Effect of mild hypothermia vs normothermia cardiopulmonary bypass on postoperative bleeding in patients undergoing coronary artery bypass grafting: protocol of a multi-center, randomized, controlled trial

Effect of mild hypothermia vs normothermia cardiopulmonary bypass on postoperative bleeding in patients undergoing coronary artery bypass grafting: protocol of a multi-center, randomized, controlled trial | 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 Study protocol Effect of mild hypothermia vs normothermia cardiopulmonary bypass on postoperative bleeding in patients undergoing coronary artery bypass grafting: protocol of a multi-center, randomized, controlled trial Jing Wang, Tianlong Wang, Han Zhang, Qiaoni Zhang, Gang Liu, Shujie Yan, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5026038/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 22 Oct, 2024 Read the published version in BMC Surgery → Version 1 posted 12 You are reading this latest preprint version Abstract Background Coronary artery bypass grafting (CABG) is often performed with hypothermic cardiopulmonary bypass (CPB) to reduce metabolic demands and protect the myocardium. However, hypothermia can increase bleeding risks and other complications. Methods This is a prospective, multi-center, randomized controlled trial. From September 2023 to December 2024, a total of 336 eligible patients planning to undergo on-pump CABG will be enrolled. All participants will be randomly divided into mild hypothermic CPB group (target oxygenator arterial outlet blood temperature at 32–33°C) or normothermia CPB group (target oxygenator arterial outlet blood temperature at 35–36°C). The primary endpoint is Universal Definition of Perioperative Bleeding (UDPB) class 2–4. Secondary endpoints are class of UDPB, levels of coagulation and inflammatory factors, in-hospital mortality, perioperative related complications, intensive care unit (ICU) length of stay, and hospital length of stay. Discussion This clinical trial aims to compare the effects of different target temperature during CPB on postoperative bleeding and to explore optimal temperature strategy to provide new clinical evidence. Trial registration Chictr.org.cn: ChiCTR2300075405. The trial was prospectively registered on 4 September 2023. Coronary artery bypass grafting Targeted temperature management Cardiopulmonary bypass. Figures Figure 1 BACKGROUND Coronary artery bypass grafting (CABG) is an effective treatment for complex coronary artery disease. In clinical practice, CABG surgery is often performed with the support of hypothermic cardiopulmonary bypass (CPB). A recent survey in United Kingdom also indicated that hypothermia remains a routine management strategy in cardiac surgery [ 1 ]. Hypothermia reduces the metabolic rate and oxygen consumption of vital tissues, such as the myocardium and neurons, thereby enhancing their tolerance to ischemia [ 2 ]. However, it is important to recognize that lowering the temperature can disrupt balance of coagulation, suppress coagulation enzyme activity, and increase the risks of bleeding and thrombosis [ 3 ]. Patients exposed hypothermia during CPB may face an increased risk of postoperative renal failure, neurocognitive dysfunction, and prolonged stays in the intensive care unit [ 4 ]. Given the advancements in cardiac surgical techniques and the increasing proficiency of surgical teams, adopting temperature management strategies that are closer to the body temperature could potentially mitigate unnecessary prolongation of surgical time associated with cooling and rewarming processes. Normothermia may also prevent the increased metabolic demand during rewarming and reduce the risk of postoperative ischemia derived by hypothermia. Recent studies have demonstrated that normothermic CPB in cardiac surgery does not increase the risks of neurological complications and mortality [ 5 , 6 ]. However, there remains a lack of contemporary evidence from randomized controlled trials (RCTs) about the impact of temperature management during on-pump CABG on patient outcomes. This study aims to conduct an RCT to compare the effects of different target temperatures during CPB on postoperative bleeding in CABG patients and to explore optimal temperature strategy. METHODS Trial Design A multi-centre, prospective, single-blinded, randomized controlled trial will be conducted. From September 2023 to December 2024, patients undergoing on-pump CABG and meet the eligibility criteria will be enrolled in this study (Fig. 1 ). Participating institutions include 10 hospitals in China. All the selected individuals will be randomly stratified by different temperature management during CPB: mild hypothermia and normothermia. Data collection will start from the accumulation of basic data until the end of follow-up (Table 1 ) . All participants will provide written informed consent. This study was approved by the Ethics Committee of Fuwai Hospital (Ethics number: 2023–2073). Table 1 Assessment schedule. STUDY PERIOD Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Assessment Baseline 7 days to 0 days CPB initiation Rewarming Within 48 hours after surgery Surgery to discharge Informed consent √ Inclusion/exclusion criteria √ Randomization √ Basic medical history √ Blood laboratory test √ √ √ √ √ Blood gas analysis √ √ √ √ √ Coagulation function √ √ √ Coagulation factors √ √ Inflammatory factors √ √ Chest tube output √ √ Blood product transfusion √ √ √ √ UDPB √ AE, SAE, and endpoints √ √ √ √ AE, adverse events; CPB, cardiopulmonary bypass; SAE, severe adverse events; UDPB, Universal Definition of Perioperative Bleeding. Participants Inclusion criteria (1) Aged ≥ 18 years. (2) Undergoing on-pump isolated CABG. (3) Able to sign the informed consent. Exclusion criteria (1) Emergency surgery. (2) Undergoing CABG combined with other procedures . (3) Preoperative hemoglobin < 90g/L. (4) Reoperation. (5) Use of antiplatelet drugs (such as aspirin, clopidogrel, etc.) within 5 days before surgery. (6) Participation in other interventional studies within the past month, with assessed significant impact on this study. (7) Patient considered unsuitable for enrolment in the present trial. Intervention The intervention involved maintaining different oxygenator arterial outlet blood temperature during CPB. Patients will be divided into two groups based on different temperature management during CPB. In the mild hypothermia group, the