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Continuous Renal Replacement Therapy
Annual Refresher Course in CRITICAL CARE
McGillCourse 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?
<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 thanPore diam cross the Mbne
CONVECTION
<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 thanPore diam cross the Mbne
CONVECTION
<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 thanPore diam cross the Mbne
CONVECTION
<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 thanPore diam cross the Mbne
CONVECTION
<30 000 Da
>30 000 Da<65 000 Da
>65000 Da
Cd <<< Csang
Pdialysat = P blood
Progressive equilibriumof the [plasma] and [dial]
ONLY SMALL MOLECULESCROSS THE MBNE
DIFFUSION
<30 000 Da
>30 000 Da<65 000 Da
>65000 Da
Cd <<< Csang
Progressive equilibriumof the [plasma] and [dial]
ONLY SMALL MOLECULESCROSS THE MBNE
DIFFUSION
Pdialysat = P blood
<30 000 Da
>30 000 Da<65 000 Da
>65000 Da
Cd << Csang
Progressive equilibriumof the [plasma] and [dial]
ONLY SMALL MOLECULESCROSS THE MBNE
DIFFUSION
Pdialysat = P blood
<30 000 Da
>30 000 Da<65 000 Da
>65000 Da
Cd < Csang
Progressive equilibriumof the [plasma] and [dial]
ONLY SMALL MOLECULESCROSS THE MBNE
DIFFUSION
Pdialysat = P blood
<30 000 Da
>30 000 Da<65 000 Da
>65000 Da
Filtration
substitution
Blood
FILTRATION RATE0 TO 2 L/Hr
SCUF& CVVH
DEFINITIONSBELLOMO et al. Am J Kidney Dis, 28, (Suppl 3) 1996
• SCUFSCUF: Use only for fluid control in overhydrated status
• CVVHCVVH: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
• CVVHDCVVHD: continuous hemodialysis. + countercurrent flow of dialysis solution. Both diffusion & convection Efficiency is limited to small molecules (low Perm filter)
• CVVHDFCVVHDF: same. Both diffusion & convection but higher dialysate flow (High Perm filter)
SCUFSlow ContinuousUltrafiltration
Maximum Pt. Fluid removal rate = 2000 ml/h
Therapy options
PRISMA
S
Access
Return
Effluent
CVVHContinuousVeno-Venous Hemofiltration
Maximum Pt. Fluid removal rate = 1000 ml/h
Therapy options
PRISMA
S
Access
Return
Effluent
Replacement
CVVHDContinuousVeno-VenousHemodialysis
Maximum Pt. fluid removal rate = 1000 ml/h
Therapy Options
PRISMA
S
Access
Return
Effluent
Dialysate
CVVHDFContinuousVeno-VenousHemodiafiltration
Maximum Pt. Fluid removal rate = 1000 ml/h
Therapy options
Replacement
PRISMA
S
Access
Return
Effluent
Dialysate
Table 2.
Multiflow 100 Pre-set
Solute K under various conditions
K delivered to the patient
QdQuf
(mL/h)
(mL/h) 0 1000 2000
0 15.3 ± 0.7 28.7 ± 0.7
15.0 ± 0.8 26.3 ± 1.114.8 ± 0.3 25.5 ± 1.0
14.4 ± 0.6 24.4 ± 1.55.6 ± 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 ± 1.18.4 ± 0.2 21.9 ± 0.5 32.7 ± 1.2
8.4 ± 0.2 21.5 ± 1.6 34.5 ± 2.54.8 ± 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 ± 3.316.6 ± 0.5 28.9 ± 1.1 38.4 ± 3.4
16.9 ± 0.7 28.6 ± 1.6 37.9 ± 2.39.1 ± 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 ± 1.224.6 ± 0.6 34.3 ± 1.1 42.0 ± 1.2
24.8 ± 1.0 33.9 ± 1.4 39.5 ± 4.911.3 ± 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 ± 3.331.4 ± 1.2 39.7 ± 1.4 46.4 ± 3.2
32.0 ± 1.9 39.9 ± 2.5 43.9 ± 3.912.4 ± 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 ± 3.137.4 ± 1.6 43.9 ± 2.0 50.9 ± 5.3
38.8 ± 2.5 43.2 ± 3.8 53.5 ± 3.114.6 ± 1.3 16.1 ± 1.8 20.5 ± 4.3
K (mL/min); Solutes: Urea
Mean Ht: 0.287 ± 0.027 Creatinine
Mean serum tot. prot.: 45.6 ± 5.9 Urates
(n = 5 patients) PO4
β2 -M
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
HYPOTHESIS FOR MODS PREVENTION
HYPOTHESIS FOR MODS PREVENTION
• Control of tissue edema
• EDTX adsorption
• Immunomodulation
CAVH after Staph Aureus in swine(Lee PA et al; Crit Care Med 1993; 21: 914-924)
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
CAVH after Staph Aureus in swine(Lee PA et al; Crit Care Med 1993; 21: 914-924)
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
EDTX & HEMOFILTRATION :In vivo experimental studies (1)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)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 & HEMOFILTRATION :EDTX & HEMOFILTRATION :In vivo experimental studiesIn vivo experimental studies
EDTX & HEMOFILTRATION :EDTX & HEMOFILTRATION :In vivo experimental studiesIn 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.
