Skip to main content
Log in

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

  • Systematic Review
  • Published:
Intensive Care Medicine Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  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 4:266–270

    CAS  PubMed  Google Scholar 

  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 29:575–578

    Article  PubMed  Google Scholar 

  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 38:345–358

    Article  PubMed Central  PubMed  Google Scholar 

  4. Carr JA, Silverman N (1999) The heparin-protamine interaction. A review. J Cardiovasc Surg (Torino) 40:659–666

    CAS  Google Scholar 

  5. Syed S, Reilly RF (2009) Heparin-induced thrombocytopenia: a renal perspective. Nat Rev Nephrol 5:501–511

    Article  PubMed  Google Scholar 

  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 308:258–261

    Article  CAS  PubMed  Google Scholar 

  7. Mehta RL, McDonald BR, Aguilar MM, Ward DM (1990) Regional citrate anticoagulation for continuous arteriovenous hemodialysis in critically ill patients. Kidney Int 38:976–981

    Article  CAS  PubMed  Google Scholar 

  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 30:260–265

    Article  PubMed  Google Scholar 

  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 67:2361–2367

    Article  CAS  PubMed  Google Scholar 

  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 16:131–137

    PubMed  Google Scholar 

  11. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group (2012) KDIGO clinical practice guideline for acute kidney injury. Kidney Inter 2:1–138

    Article  Google Scholar 

  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 38:20–28

    Article  PubMed  Google Scholar 

  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 59:810–818

    Article  CAS  PubMed  Google Scholar 

  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 61:673–685

    Article  PubMed  Google Scholar 

  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 43:1622–1629

    Article  CAS  PubMed  Google Scholar 

  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 19:9

    Article  Google Scholar 

  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 18:472

    Article  PubMed Central  PubMed  Google Scholar 

  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 15:556–564

    Article  CAS  PubMed  Google Scholar 

  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 17:1–12

    Article  CAS  PubMed  Google Scholar 

  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 8:16

    Article  PubMed Central  PubMed  Google Scholar 

  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–W94

    Article  PubMed  Google Scholar 

  22. Parmar MK, Torri V, Stewart L (1998) Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med 17:2815–2834

    Article  CAS  PubMed  Google Scholar 

  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:d4002

    Article  PubMed  Google Scholar 

  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 26:232–239

    Article  CAS  PubMed  Google Scholar 

  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 20:602–608

    CAS  PubMed  Google Scholar 

  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 30:301–307

    CAS  PubMed  Google Scholar 

  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 37:545–552

    Article  CAS  PubMed  Google Scholar 

  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 89:233–236

    Article  CAS  PubMed  Google Scholar 

  29. James MF, Roche AM (2004) Dose-response relationship between plasma ionized calcium concentration and thrombelastography. J Cardiothorac Vasc Anesth 18:581–586

    Article  CAS  PubMed  Google Scholar 

  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–94S

    Article  CAS  PubMed  Google Scholar 

  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 56:665–667

    CAS  PubMed  Google Scholar 

  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 24:806–812

    Article  CAS  PubMed  Google Scholar 

  33. Oudemans-van Straaten HM, Kellum JA, Bellomo R (2011) Clinical review: anticoagulation for continuous renal replacement therapy – heparin or citrate? Crit Care 15:202

    Article  PubMed Central  PubMed  Google Scholar 

  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 87:556–557

    CAS  PubMed  Google Scholar 

  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 255:1025–1029

    Article  CAS  PubMed  Google Scholar 

  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 19:272–278

  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 39:273–279

    Article  CAS  PubMed  Google Scholar 

  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:R162

    Article  PubMed Central  PubMed  Google Scholar 

  39. Beyersmann J, Gastmeier P, Schumacher M (2014) Incidence in ICU populations: how to measure and report it? Intensive Care Med 40:871–876

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

There was no financial support for this work.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Ming Bai or Shiren Sun.

Ethics declarations

Conflicts of interest

The authors have no potential conflicts of interest to disclose.

Additional information

M. Bai, M. Zhou, L. He, and F. Ma contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

134_2015_4099_MOESM1_ESM.tif

Supplementary Figure 1. Funnel plots of comparisons: citrate versus heparin. Outcomes: a circuit loss and b bleeding. (TIFF 10456 kb)

Supplementary material 2 (DOCX 17 kb)

Supplementary material 3 (DOCX 13 kb)

Supplementary material 4 (DOCX 14 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bai, M., Zhou, M., He, L. et al. Citrate versus heparin anticoagulation for continuous renal replacement therapy: an updated meta-analysis of RCTs. Intensive Care Med 41, 2098–2110 (2015). https://doi.org/10.1007/s00134-015-4099-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00134-015-4099-0

Keywords

Navigation