target oxygenator arterial outlet blood temperature during CPB is maintained at 32–33°C, while in the normothermia group, the target oxygenator arterial outlet blood temperature during CPB is maintained at 35–36°C. Randomization and blinding This is a single-blind study. Group randomization will be performed by a computer-generated randomization sequence with a block of 10. One researcher will be responsible for maintaining the random sequence, concealing group sizes, and communicating with the assigned researchers. After researchers confirming the participants meet the inclusion criteria and obtaining their informed consent, participants will be randomly assigned to the mild hypothermia group or the normothermia group at 1:1. If a participant is unable to undergo surgery after randomization for any reason, their trial number and randomization status will be retained. Participants and their families are not informed about the assigned group to maintain blinding throughout the study. Outcomes Primary endpoint The primary endpoint is Universal Definition of Perioperative Bleeding (UDPB) class 2–4 (moderate to massive bleeding) [ 7 ], defined as the occurrence of one or more of the following indexes: (1) delayed sternal closure; (2) chest tube output exceeding 800 mL within 12 hours postoperatively; (3) 2 or greater units of red blood cells or fresh frozen plasma (FFP) transfusions within 24 hours postoperatively; (4) any of platelets, cryoprecipitate, prothrombin complex concentrate transfusion or recombinant activated factor VII use within 24 hours postoperatively; (5) surgical re-exploration for bleeding. Secondary endpoints Efficacy endpoints include class of UDPB, rate of perioperative blood products transfusion, including red blood cells, FFP, platelets, cryoprecipitate, prothrombin complex concentrate and rFVIIa, postoperative chest tube output, levels of coagulation factors (FII, FV, FVII, FX, FVIII, FIX, FXI, FXII), levels of inflammatory factors (IL-1ß, IL-2, IL-4, IL-5,113 IL-6, IL-8, IL-10, IL-12p70, IL-17, TNF-α, IFN-α, IFN-γ), surgery time, cooling and rewarming time, aortic cross clamping time, mechanical ventilation time, intensive care unit (ICU) length of stay, and hospital length of stay. Safety endpoints Safety endpoints include in-hospital mortality, perioperative cerebrovascular events (including stroke and cerebral hemorrhage) and cognitive dysfunction, myocardial infarction, acute kidney injury, hepatic dysfunction, infection, postoperative low cardiac output syndrome, significant bleeding events such as heparin resistance, hemolysis, and re-exploration for bleeding. Sample size calculation A retrospective analysis of patients who underwent isolated CABG at our centre found that the incidence of UDPB class 2–4 was approximately 40%. With the incidence of UDPB class 2–4 as the main endpoint event, we assumed that a 15% reduction of the incidence of UDPB class 2–4 in the normothermic CPB group compared to the hypothermic CPB group. A test for equivalence method was used with a two-sided significance level (α) of 0.05 and a test power (β) of 80%, according to the ratio of 1:1 between the hypothermic group or the normothermic group. Both groups will require 150 participants. Considering a 10% dropout rate (early termination due to other reasons and random assignment), a total of 334 participants were planned to be enrolled in the study, with 167 participants in each group. The sample size was calculated by PASS 2019. Statistical analysis The primary analysis of all endpoints will be conducted using intention to treat principle, wherein participants will be analyzed according to the initial randomization, irrespective of the final assignment received. For patients who have been randomized into the trial but ultimately do not undergo CABG at the target temperature, they will be excluded from the analysis. Continuous variables with normal distribution are expressed as mean ± standard deviation, and those with non-normal distribution are expressed as median (interquartile range). The intergroup comparisons are conducted using Student's t-test or Mann-Whitney U tests according to the normality. Categorical variables are expressed as frequencies and percentages, and intergroup comparisons are conducted using chi-square tests or Fisher's exact tests. For the primary endpoint indicators, differences in endpoint occurrence rates between the two groups and 95% confidence interval estimates will be provided. Per-protocol analysis was performed excluding patients for whom there were major protocol deviation. All statistical tests are two-sided, and p < 0.05 will be considered statistically significant. SPSS V.26.0 software (IBM, New York, USA) will be used for statistical analyses. Data safety and monitoring To ensure the accuracy and authenticity of data collection quality, the research team conducts comprehensive training on data quality control. The data for this study is sourced from Electronic Medical Record System and follow-up data collected by the researchers. An independent electronic database is created using Epidata software (Version 3.1) and stored on a computer disconnected from external networks. Data entry is conducted by two researchers simultaneously, employing double-entry verification to ensure consistency and quality control. The database adhered to confidentiality principles, with all personal information anonymized. Researchers will collect and retain the informed consent forms, case report forms (CRFs) and other research documents. Adverse events Adverse event (AE) or serious adverse event (SAE) will be assessed the entire study. SAE were characterized as any adverse medical event or unintended symptom linked to the study intervention, resulting in one or more of the following complications: life-threatening conditions, cerebrovascular events, severe disability, or death. If patients occur AE or SAE, researchers should document the AE record form truthfully and in detail. AE record form should be reported to the ethics committee as part of the annual review. DISCUSSION Temperature management during CPB has long been a controversial issue, and there is no specific recommendation for an optimal temperature during on-pump cardiac surgery [ 8 ]. The temperature during CPB has significantly affects the coagulation system [ 9 ], potentially suppress the thrombin activity and function. Additionally, hypothermia may be associated with