Q - CRRT Online

CRRT Dose WorkshopWilliam R. Clark, M.D.Claudio Ronco, M.D.Rolando Claure, M.D.CRRT ConferenceFebruary 15, 2012San Diego, CA

Current Issues in Renal ReplacementTherapy for AKI• What are the indications?• When should therapy be initiated? (and when should it be stopped?)• What are the critical elements of the RRT prescription?• Type of technique (convection vs diffusion)• Vascular access and equipment selection• Membrane and anticoagulation• Frequency of the technique (Intermittent vs continuous)• Dose of RRT (mL/kg/hr vs Kt/V vs ?)• Who will manage the practical aspects of delivering RRT?

Dose of Treatment• The concept of dose has not been clearly defined• What does it mean ?– During CRRT– During IHD– During SLED• Dose of what?– Marker molecules– Utrafiltration– Biomarkers of blood purification• Adequacy and inadequacy of treatment

Molecular Transport Mechanisms• Ultrafiltration• Diffusion• Convection• Adsorption}SoluteFluid TransportTransport

Ultrafiltrationpositive pressurenegative pressureThe movement of fluid through a membrane caused by apressure gradient.

Solute Classes by Molecular WeightDaltons• Inflammatory Mediators (1,200-40,000)“large”“middle”“small”

Diffusion vs. ConvectionDiffusion is solute transport across a semi-permeable membrane - molecules move froman area of higher to an area of lower concentrationBest for small molecule clearanceConvection is a process where solutes pass across the semi-permeable membrane alongwith the solvent (“solvent drag”) in response to a positive transmembrane pressureEffectiveness less dependent onmolecular size

Clearance in %Small vs. Large Molecule Clearance10080FiltrationKidney604020Dialysis0Urea(60)2.500Creatinine(113)5.00020.000Myoglobin(17.000)35.000 55.00065.000Albumin(66.000)

AdsorptionMolecular adherence to the surface or interior of themembrane.

Cytokine Removal in CRRT (AN69 Filter)De Vriese et al, JASN 1999

Modes of Renal Replacement TherapyPre-DilutionSubstitutionPre-DilutionSubstitutionBloodFiltrateDialysate+ FiltratePost-DilutionSubstitutionDialysatePost-DilutionSubstitutionDialysateHemofiltrationHemodiafiltrationHemodialysis

Replacement FluidsAccessM100PR I S MAReturnReplacement(pre-dilution)Pre-Dilution– Lowers HCT, decreases riskof clotting– UF chemistries do notreflect true plasma soluteconcentrationsEffluent

Replacement FluidsAccessM100PR I S MAReturnReplacement(post-dilution)Post-Dilution– Typically lower replacementsolution rates– May increase anticoagulationneeds– UF chemistries reflect trueplasma solute concentrationsEffluent

Replacement Fluid Administration• Post-Dilution– reinfusion into venous line (post-filter)– disadvantage: UF rate limited to certain percentage of bloodflow rate due to hemoconcentration– advantage: relatively low volume of replacement fluids;clearance directly related to ultrafiltration rate• Pre-Dilution– reinfusion into arterial line (pre-filter)– disadvantages: reduction of solute concentrations (loweredclearances); higher replacement fluid requirements– advantage: no UF rate limitation; prolonged circuit life?

Blood Flow Rate Requirementsin Post-Dilution CVVH: Filtration Fraction = 0.30*Filtration Fraction =Q UFQ PWeight (kg)6080100120Q B (Hct=0.30)167222278333Q B (Hct=0.35)180240299359*Dose: 35 mL/hr/kg

Effect of Blood Flow Rate on TargetedDose Delivery in Pre-Dilution CVVHClark et al, Artif Organs 2003Note: Pre-dilution; 35 ml/kg/hr dose; 16 hrs/day therapy administration

Clearance (mL/min)Solute Equilibration in CVVHDBrunet et al., Am J Kidney Dis 1999454035302520151050EffluentUreaCrUrPB2-M0 500 1000 1500 2000 2500Q E (mL/h)

