0. Anticoagulation in CRRT Akash Deep, Director - PICU King’s College Hospital London

2. Children’s Critical Care Centre

3. Overview
Why do we change filters? Is everything related to clotted filters?
Why do filters/circuits clot?
Various Anticoagulants available
Is there a single best anticoagulant?
Available evidence
Anticoagulation in specific circumstances – Liver patients ( King’s experience)

4. Reasons for circuit change
Vascular access
Scheduled changes
Elective procedures
Actual clotting
Machine malfunction
Reasons for circuit change

5. Use of blood products vs circuit life

6. Effects of circuit/filter clotting
Decreased efficacy of treatment -
(important in circumstances like in ALF)
Increased blood loss especially in newborns
Increased costs
Propensity to increased haemodynamic instability during re-connection
Staff dissatisfaction

8. A newer model of the coagulation pathway

9. Coagulation in critically ill child
Pre-existing inflammatory states
Sepsis – decreased platelet count, decreased anticoagulants
trauma
Shock
hypercoagulable / thrombohemorrhagic states
Organ failure states
liver / renal (2˚coagulation abnormalities)
blood oncology / marrow failure
Perioperative
cardiopulmonary bypass
Medications
platelet effects
immunosuppressive / oncologic
thrombogenic / fibrinolytic

10. Where does thrombus form?
Any blood-artificial surface interface
Hemofilter
Bubble trap
Vascath
Areas of turbulence /Resistance
Luer lock connections
/ 3 way stopcocks
Small vascath sizes and lower blood flows add to already existing challenges in paediatric population

11. Ideal Anticoagulation
Selectively active in the circuit – minimal effects on patient hemostasis
Readily available
Consistently delivered (protocols)
Safe (?)
Easy, rapid monitoring and reversible
Prolonged filter life
Cost Effective
Uncomplicated ,easy to follow protocols- Staff training

12. Anticoagulants Saline Flushes Heparin (UFH)
Low molecular weight heparin
Citrate regional anticoagulation (not licensed for use)
Prostacyclin (not licensed for use)
Nafamostat mesilate
Danaparoid
Hirudin/Lepirudin
Argatroban (thrombin inhibitor).

13. Heparin Most commonly used anticoagulant Large experience
Short biological half-life
Availability of an efficient inhibitor
Possibility to monitor its effect with routine laboratory tests – ACT.

14. Heparin Heparin enhances binding of antithrombin III to factor II & X
Large fragments – Anti IIa Activity
Small fragments : Anti Xa activity
Acts directly and taken up by RES
Metabolised by the liver
Metabolites are eliminated by the kidneys
Plasma half-life is approximately 90 minutes

15. Heparin Protocols
Heparin infusion prior to filter with post filter ACT measurement and heparin adjustment based upon parameters
Bolus with units/kg – Not always
Infuse heparin at units/kg/hr
Adjust post filter ACT secs
Interval of checking is local standard and varies from 1-4 hr increments.

16. Heparin – Side Effects
Bleeding %
Heparin Resistance
Heparin Induced Thrombocytopenia (HIT)
(<1 to 5%) The antibody–platelet factor 4–heparin complex subsequently binds to platelets, inducing platelet activation, aggregation and activation of the coagulation pathways.
Unpredictable and complex pharmacokinetics of UFH

17. Pathogenesis of HIT
Warkentin, 2003

19. LMWH Daltaparin,enoxaprin,and nadroparin Advantages Disadvantages
Higher anti Xa/IIa activity
More reliable anticoagulant response
Reduced risk of bleeding
Less risk of HIT
Effect more prolonged in renal failure
No quick antidote
Special assays to monitor anti-Xa activity
Increased cost
No difference in filter life

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
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) in the blood thus inhibiting clotting
CITRATE
THROMBIN
NATURAL ANTICOAGULANTS
(APC, ATIII)
fibrinogen
FIBRINOLYSIS ACTIVATION
FIBRINOLYSIS INHIBITION
CLOT

21. (0.4 x citrate rate)
(1.5 x BFR)
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

22. 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
Systemic calcium infusion -aim for patient iCa of mmol/l
Lower the iCa levels in circuit- more anticoagulant effect

23. What happens to Ca-citrate?
Ca-citrate gets filtered/dialysed
More than 50% gets removed in dialysate
Remaining enters circulation – TCA cycle – citric acid ( liver, muscle, renal cortex)
1mmol citrate – 3mmol NaHCO3 (risk of metabolic alkalosis and hypernatremia)

24. Citrate – Analysis Advantages Disadvantages
Less bleeding risk – No effect on systemic anticoagulation
No need for heparin
Commercially available solutions exist (ACD-citrate-Baxter)
Simple to monitor if facilities exist
Definitive protocols exist
Metabolic alkalosis
Metabolized in liver / other tissues
Electrolyte disorders
Hypernatremia
Hypocalcemia
Hypomagnesemia
Citrate Lock
Cardiac toxicity -Neonatal hearts

25. 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
Metabolic acidosis with an enlarged anion gap
A serum total to ionic calcium ratio of ≥ 2.5 is assumed to be a critical threshold for the prediction of citrate accumulation
Rx of “citrate lock”
Decrease or stop citrate for 3-4 hrs then restart at 70% of prior rate or Increase D or FRF rate to enhance clearance.