postoperative hypocoagulability, further increasing the risk of bleeding and adverse outcomes [ 10 ]. Many studies have been demonstrated the safety of normothermic CPB [ 4 , 5 ]. Here, we plan to conduct a clinical trial to explore the potential effect on normothermic CPB on patients undergoing CABG. Through a review of our center’s data, we found that we have previously conducted a substantial number of hypothermic CABG procedures, which were associated with higher perioperative blood transfusions. Prior studies have indicated that blood transfusion may increase the risk of adverse postoperative outcomes, such as acute kidney injury and mortality [ 11 , 12 ]. Since 2018, our center has been actively engaged in blood management quality control efforts, resulting in a significant reduction in transfusion rates [ 13 ]. We observed that, with the advancement of our blood management quality control efforts, the rate of blood product transfusions has stabilized, underscoring the urgent need for more precise management. Temperature management is also an important work during CPB, and the potential impact of hypothermia on coagulation function cannot be overlooked. Therefore, investigating the optimal temperature management strategy during CPB is crucial for reducing patient bleeding and transfusion. As a result, we have selected UDPB as the primary outcome for our study, aiming to further optimize CPB management processes and enhance blood management strategies from a temperature management perspective. UDPB is a composite indicator, which comprehensively evaluates patient transfusion status, perioperative bleeding, and bleeding-related adverse events. This study has some limitations. First, the absence of long-term follow-up restricts the assessment of neurological function. Second, due to the study design, blinding of researchers and clinicians is not feasible. This trial will provide objective evidence on temperature management during CPB and may help shape guidelines and recommendations for the temperature management during CABG and other cardiac surgeries. Abbreviations AE adverse event CABG coronary artery bypass grafting CPB cardiopulmonary bypass CRFs case report forms FFP fresh frozen plasma RCTs randomized controlled trials SAE serious adverse event UDPB Universal Definition of Perioperative Bleeding Declarations Ethics approval and consent to participate This study was approved by the Ethics Committee of Fuwai Hospital (2023-2073). Informed consent will be obtained from all participants before enrollment, ensuring they understand the study’s purpose, procedures, risks, and benefits. Participants will be informed of their right to withdraw from the study at any time, and confidentiality of their data will be strictly protected. Consent for publication Not applicable. Availability of data and materials No datasets were generated or analyzed during the current study. Competing interests None declared. Funding This study was supported by the National High-level Hospital Clinical Research Funding (2023-GSP-GG-7). Author contributions Jing Wang drafted the manuscript. Tianlong Wang, Han Zhang, Qiaoni Zhang made substantial contributions to the design of the study. Gang Liu, Shujie Yan, Qian Wang, Yuan Teng, Jian Wang, Qiang Hu made substantial contributions to the conception and design of the study and provided details of the trial status. Bingyang Ji obtained funding, provided critical revision of the manuscript for important intellectual content, and approved the final version of the manuscript. All authors have read and approved the final manuscript. Acknowledgements We would like to extend our gratitude to all the participants, researchers, and institutions that participated in this study. Current trial status The current protocol version is Version 4.0 (May 2024). The current informed consent version is Version 3.0 (May 2024). The first patient was enrolled on September 21, 2023. Fifty patients have been enrolled in this study so far. We expect to complete recruitment by December 2024. The results of primary and secondary outcomes will be published after the follow-up. References National survey of variations in practice in the prevention of surgical site infections in adult cardiac surgery, United Kingdom and Republic of Ireland. J Hosp Infect. 2020;106(4):812-9. Habibi V, Habibi MR, Habibi A, Emami Zeydi A. The protective effect of hypothermia on postoperative cognitive deficit may be attenuated by prolonged coronary artery bypass time: Meta-analysis and meta-regression. Adv Clin Exp Med. 2020;29(10):1211-9. Jeppesen AN, Duez C, Kirkegaard H, Grejs AM, Hvas AM. Fibrinolysis in Cardiac Arrest Patients Treated with Hypothermia. Ther Hypothermia Temp Manag. 2022. Bianco V, Kilic A, Aranda-Michel E, Dunn-Lewis C, Serna-Gallegos D, Chen S, et al. Mild hypothermia versus normothermia in patients undergoing cardiac surgery. JTCVS Open. 2021;7:230-42. Linassi F, Maran E, De Laurenzis A, Tellaroli P, Kreuzer M, Schneider G, et al. Targeted temperature management in cardiac surgery: a systematic review and meta-analysis on postoperative cognitive outcomes. Br J Anaesth. 2022;128(1):11-25. Abbasciano RG, Koulouroudias M, Chad T, Mohamed W, Leeman I, Pellowe C, et al. Role of Hypothermia in Adult Cardiac Surgery Patients: A Systematic Review and Meta-analysis. J Cardiothorac Vasc Anesth. 2022;36(7):1883-90. Dyke C, Aronson S, Dietrich W, Hofmann A, Karkouti K, Levi M, et al. Universal definition of perioperative bleeding in adult cardiac surgery. J Thorac Cardiovasc Surg. 2014;147(5):1458-63.e1. Engelman R, Baker RA, Likosky DS, Grigore A, Dickinson TA, Shore-Lesserson L, et al. The Society of Thoracic Surgeons, The Society of Cardiovascular Anesthesiologists, and The American Society of ExtraCorporeal Technology: Clinical Practice Guidelines for Cardiopulmonary Bypass--Temperature Management During Cardiopulmonary Bypass. Ann Thorac Surg. 2015;100(2):748-57. Ho KM, Tan JA. Benefits and risks of maintaining normothermia during cardiopulmonary bypass in adult cardiac surgery: a systematic review. Cardiovasc Ther. 2011;29(4):260-79. Lopes CT, Dos Santos TR, Brunori EH, Moorhead SA, Lopes Jde L, Barros AL. Excessive bleeding predictors after cardiac surgery in adults: integrative review. J Clin Nurs. 2015;24(21-22):3046-62. Hosseini M, Griffeth EM, Schaff HV, Klompas AM, Warner MA, Stulak JM, et al. Analysis of Anemia, Transfusions, and CABG Outcomes in The Society of Thoracic Surgeons National Database. Ann Thorac Surg. 2024. Mazzeffi MA, Holmes SD, Taylor B, Ghoreishi M, McNeil JS, Kertai MD, et al. Red Blood Cell Transfusion and Postoperative Infection in Patients Having Coronary Artery Bypass Grafting Surgery: An Analysis of the Society of Thoracic Surgeons Adult Cardiac Surgery Database. Anesth Analg. 