Efficacy and Safety of Two Simplified Regional Citrate Anticoagulation for Intermittent Hemodialysis: A Randomized Cross-over Trial

Efficacy and Safety of Two Simplified Regional Citrate Anticoagulation for Intermittent Hemodialysis: A Randomized Cross-over 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 Research Article Efficacy and Safety of Two Simplified Regional Citrate Anticoagulation for Intermittent Hemodialysis: A Randomized Cross-over Trial Shizhu Yuan, Mei Tao, Qiudi Tu, Huajuan Shen, Meiling Zhou, Yanqing Jia, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4590369/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 In recent years, due to the low risk of bleeding, regional citrate anticoagulation (RCA) is being tried for intermittent hemodialysis (IHD). Simplified regional citrate anticoagulation (S-RCA) has been attempted in IHD. This randomized cross-over trial was designed to compared the efficacy and safety of two RCAs in heparin-free dialysis patients, which were named S-RCA and two-stage simplified regional citrate anticoagulation (TS-RCA). In summary, the anticoagulation effect of TS-RCA is better than that of S-RCA in IHD, especially in the anticoagulation of venous bubbles trap. And these two RCAs were safe for IHD patient with high bleeding risk. Trial Registration: Chinese Clinical Trial Registry (CHICTR): Registration Number ChiCTR2000034314; Registration date 28 September 2020. Intermittent Hemodialysis Citrate༛Anticoagulation༛Randomized Cross-over Trial༛ Figures Figure 1 Figure 2 Figure 3 Introduction RCA is well-proven to be safe and effective to heparin-free dialysis for Continuous renal replacement therapy (CRRT) [ 1 – 3 ] but limited to intermittent hemodialysis (IHD) due to complicated protocols [ 4 ] . Simplified regional citrate anticoagulation (S-RCA) using calcium-containing dialysate and constant hemodialysis trisodium citrate (TSC) infusion rate has been attempted in IHD [ 5 – 6 ] . However, several studies have shown that S-RCA may increase coagulation risk of the venous bubbles trap [ 7 – 8 ] . We tried infusing a small fraction of TSC to venous bubble s trap to enhance the anticoagulation effect, which was named two-stage simplified regional citrate anticoagulation (TS-RCA). This randomized cross-over trial aimed to compared the efficacy and safety of TS-RCA with S-RCA in heparin-free dialysis patients. Materials and Methods We recruited IHD patients ≥ 18 years, with active bleeding or high bleeding risk, without severe hypercalcemia (TC > 2.8mmol/L) and hypocalcemia(TC<1.8mmol/L), liver insufficiency, hypoxemia, shock, allergy to citrate products and hypercoagulable state such as active malignancy. The study consisted of two 4-hours periods during which S-RCA and TS-RCA IHD were performed successively separated by a 1-day washout period. Patients were randomized in a 1:1 ratio to one of two treatment sequence—S-RCA/TS-RCA or TS-RCA/S-RCA. For the S-RCA protocol, 300ml/h TSC (4%; QiShan LiKang, China) was continuously infused into the arterial port of the extracorporeal circulation (ECC) (Fig. 2 a). For the TS-RCA protocol, 250ml/h TSC was infused into the arterial port and 50ml/h TSC was infused into the venous bubbles trap (Fig. 2 b). 1.5mmol/L calcium-containing dialysate was used in both of these protocols with 500ml/min dialysate flow. And the blood flow was set to 180–250 ml/min according to the patient's own condition. Both protocols did not supplement calcium at the venous port. After consent, assessments of blood analyses were performed at the beginning, 2h and end of each hemodialysis session. At the end of hemodialysis, two investigators assessed coagulation scores of dialyzers and venous bubbles traps with ranges of 0 to 3 (Table 1 ). Arterial, venous and transmembrane pressures were measured during hemodialysis process. Hemodialysis should be terminated early when venous pressure ≥ 200mmHg, transmembrane pressure ≥ 200mmHg or severe coagulation occurred in ECC (dialyzer or venous bubbles trap coagulation score = 3 points). Adverse events such as arrhythmia, hypotension, and hypoglycemia were assessed every hour. The primary outcome was effective rate of anticoagulation which was defined as completion of 4-hours dialysis with less than 3 points of coagulation scores for both dialyzer and venous bubbles trap. The secondary outcomes included dialysis time, the coagulation score of dialyzer and venous bubbles trap, adverse events occurrence, the