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Table of Contents
Vol. 29, No. 2, 2010
Issue release date: January 2010
Blood Purif 2010;29:191–196
(DOI:10.1159/000245646)

Citrate Anticoagulation for Continuous Renal Replacement Therapy in the Critically Ill

Oudemans-van Straaten H.M.
Department of Intensive Care Medicine, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands
email Corresponding Author

Abstract

Background: Heparins are used for circuit anticoagulation during continuous renal replacement therapy (CRRT). Because heparins cause systemic anticoagulation, they increase the risk of bleeding. Citrate provides regional anticoagulation. Since citrate is a buffer as well, its use has metabolic consequences. The preferential use of citrate therefore remains controversial. Methods: A synthesis was performed of published studies comparing citrate to heparin for anticoagulation in CRRT with specific regard to feasibility, efficacy and safety. Search of the literature was made to explain the reported superiority of citrate. Results: Citrate provides good metabolic control if and when a well-designed protocol is strictly followed. Randomized studies report similar or longer circuit survival with citrate compared to heparin and less bleeding. The largest randomized trial up to now found that citrate was better tolerated than heparin and improved patient and kidney survival, especially in patients after surgery, with sepsis, a high degree of organ failure or younger age. Both citrate and heparin interfere with inflammation. Conclusion: During critical illness, regional anticoagulation with citrate for CRRT seems superior to heparin anticoagulation concerning tolerance and safety, mainly due to less bleeding. Whether circuit survival is better depends on the modality. In addition, citrate seems to improve patient and kidney survival. This finding needs to be confirmed. Citrate seems to confer a specific benefit in severe organ failure and sepsis. To what extent citrate protects or heparin does harm in the setting of multiple organ failure needs to be unraveled.


 goto top of outline Key Words

  • Heparin
  • Citrate
  • Hemofiltration
  • Hemodialysis
  • Anticoagulation
  • Hemorrhage
  • Sepsis
  • Organ failure
  • Biocompatibility
  • Survival

 goto top of outline Abstract

Background: Heparins are used for circuit anticoagulation during continuous renal replacement therapy (CRRT). Because heparins cause systemic anticoagulation, they increase the risk of bleeding. Citrate provides regional anticoagulation. Since citrate is a buffer as well, its use has metabolic consequences. The preferential use of citrate therefore remains controversial. Methods: A synthesis was performed of published studies comparing citrate to heparin for anticoagulation in CRRT with specific regard to feasibility, efficacy and safety. Search of the literature was made to explain the reported superiority of citrate. Results: Citrate provides good metabolic control if and when a well-designed protocol is strictly followed. Randomized studies report similar or longer circuit survival with citrate compared to heparin and less bleeding. The largest randomized trial up to now found that citrate was better tolerated than heparin and improved patient and kidney survival, especially in patients after surgery, with sepsis, a high degree of organ failure or younger age. Both citrate and heparin interfere with inflammation. Conclusion: During critical illness, regional anticoagulation with citrate for CRRT seems superior to heparin anticoagulation concerning tolerance and safety, mainly due to less bleeding. Whether circuit survival is better depends on the modality. In addition, citrate seems to improve patient and kidney survival. This finding needs to be confirmed. Citrate seems to confer a specific benefit in severe organ failure and sepsis. To what extent citrate protects or heparin does harm in the setting of multiple organ failure needs to be unraveled.

