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    Low bicarbonate replacement fluid normalizes metabolic alkalosis during continuous veno-venous hemofiltration with regional citrate anticoagulation. Köglberger Paul,Klein Sebastian J,Lehner Georg Franz,Bellmann Romuald,Peer Andreas,Schwärzler Daniel,Joannidis Michael Annals of intensive care BACKGROUND:Metabolic alkalosis is a frequently occurring problem during continuous veno-venous hemofiltration (CVVH) with regional citrate anticoagulation (RCA). This study aimed to evaluate the effectiveness of switching from high to low bicarbonate (HCO) replacement fluid in alkalotic critically ill patients with acute kidney injury treated by CVVH and RCA. METHODS:A retrospective-comparative study design was applied. Patients who underwent CVVH with RCA in the ICU between 09/2016 and 11/2017 were evaluated. Data were available from the clinical routine. A switch of the replacement fluid Phoxilium (30 mmol/l HCO) to Biphozyl (22 mmol/l HCO) was performed as blood HCO concentration persisted ≥ 26 mmol/l despite adjustments of citrate dose and blood flow. Data were collected from 72 h before the switch of the replacement solutions until 72 h afterwards. RESULTS:Of 153 patients treated with CVVH during that period, 45 patients were switched from Phoxilium to Biphozyl. Forty-two patients (42 circuits) were available for statistical analysis. After switching the replacement fluid from Phoxilium to Biphozyl the serum HCO concentration decreased significantly from 27.7 mmol/l (IQR 26.9-28.9) to 25.8 mmol/l (IQR 24.6-27.7) within 24 h (p < 0.001). Base excess (BE) decreased significantly from 4.0 mmol/l (IQR 3.1-5.1) to 1.8 mmol/l (IQR 0.2-3.4) within 24 h (p < 0.001). HCO and BE concentration remained stable from 24 h till the end of observation at 72 h after the replacement fluid change (p = 0.225). pH and PaCO did not change significantly after the switch of the replacement fluid until 72 h. CONCLUSIONS:This retrospective analysis suggests that for patients developing refractory metabolic alkalosis during CVVH with RCA the use of Biphozyl reduces external HCO load and sustainably corrects intracorporeal HCO and BE concentrations. Future studies have to prove whether correcting metabolic alkalosis during CVVH with RCA in critically ill patients is of relevance in terms of clinical outcome. 10.1186/s13613-021-00850-4
    The possibility of using effluent ionized calcium to assess regional citrate anticoagulation in continuous renal replacement therapy. The International journal of artificial organs AIM:This study aimed to investigate whether effluent ionized calcium was an appropriate indicator to assess anticoagulant effect in continuous renal replacement therapy with regional citrate anticoagulation instead of post-filter ionized calcium. METHODS:In total, 48 paired samples of effluent fluid and post-filter blood were obtained from critically ill patients who required continuous renal replacement therapy. All samples were taken for ionized calcium measurements and were assessed by point-of-care analyzer. Correlations and agreements between two methods were performed by Pearson linear analysis and Bland-Altman analysis accordingly. RESULTS:The mean post-filter ionized calcium was 0.42 ± 0.12 mmol/L, and mean ionized calcium level of effluent fluid was 0.39 ± 0.11 mmol/L. The ionized calcium level of effluent fluid was significantly correlated with post-filter ionized calcium in all continuous renal replacement therapy patients. Bland-Altman analysis showed that the mean difference of ionized calcium between two sampling sites in all continuous renal replacement therapy patients was -0.02 mmol/L with 95% confidence interval ranging from -0.09 to 0.04 mmol/L. The significant correlations and agreements were also demonstrated in continuous veno-venous hemofiltration, continuous veno-venous hemodialysis, and continuous veno-venous hemodiafiltration modalities separately. CONCLUSION:The effluent ionized calcium could be a considerable substitute for post-filter ionized calcium to monitor the validity of regional citrate anticoagulation in continuous renal replacement therapy with less blood loss. 10.1177/0391398819894595
    Regional citrate anticoagulation for hemodialysis in the patient at high risk for bleeding. Pinnick R V,Wiegmann T B,Diederich D A The New England journal of medicine 10.1056/NEJM198302033080506
    Continuous venovenous hemodiafiltration (CVVHDF) with citrate anticoagulation in the treatment of a patient with acute renal failure, hypercalcemia, and thrombocytopenia. Srámek V,Novák I,Matĕjovic M,Rokyta R,Nalos M,Hora P,Pittrová H Intensive care medicine A 72-year-old patient with multiple myeloma was admitted to the intensive care unit because of hypercalcemic crisis and acute renal failure. After 7 days of comprehensive therapy including diuretics steroids, calcitonin, and intermittent hemodialysis (IHD) with low-calcium dialysate, calcium still reached high levels between IHD treatments and thrombocytopenia developed after chemotherapy. CVVHDF with calcium-free bicarbonate dialysate was started. Anticoagulation with 2.2% citrate was performed in order to chelate calcium, and thus treat the hypercalcemia, and to provide regional anticoagulation, and thus reduce the risk of bleeding due to thrombocytopenia. CVVHDF with citrate anticoagulation was continued for 6 days, and standard heparin anticoagulation was started when the hypercalcemia and thrombocytopenia abated. 10.1007/s001340050562
    Citrate versus heparin anticoagulation for continuous renal replacement therapy: an updated meta-analysis of RCTs. Bai Ming,Zhou Meilan,He Lijie,Ma Feng,Li Yangping,Yu Yan,Wang Pengbo,Li Li,Jing Rui,Zhao Lijuan,Sun Shiren Intensive care medicine PURPOSE:The purpose of this study was to evaluate the effect and safety of citrate versus heparin anticoagulation for continuous renal replacement therapy (CRRT) in critically ill patients by performing a meta-analysis of updated evidence. METHODS:Medline, Embase, and Cochrane databases were searched for eligible studies, and manual searches were also performed to identify additional trials. Randomized controlled trials (RCTs) assessing the effect of citrate versus heparin anticoagulation for CRRT were considered eligible for inclusion. RESULTS:Eleven RCTs with 992 patients and 1998 circuits met the inclusion criteria. Heparin was regionally delivered in two trials and systemically delivered in nine trials. Citrate for CRRT significantly reduced the risk of circuit loss compared to regional (HR 0.52, 95 % CI 0.35–0.77, P = 0.001) and systemic (HR 0.76, 95 % CI 0.59–0.98, P = 0.04) heparin. Citrate also reduced the incidence of filter failure (RR 0.70, 95 % CI 0.50–0.98, P = 0.04). The citrate group had a significantly lower bleeding risk than the systemic heparin group (RR 0.36, 95 % CI 0.21–0.60, P < 0.001) and a similar bleeding risk to the regional heparin group (RR 0.34, 95 % CI 0.01–8.24, P = 0.51). The incidences of heparin-induced thrombocytopenia (HIT) and hypocalcemia were increased in the heparin and citrate groups, respectively. No significant survival difference was observed between the groups. CONCLUSIONS:Given the lower risk of circuit loss, filter failure, bleeding, and HIT, regional citrate should be considered a better anticoagulation method than heparin for CRRT in critically ill patients without any contraindication. 10.1007/s00134-015-4099-0
    Citrate vs. heparin for anticoagulation in continuous venovenous hemofiltration: a prospective randomized study. Monchi Mehran,Berghmans Denis,Ledoux Didier,Canivet Jean-Luc,Dubois Bernard,Damas Pierre Intensive care medicine OBJECTIVE:To compare the efficacy and safety of adjusted-dose unfractionated heparin with that of regional citrate anticoagulation in intensive care patients treated by continuous venovenous hemofiltration (CVVH). DESIGN AND SETTING:Prospective, randomized, clinical trial in a 32-bed medical and surgical ICU in a university teaching hospital. PATIENTS:ICU patients with acute renal failure requiring continuous renal replacement therapy, without cirrhosis, severe coagulopathy, or known sensitivity to heparin. INTERVENTIONS:Before the first CVVH run patients were randomized to receive anticoagulation with heparin or trisodium citrate. Patients eligible for another CVVH run received the other study medication in a cross-over fashion until the fourth circuit. MEASUREMENTS AND RESULTS:Forty-nine circuits (hemofilters) were analyzed: 23 with heparin and 26 with citrate. The median lifetime of hemofilters was 70 h (interquartile range 44-140) with citrate anticoagulation and 40 h (17-48) with heparin (p=0.0007). One major bleeding occurred during heparin anticoagulation and one metabolic alkalosis (pH=7.60) was noted with citrate after a protocol violation. Transfusion rates (units of red cells per day of CVVH) were, respectively, 0.2 (0.0-0.4) with citrate and 1.0 (0.0-2.0) with heparin (p=0.0008). CONCLUSIONS:Regional citrate anticoagulation seems superior to heparin for the filter lifetime and transfusion requirements in ICU patients treated by continuous renal replacement therapy. 10.1007/s00134-003-2047-x
    The role of ionized calcium and magnesium in regional citrate anticoagulation and its impact on inflammatory parameters. Strobl Karin,Harm Stephan,Weber Viktoria,Hartmann Jens The International journal of artificial organs INTRODUCTION:Regional anticoagulation with citrate has been found to be superior to heparin in terms of biocompatibility, and numerous protocols for regional citrate anticoagulation have been published, while a consensus on the target concentration of ionized calcium (Ca2+) in the extracorporeal circuit has not been reached so far. METHODS:The aim of this in vitro study was to assess the impact of different citrate concentrations on coagulation as well as on complement activation and cytokine secretion and to investigate the impact of ionized magnesium (Mg2+) on these parameters. RESULTS:We found that citrate effectively reduced coagulation, complement activation, and cytokine secretion in a dose-dependent manner and that a target Ca2+ concentration of 0.2-0.25 mM was required for efficient anticoagulation. Mg2+ triggered complement activation as well as interleukin (IL)-1β secretion in lipopolysaccharide (LPS)-stimulated whole blood in a dose-dependent manner and independently of Ca2+. Additionally, it was found to reduce activated clotting time (ACT) in samples with low Ca2+ levels, but not at physiological Ca2+. CONCLUSIONS:Taken together, our data support the notion that regional citrate anticoagulation results in decreased release of inflammatory mediators in the extracorporeal circuit, requiring the depletion of both, Ca2+ and Mg2+. 10.5301/ijao.5000558
    A significant proportion of patients treated with citrate containing dialysate need additional anticoagulation. Stegmayr Bernd G,Jonsson Per,Mahmood Dana The International journal of artificial organs BACKGROUND:The blood membrane interaction induced during hemodialysis (HD) activates the coagulation system. To prevent clotting and to maintain dialyzer patency, an anticoagulant such as tinzaparin is used. To increase patency of the dialyzers and to reduce the risk of bleeding related to anticoagulation, citrate-containing dialysate has been introduced in Europe. 
 PURPOSE:The aim of this randomized, cross-over study was to investigate if citrate-containing dialysate was safe and efficient enough as the sole anticoagulation agent in chronic HD patients. 
 MATERIAL AND METHODS:In this clinical setting, 23 patients on chronic hemodialysis were randomized in a cross-over design using anticoagulation either by LMWH-tinzaparin or citrate (Cit) as dialysate 
(22 completed the study). The study included paired analyses of subjective patency, ionized calcium (iCa), urea reduction rate. 
During Cit-HD, the iCa was significantly more reduced with prolonged time. The lowest iCa measured was 0.96 mmol/l. The median iCa after 210 min of HD was 1.02 for Cit-Hd and 1.16 for standard tinzaparin-HD (p = 0.001). Patency of dialyzers was estimated as clear in 14%, stripes of clotted fibers in 36%, and a red filter in 32% of HD session. The addition of approximately 40% of the patients' usual dose of tinzaparin was given to 7 of the patients as a bolus. Four Cit-HD sessions had to be interrupted prematurely due to clotting. 
