Effect of Dexmedetomidine For Thoracoscopic Surgery: A Meta-analysis of Randomized Controlled Trials

Introduction: The ecacy of dexmedetomidine for thoracoscopic surgery remains controversial. We conduct a systematic review and meta-analysis to explore the impact of dexmedetomidine for thoracoscopic surgery. Methods: We have searched PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases through September 2020 for randomized controlled trials (RCTs) assessing the effect of dexmedetomidine on thoracoscopic surgery. This meta-analysis is performed using the random-effect model. Results: Six RCTs involving 510 patients are included in the meta-analysis. Overall, compared with control group for thoracoscopic surgery, dexmedetomidine results in signicantly reduced pain scores (SMD=-1.50; 95% CI=-2.63 to -0.37; P=0.009), anesthetic consumption (SMD=-3.91; 95% CI=-6.76 to -1.05; P=0.007), mean heart rate (SMD=-0.41; 95% CI=-0.65 to -0.18; P=0.0007), and the number of ICU stay (RR=0.39; 95% CI=0.19 to 0.80; P=0.01), but showed no obvious effect on mean blood pressure (SMD=-0.07; 95% CI=-0.45 to 0.31; P=0.72) or hospital stay (SMD=-0.61; 95% CI=-1.30 to 0.08; P=0.08). Conclusions: Dexmedetomidine supplementation can substantially improve the analgesic ecacy for thoracoscopic surgery.


Introduction
Thoracoscopic surgery is widely used to treat various diseases such as esophageal cancer and lung cancer. It results the smaller incision, less pain and in ammatory response, reduced recovery times compared to traditional surgery [1][2][3]. The pain commonly occurs after the surgery, and negatively affects the postoperative recovery. Various analgesic regimens have developed for the pain management after thoracoscopic surgery, and they mainly include pharmacologic and regional interventions (e.g. nerve block) [4][5][6][7].
Dexmedetomidine, a short-acting α2 -adrenoceptor agonist, is reported to provide the sedation and analgesia for various surgeries [8,9]. Studies demonstrated that dexmedetomidine attenuated surgical stress responses in patients undergoing surgery, and is effective and safe to improve the analgesic e cacy when serving as an adjunctive analgesic [10,11]. Previous trials demonstrated that dexmedetomidine had opioid-sparing properties, maximized pain relief and minimized analgesic-related side effects [12][13][14].
However, the e cacy of dexmedetomidine supplementation for thoracoscopic surgery has not been well established. Recently, several studies on the topic have been published, and the results were con icting [7,[15][16][17]. With accumulating evidence, we therefore perform a systematic review and meta-analysis of RCTs to investigate the analgesic e cacy of dexmedetomidine supplementation for thoracoscopic surgery.

Materials And Methods
Ethical approval and patient consent are not required because this is a systematic review and meta-analysis of previously published studies. The systematic review and meta-analysis are conducted and reported in adherence to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) [18].

Search strategy and study selection
Two investigators have independently searched the following databases (inception to September 2020): PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases. The electronic search strategy was conducted using the following keywords: "dexmedetomidine", and "thoracoscopic" or "thoracoscopy". We also check the reference lists of the screened full-text studies to identify other potentially eligible trials.
The inclusive selection criteria are as follows: (i) patients underwent thoracoscopic surgery; (ii) intervention treatments were intravenous dexmedetomidine versus placebo; (iii) study design was RCT.

Data extraction and outcome measures
We have extracted the following information: author, number of patients, age, male, body mass index, American Society of Anesthesiologists (ASA) and detail methods in each group etc. Data were extracted independently by two investigators, and discrepancies are resolved by consensus. We also contacted the corresponding author to obtain the data when necessary.
The primary outcome was pain scores. Secondary outcomes included analgesic consumption, mean heart rate and blood pressure, ICU stay, and hospital stay.

Quality assessment in individual studies
Methodological quality of the included studies is independently evaluated using the modi ed Jadad scale [19]. There are 3 items for Jadad scale: randomization (0-2 points), blinding (0-2 points), dropouts and withdrawals (0-1 points). The score of Jadad Scale varies from 0 to 5 points. An article with Jadad score≤2 is considered to be of low quality. If the Jadad score≥3, the study is thought to be of high quality [20].

Statistical analysis
We estimate the standard mean difference (SMD) with 95% con dence interval (CI) for continuous outcomes (pain scores, analgesic consumption, mean heart rate and blood pressure, and hospital stay) and relative risk (RR) with 95% CI for dichotomous outcomes (ICU stay). The random-effects model was used regardless of heterogeneity. Heterogeneity was reported using the I 2 statistic, and I 2 > 50% indicated signi cant heterogeneity [21]. Whenever signi cant heterogeneity was present, we searched for potential sources of heterogeneity via omitting one study in turn for the meta-analysis or performing subgroup analysis. Publication bias was not evaluated because of the limited number (<10) of included studies. All statistical analyses were performed using Review Manager Version 5.3 (The Cochrane Collaboration, Software Update, Oxford, UK).

