Intensive Care Medicine

, Volume 41, Issue 12, pp 2098–2110 | Cite as

Citrate versus heparin anticoagulation for continuous renal replacement therapy: an updated meta-analysis of RCTs

  • Ming Bai
  • Meilan Zhou
  • Lijie He
  • Feng Ma
  • Yangping Li
  • Yan Yu
  • Pengbo Wang
  • Li Li
  • Rui Jing
  • Lijuan Zhao
  • Shiren Sun
Systematic Review



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.


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.


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.


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.


Continuous renal replacement therapy Citrate Heparin Anticoagulation Randomized controlled trial Meta-analysis 



There was no financial support for this work.

Compliance with ethical standards

Conflicts of interest

The authors have no potential conflicts of interest to disclose.

Supplementary material

134_2015_4099_MOESM1_ESM.tif (10.2 mb)
Supplementary Figure 1. Funnel plots of comparisons: citrate versus heparin. Outcomes: a circuit loss and b bleeding. (TIFF 10456 kb)
134_2015_4099_MOESM2_ESM.docx (17 kb)
Supplementary material 2 (DOCX 17 kb)
134_2015_4099_MOESM3_ESM.docx (13 kb)
Supplementary material 3 (DOCX 13 kb)
134_2015_4099_MOESM4_ESM.docx (15 kb)
Supplementary material 4 (DOCX 14 kb)


