Meta-analysis of the effects of dexmedetomidine vs esmolol for used controlled hypotension during surgery

Background: At present ,the anesthetist usally use Controlled hypotension tecnical reduced blood loss and improved surgical eld. Dexmedetomidine and esmolol have been proved effective for controlled hypotension. This meta-analysis aimed to evaluate the effects of dexmedetomidine versus esmolol on the controlled hypotension during surgery. Methods: All articles were retrieved from PubMed, Embase, Cochrane Library up to January 2020. JL and HD independently screened, extracted and evaluated the literature that meet the inclusion and exclusion criteria, and used RevMan 5.3 for statistic analysis. Results: Eight randomised trials, including 418 patients were selected in this meta-anaysis. And it’s results showed:1) The dexmedetomidine group was more favorable in reducing blood loss (MD 49.48 with 95% CI [-5.44,104.40], P =0.08 (cid:0) ;2 (cid:0) Compared with the esmolol group (cid:0) HR (cid:0) MD 3.30 with 95% CI [2.11,4.50], P <0.00001 (cid:0) ,requiring of fentany(SMD 5.96 with 95% CI [3.43,8.48], P <0.00001 (cid:0) were considerably lower in the dexmedetomidine group (cid:0) while emergence time (cid:0) MD -6.69 with 95% CI [-9.61,-3.76], P <0.0001)was more longer in the dexmedetomidine group . 3 (cid:0) Compared with the esmolol group (cid:0) duration of surgery (cid:0) MD -0.12 with 95% CI [-6.24,6.01], P = 0.97 (cid:0)(cid:0) MAP (cid:0) MD 2.29 with 95% CI [-2.02,6.60],P =0.30 (cid:0)(cid:0) the recovery period (cid:0) MD -0.52 with 95% CI [-3.07,2.04],


Background
Controlled hypotension is the effectives method to reduce intraoperative bleeding.Nevertheless, both procedure and patients pathology can increase arterial blood pressure that give rise to excessive blood loss and adverse outcomes [1]. Intra-operative bleeding is associated with poor surgical eld visibility, and increased surgical time for various surgery .Many drugs have been developed to limit blood loss during surgery. But these interventions are reported some adverse effects.Therefore, we remains to determine an ideal intervention to provide controlled hypotension.
Dexmedetomidine (a potent and highly selective 2 -adrenergic agonist) has many effecs: sedation, analgesia ,anesthesia, and sympatholytic properties. Alpha-2 adrenergic agonists can reduces sympathetic tone that results in a lower HR, blood pressure, and hemodynamic response. That drop of blood pressure are caused by the inhibited out ow of central sympathetic or the decreased norepinephrine release of presynaptic [2]. Esmolol ( a short-acting b-blocker) can effectively lower heart rate and blood pressure, resulting in controlled perioperative stress response.The fall of blood pressure are because the reduced cardiac output due to negative chronotropic or the ionotropic effects ofβ-adrenergic was blocked. Esmolol can win a stable controlled hypotension ,and bene cial for surgery and blood conservation [3].
Although many studies have con rmed that the above two drugs have signi cant clinical effects on intraoperative controlled hypotension [4,5], no systematic study has been founded to compare the e cacy of the two drugs.Therefore, this literature systematically reviews the available evidence and compares the two drugs in the control of hypotension.

Search strategy
Two reviewers (JL, HD) independently searched and retrieved relevant studies from PubMed, EMBASE, and the Cochrane Library up to January, 2020. No language or publication status restrictions were applied,and the study was limited to human. Noteexpress 3.0 was used to merge and remove duplicate documents.

