Regional Citrate Anticoagulation for Continuous Renal Replacement Therapy: The Better Alternative?
2012; Elsevier BV; Volume: 59; Issue: 6 Linguagem: Inglês
10.1053/j.ajkd.2012.03.003
ISSN1523-6838
AutoresAshita J. Tolwani, Keith Wille,
Tópico(s)Case Reports on Hematomas
ResumoRelated Article, p. 810 Related Article, p. 810 Continuous renal replacement therapy (CRRT) is the favored dialysis modality for critically ill patients who have acute kidney injury, especially those with hemodynamic instability. Extracorporeal circuit clotting is a significant source of inadequate delivery of dialytic dose and is the most frequent cause of CRRT interruptions. Thus, the primary reason for using anticoagulation in CRRT is to prevent premature circuit clotting. Although heparin is still the most commonly prescribed anticoagulant, it carries significant drawbacks, such as increased risk of bleeding and occurrence of heparin-induced thrombocytopenia (HIT). As a result, investigators have explored several other anticoagulation methods, including low-molecular-weight heparins, regional anticoagulation with heparin with protamine, thrombin inhibitors, heparinoids, regional citrate, and platelet-inhibiting agents. Of these alternative methods, regional citrate anticoagulation has gained the most interest. Citrate was first reported as an anticoagulant for hemodialysis in the 1960s1Morita Y. Johnson R.W. Dorn R.E. et al.Regional anticoagulation during hemodialysis using citrate.Am J Med Sci. 1961; 242: 32-43Crossref PubMed Scopus (77) Google Scholar and as an alternative form of regional anticoagulation for CRRT in 1990.2Mehta R.L. McDonald B.R. Aguilar M.M. et al.Regional citrate anticoagulation for continuous arteriovenous hemodialysis in critically ill patients.Kidney Int. 1990; 38: 976-981Crossref PubMed Scopus (281) Google Scholar Despite the publication of numerous regional citrate anticoagulation protocols for CRRT during the last 2 decades, its use worldwide has been limited by concerns regarding patient safety, metabolic complications, cumbersome protocols, costs, and lack of uniformity in its application. In this issue of the American Journal of Kidney Diseases, Wu et al3Wu M. Hsu Y. Bai C. et al.Regional citrate versus heparin anticoagulation for continuous renal replacement therapy: a meta-analysis of randomized controlled trials.Am J Kidney Dis. 2012; 59: 810-818Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar publish a systematic review and meta-analysis of randomized controlled trials comparing the efficacy and safety of regional citrate anticoagulation with that of heparin anticoagulation for CRRT. Six randomized controlled trials4Betjes M.G. van Oosterom D. van Agteren M. van de Wetering J. Regional citrate versus heparin anticoagulation during venovenous hemofiltration in patients at low risk for bleeding: similar hemofilter survival but significantly less bleeding.J Nephrol. 2007; 20: 602-608PubMed Google Scholar, 5Fealy N. Baldwin I. Johnstone M. Egi M. Bellomo R. A pilot randomized controlled crossover study comparing regional heparinization to regional citrate anticoagulation for continuous venovenous hemofiltration.Int J Artif Organs. 2007; 30: 301-307PubMed Google Scholar, 6Hetzel G.R. Schmitz M. Wissing H. et al.Regional citrate versus systemic heparin for anticoagulation in critically ill patients on continuous venovenous haemofiltration: a prospective randomized multicentre trial.Nephrol Dial Transplant. 