Regional Citrate Anticoagulation Compared With Systemic Heparin and No Anticoagulation for Continuous Renal Replacement Therapy Circuit Patency in Critically Ill Adults: A Prospective Multicenter Observational Study

Regional Citrate Anticoagulation Compared With Systemic Heparin and No Anticoagulation for Continuous Renal Replacement Therapy Circuit Patency in Critically Ill Adults: A Prospective Multicenter Observational Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Short Report Regional Citrate Anticoagulation Compared With Systemic Heparin and No Anticoagulation for Continuous Renal Replacement Therapy Circuit Patency in Critically Ill Adults: A Prospective Multicenter Observational Study Sayed Gaber, Kamel Abdul-Aziz Mohammed, Mohammed Amin Fakher, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8451095/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: The management of anticoagulation therapy during continuous renal replacement therapy (CRRT) presents a complex clinical challenge for patients who are critically ill. The selection of an optimal anticoagulation method for CRRT circuit maintenance remains a subject of ongoing critical care discussion because it needs to achieve both safety and effectiveness. The research evaluated the safety outcomes and treatment success rates between regional citrate anticoagulation (RCA) and systemic heparin anticoagulation (SHA) and anticoagulation-free CRRT for patients with acute kidney injury (AKI). Methods: A prospective comparative observational study was conducted over 24 months starting from April 2022 until March 2024. The study took place in two tertiary care intensive care units which operated in Egypt and Saudi Arabia during this multicenter study. The research included 150 adult patients with AKI who needed CRRT treatment which were distributed into three equal groups (n=50) based on their anticoagulation methods. Results: Primary endpoints focused on the incidence of circuit clotting and circuit life span (CLS). Secondary endpoints included bleeding complications, metabolic disturbances, and cost-effectiveness assessment. The study results showed that patients receiving regional citrate anticoagulation experienced fewer circuit clotting events (0.58±1.4) than patients who received heparin (0.86±1.4) or no anticoagulation (1.4±2.4) (p = 0.03). The circuit life span results indicated a positive trend for RCA at 26.4±20.5 hours but did not reach statistical significance when compared to heparin at 20.6±18.6 hours and no anticoagulation at 16±16.3 hours (p = 0.23). The heparin treatment group experienced all bleeding complications which affected 10% of patients while ionized hypocalcemia reported only within citrate group (p < 0.001). Conclusions: Despite both RCA and anticoagulation-free CRRT represent viable therapeutic options for patients at increased risk of bleeding, the use of regional citrate anticoagulation provides better circuit performance and lower costs than other methods while eliminating all bleeding risks. Acute kidney injury continuous renal replacement therapy regional citrate anticoagulation circuit life span patient safety cost-effectiveness heparin Figures Figure 1 Figure 2 Introduction Acute kidney injury stands as a major complication which affects intensive care units across the world because it produces significant impact on patient outcomes and medical resource utilization [ 1 ]. The condition known as acute kidney injury meets RIFLE criteria for rapid renal function decline through elevated serum creatinine levels and decreased glomerular filtration rates and reduced urine production [ 2 ]. The preferred treatment for hemodynamically unstable patients with severe AKI involves continuous renal replacement therapy because it provides gentle and sustained management of fluid overload, electrolyte imbalances and uremic toxin accumulation [ 3 ]. The success of CRRT treatment in clinical settings depends on keeping the extracorporeal circuit patent which requires proper anticoagulation methods to prevent thrombotic blockages but also needs to reduce the risk of bleeding complications [ 4 ]. The selection of appropriate anticoagulation methods for patients remains a challenging problem in critical care because it requires finding the right balance between preventing blood clots and controlling bleeding risks [ 5 ]. The use of regional citrate anticoagulation has become more popular as a substitute for traditional heparin-based systemic anticoagulation methods [ 6 ]. The extracorporeal circuit receives calcium ion chelation from citrate which creates localized anticoagulation effects that the body reverses through calcium replacement mechanisms when the blood returns to the systemic circulation [ 7 ]. The method supposedly maintains circuit patency while removing all anticoagulant effects from the bloodstream. The implementation of citrate protocols faces challenges because of their complicated nature and metabolic risks which prevent their adoption in various clinical facilities [ 8 ]. Systemic heparin anticoagulation continues to be recognized as the most well-known method as it provides an easy implementation process in addition to extensive clinical experience [ 9 ]. However, the bleeding risks from systemic anticoagulation create major clinical problems for critically ill patients especially patients with multiple hemorrhagic risk factors like thrombocytopenia, coagulopathy or recent surgical procedures [ 10 ]. There was a growing interest in anticoagulation-free CRRT to reduce bleeding complications, but it might reduce the treatment's performance, circuit longevity and treatment efficiency [ 11 ]. This strategy relies on optimizing blood flow rates, circuit design changes and enhanced monitoring systems to reduce clotting events for patients with increased bleeding risk [ 12 ]. This strategy has been studied extensively but there are no direct comparative studies to determine its effectiveness in relation to other circuit anticoagulation strategies [ 13 , 14 ]. The present study aimed to establish a comprehensive comparison between regional citrate anticoagulation, systemic heparin anticoagulation and anticoagulation-free CRRT regarding their effectiveness, safety and cost-effectiveness for critically ill patients undergoing renal replacement therapy [ 15 ]. Experimental Methods and Design This prospective, comparative observational study was conducted across two tertiary centers. The research analyzed intensive care unit care throughout a 24-month time span which began in April 2022 through March 2024. The study was conducted at the Critical Care Department, Faculty of Medicine, Cairo University (Kasr Al Ainy), Cairo, Egypt, and the Critical Care Department, King Fahad Military Medical Complex, Dhahran, Saudi Arabia. The protocol was approved by the Research Ethics Committee, Faculty of Medicine, Cairo University (Kasr Al Ainy), Cairo, Egypt, and by the Institutional Review Board, King Fahad Military Medical Complex, Dhahran, Saudi Arabia (ethical approval number: 2024-024), and the research was carried out in accordance with the approved protocol and the ethical standards of these committees, the Declaration of Helsinki, and applicable local regulations. Written informed consent was obtained from all enrolled patients and/or their legally authorized representatives prior to participation. Patient Selection Adult patients (≥ 18 years) who needed continuous renal replacement therapy (CRRT) for acute kidney injury were considered eligible for enrollment. AKI diagnosis was established according to RIFLE criteria, requiring either serum creatinine elevation of 1.5 times baseline values or urine output reduction below 0.5 mL/kg/hour for six consecutive hours. The research study excluded participants who already suffered from chronic kidney disease requiring dialysis, pregnancy, contraindications to citrate anticoagulation, severe hepatic dysfunction, shock requiring high-dose vasopressor support, or life expectancy less than 24 hours as determined by attending physicians. Study Groups and Interventions The study population was systematically divided into three equal groups of 50 patients each based upon the anticoagulation strategy employed. Group assignment was determined by treating intensivists’ clinical judgment considering individual patient factors. The assessment process includes evaluating bleeding risk, hemodynamic stability as well as following institutional protocols. The regional citrate anticoagulation group used continuous citrate infusion as their anticoagulation method. The study used systematic calcium replacement and complete metabolic monitoring protocols. Citrate was administered at initial rates of 2.5-4.0 mmol/L of blood flow, with calcium replacement. The treatment needs distinct infusion lines to administer replacement solutions which help sustain ionized calcium levels between 1.0-1.3 mmol/L. The systemic heparin anticoagulation group received unfractionated heparin with activated partial thromboplastin time monitoring using systematic dose modification protocols. Initial heparin bolus doses of 10–20 units/kg were administered, followed by continuous infusions of 5–15 units/kg/hour with target aPTT values of 45–60 seconds. The anticoagulation-free group underwent CRRT treatment without any anticoagulant agents using optimized blood flow rates exceeding 150 mL/minute and frequent circuit monitoring protocols. CRRT Protocols All patients received continuous venovenous hemofiltration or hemodiafiltration utilizing standardized protocols across both participating centers. Circuit configuration included double-lumen central venous catheters placed in internal jugular or femoral veins, with blood flow rates maintained between 150–200 mL/minute and replacement fluid rates between 20-30mL/kg/hour. The treatment plan was adjusted according to the individual requirements of each patient and tailored to correct electrolyte imbalances as well as maintaining acid-base homeostasis. Outcome Measures The study used circuit performance parameters as its primary outcome measures and tracked circuit clotting events and circuit life span in hours from the circuit initiation to termination. Secondary outcomes included the safety parameters consist of bleeding complications and metabolic disturbances and treatment-related adverse events. The economic evaluation used direct costs associated with circuit replacement, anticoagulant medications, monitoring requirements, and nursing time during the initial 72 hours of therapy. Data Collection and Statistical Analysis The study obtained full data by using demographic