CRRTCaseSimulation:AKIandEndStageLiverFailure

JorgeCerdá,MD,MS,FACP,FASNChief,Dept.ofMedicineStPeter’sHealthPartners

ClinicalProfessorofMedicineAlbanyMedicalCollege,

Albany,NY,USA

Casepresentation

2

Case

A47yearoldmalewithalcoholiccirrhosisandchronichyponatremia(serumsodium130mMol/L)istransferredfromoutsidehospitalwithalteredmentalstatus,hypotension,anddecompensatedcirrhosis.

Uponadmission,heisfoundtohave>24houranuricrenalfailure(lastcreatinine1.5mg/dl2weekspriortoadmission).YouareconsultedforCRRTasabridgetotransplantation.

• CurrentMeds:Norepinephrine;Bicarbonatedrip;Pip-tazo 2.25gm q6;Vancomycin 1.5gramsq4days;Octreotide;Midodrine;Nexium;Lactuloseenemas;IValbumin

• Nutrition:NPO• PARAMETERLASTCHARTEDMINMAX

HeartRate 105 92120Resp Rate 22 2035BPArterial 90/55 84/5095/60

• Intake:6190ml/Output:50ml(15L+sinceadmissiontoOSH),80kg• PHYSICALEXAM:

– Oxygensaturation94%on2LNasalCannula– General:Ictericconjunctivaandskin;obtunded, asterixis;Respiratory:Bilateral

rhonchi; Cardiovascular:tachycardia,Norub;Gastrointestinal:Distended,+ascites;Extremities:+3edema

CasePresentation

CasePresentation• LABRESULTS

– pH7.32,PCO225,PO283,HCO314,2LN/C

– Na120,Cl90,K5.8,HCO316mEq/L

– BUN60mg/dL,creatinine6.5mg/dL– Phosphorus2.0,Ca (corr.)9.1mg/dl– Lactate6.5mM/L– Totalbilirubin15mg/dL,,albumin2g/dl,ammonia189μg/dl– INR2.7,platelets30,000,hgb 10gm/dL– Ascitic fluidPMN>250/μL

– ChestX-ray:bilateralatelectasis,withbilateralpleuraleffusions,smalllungvolumes,Dobhoff tubeinplace

– MELDscoreMayo38UNOS34Child-Pough 13ClassC– Estimatedmortality1yr:55%2yr:65%

AKIVS.HRS

• DEFINITIONS• PATHOPHYSIOLOGYOFAKIINTHISSETTING• VOLUMESTATUS• HEMODYNAMICS• TREATMENTS

6

Assessment

• HEMODYNAMICINSTABILITY• OnNorepinephrine,Midrodine,Octreoctide

• WHATISTHEVOLUMESTATUSOFTHISPATIENT?

• Fluidoverload:+15Kg,3+edema,largeascites• Anuria1-2days• Priortoanuria,Naretentionbythekidney(Una<10mEq/l)likely• BUT!

• Copiousdiarrheamanydaysduetolactulose• NPO,nointake• Severehypoalbuminemia:Whatisthearterialeffectivevolume?

7

Assessment

• AKI?– BaselineSCr1.5,currently6.5mg/dl– Anuria24hours

– RIFLEF,AKIN3,AKIKDIGO3

8

DiagnosisofAKI:RIFLEandAKINCriteria

Cruz et al, Crit Care 2009

DiagnosisofAKI:KDIGOAKIDefinition

Assessment• ACUTEKIDNEYINJURY:Whatmechanism?

– Volume-responsive?Howlikelyispatienttorespondtovolumeexpansion?

• Decreasedintra-arterialeffectivevolume• Una<10mEq/l• Copiousdiarrhea• CXR“atelectasisandeffusions”

– ATN?• Possiblesepsis(onPip-Tazo+Vanco ?SBP)

– HRSType1?• Severeliverfailure• LikelySBP

11

MechanismsofOliguriainAKI

Cerdá, Kidney Int 80(7) 2011

SHOCK,SPLACHNICVASODILAT

SHOCK,PRESSORS

HRS

SHOCK,SEPSIS

ISCHEMIANSAIDs

RADIOCONTRASTSEPSIS

UNLIKELYHERE

ABDOMINALCOMPARTMENTSYNDROME

13Gines-Schrier NEJM 2009

Gines-Schrier NEJM 2009

Bacterialtranslocationandcytokineoverproductioninducesplachnicarterialvasodilation

Hormonalresponsetocirrhosis

15

0

2

4

6

8

10

12

PLASMARENIN NOREPINEPHRINE ADH

NOASCITES

ASCITES

ASCITES+RF

From: Asbert M Ginès P et al Gastroenterology 1993

35

Ornipressin improvesrenalfunctioninadvancedhepaticcirrhosis

16

0

5

10

15

20

25

30

35

GFR PLASMARENIN RENALFRACTION%

BASELINE

ORNIPRESSIN

From: Lenz K, Hortangl H et al Gastroenterology 1991

SomatostatinandAnalogs

17

Chan MM et al Octreotide CHEST 2013; 144(6):1937-45

18Chan Octreotide CHEST 10`2

SSTandOctreotideSimplified diagram of key signaling events after SST or Octreotide binding to RRT Receptor accounting for the major biologic effects of SST and analogs

19NEJM 1999;341:403-9

Impact of intravenous albumin on renal impairment and mortality among patients with SBP

Diagnosticcriteriaofhepato-renalsyndrome

• Cirrhosiswithascites• Serumcreatinine>133mM=1.5mg/dl• NoimprovementinSCr<1.5mg/dlafter2daysofdiureticwithdrawalandvolumeexpansionwithalbumin(1g/Kg/daymax100g/d)

