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Anticoagulation in CRRT

  • Patrick Brophy
  • Irfan Khan
  • Akash Deep
Chapter

Abstract

Critically ill patients develop acute kidney injury (AKI) and fluid overload as a complication of their illness quickly in their disease course. Many of these patients are hemodynamically unstable and are not candidates for routine intermittent hemodialysis. Continuous renal replacement therapy (CRRT) is a favored modality used to treat these patients while their kidneys recover. Unfractionated heparin has been widely used as a systemic anticoagulant to help extend the CRRT filter life and prevent any unintended interruptions in dialysis. However, systemic anticoagulation with heparin has its negative consequences like life-threatening bleeding and development of heparin-induced thrombocytopenia.

In 1990, Mehta et al. (Kidney Int 38:976–981, 1990) described a technique of regional anticoagulation using trisodium citrate. Since then multiple studies in both adults and children have tried to compare the efficacy and safety of the regional citrate anticoagulation (RCA) protocol versus systemic anticoagulation with heparin. Schilder et al. (Crit Care 18:472, 2014), recently in a large multicenter randomized control trial demonstrated that renal outcome and patient mortality were similar for citrate and heparin anticoagulation during CVVH in the critically ill patient with AKI. However, citrate was superior in terms of safety, efficacy, and costs.

In this chapter, we review the background and protocols for heparin and regional citrate anticoagulation, and a newer approach to CRRT anticoagulation-prostacyclin. We review a brief history and development of these protocols, and attempt to compare the efficacy of each of these techniques in improving circuit survival and decrease in cost.

Keywords

CRRT Prostacyclin Heparin Anticoagulation Pediatric Citrate Acute kidney injury Acute renal failure Renal replacement therapies Regional citrate anticoagulation 

