Efficacy and safety of dexmedetomidine in patients receiving mechanical ventilation: Evidence from randomized controlled trials

Abstract At present, the efficacy and safety of dexmedetomidine in patients receiving mechanical ventilation (MV) is still controversial. Therefore, the purpose of this research was to assess the efficacy and safety of dexmedetomidine in MV patients by reviewing the results of randomized controlled trials (RCT). RCTs evaluating the efficacy of dexmedetomidine in the treatment of MV patients were obtained by searching relevant online databases, including PubMed, EMbase, Web of Science, the Cochrane Library, Medline, OVID, and ClinicalTrials.gov. Literature meeting the inclusion criteria were selected and evaluated by two researchers independently. Risk ratio (RR)/standardized mean difference (SMD) and 95% confidence interval (CI) were used to express the differences between groups. Seven RCTs were included in our study, with 986 participants in the dexmedetomidine group and 862 participants in the control group. Summary analysis results displayed no reduction in 30‐day mortality (RR = 0.77, 95% CI: 0.59 to 1.02), delirium (RR = 0.77, 95% CI: 0.57 to 1.03), and adverse events (RR = 1.06, 95% CI: 0.22 to 5.08) in the dexmedetomidine group compared with the control group. As the length of stay in the intensive care unit (ICU) were presented as median and interquartile range (IQR)/standard deviation (SD), descriptive analysis of the results were performed. Generally, for 99.65% (953/986) of patients, dexmedetomidine was not better than the control group in reducing ICU length of stay. Our results demonstrate that for patients requiring MV, dexmedetomidine was not superior to the control group. However, analysis of more RCTs is required to confirm this conclusion.


| INTRODUC TI ON
For patients receiving treatment in intensive care unit (ICU), studies have shown that sedation therapy 1-3 could reduce the subjective discomfort caused by intervention, increase the tolerance to mechanical ventilation, 4,5 and reduce incidence of accidental removal of ventilation catheters, and finally reduce metabolic requirements during cardiovascular and respiratory instability. 6 However, long-term sedation has been reported to lead to serious complications, such as prolonged mechanical ventilation (MV), delusional memory and cognitive impairment, 7 and even prolonged hospitalization, 8 increased hospital costs and mortality. 9 Therefore, the selecting appropriate sedation strategy is of utmost importance to improve the prognosis and quality of life of patients treated in ICU.
Dexmedetomidine is a highly efficient and highly selective α 2 -adrenergic receptor agonist, 10,11 which is widely used in clinical surgical anesthesia and intensive care unit (ICU) sedation because of its good analgesic, sedative, and anti-sympathetic effects. 12 Moreover the stress response and the release of stress hormones such as cortisol is lowered by the anti-sympathetic effect of dexmedetomidine. 13 With in-depth study of dexmedetomidine, in recent years, investigators have found that dexmedetomidine has a protective effect on organ injury. 14,15 Furthermore, both animal-based and cell-based experiments have confirmed that α 2 -adrenoceptor agonists have an inhibitory effect on inflammatory responses [16][17][18] both due to infectious and non-infectious causes.
Additionally, dexmedetomidine has been shown to reduce ischemia-reperfusion injury in the heart 19 and the brain, 20 with main mechanism of reducing the inflammatory response mediated by oxygen free radicals and inflammatory factors.
At present, although dexmedetomidine has been commonly used as sedation therapy in ICU patients requiring MV, whether its efficacy and safety profile is superior to that of other drugs is still controversial. Some studies have shown that compared with midazolam or propofol, dexmedetomidine significantly shortens mechanical ventilation time and improves pain transmission in ICU patients. [21][22][23][24] On the contrary, other studies have revealed that the use of dexmedetomidine does not reduce mortality and ventilator-free days in patients requiring MV. [25][26][27] Based on the above controversies, the purpose of this study is to investigate the efficacy and safety of dexmedetomidine in patients undergoing MV by reviewing the results of randomized controlled trials (RCT).

