Is remote ischaemic preconditioning worthwhile for patients undergoing cardiac surgery with cardiopulmonary bypass? A meta-analysis and systematic literature review

doi:10.21203/rs.3.rs-2224408/v1

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Is remote ischaemic preconditioning worthwhile for patients undergoing cardiac surgery with cardiopulmonary bypass? A meta-analysis and systematic literature review

https://doi.org/10.21203/rs.3.rs-2224408/v1

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Background: Numerous randomized controlled trials (RCTs) investigated the clinical benefits of remote ischemic preconditioning (RIPC) prior to cardiopulmonary bypass (CPB). However, to date, there is still no consensus on the benefit of this procedure. Therefore, this meta-analysis aimed to evaluate the treatment outcomes of RIPC in patients treated with CPB.

Methods: Databases were systematically searched for eligible RCTs comparing the delivery of RIPC with no treatment or sham RIPC (control) before CPB. Two authors individually screened studies and assessed the risk of bias. The primary outcome measure was mortality. The secondary outcome measures were length of intensive care unit (ICU) or hospital stay, the incidence of myocardial injury (MI), low cardiac output syndrome (LCOS) and so on. The relative risk (RR) and the population size mean difference (SMD) at the 95% confidence interval (95%CI) were compared between the 2 groups.

Results: Forty-one RCTs met the eligibility criteria. RIPC did not reduce overall and in-hospital mortality compared with the control group (RR=0.99, 95%CI: 0.78-1.26, I²=12%). No remarkable difference was observed between the two groups regarding the length of ICU and hospital stay (SMD: -0.12, 95%CI: -0.29−0.06, I²=93%; SMD: -0.926, 95%CI: -2.103−0.251, I²=95.2%, respectively). However, RIPC reduced the incidence of MI and the ventilation duration slightly when compared to the control group (RR=0.86, 95%CI: 0.76−0.99, I²=22%; RR=-0.16 95%CI: -1.85−1.52, I²=0%, respectively).

Conclusion: RIPC did not have an impact on mortality and length of ICU/hospital stay, however, it reduced the incidence of MI and the ventilation duration. This work does not recommend RIPC for patients underwent cardiac surgery.

Cardiopulmonary bypass

Remote ischemic precondition

Cardiac surgery

Mortality

Meta-analysis

Systematic review

Patients undergoing cardiac surgery are increasingly presenting with multiple co-morbidities (1). These patients are at higher risk of mortality and at developing cardiac and kidney complications post-surgery. Recent studies reported an increase in the incidence of acute myocardial infarction (MI) and atrial fibrillation (AF) after cardiac surgery. This increase was attributed to ischemic organ reperfusion injuries during cardiac surgery (2, 3). Remote ischemic preconditioning (RIPC) is a simple, inexpensive, and non-invasive procedure that involves inducing cycles of ischemia and reperfusion to a local organ via the inflation and deflation of a blood pressure cuff applied to one of the limbs (4). The short episodes of ischemia and reperfusion applied to a local organ seem to protect the myocardium from subsequent episodes of ischemia. As a result, some medical centers apply RIPC before cardiopulmonary bypass surgery (CPB) to reduce the risk of complications after cardiac surgery (5, 6).

The role of RIPC in reducing the incidence of myocardial infarction were demonstrated by Przyklenk et al. (7) and Hausenloy et al(8), first reported in Kerendi et al(9). However, two subsequent large randomized control trials (RCTs) and other meta-analyses and systematic reviews demonstrated that RIPC failed to offer protective effect on patients (10, 11). To specify, these two studies demonstrated patients in RIPC group was not got remarkable benefits about the mortality, MI and new-onset stroke as compared with those underwent control group. New onset AF was failed to decrease by RIPC that illustrated by Kumar et al in year of 2019(12). Moreover, other clinical benefits such the length of hospital stay and ventilation duration were also concern of interest for reviewers.

The protective effect of RIPC on the myocardium has been attributed to the activation of nociceptive fibers within the distant organ. This triggers a neuronal and humoral signal transfer from the remote organ to the heart, causing the release of cardioprotective substances from the cardiac vagal and sympathetic efferent nervous system (6, 13). Furthermore, the activated nociceptive fibers might release endogenous gasotransmitter H2S that exerts a cardioprotective effect(14). Mediators of calcitonin-gene related peptide (CGRP), adenosine and bradykinin have been proposed that involved in cardioprotective role in the RIPC(15).

Despite the potential benefits of performing RIPC before cardiac surgery or cardiopulmonary bypass, the cardioprotective effect of this intervention and its impact on treatment outcomes remains controversial in the literature (16, 17) . Therefore, this meta-analysis aimed to evaluate the benefits of performing RIPC before cardiopulmonary bypass in patients undergoing cardiac surgery to inform clinical practice.

