexamethasone prophylactic use of steroids for patients undergoing thyroidectomy was safe and should be considered for routine clinical practice [21]. However, it failed to show the efficacy of dexamethasone on severity of PONV, and the data on pain relief was insufficient. In addition, a recent randomized trial by Barros et al. showed that dexamethasone did not have any effects on incidence of PONV [22]. Hence, the results reported on the use of dexamethasone for patients undergoing thyroidectomy are still variable and controversial. The objective of this study was to perform a meta-analysis to assess the overall effect of dexamethasone on PONV and pain after thyroidectomy.

Material and Methods

DATA SOURCES AND SEARCHES:

The electronic databases screened were PubMed (1990 to February 2014), EMBASE (1990 to February 2014), and the Cochrane Library (Issue 1 of 12, Jan 2014), including the Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts of Reviews of Effects (DARE), and Health Technology Assessments (HTA). The search terms were: “thyroidectomy” or “thyroid surgery” AND “dexamethasone” or “steroid”. Searches were limited to randomized controlled trials in English and were performed for all types of publications. We also screened the references of retrieved articles and contacted the authors to request additional data when key information relevant to the meta-analysis was missing. The full search strategy was developed from PubMed and was adapted for the other electronic databases (Figure 1).

DATA EXTRACTION:

Two of us (BS Lv and W Wang) independently screened the titles and abstracts of potentially eligible studies. The full text articles were examined independently by 2 of us (BS Lv and W Wang) to determine whether they met the inclusion criteria. Two of us (BS Lv and W Wang) independently extracted data (study characteristics and results) using data extraction forms, and then the collected data were entered into RevMan 5.1 using the double-entry system. Point estimates for selected variables were extracted and checked by the other 2 reviewers. All discrepancies were rechecked and consensus was achieved by discussion. A record of reasons for excluding studies was kept. We selected PONV and pain symptoms as outcome measures for dexamethasone therapy. The primary outcome was occurrence and severity of PONV, and the secondary outcomes included pain, use of analgesics, and steroid-related complications. The Jadad test (5 items) [25] was applied for assessing methodological quality as high (score 5), moderate (score 4), or low (scores 1–3).

DATA COLLECTION AND ANALYSIS:

The following data and information were collected:

For all included studies, the main outcome of PONV and pain were scored according to VRS and VAS. Because most outcomes were presented as continuous data (mean value or mean changes), we used the standardized mean difference (SMDs) as effect measures. Because they were determined in different trials using different scales, odds ratio (OR) was used in evaluating incidence of PONV. To calculate SMDs, we used means and change scores and their standard deviations. When these values were shown in a graph without any description of absolute value, we first tried to contact the authors. Measurements from the graph were used if we could not get data from the authors. It was converted into standard deviation only when the standard error was reported.

I2 statistics were used to measure heterogeneity of the RCTs. If the I2 value was less than 50%, a fixed-effects meta-analysis was applied. If the I2 value was 50% or more, the random-effects meta-analysis was used [26]. We used the following descriptors to classify meta-analysis results [27]: “strong” indicated consistent findings in multiple (at least 2) high- or moderate-quality RCTs, “moderate” indicated consistent findings in multiple low-quality RCTs or 1 high- or moderate-quality RCT, “limited” indicated 1 low-quality RCT, and “conflicting” indicated inconsistent findings among multiple RCTs.

Visual assessment of the funnel plot calculated by RevMan Analyses software was used to investigate the potential publication bias (the association of publication probability with the statistical significance of study results). Publication bias may lead to asymmetrical funnel plots [28].

Result

FLOW CHART:

The literature search yielded 1169 citations. Initially, 41 publications met our inclusion criteria. On more detailed review, an additional 30 papers were excluded for the following reasons: unrelated papers, not in English, and combination study. Four more publications were further excluded because of duplicate study and detailed data lacking. The remaining 7 studies met our selection criteria and were included in the meta-analysis [15–20,22] (Figure 1).

