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.

4

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

6

Monitoring• No complex monitoring required• Clinical – Bleeding, hypotension• Platelet aggregation tests – Costly, time

consuming• Thromboelastography (TEG) - useful

7

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 ( 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

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 -

4898

11

Baseline characteristics

12

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

14

Platelet consumption

15

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

16

• 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

18

19

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

20

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

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

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 ???

25

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

29

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.

32

CitrateHeparin