Copyright © 2010 S. Karger AG, Basel


 goto top of outline References
  1. Monchi M, Berghmans D, Ledoux D, Canivet JL, Dubois B, Damas P: Citrate vs heparin for anticoagulation in continuous venovenous hemofiltration: a prospective randomized study. Intensive Care Med 2004;30:260–265.
  2. Kutsogiannis DJ, Gibney RT, Stollery D, Gao J: Regional citrate versus systemic heparin anticoagulation for continuous renal replacement in critically ill patients. Kidney Int 2005;67:2361–2367.
  3. Betjes MG, 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;20:602–608.
  4. Oudemans-van Straaten HM, Bosman RJ, Koopmans M, van der Voort PH, Wester JP, van der Spoel JI, Dijksman LM, Zandstra DF: Citrate anticoagulation for continuous venovenous hemofiltration. Crit Care Med 2009;37:545–552.
  5. Mehta RL, McDonald BR, Aguilar MM, Ward DM: Regional citrate anticoagulation for continuous arteriovenous hemodialysis in critically ill patients. Kidney Int 1990;38:976–981.
  6. Oudemans-van Straaten HM, Wester JP, de Pont AC, Schetz MR: Anticoagulation strategies in continuous renal replacement therapy: can the choice be evidence based? Intensive Care Med 2006;32:188–202.
  7. Chadha V, Garg U, Warady BA, Alon US: Citrate clearance in children receiving continuous venovenous renal replacement therapy. Pediatr Nephrol 2002;17:819–824.
  8. Apsner R, Schwarzenhofer M, Derfler K, Zauner C, Ratheiser K, Kranz A: Impairment of citrate metabolism in acute hepatic failure. Wien Klin Wochenschr 1997;109:123–127.
  9. Kramer L, Bauer E, Joukhadar C, Strobl W, Gendo A, Madl C, Gangl A: Citrate pharmacokinetics and metabolism in cirrhotic and noncirrhotic critically ill patients. Crit Care Med 2003;31:2450–2455.
  10. Meier-Kriesche HU, Gitomer J, Finkel K, Du Bose T: Increased total to ionized calcium ratio during continuous venovenous hemodialysis with regional citrate anticoagulation. Crit Care Med 2001;29:748–752.
  11. Bakker AJ, Boerma EC, Keidel H, Kingma P, van der Voort PH: Detection of citrate overdose in critically ill patients on citrate-anticoagulated venovenous haemofiltration: use of ionised and total/ionised calcium. Clin Chem Lab Med 2006;44:962–966.
  12. Joannidis M, Oudemans-van Straaten HM: Clinical review: patency of the circuit in continuous renal replacement therapy. Crit Care 2007;11:218.
  13. Bohler J, Schollmeyer P, Dressel B, Dobos G, Horl WH: Reduction of granulocyte activation during hemodialysis with regional citrate anticoagulation: dissociation of complement activation and neutropenia from neutrophil degranulation. J Am Soc Nephrol 1996;7:234–241.
  14. Bos JC, Grooteman MP, van Houte AJ, Schoorl M, van Limbeek J, Nube MJ: Low polymorphonuclear cell degranulation during citrate anticoagulation: a comparison between citrate and heparin dialysis. Nephrol Dial Transplant 1997;12:1387–1393.
  15. Gabutti L, Ferrari N, Mombelli G, Keller F, Marone C: The favorable effect of regional citrate anticoagulation on interleukin-1beta release is dissociated from both coagulation and complement activation. J Nephrol 2004;17:819–825.
  16. Gritters M, Grooteman MP, Schoorl M, Schoorl M, Bartels PC, Scheffer PG, Teerlink T, Schalkwijk CG, Spreeuwenberg M, Nube MJ: Citrate anticoagulation abolishes degranulation of polymorphonuclear cells and platelets and reduces oxidative stress during haemodialysis. Nephrol Dial Transplant 2006;21:153–159.
  17. Bohler J, Donauer J, Birmelin M, Schollmeyer PJ, Horl WH: Mediators of complement-independent granulocyte activation during haemodialysis: role of calcium, prostaglandins and leukotrienes. Nephrol Dial Transplant 1993;8:1359–1365.
  18. Andersson T, Dahlgren C, Pozzan T, Stendahl O, Lew PD: Characterization of fMet-Leu-Phe receptor-mediated Ca2+ influx across the plasma membrane of human neutrophils. Mol Pharmacol 1986;30:437–443.
  19. Leitienne P, Fouque D, Rigal D, Adeleine P, Trzeciak MC, Laville M: Heparins and blood polymorphonuclear stimulation in haemodialysis: an expansion of the biocompatibility concept. Nephrol Dial Transplant 2000;15:1631–1637.
  20. Gritters M, Borgdorff P, Grooteman MP, Schoorl M, Schoorl M, Bartels PC, Tangelder GJ, Nube MJ: Platelet activation in clinical haemodialysis: LMWH as a major contributor to bio-incompatibility? Nephrol Dial Transplant 2008;23:2911–2917.
  21. Borawski J: Myeloperoxidase as a marker of hemodialysis biocompatibility and oxidative stress: the underestimated modifying effects of heparin. Am J Kidney Dis 2006;47:37–41.
  22. Hoffmann JN, Vollmar B, Laschke MW, Inthorn D, Kaneider NC, Dunzendorfer S, Wiedermann CJ, Romisch J, Schildberg FW, Menger MD: Adverse effect of heparin on antithrombin action during endotoxemia: microhemodynamic and cellular mechanisms. Thromb Haemost 2002;88:242–252.
  23. Kaneider NC, Forster E, Mosheimer B, Sturn DH, Wiedermann CJ: Syndecan-4-dependent signaling in the inhibition of endotoxin-induced endothelial adherence of neutrophils by antithrombin. Thromb Haemost 2003;90:1150–1157.
  24. Cornet AD, Smit EG, Beishuizen A, Groeneveld AB: The role of heparin and allied compounds in the treatment of sepsis. Thromb Haemost 2007;98:579–586.
  25. Weinberg JM, Venkatachalam MA, Roeser NF, Nissim I: Mitochondrial dysfunction during hypoxia/reoxygenation and its correction by anaerobic metabolism of citric acid cycle intermediates. Proc Natl Acad Sci USA 2000;97:2826–2831.
  26. Feldkamp T, Weinberg JM, Horbelt M, Von Kropff C, Witzke O, Nurnberger J, Kribben A: Evidence for involvement of nonesterified fatty acid-induced protonophoric uncoupling during mitochondrial dysfunction caused by hypoxia and reoxygenation. Nephrol Dial Transplant 2009;24:43–51.

