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      Continuous venovenous haemofiltration with citrate-buffered replacement solution is safe and efficacious in patients with a bleeding tendency: a prospective observational study

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          Abstract

          Background

          There is ongoing controversy concerning optimum anticoagulation and buffering in continuous venovenous haemofiltration (CVVH). Regional anticoagulation with trisodium citrate also acting as a buffer in the replacement fluid has several advantages and disadvantages over prefilter citrate administration alone. We analysed a large cohort of patients with acute kidney injury (AKI) treated by the former method and hypothesized that it is safe and efficacious.

          Methods

          Patients admitted at the intensive care unit with AKI and a high bleeding risk, without exclusion of liver disease, treated by CVVH with citrate in a custom-made replacement solution were prospectively included. Patient and CVVH characteristics, including citrate accumulation, were evaluated in outcome groups. A standardized mortality rate (SMR) was calculated using the simplified acute physiology score II.

          Results

          Ninety-seven patients were included; metabolic control was adequate and did not differ between outcome groups, apart from lower pH/bicarbonate in non-survivors. Citrate accumulation was proven in 9% and was timely identified. These patients had about threefold higher plasma transaminases and higher CVVH dose and mortality. The hospital mortality was 60% with a SMR of 1.1 (95% confidence interval 0.90-1.40): age and hyperlactatemia, rather than CVVH-characteristics and citrate accumulation, predicted mortality in multivariable analysis.

          Conclusion

          In critically ill, patients with AKI at high risk of bleeding, CVVH with citrate-containing replacement solution is safe and efficacious. The risk for citrate accumulation is 9% and best predicted by levels of transaminases. It carries, when citrate is discontinued, no attributable mortality.

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          Most cited references28

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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 pharmacokinetics and metabolism in cirrhotic and noncirrhotic critically ill patients.

            To investigate pharmacokinetics and metabolism of sodium citrate in critically ill patients. To determine the risk of citrate accumulation in the setting of liver dysfunction (cirrhosis, hepatorenal syndrome). Prospective cohort study. Intensive Care Unit, Department of Medicine IV, University Hospital Vienna. Consecutive critically ill cirrhotic (n = 16) and noncirrhotic patients (n = 16). Infusion of sodium citrate (0.5 mmol.kg-1.hr-1) and calcium chloride (0.17 mmol.kg-1.hr-1) for 2 hrs. Analysis of serial arterial blood samples. Total body clearance of citrate was normal in noncirrhotic critically ill patients but significantly reduced in cirrhotic patients (710 vs. 340 mL/min, p =.008). Citrate peak concentrations and concentration over time were increased by 65% and 114% in cirrhotic patients (p <.001), respectively; volumes of distribution were similar. Net metabolic changes were quantitatively similar, with pH and plasma bicarbonate concentrations increasing more slowly in cirrhotic patients. No citrate-related side effects were noted. Citrate clearance could not be predicted by standard liver function tests and was not appreciably influenced by renal function and Acute Physiology and Chronic Health Evaluation II scores. This first systematic study on citrate pharmacokinetics and metabolism in critically ill patients confirms a major role of hepatic citrate metabolism by demonstrating reduced citrate clearance in cirrhotic patients. Pharmacokinetic data could provide a basis for the clinical use of citrate anticoagulation in critically ill patients. Provided dose adaptation and monitoring of ionized calcium, citrate anticoagulation seems feasible even in patients with decompensated cirrhosis. Metabolic consequences of citrate infusion were not different between groups in this study but may be more pronounced in prolonged infusion.
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              Regional citrate versus systemic heparin for anticoagulation in critically ill patients on continuous venovenous haemofiltration: a prospective randomized multicentre trial.

              Continuous venovenous haemofiltration (CVVH) in the intensive care setting requires anticoagulation to prevent clotting of the extracorporeal circuit. Several protocols avoiding heparin and using regional citrate anticoagulation have been developed to diminish bleeding risks. However, data from randomized trials comparing citrate anticoagulation with systemic heparinization are very limited. One hundred and seventy-four patients on mechanical ventilation, requiring renal replacement therapy for acute renal failure, were included in this prospective randomized multicentre trial comparing regional citrate with systemic heparin. The study was performed at nine different intensive care units at university or academic teaching hospitals. The participants were randomized to either CVVH using regional citrate anticoagulation or CVVH using systemic anticoagulation with unfractionated heparin. The primary outcome was to compare treatment efficacy represented by the patients' acid base status on Day 3 and on each consecutive day. Several parameters of safety and efficacy were analysed as secondary outcomes. Comparison of standard bicarbonate from Day 3 to Day 11 revealed no difference between both treatment modalities. Use of citrate resulted in less systemic anticoagulation, a lower risk of bleeding and a longer haemofilter patency. Episodes of hypercalcaemia, hypocalcaemia and the need for additional bicarbonate infusions occurred more often under citrate. The patients' high mortality was not influenced by the mode of anticoagulation. Citrate may be used as a regional anticoagulant and the only buffering agent in CVVH with adequate treatment efficacy and safety. However, neither citrate nor heparin anticoagulation should be regarded as a therapeutic standard, since there is no advantage of one of these substances with regard to patient mortality.
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                Author and article information

                Journal
                BMC Nephrol
                BMC Nephrol
                BMC Nephrology
                BioMed Central
                1471-2369
                2013
                18 April 2013
                : 14
                : 89
                Affiliations
                [1 ]Departments of Nephrology, VU University Medical Centre, Amsterdam, The Netherlands
                [2 ]Departments of Intensive Care, VU University Medical Centre, Amsterdam, The Netherlands
                Article
                1471-2369-14-89
                10.1186/1471-2369-14-89
                3637474
                23597045
                6b80793b-e0eb-4d64-9f08-9152c5912566
                Copyright ©2013 Nurmohamed et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 15 October 2012
                : 9 April 2013
                Categories
                Research Article

                Nephrology
                continuous venovenous haemofiltration,citrate,replacement solution,efficacy,safety
                Nephrology
                continuous venovenous haemofiltration, citrate, replacement solution, efficacy, safety

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