2022;135(3):558-66. Zhang Q, Zhao W, Gao S, Yan S, Diao X, Wang Y, et al. Quality Management of a Comprehensive Blood Conservation Program During Cardiopulmonary Bypass. Ann Thorac Surg. 2022;114(1):142-50. Additional Declarations No competing interests reported. Supplementary Files SPIRITChecklist.docx Cite Share Download PDF Status: Published Journal Publication published 22 Oct, 2024 Read the published version in BMC Surgery → Version 1 posted Editorial decision: Revision requested 25 Sep, 2024 Reviews received at journal 25 Sep, 2024 Reviewers agreed at journal 17 Sep, 2024 Reviews received at journal 16 Sep, 2024 Reviewers agreed at journal 09 Sep, 2024 Reviewers agreed at journal 08 Sep, 2024 Reviews received at journal 07 Sep, 2024 Reviewers agreed at journal 07 Sep, 2024 Reviewers invited by journal 06 Sep, 2024 Editor assigned by journal 05 Sep, 2024 Submission checks completed at journal 05 Sep, 2024 First submitted to journal 03 Sep, 2024 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. 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CABG, coronary artery bypass grafting; CPB, cardiopulmonary bypass; UDPB, Universal Definition of Perioperative Bleeding.\u003c/p\u003e","description":"","filename":"fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5026038/v1/191a4d17e370be7fa9c94cee.jpg"},{"id":67683991,"identity":"c92736b0-a711-4772-8d42-4dc2589921bd","added_by":"auto","created_at":"2024-10-28 16:22:19","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1179074,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5026038/v1/41b0df4b-aa94-40ed-b285-a4d5ec4308d9.pdf"},{"id":66128271,"identity":"3cbe9a5f-f136-4fca-9f09-689efb3585e0","added_by":"auto","created_at":"2024-10-08 03:16:01","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":33899,"visible":true,"origin":"","legend":"","description":"","filename":"SPIRITChecklist.docx","url":"https://assets-eu.researchsquare.com/files/rs-5026038/v1/1d21b00366bdf9a964c78a38.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effect of mild hypothermia vs normothermia cardiopulmonary bypass on postoperative bleeding in patients undergoing coronary artery bypass grafting: protocol of a multi-center, randomized, controlled trial","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003eCoronary artery bypass grafting (CABG) is an effective treatment for complex coronary artery disease. In clinical practice, CABG surgery is often performed with the support of hypothermic cardiopulmonary bypass (CPB). A recent survey in United Kingdom also indicated that hypothermia remains a routine management strategy in cardiac surgery [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Hypothermia reduces the metabolic rate and oxygen consumption of vital tissues, such as the myocardium and neurons, thereby enhancing their tolerance to ischemia [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. However, it is important to recognize that lowering the temperature can disrupt balance of coagulation, suppress coagulation enzyme activity, and increase the risks of bleeding and thrombosis [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Patients exposed hypothermia during CPB may face an increased risk of postoperative renal failure, neurocognitive dysfunction, and prolonged stays in the intensive care unit [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eGiven the advancements in cardiac surgical techniques and the increasing proficiency of surgical teams, adopting temperature management strategies that are closer to the body temperature could potentially mitigate unnecessary prolongation of surgical time associated with cooling and rewarming processes. Normothermia may also prevent the increased metabolic demand during rewarming and reduce the risk of postoperative ischemia derived by hypothermia. Recent studies have demonstrated that normothermic CPB in cardiac surgery does not increase the risks of neurological complications and mortality [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. However, there remains a lack of contemporary evidence from randomized controlled trials (RCTs) about the impact of temperature management during on-pump CABG on patient outcomes.\u003c/p\u003e \u003cp\u003eThis study aims to conduct an RCT to compare the effects of different target temperatures during CPB on postoperative bleeding in CABG patients and to explore optimal temperature strategy.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eTrial Design\u003c/h2\u003e\n \u003cp\u003eA multi-centre, prospective, single-blinded, randomized controlled trial will be conducted. From September 2023 to December 2024, patients undergoing on-pump CABG and meet the eligibility criteria will be enrolled in this study (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Participating institutions include 10 hospitals in China. All the selected individuals will be randomly stratified by different temperature management during CPB: mild hypothermia and normothermia. Data collection will start from the accumulation of basic data until the end of follow-up (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cstrong\u003e)\u003c/strong\u003e. All participants will provide written informed consent. This study was approved by the Ethics Committee of Fuwai Hospital (Ethics number: 2023\u0026ndash;2073).\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eAssessment schedule.