Continuous Renal Replacement

Therapy
Annual Refresher Course in CRITICAL
CARE
McGill
Course Director: Peter Goldberg, MD

Didier Payen
CC Division & Dept of Anesthesiology

13/4/2000
 Content
• Physical principles
• Definitions
• Techniques
• Clinical issues
• Supportive therapy or active therapy?
– Sepsis an example
– Why?
– How?
– For what goal?
PHYSICAL PRINCIPLES
& DEFINITIONS
 PTM

Clearance =(C uf/C I) * Quf <30 000 Da

Quf = C H2O x S x Ptm >30 000 Da

<65 000 Da
All molecules lower than
Pore diam cross the Mbne
>65000 Da

CONVECTION
 PTM

Clearance =(C uf/C I) * Quf <30 000 Da

Quf = C H2O x S x Ptm >30 000 Da

<65 000 Da
All molecules lower than
Pore diam cross the Mbne
>65000 Da

CONVECTION
 PTM

Clearance =(C uf/C I) * Quf <30 000 Da

Quf = C H2O x S x Ptm >30 000 Da

<65 000 Da
All molecules lower than
Pore diam cross the Mbne
>65000 Da

CONVECTION
 PTM

Clearance =(C uf/C I) * Quf <30 000 Da

Quf = C H2O x S x Ptm >30 000 Da

<65 000 Da
All molecules lower than
Pore diam cross the Mbne
>65000 Da

CONVECTION
 Pdialysat = P blood

Cd <<< Csang

Progressive equilibrium <30 000 Da

of the [plasma] and [dial]
>30 000 Da
<65 000 Da
ONLY SMALL MOLECULES
CROSS THE MBNE
>65000 Da

DIFFUSION
 Pdialysat = P blood

Cd <<< Csang

Progressive equilibrium <30 000 Da

of the [plasma] and [dial]
>30 000 Da
<65 000 Da
ONLY SMALL MOLECULES
CROSS THE MBNE
>65000 Da

DIFFUSION
 Pdialysat = P blood

Cd << Csang

Progressive equilibrium <30 000 Da

of the [plasma] and [dial]
>30 000 Da
<65 000 Da
ONLY SMALL MOLECULES
CROSS THE MBNE
>65000 Da

DIFFUSION
 Pdialysat = P blood

Cd < Csang

Progressive equilibrium <30 000 Da

of the [plasma] and [dial]
>30 000 Da
<65 000 Da
ONLY SMALL MOLECULES
CROSS THE MBNE
>65000 Da

DIFFUSION
 FILTRATION RATE substitution
0 TO 2 L/Hr

Filtration

<30 000 Da

>30 000 Da
<65 000 Da

>65000 Da

SCUF& CVVH
Blood
 DEFINITIONS
BELLOMO et al. Am J Kidney Dis, 28, (Suppl 3) 1996
• SCUF: Use only for fluid control in overhydrated
status
• CVVH:The ultrafiltrate produced during membrane
transit is replaced in part or completely to achieve blood
purification and volume control. UF is in excess if
weight loss is mandatory: clearance of solutes equals UF
• CVVHD: continuous hemodialysis. + countercurrent
flow of dialysis solution. Both diffusion & convection
Efficiency is limited to small molecules (low Perm filter)
• CVVHDF: same. Both diffusion & convection but
higher dialysate flow (High Perm filter)
Therapy options Access

Return

SCUF
Slow Continuous P
R
I
S

Ultrafiltration M
A

Effluent

Maximum Pt. Fluid removal rate = 2000 ml/h

Therapy options Access

Return
CVVH
Continuous P
R

Veno-Venous I
S
M
A Replacement
Hemofiltration
S

Effluent

Maximum Pt. Fluid removal rate = 1000 ml/h

Therapy Options
Access
Dialysate
Return
CVVHD
Continuous P

Veno-Venous R
I
S
M

Hemodialysis A

Effluent

Maximum Pt. fluid removal rate = 1000 ml/h

Therapy options Access
Dialysate

Return
CVVHDF
Continuous P
R

Veno-Venous I
S
M
A Replacement
Hemodiafiltration
S

Effluent

Maximum Pt. Fluid removal rate = 1000 ml/h

EFFICIENCY
Table 2.