2011; 26: 232-239Crossref PubMed Scopus (166) Google Scholar, 7Monchi M. Berghmans D. Ledoux D. Canivet J.L. Dubois B. Damas P. Citrate vs. heparin for anticoagulation in continuous venovenous hemofiltration: a prospective randomized study.Intensive Care Med. 2004; 30: 260-265Crossref PubMed Scopus (277) Google Scholar, 8Kutsogiannis D.J. Gibney R.T. Stollery D. Gao J. Regional citrate versus systemic heparin anticoagulation for continuous renal replacement in critically ill patients.Kidney Int. 2005; 67: 2361-2367Crossref PubMed Scopus (227) Google Scholar, 9Oudemans-van Straaten H.M. Bosman R.J. Koopmans M. et al.Citrate anticoagulation for continuous venovenous hemofiltration.Crit Care Med. 2009; 37: 545-552Crossref PubMed Scopus (251) Google Scholar from 2004-2011 were identified and evaluated for the following outcome measures: circuit life span, bleeding events, metabolic complications, and cost. Major bleeding was defined as observation of gross bleeding with a spontaneous decrease in blood pressure, a transfusion requirement of more than 2 units of red blood cells, or a decrease in hemoglobin level ≥2 g/dL within 24 hours. Metabolic alkalosis was defined as pH >7.50. Hypocalcemia was defined as serum calcium level <2.1 mmol/L or ionized calcium level <1.1 mmol/L. The number of patients in the trials ranged from 20-200. Five studies4Betjes M.G. van Oosterom D. van Agteren M. van de Wetering J. Regional citrate versus heparin anticoagulation during venovenous hemofiltration in patients at low risk for bleeding: similar hemofilter survival but significantly less bleeding.J Nephrol. 2007; 20: 602-608PubMed Google Scholar, 5Fealy N. Baldwin I. Johnstone M. Egi M. Bellomo R. A pilot randomized controlled crossover study comparing regional heparinization to regional citrate anticoagulation for continuous venovenous hemofiltration.Int J Artif Organs. 2007; 30: 301-307PubMed Google Scholar, 6Hetzel G.R. Schmitz M. Wissing H. et al.Regional citrate versus systemic heparin for anticoagulation in critically ill patients on continuous venovenous haemofiltration: a prospective randomized multicentre trial.Nephrol Dial Transplant. 2011; 26: 232-239Crossref PubMed Scopus (166) Google Scholar, 7Monchi M. Berghmans D. Ledoux D. Canivet J.L. Dubois B. Damas P. Citrate vs. heparin for anticoagulation in continuous venovenous hemofiltration: a prospective randomized study.Intensive Care Med. 2004; 30: 260-265Crossref PubMed Scopus (277) Google Scholar, 9Oudemans-van Straaten H.M. Bosman R.J. Koopmans M. et al.Citrate anticoagulation for continuous venovenous hemofiltration.Crit Care Med. 2009; 37: 545-552Crossref PubMed Scopus (251) Google Scholar applied continuous venovenous hemofiltration (CVVH), whereas one study8Kutsogiannis D.J. Gibney R.T. Stollery D. Gao J. Regional citrate versus systemic heparin anticoagulation for continuous renal replacement in critically ill patients.Kidney Int. 2005; 67: 2361-2367Crossref PubMed Scopus (227) Google Scholar applied continuous venovenous hemodiafiltration. In their meta-analysis, Wu et al3Wu M. Hsu Y. Bai C. et al.Regional citrate versus heparin anticoagulation for continuous renal replacement therapy: a meta-analysis of randomized controlled trials.Am J Kidney Dis. 2012; 59: 810-818Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar report no statistically significant difference in circuit survival time, incidence of metabolic alkalosis, or HIT between use of regional citrate anticoagulation and heparin. One trial was excluded from the analysis for circuit survival due to inadequate data for pooling.4Betjes M.G. van Oosterom D. van Agteren M. van de Wetering J. Regional citrate versus heparin anticoagulation during venovenous hemofiltration in patients at low risk for bleeding: similar hemofilter survival but significantly less bleeding.J Nephrol. 2007; 20: 602-608PubMed Google Scholar In 3 studies,6Hetzel G.R. Schmitz M. Wissing H. et al.Regional citrate versus systemic heparin for anticoagulation in critically ill patients on continuous venovenous haemofiltration: a prospective randomized multicentre trial.Nephrol Dial Transplant. 