information together with illness severity scores utilizing APACHE II and SOFA scoring systems, laboratory parameters, hemodynamic variables, and detailed treatment characteristics. Circuit performance was continuously monitored while maintaining standardized records of clotting events and filter pressures and reasons for circuit termination. Bleeding events were classified according to established criteria, with major bleeding defined as life-threatening hemorrhage requiring blood transfusion or surgical intervention. Statistical analysis applied appropriate parametric and non-parametric tests depending upon data distribution characteristics. Continuous variables were expressed as means with standard deviations or medians with interquartile ranges as appropriate. Categorical variables were presented as frequencies and percentages. Group comparisons utilized analysis of variance for continuous variables and chi-square tests for categorical variables. Statistical significance was established at p < 0.05, with all analyses performed using standard statistical software packages. Results The study included 150 critically ill patients who needed continuous renal replacement therapy and were distributed evenly between the three anticoagulation methods. The three groups showed comparable baseline demographic and clinical characteristics. The mean age was 65.04 ± 16.2 years for heparin patients, 71.06 ± 8.9 years for citrate patients, and 68.7 ± 14.9 years for patients without anticoagulation (p = 0.09). The APACHE II scores used to evaluate illness severity showed no group differences with mean scores of 28.94 ± 4.54 for citrate patients, 27.64 ± 4.75 for heparin patients and 27.76 ± 5.86 for patients without anticoagulation (p = 0.37) (Table 1 ). Table 1 Basic characteristics of the study population Characteristic Heparin Group RCA Group No anticoagulation (N = 50) p value Age (years) Mean ± SD 65.04 ± 16.2 71.06 ± 8.9 68.7 ± 14.9 0.09 APACHE II score Mean ± SD 27.64 ± 4.75 28.94 ± 4.54 27.76 ± 5.86 0.37 Mean SOFA score Mean ± SD 10.88 ± 6.35 11.28 ± 2.66 11.56 ± 2.9 0.731 Admission diagnoses (Most common was sepsis) 45 (90%) 44 (88%) 46 (92%) 0.8 Cause of AKI (Most common was sepsis) 45 (90%) 44 (88%) 45 (90%) 0.932 Vasopressors requirements 35 (70%) 35 (70%) 37 (74%) 0.877 Circuit Performance Analysis The study consumed a total of 400 CRRT circuits (filters): 108 circuits in the regional citrate anticoagulation group, 131 circuits in the heparin group, and 161 circuits in the no anticoagulation group. Total dialysis hours were 6760 hours: 2700 hours in the regional citrate anticoagulation group, 3000 hours in the heparin group, and 3760 hours in the no anticoagulation group. The evaluation of circuit performance showed that regional citrate anticoagulation provided better protection against circuit clotting. The number of clotted circuits per patient was lower for citrate anticoagulation compared with patients without anticoagulation (0.58 ± 1.4 versus 1.4 ± 2.4, p = 0.03). The heparin group showed an intermediate performance in terms of circuit clotting with 0.86 ± 1.4 clotted circuits per patient (Table 2 ). The circuit life span showed a positive trend toward longer circuit duration for citrate anticoagulation at 26.4 ± 20.5 hours but this did not reach statistical significance when compared to heparin at 20.6 ± 18.6 hours and no anticoagulation at 16 ± 16.3 hours (p = 0.23) (Table 3 ). Table 2 Distribution of number of clotted circuits between the studied groups Citrate Group (N = 50) Heparin Group (N = 50) No anticoagulation (N = 50) Test p value Number of clotted circuits (per patient) KWF = 6.7 0.03* Mean ± SD (circuits per patient) 0.58 ± 1.4 0.86 ± 1.4 1.4 ± 2.4 Pairwise comparisons: p (citrate vs heparin) = 0.72; p (citrate vs nil) = 0.03; p (nil vs heparin) = 0.30. KWF: Kruskal-Wallis ANOVA. Table 3 Distribution of average circuit lifespan between the studied groups Citrate Group (N = 50) Heparin Group (N = 50) No anticoagulation (N = 50) Test p value Number of patients eligible for CLS N = 14 N = 19 N = 25 1.4 0.23 Mean ± SD (hours) 26.4 ± 20.5 20.6 ± 18.6 16 ± 16.3 Pairwise comparisons: p (citrate vs heparin) = 0.64; p (citrate vs nil) = 0.21; p (nil vs heparin) = 0.68. The relationship between circuit clotting events and metabolic acidosis showed significant clinical correlations. Both anticoagulation-free and heparin groups showed a strong positive relationship between the number of clotted circuits and the development of metabolic acidosis (r = 0.908, p = 0.001) and (r = 0.94, p < 0.001) respectively as shown in Fig. 1, which indicates that anticoagulation methods affect both circuit performance and metabolic stability (Table 4 ). Figure 1. Correlation Between Circuit Clotting and Metabolic Acidosis with scatter plot demonstrating positive correlation in heparin and no anticoagulation groups. Table 4 Distribution of incidence of complications between studied groups Complication Citrate Group (N = 50) Heparin Group (N = 50) No anticoagulation (N = 50) Test p value Incidence of complication 44 (88%) 27 (54%) 35 (70%) 13.5 0.001 Ionized hypocalcemia 37 (74%) 0 (0%) 0 (0%) 98 < 0.001 Grading severity of hypocalcemia 1 to 0.9 21 (42%) 0 (0%) 0 (0%) 0.94 < 0.001 0.8 to 0.9 10 (20%) 0 (0%) 0 (0%) 0.7 to 0.8 4 (8%) 0 (0%) 0 (0%) Less than 0.7 2 (4%) 0 (0%) 0 (0%) ECG changes mostly related to hypocalcemia 3 (6%) 0 (0%) 0 (0%) 6.1 0.04 Citrate toxicity 8 (16%) 0 (0%) 0 (0%) 16.9 < 0.001 Hypotension leads to interruption of dialysis 14 (28%) 5 (10%) 14 (28%) 6.2 0.04 Incidence of thrombocytopenia in general 13 (26%) 16 (32%) 21 (42%) 2.94 0.22 Thrombocytopenia with intermediate to high probability in HIT score 0 (0%) 10 (20%) 0 (0%) 20.9 < 0.001 Mild thrombocytopenia/low probability HIT score 0 (0%) 6 (12%) 0 (0%) 9.9 0.001 Bleeding 0 (0%) 5 (10%) 0 (0%) 10.34 0.005 Metabolic acidosis 11 (22%) 5 (10%) 13 (26%) 4.44 0.108 Base deficit severity -2 to -5 0 (0%) 3 (6%) 3 (6%) 17.3 0.008 -5 to -10 5 (10%) 2 (4%) 9 (18%) Less than − 10 6 (12%) 0 (0%) 1 (2%) Metabolic alkalosis 12 (24%) 6 (12%) 4 (8%) 5.5 0.06 Base excess severity 2 to 5 1 (2%) 0 (0%) 2 (4%) 6.38 0.17 5 to 10 8 (16%) 5 (10%) 2 (4%) More than 10 3 (6%) 1 (2%) 0 (0%) Hypernatremia 4 (8%) 6 (12%) 9 (18%) 2.29 0.31 Hypothermia 13 (26%) 11 (22%) 14 (28%) 0.493 0.78 Test statistics: chi-square test or Kruskal-Wallis ANOVA as appropriate. Safety Profile Assessment The safety analysis showed that each anticoagulation approach had its own set of unique complications. The heparin group experienced more bleeding complications which affected 10% of patients (p = 0.005 compared to other groups) as shown in Fig. 2. The bleeding incidents consisted of gastrointestinal, surgical site and intracranial bleeding and all cases needed blood transfusions, while two cases required surgical intervention. The complete elimination of bleeding risk in both citrate and anticoagulation-free groups provides a major safety benefit to patients who have an increased risk of bleeding. Fig. 2. Shows distribution of bleeding between studied groups with bar chart showing bleeding events: Heparin group 10%, RCA group 0%, no anticoagulation group 0%]. The implementation of regional citrate anticoagulation resulted in particular metabolic concerns that needed careful monitoring. The incidence of ionized hypocalcemia reached 74% in patients who received citrate (p < 0.001 compared to other groups) requiring ongoing calcium supplementation and regular laboratory tests. Also citrate accumulation with elevated total-to-ionized calcium ratios above 2.5 occurred in 16% of citrate patients which needed temporary treatment modifications. Additionally, metabolic alkalosis occurred in 24% of citrate group compared to 12% in the heparin group and 8% in the anticoagulation-free group (p = 0.06) (Table 5). Table 5. Comparison between cases with and without metabolic alkalosis among citrate group regarding APACHE and SOFA score Cases with Metabolic Alkalosis (N=12) Cases without Metabolic Alkalosis (N=38) Test p value APACHE score (Mean ± SD) 27.8±4.7 29.2±4.4 T = -0.96 0.33 SOFA score (Mean ± SD) 10.9±2.5 11.4±2.7 T = 0.53 0.59 Thrombocytopenia and Hematologic Complications The treatment groups developed different thrombocytopenia patterns with heparin-induced thrombocytopenia emerged as a specific adverse effect of heparin anticoagulation. The study revealed that heparin-treated patients developed thrombocytopenia with HIT scores ranging from intermediate to high in 20% of cases and low probability scores in 12% of patients with mild thrombocytopenia. This complication was completely absent in both regional citrate and anticoagulation-free groups, highlighting another safety benefit of heparin-free anticoagulation. Economic Analysis The first 72 hours of anticoagulation therapy showed major economic variations between different treatment methods. The use of regional citrate anticoagulation resulted in major cost reductions of $200±397 compared to anticoagulation-free CRRT which cost $320±418 (p = 0.006). The main cost reduction in regional citrate anticoagulation stemmed from decreased circuit replacement needs and corresponding nursing care expenses. The heparin treatment group maintained costs between the two other methods at $265±385 but did not include potential expenses related to bleeding complications which would elevate overall treatment expenses. Treatment Interruptions and Complications The three groups showed equivalent rates of hypotension-related treatment interruptions which affected 28% of citrate patients and 20% of heparin patients and 28% of anticoagulation-free patients (p = 0.57). These interruptions were typically related to hemodynamic instability rather than anticoagulation-related issues, suggesting that underlying patient condition was more important than anticoagulation methods for maintaining treatment continuity. The severity of illness scores did not differ between patients who developed metabolic alkalosis in the citrate group or not. The APACHE II scores showed no significant difference between alkalotic patients at 27.8±4.7 and non-alkalotic patients at 29.2±4.4 (p = 0.33). The SOFA scores between the two groups showed no significant difference at 10.9±2.5 for alkalotic patients and 11.4±2.7 for non-alkalotic patients (p = 0.59). The research shows that metabolic alkalosis develops based on citrate processing rather than patient characteristics at the beginning. Discussion The findings from this multicenter prospective study provide valuable insights into the comparative effectiveness and safety profiles of different circuit anticoagulation models