• Absenceofshock• Nocurrentorrecentnephrotoxicdrugs• Nointrinsicrenaldisease(hematuria,proteinuria,abnormalrenalUS)

20

InternationalAscitesClubdefinitionofHRS

21

TypesofHRS

• TYPE1– DoublingofSCrto>2.5mg/dlin<2weeks– Severemultiorgan dysfunction(heart,brain,liver,adrenals)

• Type2– Stableorlessrapidlyprogressivecoursethantype1– Refractoryascites

22

ThediagnosisofAKIincirrhoticpatientsislate

• HRS:SCr>1.5mg/dl

• Malnutrition• Atrophicmusclemass• Fluidoverload

• Newdefinitionsdeveloping(IntAscitesClub,ADQI):– IncreaseSCr>0.3mg/dlinlessthan48hours,– Ora50%increasefromastableSCrlevelobtainedwithinthepast6months

23

Wong F et al Gut 2011Wong et al Gastroenterology 2013Mehta RL Crit Care 2007Jenq CC ICM 2007Cholongitas E J Gastroent Hepatol 2009Martin-Liahi M Gastroenterology 2011

Inpatientswithcirrhosis+ascitesAKIdiagnosisisdelayed

24

ImpactofAKIincirrhoticpatients

• MostcommonprecipitantofAKIisbacterialinfection

• IfAKIdevelopsinaninfectedpatient,survivalisreducedto31%at3months

• RenaldysfunctionthemostsignificantindependentpredictorofdeathinptswithcirrhosisandSBP

25

SurvivalwithHRSispoor

26

Gines-Schrier NEJM 2009

ACID-BASESTATUS

• Whatistheacid-basedisorder?• Whatisthemechanism?• Howdowefixit?

28

Assessment

• ACID-BASESTATUS– pH7.32,PCO225,PO283,HCO314– Na120,Cl90,K5.8,CO216,AG14– (NormalAGcorrectedforalbumin2g/dl=7)– ΔAG/ΔHCO3-:7/10:CombinedHAG/NAGacidosis

– MetabolicAcidosis• Nl AG:likelyduetodiarrheallossofHCO3-,Spironolactone

• HighAG,highLA:Sepsis?liverfailure?

29

30

Assessment

• DECISIONS:– So,whatdowedo?

• GivemoreIVbicarbonate?– IsitnecessarytocorrectthepH?– Isbicarbonatelikelytobeeffective?– Whateffectsonammoniemia?

• GiveIVdiuretics?– Patientanuric1-2days:unlikelytorespond– Besides:whatwouldbethegoal?

• Startrenalreplacementtherapy?– Whatwouldbetheindications?

31

Assessment

• DECISIONS:– TimingofRRT

• INDICATIONS:– Azotemia– Encephalopathy

» Ishyperamonemiaanindication?– Hyperkalemia– Acidosis– Fluidoverload– Ishyponatremiaanindication

» Shouldwefixthenatremiainthispatient?

32

HYPONATREMIA

• Pathogenesis• Impactonoutcome• Management

33

Shouldwecorrectthehyponatremia?

34

Decision to treat — Correction of the hyponatremia has no effect on the hemodynamic abnormalities associated with the severe underlying liver disease, and there are no data that increasing the serum sodium concentration in patients with cirrhosis improves morbidity or mortality. Because of the lack of clear benefit to the patient, the potential side effects and costs of therapy, and the dismal prognosis of patients with cirrhosis who have severe hyponatremia and are not candidates for a liver transplant, some experts do not recommend efforts to raise the serum sodium in this setting

Serum sodium concentrations do not usually fall spontaneously below 120 meq/L in patients with cirrhosis until they are close to death or there has been an overly aggressive diuresis, as with the addition of a thiazide diuretic to maximum doses of a loop diuretic (usually furosemide + spironolactone). Referral for liver transplantation should be considered in pts with such severe degree of cirrhosis.

RH Sterns and BA Runyon Hyponatremia in patients with cirrhosis Uptodate Jan 2014

35

TimingofInitiationofRRT

• Needtodefinewhatconstitutes“early”vs.“late”• Needtoavoidpotentialharmfromunnecessaryearlyinitiation

• Principle:Atanygiventime,needforRRTdependsonthebalancebetweenthedemandonrenalfunctionandthecapacityoftheorgantofulfillthatneed

• Studiesareneeded

ETHICS/DECISIONS

• Shouldwedialyzethispatient?

37

Decisions

• Youdiscussextensivelywithfamilyandcolleagues– Isthepatientalivertransplantcandidate?

• Consensusisreachedtostartrenalreplacementtherapy– Consentformsaresigned– Theintensivistinsertsarightfemoraldoublelumendialysisline

38

SurvivalimpactofAKIincirrhotics

39

Among patients with cirrhosis, 30-day mortality is 10-fold higher (80%) amongthose with irreversible AKI than those partialy recovering (40%) or those without AKI (15%).

√

√

SurvivalimpactofAKIincirrhotics

40

Among patients with cirrhosis, 30-day mortality is 10-fold higher (80%) amongthose with irreversible AKI than those partialy recovering (40%) or those without AKI (15%).

15

40

80

RECOVERY PARTIALRECOVERY NONRECOVERY

30- DAYMORTALITY(%)RECOVERY PARTIALRECOVERY NONRECOVERY

Complicationsofcirrhosisandsurvivalprognosis

• Ascites resistanttodiuretics(HE,lyte abnl,HRS):meansurvival6months

• Hyponatremia (<130):25%percentsurvival1year– Saltrestriction,tolvaptanPO?

