Secondary Logo

Journal Logo

Effect of Remote Ischemic Preconditioning on Outcomes in Adult Cardiac Surgery: A Systematic Review and Meta-analysis of Randomized Controlled Studies

Xie, Jianfeng MD*; Zhang, Xiwen MD*; Xu, Jingyuan MD*; Zhang, Zhongheng MD; Klingensmith, Nathan J. MD; Liu, Songqiao MD, PhD*; Pan, Chun MD, PhD*; Yang, Yi MD, PhD*; Qiu, Haibo MD, PhD*

doi: 10.1213/ANE.0000000000002674
Cardiovascular and Thoracic Anesthesiology
Free
SDC

BACKGROUND: Remote ischemic preconditioning (RIPC) has been demonstrated to prevent organ dysfunction in cardiac surgery patients. However, recent large, prospective, multicenter, randomized controlled trials (RCTs) had controversial results. Thus, a meta-analysis of RCTs was performed to investigate whether RIPC can reduce the incidence of acute myocardial infarction (AMI), acute kidney injury (AKI), and mortality in adult cardiac surgery patients.

METHODS: Study data were collected from Medline, Elsevier, Cochrane Central Register of Controlled Trials and Web of Science databases. RCTs involving the effect of RIPC on organ protection in cardiac surgery patients, which reported the concentration or total release of creatine kinase-myocardial band, troponin I/troponin T (TNI/TNT) after operation, or the incidence of AMI, AKI, or mortality, were selected. Two reviewers independently extracted data using a standardized data extraction protocol where TNI or TNT concentrations; total TNI released after cardiac surgery; and the incidence of AKI, AMI, and mortality were recorded. Review Manager 5.3 software was used to analyze the data.

RESULTS: Thirty trials, including 7036 patients were included in the analyses. RIPC significantly decreased the concentration of TNI/TNT (standard mean difference [SMD], −0.25 ng/mL; 95% confidence interval [CI], −0.41 to −0.048 ng/mL; P = .004), creatine kinase-myocardial band (SMD, −0.22; 95% CI, −0.07–0.35 ng/mL; P = .46), and the total TNI/TNT release (SMD, −0.49 ng/mL; 95% CI, −0.93 to −0.55 ng/mL; P = .03) in cardiac surgery patients after a procedure. However, RIPC could not reduce the incidence of AMI (relative risk, 0.89; 95% CI, 0.70–1.13; P = .34) and AKI (relative risk, 0.88; 95% CI, 0.72–1.06; P = .18), and there was also no effect of RIPC on mortality in adult cardiac surgery patients. Interestingly, subgroup analysis showed that RIPC reduced incidence of AKI and mortality of cardiac surgery patients who received volatile agent anesthesia.

CONCLUSIONS: Our meta-analysis demonstrated that RIPC reduced TNI/TNT release after cardiac surgery. RIPC did not significantly reduce the incidence of AKI, AMI, and mortality. However, RIPC could reduce mortality in patients receiving volatile inhalational agent anesthesia.

From the *Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China

Department of Critical Care Medicine, Jinhua Municipal Central Hospital, Jinhua Hospital of Zhejiang University, Zhejiang, China

Department of Surgery, Emory Critical Care Center, Emory University School of Medicine, Atlanta, Georgia.

Published ahead of print November 22, 2017.

Accepted for publication October 10, 2017.

Funding: Supported by Clinical Medicine Science and Technology program of Jiangsu Province (BL2013030).

The authors declare no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website.

Reprints will not be available from the authors.

Address correspondence to Haibo Qiu, MD, PhD, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China. Address e-mail to haiboq2000@163.com.

Organ dysfunction such as myocardial injury and acute kidney injury (AKI) is associated with marked increases in morbidity and mortality in cardiac surgery patients.1 Although the mechanisms of organ dysfunction after cardiac surgery are not fully understood, these conditions may be associated with end-organ ischemia–reperfusion injuries. It has been found that brief ischemia can protect the heart from ischemia–reperfusion injury.2 Therefore, remote ischemic preconditioning (RIPC) performed by the application of ischemia–reperfusion cycles in skeletal muscle is thought to be an effective preprocedure treatment in preventing postprocedure organ dysfunction in cardiac surgery patients.