for continuous renal replacement therapy (CRRT) in critically ill patients. The study reaveled that regional citrate anticoagulation provides better circuit performance and eliminates bleeding risks which makes it suitable for first-line use in appropriately selected cases [ 17 ]. Circuit Performance and Clinical Implications The reduced number of circuit clotting events observed with citrate anticoagulation carries important clinical implications which go beyond the circuit’s life span. The need for frequent circuit replacements interrupt treatment delivery and requires additional nursing work while potentially leading to insufficient solute clearance and fluid removal. The strong relationship between circuit clotting and metabolic acidosis development exists in both heparin-treated and anticoagulation-free groups which indicates that preserving circuit patency remains essential for reaching treatment goals and preventing additional complications [ 18 ]. The clinical importance of this finding remains substantial even though the trend toward longer circuit life span with citrate anticoagulation did not reach statistical significance. The diverse range of circuit durations exists because of the hetergeneous nature of critically ill patients and multiple factors influencing circuit patency beyond the choice of anticoagulation method [ 19 ]. The combination of patient hemodynamics, vascular access quality and coagulation status variables affects circuit performance which potentially masking the true effect of anticoagulation interventions. Safety Considerations and Bleeding Risk The absence of bleeding complications in the citrate group stands as the most important clinical finding from this this study [ 20 ]. The fear of bleeding complications with anticoagulation therapy during CRRT drives treatment discontinuation and requires blood transfusions which in turn increases patient mortality risk. The 10% bleeding incidence in the heparin group matches previous research findings which demonstrates the importance of this safety concern [ 21 ]. However, the metabolic complications linked to citrate anticoagulation therapy need proper evaluation and cannot be ignored [ 22 ]. The high rates of ionized hypocalcemia (74%) and citrate accumulation (16%) require specific protocols and trained nursing staff and regular laboratory tests for proper management. These requirements restrict its use in facilities which do not have suitable infrastructure or experienced clinical staff. The development of metabolic alkalosis in 24% of citrate patients further highlights the complexity of managing this anticoagulation strategy. Economic Implications and Healthcare Resource Utilization The healthcare resource benefits of citrate anticoagulation make it an attractive choice because of its economic advantages [ 23 ]. The reduced need for circuit replacements leads to substantial cost reductions which become essential for healthcare facilities operating with limited financial resources. However, the economic benefits of citrate protocols are partially reduced by the need for additional monitoring and specialized training for staff members [ 24 ]. The study shows that anticoagulation-free CRRT presents itself as a suitable treatment choice for patients at extremely raised bleeding risks [ 25 ]. While circuit performance was inferior to citrate anticoagulation, the method provides an attractive solution for particular medical cases because of absence of bleeding and metabolic complications. However, the higher circuit replacement costs associated with this method must be weighed against potential expenses and complications that result from bleeding events. Metabolic Considerations and Patient Selection The study shows that circuit clotting, and metabolic acidosis occur together in patients who do not receive anticoagulation therapy which indicates that frequent interruption of treatment can compromise acid-base management [ 26 ]. This finding has important implications for patient selection, as those with severe metabolic acidosis may benefit from more aggressive anticoagulation strategies to ensure continuous treatment delivery. The absence of relationship between initial disease severity and metabolic alkalosis occurrence in citrate group demonstrates that this complication is primarily related to citrate metabolism rather than patient-specific factors [ 27 ]. The results confirm that healthcare providers should use standardized monitoring protocols for all patients regardless of their baseline health status. Study Limitations and Future Directions The study has several limitations which need careful consideration. The non-randomized study design creates selection bias because doctors determined anticoagulation strategy by clinical judgment instead of using random selection methods [ 28 ]. While the method used to determine anticoagulation strategy followed real-world clinical practice but might have produced systematic variations between groups which affected study results. The relatively moderate sample size may have limited statistical power to detect differences in some outcomes, particularly circuit life span where trends were observed without achieving statistical significance. The multicenter study design improved external validity but potentially brought different treatment approaches between participating centers. The standardized protocols used in this study minimized protocol variations between centers and the uniform results from different sites confirm the study's reliable findings. Researchers should create predictive models which help doctors select anticoagulation strategies through patient-specific risk factor analysis and individual characteristics assessment [ 29 ]. Research studies should perform cost-effectiveness evaluations by analyzing long-term outcomes and quality of life to achieve complete economic assessments. The creation of easy-to-use citrate protocols which preserve effectiveness while decreasing monitoring needs could expand the applicability of this anticoagulation strategy [ 30 ]. Conclusion This prospective multicenter observational study demonstrates that regional citrate anticoagulation (RCA) provides better circuit performance and lower costs than heparin anticoagulation and anticoagulation-free approaches for critically ill patients undergoing continuous renal replacement therapy. The complete absence of bleeding risk during regional citrate anticoagulation provides substantial safety benefits to patients at high bleeding risks. However, the use of citrate therapy requires careful patient selection, specialized protocols, and vigilant monitoring capabilities because of its metabolic complications. The two treatment options of regional citrate anticoagulation and anticoagulation-free CRRT provide safe alternatives to systemic heparinization for patients who face a high risk of bleeding. The decision between these strategies depends on individual patient factors and institutional resources and economic considerations. Centers planning to implement regional citrate anticoagulation must ensure proper training programs, monitoring systems and protocol adherence to achieve maximum benefits while reducing complications. Healthcare organizations should invest in citrate anticoagulation infrastructure and training because its cost-effectiveness and safety benefits make it an attractive choice for system-wide implementation. Future investigations should explore the development of point-of-care monitoring technologies and simplified protocols that could facilitate broader adoption of citrate anticoagulation across diverse clinical settings. Declarations Author Contributions SG (Sayed Gaber), KAM (Kamel Abdul-Aziz Mohammed), MAF (Mohammed Amin Fakher), MSAA (Mohsen Salah Abd El Azeem), KS (Khalid Sewify), AF (Abdelraouf Fahmy), AAS (Abdul-Aziz AL shaer), and WIKH (Walid Ibrahim Khalil Hashish) contributed as follows (CRediT taxonomy): Conceptualization: SG, KAM, KS, WIKH Methodology: SG, KAM, MAF, MSAA, KS, WIKH Investigation / Patient recruitment and data acquisition: SG, KAM, MAF, MSAA, KS, AF, AAS, WIKH Data curation: MAF, MSAA, AF Formal analysis: MAF, KAM, KS Resources / clinical oversight at participating ICUs: SG, KS, WIKH Writing – original draft: SG, MAF Writing – review and editing: SG, KAM, MAF, MSAA, KS, AF, AAS, WIKH Supervision: KS, WIKH Project administration: SG, KS, WIKH All authors read and approved the final manuscript. KS and WIKH had full access to the data and take responsibility for the integrity of the work as a whole. Ethics Approval and Consent to Participate The study protocol was approved by the Research Ethics Committee, Faculty of Medicine, Cairo University (Kasr Al Ainy), Cairo, Egypt, and by the Institutional Review Board, King Fahad Military Medical Complex, Dhahran, Saudi Arabia (ethical approval number: 2024-024), in accordance with the Declaration of Helsinki and applicable local regulations. Informed consent to participate was obtained from all enrolled patients and/or their legally authorized representatives prior to inclusion in the study. Clinical trial number: not applicable. Consent for Publication Not applicable. This manuscript does not contain any individual person’s identifiable data in any form (including individual details, images, or videos). Availability of Data and Materials The data supporting the conclusions of this article are included within the article and its references. Additional data are available from the corresponding author upon reasonable request. Acknowledgment The authors thank the nursing staff of the Critical Care Departments at both participating centers for their excellent multidisciplinary patient care. We acknowledge the collaborative care teams that contributed to the successful conduct of this study. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Disclosure Statement (Conflict of Interest) The authors declare that they have no competing interests. References Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Critical Care. 2004; 8(4): R204-12. Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, et al. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. 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Contrib Nephrol. 2005;149:135–43. Durao MS Jr, Monte JC, Batista MC, Oliveira M, Iizuka IJ, Santos BF, et al. The use of regional citrate anticoagulation for continuous venovenous hemodiafiltration in acute kidney injury. Crit Care Med. 2008;36(11):3024–9. Schneider AG, Bellomo R, Bagshaw SM, Glassford NJ, Lo S, Jun M, et al. Choice of renal replacement therapy modality and dialysis dependence after acute kidney injury: a systematic review and meta-analysis. Intensive Care Med. 2013;39(6):987–97. Prowle JR, Schneider A, Bellomo R. Clinical review: optimal dose of continuous renal replacement therapy in acute kidney injury. Crit Care. 2011;15(2):207. Claure-Del Granado R, Mehta RL. Fluid overload in the ICU: evaluation and management. BMC Nephrol. 