Multiflow 100 Pre-set

Solute K under various conditions

K delivered t o t he pat ient

Q uf
Qd (mL/ h)
(mL/ h) 0 1000 2000
0 15. 3 ± 0. 7 28. 7 ± 0. 7
15. 0 ± 0. 8 26. 3 ± 1. 1
14. 8 ± 0. 3 25. 5 ± 1. 0
14. 4 ± 0. 6 24. 4 ± 1. 5
5. 6 ± 2. 2 15. 2 ± 1. 6
500 8. 6 ± 0. 2 23. 4 ± 0. 4 35. 7 ± 1. 0
8. 7 ± 0. 3 22. 5 ± 0. 7 33. 8 ± 1. 1
8. 4 ± 0. 2 21. 9 ± 0. 5 32. 7 ± 1. 2
8. 4 ± 0. 2 21. 5 ± 1. 6 34. 5 ± 2. 5
4. 8 ± 0. 5 11. 8 ± 1. 7 16. 7 ± 2. 3
1000 16. 8 ± 0. 5 31. 7 ± 0. 9 43. 3 ± 1. 7
17. 1 ± 0. 4 29. 9 ± 1. 0 40. 0 ± 3. 3
16. 6 ± 0. 5 28. 9 ± 1. 1 38. 4 ± 3. 4
16. 9 ± 0. 7 28. 6 ± 1. 6 37. 9 ± 2. 3
9. 1 ± 1. 0 14. 5 ± 1. 6 19. 2 ± 1. 2
1500 26. 1 ± 0. 5 38. 6 ± 1. 5 49. 2 ± 1. 3
25. 5 ± 1. 1 36. 4 ± 1. 3 44. 7 ± 1. 2
24. 6 ± 0. 6 34. 3 ± 1. 1 42. 0 ± 1. 2
24. 8 ± 1. 0 33. 9 ± 1. 4 39. 5 ± 4. 9
11. 3 ± 0. 9 15. 4 ± 1. 2 20. 5 ± 3. 2
2000 34. 4 ± 1. 0 46. 6 ± 1. 3 54. 7 ± 2. 1
33. 3 ± 1. 6 42. 9 ± 2. 7 49. 2 ± 3. 3
31. 4 ± 1. 2 39. 7 ± 1. 4 46. 4 ± 3. 2
32. 0 ± 1. 9 39. 9 ± 2. 5 43. 9 ± 3. 9
12. 4 ± 1. 1 15. 2 ± 2. 0 20. 0 ± 3. 5
2500 42. 4 ± 1. 0 52. 2 ± 0. 5 60. 6 ± 2. 6
40. 5 ± 1. 6 47. 8 ± 1. 7 54. 2 ± 3. 1
37. 4 ± 1. 6 43. 9 ± 2. 0 50. 9 ± 5. 3
38. 8 ± 2. 5 43. 2 ± 3. 8 53. 5 ± 3. 1
14. 6 ± 1. 3 16. 1 ± 1. 8 20. 5 ± 4. 3
K ( mL/min) ; Solutes : Ur ea
Mean Ht: 0.287 ± 0.027 C r eatinine
Mean s er um tot. pr ot.: 45.6 ± 5.9 Ur ates
( n = 5 patients ) PO4
β 2 -M
CLINICAL ISSUES
 CLINICAL INDICATIONS
• IHD vs CRRT: no randomized trials but inferiority of IHD
manisfests itself at many levels.
– Hemodynamic stability Hypotension, volume control
– Uremic control > with CRRT than IHD (Clark et al JASNephrol,
1994)
– Metabolic control: metabolic acidosis; phosphate levels
– In ICU patients
» CRRT prevents the surge in ICP
» Cardiac disease restore dry body weight, improve V flow
» Cardiac surgical patients optimization between function and
preload
» Sepsis and inflammatory patients
CRRT AND INFLAMMATION
Sepsis an example
 HYPOTHESIS FOR MODS
PREVENTION

• Control of tissue edema

• EDTX adsorption

• Immunomodulation
 CAVH after Staph Aureus in swine
(Lee
(Lee PA
PA et
et al;
al; Crit
Crit Care
Care Med
Med 1993;
1993; 21:
21: 914-924)
914-924)

