Continuous Renal Replacement Therapy

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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

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Content

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

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PHYSICAL PRINCIPLES DEFINITIONS
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PTM
lt30 000 Da
gt30 000 Dalt65 000 Da
gt65000 Da
CONVECTION
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PTM
lt30 000 Da
gt30 000 Dalt65 000 Da
gt65000 Da
CONVECTION
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PTM
lt30 000 Da
gt30 000 Dalt65 000 Da
gt65000 Da
CONVECTION
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PTM
lt30 000 Da
gt30 000 Dalt65 000 Da
gt65000 Da
CONVECTION
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Pdialysat P blood
Cd ltltlt Csang
lt30 000 Da
Progressive equilibrium of the plasma and
dial ONLY SMALL MOLECULES CROSS THE MBNE
gt30 000 Dalt65 000 Da
gt65000 Da
DIFFUSION
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Pdialysat P blood
Cd ltltlt Csang
lt30 000 Da
gt30 000 Dalt65 000 Da
gt65000 Da
DIFFUSION
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Pdialysat P blood
Cd ltlt Csang
lt30 000 Da
gt30 000 Dalt65 000 Da
gt65000 Da
DIFFUSION
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Pdialysat P blood
Cd lt Csang
lt30 000 Da
gt30 000 Dalt65 000 Da
gt65000 Da
DIFFUSION
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substitution
FILTRATION RATE 0 TO 2 L/Hr
Filtration
lt30 000 Da
gt30 000 Dalt65 000 Da
gt65000 Da
SCUF CVVH
Blood
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DEFINITIONSBELLOMO et al. Am J Kidney Dis, 28,
(Suppl 3) 1996

• SCUF Use only for fluid control in overhydrated
  status
• CVVHThe 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)

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Therapy options
SCUFSlow Continuous Ultrafiltration
Maximum Pt. Fluid removal rate 2000 ml/h
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Therapy options
CVVHContinuous Veno-Venous Hemofiltration
Maximum Pt. Fluid removal rate 1000 ml/h
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Therapy Options
CVVHDContinuous Veno-Venous Hemodialysis
Maximum Pt. fluid removal rate 1000 ml/h
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Therapy options
CVVHDFContinuous Veno-Venous Hemodiafiltration
Replacement
Maximum Pt. Fluid removal rate 1000 ml/h
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EFFICIENCY
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CLINICAL ISSUES
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CLINICAL INDICATIONS

• IHD vs CRRT no randomized trials but
  inferiority of IHD manisfests itself at many
  levels.
• Hemodynamic stability Hypotension, volume control
• Uremic control gt 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

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CRRT AND INFLAMMATIONSepsis an example
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HYPOTHESIS FOR MODS PREVENTION

• Control of tissue edema
• EDTX adsorption
• Immunomodulation

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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
  (n65)
• 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

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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

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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
• gt other mechanisms than water balance

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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
  gt removal of cardio-depressive substances

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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.

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From Mateo et al AJRCCM 1996 (Abst)
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From Mateo et al AJRCCM 1996 (Abst)
(E.U / ML)
EDTX levels
10000
TNF- ? levels
( U.I / ML)
8000
LPS
6000

LPS HAD
p lt 0,05
4000
3000
2000


1000



0
TIME (min)
TIME (min)
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From Mateo et al AJ RCCM 1996 (Abst)
NE
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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

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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

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Extensive activation of inflammatory responses

• mediators

• vasoactive

• cardiodepressant

organ dysfunction
Supportive Therapies
Symptomatic
Symptomatic Mediator Regulation (HF)
PEEP ventilation Hemodialysis
- Removal of inflammatory mediators - Fluid
balance control - Metabolic status control
persistant SIRS
MODS
CHANGE IN MORTALITY ?
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CONVECTIVE ELIMINATION OF CYTOKINES

• The concept of the tip of the iceberg (JM
  Cavaillon)
• Plasma elevation of cytokines gt saturation of
  
• Origin cells
• Target cells
• Extracellular compartment
• Plasma removal may have then small effect in
• term of tissue/cell levels of cytokines

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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 ?

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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

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

• 20 Pts in refractory shock (PAlt55mmHG,
  Adre/Nor Met
• acidosis lt7.15 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 gt 2 hrs increase about 50
  for
• CO 25 SvO2 4 hrs pHa gt 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

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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

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CONTROL STUDIES

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

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PERSPECTIVES
Materials

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

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"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

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Initial insult (bacterial, viral, traumatic,
thermal)
from Bone
Local anti-inflammatory response
Local pro-inflammatory response
Systemic spillover of pro-inflammatory mediators
Systemic spillover of anti-inflammatory mediators
CRRT????
S Suppression of the immune system CARS predomin
ates
O Organ dysfunction SIRS predominates
H Homeo- stasis CARS and SIRS balanced
A Apoptosis (cell death) Death
with minimal inflammation
C Cardiovascular compromise (shock) SIRS predomin
ates
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Hemodiafiltration The use of hemodialysis,
hemofiltration and ultrafiltration
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Dialysis The use of diffusion (dialysis fluid) to
achieve clerance
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Slow Continuous Ultrafiltration The removal of
plasma water (ultrafiltrate) using pressures
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Hemofiltration Use of convection (solute drag)
to remove small and middle molecules
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