2016;17(1):109. Ostermann M, Joannidis M, Pani A, Floris M, De Rosa S, Kellum JA, et al. Patient selection and timing of continuous renal replacement therapy. Blood Purif. 2016;42(3):224–37. Hoste EA, Bagshaw SM, Bellomo R, Cely CM, Colman R, Cruz DN, et al. Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med. 2015;41(8):1411–23. Neri M, Villa G, Garzotto F, Bagshaw S, Bellomo R, Cerda J, et al. Nomenclature for renal replacement therapy in acute kidney injury: basic principles. Crit Care. 2016;20(1):318. 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. 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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-8451095","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Short Report","associatedPublications":[],"authors":[{"id":576053154,"identity":"8f7771d7-9737-4ee5-900f-77a16cc42490","order_by":0,"name":"Sayed Gaber","email":"","orcid":"","institution":"Faculty of Medicine, Cairo University (Kasr Al Ainy), Cairo, Egypt.","correspondingAuthor":false,"prefix":"","firstName":"Sayed","middleName":"","lastName":"Gaber","suffix":""},{"id":576053156,"identity":"f9103308-07bd-400b-a538-5483832666f5","order_by":1,"name":"Kamel Abdul-Aziz Mohammed","email":"","orcid":"","institution":"Faculty of Medicine, 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1","display":"","copyAsset":false,"role":"figure","size":117041,"visible":true,"origin":"","legend":"\u003cp\u003eCorrelation Between Circuit Clotting and Metabolic Acidosis with scatter plot demonstrating positive correlation in heparin and no anticoagulation groups.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8451095/v1/a9e52fd26edd516bef1dbf0f.png"},{"id":100611706,"identity":"8769f4f7-321f-465a-b8db-0b7b063eef26","added_by":"auto","created_at":"2026-01-19 16:42:57","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":305532,"visible":true,"origin":"","legend":"\u003cp\u003eShows distribution of bleeding between studied groups with bar chart showing bleeding events: Heparin group 10%, RCA group 0%, no anticoagulation group 0%].\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8451095/v1/6b5842cf9998e1a220f6807a.png"},{"id":102580687,"identity":"61cd1251-e555-4507-8ed3-767328c71fa3","added_by":"auto","created_at":"2026-02-13 09:12:49","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1517646,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8451095/v1/89f776b2-5f42-401b-9d19-424efbb7c65a.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Regional Citrate Anticoagulation Compared With Systemic Heparin and No Anticoagulation for Continuous Renal Replacement Therapy Circuit Patency in Critically Ill Adults: A Prospective Multicenter Observational Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAcute kidney injury stands as a major complication which affects intensive care units across the world because it produces significant impact on patient outcomes and medical resource utilization [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The condition known as acute kidney injury meets RIFLE criteria for rapid renal function decline through elevated serum creatinine levels and decreased glomerular filtration rates and reduced urine production [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe preferred treatment for hemodynamically unstable patients with severe AKI involves continuous renal replacement therapy because it provides gentle and sustained management of fluid overload, electrolyte imbalances and uremic toxin accumulation [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe success of CRRT treatment in clinical settings depends on keeping the extracorporeal circuit patent which requires proper anticoagulation methods to prevent thrombotic blockages but also needs to reduce the risk of bleeding complications [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe selection of appropriate anticoagulation methods for patients remains a challenging problem in critical care because it requires finding the right balance between preventing blood clots and controlling bleeding risks [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe use of regional citrate anticoagulation has become more popular as a substitute for traditional heparin-based systemic anticoagulation methods [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe extracorporeal circuit receives calcium ion chelation from citrate which creates localized anticoagulation effects that the body reverses through calcium replacement mechanisms when the blood returns to the systemic circulation [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The method supposedly maintains circuit patency while removing all anticoagulant effects from the bloodstream. The implementation of citrate protocols faces challenges because of their complicated nature and metabolic risks which prevent their adoption in various clinical facilities [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSystemic heparin anticoagulation continues to be recognized as the most well-known method as it provides an easy implementation process in addition to extensive clinical experience [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. However, the bleeding risks from systemic anticoagulation create major clinical problems for critically ill patients especially patients with multiple hemorrhagic risk factors like thrombocytopenia, coagulopathy or recent surgical procedures [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThere was a growing interest in anticoagulation-free CRRT to reduce bleeding complications, but it might reduce the treatment's performance, circuit longevity and treatment efficiency [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. This strategy relies on optimizing blood flow rates, circuit design changes and enhanced monitoring systems to reduce clotting events for patients with increased bleeding risk [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. This strategy has been studied extensively but there are no direct comparative studies to determine its effectiveness in relation to other circuit anticoagulation strategies [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe present study aimed to establish a comprehensive comparison between regional citrate anticoagulation, systemic heparin anticoagulation and anticoagulation-free CRRT regarding their effectiveness, safety and cost-effectiveness for critically ill patients undergoing renal replacement therapy [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e"},{"header":"Experimental Methods and Design","content":"\u003cp\u003eThis prospective, comparative observational study was conducted across two tertiary centers. The research analyzed intensive care unit care throughout a 24-month time span which began in April 2022 through March 2024. The study was conducted at the Critical Care Department, Faculty of Medicine, Cairo University (Kasr Al Ainy), Cairo, Egypt, and the Critical Care Department, King Fahad Military Medical Complex, Dhahran, Saudi Arabia. The protocol was approved by the Research Ethics Committee, Faculty of Medicine, Cairo University (Kasr Al Ainy), Cairo, Egypt, and by the Institutional Review Board, King Fahad Military Medical Complex, Dhahran, Saudi Arabia (ethical approval number: 2024-024), and the research was carried out in accordance with the approved protocol and the ethical standards of these committees, the Declaration of Helsinki, and applicable local regulations. Written informed consent was obtained from all enrolled patients and/or their legally authorized representatives prior to participation.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient Selection\u003c/h2\u003e \u003cp\u003eAdult patients (\u0026ge;\u0026thinsp;18 years) who needed continuous renal replacement therapy (CRRT) for acute kidney injury were considered eligible for enrollment.\u003c/p\u003e \u003cp\u003eAKI diagnosis was established according to RIFLE criteria, requiring either serum creatinine elevation of 1.5 times baseline values or urine output reduction below 0.5 mL/kg/hour for six consecutive hours. The research study excluded participants who already suffered from chronic kidney disease requiring dialysis, pregnancy, contraindications to citrate anticoagulation, severe hepatic dysfunction, shock requiring high-dose vasopressor support, or life expectancy less than 24 hours as determined by attending physicians.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy Groups and Interventions\u003c/h3\u003e\n\u003cp\u003eThe study population was systematically divided into three equal groups of 50 patients each based upon the anticoagulation strategy employed. Group assignment was determined by treating intensivists\u0026rsquo; clinical judgment considering individual patient factors. The assessment process includes evaluating bleeding risk, hemodynamic stability as well as following institutional protocols. The regional citrate anticoagulation group used continuous citrate infusion as their anticoagulation method. The study used systematic calcium replacement and complete metabolic monitoring protocols. Citrate was administered at initial rates of 2.5-4.0 mmol/L of blood flow, with calcium replacement. The treatment needs distinct infusion lines to administer replacement solutions which help sustain ionized calcium levels between 1.0-1.3 mmol/L.\u003c/p\u003e \u003cp\u003eThe systemic heparin anticoagulation group received unfractionated heparin with activated partial thromboplastin time monitoring using systematic dose modification protocols. Initial heparin bolus doses of 10\u0026ndash;20 units/kg were administered, followed by continuous infusions of 5\u0026ndash;15 units/kg/hour with target aPTT values of 45\u0026ndash;60 seconds. The anticoagulation-free group underwent CRRT treatment without any anticoagulant agents using optimized blood flow rates exceeding 150 mL/minute and frequent circuit monitoring protocols.\u003c/p\u003e\n\u003ch3\u003eCRRT Protocols\u003c/h3\u003e\n\u003cp\u003eAll patients received continuous venovenous hemofiltration or hemodiafiltration utilizing standardized protocols across both participating centers. Circuit configuration included double-lumen central venous catheters placed in internal jugular or femoral veins, with blood flow rates maintained between 150\u0026ndash;200 mL/minute and replacement fluid rates between 20-30mL/kg/hour. The treatment plan was adjusted according to the individual requirements of each patient and tailored to correct electrolyte imbalances as well as maintaining acid-base homeostasis.