CRRT Dose · PDF fileCRRT Dose Workshop William R. Clark, M.D. Claudio Ronco, M.D. Rolando...
Transcript of CRRT Dose · PDF fileCRRT Dose Workshop William R. Clark, M.D. Claudio Ronco, M.D. Rolando...
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CRRT Dose Workshop
William R. Clark, M.D.
Claudio Ronco, M.D.
Rolando Claure, M.D.
CRRT Conference
February 15, 2012
San Diego, CA
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Current Issues in Renal Replacement
Therapy 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?
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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
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Molecular Transport Mechanisms
• Ultrafiltration
• Diffusion
• Convection
• Adsorption
Fluid Transport
Solute Transport }
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positive pressure negative pressure
Ultrafiltration
The movement of fluid through a membrane caused by a
pressure gradient.
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Solute Classes by Molecular Weight
Daltons
• Inflammatory Mediators (1,200-40,000)
“small”
“middle”
“large”
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Diffusion vs. Convection
Diffusion is solute transport across a semi-permeable membrane - molecules move from
an area of higher to an area of lower concentration
Convection is a process where solutes pass across the semi-permeable membrane along
with the solvent (“solvent drag”) in response to a positive transmembrane pressure
Best for small molecule clearance
Effectiveness less dependent on
molecular size
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0
20
40
60
80
100
Cle
ara
nce i
n %
35.000 55.000 20.000 5.000 2.500 Urea (60)
Albumin (66.000)
Myoglobin (17.000)
65.000 Creatinine
(113)
Kidney
Filtration
Dialysis
Small vs. Large Molecule Clearance
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Adsorption
Molecular adherence to the surface or interior of the membrane.
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Cytokine Removal in CRRT (AN69 Filter) De Vriese et al, JASN 1999
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Modes of Renal Replacement Therapy
Pre-Dilution
Substitution
Dialysate
+ Filtrate
Dialysate
Post-Dilution
Substitution
Hemodiafiltration
Dialysate
Blood
Hemodialysis
Pre-Dilution
Substitution
Filtrate
Post-Dilution
Substitution
Hemofiltration
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Pre-Dilution
– Lowers HCT, decreases risk
of clotting
– UF chemistries do not
reflect true plasma solute
concentrations
Replacement Fluids
Access
Return
Effluent
Replacement (pre-dilution)
PR
I S
MA
M100
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Replacement Fluids
Post-Dilution
– Typically lower replacement
solution rates
– May increase anticoagulation
needs
– UF chemistries reflect true
plasma solute concentrations
Access
Return
Effluent
Replacement (post-dilution)
PR
I S
MA
M100
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Replacement Fluid Administration
• Post-Dilution
– reinfusion into venous line (post-filter)
– disadvantage: UF rate limited to certain percentage of blood
flow 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 (lowered
clearances); higher replacement fluid requirements
– advantage: no UF rate limitation; prolonged circuit life?