 CONCLUSION:A significant proportion of patients treated with citrate-containing dialysate need additional anticoagulation. 10.5301/ijao.5000172
    Evolution of Vascular Access and Anticoagulation. Honore Patrick M,Spapen Herbert D Contributions to nephrology Continuous renal replacement therapy (CRRT) is an important and widely used adjuvant treatment in critically ill patients. However, any CRRT protocol can be adhered to only when the technique is correctly installed and functioning properly. Within this context, an appropriate vascular access and a safe and effective circuit anticoagulation method are key requisites. The right internal jugular (RIJ) vein is the preferred route for insertion with the tip of the catheter placed in the right atrium. Both femoral veins offer a valuable alternative access, but catheters must be longer to avoid recirculation and circuit blood flow is lower as compared with that of the RIJ approach. The location of the catheter is not associated with differences in bacterial colonization/infection rate or filter/circuit lifespan. Adequate anticoagulation is imperative to avoid a system "shutdown" due to the early clotting of the filter. For a long time, unfractionated heparin (UFH) was the anticoagulant of choice. UFH is associated with an increased bleeding risk and requires the use of high circuit blood flows. The introduction of regional citrate anticoagulation (RCA) created a paradigm change in CRRT anticoagulation. RCA can be applied safely in patients with increased bleeding risk and may enhance filter and circuit survival as compared with UFH. RCA requires close monitoring for potentially serious metabolic side effects. Future perspectives include improved catheter technology and development of novel citrate solutions with less severe metabolic impact. 10.1159/000485597
    Regional citrate anticoagulation for CRRT: Still hesitating? Schneider Antoine G,Joannes-Boyau Olivier Anaesthesia, critical care & pain medicine 10.1016/j.accpm.2021.100855
    [A survey of regional citrate anticoagulation for emergency continuous renal replacement therapy]. Cui Qinghong,Sun Feng,Liu Shuyuan,Xu Jun,Zhu Huadong,Yu Xuezhong Zhonghua wei zhong bing ji jiu yi xue OBJECTIVE:To investigate the status of regional citrate anticoagulation (RCA) in continuous renal replacement therapy (CRRT) in emergency department. METHODS:Participants of a national emergency conference from August 1st to August 4th in 2019 from hospitals of different levels in different regions were interviewed by online questionnaire to collect data about the current status and limitations of the application of RCA in emergency CRRT by convenient sampling. RESULTS:Totally 407 questionnaires were collected through internet, and the completeness of the answers was as high as 100%. Twenty-three responses with logic errors were excluded, and 384 questionnaires were finally retrieved, with an effective rate of 94.35%. Representatives from 29 provinces, autonomous regions and municipalities directly under the Central Government participated in the questionnaire survey, and the hospitals in which they worked were mainly class III grade A [70.31% (270/384)]. The survey showed that 61.46% (236/384) of the emergency departments could carry out CRRT independently. There were less than 10 CRRT cases per month in most emergency departments [52.87% (166/314)]. In the emergency departments where CRRT were carried out, heparin was a widely used and well-applied anticoagulant [82.17% (258/314)], and 199 emergency departments (63.38%) were proficient in RCA. In clinical practice, heparin [49.68% (156/314)] was preferred to RCA [25.80% (81/314)] and low molecular weight heparin [23.56% (74/384)]. In the emergency departments where RCA could be used skillfully, 4% sodium citrate was the main regional anticoagulant [68.34% (136/199)]. Anticoagulation protocol came from different sources, most of which were from nephrology or dialysis center (29.65%). Most departments could adjust the ionized calcium before the filter to the target safety level [0.9-1.2 mmol/L, 88.94% (177/199)], and adjust the ionized calcium after the filter to the target ideal anticoagulation level [0.2-0.4 mmol/L, 93.47% (186/199)] within 4 hours. The common complications that emergency physicians concerned were accumulation of citrate [58.29% (116/199)], metabolic alkalosis [54.77% (109/199)] and metabolic acidosis [37.19% (74/199)]. In 281 emergency departments that could not use RCA, there were kinds of factors that limited the use of citrate, such as higher cost than heparin (31.67%), unskilled personnel (21.00%), limited source of citrate (17.08%), concerns of complications (11.74%). At present, the substitution fluids used in clinical practice were mainly the commercial products (45.54%). In most cases, emergency CRRT filters had a life span of 12-23 hours (39.49%). CONCLUSIONS:The use of RCA in domestic emergency CRRT is low. Compared with the international peers, we are still lacking of adequate understanding of RCA. Therefore, it is necessary to develop an anticoagulation protocol of RCA for emergency departments in China, and promote training of CRRT. 10.3760/cma.j.cn121430-20200119-00138
    Bench-to-bedside review: Citrate for continuous renal replacement therapy, from science to practice. Oudemans-van Straaten Heleen M,Ostermann Marlies Critical care (London, England) To prevent clotting in the extracorporeal circuit during continuous renal replacement therapy (CRRT) anticoagulation is required. Heparin is still the most commonly used anticoagulant. However, heparins increase the risk of bleeding, especially in critically ill patients. Evidence has accumulated that regional anticoagulation of the CRRT circuit with citrate is feasible and safe. Compared to heparin, citrate anticoagulation reduces the risk of bleeding and requirement for blood products, not only in patients with coagulopathy, but also in those without. Metabolic complications are largely prevented by the use of a strict protocol, comprehensive training and integrated citrate software. Recent studies indicate that citrate can even be used in patients with significant liver disease provided that monitoring is intensified and the dose is carefully adjusted. Since the citric acid cycle is oxygen dependent, patients at greatest risk of accumulation seem to be those with persistent lactic acidosis due to poor tissue perfusion. The use of citrate may also be associated with less inflammation due to hypocalcemia-induced suppression of intracellular signaling at the membrane and avoidance of heparin, which may have proinflammatory properties. Whether these beneficial effects increase patient survival needs to be confirmed. However, other benefits are the reason that citrate should become the first choice anticoagulant for CRRT provided that its safe use can be guaranteed. 10.1186/cc11645
    [Advances in the application of regional citrate anticoagulation for continuous renal replacement therapy in patients with liver failure]. Ning Q Q,Meng Q H,Zhu Y K Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology Currently, continuous renal replacement therapy (CRRT) is one of the most important means of organ support methods in critical care medicine. Anticoagulation is an essential part of the treatment process due to its prolonged duration. Patients with liver failure often have coagulation dysfunction and heparin anticoagulant can increase the risk of bleeding, but without heparin anticoagulant, coagulation can easily occur. In addition, an increased volumetric load, hemodynamic instability, nursing workload and other problems are major issues. Therefore, regional citrate anticoagulation (RCA) is the main anticoagulant method for CRRT therapy in patients with liver failure. This article reviews the mechanism, indications, advantages and disadvantages of using RCA to CRRT in hepatic failure. 10.3760/cma.j.issn.1007-3418.2018.07.015
    Some metabolic issues should not be neglected when using citrate for continuous renal replacement therapy! Jacobs Rita,Honore Patrick M,Spapen Herbert D Critical care (London, England) 10.1186/s13054-015-0766-3
    Complications of regional citrate anticoagulation: accumulation or overload? Schneider Antoine G,Journois Didier,Rimmelé Thomas Critical care (London, England) Regional citrate anticoagulation (RCA) is now recommended over systemic heparin for continuous renal replacement therapy in patients without contraindications. Its use is likely to increase throughout the world. However, in the absence of citrate blood level monitoring, the diagnosis of citrate accumulation, the most feared complication of RCA, remains relatively complex. It is therefore commonly mistaken with other conditions. This review aims at providing clarifications on RCA-associated acid-base disturbances and their management at the bedside. In particular, the authors wish to propose a clear distinction between citrate accumulation and net citrate overload. 10.1186/s13054-017-1880-1
    Is Regional Citrate Anticoagulation the Future of Hemodialysis? Buturovic-Ponikvar Jadranka Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy Citrate has many characteristics of the ideal anticoagulant for hemodialysis. In addition to immediate and complete anticoagulation in the dialysis circuit, citrate has important effects beyond anticoagulation, mainly in reducing inflammatory response induced by hemodialysis. Citrate has already become the standard anticoagulant in acute kidney injury requiring continuous renal replacement therapy (CRRT), both for adults and children, with the citrate module being a part of modern CRRT monitors. Although the citrate module is not yet available for intermittent hemodialysis, precise infusion pumps, point-of-care ionometers and high citrate clearance from high flux dialyzers increase safety while reducing the risk of metabolic complications, both in adult and pediatric patients. Slovenia has a long tradition, high volume and expansion of citrate use in hemodialysis, including long-term citrate anticoagulation in selected patients. At the Department of Nephrology, University Medical Centre Ljubljana, more than 10 000 citrate procedures were performed in 2015. We believe that regional citrate anticoagulation may replace heparin as the main anticoagulant for intermittent hemodialysis in the not so distant future. 10.1111/1744-9987.12429
    [The study of anticoagulants selection in platelet-rich plasma preparation]. Hua Lei,Lai Gui,Zhenjun Liu,Guie Ma Zhonghua zheng xing wai ke za zhi = Zhonghua zhengxing waike zazhi = Chinese journal of plastic surgery OBJECTIVE:To investigate the effect of the anticoagulants on PRP quality, so as to clarify the appropriate anticoagulant used in PRP production. METHODS:The microstructure change of platelets collected via heparin, citrate, acid citrate dextrose (ACD) and citrate-theophylline-adenosine-dipyridamole ( CTAD) was observed by TEM following time course. The extent of spontaneous activation of platelets in four groups was detected by measuring sP-selectin in plasma. The TGF-β1 release amount of activated PRP of four groups was measured. RESULTS:CTAD is superior to other anticoagulants in maintaining the integrity of platelet structures for a long time and preventing platelet spontaneous activation. ACD slightly surpassed heparin and citrate in above two aspects. ACD-PRP and CTAD-PRP released significantly more TGF-β1 compared with heparin and citrate. CONCLUSIONS:The PRP quality and biological effects were strongly associated with the type of Anticoagulants. ACD and CTAD are optimal anticoagulants in PRP production for they can maintain platelet viability at a high level.