There is evidence that acute myocardial and kidney injury, as determined by serum cardiac and renal biomarkers, can be prevented by using the RIPC procedure in cardiac surgery patients.3–7 Cheung et al3 was the first to design a randomized controlled study to confirm the effect of RIPC on children undergoing cardiac surgery and found that RIPC was myocardial protective. In addition, Zarbock et al7 found that the incidence of AKI was significantly lower in adults undergoing precardiac surgery RIPC compared to an untreated control group. However, 2 recent large, prospective, multicenter, randomized controlled trials (RCTs) failed to reproduce these protective results.8,9 Thus, studies on the effect of RIPC on cardiac surgery patients have yielded conflicting results10–14

It is still controversial whether RIPC improves organ function after cardiac surgery. To investigate the role of RIPC on cardiac surgery outcomes, we performed a meta-analysis to address the role of RIPC on outcomes of adult cardiac surgery patients. Our aim was to determine whether RIPC can reduce the incidence of acute myocardial infarction (AMI), AKI, and mortality in cardiac surgery patients through a systemic review and a meta-analysis.

Back to Top | Article Outline

METHODS

Eligibility Criteria and Information Sources

Medline, Elsevier, Embase, Cochrane Central, Register of Controlled Trials, and Web of Science databases were searched. There was no language restriction. All databases were searched for articles published since inception until November 20, 2015. Additional files and supplementary appendices of the relevant articles were also reviewed and are available as Supplemental Digital Content, http://links.lww.com/AA/C144.

Back to Top | Article Outline

Search and Study Selection

Two reviewers (J.X. and X.Z.) independently screened titles and abstracts to determine whether a particular study met the inclusion criteria. The words searched were “ischemic preconditioning” or “remote ischemic preconditioning” or “remote preconditioning” and “cardiac surgery” or “surgical coronary revascularization” or “coronary artery bypass graft surgery” or “valve surgery”. Then, all the articles were reviewed independently in accordance with the inclusion and exclusion criteria. Conflicts between 2 reviewers were resolved through a third reviewer (J. Xu) and discussion. We only included randomized controlled clinical trials with patients who received open cardiac surgery. The following outcomes were reported in the article: troponin I/troponin T (TNI/TNT) concentration level or total TNI/TNT release or creatine kinase-myocardial band (CK-MB) concentration level or incidence of AKI or AMI or mortality after cardiac surgery. We excluded retrospective studies and studies in which previously published data were reanalyzed. We also excluded studies involving children and infants.

Back to Top | Article Outline

Data Items

TNI or TNT concentrations at 6 hours (when the concentrations at exactly the 6-hour mark were not available, a range of 4–8 hours was used) and total TNI released after cardiac surgery were recorded. We also recorded the incidence of AKI, AMI, and mortality. AKI was defined according to Risk, Injury, Failure, Loss, End Stage Renal Disease; Acute Kidney Injury Network; and Kidney Disease: Improving Global Outcomes criteria in different studies. AMI was defined according the European Society of Cardiology/American College of Cardiology/American Heart Association/World Heart Federation Task Force for the Redefinition of Myocardial Infarction in most studies. The details of the definition of AKI and AMI in different studies are shown in Supplemental Digital Content, Table S1, http://links.lww.com/AA/C144. Other data, including hospital length of stay, study characteristics, inclusion and exclusion criteria, sample size, and other detailed information were also extracted.

Back to Top | Article Outline

Risk of Bias in Studies

We used the Cochrane Collaboration tool for assessing the risk of bias, which included random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, and selective reporting.

Back to Top | Article Outline

Subgroup Meta-analysis

One study showed that RIPC during isoflurane, but not propofol, anesthesia decreased myocardial damage in patients undergoing coronary artery bypass graft (CABG) surgery.15 A recent meta-analysis also showed that volatile agents reduced the mortality in cardiac surgery patients compared to intravenous anesthesia.16 Therefore, we performed a subgroup meta-analysis to assess the effectiveness of anesthesia methods on the efficiency of RIPC with regard to the outcome of cardiac surgery patients. The methods of anesthesia were classified into a total intravenous anesthesia (TIVA) group and a volatile group where an inhalational agent was used at any point. The TIVA group was defined by never receiving any volatile inhalational agents. The volatile group was defined as a group receiving 1 or more volatile agent, even if added over a TIVA regimen. If the studies did not report the method of anesthesia in the article, or did not report the outcome of different anesthesia separately, we defined it as not reported.

Back to Top | Article Outline

Summary Measures

A meta-analysis of the effect of RIPC on organ dysfunction in patients undergoing cardiac surgery was performed by using Review Manager 5.3 (The Nordic Cochrane Centre, Rigshospitalet, Copenhagen, Denmark). Continuous data are presented as mean and standard deviation (SD). However, in some of the enrolled studies, the concentrations of CK-MB, TNI, and total TNI release were expressed as median and interquartile ranges. Therefore, the median and range were used to estimate mean and SD. We calculated the SD through the following formula: SD = (P75 − P25)/1.35, where P75 is the 75th percentile and P25 is the 25th percentile, with the assumption that the data were normally distributed.17 We used relative risk (RR) to estimate the effect of RIPC on outcome in cardiac surgery patients.

