Efficacy and Safety of Dexmedetomidine Premedication in Balanced Anesthesia: A Systematic Review and Meta-Analysis in Dogs

Simple Summary Dexmedetomidine, on account of its potent sedative and analgesic properties, is commonly used in balanced anesthesia of small animal anesthesia; however, concerns regarding its cardiovascular effects prevent its full adoption into veterinary clinical practice. We conducted this meta-analysis to determine the effects of dexmedetomidine on sedation, analgesia, cardiovascular and adverse reactions in dogs compared to other premedications. The outcomes included sedation score, pain score, heart rate, systolic arterial blood pressure, mean arterial blood pressure and the incidence of adverse effects. Thirteen studies were included in this meta-analysis. The results showed that dexmedetomidine provides a satisfactory sedative and analgesic effect in balanced anesthesia of dogs. After dexmedetomidine premedication, dogs experienced lower heart rate and higher blood pressure within an acceptable range. The combinations in balanced anesthesia and routes of delivering drugs would affect heart rate, systolic arterial blood pressure, and mean arterial blood pressure of dogs. Before using dexmedetomidine, an animal’s cardiovascular status should be fully considered. Abstract Dexmedetomidine is commonly used in small animal anesthesia for its potent sedative and analgesic properties; however, concerns regarding its cardiovascular effects prevent its full adoption into veterinary clinical practice. This meta-analysis was to determine the effects of dexmedetomidine on sedation, analgesia, cardiovascular and adverse reactions in dogs compared to other premedications. Following the study protocol based on the Cochrane Review Methods, thirteen studies were included in this meta-analysis ultimately, involving a total of 576 dogs. Dexmedetomidine administration probably improved in sedation and analgesia in comparison to acepromazine, ketamine and lidocaine (MD: 1.96, 95% CI: [−0.08, 4.00], p = 0.06; MD: −0.95, 95% CI: [−1.52, −0.37] p = 0.001; respectively). Hemodynamic outcomes showed that dogs probably experienced lower heart rate and higher systolic arterial blood pressure and mean arterial blood pressure with dexmedetomidine at 30 min after premedication (MD: −13.25, 95% CI: [−19.67, −6.81], p < 0.0001; MD: 7.78, 95% CI: [1.83, 13.74], p = 0.01; MD: 8.32, 95% CI: [3.95, 12.70], p = 0.0002; respectively). The incidence of adverse effects was comparable between dexmedetomidine and other premedications (RR = 0.86, 95% CI [0.58, 1.29], p = 0.47). In summary, dexmedetomidine provides satisfactory sedative and analgesic effects, and its safety is proved despite its significant hemodynamic effects as part of balanced anesthesia of dogs.


Introduction
Dexmedetomidine, a highly selective α-2 receptor agonist with potent sedative and analgesic properties, is commonly used as premedication in balanced anesthesia in small

Literature Search Strategy
This meta-analysis was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Cochrane Review Methods [12]. We searched electronic databases PubMed and CAB Abstracts up to March 2021, and the following search terms were applied: (dog OR "dogs" [Mesh] OR canine *) AND ("dexmedetomidine" [Mesh] OR MPV-1440 OR MPV 1440 OR MPV1440 OR precedex) AND (sedation OR pain OR "analgesia" [Mesh] OR "anesthesia" [Mesh] OR balanced anesthesia OR cardiovascular OR "hemodynamics" [Mesh] OR circulatory OR heart rate OR blood pressure) AND (safety OR safe OR adverse effect * OR effect * OR undesirable effect * OR tolerability OR toxicity OR reaction * OR disease *). A filter of clinical trials was applied to the results. No language restrictions were placed on the search. Finally, the references of all articles retrieved from the search were manually reviewed and Google Scholar was queried for any relevant trials not already identified using the strategy described above.

Outcomes
Trials comparing dexmedetomidine to sedative or analgesic in premedication, investigating sedation and pain outcomes in balanced anesthesia of dogs were included in the present meta-analysis. Extracted outcomes were selected according to the standard approach described in some meta-analysis of dexmedetomidine premedication in humans [13][14][15][16]. The primary outcomes were sedation score and pain score after premedication. The sedation score was performed using a composite simple descriptive score after dexmedetomidine administration. Full consciousness and alertness were scored as 0 and unconsciousness as 20. If the score scales were different in some studies, the data were converted according to the scoring standard used by Grint and others [17]. The pain score was performed at 120 min after the dexmedetomidine premedication, when the operation was nearly ended. Perioperative pain score was evaluated according to the short form of Glasgow composite pain score (GCPS) [18]. The maximum pain score was achieved with 24 points. Secondary outcomes were hemodynamic changes, including heart rate (HR), systolic arterial blood pressure (SAP) and mean arterial blood pressure (MAP) at time points of 30 and 60 min after premedication. At this time, the animal was generally under operation in a stable state. We were also interested in the adverse effects, including the incidence of arrhythmia, apnea and rescue analgesia. Extracted trial characteristics included pre-medication of each group, the number of dogs, doses and the route of drug delivery, the medications used to induce or maintain anesthesia and other administration. We used the Cochrane Collaboration's Risk of Bias Tool (ROB 2) for randomized controlled trials to assess the methodological quality of these randomized trials [19]. Two authors (S.-Y.P. and G.L.) independently scored the bias, which considers the methods of random sequence generation, allocation concealment, blinding of participants and outcome assessment, incomplete reporting of outcome data, selective reporting and other bias risks, such as special study design. Disagreements were resolved through discussion with a third author (J.-H.L.).