• Hepatorenal syndrome:– Type1SCr>2.5:Expectedsurvival<2wk ifnottreated– Type2:Expectedmediansurvival6months

• SBP: 1yearsurvival40%

41

SurvivalstratifiedbyseverityofAKI

42

Fagundez et al J Hepatol 2013

TreatmentofHRS

• Vasopressinanalogues(terlipressin)• Alpha-adrenergicagonists(midrodine andnoradrenaline)

• Albumin20-40g/day• Octreotide combinedwithMidrodine+Alb• TIPSmayhelpbutapplicationlimitedinHRS1• RRTnotconsideredstandardtherapy

– TemporaryoptionwhennoresponsetovasoconstrictorsorfluidO/L,Metab acidosisorrefractoryhyperkalemia

• MARS,Prometheus:studiesinprogress• OLTransplant

43Cardenas-Gines Gut 2011

ExtracorporealSupportTechniquesinSevereHRS:Indications

• ECSonlyindicatedinHRSpatientswhoarepotentialcandidatesforOLT,

• Orhaveareversibledecompensation,• AfterstandardmeasuresincludinghemodynamicsupportandIValbuminhavefailedtoinduceclinicalimprovement

44Cerdá, Tolwani, Gibney and Tiranathanagul, Seminars Dialysis 2011

Whatdoyoudo?• Conservativemanagement?

– Hyperkalemia– Azotemia,AKI– Acidosis

• TimetostartRRT?– WhatkindofRRT?– HowdoIdoit?

– Hyponatremia• Aprobleminitself• Ahindrancewhentryingtomanagetheotherproblems

Decisions

• YoudecidetostartthepatientonRRT– Whatmodality?– Withineachmodality,whatoperationalcharacteristics?

– Dose?– Access?– Anticoagulation?

46

ExtracorporealSupportinHRS

47Cerdá, Tolwani, Gibney and Tiranathanagul, Seminars Dialysis 2011

NON-CELLBASEDSYSTEMS CELL-BASEDSYSTEMS(Bioartificial LiverSupport)

Intermittent, extendedandcontinuous dialysistechniques

Humanhepatocytes

Hemoperfusion techniques PorcinehepatocytesPlasmaexchangetechniquesPlasmapheresisPlasmafiltrationabsorptionSelectivePlasma FiltrationTechnology(SEPET)

Albumin dialysis-MolecularAdsorbentRecirculatingSystem(MARS)-Single PassAlbuminDialysis(SPAD)

Prometheus

Decisions

• YoudecidetostartthepatientonRRT– Whatmodality?– Withineachmodality,whatoperationalcharacteristics?

– Dose?– Access?– Anticoagulation?

48

RRTMODALITY

49

• HEMODYNAMICSTABILITY• OSMOTICANDFLUIDSHIFTS• IMPACTONTHEBRAIN

RRTMODALITY

• INTERMITTENTHEMODIALYSIS– Hemodynamictolerance– Fluidshifts,brainedema,encephalopathy– Howlowcanyoudecreasethe[Na]dialysate?

• PIRRT– Anydata?

• CRRT– Setupoptions

• PERITONEALDIALYSIS

50

Considerations in Renal Replacement Therapy for AKI

• DIALYSIS MODALITY– Intermittent hemodialysis: Daily, Every Other Day, SLED-PIRRT– Continuous renal replacement therapies: AV, VV– Peritoneal dialysis

• DIALYSIS BIOCOMPATIBILITY: MEMBRANES• DIALYZER PERFORMANCE

– Efficiency– Flux

• DIALYSIS DELIVERY– Timing of Initiation– Intensity of Dialysis: Prescription vs. Delivery– Adequacy of Dialysis: “Dose of Dialysis”

UFC Uf

Plasmafilter

Plasmafilter

Adsorbent

Adsorbent

SCUF CVVH CVVHD

CVVHDF CPF-PECVVHDF-SLED

CPFACHP HVHF

Blood In

Blood InBlood InBlood In

Blood InBlood In

Blood InBlood InBlood In V

VVV

VVV

VV

Uf D

D DUF+D UFC

Plasma Uf

R

R

R

MODALITIES OF CRRT

Qb = 100 ml/min Qf = 2-8 ml/min Qb = 100-200 ml/min Qf = 10-30 ml/minK = 15-45 L/24 h

Qb = 100-200 ml/min Qf = 2-4 ml/minQf = 10-30 ml/min K = 15-45 L/24 h

Qb = 100-200 ml/min Qf = 10-30 ml/minQd = 10-30 ml/min K = 20-50 L/24 h

Qb = 100-200 ml/min Qf = 2-8 ml/minQd = 50-200 ml/min K = 40-60 L/24 hDiffusion+Convection (Back Filtration)

Qb = 100-200 ml/min Pf = 20-30 ml/minCan be coupled with CVVH or CVVHDF

Qb = 100-200 ml/min Can be coupled with CVVH or CVVHDF Qb = 100-200 ml/min Pf = 20-30 ml/min

Can be coupled with CVVH or CVVHD/FQb = 200-300 ml/min Qf = 50-100 ml/minK = 60-120 L/24 h

Cerda & Ronco, Handbook of CRRT, 2008

IndicationsforSpecificModalitiesofRRT

THERAPEUTIC GOAL HEMODYNAMICS PREFERREDTHERAPY

FLUID REMOVAL Stable IntermittentUF(IUF)

Unstable Slow Continuous UF(SCUF)

