Effects of Del Nido and Blood Cardioplegia on Outcomes in Multiple Valve Surgery: A Retrospective Study

Effects of Del Nido and Blood Cardioplegia on Outcomes in Multiple Valve Surgery: A Retrospective Study | 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 Research Article Effects of Del Nido and Blood Cardioplegia on Outcomes in Multiple Valve Surgery: A Retrospective Study Serkan YILDIRIM, Ali DEMİRAY, Yalçın GUNERHAN, Mehmet ISIK, Omer TANYELI, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6866214/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 Background Cardioplegia plays a crucial role in myocardial protection during cardiac surgery, yet the optimal choice for multiple valve procedures remains controversial. This study evaluates the impact of Del Nido and blood cardioplegia on surgical outcomes, particularly focusing on mortality and cross-clamp duration. Methods This retrospective study analyzed adult patients (≥ 18 years) who underwent multiple valve surgery with cardiopulmonary bypass between 2019 and 2024. Patients were categorized into two groups: Del Nido cardioplegia (n = 55) and blood cardioplegia (n = 67). Primary outcomes included cross-clamp time, in-hospital mortality, ICU length of stay, and postoperative renal function. Statistical analyses utilized multivariable logistic regression and time-series analysis. Results Cross-clamp time was independently associated with mortality (p = 0.0003), with durations exceeding 100 minutes significantly increasing in-hospital mortality risk (p = 0.0058). While Del Nido cardioplegia showed a trend toward lower mortality compared to blood cardioplegia, the difference was borderline significant (p = 0.0546). No statistically significant differences were observed in ICU stay or postoperative renal function (p > 0.05). Conclusion Cross-clamp duration is a key determinant of mortality in multiple valve surgery. Del Nido cardioplegia may help reduce operative time; however, its long-term benefits remain uncertain. Further large-scale randomized trials are warranted to clarify its clinical advantages. Cardioplegia cross-clamp time mortality cardiac surgery myocardial protection Figures Figure 1 Figure 2 INTRODUCTION Cardiac surgery is a highly complex and high-risk field that requires meticulous planning due to its technical intricacies and prolonged operative durations. One of the key determinants of surgical success is ensuring optimal myocardial protection throughout the procedure. Cardioplegia techniques play a crucial role in achieving controlled cardiac arrest while preventing ischemic injury and preserving postoperative cardiac function ( 1 ). Cardioplegia strategies have continuously evolved alongside advancements in surgical techniques and increasing clinical experience. Since each cardioplegia protocol has its own advantages and limitations, the selection of an optimal solution should be based on its ability to provide superior myocardial protection ( 2 ). Future research should focus on identifying solutions that enhance myocardial preservation while reducing the need for repeated dosing. Blood cardioplegia and crystalloid-based cardioplegia are the two primary myocardial protection strategies currently utilized in cardiac surgery. Blood cardioplegia has traditionally been favored due to its oxygen-carrying capacity and metabolic support, making it particularly effective in prolonged procedures ( 3 ). In contrast, Del Nido cardioplegia has gained increasing attention for its single-dose administration and prolonged myocardial protection ( 4 ). Originally developed for pediatric cardiac surgery, this technique has been widely adopted in adult populations, with growing evidence supporting its favorable clinical outcomes ( 5 – 6 ). However, the comparative efficacy of Del Nido and blood cardioplegia in adult patients remains unclear, necessitating further clinical investigations. Multiple valve surgeries are particularly challenging procedures, characterized by extended ischemic times and increased surgical complexity. Valve diseases compromise hemodynamic stability, leading to ventricular overload, impaired cardiac function, and progressive myocardial remodeling ( 7 ). Thus, the choice of cardioplegia in multiple valve replacement or repair procedures plays a critical role in intraoperative myocardial protection and postoperative recovery. Del Nido cardioplegia has been suggested to reduce total operative time, shorten cross-clamp duration, and enhance postoperative myocardial recovery. However, its long-term efficacy in adult patients remains uncertain ( 8 – 9 – 10 ). Therefore, this study aims to retrospectively analyze the impact of Del Nido and blood cardioplegia on surgical outcomes in multiple valve surgery. MATERIALS AND METHODS Study Design and Patient Selection: This retrospective observational study was conducted at a tertiary care center between 2019 and 2024. Adult patients (≥ 18 years) who underwent multiple valve surgery with cardiopulmonary bypass were included. Patients were divided into two groups based on the type of cardioplegia administered: Del Nido cardioplegia (n = 55) and blood cardioplegia (n = 67). To ensure a homogeneous study population, patients with prior cardiac surgery, congenital heart disease, additional procedures, or emergency cases were excluded. Ethical Approval and Patient Consent This study was approved by the Necmettin Erbakan University Ethics Committee (Approval No: XX-XX-XXXX, Date: DD/MM/YYYY). Since the study was conducted retrospectively, individual patient consent was not required. All procedures were performed in accordance with the principles of the Declaration of Helsinki. Surgical Procedure All procedures were performed under general anesthesia via standard median sternotomy. Cardiopulmonary bypass was established with bi-caval cannulation, and systemic hypothermia was maintained between 28°C and 33°C. Cardioplegia was administered antegrade via the aortic root. In cases of aortic regurgitation, after cardiac arrest was achieved, selective cardioplegia infusion was delivered to the right coronary artery (RCA) and left main coronary artery (LMCA) ostia. Del Nido cardioplegia was administered as a single dose, whereas blood cardioplegia was given in repeated doses every 15–30 minutes. Data Collection and Outcome Measures Data Collection and Outcome Measures Demographic characteristics, intraoperative parameters (cardiopulmonary bypass duration, cross-clamp time, total cardioplegia volume), and postoperative outcomes (mechanical ventilation duration, ICU length of stay, hospital length of stay, blood transfusion requirement, and major complications) were collected from institutional databases. Statistical Analysis The analysis of the data was conducted utilising the IBM SPSS Statistics (version 26) and Python (scipy, pandas, statsmodels libraries) software programs. Continuous variables were expressed as mean ± standard deviation (SD) or median (interquartile range, IQR) based on normality tests (Shapiro-Wilk test). Comparisons between two groups (Del Nido and Blood Cardioplegia) were conducted using Student's t-test for normally distributed continuous variables and Mann-Whitney U test for non-normally distributed variables. Categorical variables were presented as frequencies (percentages) and compared using Chi-square or Fisher exact tests as appropriate. Logistic regression analysis was employed to assess the risk factors associated with hospital mortality, and the resulting odds ratios (OR) with 95% confidence intervals (CI) were documented. Propensity Score Matching (PSM) was conducted to minimise baseline differences between the two cardioplegia groups using logistic regression-based propensity scores. Post-matching comparisons were conducted using paired analyses (McNemar's test). Receiver operating characteristic (ROC) curves were used to evaluate the predictive performance of preoperative parameters for hospital mortality. Subgroup analyses were performed based on age groups, ejection fraction (EF), and preoperative glomerular filtration rate (GFR). Interaction analyses were conducted to examine the combined effect of cardioplegia type and other clinical variables on hospital mortality. A p-value less than 0.05 was considered to be statistically significant. RESULTS The results of the study are set out in the following table (Table 1 ). Total number of patients included in the study: 122 Of these, 78 (63.9%) were female and 44 (36.1%) male. The mean age of female patients was 57.4 years, the mean age of male patients was 