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CRRTCaseSimulation:AKIandEndStageLiverFailure
JorgeCerdá,MD,MS,FACP,FASNChief,Dept.ofMedicineStPeter’sHealthPartners
ClinicalProfessorofMedicineAlbanyMedicalCollege,
Albany,NY,USA
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Casepresentation
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Case
A47yearoldmalewithalcoholiccirrhosisandchronichyponatremia(serumsodium130mMol/L)istransferredfromoutsidehospitalwithalteredmentalstatus,hypotension,anddecompensatedcirrhosis.
Uponadmission,heisfoundtohave>24houranuricrenalfailure(lastcreatinine1.5mg/dl2weekspriortoadmission).YouareconsultedforCRRTasabridgetotransplantation.
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• 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
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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%
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AKIVS.HRS
• DEFINITIONS• PATHOPHYSIOLOGYOFAKIINTHISSETTING• VOLUMESTATUS• HEMODYNAMICS• TREATMENTS
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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?
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Assessment
• AKI?– BaselineSCr1.5,currently6.5mg/dl– Anuria24hours
– RIFLEF,AKIN3,AKIKDIGO3
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DiagnosisofAKI:RIFLEandAKINCriteria
Cruz et al, Crit Care 2009
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DiagnosisofAKI:KDIGOAKIDefinition
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Assessment• ACUTEKIDNEYINJURY:Whatmechanism?
– Volume-responsive?Howlikelyispatienttorespondtovolumeexpansion?
• Decreasedintra-arterialeffectivevolume• Una<10mEq/l• Copiousdiarrhea• CXR“atelectasisandeffusions”
– ATN?• Possiblesepsis(onPip-Tazo+Vanco ?SBP)
– HRSType1?• Severeliverfailure• LikelySBP
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MechanismsofOliguriainAKI
Cerdá, Kidney Int 80(7) 2011
SHOCK,SPLACHNICVASODILAT
SHOCK,PRESSORS
HRS
SHOCK,SEPSIS
ISCHEMIANSAIDs
RADIOCONTRASTSEPSIS
UNLIKELYHERE
ABDOMINALCOMPARTMENTSYNDROME
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13Gines-Schrier NEJM 2009
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Gines-Schrier NEJM 2009
Bacterialtranslocationandcytokineoverproductioninducesplachnicarterialvasodilation
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Hormonalresponsetocirrhosis
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0
2
4
6
8
10
12
PLASMARENIN NOREPINEPHRINE ADH
NOASCITES
ASCITES
ASCITES+RF
From: Asbert M Ginès P et al Gastroenterology 1993
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Ornipressin improvesrenalfunctioninadvancedhepaticcirrhosis
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0
5
10
15
20
25
30
35
GFR PLASMARENIN RENALFRACTION%
BASELINE
ORNIPRESSIN
From: Lenz K, Hortangl H et al Gastroenterology 1991
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SomatostatinandAnalogs
17
Chan MM et al Octreotide CHEST 2013; 144(6):1937-45
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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
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19NEJM 1999;341:403-9
Impact of intravenous albumin on renal impairment and mortality among patients with SBP
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Diagnosticcriteriaofhepato-renalsyndrome
• Cirrhosiswithascites• Serumcreatinine>133mM=1.5mg/dl• NoimprovementinSCr<1.5mg/dlafter2daysofdiureticwithdrawalandvolumeexpansionwithalbumin(1g/Kg/daymax100g/d)
• Absenceofshock• Nocurrentorrecentnephrotoxicdrugs• Nointrinsicrenaldisease(hematuria,proteinuria,abnormalrenalUS)
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InternationalAscitesClubdefinitionofHRS
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TypesofHRS
• TYPE1– DoublingofSCrto>2.5mg/dlin<2weeks– Severemultiorgan dysfunction(heart,brain,liver,adrenals)
• Type2– Stableorlessrapidlyprogressivecoursethantype1– Refractoryascites
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ThediagnosisofAKIincirrhoticpatientsislate
• HRS:SCr>1.5mg/dl
• Malnutrition• Atrophicmusclemass• Fluidoverload
• Newdefinitionsdeveloping(IntAscitesClub,ADQI):– IncreaseSCr>0.3mg/dlinlessthan48hours,– Ora50%increasefromastableSCrlevelobtainedwithinthepast6months
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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
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Inpatientswithcirrhosis+ascitesAKIdiagnosisisdelayed
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ImpactofAKIincirrhoticpatients
• MostcommonprecipitantofAKIisbacterialinfection
• IfAKIdevelopsinaninfectedpatient,survivalisreducedto31%at3months
• RenaldysfunctionthemostsignificantindependentpredictorofdeathinptswithcirrhosisandSBP
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SurvivalwithHRSispoor
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Gines-Schrier NEJM 2009
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ACID-BASESTATUS
• Whatistheacid-basedisorder?• Whatisthemechanism?• Howdowefixit?
