Anticoagulation
in CRRT
Akash Deep, Director - PICU
King’s College Hospital
London
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Children’s Critical Care Centre
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Overview
• Why do we change filters? Is everything
related to clotted filters?
• Why do filters/circuits clot?
• Various Anticoagulants available
• Is there a single best anticoagulant?
• Available evidence
• Anticoagulation in specific circumstances –
Liver patients ( King’s experience)
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Circuit problems
(Air Alarms)
3%
Wrong filter Vascath
1%
problems
4%
Vascath blocked
13%
Circuit blocked
26%
Routine or
terminated
53%
Vascular access
Scheduled changes
Elective procedures
Actual clotting
Machine malfunction
Reasons for circuit change
Wrong filter
Circuit problems
Vascath blocked
Routine or terminated
Circuit blocked
Vascath problems
% receiving within 2hrs of event
35
FFP
RBC
PLTS
HAS
CRYO
30
25
20
15
10
5
0
Use of blood products vs circuit life
Effects of circuit/filter clotting
• Decreased efficacy of treatment (important in circumstances like in ALF)
• Increased blood loss especially in
newborns
• Increased costs
• Propensity to increased haemodynamic
instability during re-connection
• Staff dissatisfaction
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A newer model of the coagulation pathway
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Coagulation in critically ill child
• Pre-existing inflammatory states
o Sepsis – decreased platelet count, decreased anticoagulants
o trauma
o Shock
• hypercoagulable / thrombohemorrhagic states
• Organ failure states
o liver / renal (2˚coagulation abnormalities)
o blood oncology / marrow failure
• Perioperative
o cardiopulmonary bypass
• Medications
o platelet effects
o immunosuppressive / oncologic
• thrombogenic / fibrinolytic
Where does thrombus form?
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•
Any blood-artificial surface interface
o Hemofilter
o Bubble trap
o Vascath
Areas of turbulence /Resistance
o Luer lock connections
/ 3 way stopcocks
Small vascath sizes and lower blood flows add to already existing
challenges in paediatric population
Ideal Anticoagulation
• Selectively active in the circuit – minimal effects on patient
hemostasis
• Readily available
• Consistently delivered (protocols)
• Safe (?)
• Easy, rapid monitoring and reversible
• Prolonged filter life
• Cost Effective
• Uncomplicated ,easy to follow protocols- Staff training
Anticoagulants
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Saline Flushes
Heparin (UFH)
Low molecular weight heparin
Citrate regional anticoagulation (not licensed for use)
Prostacyclin (not licensed for use)
Nafamostat mesilate
Danaparoid
Hirudin/Lepirudin
Argatroban (thrombin inhibitor).
Heparin
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Most commonly used anticoagulant
Large experience
Short biological half-life
Availability of an efficient inhibitor
Possibility to monitor its effect with routine
laboratory tests – ACT.
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Heparin
Heparin enhances binding of
antithrombin III to factor II & X
Large fragments – Anti IIa Activity
Small fragments : Anti Xa activity
Acts directly and taken up by RES
Metabolised by the liver
Metabolites are eliminated by the kidneys
Plasma half-life is approximately 90 minutes
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Heparin Protocols
• Heparin infusion prior to filter with post filter ACT
measurement and heparin adjustment based upon
parameters
• Bolus with 10-20 units/kg – Not always
• Infuse heparin at 10-20 units/kg/hr
• Adjust post filter ACT 180-200 secs
• Interval of checking is local standard and varies
from 1-4 hr increments.
Heparin – Side Effects
• Bleeding -10-50%
• Heparin Resistance
• Heparin Induced Thrombocytopenia (HIT)
(<1 to 5%) The antibody–platelet factor 4–heparin complex
subsequently binds to platelets, inducing platelet activation,
aggregation and activation of the coagulation pathways.