• Goals: 1) CAVH impact on morbidity and mortality

2) If UF contains mediators
• Design: prospective, randomized, controlled (n=65)
• Staph aureus (8 x 10 9 CFU) over 1 hr
• Part 1: Group 1: 5.5% plasma filtration fraction
Group 2: 16.6% " " " " "
Group 3: 33.4%
Control clean UF
• Part 2: UFiltrate concentrate from each group infused into
healthy pigs
 CAVH after Staph Aureus in swine
(Lee
(Lee PA
PA et
et al;
al; Crit
Crit Care
Care Med
Med 1993;
1993; 21:
21: 914-924)
914-924)

Measurements and results:

• In G 1, 2, 3, the survival rate increased in relation
to FF in comparison with control
• UF concentrate injection led to animal death
similarly to Staph aureus in control group.
• Conclusion: CAVH-improved survival rate might
be related to mediators removal
 EDTX & HEMOFILTRATION :
In vivo experimental studies (1)

• Stein et al, Intens. Care Med., 1991

– pig model, LPS injection

– membrane : polysulfone, zero balanced HF

– decrease in PVR, EVLW

==> other mechanisms than water balance
 EDTX & HEMOFILTRATION :
In vivo experimental studies (2)

• Gomez et al, Anesthesiology, 1990

– dog model, alive E coli ; in vitro study

– cuprophane membrane

– CHF reversed myocardial depression

– septic sera depressed ex vivo myocardial contraction, an

effect which is prevented by CHF ==> removal of cardio-
depressive substances
 EDTX
EDTX & & HEMOFILTRATION
HEMOFILTRATION ::
In
In vivo
vivo experimental
experimental studies
studies
Grootendorst et al, J. Crit. Care, 1993
- Endotoxin shock in pigs
- Polysulfone membrane
- Ultrafiltrate contains filtrable factors that increase Pap and depress
cardiac performance in healthy animals

Mateo et al, Am. Resp. J. Crit. Care Med., 1993, 1994

- Rabbit endotoxinic shock model

- AN 69 adapted circuit; Hemo-adsorption only; pre-EDTX injection

- No resuscitation; Ao BF, Pas, HR,

- EDTX clearance; TNF; ex vivo vascular reactivity.
 From Mateo et al AJR&CCM
AJR&CCM 1996
1996 (Abst)
(Abst)

Mean Arterial Pressure (%) Aortic Blood Flow Velocity (%)

*
110 110
* * *
* *
100 100

90 90

80 80

70 70
HAD + LPS HAD + LPS
60 LPS 60
LPS

50 50

0 30 60 90 120 150 180 0 30 60 90 120 150 180

TIME (min) TIME (min)

 From Mateo et al AJR&CCM 1996 (Abst)

(E.U / ML)
10000
EDTX levels TNF-  levels
( U.I / ML)
8000
6000
6000 LPS
LPS + HAD *
5000
4000 * p < 0,05
4000
3000 LPS
3000
LPS + HAD
2000
2000

1000 * *
* * 1000
*
0 0
0 10 60 120 180 0 30 60 120 180
TIME (min) TIME (min)
 From Mateo
From Mateo et
et al
al AJ
AJ R&CCM
R&CCM 1996
1996 (Abst)
(Abst)

% 180
of
KCl 160
140 *
120
100
Co n tro l
80
EDTX
60 * EDTX + HAD
40
20 *
0
10-9M 1
10-8M 10-7M 10-6M 10-5M
NE
 CAVH ATTENUATES PMN PHAGOCYTOSIS
IN PORCINE MODEL OF
PRITONITIS
A. DiScipio et al, Am J Surg. 173; 1997

– CLP model of acute peritonitis in pig

– 24 hrs of CAVH vs no CAVH

– ex vivo test of PMN phagocytosis for Candida (T0, T24, 48, 72H)

– hemodynamic, gazometric & biologic data

 CAVH ATTENUATES PMN PHAGOCYTOSIS IN
PORCINE MODEL OF PERITONITIS (A. DiScipio
et al, Am J Surg. 173; 1997)

• RESULTS
– No difference in hemodynamic & gasometric parameters between
CAVH & control
– CAVH decreases intensity of PMN phagocytosis (opsonisation) and
PMN hyperactivity until the early phase of sepsis