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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?
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Assessment
• DECISIONS:– So,whatdowedo?
• GivemoreIVbicarbonate?– IsitnecessarytocorrectthepH?– Isbicarbonatelikelytobeeffective?– Whateffectsonammoniemia?
• GiveIVdiuretics?– Patientanuric1-2days:unlikelytorespond– Besides:whatwouldbethegoal?
• Startrenalreplacementtherapy?– Whatwouldbetheindications?
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Assessment
• DECISIONS:– TimingofRRT
• INDICATIONS:– Azotemia– Encephalopathy
» Ishyperamonemiaanindication?– Hyperkalemia– Acidosis– Fluidoverload– Ishyponatremiaanindication
» Shouldwefixthenatremiainthispatient?
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HYPONATREMIA
• Pathogenesis• Impactonoutcome• Management
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Shouldwecorrectthehyponatremia?
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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
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TimingofInitiationofRRT
• Needtodefinewhatconstitutes“early”vs.“late”• Needtoavoidpotentialharmfromunnecessaryearlyinitiation
• Principle:Atanygiventime,needforRRTdependsonthebalancebetweenthedemandonrenalfunctionandthecapacityoftheorgantofulfillthatneed
• Studiesareneeded
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ETHICS/DECISIONS
• Shouldwedialyzethispatient?
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Decisions
• Youdiscussextensivelywithfamilyandcolleagues– Isthepatientalivertransplantcandidate?
• Consensusisreachedtostartrenalreplacementtherapy– Consentformsaresigned– Theintensivistinsertsarightfemoraldoublelumendialysisline
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SurvivalimpactofAKIincirrhotics
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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%).
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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
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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%
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SurvivalstratifiedbyseverityofAKI
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Fagundez et al J Hepatol 2013
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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
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ExtracorporealSupportTechniquesinSevereHRS:Indications
• ECSonlyindicatedinHRSpatientswhoarepotentialcandidatesforOLT,
• Orhaveareversibledecompensation,• AfterstandardmeasuresincludinghemodynamicsupportandIValbuminhavefailedtoinduceclinicalimprovement
44Cerdá, Tolwani, Gibney and Tiranathanagul, Seminars Dialysis 2011
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Whatdoyoudo?• Conservativemanagement?
– Hyperkalemia– Azotemia,AKI– Acidosis
• TimetostartRRT?– WhatkindofRRT?– HowdoIdoit?
– Hyponatremia• Aprobleminitself• Ahindrancewhentryingtomanagetheotherproblems
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Decisions
• YoudecidetostartthepatientonRRT– Whatmodality?– Withineachmodality,whatoperationalcharacteristics?
– Dose?– Access?– Anticoagulation?
46
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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
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Decisions
• YoudecidetostartthepatientonRRT– Whatmodality?– Withineachmodality,whatoperationalcharacteristics?
– Dose?– Access?– Anticoagulation?
48
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RRTMODALITY
49
• HEMODYNAMICSTABILITY• OSMOTICANDFLUIDSHIFTS• IMPACTONTHEBRAIN
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RRTMODALITY
• INTERMITTENTHEMODIALYSIS– Hemodynamictolerance– Fluidshifts,brainedema,encephalopathy– Howlowcanyoudecreasethe[Na]dialysate?
• PIRRT– Anydata?