2.1 Search strategy

The electronic databases, Ovid MEDLINE, Ovid Embase, and Cochrane Library, were systematically searched up until February 18, 2021, using the keywords cardiac surgery, coronary artery bypass graft (CABG), valve replacement surgery, cardiopulmonary bypass, CPB, remote ischemic preconditioning, RIPC, and randomized controlled trials. A hand search of all pertinent studies was also performed. There were no limitations of language and publication status in this meta-analysis. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist was used to report the findings of this study for this meta-analysis and systematic review (18). Since all the data used in this study was extracted from published literature, no ethical approval was required to conduct this study.

2.2 Inclusion and exclusion criteria

Only RCTs comparing the treatment outcomes of adults treated with CPB with and without RIPC (control) were included in this meta-analysis. The studies were only included if they assessed the following outcome measures, mortality in an intensive care unit (ICU) or hospital, length of ICU or hospital stay, the incidence of MI, low cardiac output syndrome (LCOS), arterial fibrillation (AF), and stroke, the postoperative left ventricular ejection fraction (LVEF) and ventilation duration.

Studies were excluded if they included children undergoing RIPC before cardiac surgery with or without CPB or if they evaluated patients undergoing RIPC before non-cardiac surgery. Studies were also excluded if the RIPC was combined with other interventions.

2.3 Data extraction and outcomes measures

The title and abstracts of all the studies identified through the literature search were screened independently by two reviewers to assess their eligibility for this study. Any discrepancies were resolved via discussion with a third reviewer. Finally, the full texts of potential studies were reviewed to confirm that they met the eligibility criteria of this meta-analysis.

Data extraction was conducted from the full-text studies as follows. The first author and published date of each study were recorded together with relevant clinical and demographic data, including the type of anesthesia, age, number of recruited patients, type of surgery, gender, co-morbidities or basic diseases, cross-clamp time (min), and CPB time (min). The outcomes of both treatment arms include the postoperative LVEF, in-hospital mortality, mortality, length of hospital or ICU stay, new set atrial fibrillation, low cardiac output syndrome, ventilation duration, myocardial infarction, and stroke. The reporting of mortality varied between the different studies. Therefore, for the purpose of this study, 30 days of mortality that death occuring within 30 days after surgery was identified as the primary outcome. In addition, long-term mortality was defined as death occurring after 60 days post-surgery. Operative death or mortality data that did not report the days after surgery were classified as unknown mortality in this meta-analysis. All other treatment outcomes were recognized as secondary outcomes.

2.4 Quality evaluation

The two investigators evaluated the methodological quality of the selected studies independently. The Cochrane Collaboration's tool (19) was utilized to assess the quality of the studies. The tool quantifies the risk of bias as low, high, or unclear based on the following criteria: random sequence generation, allocation, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other potential sources of bias.

2.5 Statistical analysis

The mean-difference effective size (MD) with a 95% confidence interval (CI) was used to compare the continuous data, and the relative risk (RR) with 95% CI was used to compare the binary data, between the two treatment arms. The fraction of variance due to heterogeneity was estimated using the I-squared (I²) statistic. A random effects model was used according to I²>40% and fixed model was used when I²≤40%. CPB time during the operation was identified as one of confounding factor, therefore an additional subgroup analysis was performed to evaluate the impact of CPB time on treatment outcomes. In the subgroup analysis, the CPB time was divided as long- or short-term using the 90 minutes of mean CPB time described in each original research. A funnel plot was used to evaluate publication bias. All statistical analyses were performed using RevMan 5.0 software.

3.1 Literature search results

A total of 1,572 potential articles were obtained initially through several databases. After screening the title, abstract, and full texts using the PRISMA tool, 41 studies met the eligibility criteria and were included in the meta-analysis (10, 11, 20-58) (Figure 1).

3.2 Characteristics of the included studies

The RCTs evaluated in the 41 studies included a total of 11,058 adult patients. All RCTs consisted of 2 treatment groups, the RIPC group, and the sham RIPC or control group. The RIPC protocol for each study involved inflating and deflating a pressure belt applied to the upper arm. A pressure of approximately 200 mmHg was applied in 3 to 4 cycles of 5 minutes.

The basic clinical characteristics of the included studies are summarized in Table 1. All studies were published from 2009 to 2019. Patients were treated with isolated coronary artery bypass graft (CABG) surgery in 14 of the included RCTs (20, 29, 34, 35, 37, 39, 44, 46-50, 52, 59). In 7 of these RCTs (n=977) (24, 33, 36, 45, 53-55), a valve replacement was applied during the CBP.

3.3 Quality of the included studies

The majority of the included studies had a "low" risk of bias for almost all items. Only the allocation concealment criterion was judged as "unclear", as most studies did not provide sufficient information to minimize the introduction of this bias. The risk of bias in all included studies is summarized in Figures 2A and B.