UREACLEARANCE Stable IntermittentHD

Unstable:CRRT Convection – CVVH

Diffusion – CVVHDBoth– CVVHDF

SEVERE HYPERKALEMIA Stable/Unstable IHDfirst, thendecideonmodality

SEVEREMETABACIDOSIS Stable IntermittentHD

Unstable CRRT

SEVEREHYPERPHOSPHATEMIA

Stable/Unstable CRRT

BRAINEDEMA, ICHTN Unstableby definition CRRTonly

Cerda-Ronco. Semin Dialysis 2009

RenalReplacementTherapiesinAcuteKidneyInjury:Moreorless,weagreeontheseconcepts:

• Timing of Initiation • ? Benefit of early vs. late initiation: Next most important study• No RCT available

• Modality• No RCT demonstrates differences• HEMODYNAMIC STABILITY SHOULD DETERMINE MODALITY

• Dose• Ronco: Yes• ATN: No• RENAL: No• Are studies really comparable: convection vs difusion• Can you realistically DELIVER the minimum dose in your critically ill patient?

• Hemodynamic Stability• Brain edema• Other non-renal apps• Renal functional recovery

• Renal Functional Recovery• Maybe better with CRRT

• Cost• CRRT more expensive

CRRTAllowsBetterFluidManagement

FluidBalance:CRRTvsIHD

Augustine et al, AJKD 2004

HemodynamicStability:CRRTvsIHD

Augustine et al, AJKD 2004

VA/NIHAcuteRenalFailureTrialNetwork(ATN)Study

1124 patients27 sites3 years

IntensiveManagement Strategy

(561 patients)

Randomization

Stable hemodynamics(SOFA 0-2)

• IHD 6x/week @ Kt/V of ~1.2/session

• IHD 3x/week @ Kt/V of ~1.2/session

Unstable hemodynamics(SOFA 3-4)

• CVVHDF @ 35 mL/kg/hr, or

• SLED/EDD 6x/week

• CVVHDF @ 20 mL/kg/hr, or

• SLED/EDD 3x/week

Less Intensive Management Strategy

(563 patients)

Sothen,whyisCRRTassociatedwithbetter hemodynamicstability?

• Maintenanceofintravascularcompartmentvolume– Prolongedtreatmentspermitlowerfluidremovalrates

• IHD:3Lin3hours =1L/hUFrate• CRRT:3Lin24hrs =0.125ml/hUFrate

– UreadiffusionisfasterwithIHDthanCRRT• IHD:Ureaclearance ~160ml/min• CRRT:Ureaclearance~15-30ml/min

– Convectivesodiumremovalrate[hemofiltration/hemodiafiltration]islessthandiffusiveremovalrate[hemodialysis]

• Decreasedcoretemperature

• Convectiveremovalofinflammatorymediatorscouldcontributetohemodynamicstability

DECREASEDCAPILLARYREFILLING

ANDLOSSOFWATERTOINTERSTITIUM DECREASED

I/VASCULARVOLUME

ULTRAFILTRATION

SystemicCapillary

êPosm

DIALYSISLossofosmoticallyactivesolutes(urea)

152

138

d dd

dd

d

ddd

dd

INTRACELLULAREDEMA

Na+

[Na+]pwaterhigher than[Na+]dialysate(canbechanged)

H 2O

H 2O

HEMODIALYSIS

d

d

d

d

d

dd

d

HIGHERPLASMAONCOTICPRESSURE

FACILITATESCAPILLARYREFILLING LITTLE

CHANGEINI/VASCULARVOLUME

REPLACEMENTFLUIDIsotonic[Na+]150mEq/L

HEMOFILTRATIONSmallsoluteconcentrationsequaltoplasma(Notranscapillary osmoticpressuregradient)

SystemicCapillary

↑πonc

ddd

d

d

d

dd

HEMOFILTRATION

Now,WhatAboutRenalReplacementTherapy

andtheBrain?

RRTISCRITICALINCERTAINSITUATIONS…

• Patientswithintracranialhypertensionorcerebraledema– Autoregulationislost– Suddenchangesinsystemicorintrabdominal pressurechange

intracranialpressure• Bewareofpatientswithpossibleabdominalcompartmentsyndrome

– Patientswithfulminantliverfailureoracutedecompensatedlivercirrhosishavevariabledegreesofbrainedema

• Patientswithsevereazotemia– Correctazotemiaslowly, toavoiddialysisdysequilibrium

• Patientswithhyponatremia– Correct[Na]pveryslowly10-12mEq/L/day– CorrectureaVERYSLOWLY:ureaprotectsagainstosmotic

demyelinationsyndrome

ChangesinIntracranialPressureduringHaemofiltrationinOliguricPatientswithGradeIVHepaticEncephalopathy

0246810121416

PRE

POST

HEMOFILTCAVHF

INTRA-CRANIALPRESSUREmmHg

PLASMAOSMOLALmOsm/Kg

DavenportAetalNephron1989;53:142-146

**

HF:GambroQb200-250Isovolemic17Lexchanges3.5-4hrs.

CAVHF:400-1000ml/h24-160hrs.