27. Citrate Anticoagulation
Well-designed and flexible protocol with proven efficacy
Adjusted to the local preferences of modality and dose
Results of ionized calcium measurement should be available 24 hours a day (Keep circuit [Ca++] levels around .30 for best results)
Training of staff – understand monitoring and side effect profile.

28. Citrate versus Heparin

29. Citrate versus Heparin
Median circuit life : Citrate - 70 hr; Heparin - 40 hr
Spontaneous circuit failure : Heparin -87%;Citrate- 57%
Transfusion requirement :Citrate- 0.2 units/day of CVVH ; Heparin- 1 units/day
Monchi M et al. Int Care Med 2004;30:260-65
Regional citrate anticoagulation was superior to heparin for the filter lifetime and transfusion requirements.

30. Heparin versus Citrate? .
Morgera S, et.al. Nephron Clin Pract. 2004; 97(4):c131-6.
Single center adults
Regional anticoagulation : trisodium citrate vs 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
On cost analysis, there was significant
cost saving due to prolonged filter life when using
citACG

31. Circuit survival censored for
Seven ppCRRT centers
138 patients/442 circuits
3 centers: hepACG only
2 centers: citACG only
2 centers: switched from hepACG to citACG
HepACG = 230 circuits
CitACG= 158 circuits
NoACG = 54 circuits
18000 hours of CRRT
Circuit survival censored for
Scheduled change
Unrelated patient issue
Death/witdrawal of support
Regain renal function/switch to intermittent HD.

32. Similar life spans with heparin and citrate but lesser bleeding complications with citrate
Life threatening bleeding complications attributable to anticoagulation were noted in the heparin ACG group but were absent in the citrate ACG group.

33. Final Decision – Citrate vs Heparin
Local familiarity with protocol ;patient profile
Heparin common as vast experience, easy to monitor, good circuit life
Problems – Systemic anticoagulation, bleeding
(sometimes life-threatening), HIT, resistance
Citrate – comparable filter life, no risk of bleeding
Why is citrate not the standard of care ?
Metabolic complications with regular monitoring, metabolism in liver disease complex
Physician’s perception, huge training resource, citrate module not available in all, cost
In UK – Heparin is the most commonly used ACG for ease of use.
Citrate
Heparin

34. A lipid molecule-eicosanoid
Epoprostenol – synthetic derivative
Reversibly inhibits platelet function by diminishing the expression of platelet fibrinogen receptors and P-selectin
Reduces heterotypic platelet-leukocyte aggregation.

35. Platelet aggregation and adhesion inhibitor Heparin sparing effect
Mechanism of action
Platelet aggregation and adhesion inhibitor
Heparin sparing effect
Thromboelastograph

36. Prostacyclin (PGI2) Kinetics Dynamics Half life – 42 seconds
Vasodilator effect at 20 ng/kg/minute
Platelet effect at 2-8 ng/kg/minute -½ life 2 hours
Limited clinical experience
Flolan – epoprostenol sodium
Anti-thrombotic
Inhibits platelet aggregation and adherence to vessel wall
Vessel tone
Reduces SMC proliferation and increased vasodilatation
Anti-proliferative
Reduces fibroblasts, increases apoptosis
Anti-inflammatory
Reduces pro-inflammatory cytokines and increased anti-inflammatory cytokines
Anti-mitogenic

37. Side effects - KCH Limited clinical experience- scant data
Hypotension, raised ICP, Hyperthermia
Cost is the use-limiting factor
Review of all Adverse relating to prostacyclin use:
Total patients treated with prostacyclin -34 (2 years)
Technical issues in delivery -1
Hypotension necessitating treatment and dose alteration – 1
Bleeding issues - 0

38. Prostacyclin- Evidence
Very little evidence on :
When to use –patient population
Optimal dose – anti-platelet effect without hypotension
Rout of administration – systemic versus pre-filter
Used alone or in combination with heparin

39. Lesser risk of systemic haemorrhage Acceptable filter life
51 patients
CVVH (230 circuits)
4 ng/kg/minute
2 indicators of safety – bleeding and hypotension
2 indicators of efficacy- circuit patency and efficacy of CRRT
Median life span – 15 hours
4 /51patients developed “bleeding”, 15.5% required intervention for hypotension
Main advantage:
Lesser risk of systemic haemorrhage
Acceptable filter life