3.4 Primary outcomes

3.4.1 Mortality

The basic mortality was reported in 31 articles (10, 22, 23, 25-29, 34, 36, 38, 44, 46-49, 56, 57, 59), as shown in Figure 3A, and demonstrated the non-significant reduced mortality with patients receiving RIPC (RR=0.99, 95%CI: 0.78-1.26, I²=12% Eighteen studies (10, 22, 23, 25-29, 34, 36, 38, 44, 46-49, 56, 57, 59), involving 5110 participants, reported the 30 days mortality (RR=0.93, 95%CI: 0.64-1.41, I²=0%) with nonsignificant difference. RIPC had no significant impact on long-term mortality (RR=1.02, 95%CI: 0.74-1.41, I²=47%). A subgroup analysis of the 30-day mortality was carried out to account for the CPB duration. No significant difference was noted between the long (RR=1.14, 95%CI: 0.71-1.81, I²=0%) and short (RR=0.09, 95%CI: 0.01-1.62, I²=NA) CPB duration groups (Figure 3B).

3.4.2 In-hospital mortality

In-hospital mortality was reported in 10 articles (20, 31, 35, 38, 42, 46, 52, 56-58), including a total of 2,339 operated patients. In-hospital mortality occurred in 41 patients and did not differ significantly between RIPC and control groups (RR=0.95, 95%CI 0.53-1.69, I²=NA). Subgroup analysis according to the CPB duration showed no statistical difference between the two groups (long duration of CPB time: RR=0.85, 95%CI:0.45-1.59, I²=0%, short duration of CPB time: not estimable). Relevant data on in-hospital mortality and subgroup analysis are illustrated in Figures 4A and 4B.

3.5 Secondary outcomes

3.5.1 Length of hospital or ICU stay

The length of hospital stay was described in 24 studies (10, 23, 24, 26-28, 30-34, 36, 38, 41, 42, 46, 48, 49, 52-54, 57-59) which included a total 5,896 patients. The length of hospital stay did not differ significantly from the control group (MD=0.10, 95%CI: −0.10-0.31, I²=0%). Similarly, the ICU stay was evaluated in 23 studies (10, 23, 24, 26-28, 30-34, 36, 37, 42, 44-49, 53, 54, 57) and did not differ significantly between the 2 groups (MD=−0.12, 95%CI: −0.29-0.06, I²=0%) as shown in Figures 5A and B. Conversely several studies reported that RIPC reduced the length of ICU stay (10, 23, 26), while Mcsarelli et al. (42) reported that RIPC increased the length of ICU stay. The subgroup analysis evaluating the CPB time on hospital stay showed no remarkable difference for both long CPB time (MD=-0.06, 95%CI: −0.33-0.21, I²=0%) and short CPB time (MD=0.25, 95%CI: −0.11-0.62, I²=5%). Similarly, the length of ICU stay did not differ between the two CPB durations (long CPB time: MD=-0.15, 95%CI: −0.42-0.11, I²=93%, short CPB time: MD=-0.0, 95%CI: −0.17-0.16, I²=79%) (Figure 5C & D).

3.5.2 Low cardiac output syndrome

LCOS, one of the complications triggered by CPB, was reported in 6 articles (20, 27, 42, 46, 48, 49). Two studies reported that none of the patients in the RIPC and control group developed LCOS (42, 48). The rest of the studies showed that RIPC had no impact on the incidence of postoperative LCOS compared with the control group (RR=0.93, 95%CI: 0.68-1.29, I²=37%) as shown in Figure 6A.

3.5.3 Myocardial injury

Postoperative MI incidence data were reported by 22 articles (10, 11, 21-23, 25-27, 31, 33, 38-42, 46, 48-50, 53, 57, 58) which included a total of 9,480 participants. Six of the studies reported no incidence of MI after surgery. The rest of the studies reported a higher incidence of postoperative MI in the sham RIPC or control group (RR=0.86, 95%CI: 0.76-0.99, I²=22%), compared with the RIPC group, as shown in Figure 6B. However, no significant difference between RIPC and control groups was reported in the CPB time subgroup analysis (long duration of CPB time: RR=0.95, 95%CI: 0.81-1.12, I²=0%, short duration of CPB time: RR=0.71, 95%CI: 0.14-0.57, I²=0%) (Figure 6C).

3.5.4 Post-operative LVEF & ventilation duration

Only 6 studies (20, 24, 32, 38, 46, 55) reported the postoperative LVEF outcome.The LVEF did not differ significantly between the RIPC and sham RIPC (or control) (RR=−0.16, 95%CI: −1.85-1.52, I²=0%). A total of 18 studies (26, 28, 30-34, 36, 37, 41, 42, 44-46, 48, 49, 56, 57) involving 3378 participants evaluated the ventilation duration. The ventilation duration in the RIPC was significantly shorter than the control group (MD=−0.39, 95%CI: −0.75-−0.03, I²=42%). Detailed data on postoperative LVEF and ventilation duration is illustrated in Figures 7A and B.