\u003c/p\u003e\n\u003ch3\u003eOutcome Measures\u003c/h3\u003e\n\u003cp\u003eThe study used circuit performance parameters as its primary outcome measures and tracked circuit clotting events and circuit life span in hours from the circuit initiation to termination.\u003c/p\u003e \u003cp\u003eSecondary outcomes included the safety parameters consist of bleeding complications and metabolic disturbances and treatment-related adverse events. The economic evaluation used direct costs associated with circuit replacement, anticoagulant medications, monitoring requirements, and nursing time during the initial 72 hours of therapy.\u003c/p\u003e\n\u003ch3\u003eData Collection and Statistical Analysis\u003c/h3\u003e\n\u003cp\u003eThe study obtained full data by using demographic information together with illness severity scores utilizing APACHE II and SOFA scoring systems, laboratory parameters, hemodynamic variables, and detailed treatment characteristics. Circuit performance was continuously monitored while maintaining standardized records of clotting events and filter pressures and reasons for circuit termination. Bleeding events were classified according to established criteria, with major bleeding defined as life-threatening hemorrhage requiring blood transfusion or surgical intervention.\u003c/p\u003e \u003cp\u003eStatistical analysis applied appropriate parametric and non-parametric tests depending upon data distribution characteristics. Continuous variables were expressed as means with standard deviations or medians with interquartile ranges as appropriate. Categorical variables were presented as frequencies and percentages. Group comparisons utilized analysis of variance for continuous variables and chi-square tests for categorical variables. Statistical significance was established at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, with all analyses performed using standard statistical software packages.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe study included 150 critically ill patients who needed continuous renal replacement therapy and were distributed evenly between the three anticoagulation methods. The three groups showed comparable baseline demographic and clinical characteristics. The mean age was 65.04\u0026thinsp;\u0026plusmn;\u0026thinsp;16.2 years for heparin patients, 71.06\u0026thinsp;\u0026plusmn;\u0026thinsp;8.9 years for citrate patients, and 68.7\u0026thinsp;\u0026plusmn;\u0026thinsp;14.9 years for patients without anticoagulation (p\u0026thinsp;=\u0026thinsp;0.09). The APACHE II scores used to evaluate illness severity showed no group differences with mean scores of 28.94\u0026thinsp;\u0026plusmn;\u0026thinsp;4.54 for citrate patients, 27.64\u0026thinsp;\u0026plusmn;\u0026thinsp;4.75 for heparin patients and 27.76\u0026thinsp;\u0026plusmn;\u0026thinsp;5.86 for patients without anticoagulation (p\u0026thinsp;=\u0026thinsp;0.37) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\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\u003eBasic characteristics of the study population\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHeparin Group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRCA Group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo anticoagulation\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years) Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e65.04\u0026thinsp;\u0026plusmn;\u0026thinsp;16.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e71.06\u0026thinsp;\u0026plusmn;\u0026thinsp;8.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e68.7\u0026thinsp;\u0026plusmn;\u0026thinsp;14.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAPACHE II score Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27.64\u0026thinsp;\u0026plusmn;\u0026thinsp;4.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28.94\u0026thinsp;\u0026plusmn;\u0026thinsp;4.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27.76\u0026thinsp;\u0026plusmn;\u0026thinsp;5.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.37\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean SOFA score Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.88\u0026thinsp;\u0026plusmn;\u0026thinsp;6.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.28\u0026thinsp;\u0026plusmn;\u0026thinsp;2.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11.56\u0026thinsp;\u0026plusmn;\u0026thinsp;2.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.731\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdmission diagnoses (Most common was sepsis)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45 (90%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e44 (88%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e46 (92%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCause of AKI (Most common was sepsis)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45 (90%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e44 (88%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e45 (90%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.932\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVasopressors requirements\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35 (70%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35 (70%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e37 (74%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.877\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eCircuit Performance Analysis\u003c/h3\u003e\n\u003cp\u003eThe study consumed a total of 400 CRRT circuits (filters): 108 circuits in the regional citrate anticoagulation group, 131 circuits in the heparin group, and 161 circuits in the no anticoagulation group. Total dialysis hours were 6760 hours: 2700 hours in the regional citrate anticoagulation group, 3000 hours in the heparin group, and 3760 hours in the no anticoagulation group.\u003c/p\u003e \u003cp\u003eThe evaluation of circuit performance showed that regional citrate anticoagulation provided better protection against circuit clotting. The number of clotted circuits per patient was lower for citrate anticoagulation compared with patients without anticoagulation (0.58\u0026thinsp;\u0026plusmn;\u0026thinsp;1.4 versus 1.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4, p\u0026thinsp;=\u0026thinsp;0.03). The heparin group showed an intermediate performance in terms of circuit clotting with 0.86\u0026thinsp;\u0026plusmn;\u0026thinsp;1.4 clotted circuits per patient (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The circuit life span showed a positive trend toward longer circuit duration for citrate anticoagulation at 26.4\u0026thinsp;\u0026plusmn;\u0026thinsp;20.5 hours but this did not reach statistical significance when compared to heparin at 20.6\u0026thinsp;\u0026plusmn;\u0026thinsp;18.6 hours and no anticoagulation at 16\u0026thinsp;\u0026plusmn;\u0026thinsp;16.3 hours (p\u0026thinsp;=\u0026thinsp;0.23) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDistribution of number of clotted circuits between the studied groups\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCitrate Group (N\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHeparin Group (N\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo anticoagulation\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTest\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of clotted circuits (per patient)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eKWF\u0026thinsp;=\u0026thinsp;6.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.03*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (circuits per patient)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e0.58\u0026thinsp;\u0026plusmn;\u0026thinsp;1.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e0.86\u0026thinsp;\u0026plusmn;\u0026thinsp;1.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e1.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003ePairwise comparisons: p (citrate vs heparin)\u0026thinsp;=\u0026thinsp;0.72; p (citrate vs nil)\u0026thinsp;=\u0026thinsp;0.03; p (nil vs heparin)\u0026thinsp;=\u0026thinsp;0.30. KWF: Kruskal-Wallis ANOVA.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDistribution of average circuit lifespan between the studied groups\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCitrate Group (N\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHeparin Group (N\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo anticoagulation\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTest\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of patients eligible for CLS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (hours)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26.4\u0026thinsp;\u0026plusmn;\u0026thinsp;20.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20.6\u0026thinsp;\u0026plusmn;\u0026thinsp;18.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16\u0026thinsp;\u0026plusmn;\u0026thinsp;16.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003ePairwise comparisons: p (citrate vs heparin)\u0026thinsp;=\u0026thinsp;0.64; p (citrate vs nil)\u0026thinsp;=\u0026thinsp;0.21; p (nil vs heparin)\u0026thinsp;=\u0026thinsp;0.68.\u003c/p\u003e \u003cp\u003eThe relationship between circuit clotting events and metabolic acidosis showed significant clinical correlations. Both anticoagulation-free and heparin groups showed a strong positive relationship between the number of clotted circuits and the development of metabolic acidosis (r\u0026thinsp;=\u0026thinsp;0.908, p\u0026thinsp;=\u0026thinsp;0.001) and (r\u0026thinsp;=\u0026thinsp;0.94, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) respectively as shown in Fig.\u0026nbsp;1, which indicates that anticoagulation methods affect both circuit performance and metabolic stability (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cb\u003eFigure\u0026nbsp;1.\u003c/b\u003e Correlation Between Circuit Clotting and Metabolic Acidosis with scatter plot demonstrating positive correlation in heparin and no anticoagulation groups.