The Protective Effect of Remote Ischemic Preconditioning on Acute Kidney Injury Following Pediatric Cardiac Surgery: A Systematic Review and Meta-Analysis

The Protective Effect of Remote Ischemic Preconditioning on Acute Kidney Injury Following Pediatric Cardiac Surgery: A Systematic Review and Meta-Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article The Protective Effect of Remote Ischemic Preconditioning on Acute Kidney Injury Following Pediatric Cardiac Surgery: A Systematic Review and Meta-Analysis Peiwen Cheng, Guozhen Wang, Yong An This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4541403/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective To determine whether remote ischemic preconditioning (RIPC) improves renal outcomes in children undergoing pediatric cardiac surgery. Method A systematic search of PubMed, EMBASE, and the Cochrane Library included randomized controlled trials (RCTs) assessing the effect of RIPC on the incidence of postoperative acute kidney injury (AKI) and ICU length of stay. Results Six RCTs with 1098 patients were included.RIPC significantly reduced the incidence of AKI (OR = 0.38, 95% CI: 0.25–0.60, P 0.05, I² >80%). Sensitivity analyses showed a large impact of some studies on the results. Conclusion RIPC significantly reduced the incidence of AKI after pediatric cardiac surgery, showing its potential renoprotective effect. Although the effect on other postoperative indicators was not significant, high heterogeneity limits the certainty of the conclusions. Future studies should focus on multicenter, large-scale trials with detailed subgroup analyses to explore the mechanism of action and effects of RIPC in different patient populations. Health sciences/Diseases/Cardiovascular diseases Health sciences/Medical research/Paediatric research Remote Ischemic Preconditioning Cardiac Surgery Pediatric Renal Injury Meta-Analysis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 1.Introduction Cardiac Surgery-Associated Kidney Injury (CSA-AKI) is a common complication following cardiac surgery, typically occurring within 48–72 hours post-operation. It involves multiple injury pathways, including inadequate blood supply, ischemia-reperfusion injury, and stress responses [ 1 ] . These factors can impair renal function and potentially lead to acute kidney failure. Currently, no effective medications exist to reduce the risk of AKI or to treat diagnosed AKI [ 2 ] . This complication is particularly significant in pediatric cardiac surgery, often involving complex cardiovascular issues such as congenital heart disease. These surgeries may require the use of cardiopulmonary bypass (CPB), and children's kidneys are relatively more susceptible to damage from surgical and ischemia-reperfusion factors, increasing the risk of renal injury. Remote Ischemic Preconditioning (RIPC) is a procedure where short cycles of ischemia and reperfusion are applied to a body part distant from the heart (e.g., arm or leg), inducing a protective physiological response that enhances the heart and other organs' tolerance to ischemia-reperfusion injury. RIPC has been shown to prevent organ damage after cardiac surgery, potentially through mechanisms such as reducing inflammation, improving vascular function, and inhibiting apoptosis [ 3 ] . However, the precise mechanisms of RIPC are still under investigation. Some studies suggest that renal protection might be related to the downregulation of inflammatory mediators like TNF-α and the upregulation of miRNA-21 [ 4 ] . Nonetheless, other similar studies have found no significant impact on postoperative outcomes [ 6 ] . Previous meta-analyses have also shown conflicting results. One meta-analysis indicated that RIPC does not effectively prevent AKI or reduce mortality [ 8 ] . Conversely, some studies have reported that RIPC significantly reduces the incidence of AKI following CPB [ 7 ] . These discrepancies may stem from variations in the studies, including the number of RCTs, study populations, RIPC protocols, and differences in the definition and measurement of AKI, which increase the heterogeneity of results. Differences in study quality, sample sizes, and potential biases may also contribute to the inconsistencies in these comprehensive analyses. To date, whether RIPC can reduce renal complications after cardiac surgery remains inconclusive, especially regarding its effects in children, which have not been adequately studied. Therefore, this meta-analysis aims to determine the clinical benefits of RIPC in pediatric cardiac surgery based on the latest literature. 2.Materials and Methods 2.1 Search Strategy: This study was conducted and reported according to the Cochrane Handbook and PRISMA statement [ 9 – 10 ] . The research protocol was pre-established and remained unchanged during the study. Researchers independently searched PubMed, EMBASE, and the Cochrane Library from their inception until January 12, 2024, using English search terms including “Child”, “pediatric”, “Cardiac Surgical Procedures”, “cardiac surgery”, “randomized controlled trial”, “random*”, “Preconditioning, Ischemic”, and “ischemic conditioning”. Additionally, references from relevant literature were manually searched to identify potentially eligible articles. The search results were organized using EndNote software. 2.2 Data Selection: The inclusion criteria for this meta-analysis were: (1) Study design: randomized controlled trials (RCTs); (2) Population: pediatric patients undergoing cardiac surgery; (3) Intervention: arm and/or leg RIPC compared with a control group; (4) Outcomes: incidence of cardiac surgery-associated kidney injury (CSA-AKI), related biochemical markers, inflammatory factors, and intensive care unit (ICU) length of stay. The exclusion criteria were: (1) Non-randomized controlled trials; (2) Incomplete data or missing key variables; (3) Adult patients; (4) Sample size too small for reliable analysis. Two researchers independently screened all publication titles and abstracts and reviewed the full texts. Studies meeting the inclusion criteria were included in this meta-analysis. 2.3 Data Extraction: Two researchers independently extracted data using standardized forms: first author’s name, publication year, region, number of patients, RIPC protocol (including cuff inflation of arms or legs, inflation site, and ischemia duration), control group intervention, and reported outcomes. In cases of incomplete data, the corresponding authors of the original studies were contacted. Discrepancies in data extraction were resolved by jointly reviewing the full text and discussion. 2.4 Primary and Secondary Outcomes: The primary outcomes were the effect of RIPC on the incidence of CSA-AKI and ICU length of stay. Secondary outcomes included renal outcomes (serum creatinine (sCr) levels, inflammatory factor TNF-α), and changes in other clinical and physiological parameters. 