• CRRT– Setupoptions
• PERITONEALDIALYSIS
50
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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”
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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
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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
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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
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CRRTAllowsBetterFluidManagement
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FluidBalance:CRRTvsIHD
Augustine et al, AJKD 2004
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HemodynamicStability:CRRTvsIHD
Augustine et al, AJKD 2004
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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)
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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
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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
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HIGHERPLASMAONCOTICPRESSURE
FACILITATESCAPILLARYREFILLING LITTLE
CHANGEINI/VASCULARVOLUME
REPLACEMENTFLUIDIsotonic[Na+]150mEq/L
HEMOFILTRATIONSmallsoluteconcentrationsequaltoplasma(Notranscapillary osmoticpressuregradient)
SystemicCapillary
↑πonc
ddd
d
d
d
dd
HEMOFILTRATION
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Now,WhatAboutRenalReplacementTherapy
andtheBrain?
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RRTISCRITICALINCERTAINSITUATIONS…
• Patientswithintracranialhypertensionorcerebraledema– Autoregulationislost– Suddenchangesinsystemicorintrabdominal pressurechange
intracranialpressure• Bewareofpatientswithpossibleabdominalcompartmentsyndrome
– Patientswithfulminantliverfailureoracutedecompensatedlivercirrhosishavevariabledegreesofbrainedema
• Patientswithsevereazotemia– Correctazotemiaslowly, toavoiddialysisdysequilibrium
• Patientswithhyponatremia– Correct[Na]pveryslowly10-12mEq/L/day– CorrectureaVERYSLOWLY:ureaprotectsagainstosmotic
demyelinationsyndrome
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ChangesinIntracranialPressureduringHaemofiltrationinOliguricPatientswithGradeIVHepaticEncephalopathy
0246810121416
PRE
POST
HEMOFILTCAVHF
INTRA-CRANIALPRESSUREmmHg
PLASMAOSMOLALmOsm/Kg
DavenportAetalNephron1989;53:142-146
**
HF:GambroQb200-250Isovolemic17Lexchanges3.5-4hrs.
CAVHF:400-1000ml/h24-160hrs.
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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
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INDUCTIONOFHEPATICENCEPHALOPATHY
• CIRRHOSIS• Hyperammonemia
• ASTROCYTICGLUTAMINEACCUMULATION• Osmo-compensatedbyInositolrelease
• EXHAUSTIONOFVOLUME-REGULATORYCAPACITY• Lowgradecerebraledema
• EXACERBATIONOFLOWGRADECEREBRALEDEMA
ADDITIONALPRECIPITATINGFACTORS
Modified from Haussinger Arch Biochem Biophys 2013
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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
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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
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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
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Liu et al JASN 2008
TheBraininAKI
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Liu et al JASN 2008
WATER CONTENTS
CAPILLARY PERMEABILITY
InAKI,increasedwaterpermeabilityandwatercontentsincreaseriskofbrainedema
Liu et al JASN 2008
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RRTMODALITY
72
• HOWDOYOUHANDLETHEHYPONATREMIA?• DOYOUNEEDANTICOAGULATION?
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YoudecidetouseCVVH
• Simplicityofprocedure• Noneedforanticoagulation
– Besides,patienthasahighINR,andtheplateletcountislow
– Andalso,thepatienthasverypoorliverfunction!• Whatcouldhappenifyoutriedusingcitrate?
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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
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[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
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Hourslater..
• Thesystemclotsafter4hoursoftreatment– Whathappened?
• Theliversynthesizesnotonlypro- butalsoanti-coagulationproteins
• NGtubefluidisnowbloody,youareafraidofusingheparin– Somebodysayssheremembers“atOSHtheysaidhehadHIT”
• Canyouusecitrateanticoagulation?– Whatabouttheliver?– Doyouhavetochangemodality?