BraindensitychangesduringrenalreplacementincriticallyillpatientswithARF

ContinuousHFvs.IHDRoncoetalJNephrol1999;12:173-178

0

10

20

30

40

50

60

PRE 4h POST 24 h POST

IHD WHITEMATTERIHD GRAYMATTERCRRT WHITE

CRRT GRAY

HounsfieldUnitsBraindensityCTscan

N=12CrossoverProspectiveRandomized

*

*

* p<0.01

INDUCTIONOFHEPATICENCEPHALOPATHY

• CIRRHOSIS• Hyperammonemia

• ASTROCYTICGLUTAMINEACCUMULATION• Osmo-compensatedbyInositolrelease

• EXHAUSTIONOFVOLUME-REGULATORYCAPACITY• Lowgradecerebraledema

• EXACERBATIONOFLOWGRADECEREBRALEDEMA

ADDITIONALPRECIPITATINGFACTORS

Modified from Haussinger Arch Biochem Biophys 2013

TheBlood-BrainBarrierinLiverDisease

Aquaporin 4

Ion Channels:Ba inhib inwardly rectifying K+

Bumetanide inhib Na,K,2Cl CoT

GLN

EDEMA

Modified from Ott and Vilstrub Metab Brain Dis 2014 Jayakumar J Hepatol 2011Rama Rao Neurobiol Dis 2014

METABOLICABNORMALITIES

H2ONH4

+

ENCEPHALOPATHY

AviciouscircleofGLNsynthesisandbreakdowngenerateshyperammonemia inliverfailure

THERE IS PLENTY OF EVIDENCE THAT THE MAIN SOURCEOF AMMONIA IS NOT INTESTINAL BACTERIA AND THAT THECRUCIAL ROLE IN PATHOGENESIS OF HYPERAMMONEMIAIS ENTEROCYTE CATABOLISM OF GLUTAMINE DELIVERED TOTHE INTESTINE BY THE BLOOD STREAM

Holecek Metab Brain Dis 2014

RRTandtheLiver

∗ Acute fulminant liver failure or acute-on-chronic liver failure

∗ Hepatic encephalopathy is, in part, determined by brain edema

∗ Hyponatremia is a common complication∗ Low blood Urea concentration increases risk∗ Low efficiency CRRT preferable

Ostermann M et al Crit Care 2010Verbalis JG et alAm J Med 2007Hoste & DhondtCritical Care 2012

Liu et al JASN 2008

TheBraininAKI

Liu et al JASN 2008

WATER CONTENTS

CAPILLARY PERMEABILITY

InAKI,increasedwaterpermeabilityandwatercontentsincreaseriskofbrainedema

Liu et al JASN 2008

RRTMODALITY

72

• HOWDOYOUHANDLETHEHYPONATREMIA?• DOYOUNEEDANTICOAGULATION?

YoudecidetouseCVVH

• Simplicityofprocedure• Noneedforanticoagulation

– Besides,patienthasahighINR,andtheplateletcountislow

– Andalso,thepatienthasverypoorliverfunction!• Whatcouldhappenifyoutriedusingcitrate?

CRRTsolutions

V V

QB

QR

200 mL/min

•BF: 200 ml/min•Fluid Removal: 100 ml/hr•Patient weight: 80 kg

Prismaflex HF1000

Replacement Fluid1.0 L/h

•CRRT FluidsRF: Na+ 130, K+ 4, Mg++ 1.5 Mm,

Ca++ 2.5 mM, HCO3- 35, Cl- 103

Effluent 1.1 L/h

[Na]pcanbepredicted

75

120.45

120.92

121.38

121.84

122.32

122.78

123.25

123.73

124.2

124.68

1 2 3 4 5 6 7 8 9 10 11

Changein[Na]p[Na]p=TBS+(10XH)

TBW-(0.1XH)

Initial status: 80 Kg, TBW 48 LTBS=120x48=5760 mEq

Each hour, fluid removed 0.1 LNet Na added=10 mEq/h

HOURS

Hourslater..

• Thesystemclotsafter4hoursoftreatment– Whathappened?

• Theliversynthesizesnotonlypro- butalsoanti-coagulationproteins

• NGtubefluidisnowbloody,youareafraidofusingheparin– Somebodysayssheremembers“atOSHtheysaidhehadHIT”

• Canyouusecitrateanticoagulation?– Whatabouttheliver?– Doyouhavetochangemodality?

• Lactate6mM,NH3 200μg/dl

76

Coagulationdefectsinlivercirrhosis

• Increasedbleedingrisk– DecreasedfactorsII,V,VII,IX,X,XI,XIII– Thrombocytopeniaandplateletdysfunction– Abnormalfibrinogen

• Increasedthromboticrisk– DecreasedproteinSandClevels– Decreasedantithrombin levels– Decreasedplasminogen– ElevatedvWF andfactorVIII

77

Decisions…

• YoudecidetouseCVVHDF– Youwilladddiffusiveclearance(“dialysis”)toclearexcesscitrate

– Also,youhopethat,byaddingdiffusiontoconvection,youwillclearammoniaandlactatemoreefficiently

78

RRTMODALITY

79

• ACIDBASECONTROL

Decisions…

• YoudecidetouseCVVHDF– Youwilladddiffusiveclearance(“dialysis”)toclearexcesscitrate

– Youhopethat,byaddingdiffusiontoconvection,youwillclearammoniaandlactatemoreefficiently

80

Really?

• Renalreplacementtherapiesdonoteffectivelyremovelactate– Enormousrateofproduction

81

CVVHDFhasanegligible effectonLactateClearance

Levrault J CCM 1997;25:58-62

Cerda,Tolwani,Warnock KidneyInt2011

BUFFERINDIALYSATE

BUFFER

HEMODIALYSIS(DIFFUSION)

HEMOFILTRATION&HEMODIAFILTRATION

(CONVECTION)

ModesofBufferDeliveryinRRT

ADDITIONOFBUFFERTODIALYSATE

CVVHDF: Continuous Venovenous Hemodiafiltration

Effluent

Access

Return

PR

I S

MA

M100

Dialysate

Replacement(pre/post dilution)BUFFER

ReplaceConsumedBuffer

AvoidDialyticLoss

RRTMODALITY

85

• COULDANTICOAGULATIONHELPWITHTHEMANAGEMENTOFACIDOSIS?

