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 membrane1 2
Two principle mechanisms of thrombus formation
Intrinsic pathway of coagulation, which start with contact activation factors ->amplifying series of enzymatic reaction -> Thrombin to fibrin clot
Platelet adhesion and activation: shape change, aggregation, secretion of thromboxane B2, release content of granules and finally platelet contraction and fusion

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
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):

10. As you know, citrate works as an anticoagulant by binding with clotting factor, calcium, at these points of the clotting cascade. This action could deplete the patient’s calcium stores if not adequately replaced. Therefore, the use of citrate requires administration of calcium supplements and rigorous monitoring of calcium levels

11. Mechanism of Regional Citrate Anticoagulant
Normal range:
Total serum calcium: mmol/L
Serum ionized calcium: mmol/L
Chelate Ca and induce deep hypoclacemia in filter
Aim post-filter iCa of mmol/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
Citrate as regional anticoagulant, had short systemic half-life of ~ 5min
Predominantly metabolized by mitochondria in liver, skeletal muscle and kidney
Also reduce inflammatory rx occurred by reducing leucocycte activation during passage through the extracorporeal circuit

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

13. What is the citrate dose required?
Citrate chelates calcium, at conc of 4-6 mmol/L to produce ionized Ca++ of <0.2mmol/L and prevent activation of both coagulation cascades and platelet

14. To achieve a steady state whole blood citrate conc. of 4 mmol/L
When blood citrate infused at 4 to 5 mmol/L, standard dialysate containing 1.25 to 1.75 mmol/L calcium maintains calcium balance and restores hemostasis during isolated and repetitive use
Avoid the risk of hypocalcemia when calcium-free dialysate is used
Flanigan MJ et al. Am J kid Dis 1996:27 (4)

15. Complementary solution Citrate dose (mmol/L blood)
Citric Acid mmol/L
Sodium Citrate mmol/L
Complementary solution
Therapy
BFR mL/min
Citrate dose (mmol/L blood)
Country
Apsner 5 10 -
CVVH
100
3.7
Austria
Dorval / Leblanc 15
Dia: 0.9% Saline (if needed)
CVVH(DF)
125
Canada
Niles
13.3
180
2.0
USA
Gabutti
Dialysate same as citrate
2.66
Switzerland
Tolwani 2%
0.9% Saline
CVVHD
150
Sramek
2.2%
Na=120, Bicar=22
CVVHDF
Czech Republic
Bunchman
ACD-A
Dia: Normocarb
CVVHD(F)
2.8
Chadha
Pre: Na=140, Bicar=20
Mitchell / Heemann
Calcium in dialysate 75
Germany
Gupta
1.9
Cointault
Calcium in dialysate & pre
3.9
France
Kustogiannis / Gibney
3.9%
Dia: Na=110, Bicar=variable
3.6
Mehta 4%
Dia: Na=117, Bicar=0
Hoffmann
Pre: 0.9% Saline
3.1
Monchi
1000
Post: Na=120 , Bicar=0
4.3
Evenepoel
1035
IHD
300
Belgium
Actual citrate delivered via CRRT typically range from 17 to 45 mmol/L

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 Citrate 113.
Gambro Prismocitrate 10/2
Fresenius multifiltrate Ci-Ca system
Tri-sodium solution varies from 2% to 30%
Lower the concentration, the higher the volume infused

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
There are two types of citrate usually used in CRRT. Tri-sodium citrate and ACD-A. This table shows the concentration of citrate in these two types. The dose of citrate used during treatment is titrated according to a set target of ionized calcium measured from the return site of the hemofilter set.
The use of citrate requires special solutions such as:
0 Ca Dialysate and or replacement solution to minimize citrate requirement
Low Na to equalize patient Na load
Low bicarbonate level to decrease bicarbonate load
Ca supplementation to correct patient’s Ca 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
Membrane fouling and deposition of fibrin and plt is much reduced with citrate compared with LMWH and standard heparin
UFH: Most pronounced cell adhesion and thrombus formation ( Fibrin network with large amt of aggregated erythrocytes, a red thrombus covering a portion of fiber surface and protruding into the fiber lumen
LMWH: Lowe dialyzer clotting
Citrate: negligible thrombus formation

25. Longer Filter Life Median time to spontaneous hemofilter failure is
Monchi study: Median lifetime of hemofilter was 70 hrs ( ) with citrate and 40h (17-48) with heparin
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
For heparin, 4/12 patients not have bleeding
For citrate, the three patients with bleeding was initially on heparin with bleeding continued into the first hr of RCA
The study however shown the filter lifespan is shorter with RCA

27. Less Transfusion requirement
Median blood transfusion required is 5.6 vs 9.7 ml/hr, but not statistically significant

