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)

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.

Heparin sparing effect Mechanism of action Heparin sparing effect Thromboelastograph

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

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

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

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

Safety and Efficacy of Prostacyclin as an anticoagulant in CRRT First ever Paediatric data (King’s PICU) 3 year period ( 2011-2013) All children with ALF on CRRT ( n=76) Efficacy Filter life Mortality Safety Bleeding episodes during CVVH Hypotension ( requirement for fluids/vasopressors) Platelet consumption

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 - 4898

Baseline characteristics

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

Complications

Platelet consumption

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

Lesser risk of systemic haemorrhage Acceptable filter life 51 patients with ARF CVVH (230 circuits) PGI2 @ 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

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 -14.3 hours Only PGI2 – 17.8 hours

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.

Heparin and Prostacyclin combined

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):1208-1212, 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

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

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 PGI2@ 5 ng/kg/min

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.

Cost factor – the biggest factor ???

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

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)

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.

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

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

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