References

  1. 1.
    Kaddourah A, Basu RK, Bagshaw SM, Goldstein SL, for the AWARE Investigators. Epidemiology of acute kidney injury in critically ill children and young adults. N Engl J Med. 2017;376:11–20.CrossRefPubMedGoogle Scholar
  2. 2.
    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(2):260–5. Epub 2003 Nov 5.CrossRefPubMedGoogle Scholar
  3. 3.
    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(6):2361–7.CrossRefPubMedGoogle Scholar
  4. 4.
    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(5):602–8.PubMedGoogle Scholar
  5. 5.
    Hetzel GR, Schmitz M, Wissing H, Ries W, Schott G, Heering PJ, Isgro F, Kribben A, Himmele R, Grabensee B, Rump LC. See comment in PubMed commons belowRegional citrate versus systemic heparin for anticoagulation in critically ill patients on continuous venovenous haemofiltration: a prospective randomized multicentre trial. Nephrol Dial Transplant. 2011;26(1):232–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Davies H, Morgan D, Leslie G. A regional citrate anticoagulation protocol for pre-dilutional CVVHDf: the ‘modified Alabama protocol’. Aust Crit Care. 2008;21(3):154–65.  https://doi.org/10.1016/j.aucc.2008.04.002. Epub 2008 Jul 16.CrossRefPubMedGoogle Scholar
  7. 7.
    Tobe SW, Aujla P, Walele AA, Oliver MJ, Naimark DM, Perkins NJ, Beardsall M. A novel regional citrate anticoagulation protocol for CRRT using only commercially available solutions. J Crit Care. 2003;18(2):121–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Tolwani AJ, Prendergast MB, Speer RR, Stofan BS, Wille KM. A practical citrate anticoagulation continuous venovenous hemodiafiltration protocol for metabolic control and high solute clearance. Clin J Am Soc Nephrol. 2006;1(1):79–87. Epub 2005 Nov 23.CrossRefPubMedGoogle Scholar
  9. 9.
    Bunchman TE, Maxvold NJ, Barnett J, Hutchings A, Benfield MR. Pediatric hemofiltration: normocarb dialysate solution with citrate anticoagulation. Pediatr Nephrol. 2002;17(3):150–4.CrossRefPubMedGoogle Scholar
  10. 10.
    Chadha V, Garg U, Warady BA, Alon US. Citrate clearance in children receiving continuous venovenous renal replacement therapy. Pediatr Nephrol. 2002;17(10):819–24. Epub 2002 Sep 7.CrossRefPubMedGoogle Scholar
  11. 11.
    Symons JM, Brophy PD, Gregory MJ, McAfee N, Somers MJ, Bunchman TE, Goldstein SL. Continuous renal replacement therapy in children up to 10 kg. Am J Kidney Dis. 2003;41(5):984–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Elhanan N, Skippen P, Nuthall G, Krahn G, Seear M. Citrate anticoagulation in pediatric continuous venovenous hemofiltration. Pediatr Nephrol. 2004;19(2):208–12. Epub 2003 Dec 11.CrossRefPubMedGoogle Scholar
  13. 13.
    Hothi DK, St George-Hyslop C, Geary D, Bohn D, Harvey E. Continuous renal replacement therapy (CRRT) in children using the AQUARIUS. Nephrol Dial Transplant. 2006;21(8):2296–300.CrossRefPubMedGoogle Scholar
  14. 14.
    Rajasekaran S, Jones DP, Avent Y, Shaffer ML, Elbahlawan L, Henderson N, Barfield RC, Morrison RR, Tamburro RF. Outcomes of hematopoietic stem cell transplant patients who received continuous renal replacement therapy in a pediatric oncology intensive care unit. Pediatr Crit Care Med. 2010;11(6):699–706.CrossRefPubMedGoogle Scholar
  15. 15.
    Symons JM, Chua AN, Somers MJ, Baum MA, Bunchman TE, Benfield MR, Brophy PD, Blowey D, Fortenberry JD, Chand D, Flores FX, Hackbarth R, Alexander SR, Mahan J, McBryde KD, Goldstein SL. Demographic characteristics of pediatric continuous renal replacement therapy: a report of the prospective pediatric continuous renal replacement therapy registry. Clin J Am Soc Nephrol. 2007;2(4):732–8. Epub 2007 May 18.CrossRefGoogle Scholar
  16. 16.