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDistribution of incidence of complications between studied groups\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComplication\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCitrate Group (N\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHeparin Group (N\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo anticoagulation\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTest\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncidence of complication\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44 (88%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27 (54%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e35 (70%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIonized hypocalcemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37 (74%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrading severity of hypocalcemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1 to 0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (42%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0.8 to 0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0.7 to 0.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLess than 0.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECG changes mostly related to hypocalcemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCitrate toxicity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (16%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypotension leads to interruption of dialysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (28%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (10%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14 (28%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncidence of thrombocytopenia in general\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (26%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (32%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21 (42%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThrombocytopenia with intermediate to high probability in HIT score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e20.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMild thrombocytopenia/low probability HIT score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBleeding\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (10%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetabolic acidosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (22%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (10%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (26%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.108\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBase deficit severity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e-2 to -5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e17.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e-5 to -10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (10%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (18%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLess than \u0026minus;\u0026thinsp;10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetabolic alkalosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (24%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBase excess severity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2 to 5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5 to 10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (16%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (10%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMore than 10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypernatremia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (18%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.31\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypothermia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (26%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (22%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14 (28%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.493\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.78\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\u003eTest statistics: chi-square test or Kruskal-Wallis ANOVA as appropriate.\u003c/p\u003e\u003ch2\u003eSafety Profile Assessment\u003c/h2\u003e\n\u003cp\u003eThe safety analysis showed that each anticoagulation approach had its own set of unique complications. The heparin group experienced more bleeding complications which affected 10% of patients (p = 0.005 compared to other groups) as shown in Fig. 2. The bleeding incidents consisted of gastrointestinal, surgical site and intracranial bleeding and all cases needed blood transfusions, while two cases required surgical intervention. The complete elimination of bleeding risk in both citrate and anticoagulation-free groups provides a major safety benefit to patients who have an increased risk of bleeding.\u003c/p\u003e\n\u003cp\u003eFig. 2. Shows distribution of bleeding between studied groups with bar chart showing bleeding events: Heparin group 10%, RCA group 0%, no anticoagulation group 0%].\u003c/p\u003e\n\u003cp\u003eThe implementation of regional citrate anticoagulation resulted in particular metabolic concerns that needed careful monitoring. The incidence of ionized hypocalcemia reached 74% in patients who received citrate (p \u0026lt; 0.001 compared to other groups) requiring ongoing calcium supplementation and regular laboratory tests. Also citrate accumulation with elevated total-to-ionized calcium ratios above 2.5 occurred in 16% of citrate patients which needed temporary treatment modifications. Additionally, metabolic alkalosis occurred in 24% of citrate group compared to 12% in the heparin group and 8% in the anticoagulation-free group (p = 0.06) (Table 5).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 5. Comparison between cases with and without metabolic alkalosis among citrate group regarding APACHE and SOFA score\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCases with Metabolic Alkalosis (N=12)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCases without Metabolic Alkalosis (N=38)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTest\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003eAPACHE score (Mean \u0026plusmn; SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e27.8\u0026plusmn;4.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e29.2\u0026plusmn;4.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003eT = -0.96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e0.33\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003eSOFA score (Mean \u0026plusmn; SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e10.9\u0026plusmn;2.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e11.4\u0026plusmn;2.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003eT = 0.53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e0.59\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003ch2\u003eThrombocytopenia and Hematologic Complications\u003c/h2\u003e\n\u003cp\u003eThe treatment groups developed different thrombocytopenia patterns with heparin-induced thrombocytopenia emerged as a specific adverse effect of heparin anticoagulation. The study revealed that heparin-treated patients developed thrombocytopenia with HIT scores ranging from intermediate to high in 20% of cases and low probability scores in 12% of patients with mild thrombocytopenia. This complication was completely absent in both regional citrate and anticoagulation-free groups, highlighting another safety benefit of heparin-free anticoagulation.\u003c/p\u003e\n\u003ch2\u003eEconomic Analysis\u003c/h2\u003e\n\u003cp\u003eThe first 72 hours of anticoagulation therapy showed major economic variations between different treatment methods. The use of regional citrate anticoagulation resulted in major cost reductions of $200\u0026plusmn;397 compared to anticoagulation-free CRRT which cost $320\u0026plusmn;418 (p = 0.006). The main cost reduction in regional citrate anticoagulation stemmed from decreased circuit replacement needs and corresponding nursing care expenses. The heparin treatment group maintained costs between the two other methods at $265\u0026plusmn;385 but did not include potential expenses related to bleeding complications which would elevate overall treatment expenses.\u003c/p\u003e\n\u003ch2\u003eTreatment Interruptions and Complications\u003c/h2\u003e\n\u003cp\u003eThe three groups showed equivalent rates of hypotension-related treatment interruptions which affected 28% of citrate patients and 20% of heparin patients and 28% of anticoagulation-free patients (p = 0.57). These interruptions were typically related to hemodynamic instability rather than anticoagulation-related issues, suggesting that underlying patient condition was more important than anticoagulation methods for maintaining treatment continuity.\u003c/p\u003e\n\u003cp\u003eThe severity of illness scores did not differ between patients who developed metabolic alkalosis in the citrate group or not. The APACHE II scores showed no significant difference between alkalotic patients at 27.8\u0026plusmn;4.7 and non-alkalotic patients at 29.2\u0026plusmn;4.4 (p = 0.33). The SOFA scores between the two groups showed no significant difference at 10.9\u0026plusmn;2.5 for alkalotic patients and 11.4\u0026plusmn;2.7 for non-alkalotic patients (p = 0.59). The research shows that metabolic alkalosis develops based on citrate processing rather than patient characteristics at the beginning.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe findings from this multicenter prospective study provide valuable insights into the comparative effectiveness and safety profiles of different circuit anticoagulation models for continuous renal replacement therapy (CRRT) in critically ill patients. The study reaveled that regional citrate anticoagulation provides better circuit performance and eliminates bleeding risks which makes it suitable for first-line use in appropriately selected cases [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eCircuit Performance and Clinical Implications\u003c/h2\u003e \u003cp\u003eThe reduced number of circuit clotting events observed with citrate anticoagulation carries important clinical implications which go beyond the circuit\u0026rsquo;s life span. The need for frequent circuit replacements interrupt treatment delivery and requires additional nursing work while potentially leading to insufficient solute clearance and fluid removal. The strong relationship between circuit clotting and metabolic acidosis development exists in both heparin-treated and anticoagulation-free groups which indicates that preserving circuit patency remains essential for reaching treatment goals and preventing additional complications [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe clinical importance of this finding remains substantial even though the trend toward longer circuit life span with citrate anticoagulation did not reach statistical significance. The diverse range of circuit durations exists because of the hetergeneous nature of critically ill patients and multiple factors influencing circuit patency beyond the choice of anticoagulation method [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The combination of patient hemodynamics, vascular access quality and coagulation status variables affects circuit performance which potentially masking the true effect of anticoagulation interventions.