Back to Top | Article Outline

Synthesis of Results

The statistical heterogeneity of all the data was predefined as P < .1with the Mantel–Haenszel χ2 test. In addition, the I2 index was used to assess heterogeneity in the meta-analysis. I2values of 25%, 50%, and 75% were defined as low, medium, and high heterogeneity thresholds, respectively. If heterogeneity was found among the included studies, a randomized-effects model was employed. We reported an RR with a 95% confidence interval (CI) for dichotomous data and weighted mean differences with 95% CIs for continuous data. A funnel plot was employed to assess publication bias. In addition, we used Begg’s test to assess for evidence of publication bias. P < .05 was defined as statistical significance. Subgroup analysis included comparisons for 3 groups, and therefore, we defined P < .017 to be statistically significant according to the Bonferroni correction.

Back to Top | Article Outline

Additional Analysis

Sensitivity analyses were used to estimate the effect of RIPC on AMI and AKI. It was conducted by sequentially omitting a single study each time, in an attempt to identify the potential influence of an individual study.

We performed a trial sequential analysis (TSA), which monitors the type I and type II errors over repetitive testing of accumulating trials over time as well as estimates the optimal total sample size for the given research question to assure adequate power.18 We conducted TSA to calculate the required information size under the following assumptions: RR reduction of 20%, control arm incidence of AMI, AKI, mortality obtained from results of meta-analysis, α (type I error) of 0.05, and 80% power. A sensitivity analysis was also performed by the sequential exclusion of each included study to access the effect of RIPC on outcome in cardiac surgical patients.

Back to Top | Article Outline

RESULTS

Study Selection

Figure 1.

Figure 1.

The initial search identified a total of 1241 titles, among which 306 were duplicates and were subsequently excluded. After assessment of the titles and abstracts, 64 articles were retrieved for full text evaluation. Then, 34 articles were excluded for a variety of reasons (Figure 1). Finally, 30 prospective randomized controlled studies,4–9,11–15,19–37 including 29 full articles and 1 abstract,19 were included into the analyses.

Back to Top | Article Outline

Study Characteristics

A total of 7036 patients in 30 studies were included in the analyses. Among the included studies, 1 was a secondary analysis of 2 randomized trials about AKI incidence which was not reported in the primary analysis.31 Seventeen trials4,8,9,11–13,15,19,20,24,27–30,32,34,35 reported the concentrations of TNI/TNT and 16 trials4–6,9,11–15,20,22,24,26,27,30,34 reported the total TNI/TNT release. Thirteen articles7–9,12,14,20,21,23,25,28,31,33,36 reported the incidence of AKI and 9 papers6–9,20,23,25,27,33 reported the incidence of AMI. Five studies reported the concentrations of CK-MB.11,14,21,33,37 Postprocedure mortality was reported in 9 trials.6–9,11,20,23,33,36 The main characteristics of the included studies are shown in Supplemental Digital Content, Table S1, http://links.lww.com/AA/C144.

Among all included trials, most patients received CABG and/or valve surgery. The method of RIPC in most studies was 3 or 4 cycles of upper limb ischemia by a cuff inflated to 200–300 mm Hg. Details of the RIPC procedure used in the studies are shown in Supplemental Digital Content, Table S1, http://links.lww.com/AA/C144. Assessment of the risk of bias is summarized in Supplemental Digital Content, Figure S1, http://links.lww.com/AA/C144.

Back to Top | Article Outline

The Effect of RIPC on Concentrations of TNI/TNT

Figure 2.

Figure 2.

The effect of RIPC on concentrations of TNI/TNT after cardiac surgery was assessed in 17 studies of 3693 patients.4,8,9,11–13,15,19,20,24,27–30,32,34,35 One thousand eight hundred sixty-four patients received RIPC, and 1829 patients did not. A significant publication bias was found after a funnel plot assessment and Begg’s test (Supplemental Digital Content, Figure S2, Figure S3a, Table S2, http://links.lww.com/AA/C144; P = .014). The concentration of TNT/TNI after surgery was highly variable among the different studies (Figure 2A). A statistically significant heterogeneity (χ2 = 80.89; df = 18; P < .00001; I2 = 78%) was identified among these studies (Figure 2A). Data pooling was performed by using the random-effects model, and the results revealed that concentrations of TNI/TNT were significantly lower in RIPC group compared to controls (standard mean difference [SMD], −0.25 ng/mL; 95% CI, −0.41 to −0.048 ng/mL; P = .004). Because of the publication bias, trim and fill test was employed, which showed that there was no trimming performed, and the results were unchanged (Supplemental Digital Content, Figure S3b, http://links.lww.com/AA/C144).