Results
Literature search, study characteristics and quality assessment A detailed owchart of the search and selection results was shown in Figure 1. 239 potentially relevant articles are identi ed initially. Finally, six RCTs that meet our inclusion criteria are included in the meta-analysis [7, 15-17, 22, 23].
The baseline characteristics of the six eligible RCTs in the meta-analysis were summarized in Table 1. The six studies were published between 2016 and 2020, and the total sample size was 510. Dexmedetomidine was used before the anesthesia [7,15,22,23], or during surgery [16,17].
Among the six studies included here, three studies reported pain scores [15,16,22], three studies reported analgesic consumption [7,16,22], four studies reported mean heart rate and blood pressure [7,15,17,22], three studies reported ICU stay [15,17,23], and three studies reported hospital stay [17,22,23]. Jadad scores of the six included studies vary from 3 to 5, and all six studies are considered to be high-quality ones according to quality assessment.
Primary outcome: pain scores This outcome data was analyzed with the random-effects model, and the pooled estimate of the three included RCTs suggested that compared to control group for thoracoscopic surgery, dexmedetomidine was associated with signi cantly reduced pain scores (SMD=-1.50; 95% CI=-2.63 to -0.37; P=0.009), with signi cant heterogeneity among the studies (I 2 =95%, heterogeneity P<0.00001) (Figure 2).

Sensitivity analysis
Signi cant heterogeneity is observed among the included studies for the primary outcomes, but there is still signi cant heterogeneity after when performing sensitivity analysis via omitting one study in turn to detect the heterogeneity.

Discussion
Thoracoscopic surgery has been widely used to treat lung cancer because of its minimally invasion, less postoperative pain and shortened hospital stay compared with open thoracotomy [24]. Postoperative pain management, particularly early postoperative pain, still remains a matter of concern for many anesthesiologists and these patients [25,26]. Opioids are essential during surgery, and many methods are developed to reduce opioid consumption due to the side effects such as delayed recovery from general anesthesia, opioid-induced nausea, and respiratory depression [27,28].
Intraoperative dexmedetomidine was reported to improve the effects of postoperative analgesia [29][30][31]. It showed analgesic, sedative and anxiolytic effects, and avoided respiratory depression and the inhibitory effect of sympathetic stimulation as an adjunct to general anesthesia [8]. Our meta-analysis included six RCTs and 510 patients. The results revealed that intravenous dexmedetomidine was associated with substantially reduced pain scores, anesthetic consumption, the number of ICU stay and mean heart rate after thoracoscopic surgery, but showed no obvious in uence on mean blood pressure or hospital stay.
In addition, dexmedetomidine bene ted to maintain the stability of the cardiovascular system and decrease the stress response [10]. Intraoperative infusion of dexmedetomidine decreased both norepinephrine and epinephrine. Dexmedetomidine can decrease the release of catecholamines and has analgesic, anxiolytic, and hypnotic effects [32]. Regarding the sensitivity analysis, there is signi cant heterogeneity. Several reasons may account for the heterogeneity. Firstly, different doses and methods of dexmedetomidine supplementation may produce some bias. For instance, Dexmedetomidine was used before the anesthesia [7,15,22,23] or during surgery [16,17]. Secondly, dexmedetomidine was applied as the adjunct to different drugs such as oxycodone and sevoflurane, which may result in various analgesic effect. Thirdly, different operation procedures produces various pain intensity, which may affect the pooling results.
This meta-analysis has several potential limitations. Firstly, our analysis is based on only six RCTs, and three of them have a relatively small sample size (n<100). Overestimation of the treatment effect was more likely in smaller trials compared with larger samples. Next, the doses, methods and combination of anesthetic drugs in included RCTs are different, which may have an in uence on the pooling results. Finally, thoracoscopic surgeries are performed for various diseases and operation procedures.

Conclusions
Dexmedetomidine bene ts to improve the analgesic e cacy for thoracoscopic surgery.  Flow diagram of study searching and selection process.

Figure 2
Forest plot for the meta-analysis of pain scores.

Figure 3
Forest plot for the meta-analysis of analgesic consumption.

Figure 4
Forest plot for the meta-analysis of mean heart rate.

Figure 5
Forest plot for the meta-analysis of mean blood pressure.

Figure 6
Forest plot for the meta-analysis of ICU stay. Forest plot for the meta-analysis of hospital stay.