40. Group -1 Heparin (6.0 +/- 0.3 IU/kg/hr for group 1),
46 patients on CVVH
Group -1 Heparin (6.0 +/- 0.3 IU/kg/hr for group 1),
Group -2 PGI2 (7.7 +/- 0.7 ng/kg/min )
Group-3 PGI2 and heparin (6.4 +/- 0.3 ng/kg/min, 5.0 +/- 0.4 IU/kg/hr)
Filter life, haemostatic variables and haemodynamic variables at various times
Mean hemofilter duration :
PGI2 + heparin 22 hours
Only heparin hours
Only PGI2 – 17.8 hours

41. Patients receiving both PGI2 and heparin showed better hemodynamic profiles and enhanced hemofilter duration compared with the other groups and no bleeding complications were observed
Thus patients treated with a combination of prostacycline and heparin can achieve better filter life using lesser dose of heparin with more haemodynamic stability and lesser bleeding risk.

42. Heparin and Prostacyclin combined

43. Is anticoagulation with PGI2 dose dependent?
Anticoagulation with prostaglandin E1 and unfractionated heparin during continuous venovenous hemofiltration
Kozek-Langenecker, Sibylle A.; Kettner, Stephan C Critical Care Medicine. 26(7): , July 1998.
24 critically ill patients requiring CRRT
Group- A - 5 ng/kg/min PGE1 and 6 IU/kg/hr heparin
Group –B 20 ng/kg/min PGE1 and 6 IU/kg/hr heparin
Results : Hemofilter usage 20 ng/kg/min PGE1 (32 +/- 3 hrs)
versus with 5 ng/kg/min PGE1(22 +/- 3 hrs)
In vitro bleeding parameters were significantly prolonged
in postfilter blood in patients receiving 20 ng/kg/min PGE1
but no effect on plasma coagulation profile or hemodynamic parameters
Conclusion: Extracorporeal administration of PGE1,
combined with low-dose heparinization, inhibits platelet
reactivity and preserves hemofilter life dose-dependently

44. Experience at King’s PICU
Start at 2 ng/kg/min
Observe Filter life- if < 48 hours, increase the dose to 4 and sequentially to 6 ng/kg/min
Filter life in 10 patients ( 64 circuits) on PGI2 observed
Filter life increased from a median duration of 20 hours
( 2 ng/kg/min) to 34 hours ( 4ng/kg/min) to 48 hours (6 ng/kg/min)
No major increase in side effects with increasing doses – 1 case of hypotension with 8ng/kg/min

45. Effect of the mode of delivery on the efficacy of prostacyclin as an annticoagulant in continuous venovenous haemofiltration
G. O’CALLAGHAN, M. SLATER, G. AUZINGER, J. WENDON
LIVER INTENSIVE CARE UNIT, KING’S COLLEGE HOSPITAL, LONDON, UK
16 liver patients 142 filter episodes : Systemic vs Pre-filter 5 ng/kg/min

46. Conclusion
Systemic administration of PGI2 does not prolong filter life during CVVHF
No evidence of decreased platelet activation with systemic PGI2
PGI2 as the sole anticoagulant during CVVHF results in acceptable circuit life.

47. Why I feel prostacyclin is safe and effective
Regional Anticoagulation
No systemic anticoagulation effect
Can be used in patients with coagulapathy
Prolongs Filter Life
Suits my patient population
Protocol easy to use and follow with no complex monitoring required
Minimal side effects

48. Cost factor – the biggest factor ???

49. Summary Heparin and citrate anticoagulation most commonly used methods
Heparin: bleeding risk
Citrate: alkalosis, citrate lock
Evidence favours the use of citrate
Prostacyclin a good alternative in patients with liver disease / bleeding diathesis
( Cost implications)

50. There was no increased bleeding or requirement for blood transfusions
On starting ACG in patients with liver failure filter life increased from 5.6 to 19 hours.
There was no increased bleeding or requirement for blood transfusions
Patients with liver disease contrary to common belief do require anticoagulation to keep CRRT going continuously

51. Conclusion No perfect choice for anticoagulation exists
Choice of anticoagulation is best decided locally
Think of patient’s disease process, access issues
For the benefit of the bedside staff who do the work come to consensus and use just one protocol
Having the “protocol” changed per whim of the physician does not add to the care of the child but subtracts due to additional confusion and work at bedside.

52. Reference tools Adqi.net-web site for information on CRRT AKIN.net
crrtonline.com
Pediatric CRRT with links to other meetings,protocols, industry

53. Acknowledgement Tim Bunchman Stuart Goldstein
Chula Goonasekera – Commonwealth Fellow KCH