CITRATEPREPUMPINFUSION

HCO3-

22-35mEq/lHCO3

-

22-35mEq/lAND

CITRATE

DIALYSISFL+ULTRAFILTRATE DIALYSATE

CITRATE HCO3-

pCO2

[H+]=24x[HCO3

-]

40mmHg[40nM]=24x

24mEq/l

CitrateAnticoagulationandAcid-BaseControl

NeedtoreduceCit infusion rateifliverfailurepresent

CRRTisSuperiortoIHDintheManagementofMetabolicAcidosis

• Morestablenormalizationofacidbasebalance

• LessergenerationofCO2

• Bettertoleratedbyhemodynamicallyunstablepatients

• Enhancedclearanceoftoxinscausingacidosis(metformin)

• SlowerthanIHD:theprosandthecons!

RRTMODALITY

88

• ANTICOAGULATIONI• YOUSTILLHAVETHEPROBLEMOFTHEHYPONATREMIA

V

DialysatePrismaSateB25GK4/0

Rate: 1000-2500mL/hr

150-200mL/min

Patient

Ca2+Gluconate

InitialRate:60mL/hr

PFiCa2+ (0.25-0.5mmol/L)

iCa2+1.1-1.3mmol/L

GambroPrismaflexwithHF1000Filter

PrefilterFluid:0.5%TrisodiumCitrateRate:1000-2000mL/hr

V

UABProtocol(CVVHDF)

Tolwani et al. CJASN 2006

PostfilterFluid:0.9%NSRate: 200mL/hr

Post-FilterIonized Ca++

Goal: <0.5 mM

SystemicIonized Ca++

Goal: 0.9-1.3 mM

CaGluconateIV infusion

60 ml/h

Pre-PumpNaCitrateInfusion1-2 L/h

CALCIUM GLUCONATE INFUSION RATE CONTROLS SYSTEMIC Ca++

SODIUM CITRATE & DIALYSATE FLOW RATES CONTROL POST FILTER Ca++

DialysateFlow Rate

1-2 L/h

EffluentFlow Rate

V

QB

QE=QR+QFR +QD

DialysatePrismaSateB25GK4/0: 5LbagNa+ 140mmol/LCl- 120.5mmol/LHCO3 22mmol/L/lactate3mmol/LK+ 4.0mmol/LMg0.75mmol/LGluc110mg/dLRate: 1000-2500mL/hr

QD

150-200mL/min

Patient

Ca2+Gluconate

38.75mmol/L

InitialRate:60mL/hr

PFiCa2+ (0.25-0.5mmol/L)

iCa2+1.1-1.3mmol/L

GambroPrismaflexwithHF1000Filter

QR

PrefilterFluid:4Lbag0.5%TrisodiumCitrateCitrate3- 18mmol/LNa+ 140mmol/L

Rate:1000-2000mL/hr

GambroPrismaPre-PumpPre-DilutionSet

V

UABProtocol(CVVHDF)

Tolwani et al. CJASN 2006

PostfilterFluid:0.9%NSRate: 200mL/hr(requiredfordeaerationchamberofprismaflex)

QR2

Butyouneed tochangefluidcomposition,right?

Oneoption…DialysisBathComposition

Electrolytes(mEq/L) Cations Anions

Na 90 Cl90

Na30 HCO3 30

K3 Cl3

Mg1.5 Cl 1.5

Ca Zero -

Totals (mEq/L) 124.5 124.5

Osmolality(mOsm/Kg) 249 249

120

OR, you could simplify your life and change the post-filter solution from 0.9%NaCl to D5%W @200 ml/hour

Decreasing[Na]inCRRTfluids

• Ifyourunyourfluids:– Prefilterfluid0.5%SodiumCitrateNa=140@1L/h– DialysateNa=140@1L/h– PostfilterfluidD5WNa=0at200ml/h– Assumingnetfluidremoval=0Fluidsdeliveredtopatient:(PF140/1000)+(140/1000)+(0/200)=280mEqNa/2200ml=127mEq/L

1 2 3 4 5 6 7 8 9 10 11 12SerumK 6.7 6.3 5.5 5.7 4.1 3.7 3.8 3.4 3.3 3.6 3.6 3.7

3

3.5

4

4.5

5

5.5

6

6.5

7

SerumK

1 2 3 4 5 6 7 8 9 10 11 12SerumNa 109 111 112 114 121 123 123 126 127 128 131 133

100

105

110

115

120

125

130

135

SerumNa

DAY1DAY2DAY3

Hourslater..

• ThefluidfromtheNGTisclearlybloodyandhematocritdecreasedfrom30to20%;patientdoesn’tlookthatgood…

• INRisstillhighat2.2• Housestaffmanagestheproblem• Youreassurethem,thatwhileoncitrateA/C,thepatientis

notsystemicallyanticoagulated

• Twohourslater,nursecallsyoutoreportthatthesystemicvenousionizedCa++ isdown,frominitial1.2mMto0.7mM

– Alltheconnectionsareright,allthesolutionsareOK– ShehandsyoutheEKG

EKG QTc 500 ms

Whathappened?

RRTMODALITY

98

• ANTICOAGULATIONII

USCRRTAnticoagulationOptions– No anticoagulation– Heparin(UFHorLMW Heparin)

• Systemic,prefilter• “Regional”Heparinwithprotaminereversalpostfilter

– Citrate• ACD• Sodiumcitrate

– Prostacyclin(hypotension &$$$)– Lepirudin orbivalrudin (noantidotes&$$$))– Argatroban (noantidote&$$$)

Anticoagulationguidanceforthepatientinourcase?