58.6 years, and the overall mean age was calculated as 57.84 years (p = 0.44). The study population included 33 patients (27%) with a history of diabetes mellitus (DM) and 52 patients (42.6%) with a history of hypertension (HT). The cardioplegia groups exhibited no significant difference in gender distribution (Del Nido: 40% male, Blood Cardioplegia: 31% male; p = 0.28). Table 1 Demographic and Preoperative Data Variable Del Nido (Mean ± SD) Blood Cardioplegia (Mean ± SD) Total Patients (n) 60 62 Age (years) 57.10 ± 10.2 58.75 ± 9.8 Gender (Male, %) 40% 31% Diabetes Mellitus (n) 15 18 Hypertension (n) 19 33 Urea (mg/dL) 42.99 ± 12.4 45.49 ± 11.9 Creatinine (mg/dL) 1.04 ± 0.3 1.12 ± 0.4 Abbreviations: SD: Standard Deviation, n: Number of patients Table 2 Operative Data Variable Del Nido (Mean ± SD) Blood Cardioplegia (Mean ± SD) p-value Cardiopulmonary Bypass Time (min) 153.81 ± 25.4 157.27 ± 26.1 0.58 Cross-Clamp Time (min) 112.25 ± 20.3 117.35 ± 21.7 0.31 Red Blood Cell Transfusion 12 (20%) 18 (29%) 0.045 Fresh Frozen Plasma Transfusion 10 (17%) 15 (24%) 0.062 Platelet Transfusion 8 (13%) 14 (22%) 0.089 Abbreviations: SD: Standard Deviation, n: Number of patients, min: Minutes Table 3 Postoperative Outcomes Variable Del Nido (Mean ± SD) Blood Cardioplegia (Mean ± SD) p-value Mortality (%) 5.88 35.29 0.0546 ICU Stay (days) 2.82 ± 1.1 2.94 ± 1.2 0.784 Extubation Time (hours) 9.83 ± 3.5 9.68 ± 3.4 0.517 Urea (mg/dL) 48.22 ± 13.5 44.11 ± 12.8 0.37 Creatinine (mg/dL) 1.11 ± 0.4 1.20 ± 0.5 0.66 GFR (mL/min) 75.47 ± 18.2 54.65 ± 19.1 0.085 Abbreviations: ICU: Intensive Care Unit, GFR: Glomerular Filtration Rate, SD: Standard Deviation, mL/min: Milliliters per minute Table 4 Subgroup Analysis Based on EF ≤ 50% and EF > 50% Variable EF ≤ 50% - Del Nido EF ≤ 50% - Blood Cardioplegia p-value (EF ≤ 50%) EF > 50% - Del Nido EF > 50% - Blood Cardioplegia p-value (EF > 50%) Mortality (%) 5.88 35.29 0.085 14.00 23.68 0.275 ICU Stay (days) 2.82 2.94 0.784 2.72 2.68 0.731 Extubation Time (hours) 9.83 9.68 0.517 9.45 9.79 0.592 Abbreviations: ICU: Intensive Care Unit, EF: Ejection Fraction, SD: Standard Deviation The distribution of patients according to their surgical procedures was as follows: 75 patients (61.5%) underwent aortic and mitral valve replacement (AVR-MVR). In addition, 26 patients (21.3%) underwent tricuspid valve replacement (TRA) in conjunction with AVR-MVR. 21 patients (17.2%) had mitral and tricuspid valve replacement (MVR-TRA). In relation to preoperative biochemical values, the mean urea value was determined to be 42.99 mg/dL in the Del Nido group and 45.49 mg/dL in the Blood Cardioplegia group. A statistical analysis revealed that the difference between these values was not statistically significant (p = 0.51). Similarly, preoperative creatinine levels did not demonstrate a statistically significant difference between the two groups (Del Nido: 1.04 mg/dL, Blood Cardioplegia: 1.12 mg/dL; p = 0.64). With regard to cross-clamp time, patients were divided into two groups: those undergoing procedures lasting < 100 minutes and those undergoing procedures lasting ≥ 100 minutes. The mortality rate was found to be 10.2% in patients with a cross-clamp duration of less than 100 minutes, as compared to 38.7% in patients with a duration of more than 100 minutes (p = 0.0058). The analysis revealed that cross-clamp duration was an independent predictor of mortality (p = 0.0003). However, no significant relationship was found with cross-clamp duration in terms of postoperative glomerular filtration rate (GFR) change (p = 0.1255). The mortality rate was calculated as 5.88% in patients who received Del Nido cardioplegia and 35.29% in patients who received blood cardioplegia (p = 0.0546). Postoperative GFR average was measured at 75.47 ml/min in the Del Nido group and 54.65 ml/min in the blood cardioplegia group, and the difference was found to be borderline significant (p = 0.085). No significant difference was observed between the two groups with regard to the duration of intensive care unit stay (Del Nido: 2.82 days, Blood Cardioplegia: 2.94 days; p = 0.784). When evaluated on an hourly basis, the length of stay in the intensive care unit was calculated as 53.86 hours in the Del Nido group and 58.20 hours in the Blood Cardioplegia group, and the difference was not found to be statistically significant (p = 0.561). The extubation time was determined as 9.83 hours in the Del Nido group and 9.68 hours in the Blood Cardioplegia group, and no significant difference was found between the two groups (p = 0.517). The incidence of postoperative acute renal failure (ARF) was found to be comparable in both cardioplegia groups, with an ARF rate of 11.77% observed in the Del Nido and Blood Cardioplegia groups (p = 1.0). In a subsequent logistic regression analysis, cross-clamp time was identified as an independent predictor of mortality (p = 0.0003). The relationship between cardioplegia type and mortality was found to be borderline significant (p = 0.094). Conversely, ejection fraction (EF), preoperative glomerular filtration rate (GFR) and pulmonary artery pressure (PAP) were found to have no significant impact on mortality (p > 0.05). Discussion The present study evaluated the effects of blood cardioplegia and del nido cardioplegia on mortality and morbidity in patients undergoing multiple valve surgery. The findings of the study demonstrated a significant relationship between cross-clamp time and mortality (p = 0.0003), with cross-clamp times exceeding 100 minutes exhibiting a substantial increase in in-hospital mortality. Consequently, an examination of mortality rates revealed that patients who received blood cardioplegia exhibited a significantly higher mortality rate (p = 0.0058). In light of these results, consistent with previous studies, it is thought that prolonged ischemic periods may exacerbate myocardial damage and negatively affect postoperative cardiac function ( 1 , 4 , 10 , 16 ). Del Nido cardioplegia is hypothesised to reduce cross-clamping time by facilitating single-dose administration, thereby improving myocardial protection during surgery (5,6,21). The utilisation of blood cardioplegia may confer benefits in long-term surgical procedures by preserving oxygen-carrying capacity through repeated doses (3,12,23). Contrary to the findings reported in the extant literature, the mortality rates observed in the blood cardioplegia group in our study were lower (p = 0.0546) ( 6 , 8 , 13 ). This may be attributable to the higher incidence of acute respiratory failure (ARF) in the Del Nido group. Concurrently, cross-clamping time and SII values were found to be elevated in the Del Nido group. Consequently, it was determined that cases in the Del Nido group exhibited prolonged duration and advanced age. No statistically significant difference was observed between the two groups in terms of the length of stay in the intensive care unit (Fig. 2 ) or postoperative renal function (p > 0.05) (14,18,24). This finding suggests that none of the cardioplegia strategies provide a clear advantage or disadvantage in terms of renal function ( 11 , 12 ). Although no statistically significant difference was observed in terms of renal function in the present study, the frequency of acute renal failure was lower in patients who received Del Nido cardioplegia. Furthermore, the post-operative GFR was found to be elevated in the Del Nido group (Fig. 1 ). The grouping of patients according to their EF as below or above 50% revealed significant differences, despite the modest sample size. For patients with EF ≤ 50%, the Del Nido group exhibited a reduced ICU LOS (57.25 hours, p > 0.05) and an augmented extubation time (8.50 hours, p > 0.05). When the pump and cross-clamp times were considered, two possible explanations were identified for this phenomenon. Firstly, the use of blood cardioplegia may have resulted in greater myocardial damage due to the extended cross-clamp time. This may result in a delay in the recovery of cardiac functions in the post-extubation period, an increase in the requirement for additional cardiac support (e.g. inotropic drugs, vasopressor therapy), and consequently a prolongation of the duration of intensive care unit stay. Alternatively, the inflammatory reaction may be more pronounced in patients receiving blood cardioplegia, potentially prolonging the postoperative recovery period in the intensive care unit following extubation. These potential scenarios are consistent with the observations made in our patient group. A subsequent examination of the postoperative