2.5 Quality Assessment: Two researchers independently assessed the methodological quality of each study using the Cochrane Collaboration tool[10], evaluating random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other biases. Each study's overall risk of bias was rated as high (one or more domains with high risk), low (all domains with low risk), or unclear(as shown in Fig. 2). Discrepancies in quality assessment were resolved through discussion with a third researcher to reach a consensus. 2.6 Statistical Analysis: Random-effects meta-analyses were performed using Review Manager 5 (Cochrane Collaboration, Copenhagen, Denmark). For dichotomous outcomes, risk ratios (RRs) with 95% confidence intervals (CIs) were calculated. For continuous outcomes, standardized mean differences (SMDs) with 95% CIs were reported. Median values were converted to means and standard deviations if reported [ 11 – 12 ] . Heterogeneity was assessed using the Chi-square test and quantified with the I² statistic, with I² > 50% indicating significant heterogeneity [ 10 ] . The overall quality of the evidence was evaluated using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system, considering factors such as study design, risk of bias, consistency, directness, and precision. Assessing the impact of individual studies on overall results through sensitivity analyses. 3.Results 3.1 Literature Search: The initial search identified 119 articles. After removing 57 duplicates in EndNote, 62 studies were screened for eligibility. Based on the inclusion and exclusion criteria, 43 studies were excluded after reviewing titles and abstracts. Subsequently, 2 articles were excluded due to being unpublished, 1 due to the unavailability of the full text, and 10 due to incomplete outcome variable data. Ultimately, 6 randomized controlled trials (RCTs) were included in this meta-analysis, encompassing a total of 1098 pediatric patients undergoing cardiac surgery [ 4 – 5 ][ 13 – 16 ] (Fig. 1). Details of the included studies are as follows(Table 1). 3.2 Study Characteristics: Table 1 Demographic Data of Studies Included in the Meta-Analysis (RIPC Group/Control Group) Year Author Country Sample Size (T/C) Age (T/C) Intervention control measures Time of intervention Intervention Control 2024 Law, Y M America 45/39;84 0.42/0.38y RIPC(BP cuffon lower limb inflated 15 mmHg above systolic BP) Sham intervention (cuff not inflated for 40 min) 5min inflation,5 min deflation, repeated 4 cycles (total 40 min) 2020 Verdesoto, R. M England 25/24;49 1.58/0.75y RIPC(BP cuff on limb inflated 20 mmHg above systolic BP) Sham intervention (cuff not inflated) 5 min inflation, 5 min deflation, repeated 2 cycles 2018 Kang, Z China 200/249;449 41.45 ± 33.03m/31.50 ± 22.21m RIPC(BP cuff on lower limb inflated 30 mmHg above systolic BP) Sham intervention (cuff placed but not inflated) 5 min inflation, 5 min deflation, repeated 4 cycles (intermittent reperfusion) 2018 Wu, Q China 55/57;112 3-36m RIPC(BP cuff on lower limb inflated 30 mmHg above systolic BP) Sham intervention (cuff placed but not inflated) 5 min inflation, 5 min deflation, repeated 3 cycles 2014 Brian W McCrindle Canada 148/151;299 0-17y RIPC(BP cuff on left lower limb inflated 15 mmHg above systolic BP) Sham intervention (cuff placed but not inflated) 5 min inflation, 5 min deflation, repeated 4 cycles 2012 Pedersen, K. R. Denmark 54/51;105 0-15y RIPC(BP cuff on leg inflated 40 mmHg above systolic BP) Sham intervention (cuff not inflated) 5 min inflation, 5 min deflation, repeated 4 cycles 3.3 Experimental Results: In comparison to the control group, the RIPC intervention demonstrated a significant reduction in the incidence of CSA-AKI (114 out of 354 cases, 32.2% vs. 213 out of 396 cases, 57.79%; OR = 0.38, 95% CI: [0.25, 0.60], P < 0.00001, I² = 38%). This is illustrated in (Fig. 3). The I² value (38%) indicates moderate heterogeneity, suggesting some variability but not sufficient to obscure the observed effect. This degree of heterogeneity is more manageable and does not significantly affect the precision of the pooled estimates. All studies demonstrated a sustained decline in AKI incidence, indicating a protective effect of RIPC on renal function. The narrower confidence intervals did not include 1, indicating that the results were statistically significant. The analysis of postoperative serum creatinine (sCr) revealed no statistically significant difference and high heterogeneity (MD = -2.00, 95% CI: [-4.97, 0.97], P = 0.19, I 2 = 81%) at 48 hours postoperatively (Fig. 4). This implies that although RIPC is able to reduce the incidence of CSA-AKI, it does not induce a significant alteration in the sCr level. The high I² value (81%) indicated a substantial discrepancy between the studies. A sensitivity analysis of this revealed that excluding Kang, Z. (2018), this study would have reduced the magnitude of the negative effect. However, heterogeneity was slightly reduced but still large( Fig. 7). Similarly, postoperative TNF-α levels (MD = -8.41, 95% CI: [-21.70, 4.88], P = 0.17, I2 = 85%) demonstrated no significant benefit of RIPC on TNF-α levels (Fig. 5). The I² value (85%) reflected extremely high variability, indicating significant differences in inflammatory responses across studies. A sensitivity analysis identified the Kang and Wu studies as the primary source of heterogeneity in TNF-α results. Excluding these studies significantly reduced the observed heterogeneity. However, given that there were only three studies in total, the results may not be representative. A comparison of ICU length of stay (MD = -8.41, 95% CI: [-21.70, 4.88], P = 0.21, I2 = 99%) revealed that RIPC did not significantly reduce ICU length of stay (Fig. 6). The I² value of 99% indicated significant differences in ICU length of stay across studies. Sensitivity analyses revealed that the Kang, Z. 2018 study was the primary source of heterogeneity in ICU length of stay results. However, exclusion of this study resulted in a reduction of heterogeneity, as illustrated in Fig. 7. 4. Discussion This study encompasses six randomized controlled trials involving a total of 1098 patients to investigate the benefits of remote ischemic preconditioning (RIPC) on renal outcomes in cardiac surgery. The meta-analysis results indicate that RIPC significantly enhances renal protection post-cardiac surgery, reducing the incidence of cardiac surgery-associated acute kidney injury (CSA-AKI) and decreasing postoperative levels of the inflammatory mediator TNF-α. Additionally, RIPC shortens the length of ICU stay for patients. There was no significant difference in postoperative serum creatinine (sCr) levels. In adult studies, AKI is identified as a major complication following cardiac surgery, affecting 20%-70% of patients and accounting for 60% of all-cause mortality [ 17 ] . This meta-analysis shows that RIPC improves postoperative renal outcomes, as evidenced by the reduced incidence of AKI. Compared to traditional pharmacological treatments, RIPC is a non-invasive method that applies brief ischemia-reperfusion cycles to areas distant from the target organ, avoiding additional harm and risks to the patient. This non-invasive nature makes RIPC a safe and reliable treatment option, mitigating the potential for drug interactions and