28. Use of citrate CVVH was safer and reduced mortality CCM37:545-552(2009)
-215 patients, 97 citrate and 103 nadroparin
-For nadroparin, loading then infusion, post-dilution with BF of 220ml/hr and UF inititanlly at 4000ml/hr, then 2L/hr is vasopressor free
-For citrate, hospital prepared and target citrate dose of 3 mmol/L, replace with combination of buffered free ( Na=109) and bicarbonate buffered fluid
-Result: Discontinuation due to adverse event: 2 in citrate and 20 in Nadroparin
Bleeding: 6 vs 16 ( P=0.08), Medium unit of RBC transfused is 0.27 vs 0.36
Metabolic acidosis less with citrate and lower plasma Ca
3-month mortality 48% vs 63%.
In post-hoc analysis, citrate reduced mortality in surgical patient, spesis, higher SORF score and lower age

29. Hospital mortality 41 vs 57% (p=0.03) 3-month Mortality 45 vs 62% (p=0.02)
Surgical
In post-hoc analysis, citrate reduced mortality in surgical patient, spesis, higher SORF score and lower age
Higher SOFA
Sepsis
Younger than 73
CCM 37: ( 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. Citrate Advantages Disadvantages 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

35. First description of Citrate-CVVHD

36. RCA CRRT circuit Options
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
CVVH
Disadv of infusing citrate as a separate external IV pump is that if CRRT device alarms, all pump except the blood pump stop, resulting in direct infusion of citrate into the patient
-For pre-dilutional separate citrate infusion: adv of separating anticoagulation effect and metabolic control. ( if UF increase and increase loss of citrate and bicarbonate, add bicarbonate into the replacement solution). The replacement solution is usu hypo Na with low anionic buffer ( ie low bicarbonate)
-If citrate is included in replacement fluid, a fixed relation between citrate flow and blood flow not guaranteed
-Disadv of combining citrate with replacement solution: Replacement fluid rate varies with UF + desired fluid removal. Ie anticoagulation and metabolic control couple and buffer can’t titrate separately
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 ( )

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. Ultrafiltration rate (mls/hr)
Blood flow requirements for CRRT to maintain filtration fraction at 25%
Ultrafiltration rate (mls/hr)
Minimum
Qb/min
1500
100
2000
130
2500
155
3000
200
4000
265

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
Significant advances in IHD include:
Development of volumetric machines with precise ultrafiltration control
Availability of bicarbonate dialysate
Highly permeable membrane

48. Fresenius Ci-Ca system4 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

51. Fresenius Ci-Ca System

52. Ci-Ca Dialysate solution

53. A Safe Citrate Anticoagulation Protocol CCM 2009;37:2018-24
-A CVVHD based citrate anticoagulation protocol using 4% trisodium cintrate, a specialized dialysate fluid and a continuous calcium infusion were used
-Study period of 6 days
Hemofilter routinely changed after 72 hours
-patients group by body weight

54. RCA—Finally on its way to standardization?
-Median filter time is 61.5 hours and hours in those clotted filter
-5% of filters need to be changed because of clotting
-When censoring the hemofilter discontinued for non-CRRT related reasons, the median filter patency exceeds the maximum in-sue time of 72 hours
-Acid base and electrolyte control is excellent
Median filter life is 61.5 hrs and 43.7 hrs in those clotted filter.
Only 5% of filters needed to be changed because of clotting

55. Gambro Prismaflex
Prisma is set-up in CVVHDF mode, either pre-dilution or post-dilution mode
Prismaflex provide flexibility of any therapy change like CVVH SCUF, or combination of both pre and post-dilution
It has five pumps and the circuit allow Pre-blood pump for hemodilution or anticoagulation
Higher blood flow of ml/min

56. RCA with Gambro Prismaflex

57. Solution for RCA--Gambro

58. Prismocitrate and PrismOcal for RCA
Tri sodium citrate mmol/l
Citric acid mmol/l Na
mmol/l
Glucose mmol/l
Prismocitrate 10 2
136
ACD-A
74.8
38.1
221
124
Zero Calcium Dialysate and or replacement solution to minimize citrate requirement
Low Na+ to equalize patient Na+ load
Low bicarbonate level to decrease bicarbonate load
Calcium supplementation to correct patient’s Calcium loss
Citrate infused close to access site
There are two types of citrate usually used in CRRT. Tri-sodium citrate and ACD-A. This table shows the concentration of citrate in these two types. The dose of citrate used during treatment is titrated according to a set target of ionized calcium measured from the return site of the hemofilter set.
The use of citrate requires special solutions such as:
0 Ca Dialysate and or replacement solution to minimize citrate requirement
Low Na to equalize patient Na load
Low bicarbonate level to decrease bicarbonate load
Ca supplementation to correct patient’s Ca loss

59. Citrate dose in Gambro RCA

60. RCA circuit in Gambro Prismaflex
How is citrate used in CRRT?
Citrate is infused as close to the access site as possible to prevent coagulation early on into the system.
In CVVH or CVVHDF, a low or 0 Ca solution is used as a replacement solution to optimize the efficiency of citrate.
For the same reason, in CVVHD or CVVHDF, a low or 0 Ca solution is used as a dialysate solution.
Ca is returned back to the patient, ideally, through a peripheral line, or at the return site.

