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