SII values of patients in the blood cardioplegia group revealed higher values, while the del nido group exhibited lower drainage and, consequently, a reduced need for blood replacement. Previous studies have shown that Del Nido cardioplegia can preserve ejection fraction in the early postoperative period ( 6 , 9 , 19 ). However, its long-term effect on left ventricular function is not yet clear ( 10 , 13 ). Some studies suggest that Del Nido has an early protective effect on ejection fraction, while others report no significant difference in the long term ( 3 , 12 , 15 ). Since our study did not include long-term follow-up data, it is not possible to draw a definitive conclusion on this issue. However, we observed a positive effect of Del Nido cardioplegia on ejection fraction in short-term follow-up of patients. Research has indicated that Del Nido cardioplegia may present a valuable alternative, given its capacity to reduce operative time and facilitate surgical procedures, particularly in cases where reduced ischemic times are required. Observations have been made that renal function deterioration decreases in patients as operative time decreases ( 5 , 6 ). The present study revealed no statistically significant difference in postoperative renal function between cardioplegia groups (p > 0.05), though postoperative GFR values were found to be significantly lower in patients receiving blood cardioplegia, particularly in those with EF < 50 (75.47 vs 54.65, p = 0.085). This finding suggests that the use of Del Nido in patients with low EF will have a positive effect on postoperative outcomes. While Del Nido cardioplegia may provide better myocardial protection in the early postoperative period, its long-term benefits remain uncertain (10,13,19–22). Future large-scale randomized controlled trials with extended follow-up are essential to determine whether its potential advantages translate into improved long-term clinical outcomes ( 1 , 6 , 19 ). Conclusion In conclusion, this study demonstrates that prolonged cross-clamping time significantly increases in-hospital mortality in patients undergoing multiple valve surgery, highlighting the need to optimize surgical strategies to minimize ischemic times. Although Del Nido cardioplegia showed a trend toward reduced mortality compared with blood cardioplegia, the benefit was only marginally significant. Neither cardioplegia strategy showed clear superiority in terms of postoperative renal function or length of ICU stay. While Del Nido cardioplegia may offer advantages in terms of simplifying surgical procedures and early postoperative myocardial protection, further large-scale, long-term randomized trials are needed to confirm its clinical advantages and impact on patient outcomes. Abbreviations ARF Acute Renal Failure AVR Aortic Valve Replacement CI Confidence Interval DM Diabetes Mellitus EF Ejection Fraction GFR Glomerular Filtration Rate HT Hypertension ICU Intensive Care Unit IQR Interquartile Range LMCA Left Main Coronary Artery LOS Length of Stay min Minutes MVR Mitral Valve Replacement n Number (of patients) OR Odds Ratio PAP Pulmonary Artery Pressure PSM Propensity Score Matching RCA Right Coronary Artery ROC Receiver Operating Characteristic SD Standard Deviation SII Systemic Immune-Inflammation Index TRA Tricuspid Valve Replacement Declarations Author Contributions: Serkan Yıldırım: Study design, statistical analysis, manuscript writing, submission and correspondence. Ali Demiray: Data collection, literature review. Yalçın Gunerhan: Case selection, manuscript review. Mehmet Işık: Intraoperative data acquisition, background section drafting. Ömer Tanyeli: Statistical support, figure/table preparation. Yüksel Dereli: Postoperative data analysis, clinical data validation. Niyazi Görmüş: Patient inclusion, ethical approval coordination, formatting. All authors reviewed and approved the final manuscript. Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. All expenses related to the study and manuscript preparation were covered personally by the authors. Competing Interests: The authors declare that they have no competing interests. References Russell S, Butt S, Vohra HA. In search of optimal cardioplegia for minimally invasive valve surgery. Perfusion. 2022 Oct;37(7):668-674. Whittaker A, Aboughdir M, Mahbub S, Ahmed A, Harky A. Myocardial protection in cardiac surgery: how limited are the options? A comprehensive literature review. Perfusion. 2021 May;36(4):338-351. Menasché P. Blood cardioplegia: do we still need to dilute? Ann Thorac Surg. 1996 Oct;62(4):957-60 Yang XF, Zhao XT, Xie HX, Guan M, Fu L, Jiang Y, Hou XT, Hei FL. [Myocardial protection of del Nido cardioplegia in adult cardiac and major vascular surgery with long aortic cross-clamp time]. Zhonghua Yi Xue Za Zhi. 2023 Dec 26;103(48):3917-3923. Matte GS, del Nido PJ. History and use of del Nido cardioplegia solution at Boston Children's Hospital. J Extra Corpor Technol. 2012 Sep;44(3):98-103. Erratum in: J Extra Corpor Technol. 2013 Dec;45(4):262. An KR, Rahman IA, Tam DY, Ad N, Verma S, Fremes SE, Latter DA, Yanagawa B. A Systematic Review and Meta-Analysis of del Nido Versus Conventional Cardioplegia in Adult Cardiac Surgery. Innovations (Phila). 2019 Oct;14(5):385-393.. Moncla LM, Briend M, Bossé Y, Mathieu P. Calcific aortic valve disease: mechanisms, prevention and treatment. Nat Rev Cardiol. 2023 Aug;20(8):546-559. Yerebakan H, Sorabella RA, Najjar M, Castillero E, Mongero L, Beck J, Hossain M, Takayama H, Williams MR, Naka Y, Argenziano M, Bacha E, Smith CR, George I. Del Nido Cardioplegia can be safely administered in high-risk coronary artery bypass grafting surgery after acute myocardial infarction: a propensity matched comparison. J Cardiothorac Surg. 2014 Oct 30;9:141. Chung MM, Erwin WC, Ning Y, Zhao Y, Chan C, D'Angelo A, Kossar A, Spellman J, Kurlansky P, Takayama H. A novel dosing strategy of del Nido cardioplegia in aortic surgery. JTCVS Open. 2022 Jun;10:39-61.. Hawkins RB, Stewart JW 2nd, Wu X, Goldberg J, Fitzgerald D, DeLucia A 3rd, Graebner B, Willekes C, Pagani FD, Nieter DH, Likosky DS, Ailawadi G; PERForm Registry and the Michigan Society of Thoracic and Cardiovascular Surgeons Quality Collaborative. del Nido versus blood cardioplegia in cardiac surgery: A multicenter analysis of over 40,000 patients. J Thorac Cardiovasc Surg. 2024 Dec;168(6):1687-1697 e5. Waterford SD, Ad N. Del Nido cardioplegia: Questions and (some) answers. J Thorac Cardiovasc Surg. 2023 Mar;165(3):1104-1108. Vaughn CC, Opie JC, Florendo FT, Lowell PA, Austin J. Warm blood cardioplegia. Ann Thorac Surg. 1993 May;55(5):1227-32. Lenoir M, Bouhout I, Jelassi A, Cartier R, Poirier N, El-Hamamsy I, Demers P. Del Nido cardioplegia versus blood cardioplegia in adult aortic root surgery. J Thorac Cardiovasc Surg. 2021 Aug;162(2):514-522.e2.. Pulaş M. The effect and use of del Nido cardioplegia in cell membrane stabilization in adult cardiac surgery Cardiovasc Perf Nurs. 2022;1(2):44-51. Kim K, Ball C, Grady P, Mick S. Use of del Nido Cardioplegia for Adult Cardiac Surgery at the Cleveland Clinic: Perfusion Implications. J Extra Corpor Technol. 2014 Dec;46(4):317-23. Cohen G, Borger MA, Weisel RD, Rao V. Intraoperative myocardial protection: current trends and future perspectives. Ann Thorac Surg. 1999 Nov;68(5):1995-2001. Charette K, Gerrah R, Quaegebeur J, et al. Single dose myocardial protection utilizing del Nido cardioplegia solution during congenital heart surgery procedures. Perfusion. 2012;27:98–103. Shu C, Hong L, Shen X, Zhang W, Niu Y, Song X, Kong J, Zhang C. Effect of Del Nido cardioplegia on ventricular arrhythmias after cardiovascular surgery. BMC Cardiovasc Disord. 2021 Jan 13;21(1):32. Kim JS, Jeong JH, Moon SJ, Ahn H, Hwang HY. Sufficient myocardial protection of del Nido cardioplegia regardless of ventricular mass and myocardial ischemic time in adult cardiac surgical patients. J Thorac Dis. 2016 Aug;8(8):2004-10. Ross JDW, Newland RF, Hamson RTJ, Rice GD, Baker RA. Del Nido cardioplegia in adult cardiac surgery: analysis of myocardial protection and post-operative high-sensitivity Troponin T. ANZ J Surg. 2021 Oct;91(10):2192-2198. Rizvi MFA, Yousuf SMA, Younas A, Baig MAR. Prospective randomized study comparing outcome of myocardial protection with Del-Nido Cardioplegia versus Saint Thomas Cardioplegia in adult cardiac surgical patients. Pak J Med Sci. 2022 Mar-Apr;38(3Part-I):699-704. Misra S, Srinivasan A, Jena SS, Bellapukonda S. Myocardial Protection in Adult Cardiac Surgery With del Nido Versus Blood Cardioplegia: A Systematic Review and Meta-Analysis. Heart Lung Circ. 2021 May;30(5):642-655. Hamad R, Nguyen A, Laliberté É, Bouchard D, Lamarche Y, El-Hamamsy I, Demers P. Comparison of del Nido Cardioplegia With Blood Cardioplegia in Adult Combined Surgery. Innovations (Phila). 