    Brophy PD, Somers MJ, Baum MA, Symons JM, McAfee N, Fortenberry JD, Rogers K, Barnett J, Blowey D, Baker C, Bunchman TE, Goldstein SL. Multi-Centre evaluation of anticoagulation in patients receiving continuous renal replacement therapy (CRRT). Nephrol Dial Transplant. 2005;20(7):1416–21. Epub 2005 Apr 26.CrossRefPubMedGoogle Scholar
  17. 17.
    Askenazi DJ, Goldstein SL, Koralkar R, Fortenberry J, Baum M, Hackbarth R, Blowey D, Bunchman TE, Brophy PD, Symons J, Chua A, Flores F, Somers MJ. Continuous renal replacement therapy for children ≤10 kg: a report from the prospective pediatric continuous renal replacement therapy registry. J Pediatr. 2013;162(3):587–592.e3.  https://doi.org/10.1016/j.jpeds.2012.08.044. Epub 2012 Oct 24.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Musielak A, Warzywoda A, Wojtalik M, Koci ński B, Kroll P, Ostalska-Nowicka D, Zachwieja J. Outcomes of continuous renal replacement therapy with regional citrate anticoagulation in small children after cardiac surgery: experience and protocol from a single center. Ther Apher Dial. 2016;20(6):639–44.CrossRefPubMedGoogle Scholar
  19. 19.
    Uchino S, Bellomo R, Morimatsu H, Morgera S, Schetz M, Tan I, Bouman C, Macedo E, Gibney N, Tolwani A, Oudemans-van Straaten H, Ronco C, Kellum JA. Continuous renal replacement therapy: a worldwide practice survey. The beginning and ending supportive therapy for the kidney (B.E.S.T. Kidney) investigators. Intensive Care Med. 2007;33(9):1563–70. Epub 2007 Jun 27.CrossRefPubMedGoogle Scholar
  20. 20.
    Hirsh J, Warkentin TE, Shaughnessy SG, Anand SS, Halperin JL, Raschke R, Granger C, Ohman EM, Dalen JE. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest. 2001;119(1 Suppl):64S–94S.CrossRefPubMedGoogle Scholar
  21. 21.
    Raymakers-Janssen PAMA, Lilien M, van Kessel IA, Veldhoen ES, Wösten-van Asperen RM, van Gestel JPJ. Citrate versus heparin anticoagulation in continuous renal replacement therapy in small children. Pediatr Nephrol. 2017;32(10):1971–8.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Stockton WM, Padilla-Tolentino E, Ragsdale CE. Antithrombin III doses rounded to available vial sizes in critically ill pediatric patients. J Pediatr Pharmacol Ther. 2017;22(1):15–21.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Ferreira JA, Johnson DW. The incidence of thrombocytopenia associated with continuous renal replacement therapy in critically ill patients. Ren Fail. 2015;37(7):1232–6.CrossRefPubMedGoogle Scholar
  24. 24.
    Verma AK, Levine M, Shalansky SJ, Carter CJ, Kelton JG. Frequency of heparin-induced thrombocytopenia in critical care patients. Pharmacotherapy. 2003;23(6):745–53.CrossRefPubMedGoogle Scholar
  25. 25.
    Selleng S, Selleng K, Wollert HG, Muellejans B, Lietz T, Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia in patients requiring prolonged intensive care unit treatment after cardiopulmonary bypass. J Thromb Haemost. 2008;6(3):428–35.CrossRefPubMedGoogle Scholar
  26. 26.
    Warkentin TE. Heparin-induced thrombocytopenia: diagnosis and management. Circulation. 2004;110(18):454–8.CrossRefGoogle Scholar
  27. 27.
    Weil R. Sodium citrate in transfusion of blood. JAMA. 1915;64:425.CrossRefGoogle Scholar
  28. 28.
    Morita Y, Johnson RW, Dorn RE, Hall DS. Regional anticoagulation during hemodialysis using citrate. Am J Med Sci. 1961;242:32–43.CrossRefPubMedGoogle Scholar
  29. 29.
    Pinnick RV, Wiegmann TB, Diederich DA. Regional citrate anticoagulation for hemodialysis in the patient at high risk for bleeding. N Engl J Med. 1983;308(5):258–61.CrossRefPubMedGoogle Scholar
  30. 30.
    Golper TA, Ronco C, Kaplan AA. Continuous arteriovenous hemofiltration: improvements, modifications, and future directions. Semin Dialysis. 1988;1:50–4.CrossRefGoogle Scholar
  31. 31.
