Does Dexmedetomidine Reduce the Risk of Atrial Fibrillation and Stroke After Adult Cardiac Surgery? A Systematic Review and Meta-analysis of Randomized Controlled Trials

Postoperative atrial fibrillation is a common consequence of cardiac sur-gery with increased stroke complications and mortality. Although dexmedetomidine is thought to prevent postoperative atrial fibrillation and stroke because of its sympa-tholytic and anti-inflammatory properties, data from different studies show the effect of dexmedetomidine on postoperative atrial fibrillation and stroke uncertain in adult patients with cardiac surgery.A database including EMBASE, PubMed, and Cochrane CENTRAL was searched for randomized controlled trials comparing dexmedetomidine with placebo or other anesthetic drugs in adult cardiac surgery. The primary outcome was the incidence of postoperative atrial fibrillation. The secondary outcomes were the incidence of postop-erative stroke, mechanical ventilation duration, intensive care unit length of stay, hospi-tal length of stay, and mortality.Eighteen trials with a total of 2933 patients were enrolled in the meta-analyses. Compared with controls, dexmedetomidine significantly reduced the incidence of post-operative atrial fibrillation [odds ratio, 0.82; 95% CI, 0.69-0.98; P = .03]. There was no sig-nificant difference between groups in stroke (odds ratio, 1.36; 95% CI, 0.59-3.16; P = .47), mechanical ventilation duration [weighted mean difference, -0.17; 95% CI, -0.35 to 0.14;P=.39], intensive care unit length of stay (weighted mean difference, -0.03; 95% CI,-0.93 to 0.87; P = .95), hospital length of stay (weighted mean difference, -0.04; 95% CI,-0.40 to 0.32; P = .83) and mortality (odds ratio, 0.72; 95% CI, 0.32-1.60; P = .42).Perioperative dexmedetomidine reduced the incidence of postoperative atrial fibrillation in adult patients undergoing cardiac surgery. But there was no signifi-cant difference in the incidence of stroke, mechanical ventilation duration, intensive care unit length of stay, hospital length of stay, and mortality.

section_content: Postoperative atrial fibrillation (POAF) is often observed in adult patients who underwent cardiac surgery with the reported incidence ranging from 15% to 40%. 1 POAF is associated with an increased incidence of postoperative stroke complications and results in not only prolonged hospital length of stay (LOS), but also increased hospital costs and mortality. 2 The mechanism of POAF is complex and remains poorly understood. It might be triggered by postoperative factors such as inflammation, oxidative stress, pre-existing clinical characteristics including age, hypertension, and surgical procedure. 3 Pre-admission interventions and rate and rhythm control were thought to be the main strategies to prevent POAF in heart surgery patients. Although amiodarone or beta-blocker is used after cardiac surgery to prevent POAF as recommended by the European Society of Cardiology (ESC)/European Association of Cardio-Thoracic Surgery (EACTS) Guidelines, 4 the POAF incidence has remained largely constant over the past few decades. Furthermore, overcoming POAF remains a challenge. Dexmedetomidine (DEX) is a novel type of highly selective α2-adrenergic receptor agonist and has been used as a sedative or adjuvant anesthetic drug to maintain more stable hemodynamic parameters for patients undergoing cardiac surgery. 5 The original application for DEX was the shortterm sedation for adult patients in the intensive care unit (ICU) who were receiving invasive mechanical ventilation. Then DEX received approval for monitored anesthesia care in adults in 2008. Based on its favorable effects from some randomized controlled studies, there is growing interest in the use of DEX for cardiac surgery. Now DEX has been a popular and assumed first-line sedation medication in cardiac surgery patients, especially for patients with hemodynamic instability, or patients with high risk for organ injury, arrhythmia, and delirium during the perioperative period. Based on the sympatholytic effect, DEX was thought to be pharmacologic prophylaxis for POAF. However, most of the present studies have some limitations because of the small number of patients or single-center study designs. Eventually, different points of view on the influence of DEX on AF occurrence emerged. ] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] The evidence on DEX for POAF remains unclear. 