From Mateo et al AJR&CCM 1996 (Abst)From Mateo et al AJR&CCM 1996 (Abst)
1801501209060300
50
60
70
80
90
100
110
LPS
HAD + LPS
Aortic Blood Flow Velocity (%)
TIME (min)
* ** * *
*
1801501209060300
50
60
70
80
90
100
110
LPS
HAD + LPS
Mean Arterial Pressure (%)
TIME (min)
From Mateo et al AJR&CCM 1996 (Abst)From Mateo et al AJR&CCM 1996 (Abst)
0 30 60 120 1800
1000
2000
3000
4000
5000
6000
LPS + HAD
LPS
TIME (min)
TNF- levels
*
*
**
* p < 0,05
( U.I / ML)
6000
8000
10000
LPSLPS + HAD
(E.U / ML)
0 10 60 120 1800
2000
4000
TIME (min)
* *
3000
1000
EDTX levels
From From Mateo et al Mateo et al AJ R&CCM 1996 (Abst)AJ R&CCM 1996 (Abst)From From Mateo et al Mateo et al AJ R&CCM 1996 (Abst)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
– 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 PHAGOCYTOSISCAVH ATTENUATES PMN PHAGOCYTOSIS
IN PORCINE MODEL OFIN PORCINE MODEL OF
PRITONITISPRITONITISA. DiScipio et al, Am J Surg. 173; 1997
CAVH ATTENUATES PMN PHAGOCYTOSIS IN PORCINE MODEL OF PERITONITIS (A. DiScipio
et al, Am J Surg. 173; 1997)
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 ± 13.8Change in PhagocytosisRateFrom Baseline CAVH No CAVH
0 -6 ± 3.9 10 ± 5.2 8 ± 4.9 0 25 ± 3.2= 19 ± 9.3 12 ± 15.5
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 ventilationHemodialysis
persistant SIRS
MODS
CONVECTIVE ELIMINATION OF CONVECTIVE ELIMINATION OF CYTOKINESCYTOKINES
CONVECTIVE ELIMINATION OF CONVECTIVE ELIMINATION OF CYTOKINESCYTOKINES
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 ELIMINATION OF CONVECTIVE ELIMINATION OF CYTOKINESCYTOKINES
CONVECTIVE ELIMINATION OF CONVECTIVE ELIMINATION OF CYTOKINESCYTOKINES
• 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 hemofiltrationmediator 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
High volume HF in severe sepsisHigh volume HF in severe sepsis(P Honoré et al . Hop St Pierre) (in press CCM)(P Honoré et al . Hop St Pierre) (in press CCM)
High volume HF in severe sepsisHigh volume HF in severe sepsis(P Honoré et al . Hop St Pierre) (in press CCM)(P Honoré et al . Hop St Pierre) (in press CCM)
• 20 Pts in refractory shock (PA<55mmHG, + Adre/Nor + Metacidosis <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%
Adequate biocompatibility– blood - membrane interaction
– induction of chronic inflammatory reaction
Substrate losses (glucose, amino-acids, ...)Hormones lossesHeat lossCatheter-associated complications/infectionsCostsNeed for prolonged anticoagulation
coating systems
How to limit adverse effects ?How to limit adverse effects ?
CONTROL STUDIES
• Substances involved ?
• Mechanisms of the inflammatory reaction ?
• Before or after renal failure appearance?
• End-points : mortality ? Organ failure ? Cost/benefit ?
design?????
PERSPECTIVESPERSPECTIVES
• Enhanced adsorption
• Definitions of cut-offs for specific molecules
• Selective or non-selective removal
• Anticoagulation coating systems
Materials
"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
Systemic reactionSIRS (pro-inflammatory)
CARS (anti-inflammatory)
MARS (mixed)
Local pro-inflammatory
response
Local anti-inflammatory
response
Systemic spillover ofpro-inflammatory mediators
Systemic spillover ofanti-inflammatory mediators
Initial insult(bacterial, viral,traumatic, thermal)
C
Cardiovascularcompromise
(shock)SIRS
predominates
H
Homeo-stasis
CARS andSIRS
balanced
A
Apoptosis (cell death)Death with
minimalinflammation
O
Organdysfunction
SIRSpredominates
S
Suppressionof the
immunesystemCARS
predominates
from Bone
CRRT????
Table 1.
Multiflow 60 Pre-set
Solute K under various conditions
K delivered to the patient
QdQuf
(mL/h)
(mL/h) 0 1000 2000
0 15.5 ± 0.3 28.5 ± 0.8
14.8 ± 0.2 26.3 ± 1.114.9 ± 0.1 26.2 ± 0.9
15.6 ± 0.1 27.2 ± 0.87.7 ± 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 ± 1.68.5 ± 0.1 21.8 ± 0.7 31.6 ± 1.1
8.9 ± 0.1 22.4 ± 0.7 32.5 ± 1.45.3 ± 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 ± 2.116.3 ± 0.3 27.1 ± 1.3 35.1 ± 1.3
17.0 ± 0.3 28.1 ± 1.3 36.2 ± 1.27.6 ± 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 ± 2.222.7 ± 0.5 31.8 ± 1.5 37.4 ± 2.2
23.9 ± 0.7 33.2 ± 1.5 39.7 ± 2.48.1 ± 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 ± 2.927.4 ± 0.8 35.0 ± 2.2 40.6 ± 2.2
29.2 ± 1.3 36.7 ± 2.2 41.8 ± 1.58.3 ± 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 ± 2.531.7 ± 0.7 37.6 ± 2.9 42.5 ± 1.8
33.5 ± 1.6 40.9 ± 2.9 44.9 ± 0.88.0 ± 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
β2 -M