changes of internal environment and activated partial thromboplastin time (APTT). Table 1 Clotting score of the extracorporeal circulation Clotting score Hemofilter Expansion chamber 0 Clear or No clotting of Hemofilter Clear or No clotting of expansion chamber 1 Area of streaky Hemofilter less than 1/3 of total Volume of thrombus less than 1/3 of expansion chamber 2 Area of streaky Hemofilter less than 2/3 of total Volume of thrombus less than 2/3 of expansion chamber 3 Area of streaky Hemofilter more than 2/3 of total Volume of thrombus more than 2/3 of expansion chamber Statistical analysis was performed using SAS 9.4 and GraphPad Prism 8. Category outcomes were presented as frequency (percentage). Continuous outcomes were presented as mean (SD) or median (interquartile range). Comparisons between groups were performed using generalized linear mixed models [ 9 ] (PROC MIXED and GLIMMIX) after adjustment for the sequence and period of treatment. For comparing pre- versus post-treatment, paired t tests or paired Wilcoxon tests were used. Results and Discussion According to the sample size calculation for 2-period crossover design [ 9 ] , 30 patients were enrolled in the trial for 1 year. Of these patients, 17 were in hemorrhage, 10 had active bleeding and 3 had severe thrombocytopenia, and the baseline characteristics is summarized in Table 2 . All of them received S-RCA and TS-RCA without lost to follow and withdrawn. Table 2 Patient baseline characteristics Variable RCA (n = 30) Male, n 19(63.3) Age, year 60.3(14.7) Weight, kg 60.3(2.3) Vascular Access arteriovenous fistula 14(46.7) Temporary catheter 11(36.7) permanent catheter 5(16.7) Causes of heparin-free dialysis Perioperation, n 17(56.7) Hemorrhage, n 10(33.3) Severe thrombocytopenia, n 3(10.0) Blood flow rate, ml/min 220(212. 250) TC, mmol/L 2.2(0.2) Hb, g/L 83.0(19.9) PLT, 10^9/L 153.0(67.5) PT, s 12.3(1.3) APTT, s 28.4(7.6) RCA, regional citrate anticoagulation; TC, Total cholesterol; Hb, Hemoglobin; PLT, Platelets; PT, Prothrombin time; APTT: Activated partial thromboplastin time For primary outcome, the effective rate of anticoagulation in TS-RCA was marginally higher than S-RCA [26(86.7%) vs.19(63.3%), P = 0.05] (Fig. 3 A). The duration of dialysis of TS-RCA was significantly longer than that of S-RCA [4(4, 4) vs. 4(3.7, 4), P = 0.03] (Fig. 1 B). There was no difference in coagulation scores for dialyzers between S-RCA and TS-RCA (P = 0.64) (Fig. 3 C). However, the coagulation score of venous bubbles trap in TS-RCA was significantly lower than S-RCA (P < 0.01) (Fig. 3 D). In terms of safety, only 5 (16.7%) hypoglycemia occurred in both protocols, and 1(3.33%) hypotension in S-RCA. And there were no other serious adverse events in both protocols. After dialysis, the serum ionized calcium levels had mildly elevated 0.06(-0.07, 0.12) mmol/L during S-RCA, but did not significantly change (P = 0.75) during TS-RCA (P = 0.05 between protocols) (Fig. 3 E). The serum sodium levels had mildly elevated 4.3(2.9) mmol/L during S-RCA and 5.0(2.4) mmol/L during TS-RCA dialysis (P = 0.15 between protocols) (Fig. 3 F). The serum bicarbonate levels had also elevated 2.2(0.4, 4.5) mmol/L during S-RCA and 1.8(1, 3.4) mmol/L during TS-RCA dialysis (P = 0.91 between protocols) (Fig. 3 G). The APTT did not significantly change during S-RCA (P = 0.05) and TS-RCA(P = 0.08) dialysis (P = 0.76 between protocols) (Fig. 1 H). Above all, we found that the two RCA protocols have similar effects on the internal environment, which can slightly increase serum sodium and bicarbonate levels, but without severe hypernatremia and metabolic alkalosis. Our work further supports previous findings reporting a significant improvement of anticoagulation effectiveness of TS-RCA compared to S-RCA (86.7%vs. 63.3%) [ 9 ] . Here, both TS-RCA and S-RCA have achieved satisfactory anticoagulation effects compared to the reported saline irrigation (54.8%) [ 10 ] . But the anticoagulation effects in this study were worse than in previous studies [ 7 , 10 , 11 ] . The reasons might be related to the higher dialysate calcium concentration and use of temporary catheter. On the other hand, we observed significant increases in serum sodium and bicarbonate levels which was consistent with previous studies [ 5 , 6 , 7 ] . We interpret this as the effects of citrate metabolism. Although mild alkalization has been reported to be beneficial to some extent in hemodialysis patients [ 11 ] . However, in