2011; 26: 232-239Crossref PubMed Scopus (166) Google Scholar, 7Monchi M. Berghmans D. Ledoux D. Canivet J.L. Dubois B. Damas P. Citrate vs. heparin for anticoagulation in continuous venovenous hemofiltration: a prospective randomized study.Intensive Care Med. 2004; 30: 260-265Crossref PubMed Scopus (277) Google Scholar, 8Kutsogiannis D.J. Gibney R.T. Stollery D. Gao J. Regional citrate versus systemic heparin anticoagulation for continuous renal replacement in critically ill patients.Kidney Int. 2005; 67: 2361-2367Crossref PubMed Scopus (227) Google Scholar the control (heparin) group had significantly shorter circuit survival than the citrate group. Four studies4Betjes M.G. van Oosterom D. van Agteren M. van de Wetering J. Regional citrate versus heparin anticoagulation during venovenous hemofiltration in patients at low risk for bleeding: similar hemofilter survival but significantly less bleeding.J Nephrol. 2007; 20: 602-608PubMed Google Scholar, 7Monchi M. Berghmans D. Ledoux D. Canivet J.L. Dubois B. Damas P. Citrate vs. heparin for anticoagulation in continuous venovenous hemofiltration: a prospective randomized study.Intensive Care Med. 2004; 30: 260-265Crossref PubMed Scopus (277) Google Scholar, 8Kutsogiannis D.J. Gibney R.T. Stollery D. Gao J. Regional citrate versus systemic heparin anticoagulation for continuous renal replacement in critically ill patients.Kidney Int. 2005; 67: 2361-2367Crossref PubMed Scopus (227) Google Scholar, 9Oudemans-van Straaten H.M. Bosman R.J. Koopmans M. et al.Citrate anticoagulation for continuous venovenous hemofiltration.Crit Care Med. 2009; 37: 545-552Crossref PubMed Scopus (251) Google Scholar included data for the occurrence of metabolic alkalosis, and 5 studies4Betjes M.G. van Oosterom D. van Agteren M. van de Wetering J. Regional citrate versus heparin anticoagulation during venovenous hemofiltration in patients at low risk for bleeding: similar hemofilter survival but significantly less bleeding.J Nephrol. 2007; 20: 602-608PubMed Google Scholar, 6Hetzel G.R. Schmitz M. Wissing H. et al.Regional citrate versus systemic heparin for anticoagulation in critically ill patients on continuous venovenous haemofiltration: a prospective randomized multicentre trial.Nephrol Dial Transplant. 2011; 26: 232-239Crossref PubMed Scopus (166) Google Scholar, 7Monchi M. Berghmans D. Ledoux D. Canivet J.L. Dubois B. Damas P. Citrate vs. heparin for anticoagulation in continuous venovenous hemofiltration: a prospective randomized study.Intensive Care Med. 2004; 30: 260-265Crossref PubMed Scopus (277) Google Scholar, 8Kutsogiannis D.J. Gibney R.T. Stollery D. Gao J. Regional citrate versus systemic heparin anticoagulation for continuous renal replacement in critically ill patients.Kidney Int. 2005; 67: 2361-2367Crossref PubMed Scopus (227) Google Scholar, 9Oudemans-van Straaten H.M. Bosman R.J. Koopmans M. et al.Citrate anticoagulation for continuous venovenous hemofiltration.Crit Care Med. 2009; 37: 545-552Crossref PubMed Scopus (251) Google Scholar reported on hypocalcemia, finding that overall it occurred in 4.8% of patients receiving citrate compared with 0.8% of patients treated with heparin. Although statistically significant, no hypocalcemia-related adverse clinical events were reported. All studies evaluated the incidences of major bleeding. A significant difference was found between the 2 groups, with fewer patients in the citrate group experiencing major bleeding. Wu et al3Wu M. Hsu Y. Bai C. et al.Regional citrate versus heparin anticoagulation for continuous renal replacement therapy: a meta-analysis of randomized controlled trials.Am J Kidney Dis. 2012; 59: 810-818Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar determined that the number of patients who required treatment to prevent one additional bad bleeding outcome (number needed to treat) was 6.87. Not enough information was available for a valid cost analysis. Wu et al3Wu M. Hsu Y. Bai C. et al.Regional citrate versus heparin anticoagulation for continuous renal replacement therapy: a meta-analysis of randomized controlled trials.Am J Kidney Dis. 2012; 59: 810-818Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar conclude that regional citrate anticoagulation is safe and effective in CRRT as long as appropriate protocols and monitoring