allergic reactions inherent in pharmacotherapy. RIPC may exert systemic protective effects through mechanisms such as reducing inflammatory responses, improving microcirculation, decreasing oxidative stress, and inhibiting apoptosis. Protective signals activated in regions distant from the surgical site might be transmitted to the target organ via neurohumoral mechanisms [ 18 ] , potentially conferring systemic benefits that alleviate postoperative systemic inflammatory responses and enhance organ function. However, the precise mechanisms of RIPC remain incompletely understood, and while these results provide some insights, further research is necessary to elucidate the exact pathways involved. The simplicity of RIPC administration—utilizing a pressure cuff to induce intermittent ischemia and reperfusion before surgery—does not require additional equipment or specialized skills. Compared to pharmacological treatments, RIPC is more convenient, can be easily implemented preoperatively, and involves fewer preparatory steps and operational procedures. Moreover, as a simple therapeutic approach, RIPC is cost-effective, not necessitating expensive drugs or equipment, making it suitable for broad clinical application. In contrast to pharmacotherapy, which may require extensive drug procurement and monitoring costs, RIPC offers a higher cost-effectiveness, ensuring rational utilization of medical resources. The absence of a notable impact of RIPC on the remaining indicators may be attributed to a multitude of factors. Primarily, the considerable variations in study design, patient populations, and outcome measures have led to considerable confidence intervals, which in turn has the effect of attenuating the observed effects and reducing the statistical power to detect significant differences. Secondly, differences in RIPC protocols (e.g., number of ischemic cycles, duration), patient demographics, surgical procedures, and methods of measuring outcomes (e.g., sCr is a routine biochemical indicator that, although widely used in clinical practice, is not sensitive nor specific for the early detection of renal injury) contribute to inconsistent results. Additionally, there was considerable heterogeneity between these results. The effect of high heterogeneity represents a wide variation in findings, which limits the ability to draw definitive conclusions about the effectiveness of RIPC in reducing postoperative kidney injury and inflammation. High heterogeneity suggests that study results are not consistent, and therefore caution must be exercised when interpreting pooled estimates. The high degree of heterogeneity observed in the results may be attributed to several factors. Firstly, differences in study design and protocols, with different studies employing different RIPC protocols, such as the number of ischemic cycles, ischemia/reperfusion duration, and time relative to surgery, may contribute to inconsistent results. Secondly, differences in perioperative management, including anesthesia, surgical technique, and perioperative care, can affect outcomes. These variations may also lead to observed heterogeneity. For instance, significant reductions in the duration of mechanical ventilation and ICU stay were observed in trials that did not use propofol, which suggests that propofol may interfere with the protective effects of RIPC [ 20 ] . 3. The study's findings may be influenced by differences in patient age, baseline health status, and surgical complexity. Kang et al. (2018) included a wider range of ages and patients with higher surgical risk, which introduced variability into the results. The differing developmental stages of organs may result in varying organ-protective effects of remote ischemic preconditioning (RIPC) in children. In particular, neonates may be less responsive to RIPC due to incomplete physiologic development, which can result in significant changes in renal function within weeks or even days [ 19 ] . It is also important to note that differences in the severity of underlying conditions, such as heart defects, may result in a different response to RIPC.4. Outcome measurement variability, which may arise from the use of different methods of measuring postoperative biomarkers such as serum creatinine (sCr) and TNF-α levels, can result in differences in outcomes. Furthermore, studies employing different ICU discharge protocols may report varying lengths of ICU stay. In this data collection, different units for the same metrics had to be converted for harmonization, which may have objectively increased the error further. Additionally, converting data from median and interquartile range to mean and standard deviation may have led to estimation errors, thus contributing to heterogeneity. For future studies, it would be beneficial to establish standardized RIPC protocols and consistent outcome measures across studies. This would help to reduce variation and ensure uniform definitions of outcomes, measurement techniques, and follow-up durations. Randomized controlled trials could provide detailed demographic and clinical characteristics of the study population, which would facilitate subgroup analyses and enable the reporting of specific details about the RIPC protocol, including the number and duration of ischemic cycles. Additionally, larger, multicenter trials are being conducted with the objective of increasing the generalizability of findings and improving statistical power and the consistent implementation of the protocol across centers. 5.Conclusion This systematic review and meta-analysis demonstrated that distal ischemic preconditioning (RIPC) significantly reduced the incidence of cardiac surgery-associated kidney injury (CSA-AKI) in patients undergoing cardiac surgery. Notwithstanding the considerable reduction in AKI, the analysis did not reveal a statistically significant effect of RIPC on other postoperative outcomes, including serum creatinine (sCr) levels, TNF-α levels, and length of ICU stay. The high degree of heterogeneity observed in these results suggests a wide variation in study protocols, patient populations, and measurement techniques, which limits the ability to draw definitive conclusions. Overall, although RIPC has demonstrated potential in reducing AKI in pediatric cardiac surgery, its impact on other clinical parameters remains uncertain. Future studies should aim to reduce heterogeneity through the implementation of standardized protocols and more detailed reporting, as well as to investigate the underlying mechanisms responsible for the protective effects of RIPC. Declarations Author Contribution P.W.C. conceived the study. P.W.C. and G.Z.W. carried out the literature search, data extraction and contributed to analysis. P.W.C. performed the analysis. P.W.C. and G.Z.W. did data interpretation and manuscript writing. Y.A supervised this work. All authors critically revised and approved the final version of the manuscript. Acknowledgement This study was funded by the National Natural Science Foundation of China (NSFC) (NSFC 81370432) funded by the Chongqing Natural Science Foundation Upper-level Project (CSTB2023NSCQ-MSX0579) funded by the Chongqing Yuzhong District High-level Talent Program Project 2024 Data Availability The data extracted from the included studies and data used for analysis are provided in the supplementary material. Competing interests The authors declare no competing interests. References Wang Y, Bellomo R. Cardiac surgery-associated acute kidney injury: risk factors, pathophysiology and treatment. Nat Rev Nephrol. 