  1. 1.
    Fealy N, Baldwin I, Bellomo R (2002) The effect of circuit “down-time” on uraemic control during continuous veno-venous haemofiltration. Crit Care Resusc 4:266–270PubMedGoogle Scholar
  2. 2.
    Uchino S, Fealy N, Baldwin I, Morimatsu H, Bellomo R (2003) Continuous is not continuous: the incidence and impact of circuit “down-time” on uraemic control during continuous veno-venous haemofiltration. Intensive Care Med 29:575–578CrossRefPubMedGoogle Scholar
  3. 3.
    Antonelli M, Bonten M, Chastre J, Citerio G, Conti G, Curtis JR, De Backer D, Hedenstierna G, Joannidis M, Macrae D, Mancebo J, Maggiore SM, Mebazaa A, Preiser JC, Rocco P, Timsit JF, Wernerman J, Zhang H (2012) Year in review in Intensive Care Medicine 2011. II. Cardiovascular, infections, pneumonia and sepsis, critical care organization and outcome, education, ultrasonography, metabolism and coagulation. Intensive Care Med 38:345–358PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Carr JA, Silverman N (1999) The heparin-protamine interaction. A review. J Cardiovasc Surg (Torino) 40:659–666Google Scholar
  5. 5.
    Syed S, Reilly RF (2009) Heparin-induced thrombocytopenia: a renal perspective. Nat Rev Nephrol 5:501–511CrossRefPubMedGoogle Scholar
  6. 6.
    Pinnick RV, Wiegmann TB, Diederich DA (1983) Regional citrate anticoagulation for hemodialysis in the patient at high risk for bleeding. N Engl J Med 308:258–261CrossRefPubMedGoogle Scholar
  7. 7.
    Mehta RL, McDonald BR, Aguilar MM, Ward DM (1990) Regional citrate anticoagulation for continuous arteriovenous hemodialysis in critically ill patients. Kidney Int 38:976–981CrossRefPubMedGoogle Scholar
  8. 8.
    Monchi M, Berghmans D, Ledoux D, Canivet JL, Dubois B, Damas P (2004) Citrate vs. heparin for anticoagulation in continuous venovenous hemofiltration: a prospective randomized study. Intensive Care Med 30:260–265CrossRefPubMedGoogle Scholar
  9. 9.
    Kutsogiannis DJ, Gibney RT, Stollery D, Gao J (2005) Regional citrate versus systemic heparin anticoagulation for continuous renal replacement in critically ill patients. Kidney Int 67:2361–2367CrossRefPubMedGoogle Scholar
  10. 10.
    Brain MJ, Roodenburg OS, Adams N, McCracken P, Hockings L, Musgrave S, Butt W, Scheinkestel C (2014) Randomised trial of software algorithm driven regional citrate anticoagulation versus heparin in continuous renal replacement therapy: the filter life in renal replacement therapy pilot trial. Crit Care Resusc 16:131–137PubMedGoogle Scholar
  11. 11.
    Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group (2012) KDIGO clinical practice guideline for acute kidney injury. Kidney Inter 2:1–138CrossRefGoogle Scholar
  12. 12.
    Zhang Z, Hongying N (2012) Efficacy and safety of regional citrate anticoagulation in critically ill patients undergoing continuous renal replacement therapy. Intensive Care Med 38:20–28CrossRefPubMedGoogle Scholar
  13. 13.
    Wu MY, Hsu YH, Bai CH, Lin YF, Wu CH, Tam KW (2012) Regional citrate versus heparin anticoagulation for continuous renal replacement therapy: a meta-analysis of randomized controlled trials. Am J Kidney Dis 59:810–818CrossRefPubMedGoogle Scholar
  14. 14.
    James M, Bouchard J, Ho J, Klarenbach S, LaFrance JP, Rigatto C, Wald R, Zappitelli M, Pannu N (2013) Canadian Society of Nephrology commentary on the 2012 KDIGO clinical practice guideline for acute kidney injury. Am J Kidney Dis 61:673–685CrossRefPubMedGoogle Scholar
  15. 15.
    Gattas DJ, Rajbhandari D, Bradford C, Buhr H, Lo S, Bellomo R (2015) A randomized controlled trial of regional citrate versus regional heparin anticoagulation for continuous renal replacement therapy in critically ill adults. Crit Care Med 43:1622–1629CrossRefPubMedGoogle Scholar
  16. 16.
    Stucker F, Ponte B, Tataw J, Martin P, Wozniak H, Pugin J, Saudan P (2015) Efficacy and safety of citrate-based anticoagulation compared to heparin in patients with acute kidney injury requiring continuous renal replacement therapy: a randomized controlled trial. Crit Care 19:9CrossRefGoogle Scholar
  17. 17.
    Schilder L, Nurmohamed SA, Bosch FH, Purmer IM, den Boer SS, Kleppe CG, Vervloet MG, Beishuizen A, Girbes AR, Ter Wee PM, Groeneveld AB (2014) Citrate anticoagulation versus systemic heparinisation in continuous venovenous hemofiltration in critically ill patients with acute kidney injury: a multi-center randomized clinical trial. Crit Care 18:472PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    Tiranathanagul K, Jearnsujitwimol O, Susantitaphong P, Kijkriengkraikul N, Leelahavanichkul A, Srisawat N, Praditpornsilpa K, Eiam-Ong S (2011) Regional citrate anticoagulation reduces polymorphonuclear cell degranulation in critically ill patients treated with continuous venovenous hemofiltration. Ther Apher Dial 15:556–564CrossRefPubMedGoogle Scholar
  19. 19.
    Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17:1–12CrossRefPubMedGoogle Scholar
  20. 20.
    Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR (2007) Practical methods for incorporating summary time-to-event data into meta-analysis. Trials 8:16PubMedCentralCrossRefPubMedGoogle Scholar