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Blood Flow Rate Requirements
in Post-Dilution CVVH: Filtration Fraction = 0.30*
Filtration Fraction =
Weight (kg)
60
80
100
120
*Dose: 35 mL/hr/kg
QB (Hct=0.30)
167
222
278
333
QB (Hct=0.35)
180
240
299
359
QUF
QP
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High Blood Flow Rate
Low Filtration Fraction
Low Blood Flow Rate
High Filtration Fraction
Blood
Blood
Shear Dependent Protein Layer and Polarization Blood Flow Rate Effects in
Post-Dilution CRRT Modalities
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Note: Pre-dilution; 35 ml/kg/hr dose; 16 hrs/day therapy administration
Effect of Blood Flow Rate on Targeted
Dose Delivery in Pre-Dilution CVVH
Clark et al, Artif Organs 2003
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Solute Equilibration in CVVHD Brunet et al., Am J Kidney Dis 1999
0
5
10
15
20
25
30
35
40
45
0 500 1000 1500 2000 2500
Effluent
Urea
Cr
Ur
P
B2-M
QE (mL/h)
Cle
ara
nce
(m
L/m
in)
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Solute Clearance in CRRT
• CVVHD/CVVHDF
K = E QD
• Post-Dilution CVVH
K = S QUF
• Pre-Dilution CVVH
K = S QUF
E =
S =
Concentration in effluent dialysate/diafiltrate
Concentration in blood
Concentration in blood
Concentration in filtrate
(
(
)
)
QBW
QBW + QR
) (
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Effluent-Based Clearance: Post-Dilution CVVH
Clearance = Blood Concentration
QACA Filter
QE
Mass Removal Rate
= CA
QVCV
QECE
QR
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Effluent-Based Clearance: Post-Dilution CVVH*
Urea K = CA
QACA Filter
QE
QECE
=
QVCV
3100 mL/hr (51.7 mL/min)
* Filtration fraction = 41%
QR
QA = 180 mL/min
QR = 3.0 L/hr
QE = 3.1 L/hr*
CE = 60 mg/dL
BUNA = 60 mg/dL
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Effluent-Based Clearance: Pre-Dilution CVVH
Clearance = Blood Concentration
QACA Filter
QE
Mass Removal Rate
= CA
QVCV
QECE
QR
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Effluent-Based Clearance: Pre-Dilution CVVH
Urea K = CA
QACA Filter
QE
QECE
=
QVCV
2356 mL/hr (39.3 mL/min)
QR
QA = 180 mL/min
QR = 3.0 L/hr
QE = 3.1 L/hr
CE = 45.9 mg/dL
BUNA = 60 mg/dL
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Effluent-Based Clearance: CVVHD
Clearance = Blood Concentration
QACA Filter
QECE QD
Mass Removal Rate
= CA
QVCV
QECE
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Effluent-Based Clearance: CVVHD
Urea K = CA
QACA Filter
QECE QD
QECE
=
QVCV
3100 mL/hr (51.7 mL/min)
QA = 180 mL/min
QD = 3.0 L/hr
QE = 3.1 L/hr
CE = 60 mg/dL
BUNA = 60 mg/dL
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Effluent-Based Clearance: CVVHDF
Clearance = Blood Concentration
QACA Filter
QECE QD
Mass Removal Rate
= CA
QVCV
QECE
QR
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Effluent-Based Clearance: CVVHDF
Urea K = CA
QACA Filter
QECE QD
QECE
=
QVCV
QR
QA = 180 mL/min
QR = 1.5 L/hr
QD = 1.5 L/hr
QE = 3.1 L/hr
CE = 52 mg/dL
BUNA = 60 mg/dL
2686 mL/hr (44.8 mL/min)
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CRRT Dose: Urea-Based Versus Effluent-Based*
Post-CVVH Pre-CVVH CVVHD CVVHDF
Urea Dose** 38.8 29.5 38.8 34.1
Effluent Dose** 38.8 38.8 38.8 38.8
*: QB = 180 mL/min; QE = 3.1 L/hr; Patient weight loss = 100 mL/hr
**: Results expressed as mL/kg/hr, based on 80 kg body weight
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Patient Groups in CVVH Dose Study Ronco et al., Lancet 2000
146 Patients
completed study
with ultrafiltration of
>85% of prescribed
139 Patients
completed study
with ultrafiltration of
>85% of prescribed
140 Patients
completed study
with ultrafiltration of
>85% of prescribed
146 assigned
ultrafiltration
at 20 mL h-1 kg-1
139 assigned
ultrafiltration
at 35 mL h-1 kg-1
140 assigned
ultrafiltration
at 45 mL h-1 kg-1
425 patients randomized
67 excluded
492 patients considered
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Dose vs Outcome in Post-Dilution CVVH Ronco et al., Lancet 2000
(45 mL/kg/hr)
(35 mL/kg/hr)
(20 mL/kg/hr)
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Trial Group No Sepsis (%) Sepsis (%) p-value
Group1 55/126 (44%) 5/20 (25 %) 0.90
Group 2 76/122 (62 %) 3/17 (18 %) 0.001
