1. ANTICOAGULATION in CRRT: Heparin vs. Citrate
Patrick D Brophy MD
Pediatric Nephrology
CS Mott Children’s Hopsital
University of Michigan

2. Outline Normal Coagulation Cascade Anticoagulation: Options Heparin
Citrate
Others
Literature & conclusions

3. Contact Phase (intrinsic) Tissue Factor (extrinsic)
Normal Coagulation
Contact Phase (intrinsic)
XII activation
XI IX
Tissue Factor (extrinsic)
TF:VIIa
platelets / monocytes / macrophages X Xa Va
VIIIa
Ca++
platelets
prothrombin
THROMBIN
fibrinogen
CLOT

4. Sites of Thrombus Formation
Any blood surface interface
Hemofilter
Bubble trap
Catheter (Especially Pediatrics)
Areas of turbulence resistance
Luer lock connections / 3 way stopcocks

5. Anticoagulation: Options
No anticoagulation
Technical aspects
cannulation / circuit
Blood flow rate
FF / predilution
Saline flush
Hemodilution
Heparin
Unfractionated
LMWH
Citrate
Others
Prostacyclin
Danaparoid
Hirudin

6. Anticoagulants Saline Flushes Heparin: systemic, regional (?)
Citrate regional anticoagulation
Low molecular weight heparin
Prostacyclin
Nafamostat mesilate
Danaparoid*
Hirudin/Lepirudin
Argatroban (thrombin inhibitor)*
* No antidote known

7. Anti-Coagulation Can you run anticoagulation free?
Having no anticoagulation shortens circuit life
Will you use Heparin?
What is the risk on
Patient bleeding
Platelet count (HIT)
Will you use Citrate?
Patient calcium

8. Heparin

9. Sites of Action of Heparin
Contact Phase (intrinsic)
XII activation
XI IX
Tissue Factor (extrinsic)
TF:VIIa
platelets / monocytes / macrophages X Xa Va
VIIIa
Ca++
platelets
LMWH
UF HEPARIN
prothrombin
THROMBIN
fibrinogen
CLOT

10. No Heparin
Systemically Heparinized
NO surface - no heparin
NO surface - heparinized

11. LMWH: Theoretic advantages
Reduced risk of bleeding
Less risk of HIT

12. LMWH No difference in risk of bleeding No quick antidote
Increased cost
No difference in filter life

13. Heparin Protocols
Heparin infusion prior to filter with post filter ACT measurement and heparin adjustment based upon parameters
Bolus with units/kg
Infuse heparin at units/kg/hr
Adjust post filter ACT secs
Interval of checking is local standard and varies from 1-4 hr increments

14. Heparin Protocols Benefit and Risks
Benefits
Heparin infusion prior to filter with post filter ACT measurement
Bolus with units/kg Infuse at units/kg/hr
Adjust post filter ACT secs
Risks
Patient Bleeding
Unable to inhibit clot bound thrombin
Ongoing thrombin generation
Activates - damages platelets / thrombocytopenia

15. Citrate

16. Citrate anticoagulation
How does it work?
Is there an advantage over heparin?
What are the side effects?
How easy is it to use?
What are the protocols?
What is needed to make it work

17. Background: Citrate anticoagulation with CRRT
(Regional citrate anticoagulation for CAVHD in critically ill
patients. Kidney Int 38; , RL Mehta)
n = 18
2652 hr CAVHD
filter survival trended longer with citrate
n = 3, metabolic alkalosis Rx iv HCl
n = 1, hypernatremia

18. What has limited citrate use in the past:
Complications of citrate protocols:
“The potential complications
Hypocalcemia
Hypercalcemia
Hypernatremia
Metabolic alkalosis
have generally made this regimen less desirable than minimal dose heparin”
Need for Designer Solutions
Method of measuring anticoagulation efficacy
E.C. Kovalik. UpToDate. Hemodialysis anticoagulation, October 19, 2000