order to avoid serious alkali poisoning, it is safe to lower dialysate bicarbonate to 28mmol/L in this study. It is suggested that the concentration of sodium and bicarbonate should be appropriately reduced to prevent the occurrence of hypernatremia and metabolic alkalosis when using sodium citrate dialysis for hemodialysis. Conclusions In summary, the anticoagulation effect of TS-RCA is better than that of S-RCA in IHD, especially in the anticoagulation of venous bubbles trap. These two RCAs were safe for IHD patient with high bleeding risk due to low incidence of adverse events and less impact on internal environment. Declarations Conflicts of Interest None declared. Funding Statement This work was supported by grants from the Medical Health Science and Technology Projects of Zhejiang Provincial Health Commission (grant no. 2021KY490). Author Contribution Mei Tao designed the study, Shizhu Yuan collected the original data, performed this trial, interpreted the results and drafted the manuscript. Qiudi Tu, Huajuan Shen, Meiling Zhou and Yanqing Jia performed this trial. Yueming Liu designed the study and performed statistical analyses. Qiang He and Xiaogang Shen interpreted the results, revised the manuscript. All authors approved its final version. Acknowledgments The authors would like to thank the volunteers who accepted Data Availability Data available on request. References ZARBOCK A, KüLLMAR M, KINDGEN-MILLES D, et al. Effect of Regional Citrate Anticoagulation vs Systemic Heparin Anticoagulation During Continuous Kidney Replacement Therapy on Dialysis Filter Life Span and Mortality Among Critically Ill Patients With Acute Kidney Injury: A Randomized Clinical Trial. Jama 2020; 324(16): 1629-39. ALVAREZ G, CHRUSCH C, HULME T, et al. Renal replacement therapy: a practical update. Can J Anaesth 2019; 66(5): 593-604. TANG X, Chen D, Zhang L, et al. Application of regional citrate anticoagulation in patients at high risk of bleeding during intermittent hemodialysis: a prospective multicenter randomized controlled trial. J Zhejiang Univ Sci B.2022;23(11):931-942. TOLWANI A, WILLE K M. Advances in continuous renal replacement therapy: citrate anticoagulation update . Blood Purif 2012; 34(2): 88-93. LIM E K, SEOW Y T, CHEN S E, et al. Simple citrate anticoagulation protocol for low flux haemodialysis. BMC Nephrol 2018; 19(1): 16. APSNER R, BUCHMAYER H, LANG T, et al. Simplified citrate anticoagulation for high-flux hemodialysis. Am J Kidney Dis 2001, 38(5): 979-87. BUTUROVIC-PONIKVAR J, GUBENSEK J, PONIKVAR R. Citrate anticoagulation for postdilutional online hemodiafiltration with calcium-containing dialysate and infusate: significant clotting in the venous bubble trap. Int J Artif Organs 2008; 31(4): 323-8. MAHMOOD D, STEGMAYR B G. Haemodialysis with Tinzaparin Versus Dialysate Citrate as Anticoagulation. Blood Purif 2018; 46(3): 257-63. DWAN K, LI T, ALTMAN D G, et al. CONSORT 2010 statement: extension to randomised crossover trials. Bmj 2019; 366: l4378. LIN T, SONG L, HUANG R, et al. Modified regional citrate anticoagulation is optimal for hemodialysis in patients at high risk of bleeding: a prospective randomized study of three anticoagulation strategies. BMC Nephrol 2019; 20(1): 472. EVENEPOEL P, MAES B, VANWALLEGHEM J, et al. Regional citrate anticoagulation for hemodialysis using a conventional calcium-containing dialysate. Am J Kidney Dis 2002; 39(2): 315-23. 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-4590369","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":321649216,"identity":"fa86b660-8a4d-4c2c-adc4-49783f45d0b7","order_by":0,"name":"Shizhu Yuan","email":"","orcid":"","institution":"Shaoxing People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shizhu","middleName":"","lastName":"Yuan","suffix":""},{"id":321649217,"identity":"545851ac-e573-4f29-a486-75eacf34696d","order_by":1,"name":"Mei Tao","email":"","orcid":"","institution":"The Affiliated Hospital of Hangzhou Normal University","correspondingAuthor":false,"prefix":"","firstName":"Mei","middleName":"","lastName":"Tao","suffix":""},{"id":321649218,"identity":"33a4770b-a278-4f2f-95da-7c8f354d024f","order_by":2,"name":"Qiudi Tu","email":"","orcid":"","institution":"People’s Hospital of Hangzhou Medical College, Zhejiang Provincial People’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Qiudi","middleName":"","lastName":"Tu","suffix":""},{"id":321649219,"identity":"5fe45565-d545-47ad-ad3c-d0d2dc982cb4","order_by":3,"name":"Huajuan