 goto top of outline Author Contacts

Heleen M. Oudemans-van Straaten
Department of Intensive Care Medicine, Onze Lieve Vrouwe Gasthuis
Oosterpark 9, NL–1091 AC Amsterdam (The Netherlands)
Tel. +31 205 993 007, Fax +31 205 992 128
E-Mail h.m.oudemans-vanstraaten@olvg.nl


 goto top of outline Article Information

Published online: January 8, 2010
Number of Print Pages : 6
Number of Figures : 0, Number of Tables : 2, Number of References : 26


 goto top of outline Publication Details

Blood Purification

Vol. 29, No. 2, Year 2010 (Cover Date: January 2010)

Journal Editor: Ronco C. (Vicenza)
ISSN: 0253-5068 (Print), eISSN: 1421-9735 (Online)

For additional information: http://www.karger.com/BPU


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Background: Heparins are used for circuit anticoagulation during continuous renal replacement therapy (CRRT). Because heparins cause systemic anticoagulation, they increase the risk of bleeding. Citrate provides regional anticoagulation. Since citrate is a buffer as well, its use has metabolic consequences. The preferential use of citrate therefore remains controversial. Methods: A synthesis was performed of published studies comparing citrate to heparin for anticoagulation in CRRT with specific regard to feasibility, efficacy and safety. Search of the literature was made to explain the reported superiority of citrate. Results: Citrate provides good metabolic control if and when a well-designed protocol is strictly followed. Randomized studies report similar or longer circuit survival with citrate compared to heparin and less bleeding. The largest randomized trial up to now found that citrate was better tolerated than heparin and improved patient and kidney survival, especially in patients after surgery, with sepsis, a high degree of organ failure or younger age. Both citrate and heparin interfere with inflammation. Conclusion: During critical illness, regional anticoagulation with citrate for CRRT seems superior to heparin anticoagulation concerning tolerance and safety, mainly due to less bleeding. Whether circuit survival is better depends on the modality. In addition, citrate seems to improve patient and kidney survival. This finding needs to be confirmed. Citrate seems to confer a specific benefit in severe organ failure and sepsis. To what extent citrate protects or heparin does harm in the setting of multiple organ failure needs to be unraveled.