Inclusion and exclusion criteria
Patients.Adult patients who have received general anesthesia and used dexmedetomidine or esmolol as hypotensive drug were required in this study. Experiment and control. Trial groups: dexmedetomidine;control groups:esmolol Outcome indicators. Anticipated indicators included blood loss,Mean arterial pressure(MAP), Heart rate(HR), duration of surgery, requiring of fentanyl, and the recovery period (The time required to reach Aldrete score > 9) [6] and emergence time [7](the interval between discontinuation of the anesthetics to response of eye opening to the verbal command).
Studies. The literature eligible for inclusion in this study should be randomized controlled trial. animal studies, reviews, case reports, or protocols were eliminated. Data Extraction and Quality Assessment J. Li and H. Deng separate review these studys for data that meet the inclusion and exclusion criteria.
After scanned, two reviewers cross-checked the data.and resolved disagreements through discussion or the third author.The Cochrane Handbook for Systematic Reviews of Interventions was used to scan each study for methodological quality. Evaluation contents included: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other bias. These categories include : low risk of bias, unclear of bias and high risk of bias.

Statistical Analysis
We choose RevMan 5.3 for this meta-analysis. The mean difference (MD) or standard error of the mean (SEM) and 95% con dence interval (CI) were described for the continuous data, and the risk ratio (RR) ,95% con dence interval (CI) for the numerical data. Follow the Cochrane guidelines, I 2 test was used for quantitative heterogeneity, and I 2 ≥ 50% means signi cant heterogeneity.When the results had no signi cant heterogeneity, the xed effect model was applied for this system review.Otherwise the random effect model was used. And p < 0.05 was speci ed as signi cance level.

Meta-Analysis Results
Blooding loss A total of there RCTs were included in the study, involving 110 patients,which compared intraoperative blood loss of dexmedetomidine and esmolol .The random effects model was used because of the high heterogeneity (I 2 = 92%).The results indicated that there was no signi cant difference between the two group in reducing intraoperative blood loss (MD 49.48 with 95% CI [-5.44,104.40], P = 0.08). The result is shown in Fig. 4 HR A total of four RCTs were included in the study, involving 230 patients, which compared HR of dexmedetomidine and esmolol. The xed effects model was applied because of signi cant heterogeneity (I2 = 34%). The results indicated that there was signi cant difference between the two group in HR. (MD 3.30 with 95% CI [2.11,4.50],P < 0.00001,I2 = 34%).The result is shown in Fig. 5 MAP A total of four RCTs were included in the study, involving 230 patients, which compared HR of dexmedetomidine and esmolol. The randomed effects model was applied because of higher heterogeneity (I2 = 95%). The results showed that there was no signi cant difference between the two group in MAP. (MD 2.29 with 95% CI [-2.02,6.60], I2 = 95%,P = 0.30) .The result is shown in Fig. 6.

Duration of surgery
All seven RCTs involving 338 patients was included. The heterogeneity test(I 2 = 56%) indicates that heterogeneity was existence between the selected literatures in this study, and the randomed effect was applied for meta analysis. The results indicated that there was no signi cant difference in duration of surgery between the esmolol group and the dexmedetomidine group (MD -0.12 with 95% CI [-6.24,6.01], P = 0.97). The result is shown in Fig. 7 Requiring of fentanyl All ve RCTS involving 278 patients were included.The heterogeneity test(I 2 = 96%) indicates that heterogeneity was existence between the selected literatures in this study, and the randomed effect was selected for meta analysis.The results indicated that the dexmedetomidine group required less fentanyl than the esmolol group. (SMD 5.96 with 95% CI [3.43,8.48], P < 0.00001). The result is shown in Fig. 8 Recovery period Three RCTs involving 148 patients were included. The heterogeneity test(I 2 = 87%) indicates that heterogeneity was existence between the selected literatures in this study, and the randomed effect was selected for meta analysis.The results of meta analysis indicated that the difference in the recovery period was not signi cant in two group. (MD -0.52 with 95% CI [-3.07,2.04], P = 0.69, I2 = 87%).The results are shown in Fig. 9.