Certainty of Evidence
The Grade of Recommendation, Assessment, Development and Evaluation (GRADE) Working Group system was used to assess the certainty of evidence for each outcome [20].

Data Extraction and Analysis
The study protocol was determined before data extraction and archived in the College of Veterinary Medicine, China Agricultural University. We set premedication with dexmedetomidine as the dexmedetomidine group no matter what the dose or route of administration used. Meanwhile, premedication with other drugs was considered as the comparisons, no matter which drug was used. Following the Cochrane Collaboration Risk of Bias tool, we assessed the included studies.
The outcome variables were the incidence or mean differences between groups. In some studies, the numerical data were extracted from graphs by "WebPlotDigitizer" (online source) [21]. According to the method of Shi J. and Luo D. et al. [22,23], we converted the median, quartile and range into mean and standard deviation before analyzing. All statistical analyses were conducted using the Review Manager software (RevMan version 5.4). The heterogeneity was evaluated by the coefficient I 2 [24]. If the I 2 statistic had a value of more than 50%, which presents moderate or high heterogeneity, the random-effects model was used. Otherwise, the fixed-effects model was applied [25].
A subgroup analysis was utilized according to the time points after premedication in an attempt to evaluate how the effect changed over time. In addition, a subgroup analysis was conducted according to the classification of the comparator. The effects caused by routes of administration and the combination of induction agent were also considered. Funnel plots were used to evaluate the risk of publication bias for the outcomes of the studies included. A sensitivity analysis was conducted to assess whether the studies caused high heterogeneity could affect the results. The results were presented as mean difference (MD) for continuous data or risk ratio (RR) for binary variables with 95% confidence interval (CI). A two-sided value of p < 0.05 was considered significant.
One study disclosed losses to follow-up without analyses were assessed as unclear risk of incomplete outcome data [27].

Pain Score
The pain assessment was reported in three studies [26,33,34].

Secondary Outcomes
Eight studies reported the hemodynamic indicators [17,26,27,[29][30][31][32]37]. All hemodynamic outcomes were influenced by dexmedetomidine. Due to the high heterogeneity, a subgroup analysis of HR, SAP and MAP at a time point of 30 min after premedication was conducted according to the classification of the comparator. The "α-2 receptor agonists" group included studies used medetomidine, xylazine and detomidine as comparator. The "Opioids" group included studies used morphine, methadone, fentanyl, butorphanol and pethidine as comparator. The "Others" group included studies used acepromazine, ketamine and lidocaine as comparator. A sensitivity analysis was conducted to address the heterogeneity.

Safety Outcome
Three studies were included in this session [27,33,34]. There was no difference between dexmedetomidine, morphine, acepromazine, fentanyl, ketamine, lidocaine and butorphanol in regard of adverse events such as apnea, arrhythmias and requirement of rescue analgesia (Moderate CoE; RR = 0.86; 95% CI [0.58, 1.29]; I 2 : 6%; p = 0.47; Figure 8). A sensitivity analysis of each outcome was performed. The results showed that none of the studies strongly influenced the outcomes.
The funnel plot of each outcome is shown in Figure 9. The funnel plot of each outcome is shown in Figure 9. The summary of findings is presented in Table 2. The summary of findings is presented in Table 2.