Phagocytosis Data

Baseline Day 1 Day 2 Day 3

Phagocytosis Rates*
CAVH 59 ± 9.7 52 ± 9.0 68 ± 11.8 65 ± 8.7
No CAVH 54 ± 10.1 79 ± 7.9$ 75 ± 9.0 62 ± 13.8
Change in Phagocytosis
Rate
From Baseline
CAVH 0 -6 ± 3.9 10 ± 5.2 8 ± 4.9
No CAVH 0 25 ± 3.2= 19 ± 9.3 12 ± 15.5
 Extensive activation of inflammatory responses
mediators
• vasoactive
• cardiodepressant

organ dysfunction

Supportive Therapies

Symptomatic Symptomatic
PEEP ventilation +
Hemodialysis Mediator Regulation (HF)
- Removal of inflammatory mediators
persistant SIRS - Fluid balance control
- Metabolic status control

MODS CHANGE IN MORTALITY ?

 CONVECTIVE
CONVECTIVE ELIMINATION
ELIMINATION OF
OF
CYTOKINES
CYTOKINES

The concept of “the tip of the iceberg” (JM Cavaillon) :

• Plasma elevation of cytokines ==> saturation of :
• Origin cells
• Target cells
• Extracellular compartment

• Plasma removal may have then small effect in

term of tissue/cell levels of cytokines
 CONVECTIVE
CONVECTIVE ELIMINATION
ELIMINATION OF
OF
CYTOKINES
CYTOKINES
• No drop in serum levels of IL except IL-1

• More rapid production than elimination

• Shift of IL from the tissues to the serum

• High volume hemofiltration ?

• Coupled HVHF + HADsorption ?

 Elimination of inflammatory mediators by
mediator elimination
hemofiltration
change study ref.

Bacterial toxins :
Endotoxin Adsorption  Ex-vivo, An. Vanholder,
Matéo
Lipid A Adsorption ? Ex-vivo Dinarello
Anaphylatoxins :
C3a Filtration  Human Hoffmann
C5a Adsorption  Human Hoffmann
Arachidonic acid derivatives :
TxB2 Filtration  Animal Heidemann
6-keto PGF2 Filtration  An. Hum Heideman,Staubach
Cytokines :
TNF no = Human
IL-1b Filtration = Human Bellomo, Hoffmann
IL-6 no = Human Hoffmann,Millar
IL-8 Filtration ? Human Hoffmann,Millar
Myocardial depressing factor :
Filtration ? An. Hum. Coraim,Gomez,Hallström
 High
High volume
volume HF HF in
in severe
severe sepsis
sepsis
(P
(P Honoré
Honoré et
et al
al .. Hop
Hop St
St Pierre)
Pierre) (in
(in press
press CCM)
CCM)

• 20 Pts in refractory shock (PA<55mmHG, + Adre/Nor + Met

acidosis <7.15; SIRS 3 to 4; +/- renal failure)

• Technique: HVHF, PAN; 4 hrs at 35 l/hr; Post-dilution

technique followed by LVHF (2 l/hr).

• Goals: Responders ==> + 2 hrs increase about 50% for

CO + 25% SvO2; + 4 hrs pHa > 7.3; Reduction 50%
vasoactive drugs.

• Results: 11 responders; 9 survivors; 1 died from MOSF and 1

from Nosoc Infect; the non responders died at 80%
 How to limit adverse effects ?

 Adequate biocompatibility
– blood - membrane interaction
– induction of chronic inflammatory reaction
 Substrate losses (glucose, amino-acids, ...)
 Hormones losses
 Heat loss
 Catheter-associated complications/infections
 Costs
 Need for prolonged anticoagulation
coating systems
 CONTROL STUDIES

• Substances involved ?
• Mechanisms of the inflammatory reaction ?
• Before or after renal failure appearance?
• End-points : mortality ? Organ failure ?
Cost/benefit ?

design?????
 PERSPECTIVES
Materials
• Enhanced adsorption
• Definitions of cut-offs for specific
molecules
• Selective or non-selective removal
• Anticoagulation coating systems
 "Facteur Dépresseur Myocardique"
L'ultrafiltrat des animaux septiques
provoque :
• in vivo un état de choc • Au cours de l'insuffisance
ou des effets cardiaque ; Coraim et al, 1995
comparables à
l'endotoxinémie.
• Au cours du choc septique ;
Parillo et al , 1985; Gomez et
• in vitro ou ex vivo une
al, 1990; Grootendorst et a l,
dépression de la 1993; Lee et al, 1993
contraction des fibres
myocardiques isolées • Amélioration de la survie
proportinnelle à la fraction
filtrée, Lee et al, 1993
 Initial insult from Bone
Local Local
pro-inflammatory
(bacterial, viral, anti-inflammatory
response traumatic, thermal) response