mechanisms are in place. A second meta-analysis of the same 6 randomized controlled trials using slightly different methodology arrived at similar conclusions.10Zhang Z. Hongying N.I. Efficacy and safety of regional citrate anticoagulation in critically ill patients undergoing continuous renal replacement therapy.Intensive Care Med. 2012; 38: 20-28Crossref PubMed Scopus (119) Google Scholar Important limitations of this analysis deserve further discussion. First, there was significant heterogeneity among the randomized controlled trials, including differences in patient characteristics, definitions of filter clotting, CRRT modalities, dialyzer types, blood flow and effluent rates, and citrate and heparin protocols. Each study used a different citrate protocol, and characteristics of the control groups' anticoagulation varied substantially among studies. Three studies used predilution replacement fluid and 3 studies used postdilution replacement fluid. Regarding the control arm, one study used nadroparin,9Oudemans-van Straaten H.M. Bosman R.J. Koopmans M. et al.Citrate anticoagulation for continuous venovenous hemofiltration.Crit Care Med. 2009; 37: 545-552Crossref PubMed Scopus (251) Google Scholar one study5Fealy N. Baldwin I. Johnstone M. Egi M. Bellomo R. A pilot randomized controlled crossover study comparing regional heparinization to regional citrate anticoagulation for continuous venovenous hemofiltration.Int J Artif Organs. 2007; 30: 301-307PubMed Google Scholar used regional heparin, and the remaining 4 studies4Betjes M.G. van Oosterom D. van Agteren M. van de Wetering J. Regional citrate versus heparin anticoagulation during venovenous hemofiltration in patients at low risk for bleeding: similar hemofilter survival but significantly less bleeding.J Nephrol. 2007; 20: 602-608PubMed Google Scholar, 6Hetzel G.R. Schmitz M. Wissing H. et al.Regional citrate versus systemic heparin for anticoagulation in critically ill patients on continuous venovenous haemofiltration: a prospective randomized multicentre trial.Nephrol Dial Transplant. 2011; 26: 232-239Crossref PubMed Scopus (166) Google Scholar, 7Monchi M. Berghmans D. Ledoux D. Canivet J.L. Dubois B. Damas P. Citrate vs. heparin for anticoagulation in continuous venovenous hemofiltration: a prospective randomized study.Intensive Care Med. 2004; 30: 260-265Crossref PubMed Scopus (277) Google Scholar, 8Kutsogiannis D.J. Gibney R.T. Stollery D. Gao J. Regional citrate versus systemic heparin anticoagulation for continuous renal replacement in critically ill patients.Kidney Int. 2005; 67: 2361-2367Crossref PubMed Scopus (227) Google Scholar used systemic heparin. Second, the number of patients studied was relatively small; only 2 studies included more than 100 participants. Third, some studies adjusted citrate dose based on postfilter ionized calcium levels, whereas others used a fixed dose of citrate in relation to blood flow. Consequently, underdosing of citrate may have had a role in the lack of difference in circuit survival in the trials that did not measure or ensure adequate citrate anticoagulation. Citrate chelates calcium, and a citrate concentration of 4-6 mmol per liter of blood flow (corresponding to ionized calcium level <0.35 mmol/L) is required to prevent activation of both coagulation cascades and platelets.11Sakariassen K.S. Ottenhof-Rovers M. Sixma J.J. Factor VIII-von Willebrand factor requires calcium for facilitation of platelet adherence.Blood. 