AF, especially postoperative new-onset AF (NOAF), has been described as a predictive risk of stroke after heart surgery. A study comprising 3008 patients showed NOAF is a significant risk factor for long-term stroke after cardiac surgery. Patients with POAF had a significantly higher incidence of postoperative stroke compared with the patients without POAF. 21 If DEX could reduce the incidence of POAF, the incidence of the postoperative stroke in theory will be lower owing to the DEX use after heart surgery. Although there were no studies mainly focused on the issue, some studies about the effect of DEX on other outcomes showed the incidence of postoperative stroke and the results were inconsistent. 8, 11, 14, 17, 22 Therefore, we performed a systemic review and meta-analyses to evaluate the effect of perioperative DEX on POAF and stroke in adult heart surgery patients.
section_name: INTRODUCTION

section_name: METHODS

section_content: Since this was a meta-analysis, ethical approval was not required under the arrangements of the Institutional Review Board in our hospital.
section_name: Ethical Statement

section_name: Search Strategy and Study Criteria

section_content: The literature review and data extraction were independently completed by two investigators (LXL and TZ). In case of duplicate records pertaining to a single study, we considered the PubMed database to take precedence. Disagreements were handled by discussion for consensus. Another two authors independently evaluated the quality of included studies, using the Cochrane risk of bias tool and the Jadad scale. Clinical characteristics such as age, the proportion of males, proportion with diabetes, proportion with history of myocardial infarction, proportion with hypertension, baseline left ventricular ejection fraction, β-blocker, and statin use were collected.
section_name: Literature Review and Data Extraction

section_content: The primary endpoint was the incidence of POAF. The secondary endpoints were the incidence of postoperative stroke, mechanical ventilation (MV) duration, ICU LOS, hospital LOS, and mortality.
section_name: Postoperative Outcomes

section_content: For dichotomous outcomes (reported with incidence), we calculated the risk ratio (RR) or odds ratio (OR) with a 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 23 and used weight (the inverse variance of the estimate) to pool the estimate (weighted mean difference, WMD) with 95% CI. Heterogeneity was assessed with the inconsistency statistic (I 2 ). Heterogeneity was assessed with the inconsistency statistic (I 2 ). Publication bias was assessed by Begg's test and
section_name: Statistical Analyses

section_content: • Perioperative dexmedetomidine reduced the risk of atrial fibrillation after adult cardiac surgery. • The effect of dexmedetomidine for postoperative atrial fibrillation (POAF) seemed to be obvious in female patients undergoing coronary artery bypass grafting (CABG) at a younger age. • Dexmedetomidine use did not decrease the incidence of stroke. 

Egger's test. Meta-regression and subgroup analyses were conducted to explore the potential sources of significant heterogeneity and a P-value of <. 1 was accepted. 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 <. 05 (2-sided) was considered to be statistically significant for hypothesis testing. All statistical analyses were performed using REVMAN (version 5. 0; Cochrane Collaboration, Oxford, UK) and Stata (version 15. 0; StataCorp LP).
section_name: HIGHLIGHTS

section_name: RESULTS

section_content: The PRISMA flowchart for the RCTs screening and selection process is shown in Figure 1 in this study. Eighteen trials [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] 22, 24, 25 with 19 groups of data enrolling 2933 patients were ultimately included and analyzed in the meta-analyses (Figure 1 ). Nine stu ies were for coronary artery bypass grafting (CABG), two for valve surgery, and nine were for combined cardiac surgery. Eight trials used placebo as a control, whereas 9 used propofol and 1 used morphine or remifentanil. DEX was continuously infused at a rate of 0. 1-1. 4 µg/kg/h after a loading dose (0. 4-1. 5 µg/kg) in five studies or infused at a rate of 0. 04-1. 5 µg/kg/h without a loading dose in 12. 

For outcomes, POAF incidence was reported in 19 trials, postoperative stroke in 5, MV use in 12, ICU LOS in 12, hospital LOS in 10, and mortality in 4. 

Study design and patient characteristics were summarized in Tables 1 and 2. Details on the quality assessment can be found in Table 3 and Figure 2.
section_name: Study Characteristics

section_content: The POAF was reported in 2933 study participants, and the overall incidence was 22. 50% (DEX group, 20. 38%; control group, 24. 64%). The POAF was significantly reduced by POAF (19 studies; RR, 0. 82; 95% CI, 0. 69-0. 98; P =. 03 I 2 = 21%; Figure 3 ). There was no evidence of significant publication bias (Begg's test, P =. 213; Egger's test, P =. 423). 

Subgroup analyses revealed similar trends to those of POAF outcomes based on different characteristics such as diabetes proportion (≥22% vs. <22%), CPB duration (≥98 minutes vs. <98 minutes), hypertension proportion (≥50% vs. <50%), loading dose (use or not), type of control (placebo vs. nonplacebo or propofol vs. others), administration timing (pre/intraoperative vs. postoperative), surgery type (combined surgery vs. CABG only), and Jadad score (Jadad ≥ 4 vs. Jadad < 4). There was a significant difference for the POAF in another two clinical subgroups according to age (≥ 63 vs. < 63 years, P =. 04) and male proportion (≥ 70% vs. < 70%, P =. 04) (Table 4 ). 