    Complications of Regional Citrate Anticoagulation for Continuous Renal Replacement Therapy: An Observational Study. Bianchi Nathan Axel,Altarelli Marco,Eckert Philippe,Schneider Antoine Guillaume Blood purification INTRODUCTION:Regional citrate anticoagulation (RCA) is the recommended anticoagulation modality for continuous renal replacement therapy (CRRT). RCA was associated with a low rate of complications in randomized controlled trials. However, little is known about the type and rate of complications in real life. We sought to describe complications associated with RCA in comparison with those associated with heparin anticoagulation. METHODS:In our institution, RCA has been the default anticoagulation modality for CRRT in all patients without contraindications since 2013. We have retrospectively reviewed all consecutive patients who received CRRT between January and December 2016 in our institution. For each CRRT session, we have assessed circuit duration, administered dose, as well as therapy-associated complications. Those parameters were compared according to whether the circuit was run in continuous veno-venous hemodialysis (CVVHD) mode with RCA or continuous veno-venous hemofiltration (CVVH) mode with heparin anticoagulation. RESULTS:We analyzed 691 CRRT sessions in 121 patients. Of those 400 (57.9%) were performed in CVVHD-RCA mode and 291 (42.1%) in CVVH-Heparin Mode. Compared with -CVVH-Heparin mode, CVVHD-RCA mode was associated with a longer circuit lifespan (median duration 54.9 interquartile range [IQR 44.6] vs. 15.3 h [IQR 22.4], p < 0.0001). It was associated with a higher rate of metabolic acidosis 77 (20.2%) vs. 18 (7.2%), (p < 0.0001), alkalosis 186 (48.7%) vs. 43 (17.1%), (p= 0.0001), and hypocalcemia 96 (25.07%) vs. 26 events (10.79%), p < 0.0001. However, the majority of these alterations were of benign or moderate severity. Only one possible citrate intoxication was observed. CONCLUSIONS:CVVHD-RCA was associated with a much longer circuit life but an increased rate of minor metabolic complications, in particular acid-base derangements. Some of these complications might have been prevented by therapy adaptation. Medical and nursing staff education is of major importance in the implementation of an RCA protocol. 10.1159/000506253
    Dialysis circuit clotting in critically ill patients with COVID-19 infection. Khoo Benjamin Zhi En,Lim Regina Shaoying,See Yong Pey,Yeo See Cheng BMC nephrology BACKGROUND:Coronavirus Disease 2019 (COVID-19) infection has been associated with a hypercoagulable state with increased reports of thrombotic events. Acute kidney injury requiring dialysis is common in critically ill patients and circuit clotting compromises efficacy of treatment. This study aims to analyze the circuit life and circuit clotting during continuous kidney replacement therapy (CKRT) and intermittent hemodialysis in patients with and without COVID-19. METHODS:This is a single-center, retrospective cohort study in critically ill patients undergoing CKRT or intermittent hemodialysis between 1 February 2020 to 22 May 2020. Patients in the intensive care unit (ICU) with COVID-19 infection and contemporary controls who tested negative were included. Co-primary outcomes were functional circuit life for patients on CKRT and all circuit clotting events for patients on CKRT and/or intermittent hemodialysis. RESULTS:Seventy CKRT circuits and 32 intermittent hemodialysis sessions for 12 COVID-19 cases and 22 CKRT circuits and 18 intermittent hemodialysis sessions for 15 controls were analyzed. CKRT circuit clotting was more common in the COVID-19 group compared to the control group (64% vs 36%, p = 0.02), despite higher anticoagulation use in the COVID-19 group (41% vs 14%, p = 0.02). Functional CKRT circuit life was similar in COVID-19 patients and controls (median 11 vs 12 h, p = 0.69). On Cox regression analysis, circuit clotting was similar with hazard ratio (HR) 1.90 [95% confidence interval (CI): 0.89-4.04]; however, clotting was increased in COVID-19 patients after adjustment for anticoagulation use (HR: 3.31 [95% CI 1.49-7.33]). In patients with COVID-19, CKRT circuits with anticoagulation had a longer circuit life compared to CKRT circuits without anticoagulation (median 22 versus 7 h respectively, p <  0.001). Circuit clotting was similar in both groups undergoing intermittent hemodialysis. CONCLUSION:Dialysis clotting amongst COVID-19 patients is increased despite more anticoagulation use and the hazard for clotting is greater especially after adjusting for anticoagulation use. Circuit life was suboptimal in COVID-19 patients on circuits without anticoagulation and therefore routine use of anticoagulation amongst COVID-19 patients should be considered whenever possible. 10.1186/s12882-021-02357-3
    Issues with heparin, and the role of citrate. Kossmann Robert J,Ahmad Suhail Nephrology news & issues
    Citrate 4% versus heparin and the reduction of thrombosis study (CHARTS). Macrae Jennifer M,Dojcinovic Ivana,Djurdjev Ognjenka,Jung Beverly,Shalansky Steven,Levin Adeera,Kiaii Mercedeh Clinical journal of the American Society of Nephrology : CJASN BACKGROUND AND OBJECTIVES:Citrate 4% has antithrombotic and antibacterial properties, which makes it a potentially superior alternative to heparin as an indwelling intraluminal locking agent. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS:Sixty-one prevalent hemodialysis (HD) patients dialyzing with a tunneled cuffed HD catheter were randomized in a pilot study to receive either heparin 5000 U/ml or citrate 4% as a locking agent after HD. The primary outcomes were the development of catheter dysfunction (defined as a blood pump speed <250 ml/min or the use of tissue plasminogen activator) and catheter-associated bacteremia. The secondary outcomes were the development of an exit-site infection or bleeding complications (either local or systemic). RESULTS:Citrate had comparable catheter dysfunction episodes to heparin (13/32 [41%] cases versus 12/29 [41%] cases, respectively). There were no differences in the development of catheter-associated bacteremia (2.2/1000 catheter days citrate versus 3.3/1000 catheter days heparin group; P = 0.607) or exit-site infection (2.2/1000 catheter days for both groups). CONCLUSIONS:The preliminary findings from our pilot study demonstrate that 4% citrate is effective in maintaining catheter patency and does not appear to have any increased incidence of infections. Because citrate is significantly cheaper and has a more favorable side effect profile than heparin, it can be considered a potentially better locking agent in HD catheters. 10.2215/CJN.01760407
    Citrate anticoagulation for continuous renal replacement therapy in the critically ill. Oudemans-van Straaten Heleen M Blood purification BACKGROUND:Heparins are used for circuit anticoagulation during continuous renal replacement therapy (CRRT). Because heparins cause systemic anticoagulation, they increase the risk of bleeding. Citrate provides regional anticoagulation. Since citrate is a buffer as well, its use has metabolic consequences. The preferential use of citrate therefore remains controversial. METHODS:A synthesis was performed of published studies comparing citrate to heparin for anticoagulation in CRRT with specific regard to feasibility, efficacy and safety. Search of the literature was made to explain the reported superiority of citrate. RESULTS:Citrate provides good metabolic control if and when a well-designed protocol is strictly followed. Randomized studies report similar or longer circuit survival with citrate compared to heparin and less bleeding. The largest randomized trial up to now found that citrate was better tolerated than heparin and improved patient and kidney survival, especially in patients after surgery, with sepsis, a high degree of organ failure or younger age. Both citrate and heparin interfere with inflammation. CONCLUSION:During critical illness, regional anticoagulation with citrate for CRRT seems superior to heparin anticoagulation concerning tolerance and safety, mainly due to less bleeding. Whether circuit survival is better depends on the modality. In addition, citrate seems to improve patient and kidney survival. This finding needs to be confirmed. Citrate seems to confer a specific benefit in severe organ failure and sepsis. To what extent citrate protects or heparin does harm in the setting of multiple organ failure needs to be unraveled. 10.1159/000245646
    Impact of experimental hypercalcemia on routine haemostasis testing. Lippi Giuseppe,Salvagno Gian Luca,Brocco Giorgio,Gelati Matteo,Danese Elisa,Favaloro Emmanuel J PloS one BACKGROUND:The blood to anticoagulant ratio is standardized according to the physiological calcium concentration in blood samples conventionally used for hemostasis testing. Specifically, one fixed volume of 0.109 mmol/L sodium citrate is added to 9 volumes of blood. Since little is known about the impact of hypercalcemia on the calcium-binding capacity of citrate, this study was planned to investigate the effect of experimental hypercalcemia on routine hemostasis testing. METHODS:Fifteen pooled citrated plasmas with matching lithium-heparin pooled plasma from patients with different values of prothrombin time (PT) were divided in three aliquots of 0.6mL each. The first paired aliquots of both citrate and lithium-heparin plasma were supplemented with 60μL of saline, the second paired aliquots with 30μL of saline and 30μL of calcium chloride and the third paired aliquots with 60μL of calcium chloride. Total and ionized calcium was measured in all aliquots of citrate and lithium-heparin plasma, whereas PT, activated partial thromboplastin time (APTT) and fibrinogen were measured in citrate plasma aliquots. RESULTS:Total calcium concentration gradually increased in both lithium-heparin and citrate plasma aliquots 2 and 3 compared to baseline aliquot 1. The concentration of ionized calcium also gradually increased in lithium-heparin plasma aliquots 2 and 3, whereas it remained immeasurable (i.e., <0.10 mmol/L) in all citrate plasma aliquots. No significant differences were observed for values of PT, APTT and fibrinogen in citrate plasma aliquots 2 and 3 compared to the baseline aliquot 1, with a mean bias was always comprised within the desirable quality specifications derived from biological variability data. CONCLUSION:Hypercalcemia, up to severe hypercalcemia does not generate significant bias in results of first-line coagulations tests, so that hypothetical consideration of adjusting citrate-blood ratio is unjustified in hypercalcemic patients. 10.1371/journal.pone.0175094
    Continuous Renal Replacement Therapy in Venovenous Extracorporeal Membrane Oxygenation: A Retrospective Study on Regional Citrate Anticoagulation. Giani Marco,Scaravilli Vittorio,Stefanini Flavia,Valsecchi Gabriele,Rona Roberto,Grasselli Giacomo,Bellani Giacomo,Pesenti Antonio M,Foti Giuseppe ASAIO journal (American Society for Artificial Internal Organs : 1992) Systemic infusion of unfractionated heparin (UFH) is the standard anticoagulation technique for continuous renal replacement therapy (CRRT) during extracorporeal membrane oxygenation (ECMO), but often fails to avoid CRRT circuit clotting. The aim of this study was to assess, in patients undergoing CRRT during venovenous ECMO (vv-ECMO), the efficacy and safety of adding regional citrate anticoagulation (RCA) for CRRT circuit anticoagulation (RCA + UFH group) compared with the sole systemic heparin anticoagulation (UFH group). We performed a retrospective chart review (2009-2018) of patients treated with CRRT during ECMO. We evaluated filter life span, rate of CRRT circuit clotting, and coagulation parameters. The incidence of citrate anticoagulation-related complications was recorded. Forty-eight consecutive adult patients underwent CRRT during vv-ECMO in the study period. The incidence of CRRT circuit clotting was lower in the RCA + UFH group (11% vs. 38% in the UFH group, p < 0.001). Log-rank survival analysis demonstrated longer circuit lifetime for RCA + UFH group. No complication ascribable to citrate anticoagulation was recorded. Regional citrate anticoagulation resulted a feasible, safe, and effective technique as additional anticoagulation for CRRT circuits during ECMO. Compared with systemic heparinization only, this technique allowed to reduce the rate of CRRT circuit clotting. 10.1097/MAT.0000000000001003
    Sustained low-efficiency dialysis with regional citrate anticoagulation in critically ill patients with COVID-19 associated AKI: A pilot study. Di Mario Francesca,Regolisti Giuseppe,Di Maria Alessio,Parmigiani Alice,Benigno Giuseppe Daniele,Picetti Edoardo,Barbagallo Maria,Greco Paolo,Maccari Caterina,Fiaccadori Enrico Journal of critical care Acute Kidney Injury (AKI) is a frequent complication in critically ill patients with Coronavirus disease 2019 (COVID-19), and it has been associated with worse clinical outcomes, especially when Kidney Replacement Therapy (KRT) is required. A condition of hypercoagulability has been frequently reported in COVID-19 patients, and this very fact may complicate KRT management. Sustained Low Efficiency Dialysis (SLED) is a hybrid dialysis modality increasingly used in critically ill patients since it allows to maintain acceptable hemodynamic stability and to overcome the increased clotting risk of the extracorporeal circuit, especially when Regional Citrate Anticoagulation (RCA) protocols are applied. Notably, given the mainly diffusive mechanism of solute transport, SLED is associated with lower stress on both hemofilter and blood cells as compared to convective KRT modalities. Finally, RCA, as compared with heparin-based protocols, does not further increase the already high hemorrhagic risk of patients with AKI. Based on these premises, we performed a pilot study on the clinical management of critically ill patients with COVID-19 associated AKI who underwent SLED with a simplified RCA protocol. Low circuit clotting rates were observed, as well as adequate KRT duration was achieved in most cases, without any relevant metabolic complication nor worsening of hemodynamic status. 10.1016/j.jcrc.2021.01.013