Discussion
Based on the result of the meta-analysis of 13 randomized controlled trials (RCTs) with 576 dogs of various breeds, the sedative effect of dexmedetomidine was better than that of acepromazine, ketamine, lidocaine and butorphanol, but inferior to that of pethidine, fentanyl and medetomidine in balanced anesthesia of dogs. Its analgesic effect was better than acepromazine, ketamine and lidocaine but not to the level of opioids. Notably, the comparisons above on the sedative and analgesic effects could be influenced by the dosage, the type and dosage of the combinations, the route of administration and the type of surgery. In small animal clinical medicine, dexmedetomidine is commonly used because it can significantly decrease the MAC of inhaled anesthetics. To increase analgesia, dexmedetomidine can be used in conjunction with opioids. Lower doses of morphine combined with dexmedetomidine may provide analgesia equivalent to or better than a higher dose of morphine alone [38].
After subgroup analysis of HR, SAP and MAP according to the classification of the comparator, the heterogeneity within some subgroups was still high. This could be owing to the inconsistent results of the effects of other drugs compared to dexmedetomidine. For example, fentanyl had a stronger effect on lowering HR and SAP of dogs than dexmedetomidine, while dexmedetomidine can decrease the HR and SAP of dogs better than methadone. Even if the same drug was used, the results were significantly different due to the difference in dosage and route of administration, which contributed to high heterogeneity. More research that meets the criteria is warranted. According to the sensitivity analysis, the results of HR and SAP would not change when studies were excluded that increased heterogeneity.
Intriguingly, although the animals in the dexmedetomidine group experienced low HR 30 and 60 min after premedication, the studies assessed suggested that the HR of dogs did not decrease significantly combined with propofol. Propofol is a short-acting intravenous anesthetic that can be used to produce sedation, as well as to induce and maintain anesthesia. The literature showed that HR of dogs after propofol induction was significantly higher, while the MAP was significantly lower [39]. It was reported that blood pressure can remained within an acceptable range in dogs given dexmedetomidine and anesthetized with propofol [8]. This could account for the drug-drug interaction that dexmedetomidine might inhibit the metabolism of propofol and improve the cardiovascular indicators of animals. Moreover, sedation with dexmedetomidine and induction with propofol can prolong the period of anesthesia and reduce the amount of all components in balanced anesthesia.
Additionally, the routes of administration influenced the effect of dexmedetomidine on hemodynamics. The blood pressure increased caused by dexmedetomidine was due to the activation of α-1 and α-2 adrenergic receptors in the vascular endothelium to produce extensive vasoconstriction [4]. In terms of pharmacokinetics, the absorption and distribution of the drug after extravascular administration are not as fast as intravenous injection [40]. Theoretically, intramuscular or other routes of administration can slow down the diffusion of the drug to the vascular endothelium, which can reduce the cardiovascular effects. A recent study suggested that oral transmucosal administration of dexmedetomidine and methadone combination provided a satisfactory level of sedation with less pronounced cardiorespiratory effects, which could be considered as a useful option for those dogs whose cardiovascular stability should be preserved [41].
As for the safety, dogs experienced lower HR and higher SAP and MAP with dexmedetomidine at 30 min after premedication; however, none needed treatment for bradycardia and hypertension [42]. Using low doses of atipamezole was an approach for treating dexmedetomidine-induced bradycardia in general anesthesia, which may also reduce arterial blood pressure via α-2 adrenoceptor blockade [43,44]. For the most part, dexmedetomidine is safe and effective for small animals with ASA 1 and ASA 2 physical status, as well as some irritable animals and even wildlife.
There were several limitations to this meta-analysis. Firstly, this meta-analysis used only HR and blood pressure as cardiovascular indicators, while it would be more comprehensive to include right atrial pressure, mean pulmonary artery pressure, cardiac index, stroke volume index, stroke vascular resistance index and other parameters [45]. Secondly, it is difficult to conduct a more detailed subgroup analysis, because there are many drugs used in balanced anesthesia, which would affect the validity of the results. In addition, some included trials had many groups with a small sample size, which decreased the statistical power within these studies [46]. Thirdly, the heterogeneity of this study was high, even if a subgroup analysis was conducted. It may be related to the dosage, type and dosage of the combinations, route of administration and type of surgery in the studies. Finally, the insufficient data related to adverse events demonstrated the need of more RCTs. Although the included studies were all RCTs, some of them did not entirely blind participants/personnel/outcome assessment due to safety concerns, increasing the risk of performance and detection bias. Therefore, well-controlled randomized studies are warranted.

Conclusions
In conclusion, this meta-analysis found that dexmedetomidine provides a satisfactory sedative and analgesic effect in balanced anesthesia of dogs. After dexmedetomidine premedication, dogs experienced lower heart rate and higher blood pressure within an acceptable range. No difference was detected between dexmedetomidine and other premedications regarding adverse events such as apnea, arrhythmias and the requirement of rescue analgesia.
Supplementary Materials: The following are available online at https://www.mdpi.com/article/10 .3390/ani11113254/s1, Figure S1: Forest plot of HR at 60 min after premedication between dexmedetomidine and control group in balanced anesthesia, Figure S2 Forest plot of SAP at 60 min after premedication between dexmedetomidine and control group in balanced anesthesia, Figure S3: Forest plot of MAP at 60 min after premedication between dexmedetomidine and control group in balanced anesthesia, Figure S4: Funnel plot of HR at 60 min after premedication between dexmedetomidine and control group in balanced anesthesia, Figure S5: Funnel plot of SAP at 60 min after premedication between dexmedetomidine and control group in balanced anesthesia. Figure S6: Funnel plot of MAP at 60 min after premedication between dexmedetomidine and control group in balanced anesthesia.

Data Availability Statement:
The data presented in this study can be made available on direct request to the corresponding author.