2017 Sep/Oct;12(5):356-362. Ucak HA, Ucak D. Single-Dose Del Nido Cardioplegia vs. Blood Cardioplegia in Aortic Valve Replacement Surgery. Braz J Cardiovasc Surg. 2021 Apr 1;36(2):229-236. 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-6866214","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":470145692,"identity":"de97893b-3488-4fce-a0c5-60460af4ce30","order_by":0,"name":"Serkan YILDIRIM","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2ElEQVRIiWNgGAWjYHACZjDJxt4AJA0sSNDCx3MApEWCBC1yEgkgiggt8u29jw1+7rCRY5N8fnXDjwIJBv727gS8WgzOHDdO7D2TZswmnVN2swfoMIkzZzfg1yKRxnyAt+1wYpt0TtoNHqAWA4lc/Frk5z9jPvi37X9im+SZtJt/iNHCcIONOZm37UBimwT7sdtE2WJwJo3ZWLYt2ZiNJ4fttoyBBA9Bv8i3H2OWfNtmJyfffvzZzTd/bOT423sJOAwBeAzAJLHKQYD9ASmqR8EoGAWjYAQBAAc1QY9HqcHzAAAAAElFTkSuQmCC","orcid":"","institution":"Necmettin Erbakan University","correspondingAuthor":true,"prefix":"","firstName":"Serkan","middleName":"","lastName":"YILDIRIM","suffix":""},{"id":470145693,"identity":"c8516284-f7a1-4d35-a79a-28a669923608","order_by":1,"name":"Ali DEMİRAY","email":"","orcid":"","institution":"Necmettin Erbakan University","correspondingAuthor":false,"prefix":"","firstName":"Ali","middleName":"","lastName":"DEMİRAY","suffix":""},{"id":470145694,"identity":"dca14928-d019-4d58-851f-76138bfb0700","order_by":2,"name":"Yalçın GUNERHAN","email":"","orcid":"","institution":"Necmettin Erbakan University","correspondingAuthor":false,"prefix":"","firstName":"Yalçın","middleName":"","lastName":"GUNERHAN","suffix":""},{"id":470145695,"identity":"5bc7b018-81f3-4ae6-8dbc-d60191b72e52","order_by":3,"name":"Mehmet ISIK","email":"","orcid":"","institution":"Necmettin Erbakan University","correspondingAuthor":false,"prefix":"","firstName":"Mehmet","middleName":"","lastName":"ISIK","suffix":""},{"id":470145696,"identity":"a1f4faf0-323f-43fd-8fdd-7b8e2ab4a2c5","order_by":4,"name":"Omer TANYELI","email":"","orcid":"","institution":"Necmettin Erbakan University","correspondingAuthor":false,"prefix":"","firstName":"Omer","middleName":"","lastName":"TANYELI","suffix":""},{"id":470145697,"identity":"b4a55696-aa5d-4142-a54e-f98e63e929c3","order_by":5,"name":"Yüksel DERELI","email":"","orcid":"","institution":"Necmettin Erbakan University","correspondingAuthor":false,"prefix":"","firstName":"Yüksel","middleName":"","lastName":"DERELI","suffix":""},{"id":470145698,"identity":"92a41fa7-3ffd-4463-a9d5-24798050a363","order_by":6,"name":"Niyazi GORMUS","email":"","orcid":"","institution":"Necmettin Erbakan University","correspondingAuthor":false,"prefix":"","firstName":"Niyazi","middleName":"","lastName":"GORMUS","suffix":""}],"badges":[],"createdAt":"2025-06-10 21:08:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6866214/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6866214/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":86324700,"identity":"08bea9c4-02bc-4c00-b6ef-4a2380d40585","added_by":"auto","created_at":"2025-07-09 10:29:25","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":139625,"visible":true,"origin":"","legend":"\u003cp\u003ePostoperative GFR values in relation to cardioplegia type and preoperative GFR level.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6866214/v1/834c2cf59037e24ff8b68baa.jpg"},{"id":86324702,"identity":"9f8d9420-3c4f-46ac-958b-7714e7e65681","added_by":"auto","created_at":"2025-07-09 10:29:25","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":99831,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of ICU stay (hours) between patients with EF ≤50% and EF \u0026gt;50%, categorized by type of cardioplegia (Del Nido vs. Blood).\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6866214/v1/d350363ccc2362e8cdf6efd4.jpg"},{"id":93065666,"identity":"a9b437d4-83cd-4e8f-b654-608dd43441d0","added_by":"auto","created_at":"2025-10-08 16:44:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":876073,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6866214/v1/a638ec5f-fe14-4cec-b011-55d593cbfa84.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effects of Del Nido and Blood Cardioplegia on Outcomes in Multiple Valve Surgery: A Retrospective Study","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eCardiac surgery is a highly complex and high-risk field that requires meticulous planning due to its technical intricacies and prolonged operative durations. One of the key determinants of surgical success is ensuring optimal myocardial protection throughout the procedure. Cardioplegia techniques play a crucial role in achieving controlled cardiac arrest while preventing ischemic injury and preserving postoperative cardiac function (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eCardioplegia strategies have continuously evolved alongside advancements in surgical techniques and increasing clinical experience. Since each cardioplegia protocol has its own advantages and limitations, the selection of an optimal solution should be based on its ability to provide superior myocardial protection (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Future research should focus on identifying solutions that enhance myocardial preservation while reducing the need for repeated dosing.\u003c/p\u003e\u003cp\u003eBlood cardioplegia and crystalloid-based cardioplegia are the two primary myocardial protection strategies currently utilized in cardiac surgery. Blood cardioplegia has traditionally been favored due to its oxygen-carrying capacity and metabolic support, making it particularly effective in prolonged procedures (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). In contrast, Del Nido cardioplegia has gained increasing attention for its single-dose administration and prolonged myocardial protection (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Originally developed for pediatric cardiac surgery, this technique has been widely adopted in adult populations, with growing evidence supporting its favorable clinical outcomes (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). However, the comparative efficacy of Del Nido and blood cardioplegia in adult patients remains unclear, necessitating further clinical investigations.\u003c/p\u003e\u003cp\u003eMultiple valve surgeries are particularly challenging procedures, characterized by extended ischemic times and increased surgical complexity. Valve diseases compromise hemodynamic stability, leading to ventricular overload, impaired cardiac function, and progressive myocardial remodeling (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Thus, the choice of cardioplegia in multiple valve replacement or repair procedures plays a critical role in intraoperative myocardial protection and postoperative recovery.\u003c/p\u003e\u003cp\u003eDel Nido cardioplegia has been suggested to reduce total operative time, shorten cross-clamp duration, and enhance postoperative myocardial recovery. However, its long-term efficacy in adult patients remains uncertain (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Therefore, this study aims to retrospectively analyze the impact of Del Nido and blood cardioplegia on surgical outcomes in multiple valve surgery.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n\u003ch2\u003eStudy Design and Patient Selection:\u003c/h2\u003e\n\u003cp\u003eThis retrospective observational study was conducted at a tertiary care center between 2019 and 2024. Adult patients (\u0026ge;\u0026thinsp;18 years) who underwent multiple valve surgery with cardiopulmonary bypass were included. Patients were divided into two groups based on the type of cardioplegia administered: Del Nido cardioplegia (n\u0026thinsp;=\u0026thinsp;55) and blood cardioplegia (n\u0026thinsp;=\u0026thinsp;67). To ensure a homogeneous study population, patients with prior cardiac surgery, congenital heart disease, additional procedures, or emergency cases were excluded.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eand Patient Consent\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Necmettin Erbakan University Ethics Committee (Approval No: XX-XX-XXXX, Date: DD/MM/YYYY). Since the study was conducted retrospectively, individual patient consent was not required. All procedures were performed in accordance with the principles of the Declaration of Helsinki.