Does dexmedetomidine reduce the risk of acute kidney injury after cardiac surgery? A meta-analysis of randomized controlled trials

Background Acute Kidney Injury (AKI) is a common complication after cardiac surgery and has been associated with poor outcomes. Dexmedetomidine (DEX) has been shown to confer direct renoprotection based on some animal and clinical studies, but data from other trials came to the opposite conclusion following cardiac surgery. This meta-analysis was conducted to evaluate the effects of perioperative DEX administration on the occurrence of AKI and the outcomes after cardiac surgery. Methods We searched databases including EMBASE, PubMed, and Cochrane CENTRAL for Randomized Controlled Trials (RCTs) focused on DEX for AKI in adult patients after cardiac surgery. The primary outcome was incidence of AKI. Secondary outcomes were Mechanical Ventilation (MV) duration, Intensive Care Unit (ICU) Length Of Stay (LOS), hospital LOS and mortality. Results Fifteen trials enrolling 2907 study patients were collected in the meta-analyses. Compared with controls, DEX reduced the incidence of postoperative AKI (Odds Ratio [OR = 0.66]; 95% Confidence Interval [95% CI 0.48–0.91]; p = 0.01), and there was no significant difference between groups in postoperative mortality (OR = 0.63; 95% CI 0.32–1.26; p = 0.19), MV duration (Weighted Mean Difference [WMD = -0.44]; 95% CI -1.50–0.63; p = 0.42), ICU LOS (WMD = -1.19; 95% CI -2.89–0.51; p = 0.17), and hospital LOS (WMD = -0.31; 95% CI -0.76–0.15; p = 0.19). Conclusions Perioperative DEX reduced the incidence of postoperative AKI in adult patients undergoing cardiac surgery. No significant decrease existed in mortality, MV duration, ICU LOS and hospital LOS owing to DEX administration.


Introduction
Acute Kidney Injury (AKI) is a recognized complication following cardiac surgery with a reported incidence between 5% and 42%. 1 Postoperative AKI results in poor outcomes, prolonged hospital Length of Stay (LOS), increased hospital costs and mortality. 2[8][9][10] Dexmedetomidine (DEX) is a highly selective a2 adrenoreceptor agonist and has been widely used for sedation during cardiac surgery.DEX differs from other sedatives by the properties of anti-inflammatory and sympatholytics. 11,12hese properties offer a hypothesis that DEX might reduce the incidence of postoperative AKI.1][22] However, the studies were limited by high heterogeneity and relatively small sample size.Moreover, some strengthened studies focused on this issue were published in recent years. 23,24Therefore, we conducted this meta-analysis to assess if DEX is associated with a protective effect of AKI after cardiac surgery.

Search strategy and study criteria
This meta-analysis was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines 25 and three electronic databases including MEDLINE (through PubMed), Embase (through OVID) and Cochrane Library were searched to identify relevant studies.The search strategy for PubMed was performed using the keywords "dexmedetomidine", "cardiac surgery", "heart surgery", "kidney", and "renal".Various combinations of key words and different search strategies were developed for another two databases.The search encompassed the period between January 1997 and November 2022.All eligible studies met the following conditions: 1) Randomized controlled trials only, and as an original article, 2) Studies published in English, 3) Adult patients undergoing cardiac surgery with or without cardiopulmonary bypass, including coronary artery bypass graft or cardiac valve replacement or coronary artery bypass graft combined with cardiac valve replacement; 4) Intervention: DEX; 5) Comparison: placebo or control (other therapy); 6) Outcome measure: the incidence of postoperative AKI.Exclusion criteria were as follows: retrospective study, observational study, conference abstracts, expert opinion, review articles, case reports, abstracts, editorials, and letters to the editor, animal studies, studies involving pediatric population, and studies lacking clinical outcome data, and failure to contact the authors.Furthermore, the references of relevant studies were also assessed.

Literature review and data extraction
The literature review and data extraction were independently completed by 2 investigators.In the case of duplicate records pertaining to a single study, we considered the PubMed database to take precedence.Disagreements were handled by discussion to reach consensus.Quality assessment was completed using the Cochrane risk of bias tool: randomization, allocation concealment, blinding, withdrawals and dropouts, and intention-to-treat analysis.Data extraction included characteristics of included studies and patients.

Postoperative outcomes
The primary end point was incidence of AKI defined based on three definitions, consisting of KDIGO (Kidney Disease: Improving Global Outcome), RIFLE (Risk, Injury, Failure, Loss of kidney function, and EndÀstage kidney disease), AKIN (Acute Kidney Injury Network) and undergoing RRT (Renal Replacement Therapy) for new onset of AKI after cardiac surgery.Secondary outcomes included mortality, Mechanical Ventilation (MV) duration, ICU LOS, and hospital LOS.

Statistical analysis
For dichotomous outcomes (reported with incidence), we calculated the Odds Ratio (OR) with 95% Confidence Interval (95% CI).For continuous outcomes (reported as mean § standard deviation, median and interquartile range, or median and range), we calculated mean differences for each study according to the statistical method of Hozo et al. 26 and used weights to pool the estimate (Weighted Mean Difference -WMD) with 95% CI.Random-effect models were used to analyze the data in light of the heterogeneity.Heterogeneity was assessed with Inconsistency statistic (I 2 ).Publication bias was assessed by Begg's test, Egger's test and Macaskill test.Meta-regression and subgroup analysis were conducted to explore the potential sources of significant heterogeneity.Sensitivity analyses were used to assess the robustness of our results by removing each included study at one time to obtain and evaluate the remaining overall estimates: p < 0.05 (2 sided) was considered to be statistically significant for hypothesis testing.All statistical analyses were performed in REVMAN (version 5.0; Cochrane Collaboration, Oxford, UK) and Stata (version 15.0; Stata-Corp LP).

