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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 - PowerPoint PPT Presentation
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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?
PHYSICAL PRINCIPLES& DEFINITIONS
<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
EFFICIENCY
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 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 INFLAMMATIONSepsis an example
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????
HemodiafiltrationThe use of hemodialysis, hemofiltration and ultrafiltration
DialysisThe use of diffusion (dialysis fluid) to achieve clerance
Slow Continuous UltrafiltrationThe 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 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