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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
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?
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
Fluid Transport
Solute Transport }
positive pressure negative pressure
Ultrafiltration
The movement of fluid through a membrane caused by a
pressure gradient.
Solute Classes by Molecular Weight
Daltons
• Inflammatory Mediators (1,200-40,000)
“small”
“middle”
“large”
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
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
Adsorption
Molecular adherence to the surface or interior of the membrane.
Cytokine Removal in CRRT (AN69 Filter) De Vriese et al, JASN 1999
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
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
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
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?
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
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
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
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)
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
) (
Effluent-Based Clearance: Post-Dilution CVVH
Clearance = Blood Concentration
QACA Filter
QE
Mass Removal Rate
= CA
QVCV
QECE
QR
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
Effluent-Based Clearance: Pre-Dilution CVVH
Clearance = Blood Concentration
QACA Filter
QE
Mass Removal Rate
= CA
QVCV
QECE
QR
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
Effluent-Based Clearance: CVVHD
Clearance = Blood Concentration
QACA Filter
QECE QD
Mass Removal Rate
= CA
QVCV
QECE
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
Effluent-Based Clearance: CVVHDF
Clearance = Blood Concentration
QACA Filter
QECE QD
Mass Removal Rate
= CA
QVCV
QECE
QR
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)
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
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
Dose vs Outcome in Post-Dilution CVVH Ronco et al., Lancet 2000
(45 mL/kg/hr)
(35 mL/kg/hr)
(20 mL/kg/hr)
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 (%
)
Treatment Parameters in Comparative Study
of CVVH and CVVHDF Saudan et al, Kidney Int 2006
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
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)
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
ATN Study: Characteristics of IHD Group
VA/NIH Trial Group, NEJM 2008
ATN Study: Characteristics of CRRT Group VA/NIH Trial Group, NEJM 2008
ATN Study: Primary Outcome VA/NIH Trial Group, NEJM 2008
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 -
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)
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
Mortality Outcomes in RENAL
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
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%
• 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