• Unpredictable and complex pharmacokinetics
of UFH
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Warkentin, 2003
Pathogenesis of HIT
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LMWH
Daltaparin,enoxaprin,and nadroparin
Advantages
Disadvantages
Higher anti Xa/IIa activity
More reliable anticoagulant response
Reduced risk of bleeding
Less risk of HIT
Effect more prolonged in renal failure
No quick antidote
Special assays to monitor anti-Xa
activity
Increased cost
No difference in filter life
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Sites of Action of Citrate
TISSUE FACTOR
TF:VIIa
CONTACT PHASE
XII activation
XI IX
monocytes /
platelets /
macrophages
X
Va
VIIIa
Ca++
platelets
Xa
Prothrombin
CITRATE
NATURAL
ANTICOAGULANTS
(APC, ATIII)
Ca+
+
Ca+
++
Ca
++
Ca
++
Ca
Phospholipid
++
Ca
surface
+
Clotting is a calcium dependent mechanism, removal
of calcium from the blood will inhibit clotting
THROMBIN
Adding citrate to blood will bind the free calcium
(ionized) in the blood thus inhibiting clotting
fibrinogen
CLOT
FIBRINOLYSIS ACTIVATION
FIBRINOLYSIS INHIBITION
(1.5 x BFR)
(0.4 x citrate rate)
•In most protocols citrate is infused post
patient but prefilter often at the “arterial”
access of the dual (or triple) lumen access
that is used for hemofiltration (HF)
•Calcium is returned to the patient
independent of the dual lumen HF access
or can be infused via the 3rd lumen of the
triple lumen access
Citrate: Technical Considerations
• Measure patient and system iCa in 2 hours
then at 6 hr increments
• Pre-filter infusion of Citrate -aim for system
iCa of 0.3-0.4 mmol/l
• Systemic calcium infusion -aim for patient
iCa of 1.1-1.3 mmol/l
• Lower the iCa levels in circuit- more
anticoagulant effect
What happens to Ca-citrate?
• Ca-citrate gets filtered/dialysed
• More than 50% gets removed in dialysate
• Remaining enters circulation – TCA cycle –
citric acid ( liver, muscle, renal cortex)
• 1mmol citrate – 3mmol NaHCO3 (risk of
metabolic alkalosis and hypernatremia)
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Citrate – Analysis
Advantages
Less bleeding risk – No effect on
systemic anticoagulation
Disadvantages
Metabolic alkalosis
Metabolized in liver / other
tissues
No need for heparin
Electrolyte disorders
Hypernatremia
Commercially available solutions exist
Hypocalcemia
(ACD-citrate-Baxter)
Hypomagnesemia
Simple to monitor if facilities exist
Citrate Lock
Definitive protocols exist
Cardiac toxicity -Neonatal hearts
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Complications of Citrate: “Citrate Lock”
• Seen with rising total calcium with dropping
patient ionized calcium
o Essentially delivery of citrate exceeds hepatic metabolism
and CRRT clearance
o Metabolic acidosis with an enlarged anion gap
o A serum total to ionic calcium ratio of ≥ 2.5 is assumed to
be a critical threshold for the prediction of citrate
accumulation
• Rx of “citrate lock”
o Decrease or stop citrate for 3-4 hrs then restart at 70% of
prior rate or Increase D or FRF rate to enhance
clearance.
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Citrate Anticoagulation
• Well-designed and flexible protocol with proven efficacy
• Adjusted to the local preferences of modality and dose
• Results of ionized calcium measurement should be
available 24 hours a day (Keep circuit [Ca++] levels around
.30 for best results)
• Training of staff – understand monitoring and side effect
profile.
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Citrate versus Heparin
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Citrate versus Heparin
• Median circuit life : Citrate - 70 hr; Heparin - 40 hr
• Spontaneous circuit failure : Heparin -87%;Citrate- 57%
• Transfusion requirement :Citrate- 0.2 units/day of CVVH ;
Heparin- 1 units/day
Monchi M et al. Int Care Med 2004;30:260-65
Regional citrate anticoagulation was
superior to heparin for the filter lifetime
and transfusion requirements.
Heparin versus Citrate?
Morgera S, et.al. Nephron Clin Pract. 2004; 97(4):c131-6.
.
• Single center - 209 adults
• Regional anticoagulation : trisodium citrate vs standard heparin
protocol
• CitACG was the sole
anticoagulant in 37 patients,
87 patients received low-dose
heparin plus citrate, and 85
patients received only hepACG.