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"6\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"5\"\u003e\n \u003cp\u003eSTUDY PERIOD\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVisit 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVisit 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVisit 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVisit 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVisit 5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAssessment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBaseline 7 days to 0 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCPB initiation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRewarming\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWithin 48 hours after surgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSurgery to discharge\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInformed consent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026radic;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInclusion/exclusion criteria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026radic;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRandomization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026radic;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBasic medical history\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026radic;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBlood laboratory test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026radic;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026radic;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026radic;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026radic;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026radic;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBlood gas analysis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026radic;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026radic;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026radic;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026radic;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026radic;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCoagulation function\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026radic;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026radic;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026radic;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCoagulation factors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026radic;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026radic;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInflammatory factors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026radic;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026radic;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChest tube output\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026radic;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026radic;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBlood product transfusion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026radic;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026radic;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026radic;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026radic;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUDPB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026radic;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAE, SAE, and endpoints\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026radic;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026radic;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026radic;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026radic;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\"\u003eAE, adverse events; CPB, cardiopulmonary bypass; SAE, severe adverse events; UDPB, Universal Definition of Perioperative Bleeding.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n \u003ch2\u003eParticipants\u003c/h2\u003e\n \u003cdiv id=\"Sec5\" class=\"Section3\"\u003e\n \u003ch2\u003eInclusion criteria\u003c/h2\u003e\n \u003cp\u003e(1) Aged\u0026thinsp;\u0026ge;\u0026thinsp;18 years.\u003c/p\u003e\n \u003cp\u003e(2) Undergoing on-pump isolated CABG.\u003c/p\u003e\n \u003cp\u003e(3) Able to sign the informed consent.\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e\n \u003ch2\u003eExclusion criteria\u003c/h2\u003e\n \u003cp\u003e(1) Emergency surgery.\u003c/p\u003e\n \u003cp\u003e(2) Undergoing CABG combined with other procedures .\u003c/p\u003e\n \u003cp\u003e(3) Preoperative hemoglobin\u0026thinsp;\u0026lt;\u0026thinsp;90g/L.\u003c/p\u003e\n \u003cp\u003e(4) Reoperation.\u003c/p\u003e\n \u003cp\u003e(5) Use of antiplatelet drugs (such as aspirin, clopidogrel, etc.) within 5 days before surgery.\u003c/p\u003e\n \u003cp\u003e(6) Participation in other interventional studies within the past month, with assessed significant impact on this study.\u003c/p\u003e\n \u003cp\u003e(7) Patient considered unsuitable for enrolment in the present trial.\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv id=\"Sec7\" class=\"Section3\"\u003e\n \u003ch2\u003eIntervention\u003c/h2\u003e\n \u003cp\u003eThe intervention involved maintaining different oxygenator arterial outlet blood temperature during CPB. Patients will be divided into two groups based on different temperature management during CPB. In the mild hypothermia group, the target oxygenator arterial outlet blood temperature during CPB is maintained at 32\u0026ndash;33\u0026deg;C, while in the normothermia group, the target oxygenator arterial outlet blood temperature during CPB is maintained at 35\u0026ndash;36\u0026deg;C.\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv id=\"Sec8\" class=\"Section3\"\u003e\n \u003ch2\u003eRandomization and blinding\u003c/h2\u003e\n \u003cp\u003eThis is a single-blind study. Group randomization will be performed by a computer-generated randomization sequence with a block of 10. One researcher will be responsible for maintaining the random sequence, concealing group sizes, and communicating with the assigned researchers. After researchers confirming the participants meet the inclusion criteria and obtaining their informed consent, participants will be randomly assigned to the mild hypothermia group or the normothermia group at 1:1. If a participant is unable to undergo surgery after randomization for any reason, their trial number and randomization status will be retained. Participants and their families are not informed about the assigned group to maintain blinding throughout the study.\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e\n \u003ch2\u003eOutcomes\u003c/h2\u003e\n \u003cdiv id=\"Sec10\" class=\"Section4\"\u003e\n \u003ch2\u003ePrimary endpoint\u003c/h2\u003e\n \u003cp\u003eThe primary endpoint is Universal Definition of Perioperative Bleeding (UDPB) class 2\u0026ndash;4 (moderate to massive bleeding) [\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e], defined as the occurrence of one or more of the following indexes: (1) delayed sternal closure; (2) chest tube output exceeding 800 mL within 12 hours postoperatively; (3) 2 or greater units of red blood cells or fresh frozen plasma (FFP) transfusions within 24 hours postoperatively; (4) any of platelets, cryoprecipitate, prothrombin complex concentrate transfusion or recombinant activated factor VII use within 24 hours postoperatively; (5) surgical re-exploration for bleeding.