1984; 63: 996-1003Crossref PubMed Google Scholar In the largest regional citrate anticoagulation trial, conducted by Oudemans-van Straaten et al,9Oudemans-van Straaten H.M. Bosman R.J. Koopmans M. et al.Citrate anticoagulation for continuous venovenous hemofiltration.Crit Care Med. 2009; 37: 545-552Crossref PubMed Scopus (251) Google Scholar 200 patients with postdilution CVVH were randomly assigned to citrate or low-molecular-weight heparin. Citrate was administered at a dose of 3 mmol per liter of blood flow without monitoring postfilter ionized calcium. This dose may have resulted in inadequate anticoagulation and negatively affected the combined pooled results of the studies regarding circuit patency with citrate. Fourth, most studies excluded patients with liver cirrhosis, high risk of bleeding, severe coagulation disorders, and HIT. Therefore, the study results cannot be applied to these patient groups. Finally, all studies were conducted outside the United States because citrate is not a US Food and Drug Administration (FDA)-approved anticoagulant for CRRT, limiting the practicality of regional citrate anticoagulation in the United States. Considering the limitations of the randomized controlled trials and their combined analysis, Wu et al3Wu M. Hsu Y. Bai C. et al.Regional citrate versus heparin anticoagulation for continuous renal replacement therapy: a meta-analysis of randomized controlled trials.Am J Kidney Dis. 2012; 59: 810-818Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar successfully show that regional citrate anticoagulation effectively lowers the risk of bleeding and maintains circuit patency. For patients at high risk of bleeding, citrate may be superior to heparin in CRRT. Currently, a large Dutch multicenter trial randomly assigning patients into CVVH with regional citrate anticoagulation or unfractionated heparin (ClinicalTrials.gov study number NCT00209378) is underway and should provide further evidence about which anticoagulant is superior in CRRT. Primary outcome measures of the study are mortality, circuit survival, and bleeding complications. The pivotal question now is how the results of this meta-analysis should be applied to daily clinical practice. Although there is mounting evidence that regional citrate anticoagulation lowers bleeding risk and may prolong filter patency compared with heparin, widespread acceptance of citrate in the United States is limited by lack of FDA approval and lack of commercially available citrate formulations specific for CRRT. The available citrate solutions have high citrate and sodium concentrations and are not intended for anticoagulation for CRRT, potentiating the development of electrolyte abnormalities. However, despite not having FDA approval, the use of citrate for CRRT is gaining support in the United States. This may be due to the advent of simplified protocols, various CRRT techniques that have been adapted to address the complications of citrate, the development of commercially available calcium-free CRRT solutions, and published randomized controlled trials showing the advantages of citrate in patients who require CRRT but are at high risk of bleeding. Full acceptance of regional citrate anticoagulation can be achieved only if risks are minimized through well-designed protocols, competent staff, the availability of suitable citrate solutions formulated and intended for CRRT, and the automation of CRRT devices for citrate delivery. Financial Disclosure: Dr Tolwani has received payment from Gambro for expert testimony on the use of citrate as anticoagulant and through the Gambro Expert Panel/Speakers Bureau for educational presentations on CRRT. Dr Tolwani has a patent on the 0.5% citrate formulation used at the University of Alabama at Birmingham for CRRT, for which she has received no payment. Dr Wille declares that he has no relevant financial interests. Regional Citrate Versus Heparin Anticoagulation for Continuous Renal Replacement Therapy: A Meta-Analysis of Randomized Controlled TrialsAmerican Journal of Kidney DiseasesVol. 59Issue 6PreviewAnticoagulation of the extracorporeal circuit is required in continuous renal replacement therapy (CRRT). Heparin is the classic choice for anticoagulation, although it may increase the risk of bleeding. Regional citrate anticoagulation reduces the risk of bleeding, but may cause hypocalcemia and metabolic disturbances. Full-Text PDF
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