3.5.5 AF & Stroke

Fifteen studies (10, 11, 22, 23, 30, 31, 38, 39, 41, 42, 46-48, 50, 59) involving a total of 5389 patients, reported on the onset of AF post-surgery. No significant difference was noted in the onset of AF between the RIPC and control group (RR=0.99 95%CI: 0.91, 1.07, I²=36%). Only 1 study reported No incidence of AF in both groups (Figure 7C). The incidence of stroke post-surgery was reported in 18 articles (10, 11, 22, 23, 25, 27, 31, 33, 35, 38, 40, 42, 48, 49, 53, 57). There are 103 patients in the RIPC group had stroke post-surgery, suggested that no significant difference between comparison RR=0.86, 95%CI: 0.76-0.99, I²=22%) (Figure 7D).

Prolonged operation time is a major challenge encountered by cardiac surgeons as it can increase the risk of myocardial ischemia and hypoxia, which is often fatal (60) (61). Aortic cross-clamping during surgery often causes ischemic-reperfusion injury leading to MI due to ischemia-reperfusion injury (62). Therefore, new treatment strategies must be developed to increase the ischemic tolerance of vital organs, particularly the heart. The ischemic preconditioning and post-conditioning induced by RIPC may have an important role in making myocardial tissue more resistant to ischemia(63-65). However, this work updated relevant RCTs to further evaluate the benefit of RIPC for patients that underwent heart surgery.

The studies by Pierce et al. 2017 and Yi et al. 2017 (64, 65) have shown that RIPC did not reduce morbidity and mortality after surgery. Similarly, our meta-analysis found that RIPC had no impact on the 30-day, long-term, and in-hospital mortality. The unknown mortality group incorporated the number of deaths during surgery and the number of patients with unspecified days of mortality from surgery. However, as reported in some meta-analyses, the non-significant reduction in mortality in the RIPC group could be attributed to patients having other co-morbidities such as diabetes Miletus and hypercholesterolemia that may have reduced the protective effect of RIPC (63). The use of RIPC had no significant impact on the length of ICU and in-hospital stays. These findings were in line with previously published meta-analyses and literature reviews (16, 18, 66). Nevertheless, further subgroup analysis in our study showed that patients with longer CPB times during cardiac surgery had longer ICU stays. This factor could have led to heterogeneity in our study and may explain why our findings differed from those published by Jin et al. and Moscarelli et al. (33, 42). These studies were not included in previous reviews.

Regarding secondary outcomes, the pooled meta-analysis data showed that RIPC failed to reduce the incidence of LOCS. However, a slight reduction in the incidence of MI was noted in the RIPC group compared to the control group. This finding was not consistent with that of Long et al. (67), possibly due to differences in the population, surgical procedures, and RIPC protocols between the 2 studies. Following subgroup analysis, we could not determine the source of heterogeneity. However, we noted considerable variation in the population characteristics in 2 of the large RCTs included in this meta-analysis (10, 11). The trial of Hausenloy et al included 1612 patients who had a greater risk of death with high score of European System for Cardiac Operative Risk Evaluation (EuroSCORE), and included some patients diagnosed LVEF>30% as well(10). The different criteria of Meybohm et al that excluded high risk of participants(11).The study by Hausenloy et al. suggested that mortality caused by cardiovascular system which is related with with remote ischemic preconditioning as compared with the sham preconditioning(10). The large trial of Meybohm et al. showed no significant difference was observed in the outcomes of rate of postoperative myocardial infarction, stroke, renal failure, and death within 90 days after cardiac surgery(11). The partial attribution to stupefacient (e.g., propofol), inadequate implement of RIPC protocol.

Our meta-analysis showed no significant difference in the onset of stroke following CPB. An interesting finding of this study was that RIPC significantly shortened the ventilation duration. Furthermore, we have presented the CPB duration has potential affect the cardioprotective role of RIPC. Ischemia reperfusion injury (IRI) triggered irreversible cell death and then developed severe damages(68). Therefore, this meta-analysis took it considered into potential factor of CPB duration and performed subgroup analysis according to CPB duration of 90 min cutoff.