Shen","email":"","orcid":"","institution":"People’s Hospital of Hangzhou Medical College, Zhejiang Provincial People’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Huajuan","middleName":"","lastName":"Shen","suffix":""},{"id":321649220,"identity":"e9714414-5dce-4a8e-9d03-08b0d7ccb326","order_by":4,"name":"Meiling Zhou","email":"","orcid":"","institution":"People’s Hospital of Hangzhou Medical College, Zhejiang Provincial People’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Meiling","middleName":"","lastName":"Zhou","suffix":""},{"id":321649221,"identity":"c37a1ddb-113f-4593-a6ed-a0aa36d6e977","order_by":5,"name":"Yanqing Jia","email":"","orcid":"","institution":"People’s Hospital of Hangzhou Medical College, Zhejiang Provincial People’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yanqing","middleName":"","lastName":"Jia","suffix":""},{"id":321649222,"identity":"bcc071c4-0b37-48d4-836e-0a685b5e94d3","order_by":6,"name":"Qiang He","email":"","orcid":"","institution":"the First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine) Zhejiang","correspondingAuthor":false,"prefix":"","firstName":"Qiang","middleName":"","lastName":"He","suffix":""},{"id":321649223,"identity":"c8c323ed-1c57-4b4c-8b9a-6367e14e96e1","order_by":7,"name":"Yueming Liu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAy0lEQVRIiWNgGAWjYBACPjBZIWHHz97Y+OADMVrYwOQZi2TJnsPNhjOI1sLYUsG4YUZ6mzQHUVokshM/FzZIMBtIPmyQZmCwk9NtIKgld7P0zB0SfObSiQ3GBQzJxmYHCGvZIM17RoLZcnZiQ/IMhgOJ24jQsvk3b5sE44abBxsO8xCpZZs0WMsNxsZm4rTwvN1mzXNGAhjIic2MMwyI8As/e+7m2zwVdcCoPP78x4cKOzmCWhgEEpB5BoSUg60haOgoGAWjYBSMeAAAdudAYDuRqoMAAAAASUVORK5CYII=","orcid":"","institution":"People’s Hospital of Hangzhou Medical College, Zhejiang Provincial People’s Hospital","correspondingAuthor":true,"prefix":"","firstName":"Yueming","middleName":"","lastName":"Liu","suffix":""},{"id":321649224,"identity":"27167d64-b1f7-428a-b714-7f00a3d31995","order_by":8,"name":"Xiaogang Shen","email":"","orcid":"","institution":"People’s Hospital of Hangzhou Medical College, Zhejiang Provincial People’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xiaogang","middleName":"","lastName":"Shen","suffix":""}],"badges":[],"createdAt":"2024-06-16 15:56:04","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4590369/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4590369/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":60428105,"identity":"59a2a34c-400d-408b-9e1c-b748e979df82","added_by":"auto","created_at":"2024-07-16 15:54:37","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":91866,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram. S-RCA, simplified regional citrate anticoagulation; TS-RCA, two-stage regional citrate anticoagulation.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4590369/v1/859d906c1b2aa6f879b3db43.jpg"},{"id":60428106,"identity":"83c5f7d2-f218-45bc-95f1-152154bf0a49","added_by":"auto","created_at":"2024-07-16 15:54:37","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":35692,"visible":true,"origin":"","legend":"\u003cp\u003eProtocols of regional citrate anticoagulation. TSC, trisodium citrate.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4590369/v1/16d68114e8f6524ac4993b6c.jpg"},{"id":60428104,"identity":"56b77220-ff6a-4841-bd6a-c8c2bce6551d","added_by":"auto","created_at":"2024-07-16 15:54:36","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":123212,"visible":true,"origin":"","legend":"\u003cp\u003eEfficacy and Safety of Two Simplified Regional Citrate Anticoagulation for Intermittent Hemodialysis. Comparison of anticoagulation efficacy(A), dialysis time(B), coagulation scores for dialyzers(C), coagulation score of venous bubbles trap(D), serum ionized calcium(E), serum sodium(F), serum bicarbonate(G), activated partial thromboplastin time (H) between s-RCA and TS-RCA. S-RCA, simplified regional citrate anticoagulation;TS-RCA, two-stage regional citrate anticoagulation; iCa2+, serum ionized calcium; Na+, serum sodium; HCO3-, serum bicarbonate; APTT, activated partial thromboplastin time.\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4590369/v1/62b19b1a6a70975dc063b677.jpg"},{"id":81400627,"identity":"d070e9d1-8a91-45cc-9587-7beb4533921b","added_by":"auto","created_at":"2025-04-25 16:31:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":657863,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4590369/v1/bdd8e66f-f644-4acb-88b5-6c18534b0296.