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eSafety Considerations and Bleeding Risk\u003c/h2\u003e \u003cp\u003eThe absence of bleeding complications in the citrate group stands as the most important clinical finding from this this study [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The fear of bleeding complications with anticoagulation therapy during CRRT drives treatment discontinuation and requires blood transfusions which in turn increases patient mortality risk. The 10% bleeding incidence in the heparin group matches previous research findings which demonstrates the importance of this safety concern [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHowever, the metabolic complications linked to citrate anticoagulation therapy need proper evaluation and cannot be ignored [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. The high rates of ionized hypocalcemia (74%) and citrate accumulation (16%) require specific protocols and trained nursing staff and regular laboratory tests for proper management. These requirements restrict its use in facilities which do not have suitable infrastructure or experienced clinical staff. The development of metabolic alkalosis in 24% of citrate patients further highlights the complexity of managing this anticoagulation strategy.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eEconomic Implications and Healthcare Resource Utilization\u003c/h2\u003e \u003cp\u003eThe healthcare resource benefits of citrate anticoagulation make it an attractive choice because of its economic advantages [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The reduced need for circuit replacements leads to substantial cost reductions which become essential for healthcare facilities operating with limited financial resources. However, the economic benefits of citrate protocols are partially reduced by the need for additional monitoring and specialized training for staff members [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe study shows that anticoagulation-free CRRT presents itself as a suitable treatment choice for patients at extremely raised bleeding risks [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. While circuit performance was inferior to citrate anticoagulation, the method provides an attractive solution for particular medical cases because of absence of bleeding and metabolic complications. However, the higher circuit replacement costs associated with this method must be weighed against potential expenses and complications that result from bleeding events.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eMetabolic Considerations and Patient Selection\u003c/h2\u003e \u003cp\u003eThe study shows that circuit clotting, and metabolic acidosis occur together in patients who do not receive anticoagulation therapy which indicates that frequent interruption of treatment can compromise acid-base management [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. This finding has important implications for patient selection, as those with severe metabolic acidosis may benefit from more aggressive anticoagulation strategies to ensure continuous treatment delivery.\u003c/p\u003e \u003cp\u003eThe absence of relationship between initial disease severity and metabolic alkalosis occurrence in citrate group demonstrates that this complication is primarily related to citrate metabolism rather than patient-specific factors [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. The results confirm that healthcare providers should use standardized monitoring protocols for all patients regardless of their baseline health status.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eStudy Limitations and Future Directions\u003c/h2\u003e \u003cp\u003eThe study has several limitations which need careful consideration. The non-randomized study design creates selection bias because doctors determined anticoagulation strategy by clinical judgment instead of using random selection methods [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. While the method used to determine anticoagulation strategy followed real-world clinical practice but might have produced systematic variations between groups which affected study results. The relatively moderate sample size may have limited statistical power to detect differences in some outcomes, particularly circuit life span where trends were observed without achieving statistical significance.\u003c/p\u003e \u003cp\u003e The multicenter study design improved external validity but potentially brought different treatment approaches between participating centers. The standardized protocols used in this study minimized protocol variations between centers and the uniform results from different sites confirm the study's reliable findings.\u003c/p\u003e \u003cp\u003eResearchers should create predictive models which help doctors select anticoagulation strategies through patient-specific risk factor analysis and individual characteristics assessment [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eResearch studies should perform cost-effectiveness evaluations by analyzing long-term outcomes and quality of life to achieve complete economic assessments. The creation of easy-to-use citrate protocols which preserve effectiveness while decreasing monitoring needs could expand the applicability of this anticoagulation strategy [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis prospective multicenter observational study demonstrates that regional citrate anticoagulation (RCA) provides better circuit performance and lower costs than heparin anticoagulation and anticoagulation-free approaches for critically ill patients undergoing continuous renal replacement therapy. The complete absence of bleeding risk during regional citrate anticoagulation provides substantial safety benefits to patients at high bleeding risks. However, the use of citrate therapy requires careful patient selection, specialized protocols, and vigilant monitoring capabilities because of its metabolic complications.\u003c/p\u003e \u003cp\u003eThe two treatment options of regional citrate anticoagulation and anticoagulation-free CRRT provide safe alternatives to systemic heparinization for patients who face a high risk of bleeding. The decision between these strategies depends on individual patient factors and institutional resources and economic considerations. Centers planning to implement regional citrate anticoagulation must ensure proper training programs, monitoring systems and protocol adherence to achieve maximum benefits while reducing complications.\u003c/p\u003e \u003cp\u003eHealthcare organizations should invest in citrate anticoagulation infrastructure and training because its cost-effectiveness and safety benefits make it an attractive choice for system-wide implementation.\u003c/p\u003e \u003cp\u003eFuture investigations should explore the development of point-of-care monitoring technologies and simplified protocols that could facilitate broader adoption of citrate anticoagulation across diverse clinical settings.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAuthor Contributions\u003c/p\u003e\n\u003cp\u003eSG (Sayed Gaber), KAM (Kamel Abdul-Aziz Mohammed), MAF (Mohammed Amin Fakher), MSAA (Mohsen Salah Abd El Azeem), KS (Khalid Sewify), AF (Abdelraouf Fahmy), AAS (Abdul-Aziz AL shaer), and WIKH (Walid Ibrahim Khalil Hashish) contributed as follows (CRediT taxonomy):\u003c/p\u003e\n\u003cp\u003eConceptualization: SG, KAM, KS, WIKH\u003c/p\u003e\n\u003cp\u003eMethodology: SG, KAM, MAF, MSAA, KS, WIKH\u003c/p\u003e\n\u003cp\u003eInvestigation / Patient recruitment and data acquisition: SG, KAM, MAF, MSAA, KS, AF, AAS, WIKH\u003c/p\u003e\n\u003cp\u003eData curation: MAF, MSAA, AF\u003c/p\u003e\n\u003cp\u003eFormal analysis: MAF, KAM, KS\u003c/p\u003e\n\u003cp\u003eResources / clinical oversight at participating ICUs: SG, KS, WIKH\u003c/p\u003e\n\u003cp\u003eWriting \u0026ndash; original draft: SG, MAF\u003c/p\u003e\n\u003cp\u003eWriting \u0026ndash; review and editing: SG, KAM, MAF, MSAA, KS, AF, AAS, WIKH\u003c/p\u003e\n\u003cp\u003eSupervision: KS, WIKH\u003c/p\u003e\n\u003cp\u003eProject administration: SG, KS, WIKH\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003eKS and WIKH had full access to the data and take responsibility for the integrity of the work as a whole.\u003c/p\u003e\n\u003cp\u003eEthics Approval and Consent to Participate\u003c/p\u003e\n\u003cp\u003eThe study protocol was approved by the Research Ethics Committee, Faculty of Medicine, Cairo University (Kasr Al Ainy), Cairo, Egypt, and by the Institutional Review Board, King Fahad Military Medical Complex, Dhahran, Saudi Arabia (ethical approval number: 2024-024), in accordance with the Declaration of Helsinki and applicable local regulations. Informed consent to participate was obtained from all enrolled patients and/or their legally authorized representatives prior to inclusion in the study. Clinical trial number: not applicable.\u003c/p\u003e\n\u003cp\u003eConsent for Publication\u003c/p\u003e\n\u003cp\u003eNot applicable. This manuscript does not contain any individual person\u0026rsquo;s identifiable data in any form (including individual details, images, or videos).\u003c/p\u003e\n\u003cp\u003eAvailability of Data and Materials\u003c/p\u003e\n\u003cp\u003eThe data supporting the conclusions of this article are included within the article and its references. Additional data are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003eAcknowledgment\u003c/p\u003e\n\u003cp\u003eThe authors thank the nursing staff of the Critical Care Departments at both participating centers for their excellent multidisciplinary patient care. We acknowledge the collaborative care teams that contributed to the successful conduct of this study.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003eDisclosure Statement (Conflict of Interest)\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Critical Care. 2004; 8(4): R204-12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, et al. