Transcript Mortality Data Review: Divisional Update: Women Mar 2008

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)
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• A lipid moleculeeicosanoid
• 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.
Mechanism of action
Thromboelastograph
Heparin sparing effect
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Prostacyclin (PGI2)
Dynamics
Kinetics
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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
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Anti-thrombotic
o Inhibits platelet aggregation and
adherence to vessel wall
Vessel tone
o Reduces SMC proliferation and
increased vasodilatation
Anti-proliferative
o Reduces fibroblasts, increases
apoptosis
Anti-inflammatory
o Reduces pro-inflammatory cytokines
and increased anti-inflammatory
cytokines
Anti-mitogenic
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Side effects
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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
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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
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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 nonepoprostenol (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
LOS (d)
WEIGHT (kg)
NON EPOPRESTENOL
AGE (y)
EPOPROSTENOL
F
M
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5
10
15
20
25
30
35
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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
Mortality
Hypotension
NON EPOPROSTENOL
EPOPROSTENOL
Bleeding
PIM2score
0
10
20
30
40
50
60
70
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Platelet consumption
PLT consumption
PLTinfused
PLTpost
PLT pre
0
200
400
600
800
1000
Non Epoprostenol
1200
1400
1600
1800
2000
Epoprostenol
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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
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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 haemorrhage
Acceptable filter life
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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.
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Heparin and Prostacyclin combined
HEPARIN
PROSTACYCLIN
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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.
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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
haemofiltration
G. 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)
INR
1.37 (0.27)
1.46 (0.87)
NS
Vas cath age
days
2.5 (2.5)
2.6 (2.2)
NS
50 (44)
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 ???
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
50ml syringe
£14.47/ syringe
Cit rat e Buf f er Syringe
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Why I feel prostacyclin is safe and effective
• Regional Anticoagulation
o 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
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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
Citrate
Why is citrate not the standard of care ?
Heparin
 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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