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Effect of dexmedetomidine for prevention of acute kidney injury after cardiac surgery: an updated systematic review and meta-analysis

Abstract Background Acute kidney injury (AKI) is a serious complication related to cardiac surgery. Several studies have been conducted to investigate the effect of dexmedetomidine administration on AKI prevention. Objective To assess if dexmedetomidine is associated with a protective effect of renal function after cardiac surgery. And the aim of conducting this meta-analysis is to summarize the literature and determine the clinical utility of dexmedetomidine administration in patients undergoing cardiac surgery. Methods PubMed, Cochrane Library, and EMBASE databases were comprehensively searched for all randomized controlled trials (RCTs) published before 1 December, 2021 that investigated the effect of dexmedetomidine on AKI prevention. Results Our analysis included 16 studies involving 2148 patients. Compared with the control group, dexmedetomidine administration significantly reduced AKI incidence (OR, 0.47; 95% CI, 0.36–0.61; p <  0.00001; I2 = 26%) and the length of stay in the intensive care unit (ICU) but did not alter mortality rate, length of stay in the hospital, and mechanical ventilation time. Furthermore, the incidence of delirium among patients treated with dexmedetomidine was significantly decreased. Conclusion Dexmedetomidine administration has a positive effect on preventing AKI and postoperative delirium after cardiac surgery and significantly reduces the length of stay in the ICU.


Introduction
Acute kidney injury (AKI) is a serious complication of cardiac surgery with an estimated incidence of 20% [1,2]. It is the second most common type of AKI in the intensive care unit, following sepsis-related AKI [3]. Coronary artery bypass graft and cardiac valve replacement can cause AKI because they are always accompanied by renal ischemia-reperfusion injury (I/RI), elevated sympathetic activity, and hemodynamic instability. Despite steps to prevent AKI, a standard for preventing AKI after cardiac surgery is lacking.
Dexmedetomidine, an a 2 -adrenoreceptor agonist, has been widely used in anesthesia procedures and intensive care. It inhibits inflammation, alleviates postoperative delirium, and exhibits neuroprotective effects. AKI incidence decreases after the use of dexmedetomidine in cardiac surgery. However, it remains unclear if dexmedetomidine can ameliorate the harmful effects of cardiac surgery on renal function. Six additional singlecenter randomized controlled trials have been concluded since the previous meta-analysis was published. Therefore, the present meta-analysis was conducted to provide updated information on the efficacy of dexmedetomidine on renal function after cardiac surgery.

Search strategy and selection criteria
This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and is registered at the International Prospective Register of Systematic Reviews (Number CRD42021253836). PubMed, EMBASE, and Cochrane Library were searched for relevant studies since inception to 1 December 2021 with no language restrictions. The following combined text and MeSH terms were used: 'Dexmedetomidine', 'Cardiac surgical procedures', and 'Renal insufficiency'. All the searched RCTs were included without bias of gender and age. Studies not reporting AKI incidence were excluded. In addition, reference lists of key published articles were manually searched.

Study selection and data extraction
Two independent investigators (LX and HQX) reviewed the published studies and extracted data. If there were disagreements, the third investigator (CQX) resolved. RCTs involving cardiac surgery and treatment with dexmedetomidine during the perioperative period and reporting AKI incidence, regardless of the criteria AKIN, KDIGO, and RIFLE, were considered eligible for inclusion. Observational or retrospective studies were excluded. If there was more than one comparison eligible for inclusion criteria in one study, all of the comparisons would be included and defined as different groups. The Cochrane risk of bias tool was used for assessing the quality of the included studies. The following data were extracted from selected studies: total number of patients and their characteristics (age, sex, proportion of patients with diabetes, and proportion of hypertension), cardiac surgical procedures, cardiopulmonary bypass (CPB) time, control drugs, and the dosage of dexmedetomidine. The primary outcome was AKI incidence after cardiac surgery within 7 days. Secondary outcomes were as follows: all-cause mortality (within 30 days), mechanical ventilation (MV) duration, and the length of stay in ICU and hospital.