Back to Top | Article Outline

The Effect of RIPC on Total TNI/TNT Release

The overall effect of RIPC on TNI/TNT release during the first 72 hours after operation was assessed in 16 articles, which included 3122 patients.4–6,9,11–15,20,22,24,26,27,30,34 Similar to the concentration of TNI/TNT, total TNI/TNT release after surgery was also highly variable among the published papers with a significant heterogeneity (χ2 = 416.40; df = 16; P < .00001; I2 = 96%) using the 16 included trials (Figure 2B). No publication bias was observed after a funnel plot assessment and Begg’s test (Supplemental Digital Content, Figure S4, Table S2, http://links.lww.com/AA/C144; P = .266). In line with the concentration level after operation, we found RIPC significantly decreased the total TNI/TNT release after surgery (SMD, −0.49 ng/mL; 95% CI, −0.93 to −0.05 ng/mL; P = .03) based on a random-effects model.

Back to Top | Article Outline

The Effect of RIPC on Concentrations of CK-MB

Five studies of all included data reported the CK-MB value.11,14,21,33,37 One study33 reported the CK-MB value several times the upper reference limited value, and another one14 reported the total of CK-MB release within 72 hours after the operation. Therefore, we analyzed the remaining 3 studies, which showed that RIPC did not significantly decrease the CK-MB (SMD, −0.22; 95% CI, 0.07–0.35; P = .46; Supplemental Digital Content, Figure S5, http://links.lww.com/AA/C144).

Back to Top | Article Outline

The Effect of RIPC on Acute Myocardial Infarction

As RIPC decreased the concentration and total release of TNI/TNT, we further evaluated the effect of RIPC on AMI. There were 9 articles identified,6–9,20,23,25,27,33 including 5388 patients, reporting the incidence of AMI after cardiac surgery (Figure 3). We did not find significant publication bias among these 9 articles (Supplemental Digital Content, Figure S6, Table S2, http://links.lww.com/AA/C144). There was no significant heterogeneity among the trials (χ2 = 10.49; df = 8; P = .23; I2 = 24%). The overall incidence of AMI in the RIPC and the control group was 275 of 2687 (10.2%) and 313 of 2701 (11.6%), respectively. Based on a random-effects model, we did not find that RIPC was able to reduce the incidence of AMI after cardiac surgery (RR, 0.89; 95% CI, 0.70–1.13; P = .34), although the concentration and total release of TNI/TNT were significantly decreased with RIPC pretreatment. A subgroup analysis showed that RIPC also did not reduce the incidence of AMI in cardiac surgery patients who received volatile agents as a part of their anesthesia (RR, 0.71; 95% CI, 0.34–1.50; P = .37; Figure 3).

Figure 3.

Figure 3.

TSA analysis showed that the calculated sample size was 7164, which was larger than the number of patients included in the present study (Supplemental Digital Content, Figure S7a, http://links.lww.com/AA/C144). A sensitivity analysis showed that the effect of RIPC on AMI persisted at each data point while excluding any other included study after adjusting for multiple testing (Supplemental Digital Content, Table S3, http://links.lww.com/AA/C144).

Back to Top | Article Outline

The Effect of RIPC on Acute Kidney Injury

The effect of RIPC on AKI was also evaluated. Among all the included studies, 13 trials7–9,14,20,21,23,25,28,31,33,36 of 5618 patients were included into the analysis (Figure 4). We detected no evidence of a publication bias after a funnel plot analysis and Begg’s test (Supplemental Digital Content, Figure S8, Table S2, http://links.lww.com/AA/C144), but there was significant heterogeneity (P = .02, I2 = 49%) among the trials evaluating the effect of RIPC on AKI. The incidence of AKI after cardiac surgery in the RIPC and the control group was 19.2% and 20.7%, respectively. As with AMI, there was no statistically significant difference in AKI incidence between RIPC and control groups with use of a random-effects model (RR, 0.88; 95% CI, 0.72–1.06; P = .18). Furthermore, the subgroup analysis showed that RIPC could significantly reduce the incidence of AKI in patients who received volatile anesthetic agents (RR, 0.71; 95% CI, 0.54–0.93; P = .01; Figure 4).

Figure 4.

Figure 4.

Similar to AMI, TSA analysis for AKI showed that the calculated sample size was 5294, which was smaller than the number of patients included in the meta-analysis (Supplemental Digital Content, Figure S7b, http://links.lww.com/AA/C144). In addition, sensitivity analysis showed that the effect of RIPC on AKI persisted at each data point while excluding any other included study (Supplemental Digital Content, Table S3, http://links.lww.com/AA/C144).