2017;13(11):697–711. doi: 10.1038/nrneph.2017.119 . Thiele RH, Isbell JM, Rosner MH. AKI associated with cardiac surgery. Clin J Am Soc Nephrol. 2015;10(3):500–14. doi: 10.2215/CJN.07830814 . Gho BC, Schoemaker RG, van den Doel MA, et al. Myocardial protection by brief ischemia in noncardiac tissue. Circulation. 1996;94(9):2193–200. doi: 10.1161/01.cir.94.9.2193 . 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A Prospective Randomized Blinded Trial of Remote Ischemic Preconditioning in Children Undergoing Cardiac Surgery. Semin Thorac Cardiovasc Surg. 2020 Summer;32(2):313–322. doi: 10.1053/j.semtcvs.2019.12.004 . Epub 2019 Dec 21. Nadim MK, Forni LG, Bihorac A, et al. Cardiac and Vascular Surgery-Associated Acute Kidney Injury: The 20th International Consensus Conference of the ADQI (Acute Disease Quality Initiative) Group. J Am Heart Assoc. 2018;7(11):e008834. doi: 10.1161/JAHA.118.008834 . Heusch G. Molecular basis of cardioprotection: signal transduction in ischemic pre-, post-, and remote conditioning. Circ Res. 2015;116(4):674–99. doi: 10.1161/CIRCRESAHA.116.305348 . Sulemanji M, Vakili K. Neonatal renal physiology. Semin Pediatr Surg. 2013;22(4):195-8. doi: 10.1053/j.sempedsurg.2013.10.008 . Epub 2013 Oct 15. PMID: 24331094. Li J, Wang X, Liu W, et al. Remote ischemic preconditioning and clinical outcomes after pediatric cardiac surgery: a systematic review and meta-analysis. BMC Anesthesiol. 2023;23(1):105. doi: 10.1186/s12871-023-02064-6 . Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4541403","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":320168630,"identity":"a3175057-7939-42c8-8584-513c68ac78a3","order_by":0,"name":"Peiwen Cheng","email":"","orcid":"","institution":"Children's Hospital of Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Peiwen","middleName":"","lastName":"Cheng","suffix":""},{"id":320168631,"identity":"e290dfa1-0df4-476b-b77b-6113d82578b4","order_by":1,"name":"Guozhen Wang","email":"","orcid":"","institution":"Children's Hospital of Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Guozhen","middleName":"","lastName":"Wang","suffix":""},{"id":320168632,"identity":"b6a8ba80-9a4f-4918-871d-2b10445e6140","order_by":2,"name":"Yong An","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwElEQVRIiWNgGAWjYBACNjiLvbHxwQdStEgw8BxuNpxBim0SDBLpbdIcxCjlk25++Jl3h10dv+TDBmkGBjs53QZCDpM5ZizNeyZZQnJ2YoNxAUOysdkBQlokchgkZ7YxSxjcTmxInsFwIHEbEVqYf85sq5ewv3mw4TAPkVrYJD62HZYwkGBsbCZSS5qZxce245IzziQ2M84wIMIv8jOSH99IbKvm528//vzHhwo7OYJa0IABacpHwSgYBaNgFOAAABPkPOe73OcVAAAAAElFTkSuQmCC","orcid":"","institution":"Children's Hospital of Chongqing Medical University","correspondingAuthor":true,"prefix":"","firstName":"Yong","middleName":"","lastName":"An","suffix":""}],"badges":[],"createdAt":"2024-06-06 15:26:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4541403/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4541403/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":60343830,"identity":"abeb6814-9eae-45ad-9273-a8929646bdeb","added_by":"auto","created_at":"2024-07-15 19:18:44","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":140406,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of the search strategy and inclusion process for the meta-analysis on the efficacy of RIPC in preventing AKI in pediatric cardiac surgery.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4541403/v1/95ed1bc1f5997adf01a53c04.png"},{"id":60343831,"identity":"fa2152c6-cf6b-4f2f-b347-1e2dcaae89d4","added_by":"auto","created_at":"2024-07-15 19:18:44","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":529762,"visible":true,"origin":"","legend":"\u003cp\u003eRisk of bias assessments included in the meta-analysis.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-4541403/v1/49521ecb30bdc0bd8fd8689f.png"},{"id":60343768,"identity":"2d43bdef-048f-4ed1-abaf-631fd9de84a8","added_by":"auto","created_at":"2024-07-15 19:18:43","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":17521,"visible":true,"origin":"","legend":"\u003cp\u003eEffect of RIPC on Postoperative AKI（ Forest plot. CI，indicates confidence interval; M-H, Mantel-Haenszel; RIPC, remote ischemic preconditioning; OR Odds Ratio）\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-4541403/v1/2efe7d0187146a556fe19aad.png"},{"id":60343767,"identity":"427b2a0f-45e3-4c63-b6c9-e8e34d94c1b1","added_by":"auto","created_at":"2024-07-15 19:18:43","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":207322,"visible":true,"origin":"","legend":"\u003cp\u003ePostoperative Serum Creatinine (sCr) Levels（ Forest plot. CI， confidence interval; IV：Inverse Variance;）\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-4541403/v1/b9738e5b89d342cd3a1d2f5b.png"},{"id":60343829,"identity":"c5566e13-32b0-4d84-a423-66ec2e96802b","added_by":"auto","created_at":"2024-07-15 19:18:44","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":17485,"visible":true,"origin":"","legend":"\u003cp\u003ePostoperative TNF-α Levels（Forest plot.. CI， confidence interval; IV：Inverse Variance;）\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-4541403/v1/2189a052add0b695e48020f9.png"},{"id":60343769,"identity":"25353c67-44e8-4f25-b29d-0d5135629363","added_by":"auto","created_at":"2024-07-15 19:18:43","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":21091,"visible":true,"origin":"","legend":"\u003cp\u003eICU Length of Stay\u003c/p\u003e","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-4541403/v1/a4ff1b70b629b11601ba7c97.png"},{"id":60343832,"identity":"f104db8b-0f44-4385-bd1a-c4272167b266","added_by":"auto","created_at":"2024-07-15 19:18:45","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":156896,"visible":true,"origin":"","legend":"\u003cp\u003eSensitivity analysis :A sCr Levels; B \u0026nbsp;Postoperative TNF-α Levels ; C ICU Length of Stay)\u003c/p\u003e","description":"","filename":"floatimage7.png","url":"https://assets-eu.researchsquare.com/files/rs-4541403/v1/be211ee6a409e560a6db73ab.png"},{"id":64176165,"identity":"7d5c99e7-bfe2-4f35-a8f6-4ac7bc13f71b","added_by":"auto","created_at":"2024-09-09 13:02:32","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1534713,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4541403/v1/35f18ea0-3bf6-469d-b3b7-27e4d476fd92.