    Anticoagulation strategies in venovenous hemodialysis in critically ill patients: a five-year evaluation in a surgical intensive care unit. Sponholz Christoph,Bayer Ole,Kabisch Björn,Wurm Karin,Ebert Katharina,Bauer Michael,Kortgen Andreas TheScientificWorldJournal Renal failure is a common complication among critically ill patients. Timing, dosage, and mode of renal replacement (RRT) are under debate, but also anticoagulation strategies and vascular access interfere with dialysis success. We present a retrospective, five-year evaluation of patients requiring RRT on a multidisciplinary 50-bed surgical intensive care unit of a university hospital with special regard to anticoagulation strategies and vascular access. Anticoagulation was preferably performed with unfractionated heparin or regional citrate application (RAC). Bleeding and suspected HIT-II were most common causes for RAC. In CVVHD mode filter life span was significantly longer under RAC compared to heparin or other anticoagulation strategies (P=0.001). Femoral vascular access was associated with reduced filter life span (P=0.012), especially under heparin anticoagulation (P=0.015). Patients on RAC had higher rates of metabolic alkalosis (P=0.001), required more transfusions (P=0.045), and showed higher illness severity measured by SOFA scores (P=0.001). RRT with unfractionated heparin represented the most common anticoagulation strategy in this study population. However, patients with bleeding risk and severe organ dysfunction were more likely placed on RAC. Citrate provided longer filter life spans regardless of vascular access site. Attention has to be paid to metabolic disturbances. 10.1155/2014/808320
    Pharmacological interventions for preventing clotting of extracorporeal circuits during continuous renal replacement therapy. Tsujimoto Hiraku,Tsujimoto Yasushi,Nakata Yukihiko,Fujii Tomoko,Takahashi Sei,Akazawa Mai,Kataoka Yuki The Cochrane database of systematic reviews BACKGROUND:Acute kidney injury (AKI) is a major comorbidity in hospitalised patients. Patients with severe AKI require continuous renal replacement therapy (CRRT) when they are haemodynamically unstable. CRRT is prescribed assuming it is delivered over 24 hours. However, it is interrupted when the extracorporeal circuits clot and the replacement is required. The interruption may impair the solute clearance as it causes under dosing of CRRT. To prevent the circuit clotting, anticoagulation drugs are frequently used. OBJECTIVES:To assess the benefits and harms of pharmacological interventions for preventing clotting in the extracorporeal circuits during CRRT. SEARCH METHODS:We searched the Cochrane Kidney and Transplant Register of Studies up to 12 September 2019 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA:We selected randomised controlled trials (RCTs or cluster RCTs) and quasi-RCTs of pharmacological interventions to prevent clotting of extracorporeal circuits during CRRT. DATA COLLECTION AND ANALYSIS:Data were abstracted and assessed independently by two authors. Dichotomous outcomes were calculated as risk ratio (RR) with 95% confidence intervals (CI). The primary review outcomes were major bleeding, successful prevention of clotting (no need of circuit change in the first 24 hours for any reason), and death. Evidence certainty was determined using the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) approach. MAIN RESULTS:A total of 34 completed studies (1960 participants) were included in this review. We identified seven ongoing studies which we plan to assess in a future update of this review. No included studies were free from risk of bias. We rated 30 studies for performance bias and detection bias as high risk of bias. We rated 18 studies for random sequence generation,  six studies for the allocation concealment, three studies for performance bias, three studies for detection bias,  nine studies for attrition bias, 14 studies for selective reporting and nine studies for the other potential source of bias, as having low risk of bias. We identified eight studies (581 participants) that compared citrate with unfractionated heparin (UFH). Compared to UFH, citrate probably reduces major bleeding (RR 0.22, 95% CI 0.08 to 0.62; moderate certainty evidence). Citrate may have little or no effect on death at 28 days (RR 1.06, 95% CI 0.86 to 1.30, moderate certainty evidence), while citrate versus UFH may have little or no effect on successful prevention of clotting (RR 1.01, 95% CI 0.77 to 1.32; moderate certainty evidence). Citrate versus UFH may reduce the number of participants who drop out of treatment due to adverse events (RR 0.47, 95% CI 0.15 to 1.49; low certainty evidence). Compared to UFH, citrate may make little or no difference to the recovery of kidney function (RR 0.95, 95% CI 0.66 to 1.36; low certainty evidence). Compared to UFH, citrate may reduce thrombocytopenia (RR 0.39, 95% CI 0.14 to 1.03; low certainty evidence). It was uncertain whether citrate reduces a cost to health care services because of inadequate data. For low molecular weight heparin (LMWH) versus UFH, six studies (250 participants) were identified. Compared to LMWH, UFH may reduce major bleeding (0.58, 95% CI 0.13 to 2.58; low certainty evidence). It is uncertain whether UFH versus LMWH reduces death at 28 days or leads to successful prevention of clotting. Compared to LMWH, UFH may reduce the number of patient dropouts from adverse events (RR 0.29, 95% CI 0.02 to 3.53; low certainty evidence). It was uncertain whether UFH versus LMWH leads to the recovery of kidney function because no included studies reported this outcome. It was uncertain whether UFH versus LMWH leads to thrombocytopenia. It was uncertain whether UFH reduces a cost to health care services because of inadequate data. For the comparison of UFH to no anticoagulation, one study (10 participants) was identified. It is uncertain whether UFH compare to no anticoagulation leads to more major bleeding. It is uncertain whether UFH improves successful prevention of clotting in the first 24 hours, death at 28 days, the number of patient dropouts due to adverse events, recovery of kidney function, thrombocytopenia, or cost to health care services because no study reported these outcomes. For the comparison of citrate to no anticoagulation, no completed study was identified. AUTHORS' CONCLUSIONS:Currently, available evidence does not support the overall superiority of any anticoagulant to another. Compared to UFH, citrate probably reduces major bleeding and probably has little or no effect on preventing clotting or death at 28 days. For other pharmacological anticoagulation methods, there is no available data showing overall superiority to citrate or no pharmacological anticoagulation. Further studies are needed to identify patient populations in which CRRT should commence with no pharmacological anticoagulation or with citrate. 10.1002/14651858.CD012467.pub2
    Comparison of different anticoagulation strategies for renal replacement therapy in critically ill patients with COVID-19: a cohort study. Arnold Frederic,Westermann Lukas,Rieg Siegbert,Neumann-Haefelin Elke,Biever Paul Marc,Walz Gerd,Kalbhenn Johannes,Tanriver Yakup BMC nephrology BACKGROUND:Critically ill coronavirus disease 2019 (COVID-19) patients have a high risk of acute kidney injury (AKI) that requires renal replacement therapy (RRT). A state of hypercoagulability reduces circuit life spans. To maintain circuit patency and therapeutic efficiency, an optimized anticoagulation strategy is needed. This study investigates whether alternative anticoagulation strategies for RRT during COVID-19 are superior to administration of unfractionated heparin (UFH). METHODS:Retrospective cohort study on 71 critically ill COVID-19 patients (≥18 years), admitted to intensive care units at a tertiary health care facility in the southwestern part of Germany between February 26 and May 21, 2020. We collected data on the disease course, AKI, RRT, and thromboembolic events. Four different anticoagulatory regimens were administered. Anticoagulation during continuous veno-venous hemodialysis (CVVHD) was performed with UFH or citrate. Anticoagulation during sustained low-efficiency daily dialysis (SLEDD) was performed with UFH, argatroban, or low molecular weight heparin (LMWH). Primary outcome is the effect of the anticoagulation regimen on mean treatment times of RRT. RESULTS:In patients receiving CVVHD, mean treatment time in the UFH group was 21.3 h (SEM: ±5.6 h), in the citrate group 45.6 h (SEM: ±2.7 h). Citrate anticoagulation significantly prolonged treatment times by 24.4 h (P = .001). In patients receiving SLEDD, mean treatment time with UFH was 8.1 h (SEM: ±1.3 h), with argatroban 8.0 h (SEM: ±0.9 h), and with LMWH 11.8 h (SEM: ±0.5 h). LMWH significantly prolonged treatment times by 3.7 h (P = .008) and 3.8 h (P = .002), respectively. CONCLUSIONS:UFH fails to prevent early clotting events in the dialysis circuit during COVID-19. For patients, who do not require effective systemic anticoagulation, regional citrate dialysis is the most effective strategy. For patients, who require effective systemic anticoagulation, the usage of LMWH results in the longest circuit life spans. The proposed anticoagulatory strategies are safe, can easily be monitored, and allow an individualized treatment. 10.1186/s12882-020-02150-8
    Citrate anticoagulation versus systemic heparinisation in continuous venovenous hemofiltration in critically ill patients with acute kidney injury: a multi-center randomized clinical trial. Schilder Louise,Nurmohamed S Azam,Bosch Frank H,Purmer Ilse M,den Boer Sylvia S,Kleppe Cynthia G,Vervloet Marc G,Beishuizen Albertus,Girbes Armand R J,Ter Wee Pieter M,Groeneveld A B Johan, Critical care (London, England) INTRODUCTION:Because of ongoing controversy, renal and vital outcomes are compared between systemically administered unfractionated heparin and regional anticoagulation with citrate-buffered replacement solution in predilution mode, during continuous venovenous hemofiltration (CVVH) in critically ill patients with acute kidney injury (AKI). METHODS:In this multi-center randomized controlled trial, patients admitted to the intensive care unit requiring CVVH and meeting inclusion criteria, were randomly assigned to citrate or heparin. Primary endpoints were mortality and renal outcome in intention-to-treat analysis. Secondary endpoints were safety and efficacy. Safety was defined as absence of any adverse event necessitating discontinuation of the assigned anticoagulant. For efficacy, among other parameters, survival times of the first hemofilter were studied. RESULTS:Of the 139 patients enrolled, 66 were randomized to citrate and 73 to heparin. Mortality rates at 28 and 90 days did not differ between groups: 22/66 (33%) of citrate-treated patients died versus 25/72 (35%) of heparin-treated patients at 28 days, and 27/65 (42%) of citrate-treated patients died versus 29/69 (42%) of heparin-treated patients at 90 days (P = 1.00 for both). Renal outcome, i.e. independency of renal replacement therapy 28 days after initiation of CVVH in surviving patients, did not differ between groups: 29/43 (67%) in the citrate-treated patients versus 33/47 (70%) in heparin-treated patients (P = 0.82). Heparin was discontinued in 24/73 (33%) of patients whereas citrate was discontinued in 5/66 (8%) of patients (P < 0.001). Filter survival times were superior for citrate (median 46 versus 32 hours, P = 0.02), as were the number of filters used (P = 0.002) and the off time within 72 hours (P = 0.002). The costs during the first 72 hours of prescribed CVVH were lower in citrate-based CVVH. CONCLUSIONS:Renal outcome and patient mortality were similar for citrate and heparin anticoagulation during CVVH in the critically ill patient with AKI. However, citrate was superior in terms of safety, efficacy and costs. TRIAL REGISTRATION:Clinicaltrials.gov NCT00209378. Registered 13th September 2005. 10.1186/s13054-014-0472-6
    [Choice and management of anticoagulation during CRRT]. Ricci Davide,Panicali Laura,Cavallari Giuseppe,Facchini Maria Grazia,Mancini Elena Giornale italiano di nefrologia : organo ufficiale della Societa italiana di nefrologia Continuous renal replacement therapies (CRRT) are widely used in the treatment of acute kidney injury. Several causes, related to the treatment itself or to the patient's condition, determine the coagulation of the extracorporeal circuit. These interruptions (or down-time) have a negative impact on the effectiveness of the treatment in terms of solute clearance and fluid balance. Historically, the choice of anticoagulant has fallen on unfractionated heparin because it is cheap and easy to use. Today, the use of citrate is recommended in most instances because of its high efficacy and safety. Several studies demonstrate the superiority of citrate in terms of filter survival. The reduction of down-time results in a reduction of the delta between the prescribed dialysis dose and the dose that is actually administered (ml/Kg/hour of collected effluent). The literature also agrees that there is a reduction in the incidence of major bleeding events when citrate is used instead of heparin, although there is no impact on mortality rates. Some technical and clinical complexities, secondary to citrate action both as anticoagulant and buffer, still exist in the use of regional citrate anticoagulation. However, complications due to citrate use, such as acid-base balance disorders and hypocalcaemia, are rare and easily reversible. There is not much data about the costs and benefits of using citrate instead of heparin; according to the experience within our own Unit, we have observed a reduction in costs when the data is normalized for 35 ml of effluent administered. Appropriate protocols, accurate surveillance and the automated management of regional citrate anticoagulation thanks to dedicated software make this technique safe and effective.