| Literature screening and data extraction
Two investigators separately screened the literature, extracted the relevant data and then cross-checked the extracted data. In the event of disagreement between the two researchers, disagreements were resolved via discussion or negotiation with a third party. During literature screening, the title of the articles were read first. After excluding apparent irrelevant literature, the abstracts of remaining literature were read, followed by the full texts to determine if the articles met the inclusion criteria. If necessary, authors of the original research were contacted by email or telephone to obtain undetermined information considered of importance to the study. The extracted information is as follows: the name of the first author or trial, the number of years published, research design, the type of mechanical ventilation, age, sex, interventions and the final outcome to be used for analysis.

| Quality evaluation of included literature
In this study, we used the Cochran risk bias assessment tool 28 to evaluate the quality of the included literature.

| Statistical analysis
In this study, Stata 11.0 software was used for statistical analysis. Risk ratio (RR) and 95% confidence interval (CI) were used as the effect indices for categorical variables. For continuous variables presenting as median and interquartile range (IQR)/median and standard deviation (SD), relevant data could not be extracted for subsequent meta-analysis, since representing median as mean for comprehensive analysis can significantly increase the unreliability of the final result. When the median and IQR were converted to mean and SD according to previous results, 29 the final result was apparently different from the included studies.
Therefore, the results presenting as median and IQR/SD were analyzed descriptively. In this analysis, the random effect model was used to analyze the results comprehensively. The heterogeneity between the included studies was assessed using I 2 and Pvalues. P > .1 or I 2 <50% suggested no significant heterogeneity between the included studies. In addition, sensitivity analysis was further done to explore the impact of individual studies on the final results and the Begg's test was performed to assess publication bias.

| Flow chart of document retrieval process
First of all, we retrieved the relevant articles by key words, and then removed irrelevant articles upon reading the titles and the abstracts.
Finally, the full texts were read to determine their suitability for inclusion in this study. The flow chart of literature retrieval is shown in Figure 1.

| Basic characteristics of the included literature
The characteristics of the included articles are shown in Table 1.

| Quality evaluation of included studies
We used the Cochran risk bias assessment tool to evaluate the quality of the included literature, and the detailed evaluation of each study is shown in Figure 2.

| Mortality at 30 days
In included studies showed no significant heterogeneity, as evident by the funnel plot and sensitivity analysis (Figures 4 and 5). In addition, no publication bias was found via Begg's test ( Figure 6, P = .286).

| Delirium
In the final included literature, three studies [23][24][25] including 312 participants in the dexmedetomidine group and 190 participants in the control group, reported delirium. Summary analysis displayed no difference between dexmedetomidine and the control group in reducing the incidence of delirium (RR = 0.77, 95% CI: 0.57-1.03, I 2 = 75.8%) (Figure 7). Similarly, the funnel plot and sensitivity analysis indicated that there was heterogeneity between the included studies, and that the heterogeneity mainly came from Riker RR study 24 (Figures 8 and 9). Besides, the Begg's test revealed no publication bias among the included studies ( Figure 10, P = .80).

| Adverse events
In the final included literature, two studies, 22   some studies did not report information that could be extracted for statistical analysis. Therefore, the results of two RCTs were eventually used to evaluate the role of dexmedetomidine in increasing the incidence of adverse events in ICU patients requiring MV. In this process of statistical analysis, there may be selection bias. The biological basis of dexmedetomidine in reducing mortality mainly comes from experimental evidence. That is, dexmedetomidine has a protective effect on brain tissue, myocardial and kidney injury, [39][40][41]  published studies have shown that dexmedetomidine significantly reduces the incidence of delirium compared to control. Therefore, it is possible that with the increase in related studies, the results of comprehensive analysis might support that dexmedetomidine significantly reduces the incidence of delirium compared to control.

| CON CLUS IONS
Our meta-analysis indicated that compared with the control group, the dexmedetomidine group showed no statistically significant

F I G U R E 11
Comparison of adverse events between dexmedetomidine and the control group difference between mortality and prognosis in ICU patients requiring MV. However, in view of several limitations of this study, this conclusion still needs to be carefully adopted in clinical practice, and more RCTs are needed to validate this conclusion.

DATA S H A R I N G A N D DATA ACCE SS I B I LIT Y
All data generated and analyzed in the study are available from the corresponding author upon reasonable request.

D I SCLOS U R E S
The authors have no conflict of interest to declare.

AUTH O R CO NTR I B UTI O N S
All authors participated in the whole process of this study and approved the final version.