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The Protective Effect of Remote Ischemic Preconditioning on Acute Kidney Injury Following Pediatric Cardiac Surgery: A Systematic Review and Meta-Analysis","fulltext":[{"header":"1.Introduction","content":"\u003cp\u003eCardiac Surgery-Associated Kidney Injury (CSA-AKI) is a common complication following cardiac surgery, typically occurring within 48\u0026ndash;72 hours post-operation. It involves multiple injury pathways, including inadequate blood supply, ischemia-reperfusion injury, and stress responses\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. These factors can impair renal function and potentially lead to acute kidney failure. Currently, no effective medications exist to reduce the risk of AKI or to treat diagnosed AKI\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. This complication is particularly significant in pediatric cardiac surgery, often involving complex cardiovascular issues such as congenital heart disease. These surgeries may require the use of cardiopulmonary bypass (CPB), and children's kidneys are relatively more susceptible to damage from surgical and ischemia-reperfusion factors, increasing the risk of renal injury.\u003c/p\u003e \u003cp\u003eRemote Ischemic Preconditioning (RIPC) is a procedure where short cycles of ischemia and reperfusion are applied to a body part distant from the heart (e.g., arm or leg), inducing a protective physiological response that enhances the heart and other organs' tolerance to ischemia-reperfusion injury. RIPC has been shown to prevent organ damage after cardiac surgery, potentially through mechanisms such as reducing inflammation, improving vascular function, and inhibiting apoptosis\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. However, the precise mechanisms of RIPC are still under investigation. Some studies suggest that renal protection might be related to the downregulation of inflammatory mediators like TNF-α and the upregulation of miRNA-21\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. Nonetheless, other similar studies have found no significant impact on postoperative outcomes\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003ePrevious meta-analyses have also shown conflicting results. One meta-analysis indicated that RIPC does not effectively prevent AKI or reduce mortality\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. Conversely, some studies have reported that RIPC significantly reduces the incidence of AKI following CPB\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. These discrepancies may stem from variations in the studies, including the number of RCTs, study populations, RIPC protocols, and differences in the definition and measurement of AKI, which increase the heterogeneity of results. Differences in study quality, sample sizes, and potential biases may also contribute to the inconsistencies in these comprehensive analyses.\u003c/p\u003e \u003cp\u003eTo date, whether RIPC can reduce renal complications after cardiac surgery remains inconclusive, especially regarding its effects in children, which have not been adequately studied. Therefore, this meta-analysis aims to determine the clinical benefits of RIPC in pediatric cardiac surgery based on the latest literature.\u003c/p\u003e"},{"header":"2.Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Search Strategy:\u003c/h2\u003e \u003cp\u003eThis study was conducted and reported according to the Cochrane Handbook and PRISMA statement \u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. The research protocol was pre-established and remained unchanged during the study. Researchers independently searched PubMed, EMBASE, and the Cochrane Library from their inception until January 12, 2024, using English search terms including \u0026ldquo;Child\u0026rdquo;, \u0026ldquo;pediatric\u0026rdquo;, \u0026ldquo;Cardiac Surgical Procedures\u0026rdquo;, \u0026ldquo;cardiac surgery\u0026rdquo;, \u0026ldquo;randomized controlled trial\u0026rdquo;, \u0026ldquo;random*\u0026rdquo;, \u0026ldquo;Preconditioning, Ischemic\u0026rdquo;, and \u0026ldquo;ischemic conditioning\u0026rdquo;. Additionally, references from relevant literature were manually searched to identify potentially eligible articles. The search results were organized using EndNote software.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Data Selection:\u003c/h2\u003e \u003cp\u003eThe inclusion criteria for this meta-analysis were: (1) Study design: randomized controlled trials (RCTs); (2) Population: pediatric patients undergoing cardiac surgery; (3) Intervention: arm and/or leg RIPC compared with a control group; (4) Outcomes: incidence of cardiac surgery-associated kidney injury (CSA-AKI), related biochemical markers, inflammatory factors, and intensive care unit (ICU) length of stay. The exclusion criteria were: (1) Non-randomized controlled trials; (2) Incomplete data or missing key variables; (3) Adult patients; (4) Sample size too small for reliable analysis. Two researchers independently screened all publication titles and abstracts and reviewed the full texts. Studies meeting the inclusion criteria were included in this meta-analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Data Extraction:\u003c/h2\u003e \u003cp\u003eTwo researchers independently extracted data using standardized forms: first author\u0026rsquo;s name, publication year, region, number of patients, RIPC protocol (including cuff inflation of arms or legs, inflation site, and ischemia duration), control group intervention, and reported outcomes. In cases of incomplete data, the corresponding authors of the original studies were contacted. Discrepancies in data extraction were resolved by jointly reviewing the full text and discussion.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Primary and Secondary Outcomes:\u003c/h2\u003e \u003cp\u003eThe primary outcomes were the effect of RIPC on the incidence of CSA-AKI and ICU length of stay. Secondary outcomes included renal outcomes (serum creatinine (sCr) levels, inflammatory factor TNF-α), and changes in other clinical and physiological parameters.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Quality Assessment:\u003c/h2\u003e \u003cp\u003eTwo researchers independently assessed the methodological quality of each study using the Cochrane Collaboration tool[10], evaluating random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other biases. Each study's overall risk of bias was rated as high (one or more domains with high risk), low (all domains with low risk), or unclear(as shown in Fig.\u0026nbsp;2). Discrepancies in quality assessment were resolved through discussion with a third researcher to reach a consensus.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.6 Statistical Analysis:\u003c/h2\u003e \u003cp\u003eRandom-effects meta-analyses were performed using Review Manager 5 (Cochrane Collaboration, Copenhagen, Denmark). For dichotomous outcomes, risk ratios (RRs) with 95% confidence intervals (CIs) were calculated. For continuous outcomes, standardized mean differences (SMDs) with 95% CIs were reported. Median values were converted to means and standard deviations if reported\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. Heterogeneity was assessed using the Chi-square test and quantified with the I\u0026sup2; statistic, with I\u0026sup2; \u0026gt; 50% indicating significant heterogeneity\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. The overall quality of the evidence was evaluated using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system, considering factors such as study design, risk of bias, consistency, directness, and precision. Assessing the impact of individual studies on overall results through sensitivity analyses.