Back to Top | Article Outline

The Effect of RIPC on Mortality

Finally, we evaluated the effect of RIPC on mortality. Nine trials6–9,11,20,23,33,36 of 5480 patients reported mortality after cardiac surgery (Figure 5). Among the studies, 5 trials7,9,11,23,36 reported in-hospital mortality, 2 trials6,8 reported 1-year mortality, and 1 did not report the time of death after surgery. The remaining 2 trials reported 6-week20 and 6-month mortality.33 After a funnel plot analysis and Begg’s test, we did not find a publication bias among included studies (Supplemental Digital Content, Figure S9, http://links.lww.com/AA/C144). There was no significant heterogeneity among these trials (χ2 = 13.73; df = 7; P = .06; I2 = 49%). Eighty-seven of 2735 (3.2%) patients died in the RIPC group and 83 of 2745 (3.0%) patients died in the control group. Based on a fixed-effects model, there was no evidence that RIPC reduced mortality after cardiac surgery (RR, 0.93; 95% CI, 0.55–1.55; P = .76). However, we interestingly found that RIPC could reduce mortality of cardiac surgical patients who received inhalational agents for anesthesia during their surgical procedure (RR, 0.41; 95% CI, 0.19–0.89; P = .03; Figure 5).

Figure 5.

Figure 5.

We also used TSA to calculate the sample size. The result showed that the calculated sample was 40,082 (Supplemental Digital Content, Figure S7c, http://links.lww.com/AA/C144), which was far larger than the number of patients included into analysis.

Back to Top | Article Outline

DISCUSSION

Cardiac surgery is associated with a high risk of end-organ ischemia and reperfusion injury, resulting in organ dysfunction such as AMI and AKI.1 There is evidence that the heart and kidney can be protected with RIPC. RIPC is performed noninvasively by simply inflating and deflating a standard blood pressure cuff placed on a limb to induce transient ischemia and reperfusion.3–7 Through this method, RIPC may be a valuable and cost-effective method to prevent organ dysfunction after cardiac surgery. However, the effectiveness of RIPC to improve the clinical prognosis of patients who receive cardiac surgery is still controversial. To further evaluate the summary of previously reported literature on the efficacy of RIPC to prevent AMI, AKI, and mortality in patients undergoing cardiac surgery, a meta-analysis of RCTs was performed. The result of our meta-analysis suggested that RIPC could reduce TNI/TNT release; however, it could not decrease the incidence of AMI, AKI, and mortality in this group of patients.

More than half of the included articles evaluated the concentration of TNI/TNT and total TNI/TNT release after cardiac surgery. Most studies demonstrated that the concentration of TNI/TNT release was highest at 6 hours after operation. The results of TNI/TNT release in our present analysis were in line with previously reported meta-analyses. However, our results showed a significant increase of TNI/TNT in the control group, and the difference was only about 10 times the upper reference limit. Domanski et al38 showed that the mortality will significant increase while TNI elevation 20–50 times the upper reference limit after cardiac surgery. Therefore, although we got a significant difference in TNI/TNT release, it might not reach a clinical significant. Therefore, we assessed the effect of RIPC on incidence of AMI, AKI, and mortality. Only 5 studies reported the value of CK-MB after cardiac operation and only 3 studies were included in the analysis. We did not find that RIPC could reduce the level of CK-MB. Nevertheless, our review only used 3 studies including 256 patients with a high heterogeneity among these studies.

AMI is common in high-risk cardiac surgery patients. Hausenloy et al8 reported that nearly one-fourth of CABG patients, with or without concurrent valve replacement, developed AMI after operation. The present analysis demonstrated that RIPC could decrease TNI/TNT release, but did not find that RIPC could reduce the incidence of AMI. Regardless, cardiac markers of myocardial injury after cardiac surgery may be associated with adverse cardiac events.39 In this study, there were more patients who had a history of coronary artery disease with chronic intermittent cardiac ischemia. This may indicate that patients without chronic intermittent cardiac ischemia may benefit more from RIPC before cardiac surgery. More importantly, our TSA results for 80% power to detect a 20% reduction gave a sample size, which was higher than the number of patients included in our analysis, indicating that the nonsignificant result may be due to the lack of statistic power.

AKI, which has been demonstrated to be a risk factor for longer hospital stay and higher mortality, can affect up to half of high-risk patients undergoing cardiac surgery. Zarbock et al reported that RIPC could significantly decrease the incidence of AKI after cardiac surgery. This was especially true for the moderate and severe cases of AKI. In addition, fewer patients in the RIPC group required renal replacement therapy compared to the control group.7 However, in our meta-analysis, we did not find that RIPC could decrease the incidence of AKI. This result did not change at each data point and was consistent with the sensitivity analysis (Supplemental Digital Content, Table S3, http://links.lww.com/AA/C144), and our results were consistent with a recent meta-analysis. In addition, the TSA-calculated sample size for 80% power to detect a 20% reduction was smaller than the available sample size for our analysis, indicating that there was enough statistical power to conclude from the current meta-analysis that RIPC does not reduce incidence of AKI in patients after cardiac surgery, given any other limitations. Given potential confounders, such as patient comorbidities, anesthetic regimens, and surgical technique, further studies will be needed to identify which patients will benefit the most from RIPC pretreatment.