    von Brecht JH, Flanigan MJ, Freeman RM, Lim VS. Regional anticoagulation: hemodialysis with hypertonic trisodium citrate. Am J Kidney Dis. 1986;8(3):196–201.CrossRefGoogle Scholar
  32. 32.
    Mehta RL, McDonald BR, Aguilar MM, Ward DM. Regional citrate anticoagulation for continuous arteriovenous hemodialysis in critically ill patients. Kidney Int. 1990;38(5):976–81.CrossRefPubMedGoogle Scholar
  33. 33.
    Tolwani AJ, Campbell RC, Schenk MB, Allon M, Warnock DG. Simplified citrate anticoagulation for continuous renal replacement therapy. Kidney Int. 2001;60(1):370–4.CrossRefPubMedGoogle Scholar
  34. 34.
    Rodriguez K, Srivaths PR, Tal L, Watson MN, Riley AA, Himes RW, Desai MS, Braun MC, Akcan Arikan A. Regional citrate anticoagulation for continuous renal replacement therapy in pediatric patients with liver failure. PLoS One. 2017;12(8):e0182134. Published online 2017 Aug 8.  https://doi.org/10.1371/journal.pone.0182134.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Soltysiak J, Warzywoda A, Koci ński B, Ostalska-Nowicka D, Benedyk A, Silska-Dittmar M, Zachwieja J. Citrate anticoagulation for continuous renal replacement therapy in small children. Pediatr Nephrol. 2014;29(3):469–75.CrossRefPubMedGoogle Scholar
  36. 36.
    Fernández SN, Santiago MJ, López-Herce J, García M, Del Castillo J, Alcaraz AJ, Bellón JM. Citrate anticoagulation for CRRT in children: comparison with heparin. Biomed Res Int. 2014;2014:786301.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Schilder L, Nurmohamed SA, Bosch FH, Purmer IM, den Boer SS, Kleppe CG, Vervloet MG, Beishuizen A, Girbes AR, Ter Wee PM, Groeneveld AB, CASH study group. 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. 2014;18(4):472.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Brain MJ, Roodenburg OS, Adams N, McCracken P, Hockings L, Musgrave S, Butt W, Scheinkestel C. 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. 2014;16(2):131–7.PubMedGoogle Scholar
  39. 39.
    Stucker F, Ponte B, Tataw J, Martin PY, Wozniak H, Pugin J, Saudan P. 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. 2015;19:91.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Bai M, Zhou M, He L, Ma F, Li Y, Yu Y, Wang P, Li L, Jing R, Zhao L, Sun S. Citrate versus heparin anticoagulation for continuous renal replacement therapy: an updated meta-analysis of RCTs. Intensive Care Med. 2015;41(12):2098–110.CrossRefPubMedGoogle Scholar
  41. 41.
    Cawello W, Schweer H, Müller R, Bonn R, Seyberth HW. Metabolism and pharmacokinetics of prostaglandin E1 administered by intravenous infusion in human subjects. Eur J Clin Pharmacol. 1994;46(3):275–7.CrossRefPubMedGoogle Scholar
  42. 42.
    Kozek-Langenecker SA, Spiss CK, Michalek-Sauberer A, Felfernig M, Zimpfer M. Effect of prostacyclin on platelets, polymorphonuclear cells, and heterotypic cell aggregation during hemofiltration. Crit Care Med. 2003;31:864–8.CrossRefPubMedGoogle Scholar
  43. 43.
    Shuman MA, Levine SP. Relationship between secretion of platelet factor 4 and thrombin generation during in vitro blood clotting. J Clin Invest. 1980;65(2):307–13.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Turney JH, Williams LC, Fewell MR, Parsons V, Weston MJ. Use of prostacyclin in regular dialysis therapy. Proc EDTA. 1980;17:318–22.Google Scholar
  45. 45.
    Davenport A, Will EJ, Davison AM. Comparison of the use of standard heparin and prostacyclin anticoagulation in spontaneous and pump-driven extracorporeal circuits in patients with combined acute renal and hepatic failure. Nephron. 1994;66(4):431–7.CrossRefPubMedGoogle Scholar
  46. 46.
    Max M, Rossaint R. Inhaled prostacyclin in the treatment of pulmonary hypertension. Eur J Pediatr. 1999;158(Suppl 1):S23–6.CrossRefPubMedGoogle Scholar
  47. 47.