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Efficacy and Safety of Two Simplified Regional Citrate Anticoagulation for Intermittent Hemodialysis: A Randomized Cross-over Trial","fulltext":[{"header":"Introduction","content":"\u003cp\u003eRCA is well-proven to be safe and effective to heparin-free dialysis for Continuous renal replacement therapy (CRRT) \u003csup\u003e[\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e but limited to intermittent hemodialysis (IHD) due to complicated protocols\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. Simplified regional citrate anticoagulation (S-RCA) using calcium-containing dialysate and constant hemodialysis trisodium citrate (TSC) infusion rate has been attempted in IHD\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. However, several studies have shown that S-RCA may increase coagulation risk of the venous bubbles trap \u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. We tried infusing a small fraction of TSC to venous bubble s trap to enhance the anticoagulation effect, which was named two-stage simplified regional citrate anticoagulation (TS-RCA). This randomized cross-over trial aimed to compared the efficacy and safety of TS-RCA with S-RCA in heparin-free dialysis patients.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eWe recruited IHD patients\u0026thinsp;\u0026ge;\u0026thinsp;18 years, with active bleeding or high bleeding risk, without severe hypercalcemia (TC\u0026thinsp;\u0026gt;\u0026thinsp;2.8mmol/L) and hypocalcemia(TC\u0026lt;1.8mmol/L), liver insufficiency, hypoxemia, shock, allergy to citrate products and hypercoagulable state such as active malignancy. The study consisted of two 4-hours periods during which S-RCA and TS-RCA IHD were performed successively separated by a 1-day washout period. Patients were randomized in a 1:1 ratio to one of two treatment sequence\u0026mdash;S-RCA/TS-RCA or TS-RCA/S-RCA. For the S-RCA protocol, 300ml/h TSC (4%; QiShan LiKang, China) was continuously infused into the arterial port of the extracorporeal circulation (ECC) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). For the TS-RCA protocol, 250ml/h TSC was infused into the arterial port and 50ml/h TSC was infused into the venous bubbles trap (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003eb). 1.5mmol/L calcium-containing dialysate was used in both of these protocols with 500ml/min dialysate flow. And the blood flow was set to 180\u0026ndash;250 ml/min according to the patient's own condition. Both protocols did not supplement calcium at the venous port.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAfter consent, assessments of blood analyses were performed at the beginning, 2h and end of each hemodialysis session. At the end of hemodialysis, two investigators assessed coagulation scores of dialyzers and venous bubbles traps with ranges of 0 to 3 (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Arterial, venous and transmembrane pressures were measured during hemodialysis process. Hemodialysis should be terminated early when venous pressure\u0026thinsp;\u0026ge;\u0026thinsp;200mmHg, transmembrane pressure\u0026thinsp;\u0026ge;\u0026thinsp;200mmHg or severe coagulation occurred in ECC (dialyzer or venous bubbles trap coagulation score\u0026thinsp;=\u0026thinsp;3 points). Adverse events such as arrhythmia, hypotension, and hypoglycemia were assessed every hour. The primary outcome was effective rate of anticoagulation which was defined as completion of 4-hours dialysis with less than 3 points of coagulation scores for both dialyzer and venous bubbles trap. The secondary outcomes included dialysis time, the coagulation score of dialyzer and venous bubbles trap, adverse events occurrence, the changes of internal environment and activated partial thromboplastin time (APTT).\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\u003eClotting score of the extracorporeal circulation\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\u003eClotting score\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHemofilter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eExpansion chamber\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eClear or No clotting of Hemofilter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eClear or No clotting of expansion chamber\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eArea of streaky Hemofilter less than 1/3 of total\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eVolume of thrombus less