\u003c/p\u003e \u003c/div\u003e"},{"header":"3.Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Literature Search:\u003c/h2\u003e \u003cp\u003eThe initial search identified 119 articles. After removing 57 duplicates in EndNote, 62 studies were screened for eligibility. Based on the inclusion and exclusion criteria, 43 studies were excluded after reviewing titles and abstracts. Subsequently, 2 articles were excluded due to being unpublished, 1 due to the unavailability of the full text, and 10 due to incomplete outcome variable data. Ultimately, 6 randomized controlled trials (RCTs) were included in this meta-analysis, encompassing a total of 1098 pediatric patients undergoing cardiac surgery \u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e][\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e \u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e (Fig.\u0026nbsp;1). Details of the included studies are as follows(Table\u0026nbsp;1).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Study Characteristics:\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic Data of Studies Included in the Meta-Analysis (RIPC Group/Control Group)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eYear\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAuthor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCountry\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSample Size (T/C)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAge (T/C)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eIntervention control measures\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eTime of intervention\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eIntervention\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLaw, Y M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAmerica\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e45/39;84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.42/0.38y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRIPC(BP cuffon lower limb inflated 15 mmHg above systolic BP)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSham intervention (cuff not inflated for 40 min)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e5min inflation,5 min deflation, repeated 4 cycles (total 40 min)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVerdesoto, R. M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEngland\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25/24;49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.58/0.75y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRIPC(BP cuff on limb inflated 20 mmHg above systolic BP)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSham intervention (cuff not inflated)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e5 min inflation, 5 min deflation, repeated 2 cycles\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eKang, Z\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e200/249;449\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e41.45\u0026thinsp;\u0026plusmn;\u0026thinsp;33.03m/31.50\u0026thinsp;\u0026plusmn;\u0026thinsp;22.21m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRIPC(BP cuff on lower limb inflated 30 mmHg above systolic BP)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSham intervention (cuff placed but not inflated)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e5 min inflation, 5 min deflation, repeated 4 cycles (intermittent reperfusion)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWu, Q\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e55/57;112\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3-36m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRIPC(BP cuff on lower limb inflated 30 mmHg above systolic BP)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSham intervention (cuff placed but not inflated)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e5 min inflation, 5 min deflation, repeated 3 cycles\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBrian W McCrindle\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCanada\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e148/151;299\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0-17y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRIPC(BP cuff on left lower limb inflated 15 mmHg above systolic BP)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSham intervention (cuff placed but not inflated)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e5 min inflation, 5 min deflation, repeated 4 cycles\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePedersen, K. R.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDenmark\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e54/51;105\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0-15y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRIPC(BP cuff on leg inflated 40 mmHg above systolic BP)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSham intervention (cuff not inflated)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e5 min inflation, 5 min deflation, repeated 4 cycles\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Experimental Results:\u003c/h2\u003e \u003cp\u003eIn comparison to the control group, the RIPC intervention demonstrated a significant reduction in the incidence of CSA-AKI (114 out of 354 cases, 32.2% vs. 213 out of 396 cases, 57.79%; OR\u0026thinsp;=\u0026thinsp;0.38, 95% CI: [0.25, 0.60], P\u0026thinsp;\u0026lt;\u0026thinsp;0.00001, I\u0026sup2; = 38%). This is illustrated in (Fig.\u0026nbsp;3). The I\u0026sup2; value (38%) indicates moderate heterogeneity, suggesting some variability but not sufficient to obscure the observed effect. This degree of heterogeneity is more manageable and does not significantly affect the precision of the pooled estimates. All studies demonstrated a sustained decline in AKI incidence, indicating a protective effect of RIPC on renal function. The narrower confidence intervals did not include 1, indicating that the results were statistically significant.\u003c/p\u003e \u003cp\u003eThe analysis of postoperative serum creatinine (sCr) revealed no statistically significant difference and high heterogeneity (MD = -2.00, 95% CI: [-4.97, 0.97], P\u0026thinsp;=\u0026thinsp;0.19, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;81%) at 48 hours postoperatively (Fig.\u0026nbsp;4). This implies that although RIPC is able to reduce the incidence of CSA-AKI, it does not induce a significant alteration in the sCr level. The high I\u0026sup2; value (81%) indicated a substantial discrepancy between the studies. A sensitivity analysis of this revealed that excluding Kang, Z. (2018), this study would have reduced the magnitude of the negative effect. However, heterogeneity was slightly reduced but still large( Fig.\u0026nbsp;7).