 goto top of outline Author Contacts

Heleen M. Oudemans-van Straaten
Department of Intensive Care Medicine, Onze Lieve Vrouwe Gasthuis
Oosterpark 9, NL–1091 AC Amsterdam (The Netherlands)
Tel. +31 205 993 007, Fax +31 205 992 128
E-Mail h.m.oudemans-vanstraaten@olvg.nl


 goto top of outline Article Information

Published online: January 8, 2010
Number of Print Pages : 6
Number of Figures : 0, Number of Tables : 2, Number of References : 26


 goto top of outline Publication Details

Blood Purification

Vol. 29, No. 2, Year 2010 (Cover Date: January 2010)

Journal Editor: Ronco C. (Vicenza)
ISSN: 0253-5068 (Print), eISSN: 1421-9735 (Online)

For additional information: http://www.karger.com/BPU


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Monchi M, Berghmans D, Ledoux D, Canivet JL, Dubois B, Damas P: Citrate vs heparin for anticoagulation in continuous venovenous hemofiltration: a prospective randomized study. Intensive Care Med 2004;30:260–265.
  2. Kutsogiannis DJ, Gibney RT, Stollery D, Gao J: Regional citrate versus systemic heparin anticoagulation for continuous renal replacement in critically ill patients. Kidney Int 2005;67:2361–2367.
  3. Betjes MG, 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;20:602–608.
  4. Oudemans-van Straaten HM, Bosman RJ, Koopmans M, van der Voort PH, Wester JP, van der Spoel JI, Dijksman LM, Zandstra DF: Citrate anticoagulation for continuous venovenous hemofiltration. Crit Care Med 2009;37:545–552.
  5. Mehta RL, McDonald BR, Aguilar MM, Ward DM: Regional citrate anticoagulation for continuous arteriovenous hemodialysis in critically ill patients. Kidney Int 1990;38:976–981.
  6. Oudemans-van Straaten HM, Wester JP, de Pont AC, Schetz MR: Anticoagulation strategies in continuous renal replacement therapy: can the choice be evidence based? Intensive Care Med 2006;32:188–202.
  7. Chadha V, Garg U, Warady BA, Alon US: Citrate clearance in children receiving continuous venovenous renal replacement therapy. Pediatr Nephrol 2002;17:819–824.
  8. Apsner R, Schwarzenhofer M, Derfler K, Zauner C, Ratheiser K, Kranz A: Impairment of citrate metabolism in acute hepatic failure. Wien Klin Wochenschr 1997;109:123–127.
  9. Kramer L, Bauer E, Joukhadar C, Strobl W, Gendo A, Madl C, Gangl A: Citrate pharmacokinetics and metabolism in cirrhotic and noncirrhotic critically ill patients. Crit Care Med 2003;31:2450–2455.
  10. Meier-Kriesche HU, Gitomer J, Finkel K, Du Bose T: Increased total to ionized calcium ratio during continuous venovenous hemodialysis with regional citrate anticoagulation. Crit Care Med 2001;29:748–752.
  11. Bakker AJ, Boerma EC, Keidel H, Kingma P, van der Voort PH: Detection of citrate overdose in critically ill patients on citrate-anticoagulated venovenous haemofiltration: use of ionised and total/ionised calcium. Clin Chem Lab Med 2006;44:962–966.
  12. Joannidis M, Oudemans-van Straaten HM: Clinical review: patency of the circuit in continuous renal replacement therapy. Crit Care 2007;11:218.
  13. Bohler J, Schollmeyer P, Dressel B, Dobos G, Horl WH: Reduction of granulocyte activation during hemodialysis with regional citrate anticoagulation: dissociation of complement activation and neutropenia from neutrophil degranulation. J Am Soc Nephrol 1996;7:234–241.
