HFCRevCCCourseMcGill2000.ppt

1. 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

2. Content
• Physical principles
• Definitions
• Techniques
• Clinical issues
• Supportive therapy or active therapy?
–Sepsis an example
–Why?
–How?
–For what goal?

3. PHYSICAL PRINCIPLES
& DEFINITIONS

4. <30 000 Da
>30 000 Da
<65 000 Da
>65000 Da
PTM
Clearance =(C uf/C I) * Quf
Quf = C H2O x S x Ptm
All molecules lower than
Pore diam cross the Mbne
CONVECTION

5. <30 000 Da
>30 000 Da
<65 000 Da
>65000 Da
PTM
Clearance =(C uf/C I) * Quf
Quf = C H2O x S x Ptm
All molecules lower than
Pore diam cross the Mbne
CONVECTION

6. <30 000 Da
>30 000 Da
<65 000 Da
>65000 Da
PTM
Clearance =(C uf/C I) * Quf
Quf = C H2O x S x Ptm
All molecules lower than
Pore diam cross the Mbne
CONVECTION

7. <30 000 Da
>30 000 Da
<65 000 Da
>65000 Da
PTM
Clearance =(C uf/C I) * Quf
Quf = C H2O x S x Ptm
All molecules lower than
Pore diam cross the Mbne
CONVECTION

8. <30 000 Da
>30 000 Da
<65 000 Da
>65000 Da
Cd <<< Csang
Pdialysat = P blood
Progressive equilibrium
of the [plasma] and [dial]
ONLY SMALL MOLECULES
CROSS THE MBNE
DIFFUSION

9. <30 000 Da
>30 000 Da
<65 000 Da
>65000 Da
Cd <<< Csang
Progressive equilibrium
of the [plasma] and [dial]
ONLY SMALL MOLECULES
CROSS THE MBNE
DIFFUSION
Pdialysat = P blood

10. <30 000 Da
>30 000 Da
<65 000 Da
>65000 Da
Cd << Csang
Progressive equilibrium
of the [plasma] and [dial]
ONLY SMALL MOLECULES
CROSS THE MBNE
DIFFUSION
Pdialysat = P blood

11. <30 000 Da
>30 000 Da
<65 000 Da
>65000 Da
Cd < Csang
Progressive equilibrium
of the [plasma] and [dial]
ONLY SMALL MOLECULES
CROSS THE MBNE
DIFFUSION
Pdialysat = P blood

12. <30 000 Da
>30 000 Da
<65 000 Da
>65000 Da
Filtration
substitution
Blood
FILTRATION RATE
0 TO 2 L/Hr
SCUF& CVVH

13. 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)

14. SCUF
Slow Continuous
Ultrafiltration
Maximum Pt. Fluid removal rate = 2000 ml/h
Therapy options
P
R
I
S
M
A
S
Access
Return
Effluent

15. CVVH
Continuous
Veno-Venous
Hemofiltration
Maximum Pt. Fluid removal rate = 1000 ml/h
Therapy options
P
R
I
S
M
A
S
Access
Return
Effluent
Replacement

16. CVVHD
Continuous
Veno-Venous
Hemodialysis
Maximum Pt. fluid removal rate = 1000 ml/h
Therapy Options
P
R
I
S
M
A
S
Access
Return
Effluent
Dialysate

17. CVVHDF
Continuous
Veno-Venous
Hemodiafiltration
Maximum Pt. Fluid removal rate = 1000 ml/h
Therapy options
Replacement
P
R
I
S
M
A
S
Access
Return
Effluent
Dialysate

18. EFFICIENCY

19. Table 2.
Multiflow 100 Pre-set
Solute K under various conditions
K delivered to the patient
Qd
Quf
(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: Urea
M
ean Ht: 0.287 ± 0.027 Creatinine
M
ean serum tot. prot.: 45.6 ± 5.9 Urates
(n = 5 patients) PO4
b 2 -M

20. CLINICAL ISSUES

21. 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

22. CRRT AND INFLAMMATION
Sepsis an example

23. HYPOTHESIS FOR MODS
PREVENTION
• Control of tissue edema
• EDTX adsorption
• Immunomodulation

24. CAVH after Staph Aureus in swine
(Lee PA et al; Crit Care Med 1993; 21: 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

25. CAVH after Staph Aureus in swine
(Lee PA et al; Crit Care Med 1993; 21: 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