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003eSecondary endpoints\u003c/h2\u003e\n \u003cp\u003eEfficacy endpoints include class of UDPB, rate of perioperative blood products transfusion, including red blood cells, FFP, platelets, cryoprecipitate, prothrombin complex concentrate and rFVIIa, postoperative chest tube output, levels of coagulation factors (FII, FV, FVII, FX, FVIII, FIX, FXI, FXII), levels of inflammatory factors (IL-1\u0026szlig;, IL-2, IL-4, IL-5,113 IL-6, IL-8, IL-10, IL-12p70, IL-17, TNF-\u0026alpha;, IFN-\u0026alpha;, IFN-\u0026gamma;), surgery time, cooling and rewarming time, aortic cross clamping time, mechanical ventilation time, intensive care unit (ICU) length of stay, and hospital length of stay.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003eSafety endpoints\u003c/h2\u003e\n \u003cp\u003eSafety endpoints include in-hospital mortality, perioperative cerebrovascular events (including stroke and cerebral hemorrhage) and cognitive dysfunction, myocardial infarction, acute kidney injury, hepatic dysfunction, infection, postoperative low cardiac output syndrome, significant bleeding events such as heparin resistance, hemolysis, and re-exploration for bleeding.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003ch2\u003eSample size calculation\u003c/h2\u003e\n \u003cp\u003eA retrospective analysis of patients who underwent isolated CABG at our centre found that the incidence of UDPB class 2\u0026ndash;4 was approximately 40%. With the incidence of UDPB class 2\u0026ndash;4 as the main endpoint event, we assumed that a 15% reduction of the incidence of UDPB class 2\u0026ndash;4 in the normothermic CPB group compared to the hypothermic CPB group. A test for equivalence method was used with a two-sided significance level (\u0026alpha;) of 0.05 and a test power (\u0026beta;) of 80%, according to the ratio of 1:1 between the hypothermic group or the normothermic group. Both groups will require 150 participants. Considering a 10% dropout rate (early termination due to other reasons and random assignment), a total of 334 participants were planned to be enrolled in the study, with 167 participants in each group. The sample size was calculated by PASS 2019.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n \u003ch2\u003eStatistical analysis\u003c/h2\u003e\n \u003cp\u003eThe primary analysis of all endpoints will be conducted using intention to treat principle, wherein participants will be analyzed according to the initial randomization, irrespective of the final assignment received. For patients who have been randomized into the trial but ultimately do not undergo CABG at the target temperature, they will be excluded from the analysis.\u003c/p\u003e\n \u003cp\u003eContinuous variables with normal distribution are expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation, and those with non-normal distribution are expressed as median (interquartile range). The intergroup comparisons are conducted using Student\u0026apos;s t-test or Mann-Whitney U tests according to the normality. Categorical variables are expressed as frequencies and percentages, and intergroup comparisons are conducted using chi-square tests or Fisher\u0026apos;s exact tests. For the primary endpoint indicators, differences in endpoint occurrence rates between the two groups and 95% confidence interval estimates will be provided. Per-protocol analysis was performed excluding patients for whom there were major protocol deviation. All statistical tests are two-sided, and \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 will be considered statistically significant. SPSS V.26.0 software (IBM, New York, USA) will be used for statistical analyses.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n \u003ch2\u003eData safety and monitoring\u003c/h2\u003e\n \u003cp\u003eTo ensure the accuracy and authenticity of data collection quality, the research team conducts comprehensive training on data quality control. The data for this study is sourced from Electronic Medical Record System and follow-up data collected by the researchers. An independent electronic database is created using Epidata software (Version 3.1) and stored on a computer disconnected from external networks. Data entry is conducted by two researchers simultaneously, employing double-entry verification to ensure consistency and quality control. The database adhered to confidentiality principles, with all personal information anonymized. Researchers will collect and retain the informed consent forms, case report forms (CRFs) and other research documents.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\n \u003ch2\u003eAdverse events\u003c/h2\u003e\n \u003cp\u003eAdverse event (AE) or serious adverse event (SAE) will be assessed the entire study. SAE were characterized as any adverse medical event or unintended symptom linked to the study intervention, resulting in one or more of the following complications: life-threatening conditions, cerebrovascular events, severe disability, or death. If patients occur AE or SAE, researchers should document the AE record form truthfully and in detail. AE record form should be reported to the ethics committee as part of the annual review.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eTemperature management during CPB has long been a controversial issue, and there is no specific recommendation for an optimal temperature during on-pump cardiac surgery [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The temperature during CPB has significantly affects the coagulation system [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], potentially suppress the thrombin activity and function. Additionally, hypothermia may be associated with postoperative hypocoagulability, further increasing the risk of bleeding and adverse outcomes [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Many studies have been demonstrated the safety of normothermic CPB [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Here, we plan to conduct a clinical trial to explore the potential effect on normothermic CPB on patients undergoing CABG.