Solute Clearance in CRRT=• CVVHD/CVVHDFK = E Q D ( EConcentration in effluent dialysate/diafiltrateConcentration in bloodQK = S Q (BWUFQ BW + Q R)• Post-Dilution CVVHK = S Q UF• Pre-Dilution CVVH( S =Concentration in filtrateConcentration in blood))

Effluent-Based Clearance: Post-Dilution CVVHQ EQ RQ A C AFilterQ V C VClearance =Mass Removal RateBlood Concentration=Q E C EC A

Effluent-Based Clearance: Post-Dilution CVVH*Q EQ RQ A = 180 mL/minQ A C AFilterQ V C VUrea K =Q E C EC AQ R = 3.0 L/hrQ E = 3.1 L/hr*C E = 60 mg/dLBUN A = 60 mg/dL=3100 mL/hr (51.7 mL/min)* Filtration fraction = 41%

Effluent-Based Clearance: Pre-Dilution CVVHQ RQ EQ A C AFilterQ V C VClearance =Mass Removal RateBlood Concentration=Q E C EC A

Effluent-Based Clearance: Pre-Dilution CVVHQ RQ EQ A C AFilterQ V C VUrea K =Q E C EC AQ A = 180 mL/minQ R = 3.0 L/hrQ E = 3.1 L/hrC E = 45.9 mg/dLBUN A = 60 mg/dL=2356 mL/hr (39.3 mL/min)

Effluent-Based Clearance: CVVHDQ E C EQ DQ A C AFilterQ V C VClearance =Mass Removal RateBlood Concentration=Q E C EC A

Effluent-Based Clearance: CVVHDQ E C EQ DQ A C AFilterQ V C VUrea K =Q E C EC AQ A = 180 mL/minQ D = 3.0 L/hrQ E = 3.1 L/hrC E = 60 mg/dLBUN A = 60 mg/dL=3100 mL/hr (51.7 mL/min)

Effluent-Based Clearance: CVVHDFQ RQ E C EQ DQ A C AFilterQ V C VClearance =Mass Removal RateBlood Concentration=Q E C EC A

Effluent-Based Clearance: CVVHDFQ RQ E C EQ DQ A C AFilterQ V C VUrea K =Q E C EC AQ A = 180 mL/minQ R = 1.5 L/hrQ D = 1.5 L/hrQ E = 3.1 L/hrC E = 52 mg/dLBUN A = 60 mg/dL=2686 mL/hr (44.8 mL/min)

CRRT Dose: Urea-Based Versus Effluent-Based*Post-CVVH Pre-CVVH CVVHD CVVHDFUrea Dose** 38.8 29.5 38.8 34.1Effluent Dose** 38.8 38.8 38.8 38.8*: Q B = 180 mL/min; Q E = 3.1 L/hr; Patient weight loss = 100 mL/hr**: Results expressed as mL/kg/hr, based on 80 kg body weight

Patient Groups in CVVH Dose StudyRonco et al., Lancet 2000492 patients considered425 patients randomized67 excluded146 assignedultrafiltrationat 20 mL h -1 kg -1139 assignedultrafiltrationat 35 mL h -1 kg -1140 assignedultrafiltrationat 45 mL h -1 kg -1146 Patientscompleted studywith ultrafiltration of>85% of prescribed139 Patientscompleted studywith ultrafiltration of>85% of prescribed140 Patientscompleted studywith ultrafiltration of>85% of prescribed

Dose vs Outcome in Post-Dilution CVVHRonco et al., Lancet 2000(45 mL/kg/hr)(35 mL/kg/hr)(20 mL/kg/hr)

Survival (%)“Sepsis Dose” in ARF?Ronco et al., Lancet 2000100OverallSeptic Patients500Group 1 Group 2 Group 3Trial Group No Sepsis (%) Sepsis (%) p-valueGroup1 55/126 (44%) 5/20 (25 %) 0.90Group 2 76/122 (62 %) 3/17 (18 %) 0.001Group 3 74/125 (59 %) 7/15 (47 %) 0.256

Treatment Parameters in Comparative Studyof CVVH and CVVHDFSaudan et al, Kidney Int 2006

Survival (%)Survival Comparison: CVVH vs CVVHDFSaudan et al, Kidney Int 2006100806042 mL/kg/hrCVVHDF4025 mL/kg/hrCVVH20020406080100Survival time (days)