INCLUDED STUDIES CHARACTERISTICS:

Table 1 shows the doses of dexamethasone, sample sizes, anesthetic technique, additional drug administration, and Jadad score of the studies. There were 611 study participants in the beginning, of which 361 patients received dexamethasone therapy, and 250 received placebo treatment. Two of 7 studies were conducted in Taiwan and the other 5 were conducted in Japan, Switzerland, Italy, Norway, and Portugal. There were 6 studies with high methodological quality (score 5) and 1 with moderate quality (score 4). The dosage of dexamethasone ranged from 5 mg to 10 mg.

INCIDENCE OF PONV:

According to χ2 test of heterogeneity (I2=66%), a random-effects model was used to evaluate the incidence of PONV. Based on Cohen categories for evaluating the magnitude of effect sizes, there was strong evidence for reducing incidence of PONV in using dexamethasone (SMD, 0.23; 95% CI, 0.13 to 0.41; P<0.00001) (Figure 2).

PONV SEVERITY:

According to χ2 test of heterogeneity (I2=77%), a random-effects model was used to evaluate the severity of PONV. There was strong evidence for a reduction of PONV severity in using dexamethasone (SMD, 0.53; 95% CI, −1.03 to −0.03; P=0.04) (Figure 3), based on Cohen categories for evaluating the magnitude of effect sizes.

PAIN SEVERITY:

According to χ2 test of heterogeneity (I2=97%), a random-effects model was used to evaluate the severity of pain. Based on Cohen categories for evaluating the magnitude of effect sizes, there was no significant difference for a reduction of pain severity in using dexamethasone (SMD, −0.83; 95% CI, −1.85 to 0.18; P=0.14) (Figure 4).

ANALGESIC CONSUMPTION:

According to χ2 test of heterogeneity (I2=59%), a random-effects model was used to evaluate the severity of pain. There was no significant difference in reduction of analgesic consumption in using dexamethasone (SMD, −0.19; 95% CI, −0.43 to 0.04; P=0.10) (Figure 5), based on Cohen categories for evaluating the magnitude of effect sizes.

ADVERSE EVENTS WITH DEXAMETHASONE THERAPY:

No postoperative wound infections or steroid-related adverse events were noted in any of the included studies.

RISK OF BIAS IN INCLUDED STUDIES:

Assessment tables of the risk of bias are presented in Figure 6A and Figure 6B. There was only 1 study, by Fujii et al., with moderate quality (score 4) because of the unclear reporting bias [17]. Sensitivity analysis was applied by excluding the study of Fujii et al. Based on Cohen categories for evaluating the magnitude of effect sizes, there was strong evidence for reducing incidence of PONV in using dexamethasone (SMD, 0.22; 95% CI, 0.12 to 0.43; P<0.00001) (Figure 7).

Discussion

LIMITATION:

Our meta-analysis has several limitations. First, there was significant heterogeneity in the results for the incidence and severity of PONV, as well as pain severity. Because of the small size effect and limited number of included studies, we did not apply a further layer of analysis and only performed the random-effects model analysis. Secondly, some statistical methods used in our study may be limited, such as using I2 to assess the amount of heterogeneity in random-effects meta-analysis [37] and visual assessment of the funnel plot for excluding publication bias. Thirdly, although we made our best effort to get the full text of all published studies, there were still some studies that were not included in our meta-analysis due to the lack of detailed data.

Conclusions

This systematic review and meta-analysis suggests the following: i) A single preoperative administration of dexamethasone in patients undergoing thyroidectomy is safe and reduces the incidence and severity of PONV; ii) Pain severity and analgesic consumption cannot be reduced by a single preoperative administration of dexamethasone; and iii) The effect of different dosage of dexamethasone is unclear, so further studies with a larger sample size using a higher dexamethasone dose are needed to analyze its beneficial effect on postoperative pain severity and analgesic consumption.