than 1/3 of expansion chamber\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eArea of streaky Hemofilter less than 2/3 of total\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eVolume of thrombus less than 2/3 of expansion chamber\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eArea of streaky Hemofilter more than 2/3 of total\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eVolume of thrombus more than 2/3 of expansion chamber\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eStatistical analysis was performed using SAS 9.4 and GraphPad Prism 8. Category outcomes were presented as frequency (percentage). Continuous outcomes were presented as mean (SD) or median (interquartile range). Comparisons between groups were performed using generalized linear mixed models\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e (PROC MIXED and GLIMMIX) after adjustment for the sequence and period of treatment. For comparing pre- versus post-treatment, paired t tests or paired Wilcoxon tests were used.\u003c/p\u003e"},{"header":"Results and Discussion","content":"\u003cp\u003eAccording to the sample size calculation for 2-period crossover design\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e, 30 patients were enrolled in the trial for 1 year. Of these patients, 17 were in hemorrhage, 10 had active bleeding and 3 had severe thrombocytopenia, and the baseline characteristics is summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. All of them received S-RCA and TS-RCA without lost to follow and withdrawn.\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\u003ePatient baseline characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\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 \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\u003eRCA (n\u0026thinsp;=\u0026thinsp;30)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale, n\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e19(63.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, year\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e60.3(14.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight, kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e60.3(2.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVascular Access\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003earteriovenous\u0026nbsp;fistula\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e14(46.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTemporary catheter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11(36.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epermanent\u0026nbsp;catheter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5(16.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCauses of heparin-free dialysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePerioperation, n\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e17(56.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemorrhage, n\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10(33.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSevere thrombocytopenia, n\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3(10.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood flow rate, ml/min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e220(212. 250)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTC, mmol/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.2(0.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHb, g/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e83.0(19.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePLT, 10^9/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e153.0(67.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePT, s\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12.3(1.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAPTT, s\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e28.4(7.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eRCA, regional citrate anticoagulation; TC, Total cholesterol; Hb, Hemoglobin; PLT, Platelets; PT, Prothrombin time; APTT: Activated partial thromboplastin time\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eFor primary outcome, the effective rate of anticoagulation in TS-RCA was marginally higher than S-RCA [26(86.7%) vs.19(63.3%), P\u0026thinsp;=\u0026thinsp;0.05] (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). The duration of dialysis of TS-RCA was significantly longer than that of S-RCA [4(4, 4) vs. 4(3.7, 4), P\u0026thinsp;=\u0026thinsp;0.03] (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). There was no difference in coagulation scores for dialyzers between S-RCA and TS-RCA (P\u0026thinsp;=\u0026thinsp;0.64) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC). However, the coagulation score of venous bubbles trap in TS-RCA was significantly lower than S-RCA (P\u0026thinsp;\u0026lt;\u0026thinsp;0.01) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eD).