    Citrate versus unfractionated heparin for anticoagulation in continuous renal replacement therapy. Liao Yu-Jie,Zhang Ling,Zeng Xiao-Xi,Fu Ping Chinese medical journal BACKGROUND:Unfractionated heparin is the most commonly used anticoagulant in continuous renal replacement therapy (CRRT), but it can increase the risk of bleeding. Citrate is a promising substitute. Our study was to assess the efficacy and safety of citrate versus unfractionated heparin in CRRT. METHODS:We searched the MEDLINE, the EMBASE, the Cochrane Central Register of Controlled Trials, and the China National Knowledge Infrastructure Database until up to November 2011 for randomized controlled trials comparing citrate with unfractionated heparin in adult patients with acute kidney injury prescribed CRRT. The primary outcome was mortality and the secondary outcomes included circuit survival, control of uremia, risk of bleeding, transfusion rates, acid-base statuses, and disturbance of sodium and calcium homeostasis. RESULTS:Four trials met the inclusion criteria. Meta-analysis found no significant difference between two anticoagulants on mortality. Less bleeding and more hypocalcemic episodes were with citrate. Citrate was superior or comparable to unfractionated heparin in circuit life. CONCLUSIONS:Citrate anticoagulation in CRRT seems to be superior in reducing bleeding risk and with a longer or similar circuit life, although there is more metabolic derangement. Mortality superiority has not been approved.
    Clinical impact of regional citrate anticoagulation in continuous renal replacement therapy in critically ill patients. Huguet Maria,Rodas Lida,Blasco Miquel,Quintana Luis F,Mercadal Jordi,Ortiz-Pérez Jose T,Rovira Irene,Poch Esteban The International journal of artificial organs BACKGROUND:Regional citrate anticoagulation (RCA) is being used increasingly in continuous renal replacement therapy (CRRT) as a safer alternative to heparin. However, complex metabolic control to avoid side effects have generated discrepancies about its introduction into everyday practice. We aimed to compare both anticoagulation techniques in terms of efficacy, safety and feasibility. METHODS:Observational retrospective study performed in 3 specialized ICUs in patients receiving CVVHDF with RCA between January 2013 and May 2016. Heparin-treated patients matched by age, sex and disease severity treated in the preceding year were selected as historic controls. Filter lifetime, number of filters used, haemorrhagic complications and metabolic complications were recorded. RESULTS:54 patients (27 treated with RCA and 27 with heparin) were included in the study. Filter lifetimes in the first 72 hours were 55.1 ± 21.8 hours in the RCA group compared to 38.8 ± 24.8 hours in the heparin group, (p = 0.004). In addition, the number of filters used in the first 72 hours was significantly higher in the heparin group (2.4 ± 1.3 vs. 1.5 ± 0.7; p = 0.004). There was a trend toward a lower incidence of bleeding in the RCA group, with a significantly lower red blood cell transfusion rate (p = 0.027) in the citrate group. No clinically significant metabolic disturbances were observed in the RCA group. Regarding outcomes, there were no significant differences between groups. CONCLUSIONS:These results suggest that the implementation of CVVHDF with RCA using concentrated citrate solutions prolongs filter lifetime, achieves a longer effective hemodiafiltration time and is a safe and feasible method. 10.5301/ijao.5000633
    Anticoagulation in Continuous Renal Replacement Therapy: Citrate Appears to Be Superior to Heparin! Bunchman Timothy E Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies 10.1097/PCC.0000000000000889
    Anticoagulation techniques in apheresis: from heparin to citrate and beyond. Lee Grace,Arepally Gowthami M Journal of clinical apheresis Anticoagulation is essential for maintaining the fluidity of extravascular blood on the apheresis circuit. Although both citrate and heparin are used as an anticoagulant during apheresis, citrate is preferred for the majority of exchange procedures because of its safety and effectiveness. Complications of citrate are primarily due to physiologic effects of hypocalcemia. Symptoms of hypocalcemia and other citrate-induced metabolic abnormalities affect neuromuscular and cardiac function and range in severity from mild dysesthesias (most common) to tetany, seizures, and cardiac arrhythmias. Oral or intravenous calcium supplementation is advised for decreased ionized calcium levels and/or symptomatic management of hypocalcemia. Heparin-based anticoagulation is limited to certain apheresis procedures (membrane-based plasma exchange, LDL apheresis, or photopheresis) or is used in combination with citrate to reduce citrate load. While effective, heparin anticoagulation is associated with an increased frequency of bleeding complications and heparin-induced thrombocytopenia. J. Clin. Apheresis 2012. © 2012 Wiley Periodicals, Inc. 10.1002/jca.21222
    Cov-hep study: heparin in standard anticoagulation based on citrate for continuous veno-venous hemodialysis in patients with COVID-19: a structured summary of a study protocol for a randomized controlled trial. Lins Paulo Ricardo Gessolo,de Albuquerque Claudia Coimbra César,Assis Camila Fernandes,Rodrigues Bruna Cristine Duarte,E Siqueira Campos Beatriz Pinto,de Oliveira Valle Eduardo,Cabrera Carla Paulina Sandoval,de Oliveira Gois Jeison,Segura Gabriela Cardoso,Strufaldi Fernando Louzada,Mainardes Lorena Catelan,Ribeiro Rayra Gomes,Via Reque Cortes Daniela Del Pilar,Lutf Luciana Gil,de Oliveira Márcia Fernanda Arantes,Sales Gabriel Teixeira Montezuma,Smolentzov Igor,Reichert Bernardo Vergara,Andrade Lucia,Seabra Victor Faria,Rodrigues Camila Eleuterio Trials OBJECTIVES:The primary objective is to test if heparin added to a standard regional anticoagulation protocol based on citrate is able to reduce dialysis circuit losses by clotting without increasing the risk of thrombocytopenia or bleeding, in patients with COVID-19 with acute kidney injury requiring dialysis. TRIAL DESIGN:Randomized, parallel-group, open-label trial, with two arms (ratio 1:1) comparing different continuous renal replacement therapy anticoagulation strategies. PARTICIPANTS:Eligibility conditions: All ICU patients of University of Sao Paulo General Hospital (Hospital das Clínicas), Brazil will be screened for eligibility conditions. Adults (> 18 years old) with confirmed COVID-19 and acute kidney injury requiring dialysis with agreement between ICU and nephrology teams for the introduction of renal continuous replacement therapy in daily ICU rounds. Continuous renal replacement therapy will be prescribed by consulting nephrologists based on standard clinical guidelines, including acute kidney injury with hemodynamic instability plus hyperkalemia, severe acidosis, volume overload, respiratory distress, multiorgan failure or some combination of these factors. DATA COLLECTION:Patients demographics and associated clinical data and comorbidities will be recorded at ICU entry. Demographic information will include the patient's age, sex, and admission dates. Clinical data comprise comorbidities, APACHE 2, SAPS 3, need for mechanical ventilation, and use of vasopressor drugs. Physiological data collected by the day of CRRT start will be vital signs, the arterial oxygen tension/fraction of inspired oxygen (PaO2/FiO2) index, and serum creatinine, blood urea nitrogen, bilirubin, hemoglobin, hematocrit, platelets, white blood cell count levels and Peak D-dimer levels. Patients will be analyzed for the first 72h of CRRT, and they will be evaluated regarding clinical variables, filter patency and any adverse events that could be related to the anticoagulation choice, as bleeding (mild or major) or low platelets counts (<100.000 ui/uL) during treatment period. Mild and major bleeding will be defined by hemorrhagic event without clinical impact or hemoglobin (Hb) fall lesser than 1g/dL and hemorrhagic event with clinical impact or Hb fall higher than 1g/dL, respectively. EXCLUSION CRITERIA:Hypersensitivity to any of the substances going to be used in the study (Citric acid dextrosol 2.2% and unfractionated heparin); Previous diagnosis of coagulopathy or thrombophilia; Contraindication to the use of unfractionated heparin; Risk of citrate poisoning - (Lactate> 30 mg/dL, international normalized ratio > 2.5, Total bilirubin> 15 mg/dL); Pregnancy; Patients unlikely to survive for more than 24 hours. The trial is being undertaken at the University of Sao Paulo General Hospital (Hospital das Clinicas), Brazil. INTERVENTION AND COMPARATOR:Group A (control) - Patients on continuous renal replacement therapy (blood flow 150 ml/min, dose of 30 mL/Kg/h) receiving anticoagulation with sodium citrate at 4 mmol/L Group B (experiment): Patients on continuous hemodialysis (blood flow 150 mL/min, dose of 30 mL/Kg/h) receiving anticoagulation with sodium citrate at 4 mmol/L associated with unfractionated heparin at 10 U/Kg/h. MAIN OUTCOMES:The percentage of clotted dialyzers within 72 hours in each of the studied groups (Primary outcome) Secondary outcomes: Number of dialyzers used in the first 72 hours of dialysis protocol, Mortality in the first 72 h of dialysis protocol, Bleeding events (Major or minor) in the first 72 h of dialysis protocol, Thrombocytopenia (less than 50.000 platelets) proportion in the first 72 h of dialysis protocol, Dialysis efficiency (Urea sieving) - variation in urea sieving between the first, second and third days of dialysis protocol, Continuous renal replacement therapy pressures (Arterial, Venous, dialysate and pre-filter pressure) in the first 72 h of dialysis protocol, in-hospital mortality. RANDOMIZATION:RedCap→ randomization - 2 blocks randomization by D-dimer level (5000ng/dL cut-off) and catheter site (Right Internal Jugular versus other sites) with 1:1 allocation ratio. BLINDING (MASKING):No blinding - Open label format NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): Total number of patients 90 (45 per group) TRIAL STATUS: Trial version 2.0 - ongoing recruitment. First recruitment: June 29, 2020 Estimated date for last recruitment: December 31, 2020 TRIAL REGISTRATION: Responsible Party: University of Sao Paulo General Hospital (Hospital das Clinicas) ClinicalTrials.gov Identifier: NCT04487990 , registered July 27, 2020, ReBec www.ensaiosclinicos.gov.br/rg/RBR-45kf9p/ Other Study ID Numbers: U1111-1252-0194 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1) In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. 10.1186/s13063-020-04814-0
    A cost comparison of regional citrate versus low-dose systemic heparin anticoagulation in continuous renal replacement therapy. Dissanayake Chathuri U,Bharat Chrianna I,Roberts Brigit L,Anstey Matthew Hr Anaesthesia and intensive care 10.1177/0310057X18824596