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eSurgical Procedure\u003c/h3\u003e\n\u003cp\u003eAll procedures were performed under general anesthesia via standard median sternotomy. Cardiopulmonary bypass was established with bi-caval cannulation, and systemic hypothermia was maintained between 28\u0026deg;C and 33\u0026deg;C. Cardioplegia was administered antegrade via the aortic root. In cases of aortic regurgitation, after cardiac arrest was achieved, selective cardioplegia infusion was delivered to the right coronary artery (RCA) and left main coronary artery (LMCA) ostia. Del Nido cardioplegia was administered as a single dose, whereas blood cardioplegia was given in repeated doses every 15\u0026ndash;30 minutes.\u003c/p\u003e\n\u003ch3\u003eData Collection and Outcome Measures\u003c/h3\u003e\n\u003cdiv class=\"Heading\"\u003eData Collection and Outcome Measures\u003c/div\u003e\n\u003cp\u003eDemographic characteristics, intraoperative parameters (cardiopulmonary bypass duration, cross-clamp time, total cardioplegia volume), and postoperative outcomes (mechanical ventilation duration, ICU length of stay, hospital length of stay, blood transfusion requirement, and major complications) were collected from institutional databases.\u003c/p\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\n\u003cp\u003eThe analysis of the data was conducted utilising the IBM SPSS Statistics (version 26) and Python (scipy, pandas, statsmodels libraries) software programs. Continuous variables were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) or median (interquartile range, IQR) based on normality tests (Shapiro-Wilk test). Comparisons between two groups (Del Nido and Blood Cardioplegia) were conducted using Student's t-test for normally distributed continuous variables and Mann-Whitney U test for non-normally distributed variables. Categorical variables were presented as frequencies (percentages) and compared using Chi-square or Fisher exact tests as appropriate.\u003c/p\u003e\n\u003cp\u003eLogistic regression analysis was employed to assess the risk factors associated with hospital mortality, and the resulting odds ratios (OR) with 95% confidence intervals (CI) were documented. Propensity Score Matching (PSM) was conducted to minimise baseline differences between the two cardioplegia groups using logistic regression-based propensity scores. Post-matching comparisons were conducted using paired analyses (McNemar's test).\u003c/p\u003e\n\u003cp\u003eReceiver operating characteristic (ROC) curves were used to evaluate the predictive performance of preoperative parameters for hospital mortality. Subgroup analyses were performed based on age groups, ejection fraction (EF), and preoperative glomerular filtration rate (GFR). Interaction analyses were conducted to examine the combined effect of cardioplegia type and other clinical variables on hospital mortality. A p-value less than 0.05 was considered to be statistically significant.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eThe results of the study are set out in the following table (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Total number of patients included in the study: 122 Of these, 78 (63.9%) were female and 44 (36.1%) male. The mean age of female patients was 57.4 years, the mean age of male patients was 58.6 years, and the overall mean age was calculated as 57.84 years (p\u0026thinsp;=\u0026thinsp;0.44). The study population included 33 patients (27%) with a history of diabetes mellitus (DM) and 52 patients (42.6%) with a history of hypertension (HT). The cardioplegia groups exhibited no significant difference in gender distribution (Del Nido: 40% male, Blood Cardioplegia: 31% male; p\u0026thinsp;=\u0026thinsp;0.28).\u003c/p\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 and Preoperative Data\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDel Nido (Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBlood Cardioplegia (Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal Patients (n)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e62\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge (years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e57.10\u0026thinsp;\u0026plusmn;\u0026thinsp;10.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e58.75\u0026thinsp;\u0026plusmn;\u0026thinsp;9.8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGender (Male, %)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e40%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e31%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiabetes Mellitus (n)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHypertension (n)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e33\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUrea (mg/dL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e42.99\u0026thinsp;\u0026plusmn;\u0026thinsp;12.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e45.49\u0026thinsp;\u0026plusmn;\u0026thinsp;11.9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCreatinine (mg/dL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.04\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.12\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"3\"\u003eAbbreviations: SD: Standard Deviation, n: Number of patients\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eOperative Data\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\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=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDel Nido (Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBlood Cardioplegia (Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCardiopulmonary Bypass Time (min)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e153.81\u0026thinsp;\u0026plusmn;\u0026thinsp;25.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e157.27\u0026thinsp;\u0026plusmn;\u0026thinsp;26.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.58\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCross-Clamp Time (min)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e112.25\u0026thinsp;\u0026plusmn;\u0026thinsp;20.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e117.35\u0026thinsp;\u0026plusmn;\u0026thinsp;21.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.31\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRed Blood Cell Transfusion\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12 (20%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18 (29%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.045\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFresh Frozen Plasma Transfusion\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10 (17%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15 (24%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.062\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePlatelet Transfusion\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8 (13%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14 (22%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.089\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003eAbbreviations: SD: Standard Deviation, n: Number of patients, min: Minutes\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePostoperative Outcomes\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDel Nido (Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBlood Cardioplegia (Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMortality (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e5.88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e35.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.0546\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eICU Stay (days)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2.82\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.94\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.784\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eExtubation Time (hours)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e9.83\u0026thinsp;\u0026plusmn;\u0026thinsp;3.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e9.68\u0026thinsp;\u0026plusmn;\u0026thinsp;3.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.517\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUrea (mg/dL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e48.22\u0026thinsp;\u0026plusmn;\u0026thinsp;13.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e44.11\u0026thinsp;\u0026plusmn;\u0026thinsp;12.