BestpracticeinCRRTanticoagulation

PierreTISSIERES,MD,PhDPediatricICUandNeonatalMedicineParisSouthUniversityHospitals

pierre.tissieres@aphp.fr

Noconflict todiscloseAcknowledge toA.Deep,King’s CollegeHospital,London

• Whydowechangefilters?Iseverythingrelatedtoclottedfilters?

• Whydofilters/circuitsclot?• VariousAnticoagulantsavailable– Actions,advantages,disadvantages

• Isthereasinglebestanticoagulant?• Availableevidence• Inpractice

3

Circuitlifespan:“Host-circuit”determinants

“circuit”factors• flowrate• Filtrationfraction• pre-dilution• cathetersize• anticoagulation

“patient”factors• primarycondition!!• PT/INR• plateletcountandF1• haemoglobin• venousaccessissues• bloodproductsuse.

Reasonforcircuitchange• Clotting• Manufacturerrecommendation(72hours)• accessmalfunction- kinking,bending,leakage,inappropriatelysmallsize

• machinemalfunction• unrelatedpatientindication(e.g.,needsCTscan)• CRRTdiscontinued

5Int J Artif Organs. 2012

Effectsofcircuit/filterclotting

• Decreasedefficacyoftreatment-(importantincircumstanceslikeinALF)

• Increasedbloodlossespeciallyinnewborns• Increasedcosts• Propensitytoincreasedhaemodynamicinstabilityduringre-connection

• Staffdissatisfaction

6

Anticoagulation« cascade »

A“newermodel”ofthecoagulationpathway:importanceofthebalancebetweenpro/anticoag factors

8Acknowledge A.Deep

2- Wheredoesthrombusform?

• Anyblood-artificialsurfaceinterfaceo Hemofiltero Bubble trapo Vascath

• Areasofturbulence/Resistanceo Luer lock connections

/ 3 way stopcocks

Smallvascath sizesandlowerbloodflowsaddtoalreadyexistingchallengesinpaediatric population

PatientrelatedAccessrelatedCircuitrelatedTreatmentrelated

1- FactorsrelatedtoprematureClotting:

IdealAnticoagulation• Readilyavailable• Safe-Selectivelyactiveinthecircuit– minimaleffectsonpatienthemostasis

• Prolongedfilterlifeideally>48hours• Monitoring– RapidandSimple• Rapidlyreversibleincaseofcomplications• Uncomplicated,easytofollowconsistentlydeliveredprotocols-Stafftraining

• CostEffective

• Saline Flushes• Heparin (UFH)• Low molecular weight heparin• Citrate regional anticoagulation• Prostacyclin• Nafamostat mesilate• Danaparoid• Dermatan sulfate• Fondaparinux• Hirudin/Lepirudin• Argatroban (thrombin inhibitor).

Minerva Urol Nefrol. 2016 Feb;68(1):87-104. Epub 2015 Oct 16.Anticoagulation for renal replacement therapy for patients with acute kidney injury.Nongnuch A1, Tangsujaritvijit V, Davenport A.

Heparin • Mostcommonlyusedanticoagulant

• Largeexperience

• Shortbiologicalhalf-life

• Availabilityofanefficientinhibitor

• Possibilitytomonitoritseffectwithroutinelaboratorytests– ACT.

Heparin enhances binding of antithrombin III to factor II & X

Large fragments – Anti IIa ActivitySmall fragments : Anti Xa activity

Acts directly and Metabolised by the liver

Metabolites are eliminated by the kidneys

Plasma half-life is approximately 90 minutes

Heparin– SideEffects

• Bleeding-10-50%(DoseACTadjusted)• HeparinResistance+++(ATreducedinsickpatients+increasedATdegradation)

• HeparinInducedThrombocytopenia(HIT)?Inchildren?(<1to5%)Theantibody–plateletfactor4–heparincomplexsubsequentlybindstoplatelets,inducingplateletactivation,aggregationandactivationofthecoagulationpathways.

• UnpredictableandcomplexpharmacokineticsofUFH

Heparine interfere with inflammation!