• Both groups receiving citACG
had prolonged filter life when
compared to the hepACG group
On cost analysis, there was significant
cost saving due to prolonged filter life when using
citACG
• Seven ppCRRT centers
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138 patients/442 circuits
3 centers: hepACG only
2 centers: citACG only
2 centers: switched from hepACG to citACG
HepACG = 230 circuits
CitACG= 158 circuits
NoACG = 54 circuits
18000 hours of CRRT
Circuit survival censored for
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Scheduled change
Unrelated patient issue
Death/witdrawal of support
Regain renal function/switch to intermittent HD.
Similar life spans with heparin and citrate but
lesser bleeding complications with citrate
Life threatening bleeding complications attributable
to anticoagulation were noted in the heparin ACG
group but were absent in the citrate ACG group.
Final Decision – Citrate vs Heparin
• Local familiarity with protocol ;patient profile
• 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
Heparin
Why is citrate not the standard of care ?
 Metabolic complications with regular monitoring,
metabolism in liver disease complex
 Physician’s perception, huge training resource, citrate module not
available in all, cost
• In UK – Heparin is the most commonly
used ACG for ease of use.
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– A lipid moleculeeicosanoid
– Epoprostenol – synthetic
derivative
– Reversibly inhibits platelet
function by diminishing the
expression of platelet
fibrinogen receptors and
P-selectin
– Reduces heterotypic
platelet-leukocyte
aggregation.
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Mechanism of action
Platelet aggregation and adhesion inhibitor
Thromboelastograph
Heparin sparing effect
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Prostacyclin (PGI2)
Dynamics
Kinetics
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Half life – 42 seconds
Vasodilator effect at 20
ng/kg/minute
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 - KCH
• Limited clinical experience- scant data
• Hypotension, raised ICP, Hyperthermia
• Cost is the use-limiting factor
Review of all Adverse relating to prostacyclin use:
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Total patients treated with prostacyclin -34 (2 years)
Technical issues in delivery -1
Hypotension necessitating treatment and dose alteration – 1
Bleeding issues - 0
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Prostacyclin- Evidence
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Very little evidence on :
When to use –patient population
Optimal dose – anti-platelet effect without
hypotension
Rout of administration – systemic versus
pre-filter
Used alone or in combination with heparin
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51 patients
CVVH (230 circuits)
PGI2 @ 4 ng/kg/minute
2 indicators of safety – bleeding and
hypotension
2 indicators of efficacy- circuit
patency and efficacy of CRRT
Median life span – 15 hours
4 /51patients developed “bleeding”,
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 2 ng/kg/min
• Observe Filter life- if < 48 hours, increase the dose to 4
and sequentially to 6 ng/kg/min
• Filter life in 10 patients ( 64 circuits) on PGI2 observed
• Filter life increased from a median duration of 20 hours
( 2 ng/kg/min) to 34 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 annticoagulant 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.
Why I feel prostacyclin is safe and effective
• Regional Anticoagulation
o No systemic anticoagulation effect
• Can be used in patients with coagulapathy
• Prolongs Filter Life
• Suits my patient population
• Protocol easy to use and follow with no complex
monitoring required
• Minimal side effects
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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Summary
• Heparin and citrate anticoagulation most
commonly used methods
• Heparin: bleeding risk
• Citrate: alkalosis, citrate lock
• Evidence favours the use of citrate
• Prostacyclin a good alternative in patients with
liver disease / bleeding diathesis
( Cost implications)
 On starting ACG in patients with liver failure filter life increased from 5.6 to 19 hours.
There was no increased bleeding or requirement for blood transfusions
 Patients with liver disease contrary to common belief do require anticoagulation to keep
CRRT going continuously
Conclusion
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No perfect choice for anticoagulation exists
Choice of anticoagulation is best decided locally
Think of patient’s disease process, access issues
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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Acknowledgement
• Tim Bunchman
• Stuart Goldstein
• Chula Goonasekera – Commonwealth
Fellow KCH