There is evidence that anesthetic regimen is likely to attenuate the benefits of RIPC via inducing alternations of cellular signaling cascades(69). However, anesthetic like sevoflurane, isoflurane, propofol has possibly generated protective effect on ischemic organ through exposing transient ischemic and reperfusion of a local organ before occurring targeted ischemic organs(70). Hence, we assumed that one possibility, with regard to controversial argues, that anesthetic have synergy with the beneficial effect of RIPC. Meanwhile, some studies have evaluated the outcomes of various sedation strategies during cardiac surgeries and concluded that RIPC might have an increased protective effect when used in combination with the anesthetic agent propofol (43, 71). On the other hand, the use of the general anesthetic agent sevoflurane in combination with RIPC had no obvious protective effect (43). Propofol may possibly amplify the protective effects of RIPC by abolishing its humoral-mediated response (72). In animal models, isoflurane was able to protect heart from ischemic damage(73), but different opinion was put forward by a trial(73), hence, a review set forth that the dosing of anesthetic should be noted in the surgery(74).

Overall the findings of this meta-analysis indicate that RIPC has no cardioprotective effect and has no impact on mortality, the length of ICU/hospital stay, and the incidence of LCOS, AF, and stroke post-surgery. Several meta-analyses declared that RIPC did not improve overall clinical outcome, despite some cardiac outcomes like the incidence of cardiac arrhythmia(75) and the concentration of myocardial biomarkers(69). This meta-analysis grabbed the concerns of interest of cardiac outcomes and outcomes that easy to overlook (the length of hospital/ICU stay and ventilation duration). However, this meta-analysis has some limitations that have to be acknowledged. Various sources of heterogeneity may have influenced the results of our meta-analysis. Current studies did not provide detailed information about the RIPC procedure, particularly about the positioning of the pressure belt and the amount and duration of the pressure. Not all studies provided information on the CPB duration, and therefore it was not possible to make a comprehensive subgroup analysis. The serum biomarkers (e.g., CKMB and chemokines interferon-γ) were not evaluated in this study as this data was not provided in the published RCTs.

Furthermore, the sedation strategies, patient characteristics, and surgical procedures varied between the studies. In addition, the reporting on mortality also varied between different studies. Therefore to overcome this problem in this meta-analysis, the mortality data was classified into 4 categories, 30-day mortality, 60-day mortality, in-hospital mortality, and unknown mortality. Although some studies evaluated the correlation between kidney failure following surgery and mortality, we could not evaluate this factor due to the limited data available. Moreover, our meta-analysis did not evaluate the impact of combining other treatment strategies such as intermittent systemic hypoxic-hyperoxic training with RIPC on treatment outcomes. Therefore further research is recommended to better understand the role of RIPC and other interventions in improving treatment outcomes in cardiac surgery.

Despite the limitations of this meta-analysis, it is important to note the strengths of our research. Our meta-analysis included a comprehensive analysis of 41 relevant RCTs, thus improving the statistical power of our findings. Furthermore, we focused mainly on real clinical outcomes such as mortality, the incidence of MI, and the length of ICU/hospital stay, rather than some blood markers, which may not reflect the actual benefit of RIPC. We also excluded studies that included children, as these may have influenced the findings of our study due to a high percentage of congenital disorders among this population.

The meta-analysis evaluated the benefits of using RIPC before cardiac surgery in adult patients. The evaluation of the 41 RCTs indicates that RIPC has no significant impact on mortality and length of ICU/hospital stay. However, RIPC significantly reduced the incidence of MI and the ventilation duration post-surgery. This meta-analysis does not recommend RIPC on patients that underwent cardiac surgery. Nevertheless, we hypothesis that a mixed strategy is likely to provide a better cardioprotective role for patients.

Ethical Approval

This article was not applicable of ethical approval

Competing interests

The authors declare no potential conflicts of interest.

Authors' contributions

CLC, YYY, and LM conceived the idea of the meta-analysis and systematic literature review. MK and MA screened the studies and extracted the relevant data from each eligible study. YYY performed the statistical analysis, and CLC supervised the analysis. YYY, BQQ, MA, and MK interpreted the findings. YYY drafted the manuscript, CLC reviewed the manuscript thoroughly, and YYY revised the manuscript for final submission. All authors have approved the final draft of the manuscript. CLC and YYY are guarantors. CLC accepts full responsibility for the work and conduct of the study, has access to the data, and controls the decision to publish. The corresponding author attests that all listed authors meet the authorship criteria and that no others meeting the criteria have been omitted.

Funding

No funding was received to conduct this research.

Availability of data and materials

Not available.