61. Gambro vs Fresenius

62. Monitoring during RCA CRRT
Every 4-6 hourly,
Na, K, iCa++, ABG
Daily
Total calcium, phosphate & magnesium
Others
Post-filter ionized Ca++ ( 0.25 to 0.35 mmol/L)

63. Titration of ionized Calcium
Target level of ionized Calcium
mmol/L
Calcium infusion
CaCl2 infusion
Ca gluconate infusion
Sign of hypocalcaemia
Paresthesia, cramps, tetany
Hypotension, decease in cardiac output
Prolonged QTc interval

64. Titration of ionized calcium
4 mmol/hr
mol/hr

65. Table for titration of ionized calcium
4mmol/hr
0.7 mmol/hr
0.35mmol/hr
No change
0.35mmol/hr
0.7mmol/hr
For 10% CaCl2, start at 6ml/hr (=4mmol/hr) via CVC and
adjust 0.5 (~0.35mmol) -1ml (0.7 mmol) /hr accordingly

66. Calcium infusion MUST via CVC!!
One lumen of the CVC is
occupied
Calcium extravasation causing tissue necrosis

67. Sign of Citrate toxicity
Clinical condition that may result in accumulation of citrate
Acute liver failure with bilirubin >=80 mol/L
Poisoning with mitochondrial inhibitors like rotenone, cyanide, antimycin
Acquired mitochrondrial cytopathies like mitochondrial encephalopathy
Increased total Ca to ionized calcium ratio>2.5
Increased metabolic acidosis
Increased anion gap
Meier_Kriesche HU: Increased total to ionized cal ratio …with RCA. CCM 2001:29:
Impaired citrate metabolism can lead to profound reduction in ionized cal, whereas the total calcium conc remains in normal or high range. (CCM2001:29:
The author suggest to use the total to ionized calcium ratio of >=2.5 and increase in anion gap

68. Use of Tot calcium/ionized calcium ratio for detection of citrate toxicity
infusion

69. Highest correlation between Citrate plasma level an total cal to ionized Calcium ratio
Am J Kidney Dis 48:
Correlation between citrate levels and other parameters on day 3 ( left) and all measurements (right) performed in 16 patients throughout the study
Am J Kidney Dis 2006; 48:

70. Titration of K, PO4 and Magnesium
Potassium
Titration according to lab result
Phosphate
Roughly requirement is 45 mmol /day for UF of 2L/hr and blood flow of 120ml/min
Magnesium
Replaced accordingly
Magnesium will accumulate in patient with impaired renal function

71. Titration of metabolic acidosis and metabolic alkalosis
Take time for citrate regime to work
High suspicion for citrate accumulation when total to ionized calcium ratio exceeds 2.5
Increase blood flow and citrate solution flow
Metabolic alkalosis
Alkalosis due to metabolic conversion of citrate to bicarbonate
Decrease blood flow or increase citrate lost by increasing the dialysis flow
Target at low citrate concentration of 3-4 mmol/L

72. Correction of metabolic acidosis with RCA CRRT
It takes
Time!
Correction of acid-base abnormalities is apparently a slow process, which is complete only after about 2days
Mongera S eta al. CCM2009;37:

73. RCA CRRT—QEH Regime

74. RCA CRRT—QEH Regime

75. RCA CRRT—QEH Regime

76. Summary of the regime Machine: Prismaflex
Pre-dilution with Primocitrate 10/2 at rate of 2500mL/hr
Blood flow at 150ml/min
Both UF and blood flow rate fixed
Separate infusion of NaHCO3 ( initial 50ml/hr for 2 hr then 30ml/hr ) and Calcium chloride infusion via CVC at 6 ml/hr
For fluid removal= desired fluid removal + flowrate of NaHCO3
Measure Na, K, BE and ionized calcium Q4-6 hr
Target ionized calcium 0.9 – 1.3 mmol/L

77. Implementation Theory Session Practical Session
For both nurses and doctors
Practical Session
By Gambro in early March
Guideline as the reference
Case selection
Avoid those with liver dysfunction, after massive transfusion and severe metabolic acidosis with pH<7.1
Start with post-op case with mild to moderate acidosis and fluid problems
Start during the daytime
Gambro technical support stand-by during the initial phase
Trouble shooting
Contact Dr Anne Leung

78. Mechanism of action
Exclusion criteria
Set up of the citrate circuit
Monitoring during RCA
Titration of electrolyte and acid-base
Citrate toxicity

79. Future direction

80. Future direction

81. With you, we should overcome!

82. Currr Opin Crit Care 8: 509-514 (2002)
RIFLE Criteria
Currr Opin Crit Care 8: (2002)

83. The Acute Kidney Injury Network Classification ( AKIN)
Crti Care 11:R31 (2007)