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn terms of safety, only 5 (16.7%) hypoglycemia occurred in both protocols, and 1(3.33%) hypotension in S-RCA. And there were no other serious adverse events in both protocols. After dialysis, the serum ionized calcium levels had mildly elevated 0.06(-0.07, 0.12) mmol/L during S-RCA, but did not significantly change (P\u0026thinsp;=\u0026thinsp;0.75) during TS-RCA (P\u0026thinsp;=\u0026thinsp;0.05 between protocols) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eE). The serum sodium levels had mildly elevated 4.3(2.9) mmol/L during S-RCA and 5.0(2.4) mmol/L during TS-RCA dialysis (P\u0026thinsp;=\u0026thinsp;0.15 between protocols) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eF). The serum bicarbonate levels had also elevated 2.2(0.4, 4.5) mmol/L during S-RCA and 1.8(1, 3.4) mmol/L during TS-RCA dialysis (P\u0026thinsp;=\u0026thinsp;0.91 between protocols) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eG). The APTT did not significantly change during S-RCA (P\u0026thinsp;=\u0026thinsp;0.05) and TS-RCA(P\u0026thinsp;=\u0026thinsp;0.08) dialysis (P\u0026thinsp;=\u0026thinsp;0.76 between protocols) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003eH). Above all, we found that the two RCA protocols have similar effects on the internal environment, which can slightly increase serum sodium and bicarbonate levels, but without severe hypernatremia and metabolic alkalosis.\u003c/p\u003e \u003cp\u003eOur work further supports previous findings reporting a significant improvement of anticoagulation effectiveness of TS-RCA compared to S-RCA (86.7%vs. 63.3%)\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. Here, both TS-RCA and S-RCA have achieved satisfactory anticoagulation effects compared to the reported saline irrigation (54.8%)\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. But the anticoagulation effects in this study were worse than in previous studies \u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. The reasons might be related to the higher dialysate calcium concentration and use of temporary catheter.\u003c/p\u003e \u003cp\u003eOn the other hand, we observed significant increases in serum sodium and bicarbonate levels which was consistent with previous studies\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. We interpret this as the effects of citrate metabolism. Although mild alkalization has been reported to be beneficial to some extent in hemodialysis patients\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. However, in order to avoid serious alkali poisoning, it is safe to lower dialysate bicarbonate to 28mmol/L in this study. It is suggested that the concentration of sodium and bicarbonate should be appropriately reduced to prevent the occurrence of hypernatremia and metabolic alkalosis when using sodium citrate dialysis for hemodialysis.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn summary, the anticoagulation effect of TS-RCA is better than that of S-RCA in IHD, especially in the anticoagulation of venous bubbles trap. These two RCAs were safe for IHD patient with high bleeding risk due to low incidence of adverse events and less impact on internal environment.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflicts of Interest\u003c/h2\u003e \u003cp\u003eNone declared.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding Statement\u003c/h2\u003e \u003cp\u003eThis work was supported by grants from the Medical Health Science and Technology Projects of Zhejiang Provincial Health Commission (grant no. 2021KY490).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eMei Tao designed the study, Shizhu Yuan collected the original data, performed this trial, interpreted the results and drafted the manuscript. Qiudi Tu, Huajuan Shen, Meiling Zhou and Yanqing Jia performed this trial. Yueming Liu designed the study and performed statistical analyses. Qiang He and Xiaogang Shen interpreted the results, revised the manuscript. All authors approved its final version.