• Lactate6mM,NH3 200μg/dl
76
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Coagulationdefectsinlivercirrhosis
• Increasedbleedingrisk– DecreasedfactorsII,V,VII,IX,X,XI,XIII– Thrombocytopeniaandplateletdysfunction– Abnormalfibrinogen
• Increasedthromboticrisk– DecreasedproteinSandClevels– Decreasedantithrombin levels– Decreasedplasminogen– ElevatedvWF andfactorVIII
77
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Decisions…
• YoudecidetouseCVVHDF– Youwilladddiffusiveclearance(“dialysis”)toclearexcesscitrate
– Also,youhopethat,byaddingdiffusiontoconvection,youwillclearammoniaandlactatemoreefficiently
78
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RRTMODALITY
79
• ACIDBASECONTROL
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Decisions…
• YoudecidetouseCVVHDF– Youwilladddiffusiveclearance(“dialysis”)toclearexcesscitrate
– Youhopethat,byaddingdiffusiontoconvection,youwillclearammoniaandlactatemoreefficiently
80
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Really?
• Renalreplacementtherapiesdonoteffectivelyremovelactate– Enormousrateofproduction
81
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CVVHDFhasanegligible effectonLactateClearance
Levrault J CCM 1997;25:58-62
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Cerda,Tolwani,Warnock KidneyInt2011
BUFFERINDIALYSATE
BUFFER
HEMODIALYSIS(DIFFUSION)
HEMOFILTRATION&HEMODIAFILTRATION
(CONVECTION)
ModesofBufferDeliveryinRRT
ADDITIONOFBUFFERTODIALYSATE
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CVVHDF: Continuous Venovenous Hemodiafiltration
Effluent
Access
Return
PR
I S
MA
M100
Dialysate
Replacement(pre/post dilution)BUFFER
ReplaceConsumedBuffer
AvoidDialyticLoss
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RRTMODALITY
85
• COULDANTICOAGULATIONHELPWITHTHEMANAGEMENTOFACIDOSIS?
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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
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CRRTisSuperiortoIHDintheManagementofMetabolicAcidosis
• Morestablenormalizationofacidbasebalance
• LessergenerationofCO2
• Bettertoleratedbyhemodynamicallyunstablepatients
• Enhancedclearanceoftoxinscausingacidosis(metformin)
• SlowerthanIHD:theprosandthecons!
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RRTMODALITY
88
• ANTICOAGULATIONI• YOUSTILLHAVETHEPROBLEMOFTHEHYPONATREMIA
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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
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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
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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?
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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
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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
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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
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Hourslater..
• ThefluidfromtheNGTisclearlybloodyandhematocritdecreasedfrom30to20%;patientdoesn’tlookthatgood…
• INRisstillhighat2.2• Housestaffmanagestheproblem• Youreassurethem,thatwhileoncitrateA/C,thepatientis
notsystemicallyanticoagulated
• Twohourslater,nursecallsyoutoreportthatthesystemicvenousionizedCa++ isdown,frominitial1.2mMto0.7mM
– Alltheconnectionsareright,allthesolutionsareOK– ShehandsyoutheEKG
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EKG QTc 500 ms
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Whathappened?
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RRTMODALITY
98
• ANTICOAGULATIONII
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USCRRTAnticoagulationOptions– No anticoagulation– Heparin(UFHorLMW Heparin)
• Systemic,prefilter• “Regional”Heparinwithprotaminereversalpostfilter
– Citrate• ACD• Sodiumcitrate
– Prostacyclin(hypotension &$$$)– Lepirudin orbivalrudin (noantidotes&$$$))– Argatroban (noantidote&$$$)
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Anticoagulationguidanceforthepatientinourcase?
• FDA?– Noguidance/approvalforCRRTanticoagulationforheparin,LMWH,citrate,-rudins,argatroban,prostacyclin
– NoFDAapprovedcitratedrugproductonUSmarket
• KDIGO?– Yes!
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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)
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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)
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NoAnticoagulation• Usuallyusedinpatientswithintrinsiccoagulopathiessuchas
hepaticfailureorlowplateletcounts
• Methods:– Primecircuit:SalineorHeparinprime– Intermittent0.9%NSflush50-200mlq30-60mins
• Results:– Ratesoffilterclottingvarywidely– Meanfilterlifebetween16- 70hrs ifcoagulopathic– Shorterfilterlife6-18hrs unlessseverecoagulopathy
• Thesecrettosuccesswhennotusinganticoagulation?