    McIntyre CM, Hanna BD, Rintoul N, Ramsey EZ. Safety of epoprostenol and treprostinil in children less than 12 months of age. Pulm Circ. 2013;3(4):862–9.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Habib M, Roberts LN, Patel RK, Wendon J, Bernal W, Arya R. Evidence of rebalanced coagulation in acute liver injury and acute liver failure as measured by thrombin generation. Liver Int. 2014;34(5):672–8.CrossRefPubMedGoogle Scholar
  49. 49.
    Zobel G, Ring E, Müller W. Continuous arteriovenous hemofiltration in premature infants. Crit Care Med. 1989;17(6):534–6.CrossRefPubMedGoogle Scholar
  50. 50.
    Goonasekera CD Wang J, Bunchman TE, Deep A. Factors affecting circuit life during continuous renal replacement therapy in children with liver failure. Ther Apher Dial. 2015;19(1):16–22.  https://doi.org/10.1111/1744-9987.12224. PMID: 25195689.CrossRefPubMedGoogle Scholar
  51. 51.
    Zobel G, Trop M, Muntean W, Ring E, Gleispach H. Anticoagulation for continuous arteriovenous hemofiltration in children. Blood Purif. 1988;6(2):90–5.CrossRefPubMedGoogle Scholar
  52. 52.
    Langenecker SA, Felfernig M, Werba A, Mueller CM, Chiari A, Zimpfer M. Anticoagulation with prostacyclin and heparin during continuous venovenous hemofiltration. Crit Care Med. 1994;22(11):1774–81.CrossRefPubMedGoogle Scholar
  53. 53.
    Gainza F, Quintanilla N, Pijoan JI, Delgado S, Urbizu JM, Lampreabe I. Role of prostacyclin (epoprostenol) as anticoagulant in continuous renal replacement therapies: efficacy, security and cost analysis. J Nephrol. 2006;19(5):648–55. PMID: 17136695.PubMedGoogle Scholar
  54. 54.
    Fabbri LP, Nucera M, Al Malyan M, Becchi C. Regional anticoagulation and anti-aggregation for CVVH in critically ill patients: a prospective, randomized, controlled pilot study. Acta Anaesthesiol Scand. 2010;54(1):92–7.CrossRefPubMedGoogle Scholar
  55. 55.
    Balik M, Waldauf P, Plásil P, Pachl J. Prostacyclin versus citrate in continuous haemodiafiltration: an observational study in patients with high risk of bleeding. Blood Purif. 2005;23(4):325–9. Epub 2005 Aug 23. PMID:16118487.CrossRefPubMedGoogle Scholar
  56. 56.
    Herrera-Gutiérrez ME, Seller-Pérez G, Lebrón-Gallardo M, De La Cruz-Cortés JP, González-Correa JA. Use of isolated epoprostenol or associated to heparin for the maintenance of the patency of the continuous renal replacement technical circuits. Med Intensiva. 2006;30(7):314–21. Spanish. PMID: 17067504.CrossRefPubMedGoogle Scholar
  57. 57.
    Fiaccadori E, Maggiore U, Parenti E, Giacosa R, Picetti E, Rotelli C, Tagliavini D, Cabassi A. Sustained low-efficiency dialysis (SLED) with prostacyclin in critically ill patients with acute renal failure. Nephrol Dial Transplant. 2007;22:529–37.CrossRefPubMedGoogle Scholar
  58. 58.
    Schultheiß C, Saugel B, Phillip V, Thies P, Noe S, Mayr U, Haller B, Einwächter H, Schmid RM, Huber W. Continuous venovenous hemodialysis with regional citrate anticoagulation in patients with liver failure: a prospective observational study. Crit Care. 2012;16(4):1–10.CrossRefGoogle Scholar
  59. 59.
    Kozek-Langenecker SA, Kettner SC, Oismueller C, Gonano C, Speiser W, Zimpfer M. Anticoagulation with prostaglandin E1 and unfractionated heparin during continuous venovenous hemofiltration. Crit Care Med. 1998;26:1208–12.CrossRefPubMedGoogle Scholar
  60. 60.

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of PediatricsUniversity of Rochester School of Medicine and DentistryRochesterUSA
  2. 2.Golisano Children’s HospitalUniversity of Rochester Medical CenterRochesterUSA
  3. 3.Presbyterian HospitalAlbuquerqueUSA
  4. 4.Paediatric Intensive Care Unit, King’s College HospitalLondonUK
  5. 5.Renal/CRRT Section of the European Society of Pediatric and Neonatal Intensive Care (ESPNIC)GenevaSwitzerland

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