1. Anticoagulation during CRRT Akash Deep Director - PICU King’s College Hospital London Chair Renal/CRRT Section European Society of Paediatric and Neonatal Intensive Care (ESPNIC)

2. DISCLOSURE Research grant from Mallinckrodt Pharmaceuticals
Taskforce member for ESPNIC/SCCM joint septic shock guidelines – Adjunctive therapies in septic shock (CRRT,TPE, ECMO)

3. Overview
Why do we change filters? Is everything related to clotted filters?
Why do filters/circuits clot?
Various Anticoagulants available – Actions, Monitoring advantages, disadvantages
Is there a single best anticoagulant?
Available evidence

4. Reason for circuit change
Clotting
Manufacturer recommendation(72 hours)
access malfunction- kinking, bending, leakage, inappropriately small size
machine malfunction
unrelated patient indication (e.g., needs CT scan)
CRRT discontinued

7. 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. ICP Vs TMP
Filter clots
ALF patient on CRRT from King’s College Hospital

9. 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

10. 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
18000 hours of CRRT
HepACG = 230 circuits (52%)
CitACG= 158 circuits(36%)
NoACG = 54 circuits(12%)
Circuit survival censored for
Scheduled change
Unrelated patient issue
Death/witdrawal of support
Regain renal function/switch to intermittent HD.

11. Similar life spans with heparin and citrate but lesser bleeding complications with citrate
Mean circuit life – 41 hours
Circuits functional at 60 hrs – 69% with Hep & Citrate; 28% with no ACG
Life threatening bleeding complications attributable to anticoagulation noted in the heparin ACG group but were absent in the citrate ACG group.

12. Ideal Anticoagulation
Readily available
Safe -Selectively active in the circuit – minimal effects on patient hemostasis
Prolonged filter life ideally > 48 hours
Monitoring – Rapid and Simple
Rapidly reversible in case of complications
Uncomplicated ,easy to follow consistently delivered protocols- Staff training
Cost Effective

13. Anticoagulants Saline Flushes Heparin (UFH)
Low molecular weight heparin
Citrate regional anticoagulation
Prostacyclin
Nafamostat mesilate
Danaparoid
Hirudin/Lepirudin
Argatroban (thrombin inhibitor).

14. The elements of haemostasis

15. 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.

16. Heparin Heparin enhances binding of anti-thrombin 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

17. 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.
Personal practice – doses < 20 U/kg/hr – not very efficacious

18. Heparins and LMWH

20. Courtesy –Andrew Durward

21. Heparin – Side Effects
Bleeding % ( Dose ACT adjusted)
Heparin Resistance ( AT reduced in sick patients + increased AT degradation)
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

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

23. Heparin- Summary Most commonly used
Easy to use, monitor but recent evidence suggests lack of correlation between effect and ACT
No evidence on dose
Systemic side-effects
Contraindicated in bleeding patients

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

25. (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

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. Titrate the Citrate infusion according to the citrate sliding scale below :

28. Advantages of citrate anticoagulation
Zero effect upon patient bleeding
Monitor with ionized calcium assay- ACT nor PTT is needed
Various 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. 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
Decrease or stop citrate for 3-4 hrs then restart at 70% of prior rate or Increase D or FRF rate to enhance clearance

31. Citrate versus Heparin

33. Heparin – 3723 hours
Citrate – 4530 hours
Heparin – 21 hours
Citrate – 45.2 hours
RBC units with Heparin – 6.5
RBC unis with citrate -3
Actually administered effluent dose as compared to prescribed dose:
85% heparin vs 92% with citrate

34. Final Decision – Citrate vs Heparin
Local familiarity with protocol, patient population
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 ?
Physician’s perception- use of citrate complex,
Citrate module not in every machine
Metabolic complications with regular monitoring, metabolism in liver disease complex
Huge training resource
Cost
In UK – Heparin is the most commonly used ACG for ease of use and familiarity .
Citrate
Heparin

35. A lipid molecule-eicosanoid
Epoprostenol – synthetic derivative
Platelet aggregation and adhesion inhibitor (PGI2)
Heparin sparing effect
Reversibly inhibits platelet function by diminishing the expression of platelet fibrinogen receptors and P-selectin
Reduces heterotypic platelet-leukocyte aggregation.

37. Monitoring Kinetics : 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
Monitoring
No complex monitoring required
Clinical – Bleeding, hypotension
Platelet aggregation tests – Costly, time consuming
Thromboelastography (TEG) - useful

39. Guideline PICU KCH Start 4 ng/kg/min (range 4-8 ng/kg/min)
Monitor circuit Life
8ng/kg/min
max
Infusion:
12 mcg/kg of EPO
in 0.9% NaCl to make a total of 50 ml
1ml/h = 4ng/kg/min
Closely observe for side effects
<48 h

42. Safety and Efficacy of Prostacyclin as an anticoagulant in CRRT
First ever Paediatric data (King’s PICU)
7 year period ( )
All children on CRRT ( n= 119)
Efficacy
Filter life
Mortality
Safety
Bleeding episodes during CVVH
Hypotension ( requirement for fluids/vasopressors)
Units of platelet and red blood cell consumed

43. Results Total 119 Epoprostenol ( n= 86) Heparin or None) ( n=33)
502 filters utilised
Total hours of treatment – 18,258 hours
Epoprostenol hours Non-epoprostenol group – 7246 hours
( 4 ng/kg/min)
Heparin hours No anticoagulation – 2348

44. Copyright © BMJ Publishing Group Ltd & Royal College of Paediatrics and Child Health. All rights reserved.
0.44 /1000 hours – 6.7% vs 34.6%
8.9% versus 34%

45. Conclusion Prostacyclin used as a sole anti-haemostatic agent:
Increases filter life
Decreases bleeding risk without increasing platelet consumption, hypotensive episodes or mortality.
Cost effectiveness is being established

46. Heparin and Prostacyclin combined

47. Cost factor – the biggest factor ???

48. Conclusion
No perfect choice for anticoagulation exist- best decided locally
Heparin and citrate anticoagulation most commonly used methods
Prostacyclin – good alternative – safety, efficacy, monitoring
Think of patient’s disease process, access issues, blood product use
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.