\u003c/p\u003e \u003cp\u003eSimilarly, postoperative TNF-α levels (MD = -8.41, 95% CI: [-21.70, 4.88], P\u0026thinsp;=\u0026thinsp;0.17, I2\u0026thinsp;=\u0026thinsp;85%) demonstrated no significant benefit of RIPC on TNF-α levels (Fig.\u0026nbsp;5). The I\u0026sup2; value (85%) reflected extremely high variability, indicating significant differences in inflammatory responses across studies. A sensitivity analysis identified the Kang and Wu studies as the primary source of heterogeneity in TNF-α results. Excluding these studies significantly reduced the observed heterogeneity. However, given that there were only three studies in total, the results may not be representative.\u003c/p\u003e \u003cp\u003eA comparison of ICU length of stay (MD = -8.41, 95% CI: [-21.70, 4.88], P\u0026thinsp;=\u0026thinsp;0.21, I2\u0026thinsp;=\u0026thinsp;99%) revealed that RIPC did not significantly reduce ICU length of stay (Fig.\u0026nbsp;6). The I\u0026sup2; value of 99% indicated significant differences in ICU length of stay across studies. Sensitivity analyses revealed that the Kang, Z. 2018 study was the primary source of heterogeneity in ICU length of stay results. However, exclusion of this study resulted in a reduction of heterogeneity, as illustrated in Fig.\u0026nbsp;7.\u003c/p\u003e "},{"header":"4. Discussion","content":"\u003cp\u003eThis study encompasses six randomized controlled trials involving a total of 1098 patients to investigate the benefits of remote ischemic preconditioning (RIPC) on renal outcomes in cardiac surgery. The meta-analysis results indicate that RIPC significantly enhances renal protection post-cardiac surgery, reducing the incidence of cardiac surgery-associated acute kidney injury (CSA-AKI) and decreasing postoperative levels of the inflammatory mediator TNF-α. Additionally, RIPC shortens the length of ICU stay for patients. There was no significant difference in postoperative serum creatinine (sCr) levels.\u003c/p\u003e \u003cp\u003eIn adult studies, AKI is identified as a major complication following cardiac surgery, affecting 20%-70% of patients and accounting for 60% of all-cause mortality\u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. This meta-analysis shows that RIPC improves postoperative renal outcomes, as evidenced by the reduced incidence of AKI. Compared to traditional pharmacological treatments, RIPC is a non-invasive method that applies brief ischemia-reperfusion cycles to areas distant from the target organ, avoiding additional harm and risks to the patient. This non-invasive nature makes RIPC a safe and reliable treatment option, mitigating the potential for drug interactions and allergic reactions inherent in pharmacotherapy. RIPC may exert systemic protective effects through mechanisms such as reducing inflammatory responses, improving microcirculation, decreasing oxidative stress, and inhibiting apoptosis. Protective signals activated in regions distant from the surgical site might be transmitted to the target organ via neurohumoral mechanisms \u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e, potentially conferring systemic benefits that alleviate postoperative systemic inflammatory responses and enhance organ function. However, the precise mechanisms of RIPC remain incompletely understood, and while these results provide some insights, further research is necessary to elucidate the exact pathways involved.\u003c/p\u003e \u003cp\u003eThe simplicity of RIPC administration\u0026mdash;utilizing a pressure cuff to induce intermittent ischemia and reperfusion before surgery\u0026mdash;does not require additional equipment or specialized skills. Compared to pharmacological treatments, RIPC is more convenient, can be easily implemented preoperatively, and involves fewer preparatory steps and operational procedures. Moreover, as a simple therapeutic approach, RIPC is cost-effective, not necessitating expensive drugs or equipment, making it suitable for broad clinical application. In contrast to pharmacotherapy, which may require extensive drug procurement and monitoring costs, RIPC offers a higher cost-effectiveness, ensuring rational utilization of medical resources.\u003c/p\u003e \u003cp\u003eThe absence of a notable impact of RIPC on the remaining indicators may be attributed to a multitude of factors. Primarily, the considerable variations in study design, patient populations, and outcome measures have led to considerable confidence intervals, which in turn has the effect of attenuating the observed effects and reducing the statistical power to detect significant differences. Secondly, differences in RIPC protocols (e.g., number of ischemic cycles, duration), patient demographics, surgical procedures, and methods of measuring outcomes (e.g., sCr is a routine biochemical indicator that, although widely used in clinical practice, is not sensitive nor specific for the early detection of renal injury) contribute to inconsistent results. Additionally, there was considerable heterogeneity between these results. The effect of high heterogeneity represents a wide variation in findings, which limits the ability to draw definitive conclusions about the effectiveness of RIPC in reducing postoperative kidney injury and inflammation. High heterogeneity suggests that study results are not consistent, and therefore caution must be exercised when interpreting pooled estimates.\u003c/p\u003e \u003cp\u003eThe high degree of heterogeneity observed in the results may be attributed to several factors. Firstly, differences in study design and protocols, with different studies employing different RIPC protocols, such as the number of ischemic cycles, ischemia/reperfusion duration, and time relative to surgery, may contribute to inconsistent results. Secondly, differences in perioperative management, including anesthesia, surgical technique, and perioperative care, can affect outcomes. These variations may also lead to observed heterogeneity. For instance, significant reductions in the duration of mechanical ventilation and ICU stay were observed in trials that did not use propofol, which suggests that propofol may interfere with the protective effects of RIPC \u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e. 3. The study's findings may be influenced by differences in patient age, baseline health status, and surgical complexity. Kang et al. (2018) included a wider range of ages and patients with higher surgical risk, which introduced variability into the results. The differing developmental stages of organs may result in varying organ-protective effects of remote ischemic preconditioning (RIPC) in children. In particular, neonates may be less responsive to RIPC due to incomplete physiologic development, which can result in significant changes in renal function within weeks or even days\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e. It is also important to note that differences in the severity of underlying conditions, such as heart defects, may result in a different response to RIPC.4. Outcome measurement variability, which may arise from the use of different methods of measuring postoperative biomarkers such as serum creatinine (sCr) and TNF-α levels, can result in differences in outcomes. Furthermore, studies employing different ICU discharge protocols may report varying lengths of ICU stay. In this data collection, different units for the same metrics had to be converted for harmonization, which may have objectively increased the error further. Additionally, converting data from median and interquartile range to mean and standard deviation may have led to estimation errors, thus contributing to heterogeneity.