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care. 2007;11(2):R31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTolwani A. Continuous renal-replacement therapy for acute kidney injury. N Engl J Med. 2012;367(26):2505\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJoannidis M, Oudemans-van Straaten HM. Clinical review: Patency of the circuit in continuous renal replacement therapy. Crit Care. 2007;11(4):218.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKidney Disease. Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Int Supplements. 2012;2:1\u0026ndash;138.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOudemans-van Straaten HM, Bosman RJ, van der Koopmans M, van der Wester JP, et al. Citrate anticoagulation for continuous venovenous hemofiltration. Crit Care Med. 2009;37(2):545\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHetzel GR, Schmitz M, Wissing H, Ries W, Schott G, Heering PJ, et al. Regional citrate versus systemic heparin for anticoagulation in critically ill patients on continuous venovenous haemofiltration: a prospective randomized multicentre trial. Nephrol Dialysis Transplantation. 2011;26(1):232\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMonchi M, Berghmans D, Ledoux D, Canivet JL, Dubois B, Damas P. Citrate vs. heparin for anticoagulation in continuous venovenous hemofiltration: a prospective randomized study. Intensive Care Med. 2004;30(2):260\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOudemans-van Straaten HM, Wester JP, de Pont AC, Schetz MR. Anticoagulation strategies in continuous renal replacement therapy: can the choice be evidence based? Intensive Care Med. 2006;32(2):188\u0026ndash;202.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchiffl H, Lang SM, Fischer R. Daily hemodialysis and the outcome of acute renal failure. N Engl J Med. 2002;346(5):305\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUchino S, Bellomo R, Morimatsu H, Morgera S, Schetz M, Tan I, et al. Continuous renal replacement therapy: a worldwide practice survey. Intensive Care Med. 2007;33(9):1563\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGattas DJ, Rajbhandari D, Bradford C, Buhr H, Lo S, Bellomo R. A randomized controlled trial of regional citrate versus regional heparin anticoagulation for continuous renal replacement therapy in critically ill adults. Crit Care Med. 2015;43(8):1622\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang Z, Hongying N. Efficacy and safety of regional citrate anticoagulation in critically ill patients undergoing continuous renal replacement therapy. Intensive Care Med. 2012;38(1):20\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStucker F, Ponte B, Tataw J, Martin PY, Wozniak H, Pugin J, et al. Efficacy and safety of citrate-based anticoagulation compared to heparin in patients with acute kidney injury requiring continuous renal replacement therapy: a randomized controlled trial. Crit Care. 2015;19:91.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchilder L, Nurmohamed SA, Bosch FH, Purmer IM, den Boer SS, Kleppe CG, et al. Citrate anticoagulation versus systemic heparinisation in continuous venovenous hemofiltration in critically ill patients with acute kidney injury: a multi-center randomized clinical trial. Crit Care. 2014;18(4):472.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSlowinski T, Morgera S, Joannidis M, Henneberg T, Stocker R, Helset E, et al. Safety and efficacy of regional citrate anticoagulation in continuous venovenous Citrate Anticoagulation in CRRT 22 hemodialysis in the presence of liver failure: the Liver Citrate Anticoagulation Threshold (L-CAT) observational study. Crit Care. 2015;19:349.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKhadzhynov D, Schelter C, Lieker I, Mika A, Staeck O, Neumayer HH, et al. Incidence and outcome of metabolic disarrangements consistent with citrate accumulation in critically ill patients undergoing continuous venovenous hemodialysis with regional citrate anticoagulation. J Crit Care. 2014;29(2):265\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLink A, Klingele M, Speer T, Rbah R, Poss J, Lerner-Gr\u0026auml;ber A, et al. Total-toionized calcium ratio predicts mortality in continuous renal replacement therapy with citrate anticoagulation in critically ill patients. Crit Care. 2012;16(3):R97.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchneider AG, Journois D, Rimmel\u0026eacute; T. Complications of regional citrate anticoagulation: accumulation or overload? Crit Care. 2017;21(1):281.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZarbock A, K\u0026uuml;llmar M, Kindgen-Milles D, Wempe C, Gerss J, Brandenburger T, 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\u0026ndash;39.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchwarzer P, Kuhn SO, Stracke S, Gr\u0026uuml;ndling M, Knigge S, Selleng S, et al. Discrepant post filter ionized calcium concentrations by common blood gas analyzers in CRRT using regional citrate anticoagulation. Crit Care. 2015;19:321.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePistolesi V, Morabito S, Di Mario F, Regolisti G, Cantarelli C, Fiaccadori E. A guide to understanding antimicrobial drug dosing in critically ill patients on renal replacement therapy. Antimicrob Agents Chemother. 2019;63(8):e00583\u0026ndash;19.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMariano F, Morselli M, Bergamo D, Hollo Z, Scella S, Maio M, et al. Blood and ultrafiltrate phosphate removal during different dialysis modalities. Contrib Nephrol. 2005;149:135\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDurao MS Jr, Monte JC, Batista MC, Oliveira M, Iizuka IJ, Santos BF, et al. The use of regional citrate anticoagulation for continuous venovenous hemodiafiltration in acute kidney injury. Crit Care Med. 2008;36(11):3024\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchneider AG, Bellomo R, Bagshaw SM, Glassford NJ, Lo S, Jun M, et al. Choice of renal replacement therapy modality and dialysis dependence after acute kidney injury: a systematic review and meta-analysis. Intensive Care Med. 2013;39(6):987\u0026ndash;97.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eProwle JR, Schneider A, Bellomo R. Clinical review: optimal dose of continuous renal replacement therapy in acute kidney injury. Crit Care. 2011;15(2):207.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eClaure-Del Granado R, Mehta RL. Fluid overload in the ICU: evaluation and management. BMC Nephrol. 2016;17(1):109.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOstermann M, Joannidis M, Pani A, Floris M, De Rosa S, Kellum JA, et al. Patient selection and timing of continuous renal replacement therapy. Blood Purif. 2016;42(3):224\u0026ndash;37.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHoste EA, Bagshaw SM, Bellomo R, Cely CM, Colman R, Cruz DN, et al. Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med. 2015;41(8):1411\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNeri M, Villa G, Garzotto F, Bagshaw S, Bellomo R, Cerda J, et al. Nomenclature for renal replacement therapy in acute kidney injury: basic principles. Crit Care. 2016;20(1):318.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Acute kidney injury, continuous renal replacement therapy, regional citrate anticoagulation, circuit life span, patient safety, cost-effectiveness, heparin","lastPublishedDoi":"10.21203/rs.3.rs-8451095/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8451095/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e The management of anticoagulation therapy during continuous renal replacement therapy (CRRT) presents a complex clinical challenge for patients who are critically ill. The selection of an optimal anticoagulation method for CRRT circuit maintenance remains a subject of ongoing critical care discussion because it needs to achieve both safety and effectiveness.\u003c/p\u003e\n\u003cp\u003eThe research evaluated the safety outcomes and treatment success rates between regional citrate anticoagulation (RCA) and systemic heparin anticoagulation (SHA) and anticoagulation-free CRRT for patients with acute kidney injury (AKI).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e A prospective comparative observational study was conducted over 24 months starting from April 2022 until March 2024. The study took place in two tertiary care intensive care units which operated in Egypt and Saudi Arabia during this multicenter study. The research included 150 adult patients with AKI who needed CRRT treatment which were distributed into three equal groups (n=50) based on their anticoagulation methods.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Primary endpoints focused on the incidence of circuit clotting and circuit life span (CLS). Secondary endpoints included bleeding complications, metabolic disturbances, and cost-effectiveness assessment. The study results showed that patients receiving regional citrate anticoagulation experienced fewer circuit clotting events (0.58±1.4) than patients who received heparin (0.86±1.4) or no anticoagulation (1.4±2.4) (p = 0.03). The circuit life span results indicated a positive trend for RCA at 26.4±20.5 hours but did not reach statistical significance when compared to heparin at 20.6±18.6 hours and no anticoagulation at 16±16.3 hours (p = 0.23). The heparin treatment group experienced all bleeding complications which affected 10% of patients while ionized hypocalcemia reported only within citrate group (p \u0026lt; 0.001).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e Despite both RCA and anticoagulation-free CRRT represent viable therapeutic options for patients at increased risk of bleeding, the use of regional citrate anticoagulation provides better circuit performance and lower costs than other methods while eliminating all bleeding risks.\u003c/p\u003e","manuscriptTitle":"Regional Citrate Anticoagulation Compared With Systemic Heparin and No Anticoagulation for Continuous Renal Replacement Therapy Circuit Patency in Critically Ill Adults: A Prospective Multicenter Observational Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-19 15:39:30","doi":"10.21203/rs.3.rs-8451095/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":"afde218d-c683-49e5-8dd6-e11734c33298","owner":[],"postedDate":"January 19th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-13T09:12:08+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-19 15:39:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8451095","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8451095","identity":"rs-8451095","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}