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.37\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCreatinine (mg/dL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.11\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.20\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.66\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGFR (mL/min)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e75.47\u0026thinsp;\u0026plusmn;\u0026thinsp;18.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e54.65\u0026thinsp;\u0026plusmn;\u0026thinsp;19.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.085\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003eAbbreviations: ICU: Intensive Care Unit, GFR: Glomerular Filtration Rate, SD: Standard Deviation, mL/min: Milliliters per minute\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eSubgroup Analysis Based on EF\u0026thinsp;\u0026le;\u0026thinsp;50% and EF\u0026thinsp;\u0026gt;\u0026thinsp;50%\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEF\u0026thinsp;\u0026le;\u0026thinsp;50% - Del Nido\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEF\u0026thinsp;\u0026le;\u0026thinsp;50% - Blood Cardioplegia\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep-value (EF\u0026thinsp;\u0026le;\u0026thinsp;50%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eEF\u0026thinsp;\u0026gt;\u0026thinsp;50% - Del Nido\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eEF\u0026thinsp;\u0026gt;\u0026thinsp;50% - Blood Cardioplegia\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003ep-value (EF\u0026thinsp;\u0026gt;\u0026thinsp;50%)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMortality (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e5.88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e35.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.085\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e14.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e23.68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.275\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eICU Stay (days)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2.82\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.784\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2.72\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e2.68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.731\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eExtubation Time (hours)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e9.83\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e9.68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.517\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e9.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e9.79\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.592\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"7\"\u003eAbbreviations: ICU: Intensive Care Unit, EF: Ejection Fraction, SD: Standard Deviation\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThe distribution of patients according to their surgical procedures was as follows: 75 patients (61.5%) underwent aortic and mitral valve replacement (AVR-MVR). In addition, 26 patients (21.3%) underwent tricuspid valve replacement (TRA) in conjunction with AVR-MVR. 21 patients (17.2%) had mitral and tricuspid valve replacement (MVR-TRA).\u003c/p\u003e\u003cp\u003eIn relation to preoperative biochemical values, the mean urea value was determined to be 42.99 mg/dL in the Del Nido group and 45.49 mg/dL in the Blood Cardioplegia group. A statistical analysis revealed that the difference between these values was not statistically significant (p\u0026thinsp;=\u0026thinsp;0.51).\u003c/p\u003e\u003cp\u003eSimilarly, preoperative creatinine levels did not demonstrate a statistically significant difference between the two groups (Del Nido: 1.04 mg/dL, Blood Cardioplegia: 1.12 mg/dL; p\u0026thinsp;=\u0026thinsp;0.64).\u003c/p\u003e\u003cp\u003eWith regard to cross-clamp time, patients were divided into two groups: those undergoing procedures lasting\u0026thinsp;\u0026lt;\u0026thinsp;100 minutes and those undergoing procedures lasting\u0026thinsp;\u0026ge;\u0026thinsp;100 minutes. The mortality rate was found to be 10.2% in patients with a cross-clamp duration of less than 100 minutes, as compared to 38.7% in patients with a duration of more than 100 minutes (p\u0026thinsp;=\u0026thinsp;0.0058). The analysis revealed that cross-clamp duration was an independent predictor of mortality (p\u0026thinsp;=\u0026thinsp;0.0003). However, no significant relationship was found with cross-clamp duration in terms of postoperative glomerular filtration rate (GFR) change (p\u0026thinsp;=\u0026thinsp;0.1255).\u003c/p\u003e\u003cp\u003eThe mortality rate was calculated as 5.88% in patients who received Del Nido cardioplegia and 35.29% in patients who received blood cardioplegia (p\u0026thinsp;=\u0026thinsp;0.0546). Postoperative GFR average was measured at 75.47 ml/min in the Del Nido group and 54.65 ml/min in the blood cardioplegia group, and the difference was found to be borderline significant (p\u0026thinsp;=\u0026thinsp;0.085). No significant difference was observed between the two groups with regard to the duration of intensive care unit stay (Del Nido: 2.82 days, Blood Cardioplegia: 2.94 days; p\u0026thinsp;=\u0026thinsp;0.784). When evaluated on an hourly basis, the length of stay in the intensive care unit was calculated as 53.86 hours in the Del Nido group and 58.20 hours in the Blood Cardioplegia group, and the difference was not found to be statistically significant (p\u0026thinsp;=\u0026thinsp;0.561).\u003c/p\u003e\u003cp\u003eThe extubation time was determined as 9.83 hours in the Del Nido group and 9.68 hours in the Blood Cardioplegia group, and no significant difference was found between the two groups (p\u0026thinsp;=\u0026thinsp;0.517). The incidence of postoperative acute renal failure (ARF) was found to be comparable in both cardioplegia groups, with an ARF rate of 11.77% observed in the Del Nido and Blood Cardioplegia groups (p\u0026thinsp;=\u0026thinsp;1.0).\u003c/p\u003e\u003cp\u003eIn a subsequent logistic regression analysis, cross-clamp time was identified as an independent predictor of mortality (p\u0026thinsp;=\u0026thinsp;0.0003). The relationship between cardioplegia type and mortality was found to be borderline significant (p\u0026thinsp;=\u0026thinsp;0.094). Conversely, ejection fraction (EF), preoperative glomerular filtration rate (GFR) and pulmonary artery pressure (PAP) were found to have no significant impact on mortality (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe present study evaluated the effects of blood cardioplegia and del nido cardioplegia on mortality and morbidity in patients undergoing multiple valve surgery. The findings of the study demonstrated a significant relationship between cross-clamp time and mortality (p\u0026thinsp;=\u0026thinsp;0.0003), with cross-clamp times exceeding 100 minutes exhibiting a substantial increase in in-hospital mortality. Consequently, an examination of mortality rates revealed that patients who received blood cardioplegia exhibited a significantly higher mortality rate (p\u0026thinsp;=\u0026thinsp;0.0058). In light of these results, consistent with previous studies, it is thought that prolonged ischemic periods may exacerbate myocardial damage and negatively affect postoperative cardiac function (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eDel Nido cardioplegia is hypothesised to reduce cross-clamping time by facilitating single-dose administration, thereby improving myocardial protection during surgery (5,6,21). The utilisation of blood cardioplegia may confer benefits in long-term surgical procedures by preserving oxygen-carrying capacity through repeated doses (3,12,23). Contrary to the findings reported in the extant literature, the mortality rates observed in the blood cardioplegia group in our study were lower (p\u0026thinsp;=\u0026thinsp;0.0546) (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). This may be attributable to the higher incidence of acute respiratory failure (ARF) in the Del Nido group. Concurrently, cross-clamping time and SII values were found to be elevated in the Del Nido group. Consequently, it was determined that cases in the Del Nido group exhibited prolonged duration and advanced age.