• FDA?– Noguidance/approvalforCRRTanticoagulationforheparin,LMWH,citrate,-rudins,argatroban,prostacyclin

– NoFDAapprovedcitratedrugproductonUSmarket

• KDIGO?– Yes!

KDIGO- KidneyInt Suppl(2012)2,8–12• 5.3.2:Forpatientswithoutanincreasedbleedingriskorimpairedcoagulationandnotalreadyreceivingeffectivesystemicanticoagulation,wesuggestthefollowing:– 5.3.2.2:ForanticoagulationinCRRT,wesuggestusingregionalcitrateanticoagulationratherthanheparininpatientswhodonothavecontraindicationsforcitrate.(2B)

– 5.3.2.3:ForanticoagulationduringCRRTinpatientswhohavecontraindicationsforcitrate,wesuggestusingeitherunfractionatedorLMWH,ratherthanotheranticoagulants.(2C)

KDIGO:KidneyInt Suppl (2012)2,8–12• 5.3.3:Forpatientswithincreasedbleedingriskwhoarenotreceivinganticoagulation,wesuggestthefollowingforanticoagulationduringRRT:– 5.3.3.1:Wesuggestusingregionalcitrateanticoagulation,ratherthannoanticoagulation,duringCRRTinapatientwithoutcontraindicationsforcitrate.(2C)

– 5.3.3.2:Wesuggestavoidingregionalheparinization duringCRRTinapatientwithincreasedriskofbleeding.(2C)

NoAnticoagulation• Usuallyusedinpatientswithintrinsiccoagulopathiessuchas

hepaticfailureorlowplateletcounts

• Methods:– Primecircuit:SalineorHeparinprime– Intermittent0.9%NSflush50-200mlq30-60mins

• Results:– Ratesoffilterclottingvarywidely– Meanfilterlifebetween16- 70hrs ifcoagulopathic– Shorterfilterlife6-18hrs unlessseverecoagulopathy

• Thesecrettosuccesswhennotusinganticoagulation?

– Higherbloodflowrates!

UnfractionatedHeparinAdvantages

• Effective• Widelyavailable• Simplemonitoring(aPTT)• Reversedwithprotamine• Inexpensive• Shorthalflife

Disadvantages• Systemicbleeding• Unpredictablekinetics• PTTnotreliablepredictorfor

bleeding• Heparinresistanceduetolow

patientantithrombin levels• HIT

Heparin

TypicalUnfractionatedHeparinProtocol

Dialysate

Effluent

Patient aPTT Circuit aPTT

Arterial line

Venous line

Bolus 2000-5000 IU (25-30 IU/kg)

Continuous infusion 5-20 IU/kg/hr

aPTT 34-45 seconds (1.5-2.0 X normal)

Reported circuit patency 20-40 hrs

LowMolecularWeightHeparin

Advantages

• Effective• Predictablepharmacokinetics

• LowerincidenceofHIT

• Lesseffectonlipids

Disadvantages• Systemicbleeding• Onlypartiallyreversedwithprotamine

• antiXa activitynoteverywhereavailable

• Expensive

LowMolecularWeightHeparinProtocols

• Fixeddosevs.dosebasedonanti-Xa• Targetanti-Xalevel0.25-0.35U/ml• Enoxaparin

– Loadingdose0.15mg/kg– Maintenancedose0.05mg/kg/hr– Meanfilterlife31hrs

• Nadroparin,dalteparin– Loadingdose15-25IU/kg– Maintenancedose5-10IU/kg/hr– Medianfilterlife18-50hrs

Pont AC de et al. Crit Care Med 2000

Reeves JH et al. Crit Care Med 1999

Journois D et al. Ann Fr Anesth Reanim 1990

Joannidis M et al. Intensive Care Med 2007

CitrateAnticoagulation

Intrinsic pathway

Extrinsic pathwayXII

XIIaXI

XIaIX IXa

VIIVIIa

VIII Ca++Tissue factorX Xa

Ca++V

Prothrombin Thrombin

FibrinogenFibrin

Cross linked fibrinXIIIa

Coagulant active phospholipid(e.g. platelet membrane)

Calcium-freedialysate

Citrate chelatesfree ionized Ca2+

Citrate

Effluent

Post filter iCa2+ is monitoredand used to titrate citrate rateto assure anticoagulation

Citrate is metabolizedprimarily in liver to HCO3

-

Bound Ca2+ is released

Calcium is infusedthrough a separatecentral line to replaceCa2+ lost in ultrafiltrate

Returning blood combineswith venous blood in body,normalizing iCa2+ and preventingsystemic anticoagulation

Citrate Anticoagulation in CRRT: Regional Effect in the Circuit

CitrateAnticoagulation

• ChelatesfreeCa+2 inextracorporealcircuit• PreventsactivationofCa+2-dependentprocoagulants

• AnticoagulanteffectmeasuredbyiCa+2

• AnticoagulationreversedbyCa+2 infusion

Citrate+iCa Calcium citrateBiologically inactivemeasurable as total Ca

CitrateMetabolism

• Citricacidhasplasmahalflifeof5mins• Rapidlymetabolizedbyliver,kidneyandmusclecells

Na3Citrate + 3H2CO3

Citric Acid + 3NaHCO3

3H2CO3 + H2O + 3NaHCO3

4H2O + 6CO2

Flanagan MJ et al. AJKD 27: 519-24, 1996

Why Citrate? Citrate and Bleeding

Zhang et al. Int Care Med. 2012

WhyCitrate?CitrateandCircuitPatency

Zhang et al. Int Care Med. 2012

LargestCitrateRCT(vsLMWH)