    Regional citrate anticoagulation versus low molecular weight heparin anticoagulation for continuous venovenous hemofiltration in patients with severe hypercalcemia: a retrospective cohort study. Yu Yan,Bai Ming,Wei Zhang,Zhao Lijuan,Li Yangping,Ma Feng,Sun Shiren Renal failure PURPOSE:We conducted a retrospective study to evaluate the efficacy and safety of regional citrate anticoagulation (RCA) versus those of low molecular weight heparin (LMWH) anticoagulation for CVVH in severe hypercalcemia patients. METHODS:Between January 2014 and May 2019, 33 severe hypercalcemia patients underwent CVVH. Patients were divided into the RCA and LMWH groups. Calcium-free replacement solution was used. Serum total calcium reduction rate (RRSeCa), filter lifespan, bleeding, totCa/ionCa ratio, citrate accumulation, and catheter occlusion were evaluated as outcomes. RESULTS:RCA and LMWH were employed for CVVH in 14 and 43 filters, respectively. RRSeCa was not significantly different between the LMWH and RCA groups ( = .320), but RCA-CVVH was more effective in reducing ionized calcium at half of the time points ( < .05). RCA significantly prolonged the median filter lifespan (>72 h vs. 24.0 h [IQR, 15.0-26.0],  = .012). The incidence of filter failure was 55.8% (24/43) in the LMWH group and 21.4% (3/14) in the RCA group ( = .033). The adjusted results demonstrated that RCA could significantly reduce the risk of filter failure ( = .043, 95% CI 0.059-0.957, HR = 0.238). No citrate accumulation or bleeding episodes were observed in the RCA-CVVH group. Seven bleeding episodes (7/43, 16.3%) occurred in the LMWH-CVVH group. CONCLUSIONS:In patients with severe hypercalcemia who underwent CVVH, RCA more effectively decreased calcium levels and had a superior filter lifespan and no obvious adverse events compared with LMWH. Further prospective, randomized, controlled studies are warranted to obtain robust evidence. 10.1080/0886022X.2020.1795879
    Heparin-Free Prolonged Intermittent Hemodialysis Using Calcium-Free Citrate Dialysate in Critically Ill Patients. Faguer Stanislas,Saint-Cricq Morgane,Nogier Marie-Béatrice,Labadens Isabelle,Lavayssiere Laurence,Kamar Nassim,Cointault Olivier Critical care medicine OBJECTIVES:Critically ill patients who have a high risk of bleeding but require prolonged intermittent dialysis need a heparin-free easy-to-use alternative type of anticoagulation within the dialysis circuit. We assessed the safety and efficiency of heparin-free regional citrate anticoagulation of the dialysis circuit using a calcium-free citrate-containing dialysate, with calcium reinjected according to ionic dialysance. DESIGN:Prospective cohort study. SETTING:Critical care units. PATIENTS:Critically ill patients who required renal replacement therapy. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:A total of 101 dialysis sessions were performed in 35 patients (mechanical ventilation n = 78; norepinephrine n = 13). Median duration of dialysis was 294 minutes (interquartile range, 240-300), and median ultrafiltration volume was 2.3 L (1-2.8). Urea and β2-microglobulin reduction rates were 64.5% ± 0.4% and 48% ± 0.13%, respectively. Postfilter ionized calcium was 0.35 ± 0.17 and 0.38 ± 0.14 mmol/L at 1 and 3 hours, respectively, within the extracorporeal circuit. A major clotting event that led to premature termination of the session occurred in only three of 101 sessions. In these three cases, major catheter dysfunction occurred before clotting within the circuit. Prefilter ionized calcium remained within narrow ranges (before/after change +0.07 ± 0.006 mmol/L), and total-to-ionized calcium ratio, a surrogate marker for citratemia, was unchanged. CONCLUSIONS:Dialysis anticoagulation with calcium-free citrate-containing dialysate and calcium reinjection according to ionic dialysance is an easy-to-use, efficient, and inexpensive form of heparin-free regional anticoagulation. It allows prolonged hemodialysis sessions in critically ill patients without the need to systemically monitor ionized calcium. Furthermore, sessions can be safely extended according to the hemodynamic tolerance to ensure an adequate dose of dialysis and a negative water balance, a major point in patients with severe acute kidney disease. 10.1097/CCM.0000000000002694
    Application of regional citrate anticoagulation in membrane therapeutic plasma exchange. Yuan Fang,Li Zheng,Li Xiejia,Liu Hong International urology and nephrology BACKGROUND:Both regional citrate anticoagulation (RCA) and heparin are used as anticoagulants during membrane therapeutic plasma exchange (mTPE). However, there are few reports of comparisons of the two methods. The aim of this study was to compare different anticoagulants in mTPE and observe the effectiveness, safety, and advantages of RCA. METHODS:We retrospectively included 85 patients who underwent mTPE in the past 1 year, and divided them into three groups. Patients with no bleeding tendency were administered heparin anticoagulation; patients with bleeding tendency/with liver dysfunction/who had undergone an operation were treated with RCA, or did not receive anticoagulation. In the heparin group, low-dose heparin anticoagulation was administered; in the RCA group, 4% sodium citrate solution was administered, and 10% calcium gluconate solution was pumped from the venous circuit tube. The peripheral blood platelet count, prothrombin time (PT), activated partial thromboplastin time (APTT), and electrolytes were detected before and after treatment in all patients. RESULTS:A total of 255 sessions of mTPE were performed in 85 patients (2-7 times/case) with 120 sessions of heparin anticoagulation, 93 sessions of RCA, and 42 sessions of no anticoagulation. Compared with pretreatment values, the platelet count decreased by 53.7% and the PT and APTT increased (p < 0.05) in the heparin group after treatment. There were no differences in platelet count and PT before and after treatment in the RCA group. In the RCA group, the patients did not experience hypocalcemia or hypercalcemia, and no separator clotting occurred. CONCLUSION:RCA is safe, feasible, and effective in mTPE, especially for patients with bleeding tendency and frequent monitoring is needed. It is worth widely developing and applying it in clinical practice. 10.1007/s11255-020-02581-0
    Circuit Lifetime With Citrate Versus Heparin in Pediatric Continuous Venovenous Hemodialysis. Zaoral Tomáš,Hladík Michal,Zapletalová Jana,Trávníček Bořek,Gelnarová Eliška Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies OBJECTIVES:To determine if there is a difference between regional citrate and global heparinized anticoagulation on circuit lifetimes during continuous venovenous hemodialysis in children. DESIGN:Prospective "cross-over" trial. SETTING:PICU, Department of Pediatrics, University Hospital Ostrava. PATIENTS:Children 0-18 years old. INTERVENTIONS:From 2009 to 2014, 63 eligible children (age, 89.24 ± 62.9 mo; weight, 30.37 ± 20.62 kg) received at least 24 hours of continuous venovenous hemodialysis. Each child received four continuous venovenous hemodialysis circuits with anticoagulants in the following order: heparin, citrate, heparin, citrate. Circuit life ended when transmembrane pressure was greater than or equal to 250 mm Hg for more than 60 minutes. MEASUREMENTS AND MAIN RESULTS:The total mean circuit lifetime was 39.75 ± 10.73 hours. Citrate had a significantly longer median circuit lifetime (41.0 hr; CI, 37.6-44.4) than heparin (36.0 hr; CI, 35.4-36.6; p = 0.0001). Mortality was 33.33%. Circuit lifetime was significantly correlated to patient age (r = 0.606), weight (r = 0.763), and blood flow rate (r = 0.697). Transfusion rates (units of red cells per circuit of continuous venovenous hemodialysis) were 0.17 (0.0-1.0) with citrate and 0.36 (0.0-2.0) with heparin (p = 0.002). CONCLUSIONS:We showed in our study that citrate provided significantly longer circuit lifetimes than heparin for continuous venovenous hemodialysis in children. Citrate was superior to heparin for the transfusion requirements. Citrate was feasible and safe in children and infants. 10.1097/PCC.0000000000000860
    A noninferiority trial comparing a heparin-grafted membrane plus citrate-containing dialysate versus regional citrate anticoagulation: results of the CiTED study. Meijers Björn,Metalidis Christoph,Vanhove Thomas,Poesen Ruben,Kuypers Dirk,Evenepoel Pieter Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association Background:Anticoagulation is a prerequisite for successful haemodialysis. Heparin and low-molecular weight heparins are routinely used despite increased bleeding risk. Regional citrate anticoagulation (RCA) is efficacious, but is laborious and may induce metabolic disturbances. Heparin-grafted membranes are less efficacious. It is not known whether combining citrate-containing dialysate and a heparin-grafted membrane is a valid anticoagulation strategy. Methods:We performed a randomized crossover noninferiority trial, with a prespecified noninferiority threshold of 10% in maintenance dialysis patients ( n  = 25). We compared the combination of citrate-containing dialysate plus a heparin-grafted membrane [CiTrate and EvoDial (CiTED) protocol] with RCA. The primary endpoint was completion of dialysis without significant clotting. Secondary endpoints included time to clotting, achieved Kt / V urea , loss of total cell volume, venous air chamber clotting score and systemic-ionized calcium concentration. Results:In total, 1284 sessions were performed according to study protocol, 636 in the CiTED arm and 648 in the RCA arm. The primary outcome of preterm interruption due to clotting occurred in 36 (5.7%) of sessions in the CiTED arm, and in 40 (6.2%) sessions in the RCA arm, thereby meeting noninferiority criteria (P < 0.0001). Most of the clotting events occurred in the fourth hour of dialysis. Repetitive clotting occurred in four patients in the CiTED arm and one patient in the RCA arm. Time to preterm interruption due to clotting and achieved Kt / V urea was not significantly different. Systemic-ionized calcium levels during treatment were significantly lower in the RCA arm and clinically relevant hypocalcaemia was noted only in the RCA arm. Conclusion:The combination of citrate-containing dialysate and a heparin-grafted membrane is a valid alternative to RCA. 10.1093/ndt/gfw461