Group 3 74/125 (59 %) 7/15 (47 %) 0.256
100
0
Group 1 Group 2 Group 3
50
Overall Septic Patients
Ronco et al., Lancet 2000
“Sepsis Dose” in ARF? S
urv
ival (%
)
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Treatment Parameters in Comparative Study
of CVVH and CVVHDF Saudan et al, Kidney Int 2006
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Survival time (days)
100806040200
Su
rviv
al (
%)
100
80
60
40
20
CVVHDF
CVVH
Survival Comparison: CVVH vs CVVHDF
Saudan et al, Kidney Int 2006
42 mL/kg/hr
25 mL/kg/hr
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ATN Trial
1164 patients
31 sites (24 VA, 7 other)
3 years
Intensive
Management Strategy
(582 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
Conventional
Management Strategy
(582 patients)
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Modality Prescription in ATN Study VA/NIH Trial Group, NEJM 2008
Hemodynamic Status Modality Number of Percentage
Treatments of Treatments
Stable* IHD 5077 100%
Unstable** CRRT 5967 95.2%
SLED 299 4.8%
*: SOFA score: 0, 1, or 2
**: SOFA score: 3 or 4
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ATN Study: Characteristics of IHD Group
VA/NIH Trial Group, NEJM 2008
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ATN Study: Characteristics of CRRT Group VA/NIH Trial Group, NEJM 2008
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ATN Study: Primary Outcome VA/NIH Trial Group, NEJM 2008
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Comparison of Major CRRT Dose Trials
Ronco Saudan Tolwani ATN
Number of patients 425 206 200 1124
Multi-center RCT No No No Yes
CKD (%) NA 33 42 Exclusion
Predominant AKI cause Surgical Sepsis Sepsis Ischemia
APACHE II ~23 25 26 ~29
Initiation BUN (mg/dL) 53 83 75 65
Modality post CVVH pre CVVHDF pre CVVHDF pre CVVHDF
% Convective 100 ~60 43-44 50
Prescribed dose (mL/kg/h) 20/35/45 25/42 20/35 20/35
Effective dose (mL/kg/h) 20/35/45 ~20/37 ~17/29 ~17/27
ICU wait (days) NA NA 8 6.9 -
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R.E.N.A.L. Trial
1508 patients
35 sites
3 years
Intensive
CRRT
(post-dilution
CVVHDF at 40 ml/kg/hr
of effluent)
(750 patients)
Randomization
Conventional
CRRT
(post-dilution
CVVHDF at 25 ml/kg/hr
of effluent)
(750 patients)
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Low dose High dose p
Number of patients 743 722
Total number of study days 4190 4179
Mean Days of Study treatment/patient 5.9 (7.7) 6.3 ( 8.7) 0.35
Daily effluent (mls/hr)/patient 1772 (1257) 2698 (1154) <0.001
Dose delivered mls/kg/hr 22.0 (17.8) 33.4 (12.8) <0.001
% of prescribed 88 84 <0.001
Filters/day/patient 0.84 (0.81) 0.93 (0.86) <0.001
Patients treated with IHD in ICU 52 (7.0%) 55 (7.6%) 0.64
Process of Care in RENAL
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Mortality Outcomes in RENAL
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Comparison of RENAL with ATN
Variable RENAL VA/NIH
Enrolled 1508 1124
Mean age (yrs) 64.5 59.7
Ventilation 74% 81%
Sepsis (%) 49.5 63
Urea at baseline (mg/dL) 65 66
APACHE II ~26 26.4
Total SOFA score 7.55 7.40
CRRT as initial therapy (%) 100 ~70
ICU Days before RRT initiation 2.1 6.7
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Comparison of RENAL with ATN
Variable RENAL VA/NIH
Mortality 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%
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• Recent multicenter RCTs have failed to confirm earlier trials suggesting a
benefit of higher CRRT dose in critically ill patients
• Nevertheless, these RCTs have confirmed that CRRT is standard therapy for
AKI in the ICU, especially for hemodynamically unstable patients
• Several differences (total effluent dose, convective contribution, timing of
treatment 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 to
make sure no less than 25 mL/kg/hr is effectively delivered
• The excellent patient outcomes in RENAL mandate a careful analysis of
RRT application and other processes of care in the study
• Based on standard practice in chronic dialysis, routine assessment of
delivered CRRT dose should be an integral aspect of AKI patient
management in the future
Summary