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Table 1 Characteristics of the studies included in the meta-analysis

Study	Sample	Type of surgery	RIPC protocol	Co-morbidities or basic diseases	CPB time (min) RIPC vs. Control	Cross-clamp time (min) RIPC vs. Control	Type of anesthesia	Timing of RIPC
Ahmad 2014	67	CABG	Right arm, 3 x 5 minutes cycle, 200 mmHg	Diabetes, Hypertension	110.09±32.01; 105.53±28.82;	65.69±19.65; 66.31±23.60;	Sevoflurane/isoflurane	After the induction anesthesia
Carera-Fuentes 2015	26	Complex cardiac surgery with CPB	Left arm, 4 x 5 minutes cycle, 200mmHg	None	119±81; 74±36	47±23; 38±12	Propofol and halothane	After the induction anesthesia but before start of the extracorpo-real circulation
Candilio 2015	180	CABG and/or valve surgery on CPB	Upper arm and lower lib, 2*5min cycle, 200mmHg	Hypercholesterolemia, Hypertension, COPD, CVA/TIA, Diabetes, Peripheral vascular disease, MI	89.6±31.0; 96.7±32.6	61.5±26.9; 64.8±26.4	Volatile (isoflurane or sevoflurane)	After anesthesia induction but prior to sternotomy
Cao 2017	63	elective valve replacement on CPB	right lower limb, 3 x 5 minutes cycle, 200 mmHg	None	115 ± 29; 115 ± 27	77 ± 21; 77 ± 24	Volatile (sevoflurane)	After intubation
Cho 2016	1280	Complex cardiac surgery with CPB	Upper arm, 4 x 5 minutes cycle, 200mmHg	Diabetes, Hypertension, Dyslipidemia, Renal insufficiency, Liver disease, COPD, Stroke	NR	NR	Propofol	Before and after CPB or coronary anastomoses
Choi 2011	76	Valve surgery on CPB	Lower limb, 3*10min cycle, 250mmHg	AKI, CK-MB	132± 34; 145± 42	98± 27; 108±29	Volatile(sevoflurane)	After the induction anesthesia
Coverdale 2017	428	cardiac or vascular surgical	Upper arm, 3 x 5 minutes cycle, 200mmHg	Diabetes, Hypertension, Dyslipidemia, Renal insufficiency, COPD, Stroke	102 ± 48; 99 ± 63	78 ± 39; 77 ± 48	desflurane, sevoflurane, or propofol	Before transferring to the operating room
Gallagher 2015	86	CABG and/or valve surgery on CPB or coronary anastomoses	Forearm, 3 x 5 minutes cycle, 200 mmHg	Diabetes, Hypertension, Hypercholesterolemia, Peripheral vascular disease, COPD, stroke or TIA, MI	94(78–119; 94(74–123)	66 (49–90); 58 (45–77)	NR	After the induction anesthesia
Hausenloy 2015	1612	CABG and/or valve surgery on CPB	Upper limb, 4*5min cycle 200mmHg	Diabetes, Hypertension, Hypercholesterolemia, MI	105(34–585); 107(29–422)	69(18–324); 71(15–292)	Volatile or TIVA	After the induction anesthesia, before surgery incision
Heusch 2012	12	CABG	Left upper limb, 3*5min cycle,≥200mmHg	NA	104 ± 4; 104 ± 4	69 ± 4; 65 ±3	Volatile(isoflurane)	After the induction anesthesia
Holmberg 2014	41	Complex cardiac surgery with CPB	right upper limb, 3*5min cycle, 200mmHg	Diabetes, Hypertension, COPD, Hypercholesterolemia	95.8 ± 54.8; 104.7 ±36.9	64.8± 37.2; 71.1±28.7	Volatile(sevoflurane)	After the induction anesthesia
Hong 2014	1280	Complex cardiac surgery with CPB	Upper limb, 3*5min cycle, 200mmHg before and after bypass or anastomoses	Diabetes, Hypertension, COPD, Renal insufficiency, Dyslipidemia, Congestive heart failure	161.8±65.3 157.6±60.1	99.7±45.2; 97.8±42.7	TIVA (propofol)	After induction of anesthesia, before CPB
Hudetz 2014	30	CABG and/or valve surgery on CPB	Upper limb, 4*5min cycle 200mmHg	Diabetes, Hypertension, Hypercholesterolemia, Congestive heart failure	145 ±43; 146 ±59;	117±38; 122± 52	Volatile(isoflurane)	After anesthetic induction and endotracheal intubation
Jin 2018	121	valve replacement on CPB	Upper limb, 2*5min cycle 200mmHg	NA	114.07±31.04; 112.80±33.87	77.87±28.09; 80.53±26.32	NR	After the induction anesthesia
Karuppasamy 2011	54	CABG on CPB	Left upper arm, 3*5min cycle, 200mmHg	Diabetes, Hypertension, Hypercholesterolemia, MI	88.1±32.5; 104 ±61.2	43.4± 15.2; 56.6 ±27.1	Volatile (isoflurane)	After the induction anesthesia
Kottenberg 2012	72	CABG on CPB	Left upper arm, 3*5min cycle, 200mmHg	NR	Propofol:109 ± 27; 112 ±31 Isoflurane: 99±18; 112 ±34	Propofol:74 ± 22; 78 ±22 Isoflurane: 66±21; 66 ±28	Volatile (isoflurane) or TIVA (propofol)	After induction of anesthesia and placement of the endo-tracheal tube
Krogstad 2015	92	CABG on CPB	Right upper arm, 3*5min cycle, 200mmHg	Diabetes, Hypertension, Hypothyroidism, COPD, Peripheral vascular disease, MI, Stroke	79.8±21.3; 71.8±21.7	49.4±16.3; 44.3±15.2	Volatile (isoflurane) and TIVA (propofol)	After the induction anesthesia, before surgery incision
Li 2010	81	Valve replacement	Right lower limb, 3*4min cycle, 600mmHg	NR	71.9 ±23.8; 67.7±19.1	47.3±17.9; 47.4±17.3	Volatile (isoflurane) and TIVA (propofol)	After the induction anesthesia
Lomivorotov 2012	80	CABG on CPB	Right upper limb, 3*5min cycle 200mmHg	NR	62 ± 17.7; 67.1 ± 20.3	36.6±14.8; 38.8±13.9	Volatile (isoflurane) and TIVA (propofol)	After the induction anesthesia
Lotfi 2016	102	CABG and/or valve surgery on CPB	Upper limb, 3*5min cycle, 200mmHg	Diabetes, Hypertension, COPD, Dyslipidemia, heart failure	NR	93.0±38.5; 88.7±44.8	Volatile (isoflurane)	After the induction anesthesia, before surgery incision