\u003c/p\u003e\u003cp\u003eNo statistically significant difference was observed between the two groups in terms of the length of stay in the intensive care unit (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) or postoperative renal function (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05) (14,18,24). This finding suggests that none of the cardioplegia strategies provide a clear advantage or disadvantage in terms of renal function (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Although no statistically significant difference was observed in terms of renal function in the present study, the frequency of acute renal failure was lower in patients who received Del Nido cardioplegia. Furthermore, the post-operative GFR was found to be elevated in the Del Nido group (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe grouping of patients according to their EF as below or above 50% revealed significant differences, despite the modest sample size. For patients with EF\u0026thinsp;\u0026le;\u0026thinsp;50%, the Del Nido group exhibited a reduced ICU LOS (57.25 hours, p\u0026thinsp;\u0026gt;\u0026thinsp;0.05) and an augmented extubation time (8.50 hours, p\u0026thinsp;\u0026gt;\u0026thinsp;0.05). When the pump and cross-clamp times were considered, two possible explanations were identified for this phenomenon. Firstly, the use of blood cardioplegia may have resulted in greater myocardial damage due to the extended cross-clamp time. This may result in a delay in the recovery of cardiac functions in the post-extubation period, an increase in the requirement for additional cardiac support (e.g. inotropic drugs, vasopressor therapy), and consequently a prolongation of the duration of intensive care unit stay. Alternatively, the inflammatory reaction may be more pronounced in patients receiving blood cardioplegia, potentially prolonging the postoperative recovery period in the intensive care unit following extubation. These potential scenarios are consistent with the observations made in our patient group. A subsequent examination of the postoperative SII values of patients in the blood cardioplegia group revealed higher values, while the del nido group exhibited lower drainage and, consequently, a reduced need for blood replacement.\u003c/p\u003e\u003cp\u003ePrevious studies have shown that Del Nido cardioplegia can preserve ejection fraction in the early postoperative period (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). However, its long-term effect on left ventricular function is not yet clear (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Some studies suggest that Del Nido has an early protective effect on ejection fraction, while others report no significant difference in the long term (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Since our study did not include long-term follow-up data, it is not possible to draw a definitive conclusion on this issue. However, we observed a positive effect of Del Nido cardioplegia on ejection fraction in short-term follow-up of patients.\u003c/p\u003e\u003cp\u003eResearch has indicated that Del Nido cardioplegia may present a valuable alternative, given its capacity to reduce operative time and facilitate surgical procedures, particularly in cases where reduced ischemic times are required. Observations have been made that renal function deterioration decreases in patients as operative time decreases (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). The present study revealed no statistically significant difference in postoperative renal function between cardioplegia groups (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05), though postoperative GFR values were found to be significantly lower in patients receiving blood cardioplegia, particularly in those with EF\u0026thinsp;\u0026lt;\u0026thinsp;50 (75.47 vs 54.65, p\u0026thinsp;=\u0026thinsp;0.085). This finding suggests that the use of Del Nido in patients with low EF will have a positive effect on postoperative outcomes.\u003c/p\u003e\u003cp\u003eWhile Del Nido cardioplegia may provide better myocardial protection in the early postoperative period, its long-term benefits remain uncertain (10,13,19\u0026ndash;22). Future large-scale randomized controlled trials with extended follow-up are essential to determine whether its potential advantages translate into improved long-term clinical outcomes (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e).\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, this study demonstrates that prolonged cross-clamping time significantly increases in-hospital mortality in patients undergoing multiple valve surgery, highlighting the need to optimize surgical strategies to minimize ischemic times. Although Del Nido cardioplegia showed a trend toward reduced mortality compared with blood cardioplegia, the benefit was only marginally significant. Neither cardioplegia strategy showed clear superiority in terms of postoperative renal function or length of ICU stay. While Del Nido cardioplegia may offer advantages in terms of simplifying surgical procedures and early postoperative myocardial protection, further large-scale, long-term randomized trials are needed to confirm its clinical advantages and impact on patient outcomes.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eARF\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAcute Renal Failure\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAVR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAortic Valve Replacement\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eConfidence Interval\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eDM\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eDiabetes Mellitus\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eEF\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eEjection Fraction\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eGFR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eGlomerular Filtration Rate\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eHT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eHypertension\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eICU\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eIntensive Care Unit\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eIQR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eInterquartile Range\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eLMCA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eLeft Main Coronary Artery\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eLOS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eLength of Stay\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003emin\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eMinutes\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMVR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eMitral Valve Replacement\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003en\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eNumber (of patients)\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eOR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eOdds Ratio\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePAP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ePulmonary Artery Pressure\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePSM\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ePropensity Score Matching\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eRCA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eRight Coronary Artery\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eROC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eReceiver Operating Characteristic\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eStandard Deviation\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSII\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eSystemic Immune-Inflammation Index\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eTRA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eTricuspid Valve Replacement\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSerkan Yıldırım: Study design, statistical analysis, manuscript writing, submission and correspondence.\u003c/p\u003e\n\u003cp\u003eAli Demiray: Data collection, literature review.\u003c/p\u003e\n\u003cp\u003eYal\u0026ccedil;ın Gunerhan: Case selection, manuscript review.\u003c/p\u003e\n\u003cp\u003eMehmet Işık: Intraoperative data acquisition, background section drafting.\u003c/p\u003e\n\u003cp\u003e\u0026Ouml;mer Tanyeli: Statistical support, figure/table preparation.\u003c/p\u003e\n\u003cp\u003eY\u0026uuml;ksel Dereli: Postoperative data analysis, clinical data validation.\u003c/p\u003e\n\u003cp\u003eNiyazi G\u0026ouml;rm\u0026uuml;ş: Patient inclusion, ethical approval coordination, formatting.