26. 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

27. 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

28. EDTX & HEMOFILTRATION :
In vivo experimental 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.

29. From Mateo et al AJR&CCM 1996 (Abst)
180
150
120
90
60
30
0
50
60
70
80
90
100
110
LPS
HAD + LPS
Aortic Blood Flow Velocity (%)
TIME (min)
* *
* * *
*
180
150
120
90
60
30
0
50
60
70
80
90
100
110
LPS
HAD + LPS
Mean Arterial Pressure (%)
TIME (min)

30. From Mateo et al AJR&CCM 1996 (Abst)
0 30 60 120 180
0
1000
2000
3000
4000
5000
6000
LPS + HAD
LPS
TIME (min)
TNF-  levels
*
*
*
*
* p < 0,05
( U.I / ML)
6000
8000
10000
LPS
LPS + HAD
(E.U / ML)
0 10 60 120 180
0
2000
4000
TIME (min)
* *
3000
1000
EDTX levels

31. From Mateo et al AJ R&CCM 1996 (Abst)
0
20
40
60
80
100
120
140
160
180
1
Co ntro l
EDTX
EDTX + HAD
10-9M 10-8M 10-7M 10-6M 10-5M
%
of
KCl
*
*
*
NE

32. – 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
PRITONITIS
A. DiScipio et al, Am J Surg. 173; 1997

33. 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

34. Extensive activation of inflammatory responses
mediators
• vasoactive
• cardiodepressant
organ dysfunction
Supportive Therapies
Symptomatic Symptomatic
+
Mediator Regulation (HF)
- Removal of inflammatory mediators
- Fluid balance control
- Metabolic status control
CHANGE IN MORTALITY ?
PEEP ventilation
Hemodialysis
persistant SIRS
MODS

35. CONVECTIVE ELIMINATION OF
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

36. CONVECTIVE ELIMINATION OF
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 ?

37. Elimination of inflammatory mediators by hemofiltration
mediator elimination 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

38. High volume HF in severe sepsis
(P Honoré et al . Hop St Pierre) (in press 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%

39.  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
How to limit adverse effects ?

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

41. PERSPECTIVES
• Enhanced adsorption
• Definitions of cut-offs for specific
molecules
• Selective or non-selective removal
• Anticoagulation coating systems
Materials

43. "Facteur Dépresseur Myocardique"
L'ultrafiltrat des animaux septiques
provoque :
• in vivo un état de choc
ou des effets
comparables à
l'endotoxinémie.
• in vitro ou ex vivo une
dépression de la
contraction des fibres
myocardiques isolées
• Au cours de l'insuffisance
cardiaque ; Coraim et al, 1995
• Au cours du choc septique ;
Parillo et al , 1985; Gomez et
al, 1990; Grootendorst et a l,
1993; Lee et al, 1993
• Amélioration de la survie
proportinnelle à la fraction
filtrée, Lee et al, 1993

44. Systemic reaction
SIRS (pro-inflammatory)
CARS (anti-inflammatory)
MARS (mixed)
Local
pro-inflammatory
response
Local
anti-inflammatory
response
Systemic spillover of
pro-inflammatory mediators
Systemic spillover of
anti-inflammatory mediators
Initial insult
(bacterial, viral,
traumatic, thermal)
C
Cardiovascular
compromise
(shock)
SIRS
predominates
H
Homeo-
stasis
CARS and
SIRS
balanced
A
Apoptosis
(cell death)
Death with
minimal
inflammation
O
Organ
dysfunction
SIRS
predominates
S
Suppression
of the
immune
system
CARS
predominates
from Bone
CRRT????

45. Hemodiafiltration
The use of hemodialysis, hemofiltration and ultrafiltration

46. Dialysis
The use of diffusion (dialysis fluid) to achieve clerance

47. Slow Continuous Ultrafiltration
The removal of plasma water (ultrafiltrate)
using pressures

48. Hemofiltration
Use of convection (solute drag)
to remove small and middle molecules

49. Table 1.
Multiflow 60 Pre-set
Solute K under various conditions
K delivered to the patient
Qd
Quf
(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: Urea
Mean Ht: 0.273 ± 0.016 Creatinine
Mean serum tot. prot.: 55.2 ± 8.4 Urates
(n = 5 patients) PO4
b 2 -M