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1
Prostacyclin as an anticoagulant in CRRT
Akash DeepDirector - PICU
King’s College Hospital London
ChairRenal/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.
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Thromboelastograph
Mechanism of action
Heparin sparing effect
Prostacyclin (PGI2)Kinetics
• 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
Dynamics
• Anti-thrombotico Inhibits platelet aggregation and
adherence to vessel wall
• Vessel toneo Reduces SMC proliferation and
increased vasodilatation
• Anti-proliferativeo Reduces fibroblasts, increases
apoptosis
• Anti-inflammatoryo Reduces pro-inflammatory cytokines
and increased anti-inflammatory cytokines
• Anti-mitogenic5
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
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Monitoring• No complex monitoring required• Clinical – Bleeding, hypotension• Platelet aggregation tests – Costly, time
consuming• Thromboelastography (TEG) - useful
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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
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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
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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
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Baseline characteristics
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Children on CRRT - 76Total filters used- 210 (Prostacyclin 127, Heparin 45 , None-38)
Filter life - hours
Target event – clotted filterCensored – filter removed due to other
reasons
Complications
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Platelet consumption
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ConclusionProstacyclin used as a sole anti-haemostatic agent: Increases filter lifeDecreases bleeding risk without increasing platelet consumption, hypotensive episodes or mortality.Cost effectiveness is being established
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• 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 haemorrhageAcceptable filter life
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
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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
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PROSTACYCLIN
HEPARIN
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
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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
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Effect of the mode of delivery on the efficacy of prostacyclin as an anticoagulant in continuous venovenous
haemofiltrationG. O’CALLAGHAN, M. SLATER, G. AUZINGER, J. WENDON
LIVER INTENSIVE CARE UNIT, KING’S COLLEGE HOSPITAL, LONDON, UK
Systemic pre-filter p value
Filter life min
1177 (1252) 1139 (1057) NS
Platelet count 109/L
49 (28) 50 (44) NS
INR 1.37 (0.27) 1.46 (0.87) NS
Vas cath age days
2.5 (2.5) 2.6 (2.2) NS
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 ???
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Drug Strength Cost
Epoprostenol 500 microgram vial £16/vial
Heparin 10,000 units/10ml
£21.80/ 10amps
1000 units/ml
£6.55/ 10amps
20,000 units/20ml
£42/ 10amps
5000 units/5ml (preservative free)
£13.95/10amps
5000 units/0.2ml
£16.85/10amps
1000 units/ml (5ml) £13.27/10amps
Citrate Buffer Syringe 50ml syringe
£14.47/syringe
Why I feel prostacyclin is safe and effective
• Regional Anticoagulationo 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
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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.
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CitrateHeparin