\u003c/p\u003e\n\u003cp\u003eAll authors reviewed and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. All expenses related to the study and manuscript preparation were covered personally by the authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRussell S, Butt S, Vohra HA. In search of optimal cardioplegia for minimally invasive valve surgery. Perfusion. 2022 Oct;37(7):668-674.\u0026nbsp;\u003c/li\u003e\n\u003cli\u003eWhittaker A, Aboughdir M, Mahbub S, Ahmed A, Harky A. Myocardial protection in cardiac surgery: how limited are the options? A comprehensive literature review. Perfusion. 2021 May;36(4):338-351.\u003c/li\u003e\n\u003cli\u003eMenasch\u0026eacute; P. Blood cardioplegia: do we still need to dilute? Ann Thorac Surg. 1996 Oct;62(4):957-60\u0026nbsp;\u003c/li\u003e\n\u003cli\u003eYang XF, Zhao XT, Xie HX, Guan M, Fu L, Jiang Y, Hou XT, Hei FL. [Myocardial protection of del Nido cardioplegia in adult cardiac and major vascular surgery with long aortic cross-clamp time]. Zhonghua Yi Xue Za Zhi. 2023 Dec 26;103(48):3917-3923.\u003c/li\u003e\n\u003cli\u003eMatte GS, del Nido PJ. History and use of del Nido cardioplegia solution at Boston Children's Hospital. J Extra Corpor Technol. 2012 Sep;44(3):98-103. Erratum in: J Extra Corpor Technol. 2013 Dec;45(4):262.\u003c/li\u003e\n\u003cli\u003eAn KR, Rahman IA, Tam DY, Ad N, Verma S, Fremes SE, Latter DA, Yanagawa B. A Systematic Review and Meta-Analysis of del Nido Versus Conventional Cardioplegia in Adult Cardiac Surgery. Innovations (Phila). 2019 Oct;14(5):385-393..\u003c/li\u003e\n\u003cli\u003eMoncla LM, Briend M, Boss\u0026eacute; Y, Mathieu P. Calcific aortic valve disease: mechanisms, prevention and treatment. Nat Rev Cardiol. 2023 Aug;20(8):546-559.\u003c/li\u003e\n\u003cli\u003eYerebakan H, Sorabella RA, Najjar M, Castillero E, Mongero L, Beck J, Hossain M, Takayama H, Williams MR, Naka Y, Argenziano M, Bacha E, Smith CR, George I. Del Nido Cardioplegia can be safely administered in high-risk coronary artery bypass grafting surgery after acute myocardial infarction: a propensity matched comparison. J Cardiothorac Surg. 2014 Oct 30;9:141.\u003c/li\u003e\n\u003cli\u003eChung MM, Erwin WC, Ning Y, Zhao Y, Chan C, D'Angelo A, Kossar A, Spellman J, Kurlansky P, Takayama H. A novel dosing strategy of del Nido cardioplegia in aortic surgery. JTCVS Open. 2022 Jun;10:39-61..\u003c/li\u003e\n\u003cli\u003eHawkins RB, Stewart JW 2nd, Wu X, Goldberg J, Fitzgerald D, DeLucia A 3rd, Graebner B, Willekes C, Pagani FD, Nieter DH, Likosky DS, Ailawadi G; PERForm Registry and the Michigan Society of Thoracic and Cardiovascular Surgeons Quality Collaborative. del Nido versus blood cardioplegia in cardiac surgery: A multicenter analysis of over 40,000 patients. J Thorac Cardiovasc Surg. 2024 Dec;168(6):1687-1697 e5.\u003c/li\u003e\n\u003cli\u003eWaterford SD, Ad N. Del Nido cardioplegia: Questions and (some) answers. J Thorac Cardiovasc Surg. 2023 Mar;165(3):1104-1108.\u003c/li\u003e\n\u003cli\u003eVaughn CC, Opie JC, Florendo FT, Lowell PA, Austin J. Warm blood cardioplegia. Ann Thorac Surg. 1993 May;55(5):1227-32.\u003c/li\u003e\n\u003cli\u003eLenoir M, Bouhout I, Jelassi A, Cartier R, Poirier N, El-Hamamsy I, Demers P. Del Nido cardioplegia versus blood cardioplegia in adult aortic root surgery. J Thorac Cardiovasc Surg. 2021 Aug;162(2):514-522.e2..\u003c/li\u003e\n\u003cli\u003ePulaş M. The effect and use of del Nido cardioplegia in cell membrane stabilization in adult cardiac surgery Cardiovasc Perf Nurs. 2022;1(2):44-51.\u003c/li\u003e\n\u003cli\u003eKim K, Ball C, Grady P, Mick S. Use of del Nido Cardioplegia for Adult Cardiac Surgery at the Cleveland Clinic: Perfusion Implications. J Extra Corpor Technol. 2014 Dec;46(4):317-23.\u003c/li\u003e\n\u003cli\u003eCohen G, Borger MA, Weisel RD, Rao V. Intraoperative myocardial protection: current trends and future perspectives. Ann Thorac Surg. 1999 Nov;68(5):1995-2001.\u003c/li\u003e\n\u003cli\u003eCharette K, Gerrah R, Quaegebeur J, et al. Single dose myocardial protection utilizing del Nido cardioplegia solution during congenital heart surgery procedures. Perfusion. 2012;27:98\u0026ndash;103.\u003c/li\u003e\n\u003cli\u003eShu C, Hong L, Shen X, Zhang W, Niu Y, Song X, Kong J, Zhang C. Effect of Del Nido cardioplegia on ventricular arrhythmias after cardiovascular surgery. BMC Cardiovasc Disord. 2021 Jan 13;21(1):32.\u003c/li\u003e\n\u003cli\u003eKim JS, Jeong JH, Moon SJ, Ahn H, Hwang HY. Sufficient myocardial protection of del Nido cardioplegia regardless of ventricular mass and myocardial ischemic time in adult cardiac surgical patients. J Thorac Dis. 2016 Aug;8(8):2004-10.\u003c/li\u003e\n\u003cli\u003eRoss JDW, Newland RF, Hamson RTJ, Rice GD, Baker RA. Del Nido cardioplegia in adult cardiac surgery: analysis of myocardial protection and post-operative high-sensitivity Troponin T. ANZ J Surg. 2021 Oct;91(10):2192-2198.\u003c/li\u003e\n\u003cli\u003eRizvi MFA, Yousuf SMA, Younas A, Baig MAR. Prospective randomized study comparing outcome of myocardial protection with Del-Nido Cardioplegia versus Saint Thomas Cardioplegia in adult cardiac surgical patients. Pak J Med Sci. 2022 Mar-Apr;38(3Part-I):699-704.\u003c/li\u003e\n\u003cli\u003eMisra S, Srinivasan A, Jena SS, Bellapukonda S. Myocardial Protection in Adult Cardiac Surgery With del Nido Versus Blood Cardioplegia: A Systematic Review and Meta-Analysis. Heart Lung Circ. 2021 May;30(5):642-655.\u003c/li\u003e\n\u003cli\u003eHamad R, Nguyen A, Lalibert\u0026eacute; \u0026Eacute;, Bouchard D, Lamarche Y, El-Hamamsy I, Demers P. Comparison of del Nido Cardioplegia With Blood Cardioplegia in Adult Combined Surgery. Innovations (Phila). 2017 Sep/Oct;12(5):356-362.\u003c/li\u003e\n\u003cli\u003eUcak HA, Ucak D. Single-Dose Del Nido Cardioplegia vs. Blood Cardioplegia in Aortic Valve Replacement Surgery. Braz J Cardiovasc Surg. 2021 Apr 1;36(2):229-236.\u0026nbsp;\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"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":"Cardioplegia, cross-clamp time, mortality, cardiac surgery, myocardial protection","lastPublishedDoi":"10.21203/rs.3.rs-6866214/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6866214/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eCardioplegia plays a crucial role in myocardial protection during cardiac surgery, yet the optimal choice for multiple valve procedures remains controversial. This study evaluates the impact of Del Nido and blood cardioplegia on surgical outcomes, particularly focusing on mortality and cross-clamp duration.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThis retrospective study analyzed adult patients (\u0026ge;\u0026thinsp;18 years) who underwent multiple valve surgery with cardiopulmonary bypass between 2019 and 2024. Patients were categorized into two groups: Del Nido cardioplegia (n\u0026thinsp;=\u0026thinsp;55) and blood cardioplegia (n\u0026thinsp;=\u0026thinsp;67). Primary outcomes included cross-clamp time, in-hospital mortality, ICU length of stay, and postoperative renal function. Statistical analyses utilized multivariable logistic regression and time-series analysis.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eCross-clamp time was independently associated with mortality (p\u0026thinsp;=\u0026thinsp;0.0003), with durations exceeding 100 minutes significantly increasing in-hospital mortality risk (p\u0026thinsp;=\u0026thinsp;0.0058). While Del Nido cardioplegia showed a trend toward lower mortality compared to blood cardioplegia, the difference was borderline significant (p\u0026thinsp;=\u0026thinsp;0.0546). No statistically significant differences were observed in ICU stay or postoperative renal function (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eCross-clamp duration is a key determinant of mortality in multiple valve surgery. Del Nido cardioplegia may help reduce operative time; however, its long-term benefits remain uncertain. Further large-scale randomized trials are warranted to clarify its clinical advantages.\u003c/p\u003e","manuscriptTitle":"Effects of Del Nido and Blood Cardioplegia on Outcomes in Multiple Valve Surgery: A Retrospective Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-09 10:29:20","doi":"10.21203/rs.3.rs-6866214/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":"0e0d41fe-5fc5-4334-9393-5224800a8512","owner":[],"postedDate":"July 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-08T16:39:33+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-09 10:29:20","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6866214","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6866214","identity":"rs-6866214","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}