0. Prostacyclin as an anticoagulant in CRRT Akash Deep Director - PICU King’s College Hospital London Chair Renal/CRRT Section European Society of Paediatric and Neonatal Intensive Care (ESPNIC)

2. 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.

3. Heparin sparing effect
Mechanism of action
Heparin sparing effect
Thromboelastograph

4. Prostacyclin (PGI2) Kinetics Dynamics
Vasodilator effect at 20 ng/kg/minute- Hypotension
Half life – 2 mins
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

5. Side effects Limited clinical experience
Scant data on efficacy and safety
Hypotension, raised ICP
Facial flushing, headache, Hyperthermia
Ventilation-perfusion mismatching
Cost is the use-limiting factor

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

8. Evidence for use of Prostacyclin
None out there especially in Paediatrics
Dose ???
Route -?
Indications -?
Most work carried out in patients where there is contraindication to heparin/citrate

9. Safety and Efficacy of Prostacyclin as an anticoagulant in CRRT
First ever Paediatric data (King’s PICU)
3 year period ( )
All children with ALF on CRRT ( n=76)
Efficacy
Filter life
Mortality
Safety
Bleeding episodes during CVVH
Hypotension ( requirement for fluids/vasopressors)
Platelet consumption

10. Results
Epoprostenol ( n= 48) versus non-epoprostenol (Heparin or None) ( n=28)
210 filters utilised (5.5 circuits /patient)
Epoprostenol hours of treatment- 6761
( 4 ng/kg/min)
Non-epoprostenol hours of treatment

11. Baseline characteristics

12. Total filters used- 210 (Prostacyclin 127, Heparin 45 , None-38)
Children on CRRT - 76
Total filters used- 210 (Prostacyclin 127, Heparin 45 , None-38)
Filter life - hours
Target event – clotted filter
Censored – filter removed due to other reasons

13. Complications

14. Platelet consumption

15. 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

16. Lesser risk of systemic haemorrhage Acceptable filter life
51 patients with ARF
CVVH (230 circuits)
4 ng/kg/minute
2 indicators of safety – bleeding & no. of sessions complicated by hypotension
2 indicators of efficacy- circuit patency and efficacy of CRRT
Median life span – 15 hours
4 /51patients developed “bleeding”(1 episode/1000 hrs), 15.5% required intervention for hypotension
Main advantage:
Lesser risk of systemic haemorrhage
Acceptable filter life

17. 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

18. 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.

19. Heparin and Prostacyclin combined

20. 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

21. Experience at King’s PICU
Start at 4 ng/kg/min
Observe Filter life- if < 48 hours, increase the dose to 6 and sequentially to 8 ng/kg/min
Filter life in 10 patients ( 34 circuits) on PGI2 observed
Filter life increased from a median duration of 20 hours
( 2 ng/kg/min) to 39 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

22. Effect of the mode of delivery on the efficacy of prostacyclin as an anticoagulant 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

23. 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.

24. Cost factor – the biggest factor ???

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

26. Summary Heparin and citrate anticoagulation most commonly used methods
Heparin: bleeding risk
Citrate: alkalosis, citrate lock
Evidence favors the use of citrate ( not universally used)
Prostacyclin a good alternative in patients with liver disease / bleeding diathesis
( Cost implications)

27. Conclusion No perfect choice for anticoagulation exists
Think of patient’s disease process, access issues, blood product use
Choice of anticoagulation is best decided locally
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.

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

29. Acknowledgements pCRRT foundation Tim Bunchman
Chula Goonasekera – Commonwealth Fellow KCH
Research team at KCH- PICU

31. 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.
Citrate
Heparin