Statistical analysis
The incidence of AKI after cardiac surgery, mortality, mechanical ventilation duration, the length of stay in ICU, and the length of stay in the hospital were analyzed. Data were pooled from all eligible RCTs and the Mantel-Haenszel method was used to calculate the risk ratio (RR) with 95% confidence intervals (CIs) for these dichotomous outcomes. A pooled estimate of RR was computed using the DerSimonian and Laird randomeffects model. This model provides an appropriate assessment of the average treatment effect when studies are statistically heterogeneous, and it typically yields relatively wide CIs resulting in a more conservative statistical claim.
Cochran's Q test and Higgins' I 2 statistical test were used to assess the statistical heterogeneity of the pooled results [4]. If 0% I 2 <25%, the results showed no heterogeneity; if 25% I 2 <50%, the results showed a low level of heterogeneity; if 50% I 2 <75%, the results showed a medium level of heterogeneity; if 75% I 2 100%, the results showed a high level of heterogeneity. Risk of bias assessment was done using the Cochrane Collaboration tool (Cochrane, London, UK).
Begg's test and Egger's test were used to determine publication bias, and a p-value <0.1 indicated significant bias. Trim-and-fill computation was performed to estimate the effect of publication bias on the interpretation of the results. p < 0.05 (two-sided) indicated statistical significance. We used REVMAN (version 5.4; Cochrane Collaboration, Oxford, UK) and Stata (version 12.0; Stata Corp LP) for statistical analyses.
The risk of bias graph ( Figure 2) shows two studies rated as high risk for attrition bias, in which complete outcome data were not available. Supplementary Figure 3 shows no significant asymmetry in the funnel plot, which means no significant publication bias.
Subgroup analyses to identify the effect of a potential source of heterogeneity on AKI were performed by classifying these included studies according to gender (proportion of male !50 vs.  Table 2. The results indicated no significant differences in the AKI incidence.
Effect of dexmedetomidine on the incidence of adverse events during the perioperative period The incidence of delirium was significantly reduced by administration of dexmedetomidine (p < 0.001), while no significant change in the incidence of arrhythmias (p ¼ 0.06), bradycardia (p ¼ 0.08), hypotension (p ¼ 0.41), and stroke (p ¼ 1.00) was observed ( Figure 5).

