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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

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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