    Transition From Heparin to Citrate Anticoagulation for Continuous Renal Replacement Therapy: Safety, Efficiency, and Cost. Gutierrez-Bernays David,Ostwald Matthew,Anstey Chris,Campbell Victoria Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy Regional citrate anticoagulation (RCA) for continuous renal replacement therapy (CRRT) has recently been recommended as first-line over heparin. Evidence suggests that RCA prolongs filter life and may reduce bleeding risk, but there is little research on the benefits to dialysis dose delivery or cost, or the effectiveness of transitioning to RCA first-line. The aim of the present study was to assess the effect on dialysis delivery, cost and safety when transitioning from systemic heparin to RCA for first-line anticoagulation for CRRT. A single-center, retrospective observational study was conducted from 2006 to 2012, during which a transition from heparin to a simplified RCA protocol occurred. Demographic and dialysis data, pathology results and costs were obtained. Data were analyzed for both heparin and RCA, and for before and after the transition. 166 patients had 992 dialysis days (heparin 334 vs. RCA 658); demographics were well matched; RCA used less filters per day (P = 0.03), had more days when prescribed dialysis was achieved (85% vs. 60%, P < 0.001), and less filter "down-time" per day (2.4 vs. 6.1 h, P = 0.02). RCA was estimated to cost AU$487 per day, compared to heparin at $479 per day. When the data were analyzed, comparing before and after the transition, these results remained statistically significant. There was no statistical difference in clinical safety events. Transition to first-line RCA was safe, provided more time on filter and consumed less filter circuits using a simple and user friendly protocol. The adjusted cost difference appears negligible. 10.1111/1744-9987.12331
    Regional citrate versus heparin anticoagulation for continuous renal replacement therapy in critically ill patients: a meta-analysis with trial sequential analysis of randomized controlled trials. Liu Chao,Mao Zhi,Kang Hongjun,Hu Jie,Zhou Feihu Critical care (London, England) BACKGROUND:Regional citrate or heparin is often prescribed as an anticoagulant for continuous renal replacement therapy (CRRT). However, their efficacy and safety remain controversial. Therefore, we performed this meta-analysis to compare these two agents and to determine whether the currently available evidence is sufficient and conclusive by using trial sequential analysis (TSA). METHODS:We searched for relevant studies in PubMed, Embase, the Cochrane Library databases and the China National Knowledge Infrastructure (CNKI) Database from database inception until September 2015. We selected randomized controlled trials comparing regional citrate with heparin in adult patients with acute kidney injury (AKI) who were prescribed CRRT. RESULTS:Fourteen trials (n = 1134) met the inclusion criteria. Pooled analyses showed that there was no difference in mortality between the regional citrate and heparin groups (relative risk (RR) 0.97, 95 % confidence interval (CI) 0.84, 1.13, P > 0.05), which was confirmed by TSA. Compared with heparin, regional citrate significantly prolonged the circuit life span in the continuous venovenous haemofiltration (CVVH) subgroup (mean difference (MD) 8.18, 95 % CI 3.86, 12.51, P < 0.01) and pre-dilution subgroup (MD 17.51, 95 % CI 9.85, 25.17, P < 0.01) but not in the continuous venovenous haemodiafiltration (CVVHDF) subgroup (MD 28.60, 95 % CI -3.52, 60.73, P > 0.05) or post-dilution subgroup (MD 13.06, 95 % CI -2.36, 28.48, P > 0.05). However, the results were not confirmed by TSA. A reduced risk of bleeding was found in the regional citrate compared with the systemic heparin group (RR 0.31, 95 % CI 0.19, 0.51, P < 0.01) and TSA provided conclusive evidence. Fewer episodes of heparin-induced thrombocytopoenia (HIT) (RR 0.41, 95 % CI 0.19, 0.87, P = 0.02) and a greater number of episodes of hypocalcaemia (RR 3.96, 95 % CI 1.50, 10.43, P < 0.01) were found in the regional citrate group. However, TSA did not provide conclusive evidence. CONCLUSION:In adult patients with AKI, there is no difference in mortality between the regional citrate and heparin treated groups. However, regional citrate is more efficacious in prolonging circuit life span and reducing the risk of bleeding and should be recommended as the priority anticoagulant for critically ill patients who require CRRT. 10.1186/s13054-016-1299-0
    A novel citrate-based protocol versus heparin anticoagulation for sustained low-efficiency dialysis in the ICU: safety, efficacy, and cost. Wen Ming,Küchle Claudius,Steubl Dominik,Satanovskji Robin,Heemann Uwe,Suttmann Yana,Angermann Susanne,Kemmner Stephan,Rehbehn Lisa,Huber Monika,Hauser Christine,Schmaderer Christoph,Reichelt Anna-Lena,Haller Bernhard,Renders Lutz BMC nephrology BACKGROUND:The high cost, complexity of the available protocols, and metabolic complications are the major barriers that impede the clinical utilization of regional citrate anticoagulation (RCA) for sustained low efficiency dialysis (SLED) in critically ill patients. By comparing a novel protocol for SLED using 30% citrate solution with common protocol using unfractionated heparin, this study aimed to provide new insights for clinical applications of RCA. METHODS:In this retrospective study, a total of 282 critically ill patients who underwent SLED with citrate and/or heparin anticoagulation in six adult ICUs were enrolled. These patients were divided into three groups based on the anticoagulation regimens they had received during the treatment in ICU: Group 1 (Citrate) had only received treatment with citrate anticoagulation (n=75); Group 2 (Heparin) only with heparin anticoagulation (n=79); and Group 3 (Both) with both citrate and heparin anticoagulation (n=128). We compared the mortality, metabolic complications as well as cost among these groups using different anticoagulation regimens. RESULTS:The in-hospital mortality did not significantly differ among groups (p> 0.1). However, three patients in heparin group suffered from severe bleeding which led to death, while none in citrate group. Overall, 976 SLED sessions with heparin anticoagulation and 808 with citrate were analyzed. The incidence of extracorporeal circuit clotting was significantly less in citrate (5%), as compared to that in heparin (10%) (p< 0.001). Metabolic complications and hypotension which led to interruption of SLED occurred more frequently, though not significantly, in citrate (p= 0.06, p= 0.23). Furthermore, with 30% citrate solution, the cost of anticoagulant was reduced by 70% in comparison to previously reported protocol using Acid Citrate Dextrose solution A (ACD-A). CONCLUSIONS:Our results indicated that anticoagulation regimens for SLED did not significantly affect the mortality of patients. Citrate anticoagulation was superior to heparin in preventing severe bleeding and circuit clotting. The protocol adopted in this study using 30% citrate solution was safe as well as efficacious. In the meantime, it was much more cost-efficient than other citrate-based protocol. 10.1186/s12882-018-0879-4
    A Randomized Controlled Trial of Regional Citrate Versus Regional Heparin Anticoagulation for Continuous Renal Replacement Therapy in Critically Ill Adults. Gattas David J,Rajbhandari Dorrilyn,Bradford Celia,Buhr Heidi,Lo Serigne,Bellomo Rinaldo Critical care medicine OBJECTIVE:To determine whether regional anticoagulation of continuous renal replacement therapy circuits using citrate and calcium prolongs circuit life and/or affects circulating cytokine levels compared with regional anticoagulation using heparin and protamine. DESIGN:Multicenter, parallel group randomized controlled trial. SETTING:Seven ICUs in Australia and New Zealand. PATIENTS:Critically ill adults requiring continuous renal replacement therapy. INTERVENTIONS:Patients were randomized to receive one of two methods of regional circuit anticoagulation: citrate and calcium or heparin and protamine. MEASUREMENTS AND MAIN RESULTS:The primary outcome was functional circuit life measured in hours, assessed using repeated events survival analysis. In addition, we measured changes in interleukin-6, interleukin-8, and interleukin-10 blood levels. We randomized 212 subjects who were treated with 857 continuous renal replacement therapy circuits (median 2 circuits per patient [interquartile range, 1-6], 390 in citrate group vs 467 in heparin group). The groups were well matched for baseline characteristics. Patients receiving regional continuous renal replacement therapy anticoagulation with heparin and protamine were more likely to experience circuit clotting than those receiving citrate and calcium (hazard ratio, 2.03 [1.36-3.03]; p < 0.0005; 857 circuits). The median lifespan of the first study circuit in each patient was 39.2 hours (95% CI, 32.1-48.0 hr) in the citrate and calcium group versus 22.8 hours (95% CI, 13.3-34.0 hr) in the heparin and protamine group (log rank p = 0.0037, 204 circuits). Circuit anticoagulation with citrate and calcium had similar effects on cytokine levels compared with heparin and protamine anticoagulation. There were more adverse events in the group assigned to heparin and protamine anticoagulation (11 vs 2; p = 0.011). CONCLUSIONS:Regional citrate and calcium anticoagulation prolongs continuous renal replacement therapy circuit life compared with regional heparin and protamine anticoagulation, does not affect cytokine levels, and is associated with fewer adverse events. 10.1097/CCM.0000000000001004
    Continuous Renal Replacement Therapy with Low Dose Systemic Heparin in Liver Transplant Recipients. Rabbani Amirhassan,Dalili Nooshin,Ashrafi Sadra,Hassanzadeh Katayoun,Aliabbar Shiva,Nikeghbalian Saman,Malekhoseini Seyed Ali,Nadiri Aylar Iranian journal of kidney diseases INTRODUCTION:Continuous renal replacement therapy (CRRT) is an effective dialysis method in critically ill patients. Citrate and heparin are commonly used as anticoagulants to prevent premature circuit clotting. The aim of this study was to evaluate the safety and efficacy of using low dose systemic heparin while on CRRT in liver transplant recipients. METHODS:We retrospectively evaluated and analyzed data from 29 liver transplant recipients undergoing CRRT in the postoperative course in this cross-sectional study. Numerous variables were recorded, such as coagulation parameters, duration of intensive care unit (ICU) stay, duration of dialysis, heparin dose, circuit life span, and anticoagulant complications. RESULTS:Out of 29 recipients, there were 16 (55%) female and 13 (45%) male. All participants underwent whole organ liver transplantation with a median age of 45 years. Overall, 98 successful dialysis sessions were recorded in this study with a mean circuit life span of 36 hours. Mean ± SD duration of CRRT for each recipient was 4.8 ± 3.1 days. The median total dose of heparin used for each recipient was 25,000 units , and the median dose of heparin per-day for each recipient was about 3,300 units. There were no episodes of anticoagulant-related bleeding complications. Thirteen (13.2%) episodes of premature circuit clotting occurred. We found a significant association between the first dose and total dose of heparin usage with first postoperative INR and PTT level (P < .05, P < .05, P < .001, and P < .05). CONCLUSION:In liver transplant recipients, low dose heparin during CRRT for patency of circuit is well tolerated.