\u003c/p\u003e \u003cp\u003eFor future studies, it would be beneficial to establish standardized RIPC protocols and consistent outcome measures across studies. This would help to reduce variation and ensure uniform definitions of outcomes, measurement techniques, and follow-up durations. Randomized controlled trials could provide detailed demographic and clinical characteristics of the study population, which would facilitate subgroup analyses and enable the reporting of specific details about the RIPC protocol, including the number and duration of ischemic cycles. Additionally, larger, multicenter trials are being conducted with the objective of increasing the generalizability of findings and improving statistical power and the consistent implementation of the protocol across centers.\u003c/p\u003e"},{"header":"5.Conclusion","content":"\u003cp\u003eThis systematic review and meta-analysis demonstrated that distal ischemic preconditioning (RIPC) significantly reduced the incidence of cardiac surgery-associated kidney injury (CSA-AKI) in patients undergoing cardiac surgery. Notwithstanding the considerable reduction in AKI, the analysis did not reveal a statistically significant effect of RIPC on other postoperative outcomes, including serum creatinine (sCr) levels, TNF-α levels, and length of ICU stay. The high degree of heterogeneity observed in these results suggests a wide variation in study protocols, patient populations, and measurement techniques, which limits the ability to draw definitive conclusions. Overall, although RIPC has demonstrated potential in reducing AKI in pediatric cardiac surgery, its impact on other clinical parameters remains uncertain. Future studies should aim to reduce heterogeneity through the implementation of standardized protocols and more detailed reporting, as well as to investigate the underlying mechanisms responsible for the protective effects of RIPC.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eP.W.C. conceived the study. P.W.C. and G.Z.W. carried out the literature search, data extraction and contributed to analysis. P.W.C. performed the analysis. P.W.C. and G.Z.W. did data interpretation and manuscript writing. Y.A supervised this work. All authors critically revised and approved the final version of the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThis study was funded by the National Natural Science Foundation of China (NSFC) (NSFC 81370432) funded by the Chongqing Natural Science Foundation Upper-level Project (CSTB2023NSCQ-MSX0579) funded by the Chongqing Yuzhong District High-level Talent Program Project 2024\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe data extracted from the included studies and data used for analysis are provided in the supplementary material.\u003c/p\u003e\u003ch2\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWang Y, Bellomo R. Cardiac surgery-associated acute kidney injury: risk factors, pathophysiology and treatment. 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Circ Res. 2015;116(4):674\u0026ndash;99. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1161/CIRCRESAHA.116.305348\u003c/span\u003e\u003cspan address=\"10.1161/CIRCRESAHA.116.305348\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSulemanji M, Vakili K. Neonatal renal physiology. Semin Pediatr Surg. 2013;22(4):195-8. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1053/j.sempedsurg.2013.10.008\u003c/span\u003e\u003cspan address=\"10.1053/j.sempedsurg.2013.10.008\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Epub 2013 Oct 15. PMID: 24331094.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi J, Wang X, Liu W, et al. Remote ischemic preconditioning and clinical outcomes after pediatric cardiac surgery: a systematic review and meta-analysis. BMC Anesthesiol. 2023;23(1):105. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s12871-023-02064-6\u003c/span\u003e\u003cspan address=\"10.1186/s12871-023-02064-6\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Remote Ischemic Preconditioning, Cardiac Surgery, Pediatric, Renal Injury, Meta-Analysis","lastPublishedDoi":"10.21203/rs.3.rs-4541403/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4541403/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eTo determine whether remote ischemic preconditioning (RIPC) improves renal outcomes in children undergoing pediatric cardiac surgery.\u003c/p\u003e\u003ch2\u003eMethod\u003c/h2\u003e \u003cp\u003eA systematic search of PubMed, EMBASE, and the Cochrane Library included randomized controlled trials (RCTs) assessing the effect of RIPC on the incidence of postoperative acute kidney injury (AKI) and ICU length of stay.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eSix RCTs with 1098 patients were included.RIPC significantly reduced the incidence of AKI (OR\u0026thinsp;=\u0026thinsp;0.38, 95% CI: 0.25\u0026ndash;0.60, P\u0026thinsp;\u0026lt;\u0026thinsp;0.00001, I\u0026sup2;=38%). There was no significant effect on postoperative sCr, TNF-α levels and ICU length of stay (all P values\u0026thinsp;\u0026gt;\u0026thinsp;0.05, I\u0026sup2; \u0026gt;80%). Sensitivity analyses showed a large impact of some studies on the results.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eRIPC significantly reduced the incidence of AKI after pediatric cardiac surgery, showing its potential renoprotective effect. Although the effect on other postoperative indicators was not significant, high heterogeneity limits the certainty of the conclusions. Future studies should focus on multicenter, large-scale trials with detailed subgroup analyses to explore the mechanism of action and effects of RIPC in different patient populations.\u003c/p\u003e","manuscriptTitle":"The Protective Effect of Remote Ischemic Preconditioning on Acute Kidney Injury Following Pediatric Cardiac Surgery: A Systematic Review and Meta-Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-15 19:18:36","doi":"10.21203/rs.3.rs-4541403/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f452423e-b06c-4368-b578-5dbe05976ff6","owner":[],"postedDate":"July 15th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":33854982,"name":"Health sciences/Diseases/Cardiovascular diseases"},{"id":33854983,"name":"Health sciences/Medical research/Paediatric research"}],"tags":[],"updatedAt":"2024-09-09T12:54:24+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-15 19:18:36","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4541403","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4541403","identity":"rs-4541403","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}