Since there were no significant differences in the incidence of AKI and AMI after cardiac surgery, it is not surprising that mortality would also not be reduced. However, the calculated sample size from TSA analysis was far greater than the number of patients included in our analysis, indicating inadequate power to make a firm negative conclusion for mortality. In addition, we found that RIPC was able to reduce mortality, as well as had a trend to reduce the incidence of AMI and AKI, in a subgroup of patients who received volatile anesthetic agents. This result was in line with a previous study by Kottenberg et al.15 Inhalational anesthetics, such as isoflurane, may alter the effect of RIPC on organ protection. Previous work has demonstrated that volatile agents can mimic the early phase of ischemic preconditioning.40 Therefore, volatile anesthetic agents may have a synergistic effect with RIPC, which can provide greater organ function protection. In addition, volatile agents have demonstrated a mortality reduction in cardiac surgery patients in some studies. Therefore, cardiac surgery anesthetists should consider the use of volatile agents. However, these studies reporting this combined effect of RIPC with volatile agents were relatively small. Large, multicenter, RCTs need to be performed to confirm our results.

The present analysis must be interpreted in light of the strengths and limitations of the included trials. Different from previous meta-analysis with small samples, we included several large, multicenter, randomized studies8,9,23 and >7000 patients in our analysis, which strengthens our results.

However, we also have limitations. First, the heterogeneity was large among included studies. The method of measurement of TNI/TNT may be a potential source of this heterogeneity. Among the enrolled studies, the different measurement methods resulted in a different upper reference limit value (ULR). To better standardize the results from these articles, transformation of the data based on the ULR would bring a more accurate result. However, nearly half of the articles included here did not report the ULR, and hence, we could not perform the transformation for analysis. Therefore, we used a standardized mean difference to analyze the data to attempt to identify potential sources of bias. Differential sampling and timing of events in all the studies may have also caused difficulties in data interpretation. For example, subgroup analysis showed that RIPC decreased the incidence of AMI in patients with inhalational anesthesia. However, the study by Thielmann et al largely skewed the results. If we exclude this study, the results showed that RIPC was unable to decrease the incidence of AMI (RR, 1.31; 95% CI, 0.33–5.12; P = .70). Therefore, a larger study is needed to confirm these results.

Second, we did not analyze other factors influencing the effect of RIPC. These factors included whether patients were on or off coronary bypass during the procedure,23 presence of comorbid conditions such as diabetes or hyperlipidemia, and the use of specific medications. However, most studies did not provide all aspects of this patient information. Therefore, further studies removing these potential biases need to be performed to identify the patients who would benefit the most from RIPC.

Third, we detected a significant publication bias among studies, which reported the concentration of TNI/TNT, although there was no trimming performed in trim and fill test. In addition, mostly all of the power results were small. These indicated that larger, more stringent studies need to be performed to confirm the effect of RIPC on the outcome in cardiac surgery patients.

Back to Top | Article Outline

CONCLUSIONS

Our meta-analysis demonstrated that RIPC reduced TNI/TNT release after cardiac surgery. RIPC did not significantly reduce the incidence of AKI, AMI, and mortality. However, RIPC was able to reduce the incidence of AKI and mortality of patients who received volatile inhalational agents for anesthesia during their cardiac procedure. Further research will need to be performed to investigate which adult cardiac surgery patients will benefit most from RIPC.

Back to Top | Article Outline

DISCLOSURES

Name: Jianfeng Xie, MD.

Contribution: This author helped develop the idea and a protocol for this study, extract and analyze the data, and write the manuscript.

Name: Xiwen Zhang, MD.

Contribution: This author helped develop a protocol, extract and analyze the data, and write the manuscript.

Name: Jingyuan Xu, MD.

Contribution: This author helped develop a protocol, extract and analyze the data, and write the manuscript.

Name: Zhongheng Zhang, MD.

Contribution: This author helped develop a protocol, analyze the data, and critically revise the manuscript.

Name: Nathan J. Klingensmith, MD.

Contribution: This author helped develop a protocol, analyze the data, and critically revise the manuscript.

Name: Songqiao Liu, MD, PhD.

Contribution: This author helped extract and analyze the data and write the manuscript.

Name: Chun Pan, MD, PhD.

Contribution: This author helped extract and analyze the data and write the manuscript.

Name: Yi Yang, MD, PhD.

Contribution: This author helped develop a protocol, analyze the data, and write the manuscript.