  21. 21.
    Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med 151:W65–W94CrossRefPubMedGoogle Scholar
  22. 22.
    Parmar MK, Torri V, Stewart L (1998) Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med 17:2815–2834CrossRefPubMedGoogle Scholar
  23. 23.
    Sterne JA, Sutton AJ, Ioannidis JP, Terrin N, Jones DR, Lau J, Carpenter J, Rucker G, Harbord RM, Schmid CH, Tetzlaff J, Deeks JJ, Peters J, Macaskill P, Schwarzer G, Duval S, Altman DG, Moher D, Higgins JP (2011) Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ 343:d4002CrossRefPubMedGoogle Scholar
  24. 24.
    Hetzel GR, Schmitz M, Wissing H, Ries W, Schott G, Heering PJ, Isgro F, Kribben A, Himmele R, Grabensee B, Rump LC (2011) Regional citrate versus systemic heparin for anticoagulation in critically ill patients on continuous venovenous haemofiltration: a prospective randomized multicentre trial. Nephrol Dial Transplant 26:232–239CrossRefPubMedGoogle Scholar
  25. 25.
    Betjes MG, van Oosterom D, van Agteren M, van de Wetering J (2007) Regional citrate versus heparin anticoagulation during venovenous hemofiltration in patients at low risk for bleeding: similar hemofilter survival but significantly less bleeding. J Nephrol 20:602–608PubMedGoogle Scholar
  26. 26.
    Fealy N, Baldwin I, Johnstone M, Egi M, Bellomo R (2007) A pilot randomized controlled crossover study comparing regional heparinization to regional citrate anticoagulation for continuous venovenous hemofiltration. Int J Artif Organs 30:301–307PubMedGoogle Scholar
  27. 27.
    Oudemans-van Straaten HM, Bosman RJ, Koopmans M, van der Voort PH, Wester JP, van der Spoel JI, Dijksman LM, Zandstra DF (2009) Citrate anticoagulation for continuous venovenous hemofiltration. Crit Care Med 37:545–552CrossRefPubMedGoogle Scholar
  28. 28.
    Calatzis A, Toepfer M, Schramm W, Spannagl M, Schiffl H (2001) Citrate anticoagulation for extracorporeal circuits: effects on whole blood coagulation activation and clot formation. Nephron 89:233–236CrossRefPubMedGoogle Scholar
  29. 29.
    James MF, Roche AM (2004) Dose-response relationship between plasma ionized calcium concentration and thrombelastography. J Cardiothorac Vasc Anesth 18:581–586CrossRefPubMedGoogle Scholar
  30. 30.
    Hirsh J, Warkentin TE, Shaughnessy SG, Anand SS, Halperin JL, Raschke R, Granger C, Ohman EM, Dalen JE (2001) Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest 119:64S–94SCrossRefPubMedGoogle Scholar
  31. 31.
    Cohen JR, Sarfati I, Birnbaum E, Benacquista T, Wise L (1990) The inactivation of antithrombin III by serum elastase in patients with surgical infections. Am Surg 56:665–667PubMedGoogle Scholar
  32. 32.
    Martin PY, Chevrolet JC, Suter P, Favre H (1994) Anticoagulation in patients treated by continuous venovenous hemofiltration: a retrospective study. Am J Kidney Dis 24:806–812CrossRefPubMedGoogle Scholar
  33. 33.
    Oudemans-van Straaten HM, Kellum JA, Bellomo R (2011) Clinical review: anticoagulation for continuous renal replacement therapy – heparin or citrate? Crit Care 15:202PubMedCentralCrossRefPubMedGoogle Scholar
  34. 34.
    Jaichenko J, Schustack A, Abraham D, Gotloib L (1987) Regional heparinization facilitates safe hemodialysis and/or hemofiltration in the critically ill patient. Am J Clin Pathol 87:556–557PubMedGoogle Scholar
  35. 35.
    Gordon LA, Perkins HA, Richards V (1956) Studies in regional heparinization. I. The use of simultaneous neutralization with protamine; preliminary studies. N Engl J Med 255:1025–1029CrossRefPubMedGoogle Scholar
  36. 36.
    De Vico P, Messino V, Tartaglione A, Beccaris C, Buonomo C, Talarico D, Prati P, Sabato AF, Colella DF (2015) Safety and efficacy of citrate anti-coagulation continuous renal replacement therapies in post-cardiac surgery patients with liver dysfunction. Ther Apher Dial 19:272–278Google Scholar
  37. 37.
    Faybik P, Hetz H, Mitterer G, Krenn CG, Schiefer J, Funk GC, Bacher A (2011) Regional citrate anticoagulation in patients with liver failure supported by a molecular adsorbent recirculating system. Crit Care Med 39:273–279CrossRefPubMedGoogle Scholar
  38. 38.
    Schultheiss C, Saugel B, Phillip V, Thies P, Noe S, Mayr U, Haller B, Einwachter H, Schmid RM, Huber W (2012) Continuous venovenous hemodialysis with regional citrate anticoagulation in patients with liver failure: a prospective observational study. Crit Care 16:R162PubMedCentralCrossRefPubMedGoogle Scholar
  39. 39.
    Beyersmann J, Gastmeier P, Schumacher M (2014) Incidence in ICU populations: how to measure and report it? Intensive Care Med 40:871–876CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg and ESICM 2015

Authors and Affiliations

  • Ming Bai
    • 1
  • Meilan Zhou
    • 1
  • Lijie He
    • 1
  • Feng Ma
    • 1
  • Yangping Li
    • 1
  • Yan Yu
    • 1
  • Pengbo Wang
    • 1
  • Li Li
    • 1
  • Rui Jing
    • 1
  • Lijuan Zhao
    • 1
  • Shiren Sun
    • 1
  1. 1.Department of Nephrology, Xijing HospitalThe Fourth Military Medical UniversityXi’anChina

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