\u003c/p\u003e \u003cp\u003e Through a review of our center\u0026rsquo;s data, we found that we have previously conducted a substantial number of hypothermic CABG procedures, which were associated with higher perioperative blood transfusions. Prior studies have indicated that blood transfusion may increase the risk of adverse postoperative outcomes, such as acute kidney injury and mortality [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Since 2018, our center has been actively engaged in blood management quality control efforts, resulting in a significant reduction in transfusion rates [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. We observed that, with the advancement of our blood management quality control efforts, the rate of blood product transfusions has stabilized, underscoring the urgent need for more precise management. Temperature management is also an important work during CPB, and the potential impact of hypothermia on coagulation function cannot be overlooked. Therefore, investigating the optimal temperature management strategy during CPB is crucial for reducing patient bleeding and transfusion. As a result, we have selected UDPB as the primary outcome for our study, aiming to further optimize CPB management processes and enhance blood management strategies from a temperature management perspective. UDPB is a composite indicator, which comprehensively evaluates patient transfusion status, perioperative bleeding, and bleeding-related adverse events.\u003c/p\u003e \u003cp\u003eThis study has some limitations. First, the absence of long-term follow-up restricts the assessment of neurological function. Second, due to the study design, blinding of researchers and clinicians is not feasible.\u003c/p\u003e \u003cp\u003e This trial will provide objective evidence on temperature management during CPB and may help shape guidelines and recommendations for the temperature management during CABG and other cardiac surgeries.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"459\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eadverse event\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCABG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ecoronary artery bypass grafting\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCPB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ecardiopulmonary bypass\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCRFs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ecase report forms\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eFFP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003efresh frozen plasma\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eRCTs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003erandomized controlled trials\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eSAE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eserious adverse event\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eUDPB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eUniversal Definition of Perioperative Bleeding\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee of Fuwai Hospital (2023-2073). Informed consent will be obtained from all participants before enrollment, ensuring they understand the study’s purpose, procedures, risks, and benefits. Participants will be informed of their right to withdraw from the study at any time, and confidentiality of their data will be strictly protected.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo datasets were generated or analyzed during the current study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone declared.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the National High-level Hospital Clinical Research Funding (2023-GSP-GG-7).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJing Wang drafted the manuscript. Tianlong Wang, Han Zhang, Qiaoni Zhang made substantial contributions to the design of the study. Gang Liu, Shujie Yan, Qian Wang, Yuan Teng, Jian Wang, Qiang Hu made substantial contributions to the conception and design of the study and provided details of the trial status. Bingyang Ji obtained funding, provided critical revision of the manuscript for important intellectual content, and approved the final version of the manuscript. All authors have read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to extend our gratitude to all the participants, researchers, and institutions that participated in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCurrent trial status\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe current protocol version is Version 4.0 (May 2024). The current informed consent version is Version 3.0 (May 2024). The first patient was enrolled on September 21, 2023. Fifty patients have been enrolled in this study so far. We expect to complete recruitment by December 2024. The results of primary and secondary outcomes will be published after the follow-up.\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eNational survey of variations in practice in the prevention of surgical site infections in adult cardiac surgery, United Kingdom and Republic of Ireland. J Hosp Infect. 2020;106(4):812-9.\u003c/li\u003e\n \u003cli\u003eHabibi V, Habibi MR, Habibi A, Emami Zeydi A. The protective effect of hypothermia on postoperative cognitive deficit may be attenuated by prolonged coronary artery bypass time: Meta-analysis and meta-regression. Adv Clin Exp Med. 2020;29(10):1211-9.\u003c/li\u003e\n \u003cli\u003eJeppesen AN, Duez C, Kirkegaard H, Grejs AM, Hvas AM. Fibrinolysis in Cardiac Arrest Patients Treated with Hypothermia. Ther Hypothermia Temp Manag. 2022.\u003c/li\u003e\n \u003cli\u003eBianco V, Kilic A, Aranda-Michel E, Dunn-Lewis C, Serna-Gallegos D, Chen S, et al. Mild hypothermia versus normothermia in patients undergoing cardiac surgery. JTCVS Open. 2021;7:230-42.\u003c/li\u003e\n \u003cli\u003eLinassi F, Maran E, De Laurenzis A, Tellaroli P, Kreuzer M, Schneider G, et al. Targeted temperature management in cardiac surgery: a systematic review and meta-analysis on postoperative cognitive outcomes. Br J Anaesth. 2022;128(1):11-25.\u003c/li\u003e\n \u003cli\u003eAbbasciano RG, Koulouroudias M, Chad T, Mohamed W, Leeman I, Pellowe C, et al. Role of Hypothermia in Adult Cardiac Surgery Patients: A Systematic Review and Meta-analysis. J Cardiothorac Vasc Anesth. 2022;36(7):1883-90.