•Post-dilutional CVVH

•Blood flow 220 ml/min

•Citrate 3 mmol/L blood flow

Oudemans-van Straaten et al. Crit Care Med 2009

Results

Patient Characteristics

CommercialCitrateSolutionsComponent

s4%

Sodium Citrate

ACD A: 2.2%

Sodium Citrate

Prismocitrate(10/2)

(only available in Europe)

Prismacitrate(18/0)

(only available in Europe)

Na (meq/L) 408 224 136 140

Sodium Citrate (mmol/L)

136 113 10 18

Citric Acid (g/L)

7.3 4.2

Dextrose (g/L)

24.5

Bag Size (mL)

250 & 500

500 & 1000 5000 5000

QB (mL/min)

4% TSC (mL/hr)

ACD-A (mL/hr)

100 175 210125 218 262150 262 315

200 350 420

Citrate Delivery: Fixed

Amount of citrate delivered to achieve blood citrate concentration of 4 mmol/L depends on blood flow

Flanagan MJ et al. AJKD 27: 519-24, 1996

Citrate• Advantages

– Regional,avoidsbleedingcomplications– Doublesasbuffer– Highlyeffectiveinstudies(>heparin)– Nothrombocytopenia

• Disadvantages– Metaboliccomplications– Complexprotocols– NocommercialproductdesignedforthisuseinUS

Backtoourcase…

• Administeredhugecitrateload– ThepatientreceivedFFPandBlood– Alreadyreceivingcitrateanticoagulation

• Hasliverdisease,socannotmetabolizecitrateefficiently

• Systemicionizedcalciumlow,EKGChanges• Serum bicarb willeventuallyriseoncethiscitrategetsmetabolized…

118

Citrate’sMetabolicConsequences• Metabolicalkalosis

– Citrateoverdose/toxicity– Centersusingcitratewillchoosealowerbicarb-

containingdialysate/effluentsolution

• Metabolicacidosis– Citratetoxicityinsettingofsevereliverdiseaseor

hypoperfusion

• Hypernatremia– Hyperosmolarcitratesolutions– Centersusingcitratewillchoosealowersodium-

containingdialysate/effluentsolution

• Hypocalcemia andhypercalcemia– Inappropriatecalciumsupplementation

CitrateToxicity– Asseeninourcase• RiskFactors

– LiverDisease– Nursingorpharmacyerrors:overdose– Shockliver;severehypoperfusion states

• Detection– Risinganiongap,worseningmetabolicacidosis– FallingsystemiciCa2+

– EscalatingCa2+ infusionrequirements– TotalCa2+ :SystemiciCa2+ Ratio>2.5:1(increasedCa2+ gap)

)/(25.0)/(

2

2

LmmolCaionSystemicdLmgCaTotalRatioCalcium+

+ ⋅=

Meier-Kriesche HU et al. Crit Care Med. 2001, 29:748-752

If citrate cannot be metabolized, then the total serum calcium concentration appears to increase, with a corresponding fall in ionized calcium due to the increase in calcium

complexed with citrate, as the calcium–citrate complex is not directly measured it is termed the ‘calcium gap’ as causing an increasing difference between total and ionized calcium.

Davenport A , and Tolwani A NDT Plus 2009;ndtplus.sfp136

© The Author 2009. Published by Oxford University Press [on behalf of ERA-EDTA]. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Whattodoforourcase?

• AdministerCalcium• ChangeoradjustCRRTanticoagulation?

Canweenhancecitrateremoval?• Citrateisasmallmolecule

– Extracorporealclearancesameasurea– Sievingcoefficient0.87- 1.0– CVVH=CVVHDclearance

• Increasedialysaterate toincreaseClearance• Whatshouldwedowithbloodflowrate?

www.nikkiso.co.jp

Ultrafiltrate or Effluent/Spent Dialysate

Arterial or Pre-Filter

Dialysate

Venous or Post-Filter

Monitoring

• Circuitserumionizedcalciumq6-8H

–keep0.25-0.35mmol/l

• Systemicserumionizedcalciumq6-8H

–keep0.90-1.0mmol/l

• SerumTotalCa,PO4 andMgq12-24H

Concerned aboutusingcitrateinpatientswithliverdisease?

• Worriedabout“citratelock”?– risingtotalcalciumwithdroppingpatientionizedcalcium

– DeliveryofcitrateexceedshepaticmetabolismandCRRTclearance

• Keepbloodflowrelativelylow– Citratedoseistiedtobloodflow

• Usehigherdialysateflowratestoclearcitrate

ManyCRRTcitrateprotocolsavailable

• Googlesearchon2/16/2013for“crrt citrateprotocol”yielded12,200hits

• HereistheUMichigan’sACDprotocol:– http://www.med.umich.edu/intmed/nephrology/docs/AdultCitrateProtocol_6-2013.pdf

Keyquestionsaddressedbythissession:

• Indicationsforinitiation?YES• Modality?YES,ESPECIALLYWHATAPPLIESTOLIVERFAILUREPTS

ANDBRAINPROBLEMS• ReplacementFluidpreorpost?NOTNECESSARILY• Solutioncomposition?(whataboutthehyponatremia?)VERY

MUCHSO,BUTBRIEFLY• Dose?NO• BloodFlow?NO• Anticoagulation?INDEED!CITRATEANDLIVER• FiltrationFraction?NOTREALLY• NursingSURE• EthicsVERYMUCHSO:SHOULDWEDIALYZEACIRRHOTIC

ALCOHOLICPATIENT?