Discussion
The present meta-analysis indicated that the administration of dexmedetomidine can reduce AKI incidence during the perioperative period in cardiac patients. Compared with previous meta-analysis [21], our subgroup analysis indicated no significant differences in age and the usage time of dexmedetomidine. Perioperative dexmedetomidine treatment significantly reduced the length of stay in the ICU. Mortality rate and MV duration did not differ significantly between the groups. Moreover, dexmedetomidine treatment significantly reduce the incidence of delirium, but the incidence of arrhythmias, bradycardia, hypotension, and stroke in the perioperative period was not significantly altered.   [22]. In our meta-analysis, pooled results of 10 studies indicated that preoperative or intraoperative administration of dexmedetomidine cannot reduce the incidence of AKI compared with postoperative administration of dexmedetomidine (p ¼ 0.06). In addition, subgroup analysis suggested that the relatively low dose of dexmedetomidine ( 0.4 lg/kg/min) had a similar protective effect to the high dose (>0.4 lg/kg/min; p ¼ 0.46). Moreover the previous meta-analysis suggested that the use of dexmedetomidine might reduce the incidence of AKI in adult patients [21,23]. However, they excluded children, which might conceal the true effect of dexmedetomidine on AKI, as the occurrence of AKI in children can also lead to adverse outcomes during the perioperative and postoperative periods. The present study showed no significant difference in the ability of dexmedetomidine to reduce AKI incidence between children and adults. Furthermore, both previous studies excluded trials involving patients with basic renal dysfunction, which might increase the heterogeneity among the studies. However, our results indicated that the inclusion of our study did not significantly increase heterogeneity (I 2 ¼ 26% vs. I 2 ¼ 8%). Linda et al. found that the increased prevalence of chronic kidney disease among elderly patients, excluding patients with renal dysfunction, might conceal the nephroprotective effect of dexmedetomidine in patients with CKD [24].
The current meta-analysis indicated that perioperative treatment with dexmedetomidine might reduce the incidence of delirium, consistent with the results of several other studies focusing on the incidence of delirium among patients undergoing cardiac surgery [25]. Lower rates of delirium have been reported in ICU patients sedated with dexmedetomidine than patients sedated with benzodiazepines and propofol [26,27]. Moreover, the incidences of arrhythmias, bradycardia, hypotension, and stroke were not significantly different in compared groups. These adverse events might prolong the length of stay in ICU and hospital and even increase the mortality rate. Hypotension and bradycardia are the most common adverse effects during the use of dexmedetomidine due to its inhibition of the sympathetic nervous system. Patients in the dexmedetomidine treatment group had a lower incidence of AKI despite more adverse hemodynamic events. However,   these adverse effects could be easily handled if the atropine or vasoactive agents were administrated timely. Findings from our meta-analysis showed a protective effect of dexmedetomidine on renal function in patients undergoing cardiac surgery. We comprehensively reviewed RCTs designed to detect the effect of dexmedetomidine on cardiac surgery patients, pediatric patients, and patients with renal impairment. The heterogeneity was 26% for the primary outcome, which suggested that the interpretation of the current finding was reliable.
The mean blood pressure may relatively decrease during CPB in cardiac surgery, and the blood pressure may return to normal after the CPB procedure. The protective effect of dexmedetomidine on attenuating the I/Rinjury in mice was related to sirtuin 3 activation [28]. Zhao et al. indicated that dexmedetomidine might reduce kidney injury by increasing autophagy through inhibition of the PI3K/AKT/mTOR pathway in lipopolysaccharide-induced rat AKI models [29]. However, further studies are needed to understand the exact mechanisms of the nephroprotective effects of dexmedetomidine.
The current study extends the scope of our understanding by summarizing the effect of dexmedetomidine on renal function after cardiac surgery. Several limitations exist in this meta-analysis. First, a previous study revealed that a higher incidence of AKI in patients with a long duration of cardiac surgery [30]. The duration of operation and ischemia might differ because the trials included in the previous meta-analysis were conducted at different medical centers, which could greatly affect renal function. Subgroup analysis suggested no significant difference in the AKI incidence between CPB time of more than 3 h or not. More eligible trials are required to further investigate the exact influence of CPB duration on the protective effect of dexmedetomidine. The same limitation was also noted for the length of MV duration, length of stay in ICU, and length of stay in hospital. Second, many factors could influence renal function, such as age, degree of hypertension, pulsatility of blood flow and central venous pressure during the surgery period, and drugs used for treating hypertension and diabetes mellitus; however, we only estimated the effect of dexmedetomidine. Further robust evidence is required to confirm the effect of dexmedetomidine on patients undergoing cardiac surgery. Third, based on the included data, there are four different definitions of AKI, including RIFLE, AKIN, KDIGO, and Cr >115 lmol/L. There are still 4 studies that have not mentioned the definition of AKI. Indeed, a subgroup analysis based on AKI definition would be appropriate, but some of the subgroup analysis may only include 3 or less studies, too few studies might draw a misleading conclusion and this is a limitation of our study. Finally, some of the primary results were calculated based on the statistical methods of Luo et al. and Wan et al., which might influence the detection of differences in this study.

Conclusion
The perioperative administration of dexmedetomidine could reduce AKI incidence in patients undergoing cardiac surgery. Dexmedetomidine treatment may also reduce the length of stay in ICU and the incidence of postoperative delirium.

Disclosure statement
No potential conflict of interest was reported by the author(s).