    Citrate versus heparin anticoagulation in continuous renal replacement therapy in small children. Raymakers-Janssen Paulien A M A,Lilien Marc,van Kessel Ingrid A,Veldhoen Esther S,Wösten-van Asperen Roelie M,van Gestel Josephus P J Pediatric nephrology (Berlin, Germany) BACKGROUND:Citrate is preferred over heparin as an anticoagulant in adult continuous renal replacement therapy (CRRT). However, its potential adverse effects and data on use in CRRT in infants and toddlers is limited. We conducted a prospective study on using citrate in CRRT in critically ill small children. METHODS:Children who underwent CRRT with the smallest filter in our PICU between November 2011 and November 2016 were included. Both heparin and citrate were applied according to a strict protocol. Our primary outcome was circuit survival time. Secondary outcomes were alkalosis, citrate toxicity, and number of red blood cell transfusions. RESULTS:Heparin was used in six patients (121 circuits, total CRRT time 3723 h). Citrate was used in 14 patients (105 circuits, total CRRT time 4530 h). Median circuit survival time with heparin was 21 h (IQR 14.5-27.5) compared to 45.2 h (IQR 37.5-52.8) with citrate (p < 0.001). Actual administered effluent dose compared to prescribed dose was 85% (IQR 69-98%) with heparin compared to 92% (IQR 88-98%) with citrate (p = 0.31). No patient treated with citrate developed citrate toxicity. No other differences in electrolytes were found between the two CRRT regimes. In the heparin group, a median of 6.5 units of red blood cells (IQR 1.5-23.8) were given during CRRT, compared to three in the citrate group (IQR 2.0-5.0, p = 0.12). CONCLUSIONS:Use of regional citrate significantly prolongs circuit survival time and thereby should increase CRRT efficiency when compared to heparin. In addition, citrate appears safe for CRRT in critically ill small children. 10.1007/s00467-017-3694-4
    [Regional citrate versus heparin anticoagulation in continuous renal replacement therapy in critically ill patients: a Meta-analysis]. Feng Xuanlin,Deng Lei,Zhang Yang,Chang Li Zhonghua wei zhong bing ji jiu yi xue OBJECTIVE:To evaluate the efficacy and safety of regional citrate and heparin anticoagulation in continuous renal replacement therapy (CRRT) in critically ill patients by Meta-analysis. METHODS:Randomized controlled trials (RCT) comparing the efficacy and safety of regional citrate and heparin anticoagulation in English or Chinese were retrieved from Medline, Embase, Cochrane library, Web of Science, CNKI, Wanfang Database by electronic and manual search before December 2019. The primary outcomes were mortality and circuit life span, and the secondary outcomes were complications such as bleeding, heparin-induced thrombocytopenia (HIT), metabolic alkalosis, and hypocalcemia. Meta-analysis of the literature was conducted using the methods recommended by the Cochrane Collaboration's software RevMan 5.3 and funnel plot was used to analyze whether there was publication bias in each study. RESULTS:Sixteen RCTs with 1 229 patients were included. Meta-analysis showed that there was no significant difference in mortality between the regional citrate and heparin anticoagulation in CRRT [relative risk (RR) = 0.95, 95% confidence interval (95%CI) was 0.83-1.09, P = 0.47]. The circuit life span in the regional citrate group was 15.37 hours (95%CI was 10.09-20.65, P < 0.000 01) longer than that in the heparin group. Bleeding risk (RR = 0.29, 95%CI was 0.19-0.44, P < 0.000 01) and HIT (RR = 0.35, 95%CI was 0.16-0.74, P = 0.006) were lower in the regional citrate group than those in the heparin group, whereas the regional citrate anticoagulation could cause hypocalcemia (RR = 4.67, 95%CI was 1.88-11.60, P = 0.000 9). There was no significant difference in the incidence of metabolic alkalosis between the two groups (RR = 0.76, 95%CI was 0.42-1.37, P = 0.36). The funnel plot showed that there were no significant publication bias in the included studies. CONCLUSIONS:Regional citrate anticoagulation could significantly prolong circuit life span and decrease the risk of bleeding, and should be preferentially selected for the CRRT anticoagulation in critically ill patients. 10.3760/cma.j.cn121430-20200122-00068
    Regional citrate versus systemic heparin anticoagulation for continuous renal replacement therapy in critically ill children. The International journal of artificial organs OBJECTIVES:Anticoagulation is used to prevent filter clotting in patients undergoing continuous renal replacement therapy. Regional citrate anticoagulation is associated with lower rates of bleeding complications and prolongs the filter life span; however, a number of metabolic side effects had been associated with this therapy. The aim of this study was to evaluate the effect and safety of citrate versus heparin anticoagulation for continuous renal replacement therapy in critically ill children. METHODS:A retrospective comparative cohort study. Department of Pediatric Intensive Care, Acibadem Mehmet Ali Aydınlar University School of Medicine. RESULTS:From August 2016 to August 2018, 45 patients (19 in the citrate group and 26 in the heparin group) were included. A total of 101 hemofilters were used in all therapies: 44 in the citrate group (total continuous renal replacement therapy time: 2699 h) and 57 in the heparin group (total continuous renal replacement therapy time: 2383 h). The median circuit lifetime was significantly longer for regional citrate anticoagulation (53.0; interquartile range, 40-70 h) than for heparin anticoagulation (40.25; interquartile range, 22.75-53.5 h; p = 0.025). Mortality rates were similar in both groups (31.58% vs 30.77%). The most common indication for dialysis was hypervolemia in both groups. Transfusion rates were 1.65 units (interquartile range, 0.5-2.38) with heparin and 0.8 units (interquartile range, 0.3-2.0) with citrate (p = 0.32). Clotting-related hemofilter failure occurred in 11.36% of filters in the citrate group compared with 26.31% of filters in the heparin group. CONCLUSION:Our study showed that citrate is superior in terms of safety and efficacy, with longer filter life span. Regional citrate should be considered as a better anticoagulation method than heparin for continuous renal replacement therapy in critically ill children. 10.1177/0391398819893382
    Proteins adsorbed to a polysulfone hemodialysis membrane under heparin and citrate anticoagulation regimens. Mares Jan,Tuma Zdenek,Moravec Jiri,Pavlina Richtrova,Matejovic Martin Artificial organs The study aim was to compare molecular-level effects (blood-dialyzer interactions) of heparin and citrate anticoagulation using proteome-wide analysis of biofilm adsorbed to dialysis membrane. Ten patients receiving maintenance hemodialysis were examined in a crossover design under three different anticoagulation regimens, namely citrate, heparin, and anticoagulation-free (control). Following a regular hemodialysis session (4 hours, polysulfone membrane), dialyzers were flushed and the surface biofilm eluted by acetic acid. Protein composition of the eluates was determined by 2-dimensional gel electrophoresis and resulting patterns compared between regimens. Proteins responsible for the difference were identified by mass spectrometry. Citrate anticoagulation was associated with significantly less protein adsorption to the membrane than heparin (2.2 [1.1-2.9] mg vs. 6.5 [2.9-11.6] mg, P = 0.009). Among the proteins identified as major discriminators between citrate and the other regimens, fibrin α-chain fragments of molecular weight below 40 kDa prevailed. In these fragments, an analysis of the amino acid sequence has been performed by comparison with the UniProt database. It showed missing α-chain cross-links. On the contrary, heparin prevented adsorption and cleavage of several heparin-binding proteins; especially complement factor H-related protein 3, insulin-like growth factor binding proteins (2, 4, and 5), and chemerin. Compared to heparin, citrate is associated with less protein adsorption and imperfectly crosslinked fibrin clot formation. Membrane adsorptive properties are significantly modified by the anticoagulation regimen. 10.1111/aor.13506
    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. Zarbock Alexander,Küllmar Mira,Kindgen-Milles Detlef,Wempe Carola,Gerss Joachim,Brandenburger Timo,Dimski Thomas,Tyczynski Bartosz,Jahn Michael,Mülling Nils,Mehrländer Martin,Rosenberger Peter,Marx Gernot,Simon Tim Philipp,Jaschinski Ulrich,Deetjen Philipp,Putensen Christian,Schewe Jens-Christian,Kluge Stefan,Jarczak Dominik,Slowinski Torsten,Bodenstein Marc,Meybohm Patrick,Wirtz Stefan,Moerer Onnen,Kortgen Andreas,Simon Philipp,Bagshaw Sean M,Kellum John A,Meersch Melanie, JAMA Importance:Although current guidelines suggest the use of regional citrate anticoagulation (which involves the addition of a citrate solution to the blood before the filter of the extracorporeal dialysis circuit) as first-line treatment for continuous kidney replacement therapy in critically ill patients, the evidence for this recommendation is based on few clinical trials and meta-analyses. Objective:To determine the effect of regional citrate anticoagulation, compared with systemic heparin anticoagulation, on filter life span and mortality. Design, Setting, and Participants:A parallel-group, randomized multicenter clinical trial in 26 centers across Germany was conducted between March 2016 and December 2018 (final date of follow-up, January 21, 2020). The trial was terminated early after 596 critically ill patients with severe acute kidney injury or clinical indications for initiation of kidney replacement therapy had been enrolled. Interventions:Patients were randomized to receive either regional citrate anticoagulation (n = 300), which consisted of a target ionized calcium level of 1.0 to 1.40 mg/dL, or systemic heparin anticoagulation (n = 296), which consisted of a target activated partial thromboplastin time of 45 to 60 seconds, for continuous kidney replacement therapy. Main Outcomes and Measures:Coprimary outcomes were filter life span and 90-day mortality. Secondary end points included bleeding complications and new infections. Results:Among 638 patients randomized, 596 (93.4%) (mean age, 67.5 years; 183 [30.7%] women) completed the trial. In the regional citrate group vs systemic heparin group, median filter life span was 47 hours (interquartile range [IQR], 19-70 hours) vs 26 hours (IQR, 12-51 hours) (difference, 15 hours [95% CI, 11 to 20 hours]; P < .001). Ninety-day all-cause mortality occurred in 150 of 300 patients vs 156 of 296 patients (Kaplan-Meier estimator percentages, 51.2% vs 53.6%; unadjusted difference, -2.4% [95% CI, -10.5% to 5.8%]; unadjusted hazard ratio, 0.91 [95% CI, 0.72 to 1.13]; unadjusted P = .38; adjusted difference, -6.1% [95% CI, -12.6% to 0.4%]; primary adjusted hazard ratio, 0.79 [95% CI, 0.63 to 1.004]; primary adjusted P = .054). Of 38 prespecified secondary end points, 34 showed no significant difference. Compared with the systemic heparin group, the regional citrate group had significantly fewer bleeding complications (15/300 [5.1%] vs 49/296 [16.9%]; difference, -11.8% [95% CI, -16.8% to -6.8%]; P < .001) and significantly more new infections (204/300 [68.0%] vs 164/296 [55.4%]; difference, 12.6% [95% CI, 4.9% to 20.3%]; P = .002). Conclusions and Relevance:Among critically ill patients with acute kidney injury receiving continuous kidney replacement therapy, anticoagulation with regional citrate, compared with systemic heparin anticoagulation, resulted in significantly longer filter life span. The trial was terminated early and was therefore underpowered to reach conclusions about the effect of anticoagulation strategy on mortality. Trial Registration:ClinicalTrials.gov Identifier: NCT02669589. 10.1001/jama.2020.18618
    Continuous renal replacement therapy in COVID-19-associated AKI: adding heparin to citrate to extend filter life-a retrospective cohort study. Valle Eduardo de Oliveira,Cabrera Carla Paulina Sandoval,Albuquerque Claudia Coimbra César de,Silva Giovanio Vieira da,Oliveira Márcia Fernanda Arantes de,Sales Gabriel Teixeira Montezuma,Smolentzov Igor,Reichert Bernardo Vergara,Andrade Lucia,Seabra Victor Faria,Lins Paulo Ricardo Gessolo,Rodrigues Camila Eleuterio Critical care (London, England) BACKGROUND:Coronavirus disease 2019 (COVID-19) may predispose patients to thrombotic events. The best anticoagulation strategy for continuous renal replacement therapy (CRRT) in such patients is still under debate. The purpose of this study was to evaluate the impact that different anticoagulation protocols have on filter clotting risk. METHODS:This was a retrospective observational study comparing two different anticoagulation strategies (citrate only and citrate plus intravenous infusion of unfractionated heparin) in patients with acute kidney injury (AKI), associated or not with COVID-19 (COV + AKI and COV - AKI, respectively), who were submitted to CRRT. Filter clotting risks were compared among groups. RESULTS:Between January 2019 and July 2020, 238 patients were evaluated: 188 in the COV + AKI group and 50 in the COV - AKI group. Filter clotting during the first filter use occurred in 111 patients (46.6%). Heparin use conferred protection against filter clotting (HR = 0.37, 95% CI 0.25-0.55), resulting in longer filter survival. Bleeding events and the need for blood transfusion were similar between the citrate only and citrate plus unfractionated heparin strategies. In-hospital mortality was higher among the COV + AKI patients than among the COV - AKI patients, although it was similar between the COV + AKI patients who received heparin and those who did not. Filter clotting was more common in patients with D-dimer levels above the median (5990 ng/ml). In the multivariate analysis, heparin was associated with a lower risk of filter clotting (HR = 0.28, 95% CI 0.18-0.43), whereas an elevated D-dimer level and high hemoglobin were found to be risk factors for circuit clotting. A diagnosis of COVID-19 was marginally associated with an increased risk of circuit clotting (HR = 2.15, 95% CI 0.99-4.68). CONCLUSIONS:In COV + AKI patients, adding systemic heparin to standard regional citrate anticoagulation may prolong CRRT filter patency by reducing clotting risk with a low risk of complications. 10.1186/s13054-021-03729-9
    Safe use of citric acid-based dialysate and heparin removal in postdilution online hemodiafiltration. Aniort Julien,Petitclerc Thierry,Créput Caroline Blood purification BACKGROUND:Anticoagulation of the blood circuit with heparin is essential for hemodialysis, but exposes patients to several risks (bleeding, thrombocytopenia, etc.). The use of citric acid-based dialysate (CitA-D) allows the reduction of heparin in conventional hemodialysis. We evaluated the feasibility of using CitA-D in postdilution online hemodiafiltration (OL-HDF) and of removing heparin. METHODS:We prospectively compared chlorhydric acid-based dialysate with CitA-D in 10 patients treated by OL-HDF. First, we reduced heparin by half the dose and then we totally removed anticoagulation. RESULTS:For all 120 sessions using heparin-free CitA-D, only one clotting episode related to an arteriovenous fistula stenosis was observed. No adverse clinical effect was observed. (Kt/V)sp, predialytic serum bicarbonate, calcium, phosphate, parathroid hormone, and β2-microglobulin remained the same in all cases. CONCLUSION:Our data suggest that the use of CitA-D in OL-HDF is safe and allows heparin removal in most patients. 10.1159/000345342