Lucchinetti 2012	55	CABG on CPB	Lower limb, 4*5min cycle 300mmHg	Hyperlipidemia, Hypertension	109±30; 94±24	74±33; 63±24	Volatile(isoflurane)	After induction of anesthesia before CPB
Mscarelli 2019	124	CABG and/or valve surgery on CPB	Upper limb, 4*5min cycle, 200mmHg	Hypercholesterolemia, Hypertension, Hypothyroidism, COPD, CVA/TIA, Diabetes	CABG: 77.5 (71.5–85.5); 85 (68.5–95) AVR: 93 (75–112); 91(80-110)	CABG: 40.0(32.5–49.5); 42 (33–49) AVR: 66 (55–79); 63(52-85)	Volatile (isoflurane) and TIVA (propofol)	After anesthesia induction, before sternotomy
Meybohm 2013	180	Complex cardiac surgery	Upper limb, 4*5min cycle, 200mmHg	Chronic pulmonary disease, MI, Stroke, Diabetes mellitus, Hypertension	116 (54–299); 121 (46–302)	79 (32–195); 80 (32–204)	TIVA (propofol)	After the induction anesthesia
Meybohm 2015	1385	Complex cardiac surgery with CPB	Upper limb, 4*5min cycle, 200mmHg but at least 15mmHg higher than SAP	COPD, Chronic arterial hypertension, Diabetes mellitus, Chronic kidney disease, Peripheral vascular disease, Heart failure, etc.	NR	NR	TIVA (propofol)	After the induction anesthesia
Meybohm 2018	1403	Complex cardiac surgery with CPB	4*5min cycle	NA	NR	NR	TIVA (propofol)	After the induction anesthesia
Nouraeui 2016	99	CABG on CPB	Upper thigh, 3*5min cycle, ≥20mmHg higher than the resting systolic arterial pressure	Diabetes, hypercholesterolemia, Hypertension,	66.2±9; 67.3±9.6	40.7±8.3; 42.2±8.6	Volatile (isoflurane) and TIVA (propofol)	After the induction anesthesia, before surgery incision
Pinaud 2015	100	Aortic valve replacement	Upper limb, 3*5min cycle, 200mmHg	Hypertension, Hyperlipidemia, COPD, Diabetes	82.9±30.2; 79.9±21.8	59.5±25.2; 55.3±18.8	Volatile (isoflurane or sevoflurane)	After the induction anesthesia, before surgery incision
Rahman 2010	162	CABG on CPB	Upper limb, 3*5min cycle, 200mmHg	NR	100±23; 96±22	76±21; 71±18	Volatile (enflurane or sevoflurane)	After the induction anesthesia
Slagsvold 2014	60	CABG on CPB	Upper limb, 3*5min cycle, 200mmHg	Hypertension, COPD, Diabetes	71.1±14; 76.3±23	41.1±11; 41.8±11	Volatile (isoflurane)	After the induction anesthesia
Thielmann 2010	53	CABG on CPB	Upper limb, 3*5min cycle, 200mmHg	Hypertension, Hyperlipidemia, COPD,	109±23; 110±29	71±18; 76±19	Volatile (isoflurane) and TIVA (propofol)	After the induction anesthesia
Thielmann 2013	329	CABG on CPB	Upper limb, 3*5min cycle, 200mmHg	Peripheral vessel disease, Diabetes, Hypercholesterolemia, Hypertension, Renal disease, COPD	NR	67±19; 67±19	Volatile (isoflurane) or TIVA (propofol)	After the induction anesthesia, before skin incision
Tuter 2018	40	CABG on CPB and antegrade cardioplegia	right lower limb, 3*10min cycle, 200mmHg	hypertensive heart disease, COPD, MI	61±15.9; 59±15.1	45±8.4; 43±7.8	TIVA (propofol)	Before the induction anesthesia
Venugopal 2009	45	CABG and/or valve surgery on CPB	Upper limb, 3*5min cycle, 200mmHg	Peripheral vessel disease, Stoke, Hypercholesterolemia, Hypertension, MI	86±16; 97±38	53±14; 65±30	Volatile (halogenated) or TIVA (propofol)	After the induction anesthesia, before surgery incision
Venugopal 2010	78	CABG on CPB	Upper limb, 3*5min cycle, 200mmHg	Peripheral vessel disease, cerebrovascular accident, MI Hypercholesterolemia, Hypertension,	80±17; 91±33	45±16; 58±29	Volatile or TIVA	After the induction anesthesia, before surgery incision
Walsh 2015	258	valve surgery on CPB	Lower limb, 3*5min cycle, 300mmHg	Diabetes, MI, Hypertension, Stroke, Congestive heart failure, Peripheral vessel disease	142.6±86.9; 132.7±63.7	100.3±48.0; 97.9±51.2	Volatile or TIVA (propofol)	After induction of anesthesia, before CPB
Wu 2011	75	Mitral Valve replacement on CPB	LIPC I: Right upper limb, 35min cycle; LIPC II: LIPC and right lower limb,210min cycle 450mmHg	NA	LIPC I: 90.0±25.4 LIPC II: 92.1±24.4 Control: 82.1±8.3	LIPC I: 59.3±19.8 LIPC II: 63.5±19.8 Control: 51.7±7.4	TIVA	After the induction anesthesia, before surgery incision
Xie 2012	73	Valve replacement	Upper limb, 3*5min cycle, 200mmHg	Diabetes, hypercholesterolemia, Hypertension, Stroke, etc.	113.2±39.9; 121.2±48.9;	81.9±35.7; 77.7±44.9	TIVA (sufentanil)	After the induction anesthesia, before surgery incision
Young 2012	96	CABG and/or valve surgery on CPB	Upper limb, 3*5min cycle, 200mmHg	NA	NR	117.4±50.3; 104.7±40.6	Volatile (isoflurane) and TIVA (propofol)	Began with the first surgical incision
Zarbock 2015	240	Cardiac surgery on CPB	Upper limb, 3*5min cycle, 50mmHg higher than SAP	COPD, hypertension, Diabetes mellitus, Chronic kidney disease, Heart failure	120.0(99.5-150.0); 116.0(89.5-165.0)	86.0(65.0-105.0); 78.0 (58.5-112.0)	Volatile	After the induction anesthesia, before skin incision
Zimmerman 2011	120	CABG and/or valve surgery on CPB	Lower limb, 3*5min cycle, 200mmHg	COPD, Hypertension, Diabetes mellitus, Peripheral vascular disease, Congestive Heart failure, etc.	115±37; 113±37	73±38; 68±35	Volatile(isoflurane)	After the induction anesthesia