Meta-regression analyses performed for the potential sources of significant heterogeneity were listed in Table 5, and there were no significant differences for POAF in all the subgroups. 

Sensitivity analyses excluding each included study at a time revealed that all the studies were consistent with the who underwent cardiac surgery. However, we demonstrated that DEX did not result in a decrease in stroke, mortality, MV duration, ICU, and hospital LOS. 

POAF is one of the most common complications after cardiac surgery. Although sometimes transient, POAF could result in an increased risk of complications such as stroke, heart failure, and acute kidney injury. 26, 27 The cardiac surgery patients with POAF had a double risk of death according to the research conducted by Almassi et al. 28 For this reason, strategies to lower the incidence of POAF are of high interest to clinicians. 

The possible antiarrhythmic mechanism of DEX included activating vagus nerve, 29, 30 reducing myocardial ischemiareperfusion injury [31] [32] [33] [34] and inhibiting the inflammatory response. 35, 36 Some randomized controlled studies indicated that DEX might prevent POAF after cardiac surgery. However, there were also controversial or negative studies pertaining to the antiarrhythmic effect of DEX. A few metaanalyses and reviews have evaluated the effect of DEX on POAF after cardiac surgery. 9 our meta-analysis was an updated research and included 5 more studies and nearly double the sample size of patients, especially 5 were newly published studies and two more strengthened studies with negative results of DEX for POAF. Also, we added stroke as a new outcome after cardiac surgery. DEX is a useful and attractive drug, and we routinely used it in carefully selected patients undergoing cardiac surgery to reduce adverse events such as hypotension, bradycardia, or cardiac arrest. However, the antiarrhythmic mechanism of DEX is not completely understood, and clinical experience with DEX has only been shown in the pediatric population for the treatment of tachyarrhythmias. 41 Current data support its use only for short-term sedation and analgesic adjuvant in the adult population. Certain extended applications of DEX for anti-arrhythmias and anti-delirium require further evaluation. 

Stroke remains a devastating complication after cardiac surgery, with reported incidences between 0. 4% and 13. 8%. 42 Risk factors of postoperative stroke include advanced age, diabetes mellitus, cerebrovascular disease, atherosclerotic disease, and perioperative AF. 43, 44 A study conducted by Wang et al 21 indicated that patients who developed new-onset AF had an increased risk of postoperative stroke (OR, 1. 53; 95% CI, 1. 08-2. 18; P =. 017) and higher mortality (HR, 1. 49; 95% CI, 1. 22-1. 81; P <. 001) compared with patients without AF after cardiac surgery. 21 The key question is: if we were able to reduce the incidence of POAF through DEX use, would we then lower the incidence of postoperative stroke? As far as we know, there were no studies that considered the effect of DEX for postoperative stroke after heart surgery as their principal objective of the research. Although some studies show the incidence of postoperative stroke not as the primary outcome, previous meta-analyses focused on POAF did not assess the effect of DEX on the postoperative stroke. Our study enrolling 1525 patients showed that there was no statistically significant difference in postoperative stroke owing to DEX use. Unlike our study, in some experimental studies, neuroprotective effect of DEX was proposed. 45 The difference between theory and the results of clinical studies may be ascribed to small sample size and publication bias which no studies was primarily designed to evaluate the effect of DEX on stroke. Future high quality research mainly focused on the DEX for postoperative stroke are required to elucidate the relationship between DEX and stroke. 

Subgroup analyses were used to explore the potential sources of significant heterogeneity. Risk factors for AF are reported as age, gender, hypertension, and diabetes mellitus. 46 In our study, the subgroup with younger age (≤63 years) or less male proportion (≤70%) showed a more significant reducing effect on POAF. The possible mechanism includes the loss of myocardial fibers, increased fibrosis, and collagen deposition in the atria in male patients with advanced age. 47 date, when to start DEX and the optimal dose of DEX to prevent POAF after cardiac surgery is emerging as important consideration. Research conducted by Liu et al 6 implied that DEX started after cardiac surgery rather than at induction had a 72% decrease in POAF. Another study performed by Zi et al 7 showed a similar result and DEX use during ICU stay was associated with a significant reduction in POAF. However, the small sample size in the two studies makes their results highly fragile. Our meta-analyses included 2933 patients and 660 events indicated that DEX might be more effective in preemptive strategy compared with postoperative administration, although there was no significant difference (P =. 09). Yet there has been very little research into the optimal dose of DEX for POAF. We found that DEX infusion without loading dose appeared to be possibly more safe and effective for antiarrhythmia by avoiding unstable hemodynamics compared to those with loading dose (P =. 09). Most of the adverse events associated with DEX occur during or shortly after a loading infusion. We recommended that DEX should be infused in a slow titration to maintain the infusion rate without the administration of a loading dose to reduce the incidence of side effects. 