Systemic spillover of Systemic spillover of

pro-inflammatory mediators anti-inflammatory mediators

Systemic reaction
SIRS (pro-inflammatory)
CRRT????
CARS (anti-inflammatory)
MARS (mixed)

C S
H A O
Cardiovascular Suppression
Homeo- Apoptosis Organ of the
compromise stasis (cell death) dysfunction
(shock) immune
CARS and Death with SIRS system
SIRS SIRS minimal predominates
predominates CARS
balanced inflammation predominates
 Hemodiafiltration
The use of hemodialysis, hemofiltration and ultrafiltration
 Dialysis
The use of diffusion (dialysis fluid) to achieve clerance
Slow Continuous Ultrafiltration
The removal of plasma water (ultrafiltrate)
using pressures
 Hemofiltration
Use of convection (solute drag)
to remove small and middle molecules
Table 1.

Multiflow 60 Pre-set
Solute K under various conditions

K delivered t o t he pat ient

Q uf
Qd (mL/ h)
(mL/ h) 0 1000 2000
0 15. 5 ± 0. 3 28. 5 ± 0. 8
14. 8 ± 0. 2 26. 3 ± 1. 1
14. 9 ± 0. 1 26. 2 ± 0. 9
15. 6 ± 0. 1 27. 2 ± 0. 8
7. 7 ± 1. 6 17. 4 ± 0. 7
500 8. 6 ± 0. 2 23. 2 ± 1. 0 35. 1 ± 1. 0
8. 5 ± 0. 3 21. 9 ± 0. 4 31. 9 ± 1. 6
8. 5 ± 0. 1 21. 8 ± 0. 7 31. 6 ± 1. 1
8. 9 ± 0. 1 22. 4 ± 0. 7 32. 5 ± 1. 4
5. 3 ± 0. 7 9. 3 ± 1. 3 15. 0 ± 1. 1
1000 17. 3 ± 0. 2 29. 8 ± 1. 6 40. 9 ± 0. 4
16. 6 ± 0. 8 28. 0 ± 0. 7 36. 5 ± 2. 1
16. 3 ± 0. 3 27. 1 ± 1. 3 35. 1 ± 1. 3
17. 0 ± 0. 3 28. 1 ± 1. 3 36. 2 ± 1. 2
7. 6 ± 0. 7 10. 7 ± 1. 5 15. 0 ± 1. 1
1500 25. 6 ± 0. 6 37. 8 ± 1. 8 47. 9 ± 2. 0
23. 7 ± 1. 2 33. 7 ± 2. 0 40. 7 ± 2. 2
22. 7 ± 0. 5 31. 8 ± 1. 5 37. 4 ± 2. 2
23. 9 ± 0. 7 33. 2 ± 1. 5 39. 7 ± 2. 4
8. 1 ± 1. 1 11. 8 ± 1. 8 14. 6 ± 0. 5
2000 33. 1 ± 0. 9 43. 8 ± 2. 0 51. 6 ± 1. 8
30. 1 ± 1. 5 37. 9 ± 1. 4 43. 3 ± 2. 9
27. 4 ± 0. 8 35. 0 ± 2. 2 40. 6 ± 2. 2
29. 2 ± 1. 3 36. 7 ± 2. 2 41. 8 ± 1. 5
8. 3 ± 0. 8 11. 6 ± 1. 3 15. 4 ± 1. 0
2500 40. 0 ± 0. 4 49. 0 ± 1. 9 56. 0 ± 1. 4
35. 1 ± 1. 4 41. 8 ± 1. 4 46. 8 ± 2. 5
31. 7 ± 0. 7 37. 6 ± 2. 9 42. 5 ± 1. 8
33. 5 ± 1. 6 40. 9 ± 2. 9 44. 9 ± 0. 8
8. 0 ± 0. 7 11. 7 ± 0. 5 14. 0 ± 1. 1
K ( mL/min) ; Solutes : Ur ea
Mean Ht: 0.273 ± 0.016 C r eatinine
Mean s er um tot. pr ot.: 55.2 ± 8.4 Ur ates
( n = 5 patients ) PO4
β 2 -M