– Higherbloodflowrates!
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UnfractionatedHeparinAdvantages
• Effective• Widelyavailable• Simplemonitoring(aPTT)• Reversedwithprotamine• Inexpensive• Shorthalflife
Disadvantages• Systemicbleeding• Unpredictablekinetics• PTTnotreliablepredictorfor
bleeding• Heparinresistanceduetolow
patientantithrombin levels• HIT
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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
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LowMolecularWeightHeparin
Advantages
• Effective• Predictablepharmacokinetics
• LowerincidenceofHIT
• Lesseffectonlipids
Disadvantages• Systemicbleeding• Onlypartiallyreversedwithprotamine
• antiXa activitynoteverywhereavailable
• Expensive
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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
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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)
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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
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CitrateAnticoagulation
• ChelatesfreeCa+2 inextracorporealcircuit• PreventsactivationofCa+2-dependentprocoagulants
• AnticoagulanteffectmeasuredbyiCa+2
• AnticoagulationreversedbyCa+2 infusion
Citrate+iCa Calcium citrateBiologically inactivemeasurable as total Ca
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CitrateMetabolism
• Citricacidhasplasmahalflifeof5mins• Rapidlymetabolizedbyliver,kidneyandmusclecells
Na3Citrate + 3H2CO3
Citric Acid + 3NaHCO3
3H2CO3 + H2O + 3NaHCO3
4H2O + 6CO2
Flanagan MJ et al. AJKD 27: 519-24, 1996
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Why Citrate? Citrate and Bleeding
Zhang et al. Int Care Med. 2012
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WhyCitrate?CitrateandCircuitPatency
Zhang et al. Int Care Med. 2012
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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
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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
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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
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Citrate• Advantages
– Regional,avoidsbleedingcomplications– Doublesasbuffer– Highlyeffectiveinstudies(>heparin)– Nothrombocytopenia
• Disadvantages– Metaboliccomplications– Complexprotocols– NocommercialproductdesignedforthisuseinUS
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Backtoourcase…
• Administeredhugecitrateload– ThepatientreceivedFFPandBlood– Alreadyreceivingcitrateanticoagulation
• Hasliverdisease,socannotmetabolizecitrateefficiently
• Systemicionizedcalciumlow,EKGChanges• Serum bicarb willeventuallyriseoncethiscitrategetsmetabolized…
118
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Citrate’sMetabolicConsequences• Metabolicalkalosis
– Citrateoverdose/toxicity– Centersusingcitratewillchoosealowerbicarb-
containingdialysate/effluentsolution
• Metabolicacidosis– Citratetoxicityinsettingofsevereliverdiseaseor
hypoperfusion
• Hypernatremia– Hyperosmolarcitratesolutions– Centersusingcitratewillchoosealowersodium-
containingdialysate/effluentsolution
• Hypocalcemia andhypercalcemia– Inappropriatecalciumsupplementation
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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
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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: [email protected]
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Whattodoforourcase?
• AdministerCalcium• ChangeoradjustCRRTanticoagulation?
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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
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Monitoring
• Circuitserumionizedcalciumq6-8H
–keep0.25-0.35mmol/l
• Systemicserumionizedcalciumq6-8H
–keep0.90-1.0mmol/l
• SerumTotalCa,PO4 andMgq12-24H
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Concerned aboutusingcitrateinpatientswithliverdisease?
• Worriedabout“citratelock”?– risingtotalcalciumwithdroppingpatientionizedcalcium
– DeliveryofcitrateexceedshepaticmetabolismandCRRTclearance
• Keepbloodflowrelativelylow– Citratedoseistiedtobloodflow
• Usehigherdialysateflowratestoclearcitrate
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ManyCRRTcitrateprotocolsavailable
• Googlesearchon2/16/2013for“crrt citrateprotocol”yielded12,200hits
• HereistheUMichigan’sACDprotocol:– http://www.med.umich.edu/intmed/nephrology/docs/AdultCitrateProtocol_6-2013.pdf
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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?