0 anticoagulation in crrt akash deep, director - picu king’s college hospital london
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Anticoagulationin 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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Reasons for circuit changeReasons for circuit change
Vascular accessScheduled changesElective proceduresActual clottingMachine malfunction
Vas
cath
pro
blem
s
Circ
uit
bloc
ked
Rou
tine
or t
erm
inat
ed
Vas
cath
blo
cked
Circ
uit
prob
lem
s
Wro
ng fi
lter
% r
ece
ivin
g w
ithin
2hr
s o
f eve
nt
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FFP RBC PLTS HAS CRYO
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 stateso Sepsis – decreased platelet count, decreased anticoagulantso traumao Shock
• hypercoagulable / thrombohemorrhagic states
• Organ failure stateso liver / renal (2˚coagulation abnormalities) o blood oncology / marrow failure
• Perioperativeo cardiopulmonary bypass
• Medicationso platelet effectso immunosuppressive / oncologic
• thrombogenic / fibrinolytic
Where does thrombus form?
• Any blood-artificial surface interfaceo Hemofiltero Bubble trapo Vascath
• Areas of turbulence /Resistanceo 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• 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
• 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
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Heparin enhances binding of antithrombin III to factor II & X
Large fragments – Anti IIa ActivitySmall fragments : Anti Xa activityActs directly and taken up by RES
Metabolised by the liverMetabolites are eliminated by the kidneys
Plasma half-life is approximately 90 minutes
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 17
Pathogenesis of HITWarkentin, 2003
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LMWH
Advantages Disadvantages
Higher anti Xa/IIa activityMore reliable anticoagulant response Reduced risk of bleedingLess risk of HIT
Effect more prolonged in renal failureNo quick antidoteSpecial assays to monitor anti-Xa activityIncreased costNo difference in filter life
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Daltaparin,enoxaprin,and nadroparin
Sites of Action of Citrate
CONTACT PHASECONTACT PHASEXII activationXII activation
XI IXXI IX
TISSUE FACTOR TISSUE FACTOR TF:VIIaTF:VIIa
THROMBINTHROMBIN
fibrinogenfibrinogen
ProthrombinProthrombin
XaXa
Va Va VIIIa VIIIa CaCa++++
plateletsplatelets
CLOTCLOT
monocytes / monocytes / platelets / platelets /
macrophages macrophages
FIBRINOLYSIS ACTIVATIONFIBRINOLYSIS ACTIVATION
FIBRINOLYSIS INHIBITIONFIBRINOLYSIS INHIBITION
NATURAL NATURAL ANTICOAGULANTSANTICOAGULANTS
(APC, ATIII)(APC, ATIII)
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Phospholipid Phospholipid surfacesurface
CaCa++
++CaCa++
++CaCa++
++CaCa++
++CaCa++
++CaCa++
++
CITRATECITRATEClotting is a calcium dependent mechanism, removal of calcium from the blood will inhibit clotting
Adding citrate to blood will bind the free calcium (ionized) in the blood thus inhibiting clotting
(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 Disadvantages
Less bleeding risk – No effect on systemic anticoagulation
No need for heparin
Commercially available solutions exist (ACD-citrate-Baxter)
Simple to monitor if facilities exist
Definitive protocols exist
Metabolic alkalosisMetabolized in liver / other tissues
Electrolyte disordersHypernatremiaHypocalcemiaHypomagnesemia
Citrate Lock
Cardiac toxicity -Neonatal hearts
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Complications of Citrate: “Citrate Lock”• Seen with rising total calcium with dropping
patient ionized calciumo Essentially delivery of citrate exceeds hepatic metabolism
and CRRT clearanceo Metabolic acidosis with an enlarged anion gapo 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?.
• Single center - 209 adults
• Regional anticoagulation : trisodium citrate vs standard heparin protocol
• CitACG was the soleanticoagulant in 37 patients,87 patients received low-doseheparin plus citrate, and 85patients received only hepACG.
• Both groups receiving citACGhad prolonged filter life whencompared to the hepACG group
On cost analysis, there was significant cost saving due to prolonged filter life when using
citACG
Morgera S, et.al. Nephron Clin Pract. 2004; 97(4):c131-6.
• Seven ppCRRT centerso 138 patients/442 circuitso 3 centers: hepACG onlyo 2 centers: citACG onlyo 2 centers: switched from hepACG to citACG
• HepACG = 230 circuits• CitACG= 158 circuits• NoACG = 54 circuits• 18000 hours of CRRT• Circuit survival censored for
o Scheduled changeo Unrelated patient issueo Death/witdrawal of supporto Regain renal function/switch to intermittent HD.
Life threatening bleeding complications attributable to anticoagulation were noted in the heparin ACG group but were absent in the citrate ACG group.
Similar life spans with heparin and citrate but lesser bleeding complications with citrate
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 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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CitrateHeparin
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– A lipid molecule-eicosanoid
– 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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Thromboelastograph
Mechanism of action
Heparin sparing effect
Platelet aggregation and adhesion inhibitor
Prostacyclin (PGI2)Kinetics
• 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
Dynamics
• Anti-thrombotico Inhibits platelet aggregation and
adherence to vessel wall• Vessel tone
o Reduces SMC proliferation and increased vasodilatation
• Anti-proliferativeo Reduces fibroblasts, increases
apoptosis• Anti-inflammatory
o Reduces pro-inflammatory cytokines and increased anti-inflammatory cytokines
• Anti-mitogenic37
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:
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 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
• 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 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 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/min45
Effect of the mode of delivery on the efficacy of prostacyclin as an annticoagulant 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.
Why I feel prostacyclin is safe and effective
• Regional Anticoagulationo 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 ???
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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
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
• 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• 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
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