Regional Citrate Anticoagulation (RCA) in CRRT

1. Regional Citrate Anticoagulation (RCA) in CRRT Dr Anne Leung QEH ICU 2010

2. Overview • Mechanism of action and metabolism of citrate • Formulation of citrate • Advantage and disadvantage of using citrate anticoagulant • RCA CRRT circuit options –Gambro vs Fresenius • Monitoring during citrate anticoagulation • QEH ICU Citrate anticoagulation regime

3. CRRT circuit • Vascular access • Blood Flow • Machinery • Dialyzer • Circuit volume • Dialysate/Replacement fluid • Anticoagulant

4. Anticoagulation for CRRT • CRRT increasing in popularity in management of acute renal failure in critically ill • Need ongoing anticoagulation • Risk of bleeding with heparin • 2% per day • 3.5-10% of deaths • 25% of new hemorrhagic episodes Bleeding Clotting CRRT

5. Contact activation by membrane 1 2

6. Impact of filter clotting • Decrease in dialysis dose • Blood loss through the circuit with increase in transfusion requirement • Wasted nursing time • Increase in cost

7. Anticoagulation options • None (- if marked coagulopathy) • Unfractionated heparin • LMW Heparin • Citrate • Direct Thrombin Inhibitors • r-Hirudin • Argatroban • Prostacycline

8. Continuous renal replacement therapy: B.E.S.T. Kidney (The Beginning and Ending Supportive Therapy for the kidney).a worldwide practice survey. 23 Countries, 54 ICUs, 1006 patients with ARF on CRRT Intensive Care Med. 2007;33(9):1563-70

11. Mechanism of Regional Citrate Anticoagulant • Normal range: • Total serum calcium: 2.2-2.6 mmol/L • Serum ionized calcium: 0.9 -1.2 mmol/L • Chelate Ca and induce deep hypoclacemia in filter • Aim post-filter iCa of0.25-0.35mmol/l • Fate of the citrate-calcium complex in the CRRT circuit • Partly lost in ultrafiltrate across the membrane • Those enter the systemic circulation is diluted in venous blood • Citrate entering the body will be cleared by liver, skeletal muscle or kidney to HCO3 in 1:3 ratio • Half-life of calcium-citrate complex is ~ 5 minutes, therefore systemic effect on anticoagulation not occurred

12. Fate of the citrate calcium complex in the CRRT circuit

13. What is the citrate dose required?

14. To achieve a steady state whole blood citrate conc. of 4 mmol/L Flanigan MJ et al. Am J kid Dis 1996:27 (4) 519-524

15. Citrate dose

16. Citrate dose = 240/60( ml/min) x 113 / 160 = 2.83 mmol/L

18. Citrate Formulation • Trisodium Citrate 4% • Na 420. Citrate 136. • Acid Citrate Dextrose (ACD-A) • Dextrose 2.45% • Citric acid 0.8% (38 mmol/L). Trisodium Citrate 2.2% (74.8mmol/L), • Na 224. Citrate 113. • Gambro Prismocitrate 10/2 • Fresenius multifiltrate Ci-Ca system

19. Difference between TSC and ACDA • Each millimole of TSC yields 3 mmol/L NaHCO3 • At physiological pH of 7.4, each millimole of citric acid combines with 3 mmol/L NaHCO3 and converted to TSC or Na citrate • For equimolar infusion of ACD and TSC, ACD produces 203 mmol/L NaHCO3 instead of 320 by TSC

21. Complex metabolic consequence of using RCA • Metabolic acidosis or metabolic alkalosis • Citrate is both the anticoagulant and buffer • Acid-base affect by • composition of citrate solution, • citrate infusion rate, • loss by filtration : amt of citrate in UF varies, hence amt of buffer entering in systemic circulation varies • metabolism of citric acid :If liver and muscle skeletal muscle fail to metabolized citrate, bicarbonate not produce and citrate accumulate • Hypernatremia • The tri-sodium citrate (TSC) contains substantial amt of sodium • Hypocalcemia • Amt of calcium lost in UF, bound to citrate is greater than during HF or HD with heparin • Use of calcium free dialysate or replacement fluid to improve the anticoagulation effect of citrate

22. Citrate - Solutions Requirements • Zero Ca2+ Dialysate and or replacement solution to minimize citrate requirement • Low Na+ to counter-act the potential problem of hypernatremia • Low bicarbonate level to decrease bicarbonate load • Low or zero Magnesium • Calcium supplementation to correct patient’s Ca2+ loss