19. How does citrate work
Clotting is a calcium dependent mechanism, removal of calcium from the blood will inhibit clotting
Adding citrate to blood will bind the free calcium (ionized) calcium in the blood thus inhibiting clotting
Common example of this is blood banked blood

20. Sites of Action of Citrate
TISSUE FACTOR
TF:VIIa
CONTACT PHASE
XII activation
XI IX
monocytes / platelets / macrophages
Ca++ X Va
VIIIa
Ca++
platelets Xa
Phospholipid surface
prothrombin
CITRATE
THROMBIN
NATURAL ANTICOAGULANTS
(APC, ATIII)
FIBRINOLYSIS ACTIVATION
FIBRINOLYSIS INHIBITION
fibrinogen
CLOT

21. Citrate: Pediatric Dosage
Unclear from literature
Pediatric clinical experience
Animal study: initial citrate flow rates
Require a citrate concentration ~ 6mmol/L to achieve iCa++ < 0.4mmol/L
Pre-filter [citrate] =
Qc x Cc
Qb + Qc + QR
Qc = citrate flow
Cc = citrate concentration
Qb = blood flow rate
QR = replacement fluid flow rate

22. Citrate: Mechanism of Action
Binds calcium - essential co-factor

23. Laboratory Research

24. How is citrate used?
In most protocols citrate is infused post patient but prefilter often at the “arterial” access of the dual (or triple) lumen access that is used for hemofiltration (HF)
Calcium is returned to the patient independent of the dual lumen HF access or can be infused via the 3rd lumen of the triple lumen access

25. (1.5 x BFR)
(0.4 x citrate rate)

26. Citrate: Technical Considerations
Measure patient and system iCa in 2 hours then at 6 hr increments
Pre-filter infusion of Citrate
Aim for system iCa of mmol/l
Adjust for levels
Systemic calcium infusion
Aim for patient iCa of mmol/l

27. Citrate: Advantages No need for heparin
Commercially available solutions exist (ACD-citrate-Baxter)
Less bleeding risk
Simple to monitor
Many protocols exist

28. Advantages of Citrate
Has zero effect upon patient bleeding as opposed to heparin which effects system and patient bleeding
Easy to monitor with ionized calcium assay
Activated Clotting Time (ACT) nor PTT needed
Programs report less clotted circuits = less disposable cost and less overtime nursing hours
Bedside surveys demonstrate less work of machinery allowing more attention to patient

29. Citrate: Problems Metabolic alkalosis
Metabolized in liver / other tissues
Electrolyte disorders
Hypernatremia
Hypocalcemia
Hypomagnesemia
Cardiac toxicity
Neonatal hearts

30. Complications of Citrate: Metabolic alkalosis
Metabolic alkalosis due to
citrate conversion to HCO3
Solutions with 35 meq/l HCO3
NG losses
TPN with acetate component

31. Complications of Citrate: Rx of Metabolic alkalosis
Rx Metabolic alkalosis by
Solutions with 35 meq/l HCO3
Decrease bicarbonate dialysis rate and replace at the same rate with NS (pH 5) to allow for the total solution exposure to be identical (ie no change in solute clearance) yet this will give less HCO3 exposure and an acid replacement
NG losses
Replace with ½-2/3 NS
TPN with acetate component
Use high Cl ratio

32. Complications of Citrate: “Citrate Lock”
Seen with rising total calcium with dropping patient ionized calcium
Essentially delivery of citrate exceeds hepatic metabolism and CRRT clearance
Rx of “citrate lock”
Decrease or stop citrate for 3-4 hrs then restart at 70% of prior rate

33. Citrate Pearls Frequent clotting is a vascular access problem.
High flow CVVHDF is more effective at clearing citrate from circulation….keep dialysate + replacement = 40 – 50 ml/min/1.73 m2
Keep circuit [Ca++] levels around .30 for best results.
Lock catheter with tPA between every circuit change.