LMWH

Advantages DisadvantagesHigher anti Xa activityMore predictable pharmacokinetics-hence more reliable anticoagulant response Reduced risk of bleedingLess risk of HIT

No quick antidoteEffect more prolonged in renal failureSpecial assays to monitor anti-Xa activityIncreased costNo difference in filter life

16

Daltaparin,enoxaprin,and nadroparin

17

Heparin- Summary

• Mostcommonlyused• Easytouse,monitor• Noevidenceondose• Systemicside-effects• Contraindicatedinbleedingpatients

18

Citrateanticoagulation

• Howdoesitwork?• Isthereanadvantageoverheparin?• Whatarethesideeffects?• Howeasyisittouse?• Whataretheprotocols?• Whatisneededtomakeitwork?

Howdoescitratework

• Clottingisacalciumdependentmechanism,removalofcalciumfromthebloodwillinhibitclotting

• Addingcitratetobloodwillbindthefreecalcium(ionized)calciuminthebloodthusinhibitingclotting

• Commonexampleofthisisbankedblood

CONTACT PHASEXII activation

XI IX

TISSUE FACTOR TF:VIIa

THROMBIN

fibrinogen

prothrombin

Xa

Va VIIIa Ca++

platelets

CLOT

monocytes / platelets /

macrophages

FIBRINOLYSIS ACTIVATIONFIBRINOLYSIS INHIBITION

NATURAL ANTICOAGULANTS

(APC, ATIII)

X

Phospholipid surface

Ca+

+Ca+

+Ca+

+Ca+

+Ca+

+Ca+

+

CITRATE

Howiscitrateused?

• Inmostprotocolscitrateisinfusedpostpatientbutprefilter oftenatthe“arterial”accessofthedual(ortriple)lumenaccessthatisusedforhemofiltration(HF)…

• CalciumisreturnedtothepatientindependentoftheduallumenHFaccessorcanbeinfusedviathe3rd lumenofthetriplelumenaccess

(1.5 x BFR) (0.4 x citrate rate)

WhathappenstoCa- citrate?

• Ca-citrategetsfiltered/dialysed• Morethan50%getsremovedindialysate• Remainingenterscirculation– TCAcycle– citricacid(liver,muscle,renalcortex)

• 1mmolcitrate– 3mmolNaHCO3(riskofmetabolicalkalosisandhypernatremia)

• Citrate/Camismatchà hypocalcemia

24

Citrate:TechnicalConsiderations

• MeasurepatientandsystemiCain2hoursthenat6hrincrements

• Pre-filterinfusionofCitrate• AimforsystemiCaof0.3-0.4mmol/l

• Adjustforlevels• Systemiccalciuminfusion

• AimforpatientiCaof1.1-1.3mmol/l• Adjustforlevels

ComplicationsofCitrate:“CitrateLock”

• Seenwithrisingtotalcalciumwithdroppingpatientionizedcalcium

• EssentiallydeliveryofcitrateexceedshepaticmetabolismandCRRTclearance

• Metabolicacidosiswithanenlargedaniongap• Aserumtotaltoioniccalciumratioof≥2.5isassumedtobeacriticalthresholdforthepredictionofcitrateaccumulation

• Rxof“citratelock”• Decreaseorstopcitratefor3-4hrs thenrestartat70%ofpriorrateor Increase D or FRF rate to enhance clearance

CitrateinALFandcardiacfailure?

• Metabolicalkalosis• Metabolizedinliver/othertissues

• Electrolytedisorders• Hypernatremia• Hypocalcemia• Hypomagnesemia

• “Cardiactoxicity”- dysrhythmia• Neonatalhearts

28

CitrateAnticoagulation

• Well-designedandflexibleprotocol• Adjustedtothelocalpreferencesofmodalityanddose• Resultsofionizedcalciummeasurementshouldbeavailable24hoursaday(Keepcircuit[Ca++]levelsaround.30forbestresults)

• Trainingofstaff– understandmonitoringandsideeffectprofile

29

CitrateversusHeparin

P=0.03

Intensive Care Med. 2004 Feb;30(2):260-5. Epub 2003 Nov 5.Citrate vs. heparin for anticoagulation in continuous venovenoushemofiltration: a prospective randomized study.Monchi M1, Berghmans D, Ledoux D, Canivet JL, Dubois B, Damas P.