Name: Haibo Qiu, MD, PhD.

Contribution: This author helped develop the idea and a protocol for this study, extract and analyze the data, and write the manuscript.

This manuscript was handled by: W. Scott Beattie, PhD, MD, FRCPC.

Back to Top | Article Outline

REFERENCES

1. Muehlschlegel JD, Perry TE, Liu KYCABG Genomics Investigators. Troponin is superior to electrocardiogram and creatinine kinase MB for predicting clinically significant myocardial injury after coronary artery bypass grafting. Eur Heart J. 2009;30:1574–1583.
2. Gho BC, Schoemaker RG, van den Doel MA, Duncker DJ, Verdouw PDMyocardial protection by brief ischemia in noncardiac tissue. Circulation. 1996;94:2193–2200.
3. Cheung MM, Kharbanda RK, Konstantinov IERandomized controlled trial of the effects of remote ischemic preconditioning on children undergoing cardiac surgery: first clinical application in humans. J Am Coll Cardiol. 2006;47:2277–2282.
4. Hausenloy DJ, Mwamure PK, Venugopal VEffect of remote ischaemic preconditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery: a randomised controlled trial. Lancet. 2007;370:575–579.
5. Venugopal V, Hausenloy DJ, Ludman ARemote ischaemic preconditioning reduces myocardial injury in patients undergoing cardiac surgery with cold-blood cardioplegia: a randomised controlled trial. Heart. 2009;95:1567–1571.
6. Thielmann M, Kottenberg E, Kleinbongard PCardioprotective and prognostic effects of remote ischaemic preconditioning in patients undergoing coronary artery bypass surgery: a single-centre randomised, double-blind, controlled trial. Lancet. 2013;382:597–604.
7. Zarbock A, Schmidt C, Van Aken HRenalRIPC Investigators. Effect of remote ischemic preconditioning on kidney injury among high-risk patients undergoing cardiac surgery: a randomized clinical trial. JAMA. 2015;313:2133–2141.
8. Hausenloy DJ, Candilio L, Evans RERICCA Trial Investigators. Remote ischemic preconditioning and outcomes of cardiac surgery. N Engl J Med. 2015;373:1408–1417.
9. Meybohm P, Bein B, Brosteanu ORIPHeart Study Collaborators. A multicenter trial of remote ischemic preconditioning for heart surgery. N Engl J Med. 2015;373:1397–1407.
10. Lee JH, Park YH, Byon HJ, Kim HS, Kim CS, Kim JTEffect of remote ischaemic preconditioning on ischaemic-reperfusion injury in pulmonary hypertensive infants receiving ventricular septal defect repair. Br J Anaesth. 2012;108:223–228.
11. Lomivorotov VV, Shmyrev VA, Nepomnyaschih VARemote ischaemic preconditioning does not protect the heart in patients undergoing coronary artery bypass grafting. Interact Cardiovasc Thorac Surg. 2012;15:18–22.
12. Rahman IA, Mascaro JG, Steeds RPRemote ischemic preconditioning in human coronary artery bypass surgery: from promise to disappointment? Circulation. 2010;122:S53–S59.
13. Karuppasamy P, Chaubey S, Dew TRemote intermittent ischemia before coronary artery bypass graft surgery: a strategy to reduce injury and inflammation? Basic Res Cardiol. 2011;106:511–519.
14. Pinaud F, Corbeau JJ, Baufreton CRemote ischemic preconditioning in aortic valve surgery: results of a randomized controlled study. J Cardiol. 2016;67:36–41.
15. Kottenberg E, Thielmann M, Bergmann LProtection by remote ischemic preconditioning during coronary artery bypass graft surgery with isoflurane but not propofol—a clinical trial. Acta Anaesthesiol Scand. 2012;56:30–38.
16. Landoni G, Greco T, Biondi-Zoccai GAnaesthetic drugs and survival: a Bayesian network meta-analysis of randomized trials in cardiac surgery. Br J Anaesth. 2013;111:886–896.
17. Hozo SP, Djulbegovic B, Hozo IEstimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol. 2005;5:13.
18. Wetterslev J, Thorlund K, Brok J, Gluud CTrial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis. J Clin Epidemiol. 2008;61:64–75.
19. Bautin AE, Galagudza MM, Datsenko SV, et al.[Effects of remote ischemic preconditioning on perioperative period in elective aortic valve replacement]. Anesteziologiia i reanimatologiia. 2014:11–7.
20. Candilio L, Malik A, Ariti CEffect of remote ischaemic preconditioning on clinical outcomes in patients undergoing cardiac bypass surgery: a randomised controlled clinical trial. Heart. 2015;101:185–192.