23. Advantage of RCA • Effective anticoagulation of the extracorporeal circuit • Less Clotting • Longer filter lifetimes • No systemic anticoagulation • No systemic bleeding risk • Less bleeding complications • Less transfusion requirement

24. Less clotting in Hollow Fibers membrane Kid Int 1999

25. Longer Filter Life Median time to spontaneous hemofilter failure is 140 hr with citrate vs 45 hr with heparin

26. Less Bleeding Episode 9 put of 12 4 out of 12

27. Less Transfusion requirement

28. Use of citrate CVVH was safer and reduced mortality CCM37:545-552(2009)

29. Hospital mortality 41 vs 57% (p=0.03)3-month Mortality 45 vs 62% (p=0.02) Surgical HigherSOFA Sepsis Younger than 73 CCM 37: 545 - 552 ( 2009)

30. Disadvantage of RCA • Direct anticoagulation control difficult • Need for complex protocol with meticulous calculation and many titration required • Complex metabolic consequences • Metabolic Alkalosis or acidosis • Hyper or hyponatremia • Calcium and magnesium loss • Citrate solution are either customized or hospital pharmacy-formulated ( Zero calcium, low sodium and low or buffer free solution) • Labor intensive and close monitoring of electrolyte and acid-base required • Requiring well-trained nursing staffs and well trained nephrologists

31. Metabolic complication of RCA CRRT

32. Citrate clearance

33. Citrate Clearance

34. Advantages Anticoagulation restricted EC Decreased risk of systemic bleeding Does not induce thrombocytopenia Longer filter life Disadvantages Labour intensive Close monitoring of ionized Ca, Na and pH, Risk of metabolic alkalosis, hypernatremia, hypocalcemia Costly Citrate

35. First description of Citrate-CVVHD

36. RCA CRRT circuit Options CVVH • Citrate infuse pre-filter close to the point where blood exits the patient via a 3-way stopcock • For CVVH: • Citrate infused as separate solution or • With prefilter or post-filter replacement solution • Predilution reduces efficacy, compensate by higher UF • For CVVHD, • calcium-free dialysate is required • Fixed ratio between blood and citrate infusion • Calcium infused via a separate line, usu CVC CVVHD

37. Palsson and Niles KI 1999;55:1991-7 Combining citrate with RF Mehta et al KI 1990

38. Who can do that ? Genius Brain

39. PYNEH ICU (1995-2003)

40. PYNEH ICU ( 2004 …..

41. Clues to the success use of RCA • Optimal anticoagulation: • Target citrate of 3-5 mmol/L to attain ionized calcium of  0.35 mmol/L • Control of anticoagulation best with citrate administered in a separate solution • A fixed blood flow/citrate flow is advocated such that monitoring of anticoagulation in extracorporal circuit is not necessary

42. Blood flow requirements for CRRT to maintain filtration fraction at 25%

43. Filtration Fraction • Degree of blood dehydration can be estimated by determining the filtration fraction ( FF), which is the fraction of plasma water removed by ultrafiltration • FF(%) = (UFR x 100) / Qp • Where Qp is the filter plasma flow rate in ml/min • Qp = BFR x ( 1-Hct)

44. Filtration Fraction • FF(%) = (UFR x 100 ) / Qp • Qp = BFR x (1-Hct) • When BFR = 100ml/min, Hct=0.3 Qp=70ml/min • If FF >30%, promote filter clotting • If FF=30%, BFR of 100 ml/min, UF = 21ml/min

46. PYICU RCA CRRT regime

47. Problem from non-integrated approach • Inaccuracy arise from the use of stand alone infusion pump • If CRRT device alarms for bag changes or other reasons, all pump except the blood pump stop, resulting in direct infusion of citrate into the patient • Cumbersome in set-up

48. Fresenius Ci-Ca system 4 3 5 2 1

49. Fresenius Ci-Ca System • 4+2 pump-system • Coupling the citrate infusion to the blood flow • Citrate and calcium infusion is automatically taken into account for fluid balancing • Dedicated Zero-Ca, Low-Bicarb dialysate and Ci-Ca cassette with pre-connected citrate and calcium lines

50. Ci-Ca System: Completely Integrated Regional Citrate Anticoagulation CVVHD