ATN Trial1164 patients31 sites (24 VA, 7 other)3 yearsRandomizationStablehemodynamics(SOFA 0-2)Unstablehemodynamics(SOFA 3-4)IntensiveManagement Strategy(582 patients)• IHD 6x/week @ Kt/V of~1.2/session• CVVHDF @35 mL/kg/hr, or• SLED/EDD 6x/weekConventionalManagement Strategy(582 patients)• IHD 3x/week @ Kt/V of~1.2/session• CVVHDF @20 mL/kg/hr, or• SLED/EDD 3x/week

Modality Prescription in ATN StudyVA/NIH Trial Group, NEJM 2008Hemodynamic Status Modality Number of PercentageTreatments of TreatmentsStable* IHD 5077 100%Unstable** CRRT 5967 95.2%SLED 299 4.8%*: SOFA score: 0, 1, or 2**: SOFA score: 3 or 4

ATN Study: Characteristics of IHD GroupVA/NIH Trial Group, NEJM 2008

ATN Study: Characteristics of CRRT GroupVA/NIH Trial Group, NEJM 2008

ATN Study: Primary OutcomeVA/NIH Trial Group, NEJM 2008

Comparison of Major CRRT Dose TrialsRonco Saudan Tolwani ATNNumber of patients 425 206 200 1124Multi-center RCT No No No YesCKD (%) NA 33 42 ExclusionPredominant AKI cause Surgical Sepsis Sepsis IschemiaAPACHE II ~23 25 26 ~29Initiation BUN (mg/dL) 53 83 75 65Modality post CVVH pre CVVHDF pre CVVHDF pre CVVHDF% Convective 100 ~60 43-44 50Prescribed dose (mL/kg/h) 20/35/45 25/42 20/35 20/35Effective dose (mL/kg/h) 20/35/45 ~20/37 ~17/29 ~17/27ICU wait (days) NA NA 8 6.9

R.E.N.A.L. Trial1508 patients35 sites3 yearsRandomizationIntensiveCRRT(post-dilutionCVVHDF at 40 ml/kg/hrof effluent)(750 patients)ConventionalCRRT(post-dilutionCVVHDF at 25 ml/kg/hrof effluent)(750 patients)

Process of Care in RENALLow dose High dose pNumber of patients 743 722Total number of study days 4190 4179Mean Days of Study treatment/patient 5.9 (7.7) 6.3 ( 8.7) 0.35Daily effluent (mls/hr)/patient 1772 (1257) 2698 (1154)

Mortality Outcomes in RENAL

Comparison of RENAL with ATNVariable RENAL VA/NIHEnrolled 1508 1124Mean age (yrs) 64.5 59.7Ventilation 74% 81%Sepsis (%) 49.5 63Urea at baseline (mg/dL) 65 66APACHE II ~26 26.4Total SOFA score 7.55 7.40CRRT as initial therapy (%) 100 ~70ICU Days before RRT initiation 2.1 6.7

Comparison of RENAL with ATNVariable RENAL VA/NIHMortality day 90 44.7%Mortality day 60 52.5%RRT days (at 28 days) 7.4 -Hospital LOS (days) 25.2 -Dialysis dependence @day 28 13.3% 45.2%Dialysis dependence @day 60 24.6%Dialysis dependence @day 90 5.6%

Summary• Recent multicenter RCTs have failed to confirm earlier trials suggesting abenefit of higher CRRT dose in critically ill patients• Nevertheless, these RCTs have confirmed that CRRT is standard therapy forAKI in the ICU, especially for hemodynamically unstable patients• Several differences (total effluent dose, convective contribution, timing oftreatment initiation) exist among the various CRRT dose/outcome trials,making it difficult to establish a “standard“ dose• For the time being, 30 to 35 mL/kg/hr is a reasonable target for prescription tomake sure no less than 25 mL/kg/hr is effectively delivered• The excellent patient outcomes in RENAL mandate a careful analysis ofRRT application and other processes of care in the study• Based on standard practice in chronic dialysis, routine assessment ofdelivered CRRT dose should be an integral aspect of AKI patientmanagement in the future