21. Choi YS, Shim JK, Kim JCEffect of remote ischemic preconditioning on renal dysfunction after complex valvular heart surgery: a randomized controlled trial. J Thorac Cardiovasc Surg. 2011;142:148–154.
22. Hong DM, Jeon Y, Lee CSEffects of remote ischemic preconditioning with postconditioning in patients undergoing off-pump coronary artery bypass surgery—randomized controlled trial. Circ J. 2012;76:884–890.
23. Hong DM, Lee EH, Kim HJDoes remote ischaemic preconditioning with postconditioning improve clinical outcomes of patients undergoing cardiac surgery? Remote Ischaemic Preconditioning with Postconditioning Outcome Trial. Eur Heart J. 2014;35:176–183.
24. Hong DM, Mint JJ, Kim JHThe effect of remote ischaemic preconditioning on myocardial injury in patients undergoing off-pump coronary artery bypass graft surgery. Anaesth Intensive Care. 2010;38:924–929.
25. Kim JC, Shim JK, Lee S, Yoo YC, Yang SY, Kwak YLEffect of combined remote ischemic preconditioning and postconditioning on pulmonary function in valvular heart surgery. Chest. 2012;142:467–475.
26. Li L, Luo W, Huang LRemote perconditioning reduces myocardial injury in adult valve replacement: a randomized controlled trial. J Surg Res. 2010;164:e21–e26.
27. Lucchinetti E, Bestmann L, Feng JRemote ischemic preconditioning applied during isoflurane inhalation provides no benefit to the myocardium of patients undergoing on-pump coronary artery bypass graft surgery: lack of synergy or evidence of antagonism in cardioprotection? Anesthesiology. 2012;116:296–310.
28. Meybohm P, Renner J, Broch OPostoperative neurocognitive dysfunction in patients undergoing cardiac surgery after remote ischemic preconditioning: a double-blind randomized controlled pilot study. PLoS One. 2013;8:e64743.
29. Saxena P, Aggarwal S, Misso NLRemote ischaemic preconditioning down-regulates kinin receptor expression in neutrophils of patients undergoing heart surgery. Interact Cardiovasc Thorac Surg. 2013;17:653–658.
30. Thielmann M, Kottenberg E, Boengler KRemote ischemic preconditioning reduces myocardial injury after coronary artery bypass surgery with crystalloid cardioplegic arrest. Basic Res Cardiol. 2010;105:657–664.
31. Venugopal V, Laing CM, Ludman A, Yellon DM, Hausenloy DEffect of remote ischemic preconditioning on acute kidney injury in nondiabetic patients undergoing coronary artery bypass graft surgery: a secondary analysis of 2 small randomized trials. Am J Kidney Dis. 2010;56:1043–1049.
32. Wagner R, Piler P, Bedanova H, Adamek P, Grodecka L, Freiberger TMyocardial injury is decreased by late remote ischaemic preconditioning and aggravated by tramadol in patients undergoing cardiac surgery: a randomised controlled trial. Interact Cardiovasc Thorac Surg. 2010;11:758–762.
33. Walsh M, Whitlock R, Garg AXRemote IMPACT Investigators. Effects of remote ischemic preconditioning in high-risk patients undergoing cardiac surgery (Remote IMPACT): a randomized controlled trial. CMAJ. 2016;188:329–336.
34. Xie JJ, Liao XL, Chen WGRemote ischaemic preconditioning reduces myocardial injury in patients undergoing heart valve surgery: randomised controlled trial. Heart. 2012;98:384–388.
35. Young PJ, Dalley P, Garden AA pilot study investigating the effects of remote ischemic preconditioning in high-risk cardiac surgery using a randomised controlled double-blind protocol. Basic Res Cardiol. 2012;107:256.
36. Zimmerman RF, Ezeanuna PU, Kane JCIschemic preconditioning at a remote site prevents acute kidney injury in patients following cardiac surgery. Kidney Int. 2011;80:861–867.
37. Ali N, Rizwi F, Iqbal A, Rashid AInduced remote ischemic pre-conditioning on ischemia-reperfusion injury in patients undergoing coronary artery bypass. J Coll Physicians Surg Pak. 2010;20:427–431.
38. Domanski MJ, Mahaffey K, Hasselblad VAssociation of myocardial enzyme elevation and survival following coronary artery bypass graft surgery. JAMA. 2011;305:585–591.
39. Lattouf OM, Thourani VH, Kilgo PDInfluence of on-pump versus off-pump techniques and completeness of revascularization on long-term survival after coronary artery bypass. Ann Thorac Surg. 2008;86:797–805.
40. Swyers T, Redford D, Larson DFVolatile anesthetic-induced preconditioning. Perfusion. 2014;29:10–15.

Supplemental Digital Content

Back to Top | Article Outline
Copyright © 2018 International Anesthesia Research Society