\u003c/li\u003e\n \u003cli\u003eDyke C, Aronson S, Dietrich W, Hofmann A, Karkouti K, Levi M, et al. Universal definition of perioperative bleeding in adult cardiac surgery. J Thorac Cardiovasc Surg. 2014;147(5):1458-63.e1.\u003c/li\u003e\n \u003cli\u003eEngelman R, Baker RA, Likosky DS, Grigore A, Dickinson TA, Shore-Lesserson L, et al. The Society of Thoracic Surgeons, The Society of Cardiovascular Anesthesiologists, and The American Society of ExtraCorporeal Technology: Clinical Practice Guidelines for Cardiopulmonary Bypass--Temperature Management During Cardiopulmonary Bypass. Ann Thorac Surg. 2015;100(2):748-57.\u003c/li\u003e\n \u003cli\u003eHo KM, Tan JA. Benefits and risks of maintaining normothermia during cardiopulmonary bypass in adult cardiac surgery: a systematic review. Cardiovasc Ther. 2011;29(4):260-79.\u003c/li\u003e\n \u003cli\u003eLopes CT, Dos Santos TR, Brunori EH, Moorhead SA, Lopes Jde L, Barros AL. Excessive bleeding predictors after cardiac surgery in adults: integrative review. J Clin Nurs. 2015;24(21-22):3046-62.\u003c/li\u003e\n \u003cli\u003eHosseini M, Griffeth EM, Schaff HV, Klompas AM, Warner MA, Stulak JM, et al. Analysis of Anemia, Transfusions, and CABG Outcomes in The Society of Thoracic Surgeons National Database. Ann Thorac Surg. 2024.\u003c/li\u003e\n \u003cli\u003eMazzeffi MA, Holmes SD, Taylor B, Ghoreishi M, McNeil JS, Kertai MD, et al. Red Blood Cell Transfusion and Postoperative Infection in Patients Having Coronary Artery Bypass Grafting Surgery: An Analysis of the Society of Thoracic Surgeons Adult Cardiac Surgery Database. Anesth Analg. 2022;135(3):558-66.\u003c/li\u003e\n \u003cli\u003eZhang Q, Zhao W, Gao S, Yan S, Diao X, Wang Y, et al. Quality Management of a Comprehensive Blood Conservation Program During Cardiopulmonary Bypass. Ann Thorac Surg. 2022;114(1):142-50.\u003cstrong\u003e\u003cbr\u003e\u003c/strong\u003e\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-surgery","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bsur","sideBox":"Learn more about [BMC Surgery](http://bmcsurg.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bsur/default.aspx","title":"BMC Surgery","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Coronary artery bypass grafting, Targeted temperature management, Cardiopulmonary bypass.","lastPublishedDoi":"10.21203/rs.3.rs-5026038/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5026038/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003eCoronary artery bypass grafting (CABG) is often performed with hypothermic cardiopulmonary bypass (CPB) to reduce metabolic demands and protect the myocardium. However, hypothermia can increase bleeding risks and other complications.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThis is a prospective, multi-center, randomized controlled trial. From September 2023 to December 2024, a total of 336 eligible patients planning to undergo on-pump CABG will be enrolled. All participants will be randomly divided into mild hypothermic CPB group (target oxygenator arterial outlet blood temperature at 32\u0026ndash;33\u0026deg;C) or normothermia CPB group (target oxygenator arterial outlet blood temperature at 35\u0026ndash;36\u0026deg;C). The primary endpoint is Universal Definition of Perioperative Bleeding (UDPB) class 2\u0026ndash;4. Secondary endpoints are class of UDPB, levels of coagulation and inflammatory factors, in-hospital mortality, perioperative related complications, intensive care unit (ICU) length of stay, and hospital length of stay.\u003c/p\u003e\u003cp\u003e\u003cb\u003eDiscussion\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThis clinical trial aims to compare the effects of different target temperature during CPB on postoperative bleeding and to explore optimal temperature strategy to provide new clinical evidence.\u003c/p\u003e\u003cp\u003e\u003cb\u003eTrial registration\u003c/b\u003e\u003c/p\u003e \u003cp\u003eChictr.org.cn: ChiCTR2300075405. The trial was prospectively registered on 4 September 2023.\u003c/p\u003e","manuscriptTitle":"Effect of mild hypothermia vs normothermia cardiopulmonary bypass on postoperative bleeding in patients undergoing coronary artery bypass grafting: protocol of a multi-center, randomized, controlled trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-08 03:07:57","doi":"10.21203/rs.3.rs-5026038/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-09-25T18:59:29+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-09-25T17:43:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"226238427376042451456536354718506509857","date":"2024-09-17T19:29:33+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-09-16T08:36:16+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"78811197513298326669481175738273906244","date":"2024-09-09T06:19:16+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"182271014506561963754400780918201873691","date":"2024-09-08T22:17:53+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-09-07T08:09:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"243696696176264003323366472486272761341","date":"2024-09-07T07:44:49+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-09-06T16:31:16+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-09-05T10:46:56+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-09-05T10:44:20+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Surgery","date":"2024-09-03T15:07:05+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-surgery","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bsur","sideBox":"Learn more about [BMC Surgery](http://bmcsurg.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bsur/default.aspx","title":"BMC Surgery","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"00da0bb9-b531-457b-8359-e210421690ac","owner":[],"postedDate":"October 8th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-10-28T16:09:00+00:00","versionOfRecord":{"articleIdentity":"rs-5026038","link":"https://doi.org/10.1186/s12893-024-02634-6","journal":{"identity":"bmc-surgery","isVorOnly":false,"title":"BMC Surgery"},"publishedOn":"2024-10-22 15:57:07","publishedOnDateReadable":"October 22nd, 2024"},"versionCreatedAt":"2024-10-08 03:07:57","video":"","vorDoi":"10.1186/s12893-024-02634-6","vorDoiUrl":"https://doi.org/10.1186/s12893-024-02634-6","workflowStages":[]},"version":"v1","identity":"rs-5026038","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5026038","identity":"rs-5026038","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}