\u003c/p\u003e\u003ch2\u003eAcknowledgments\u003c/h2\u003e \u003cp\u003eThe authors would like to thank the volunteers who accepted\u003c/p\u003e\n\u003ch3\u003eData Availability\u003c/h3\u003e\n\u003cp\u003eData available on request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eZARBOCK A, K\u0026uuml;LLMAR M, KINDGEN-MILLES D, et al. Effect of Regional Citrate Anticoagulation vs Systemic Heparin Anticoagulation During Continuous Kidney Replacement Therapy on Dialysis Filter Life Span and Mortality Among Critically Ill Patients With Acute Kidney Injury: A Randomized Clinical Trial. Jama 2020; 324(16): 1629-39.\u003c/li\u003e\n\u003cli\u003eALVAREZ G, CHRUSCH C, HULME T, et al. Renal replacement therapy: a practical update. Can J Anaesth 2019; 66(5): 593-604.\u003c/li\u003e\n\u003cli\u003eTANG X, Chen D, Zhang L, et al. Application of regional citrate anticoagulation in patients at high risk of bleeding during intermittent hemodialysis: a prospective multicenter randomized controlled trial. J Zhejiang Univ Sci B.2022;23(11):931-942.\u003c/li\u003e\n\u003cli\u003eTOLWANI A, WILLE K M. Advances in continuous renal replacement therapy: citrate anticoagulation update . Blood Purif 2012; 34(2): 88-93.\u003c/li\u003e\n\u003cli\u003eLIM E K, SEOW Y T, CHEN S E, et al. Simple citrate anticoagulation protocol for low flux haemodialysis. BMC Nephrol 2018; 19(1): 16.\u003c/li\u003e\n\u003cli\u003eAPSNER R, BUCHMAYER H, LANG T, et al. Simplified citrate anticoagulation for high-flux hemodialysis. Am J Kidney Dis 2001, 38(5): 979-87.\u003c/li\u003e\n\u003cli\u003eBUTUROVIC-PONIKVAR J, GUBENSEK J, PONIKVAR R. Citrate anticoagulation for postdilutional online hemodiafiltration with calcium-containing dialysate and infusate: significant clotting in the venous bubble trap. Int J Artif Organs 2008; 31(4): 323-8.\u003c/li\u003e\n\u003cli\u003eMAHMOOD D, STEGMAYR B G. Haemodialysis with Tinzaparin Versus Dialysate Citrate as Anticoagulation. Blood Purif 2018; 46(3): 257-63.\u003c/li\u003e\n\u003cli\u003eDWAN K, LI T, ALTMAN D G, et al. CONSORT 2010 statement: extension to randomised crossover trials. Bmj 2019; 366: l4378.\u003c/li\u003e\n\u003cli\u003eLIN T, SONG L, HUANG R, et al. Modified regional citrate anticoagulation is optimal for hemodialysis in patients at high risk of bleeding: a prospective randomized study of three anticoagulation strategies. BMC Nephrol 2019; 20(1): 472.\u003c/li\u003e\n\u003cli\u003eEVENEPOEL P, MAES B, VANWALLEGHEM J, et al. Regional citrate anticoagulation for hemodialysis using a conventional calcium-containing dialysate. Am J Kidney Dis 2002; 39(2): 315-23.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Intermittent Hemodialysis, Citrate༛Anticoagulation༛Randomized Cross-over Trial༛","lastPublishedDoi":"10.21203/rs.3.rs-4590369/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4590369/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIn recent years, due to the low risk of bleeding, regional citrate anticoagulation (RCA) is being tried for intermittent hemodialysis (IHD). Simplified regional citrate anticoagulation (S-RCA) has been attempted in IHD. This randomized cross-over trial was designed to compared the efficacy and safety of two RCAs in heparin-free dialysis patients, which were named S-RCA and two-stage simplified regional citrate anticoagulation (TS-RCA). In summary, the anticoagulation effect of TS-RCA is better than that of S-RCA in IHD, especially in the anticoagulation of venous bubbles trap. And these two RCAs were safe for IHD patient with high bleeding risk. Trial Registration: Chinese Clinical Trial Registry (CHICTR): Registration Number ChiCTR2000034314; Registration date 28 September 2020.\u003c/p\u003e","manuscriptTitle":"Efficacy and Safety of Two Simplified Regional Citrate Anticoagulation for Intermittent Hemodialysis: A Randomized Cross-over Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-16 15:54:31","doi":"10.21203/rs.3.rs-4590369/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":"774195ed-e3f6-4d25-9522-8c22ccef6f24","owner":[],"postedDate":"July 16th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-04-25T16:23:27+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-16 15:54:31","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4590369","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4590369","identity":"rs-4590369","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}