Emergence time
Three RCTs involving 188 patients was included. The heterogeneity test(I 2 = 95%) indicates that heterogeneity was existence between the selected literatures in this study, and the randomed effect was selected for meta analysis.The results of meta analysis indicated that the interval between discontinuation of the anesthetics to response of eye opening to the verbal command in the esmolol group was more shorter than dexmedetomidine group.(MD -6.69 with 95% CI [-9.61,-3.76], P < 0.0001), I2 = 95%). The results are shown in Fig. 10.

Discussion
Deliberate hypotension is an important method to reduce intraoperative bleeding and maintain the perfusion of vital organs.The reduction of bleeding at the surgical site improves the quality of surgical eld, reduces the number of operations and the occurrence of adverse reactions, and shorten the operation time [16,17].This is the underlying concept for controlled hypotensive anesthesia [18],which is frequently used in neurosurgery, orthopaedic surgery, lumbar spine surgeries and middle ear and nose surgery [19,20]. A variety of hypotensive drugs included sodium nitroprusside,volatile anaesthetics, nitroglycerin, adenosine, sympathetic antagonists, hydralazine, trimethaphan,fenoldopam and α2 agonists have been applied to achieve controlled hypotension. These drugs have adverse effects [21] such as resistance to vasodilators, a longer post-sensory recovery period, cyanide toxicity, and the possibility of myocardial inhibition, which often limited the use in controlled hypotension.
The result of dexmedetomidine and esmolol in reducing blood loss of surgical site indicated the difference between two groups in reducing blood loss was not signi cant, but the outcomes indicated that dexmedetomidine group showed better reduction of bleeding. It may be resulted from two main reason: on the one hand,previous studies demonstrated that hemodynamic control and peripheral vasoconstriction of dexmedetomidine can reduce intraoperative bleeding and improve the operative eld of vision;On the other hand,relevant studies [5] have shown that reduced the HR can signi cantly improve the eld of vision in the operative area, rather than reduced the MAP to a dangerously low level and affected the perfusion of vital organs.In our study,compared with esmolol, HR was lower in the dexmedetomidine group,while MAP was not signi cant difference. The results were consistent with our study description of the advantages of dexmedetomidine in reducing blood loss.
The effect of the two drugs on the duration of surgery showed no signi cant difference between the two groups. In addition,this study has found dexmedetomidine can decrease the necessity of fentanyl administration during operation. This can be due to sedative, analgesic and anaesthetic sparing effects, and sympatholytic properties of dexmedetomidine [22].
In our study,we used two approach to assesse objectively the quality of postoperative recovery ,including recovery period and emergence time. The recovery period of patients were reported in all three studies,and the outcome from analysis indicated the recovery condition was not signi cant in two group.But form the result of emergence time,it was observed that patients receiveing dexmedetomidine needed longer time to response of eye opening to the verbal command.It could be explained that dexmedetomidine selectively binds to alpha-2adrenergic receptor with greater a nity ,and it need to take longer time to restoration when the drug diffuses out of its receptors.
Finally, the limitations of this study need to be taken into account.Although we conduct a comprehensive retrieval from the two aspects of retrieval strategy and retrieval database to the greatest extent, the sample size of this study was still insu cient.In addition, we did not conduct further subgroup analysis of surgical types to avoid heterogeneity in our meta-analysis.The next work is to further compare the adverse effects of two drugs in the perioperative period.To sum up, in order to ensure the reliability of the research conclusion, large sample size and more high-quality evidence is needed in the following work.

Conclusion
Both esmolol and dexmedetomidine was effective for controlled hypotension, but compared with esmolol, dexmedetomidine is more better in reducing blood loss, and less requiring of fentanyl.But The risk of bias assessment of the included trials.

Figure 2
The risk of bias summary of the included trials. The effects of dexmedetomidine and esmolol in HR Figure 5 The effects of dexmedetomidine and esmolol in MAP Figure 6 The effects of dexmedetomidine and esmolol in duration of surgery Page 12/13 Figure 7 The effects of dexmedetomidine and esmolol in requiring of fentanyl Figure 8 The effects of dexmedetomidine and esmolol in the recovery period The effects of dexmedetomidine and esmolol in emergence time