The incidence of POAF varied according to the cardiac surgery type and occur almost 30% after CABG, 30%-40% after valve replacement surgery, and 40%-60% after combined surgical procedures. 1, 48, 49 Our study showed the incidence of POAF was 12% in subgroup CABG, 37. 5% in subgroup valve surgery, and 28. 2% in subgroup combined surgery. Perioperative DEX was associated with a significant reduction of POAF in patients undergoing CABG (P =. 01). However, there was no statistically significant difference between subgroup CABG and subgroup others (P =. 08). 

Several disadvantages also exist in our meta-analyses. First, although the method of pooling data from different studies was performed to reduce the risk of a false negative finding, there was potential heterogeneity among these trials, which may limit the quality of the results. Second, among the 19 included trials, only 3 were primarily designed to evaluate the effect of DEX on POAF. Third, with the primary outcome of POAF, this meta-analysis may be underpowered to detect the difference in other outcomes, including stroke, mortality, MV duration, ICU LOS, and hospital LOS. Fourthly, the sample size in the study is relatively small. Lastly, many design differences among these studies made it difficult to reduce clinical heterogeneity. Future large and well-designed multicenter studies with larger sample sizes are required to confirm the effect of DEX on POAF as well as a more appropriate dose and time of DEX.
section_name: Effect of DEX on Incidence of POAF

section_content: This meta-analysis reveals evidence that perioperative administration of DEX reduces the incidence of POAF in adult cardiac surgery. The reduction of POAF seems to be obvious in female patients undergoing CABG at a younger age. 

There is no significant difference in the incidence of stroke, mortality, MV duration, ICU LOS, and hospital LOS.
section_name: CONCLUSIONS

section_content: Funding: This work was supported by the National Science Foundation of Hunan Province [2019JJ50911] and Health Public Welfare Scientific Research Project of Futian District of Shenzhen [ FTWS2020080 ].

section_name: Data Availability Statement:

section_content: The data used to support the findings of this study are included within the supplementary information file. 

Ethics Committee Approval: Ethical committee approval was not required under the arrangements of the Ethics Committee of Beijing Shijitan Hospital, Capital Medical University. 

Peer-review: Externally peer-reviewed.
section_name: Data Availability Statement:

section_name: Effect of DEX on Incidence of Stroke and Mortality

section_content: direction and size of the overall AF-reducing effect of dexmedetomidine (P for all <. 05) except Liu et al 6 and Zi et al. 7

section_content: The stroke was reported in five studies including 1525 study participants, 8, 11, 14, 17, 22 and the overall incidence was 1. 51% (DEX group, 1. 71%; control group, 1. 31%). There was no statistically significant reduction in stroke owing to perioperative DEX (five studies; OR, 1. 36; 95% CI, 0. 59-3. 16; P =. 47; I 2 = 0%; Figure 4 ). 

The mortality was reported in four studies enrolling 1504 study participants, and the overall incidence was 1. 60% (DEX group, 1. 33%; control group, 1. 87%). There was no statistically significant reduction in mortality owing to perioperative DEX (four studies; OR, 0. 72; 95% CI, 0. 32-1. 60; P =. 42; I 2 = 0%; Figure 5 ).
section_name: Effect of DEX on Incidence of Stroke and Mortality

section_content: There was no statistically significant reduction of postoperative MV duration (12 studies WMD, -0. 17; 95% CI, -0. 35 to 0. 14; P =. 39; I 2 = 76%; Figure 6 ), ICU LOS (12 studies; WMD, -0. 03; 95% CI, -0. 93 to 0. 87; P =. 95; I 2 = 8%; Figure 7 ), and hospital LOS (10 studies; WMD, -0. 04; 95% CI, -0. 40 to 0. 32; P =. 83; I 2 = 60%; Figure 8 ) by DEX.
section_name: Effect of Dexmedetomidine on MV Duration, ICU LOS, and Hospital LOS

section_content: This meta-analysis showed that perioperative DEX was associated with a significant reduction in POAF in adult patients
section_name: DISCUSSION