Note: MI: myocardial injury; CABG: coronary artery bypass graft; CHD: congenital heart defects; CPB: cardiopulmonary bypass; AVR: Aortic valve replacement; RIPC: remote ischemic preconditioning; LIPC: limb ischemic preconditioning; COPD: Chronic Obstructive Pulmonary Disease; CVA: cerebral vascular accident; TIA: transient ischemic attack. NA: not available; NR: Not Reported.

No competing interests reported.

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Is remote ischaemic preconditioning worthwhile for patients undergoing cardiac surgery with cardiopulmonary bypass? A meta-analysis and systematic literature review

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1. Introduction

2. Materials And Methods

2.1 Search strategy

2.2 Inclusion and exclusion criteria

2.3 Data extraction and outcomes measures

2.4 Quality evaluation

2.5 Statistical analysis

3. Results

3.1 Literature search results

3.2 Characteristics of the included studies

3.3 Quality of the included studies

3.4 Primary outcomes

3.4.1 Mortality

3.4.2 In-hospital mortality

3.5 Secondary outcomes

3.5.1 Length of hospital or ICU stay

3.5.2 Low cardiac output syndrome

3.5.3 Myocardial injury

3.5.4 Post-operative LVEF & ventilation duration

3.5.5 AF & Stroke

4. Discussion

5. Strengths And Limitations Of The Study

6. Conclusion

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