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      Efficacy and safety of citrate-based anticoagulation compared to heparin in patients with acute kidney injury requiring continuous renal replacement therapy: a randomized controlled trial

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          Abstract

          Introduction

          A systemic anticoagulation is often required to prevent circuit and filter clotting in ICU patients undergoing continuous renal replacement therapy (CRRT). A regional citrate-based anticoagulation (RCA) does not induce a systemic anticoagulation and prolongs the filter lifespan, but metabolic side-effects have been associated with this therapy. We conducted a randomized controlled trial with patients requiring CRRT to determine whether RCA using a balanced predilution replacement fluid is more effective than heparin in terms of renal replacement delivered dose and safety profile.

          Methods

          One hundred and three patients with AKI requiring CRRT were included. The patients were randomized to either CRRT with RCA or heparin anticoagulation. Primary endpoints were effective daily delivered RRT dose during the first 3 days of CRRT and filter lifespan. Secondary endpoints were 28-day and 90-day survival and severe metabolic complications and bleeding disorders.

          Results

          Median CRRT duration was 3.0 (2–6) days. Effective delivered daily RRT doses were 29 ± 3 and 27 ± 5 mL/kg/hr in the RCA and heparin groups, respectively (p = 0.005). Filter lifespans were 49 ± 29 versus 28 ± 23 hrs in the RCA and heparin groups (p = 0.004). Survival rates at 28 and 90 days were 80-74% in the RCA and 74-73% in the heparin group. Electrolytes and acid–base disturbances were uncommon and transient in patients treated with RCA.

          Conclusions

          These results show that RCA is superior to heparin-based anticoagulation in terms of delivered RRT dose and filter life span and is a safe and feasible method. This does not translate into an improvement in short term survival.

          Trial registration

          ClinicalTrials.gov NCT01269112. Registered 3rd January 2011.

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          Most cited references22

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          Continuous renal replacement therapy: a worldwide practice survey. The beginning and ending supportive therapy for the kidney (B.E.S.T. kidney) investigators.

          Little information is available regarding current practice in continuous renal replacement therapy (CRRT) for the treatment of acute renal failure (ARF) and the possible clinical effect of practice variation. Prospective observational study. A total of 54 intensive care units (ICUs) in 23 countries. A cohort of 1006 ICU patients treated with CRRT for ARF. Collection of demographic, clinical and outcome data. All patients except one were treated with venovenous circuits, most commonly as venovenous hemofiltration (52.8%). Approximately one-third received CRRT without anticoagulation (33.1%). Among patients who received anticoagulation, unfractionated heparin (UFH) was the most common choice (42.9%), followed by sodium citrate (9.9%), nafamostat mesilate (6.1%), and low-molecular-weight heparin (LMWH; 4.4%). Hypotension related to CRRT occurred in 19% of patients and arrhythmias in 4.3%. Bleeding complications occurred in 3.3% of patients. Treatment with LMWH was associated with a higher incidence of bleeding complications (11.4%) compared to UFH (2.3%, p = 0.0083) and citrate (2.0%, p = 0.029). The median dose of CRRT was 20.4 ml/kg/h. Only 11.7% of patients received a dose of > 35 ml/kg/h. Most (85.5%) survivors recovered to dialysis independence at hospital discharge. Hospital mortality was 63.8%. Multivariable analysis showed that no CRRT-related variables (mode, filter material, drug for anticoagulation, and prescribed dose) predicted hospital mortality. This study supports the notion that, worldwide, CRRT practice is quite variable and not aligned with best evidence.
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            Citrate anticoagulation for continuous venovenous hemofiltration.

            Continuous venovenous hemofiltration (CVVH) is applied in critically ill patients with acute renal failure for renal replacement. Heparins used to prevent circuit clotting may cause bleeding. Regional anticoagulation with citrate reduces bleeding, but has metabolic risks. The aim was to compare the safety and efficacy of the two. Randomized, nonblinded, controlled single-center trial. General intensive care unit of a teaching hospital. Adult critically ill patients needing CVVH for acute renal failure and without an increased bleeding risk. Regional anticoagulation with citrate or systemic anticoagulation with the low-molecular weight heparin nadroparin. End points were adverse events necessitating discontinuation of study anticoagulant, transfusion, metabolic and clinical outcomes, and circuit survival. Of the 215 randomized patients, 200 received CVVH per protocol (97 citrate and 103 nadroparin). Adverse events required discontinuation of citrate in two patients (accumulation and clotting) of nadroparin in 20 (bleeding and thrombocytopenia) (p < 0.001). Bleeding occurred in 6 vs. 16 patients (p = 0.08). The median number of red blood cell units transfused per CVVH day was 0.27 (interquartile range, 0.0-0.63) for citrate, 0.36 (interquartile range, 0-0.83) for nadroparin (p = 0.31). Citrate conferred less metabolic alkalosis (p = 0.001) and lower plasma calcium (p < 0.001). Circuit survival was similar. Three-month mortality on intention-to-treat was 48% (citrate) and 63% (nadroparin) (p = 0.03), per protocol 45% and 62% (p = 0.02). Citrate reduced mortality in surgical patients (p = 0.007), sepsis (p = 0.01), higher Sepsis-Related Organ Failure Assessment score (p = 0.006), and lower age (p = 0.009). The efficacy of citrate and nadroparin anticoagulation for CVVH was similar, however, citrate was safer. Unexpectedly, citrate reduced mortality. Less bleeding could only partly explain this benefit, less clotting could not. Post hoc citrate appeared particularly beneficial after surgery, in sepsis and severe multiple organ failure, suggesting interference with inflammation.
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              Citrate vs. heparin for anticoagulation in continuous venovenous hemofiltration: a prospective randomized study.

              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). Prospective, randomized, clinical trial in a 32-bed medical and surgical ICU in a university teaching hospital. ICU patients with acute renal failure requiring continuous renal replacement therapy, without cirrhosis, severe coagulopathy, or known sensitivity to heparin. 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. 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). Regional citrate anticoagulation seems superior to heparin for the filter lifetime and transfusion requirements in ICU patients treated by continuous renal replacement therapy.
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                Author and article information

                Contributors
                Fabien.Stucker@providence.ch
                Belen.Ponte@hcuge.ch
                James.Tataw@hopitalvs.ch
                Pierre-Yves.Martin@hcuge.ch
                Hannah.Wozniak@hcuge.ch
                Jerome.Pugin@hcuge.ch
                Patrick.Saudan@hcuge.ch
                Journal
                Crit Care
                Critical Care
                BioMed Central (London )
                1364-8535
                1466-609X
                18 March 2015
                18 March 2015
                2015
                : 19
                : 1
                : 91
                Affiliations
                [ ]Nephrology Unit, Geneva University Hospitals, Rue Gabrielle-Perret Gentil 4, Genève, 1205 Switzerland
                [ ]Intensive Care Unit, Geneva University Hospitals, Rue Gabrielle-Perret Gentil 4, Genève, Switzerland
                Article
                822
                10.1186/s13054-015-0822-z
                4364313
                25777912
                ba549877-3931-42bb-9ea4-bd94d889e401
                © Stucker et al.; licensee BioMed Central. 2015

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 21 August 2014
                : 18 February 2015
                Categories
                Research
                Custom metadata
                © The Author(s) 2015

                Emergency medicine & Trauma
                Emergency medicine & Trauma

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