Regional citrate anticoagulation was superior to heparin for the filter lifetime

and transfusion requirements in ICU patients treated with CRRT

• Median filter life : Citrate - 70 hr; Heparin - 40 hr

• Spontaneous circuit failure : Heparin -87%;Citrate- 57%

• Median time to spontaneous circuit failure: Heparin 45 hrs; Citrate -140 hrs

• Transfusion requirement :Citrate- 0.2 units/day of CVVH ; Heparin- 1 units/day

FinalDecision– CitratevsHeparin

• Localfamiliaritywithprotocol,patientpopulation

• Heparincommonasvastexperience,easytomonitor,goodcircuitlife

• Problems– Systemicanticoagulation,bleeding

(sometimeslife-threatening),HIT,resistance

• Citrate– comparablefilterlife,noriskofbleeding

Whyiscitratenotthestandardofcare?

v Physician’sperception- useofcitratecomplex,

v Citratemodulenotineverymachine

v Metaboliccomplicationswithregularmonitoring,metabolisminliverdiseasecomplexv Hugetrainingresource

v Cost

• InUK– HeparinisthemostcommonlyusedACGforeaseofuse.

33

CitrateHeparin

• A lipid molecule-eicosanoid • Epoprostenol – synthetic

derivative (Flolan)• 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.

Prostacyclin PGI2

Prostacyclin(PGI2):morethananti-thrombotic!

Kinetics• Halflife– 42seconds

• Vasodilatoreffectat20ng/kg/minute

• Plateleteffectat2-8ng/kg/minute-½life2hours

• Limitedclinicalexperience

• Flolan – epoprostenol sodium

Dynamics• Anti-thrombotic

o Inhibitsplateletaggregationandadherencetovesselwall

• Vesseltoneo ReducesSMCproliferationandincreasedvasodilatation

• Anti-proliferativeo Reducesfibroblasts,increasesapoptosis

• Anti-inflammatoryo Reducespro-inflammatorycytokinesandincreasedanti-inflammatorycytokines

• Anti-mitogenic

Sideeffects

• Limitedclinicalexperience• Scantdataonefficacyandsafety• Hypotension,raisedICP,Hyperthermia• Facialflushing,headache• Ventilation-perfusionmismatching• Costistheuse-limitingfactor

EvidenceforuseofProstacyclin

• NoneoutthereespeciallyinPaediatrics• Dose???• Route-?• Indications-?• Mostworkcarriedoutinpatientswherethereiscontraindicationtoheparin/citrate

Ther Apher Dial. 2015 Feb;19(1):16-22. doi: 10.1111/1744-9987.12224. Epub 2014 Sep 4.Factors affecting circuit life during continuous renal replacement therapy in children with liver failure.Goonasekera CD1, Wang J, Bunchman TE, Deep A.

Plattlets sparing effect !

46patientsonCVVH• Group-1Heparin(6.0+/- 0.3IU/kg/hrforgroup1),• Group-2PGI2(7.7+/- 0.7ng/kg/min)• Group-3PGI2andheparin(6.4+/- 0.3ng/kg/min,5.0+/- 0.4IU/kg/hr)• Filterlife,haemostaticvariablesandhaemodynamicvariablesatvarious

times• Meanhemofilter duration:

ü PGI2+heparin22hoursü Onlyheparin-14.3hoursü OnlyPGI2– 17.8hours

Heparin+PGI2:BetterhemodynamicprofilesEnhancedhemofilter duration

Acknowledge toA.Deep,KCH,London

Summary

• Heparinandcitrateanticoagulationmostcommonlyusedmethods

• Heparin:bleedingrisk• Citrate:alkalosis,citratelock!!!• Evidencefavorstheuseofcitrate(notuniversallyused)

• Prostacyclin:plateletssparingeffect,agoodalternativeinpatientswithliverdisease/bleedingdiathesis,butcostimplications

AnticoagulationinSpecialCircumstances

• Inachild with advanced liver disease ?• Inachild with postarrest /cardiac failure ?• Inachild onECMO?• Inachild inseptic shock ?• Inachild heparin induced thrombocytopenia ?• Inaneonates /premies ?

AnticoagulationinSpecialCircumstances

• Inachild with advanced liver disease:No(orPGI2?)• Inachild with postarrest /cardiac failure:Heparin• Inachild onECMO:Heparin,Citrate(PGI2?)• Inachild inseptic shock:No,heparin• Inachild heparin induced thrombocytopenia:Irudin• Inaneonates /premies:Heparin (PGI2?)

Bestpractice- conclusion

• Noperfectchoiceforanticoagulationexists• Choiceofanticoagulationisbestdecidedlocally• Thinkofpatient’sdiseaseprocess,accessissues,bloodproductuse

Thank you

Andsee you inLisbon forESPNIC2017