Study characteristics
Figure 1 shows the flow chart for the study screening and selection process in this meta-analysis.,24,[27][28][29][30][31][32][33][34][35] Two studies were for coronary artery bypass grafting, nine were for combined cardiac surgery, two for valve replacement surgery, and two for aortic vascular surgery.Nine trials used placebo as control, whereas four used propofol, one used morphine or remifentanil.DEX was continuously infused at a rate of approximately 0.2 to 0.8 mcg.kgÀ1 .hÀ1 for 24 hours after a loading dose (0.4−1 mcg.kgÀ1 ) in six studies or infused at a rate of approximately 0.04 to 1.5 mcg.kgÀ1 .hÀ1 without a loading dose in nine.DEX was used intraoperatively in eleven studies and postoperatively in four.
For primary outcomes, AKI incidence was reported in fifteen trials, including two showing the number of patients needed for dialysis owing to the new onset of AKI after cardiac surgery; For second endpoint, mortality, in seven; mechanical ventilation duration, in twelve; ICU LOS, in thirteen; and hospital LOS, in ten.
Study design and patient characteristics are summarized in Tables 1 and 2. The quality assessment is listed in Figure 2 and Table 3.
Meta-regression analyses performed for the potential sources of significant heterogeneity are listed in Supplementary Table 2, and there were no significant differences for postoperative AKI in all the subgroups.
Sensitivity analyses excluding each included study at a time revealed that all the studies were consistent with the direction and size of the overall AKI-reducing effect of DEX (p < 0.05 for all) except Cho.

Discussion
In this meta-analysis of fifteen RCTs involving 2907 adult patients undergoing cardiac surgery, we found that perioperative DEX was associated with a decrease in postoperative AKI.However, postoperative parameters including MV duration, ICU, hospital LOS and mortality did not seem to present a significant reduction as a result of the DEX.AKI is common after cardiac surgery and small increases in postoperative serum creatinine levels have been reported to be related with worse outcome, even when renal function returns to normal ultimately. 36,37The reason that cardiac surgery can cause AKI is always accompanied by renal Ischemia-Reperfusion Injury (I/RI), elevated sympathetic activity, and hemodynamic instability.2][43][44][45] There is a hypothesis that the incidence of AKI may be reduced owing to the use of DEX in cardiac surgery. 46,47everal studies have compared the efficacy of DEX at enhancing urine output and at decreasing the concentration of blood urea nitrogen and creatinine after surgery, 19,48,49 and other randomized controlled trials have reported a lower rate of kidney injury. 17,50,513][54] A few meta-analyses have been conducted to address this issue.However, a meta-analysis performed by Peng, 20   RCTs with a total of 1308 patients, showed low heterogeneity (I 2 = 30%).Another meta-analysis by Liu [21] including ten RCTs with a total of 1575 patients showed only eight groups of data from seven studies on the main outcome.Our study with an almost two times larger sample size collected some high-quality research published in recent years and provided a more convincing conclusion.Based on our literature review, positive reno-protective effects were reported in two studies.Moreover, in our data analysis, the combined results with a random-effects model revealed lower AKI incidence in patients with DEX, and the pooled OR succeeded to reach statistical significance.
However, this benefit did not translate into the second outcomes, such as MV duration, ICU LOS, hospital LOS and mortality.A possible explanation is that our meta-analysis with a relatively small sample size may account for such differences.Another is that heterogeneity for the MV duration, ICU and hospital LOS is almost over 50%.In fact, there are trends toward lower MV duration, ICU LOS, hospital LOS and mortality.Further randomized studies with large sample sizes are encouraged to verify the current findings.
Our analysis has several limitations.Firstly, many factors could influence AKI after cardiac surgery, such as age, degree of hypertension, and drugs used for treating Table 3 Summarized quality assessment of included randomized trials.

Study
Random sequencegeneration hypertension and diabetes mellitus.We were unable to access individual patient data, so the influences of confounding factors may be underestimated.Secondly, we only included English language trials and published studies, which may lead to publication bias.Thirdly, many design differences among these studies made it difficult to reduce clinical heterogeneity.Subgroup analyses and meta-regression were performed for the potential sources of heterogeneity.Finally, based on the included data, there are four different definitions of AKI, including RIFLE, AKIN, KDIGO, and need for RRT.Six studies did not mention the definition of AKI.
According to previous studies, 55,56 the incidence of AKI can vary greatly according to the definition used, and our study might draw a misleading conclusion.Given only three or less studies were included, a subgroup analysis based on AKI definition was not performed.

Conclusion
In summary, our meta-analysis indicated that perioperative DEX use reduced postoperative AKI in patients receiving cardiac surgery.However, DEX use is not associated with MV duration, ICU LOS, hospital LOS and mortality.Future, much larger trials are needed to verify the current findings.

Figure 1
Figure 1 Flow diagram of studies included into meta-analyses.
which included nine Table 2 Summarized patient characteristics of the included randomized trials.are given as means unless otherwise specified.DM, Diabetes Mellitus; HP, Hypertension; PreMI, Previous Myocardial Infarction; LVEF, Left Ventricular Ejection Fraction; CPB, Cardiopulmonary Bypass; NA, Not Available.

Figure 2
Figure 2 Quality assessment of studies included into metaanalyses.