34. Citrate or Heparin: literature

35. Citrate
Hoffbauer R et al. Kidney Int. 1999;56:

36. Unfractionated Heparin
Hoffbauer R et al. Kidney Int. 1999;56:

37. Heparin or Citrate? .
Morgera S, et.al. Nephron Clin Pract. 2004; 97(4):c131-6.
single center analysis in 209 adults
regional anticoagulation with trisodium citrate in combination with a customized calcium-free dialysate was utilized in comparison to a standard heparin protocol.
CitACG was the sole anticoagulant in 37 patients, 87 patients received low-dose heparin plus citrate, and 85 patients received only hepACG.
Both groups receiving citACG had prolonged filter life when compared to the hepACG group.
complications included; metabolic alkalosis (50% of patients on citACG), alkalosis (resolved by increasing the dialysate flow rate) and hypercalcemia.
This study also demonstrated a significant cost saving due to prolonged filter life when using citACG.

38. Heparin or Citrate? (M Golberg RN et al, Edmonton pCRRT 2002)
39 children with CRRT from
System
Gambro PRISMA
13 patients underwent heparin anticoagulation
16 patients underwent citrate anticoagulation

39. Heparin or Citrate? Heparin circuits 13 patients with 45 filters
hrs average length of circuit
Citrate circuits
16 patients with 51 filters
hrs average length of circuit
(p < 0.001)

40. Brophy et.al. NDT 2005 Jul;20(7):1416-21
Comparison of CRRT circuit life for all circuits with: no anticoagulation (filled squares), heparin anticoagulation (filled circles) or citrate anticoagulation (filled triangles). Mean circuit survival was no different for circuits receiving hepACG (42.1±27.1 h) and citACG (44.7±35.9 h), but was significantly lower for circuits with noACG (27.2±21.5 h, P<0.005).

41. Brophy et.al. NDT 2005 Jul;20(7):1416-21
Comparison of CRRT circuit life for PRISMA circuits with: no anticoagulation (filled squares), heparin anticoagulation (filled circles) or citrate anticoagulation (filled triangles). Mean circuit survival was no different for circuits receiving hepACG and citACG but was significantly lower for circuits with noACG (P<0.005).

42. Why I feel citrate is superior to systemic Heparinization
Regional Anticoagulation
No systemic anticoagulation effect
Can be used in patients with HIT
Prolongs Filter Life

43. Other Considerations & Final Thoughts

44. Dialysis solutions and anticoagulant
Normocarb (DSI)
Hemofiltration soln (Baxter)
Hemosol LO (Hospal)
Hemosol BO (Hospal)
Dianeal (Baxter)
None √
NS flush
Heparin
Citrate

45. Dialysis Solutions Na 140 132 Ca 3.5 1.75 1.25 K 2 Mg 1.5 0.5 0.25 Cl
Electrolyte
(mmol/l)
Normocarb (DSI)
Hemofiltration soln (Baxter)
Hemosol LO (Hospal)
Hemosol BO (Hospal)
Dianeal (Baxter) Na
140
132 Ca
3.5
1.75
1.25 K 2 Mg
1.5
0.5
0.25 Cl
107
117
105
110 95
Lactate 30 40 3
Bicarb 35 32
%Glu 1
.5-1.5
FDA
YES NO

46. Protocols for Citrate anticoagulation
Web Sites:
Pioneering work:
adults– Mehta, Gibney, Tobe, Niles
Bunchman

47. Ideal Setup for CRRT All commercially available solutions
Citrate Regional Anticoagulation
Minimal Set up/Pharmacy involvement
Regulates/Nursing Algorithms:
Clearance
Citrate monitoring (post filter iCa)
Calcium Monitoring
Acid/Base balance
Volume/electrolyte

48. Final Thoughts ppCRRT group
Dr. Stu Goldstein (TCH)/Dr. Peter Skippen (BC Children’s Hospital)
Theresa Mottes
Hemodialysis Staff
Organizers for such a wonderful meeting!