  14. Bos JC, Grooteman MP, van Houte AJ, Schoorl M, van Limbeek J, Nube MJ: Low polymorphonuclear cell degranulation during citrate anticoagulation: a comparison between citrate and heparin dialysis. Nephrol Dial Transplant 1997;12:1387–1393.
  15. Gabutti L, Ferrari N, Mombelli G, Keller F, Marone C: The favorable effect of regional citrate anticoagulation on interleukin-1beta release is dissociated from both coagulation and complement activation. J Nephrol 2004;17:819–825.
  16. Gritters M, Grooteman MP, Schoorl M, Schoorl M, Bartels PC, Scheffer PG, Teerlink T, Schalkwijk CG, Spreeuwenberg M, Nube MJ: Citrate anticoagulation abolishes degranulation of polymorphonuclear cells and platelets and reduces oxidative stress during haemodialysis. Nephrol Dial Transplant 2006;21:153–159.
  17. Bohler J, Donauer J, Birmelin M, Schollmeyer PJ, Horl WH: Mediators of complement-independent granulocyte activation during haemodialysis: role of calcium, prostaglandins and leukotrienes. Nephrol Dial Transplant 1993;8:1359–1365.
  18. Andersson T, Dahlgren C, Pozzan T, Stendahl O, Lew PD: Characterization of fMet-Leu-Phe receptor-mediated Ca2+ influx across the plasma membrane of human neutrophils. Mol Pharmacol 1986;30:437–443.
  19. Leitienne P, Fouque D, Rigal D, Adeleine P, Trzeciak MC, Laville M: Heparins and blood polymorphonuclear stimulation in haemodialysis: an expansion of the biocompatibility concept. Nephrol Dial Transplant 2000;15:1631–1637.
  20. Gritters M, Borgdorff P, Grooteman MP, Schoorl M, Schoorl M, Bartels PC, Tangelder GJ, Nube MJ: Platelet activation in clinical haemodialysis: LMWH as a major contributor to bio-incompatibility? Nephrol Dial Transplant 2008;23:2911–2917.
  21. Borawski J: Myeloperoxidase as a marker of hemodialysis biocompatibility and oxidative stress: the underestimated modifying effects of heparin. Am J Kidney Dis 2006;47:37–41.
  22. Hoffmann JN, Vollmar B, Laschke MW, Inthorn D, Kaneider NC, Dunzendorfer S, Wiedermann CJ, Romisch J, Schildberg FW, Menger MD: Adverse effect of heparin on antithrombin action during endotoxemia: microhemodynamic and cellular mechanisms. Thromb Haemost 2002;88:242–252.
  23. Kaneider NC, Forster E, Mosheimer B, Sturn DH, Wiedermann CJ: Syndecan-4-dependent signaling in the inhibition of endotoxin-induced endothelial adherence of neutrophils by antithrombin. Thromb Haemost 2003;90:1150–1157.
  24. Cornet AD, Smit EG, Beishuizen A, Groeneveld AB: The role of heparin and allied compounds in the treatment of sepsis. Thromb Haemost 2007;98:579–586.
  25. Weinberg JM, Venkatachalam MA, Roeser NF, Nissim I: Mitochondrial dysfunction during hypoxia/reoxygenation and its correction by anaerobic metabolism of citric acid cycle intermediates. Proc Natl Acad Sci USA 2000;97:2826–2831.
  26. Feldkamp T, Weinberg JM, Horbelt M, Von Kropff C, Witzke O, Nurnberger J, Kribben A: Evidence for involvement of nonesterified fatty acid-induced protonophoric uncoupling during mitochondrial dysfunction caused by hypoxia and reoxygenation. Nephrol Dial Transplant 2009;24:43–51.