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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

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Continuous renal replacement therapy
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
Content

  • Physical principles

  • Definitions

  • Techniques

  • Clinical issues

  • Supportive therapy or active therapy?

    • Sepsis an example

    • Why?

    • How?

    • For what goal?


Physical principles definitions

PHYSICAL PRINCIPLES& DEFINITIONS


Clearance =(C uf/C I) * Quf

Quf = C H2O x S x Ptm

All molecules lower than

Pore diam cross the Mbne

PTM

<30 000 Da

>30 000 Da<65 000 Da

>65000 Da

CONVECTION


Clearance =(C uf/C I) * Quf

Quf = C H2O x S x Ptm

All molecules lower than

Pore diam cross the Mbne

PTM

<30 000 Da

>30 000 Da<65 000 Da

>65000 Da

CONVECTION


Clearance =(C uf/C I) * Quf

Quf = C H2O x S x Ptm

All molecules lower than

Pore diam cross the Mbne

PTM

<30 000 Da

>30 000 Da<65 000 Da

>65000 Da

CONVECTION


Clearance =(C uf/C I) * Quf

Quf = C H2O x S x Ptm

All molecules lower than

Pore diam cross the Mbne

PTM

<30 000 Da

>30 000 Da<65 000 Da

>65000 Da

CONVECTION


Pdialysat = P blood

Cd <<< Csang

<30 000 Da

Progressive equilibrium

of the [plasma] and [dial]

ONLY SMALL MOLECULES

CROSS THE MBNE

>30 000 Da<65 000 Da

>65000 Da

DIFFUSION


Progressive equilibrium

of the [plasma] and [dial]

ONLY SMALL MOLECULES

CROSS THE MBNE

Pdialysat = P blood

Cd <<< Csang

<30 000 Da

>30 000 Da<65 000 Da

>65000 Da

DIFFUSION


Progressive equilibrium

of the [plasma] and [dial]

ONLY SMALL MOLECULES

CROSS THE MBNE

Pdialysat = P blood

Cd << Csang

<30 000 Da

>30 000 Da<65 000 Da

>65000 Da

DIFFUSION


Progressive equilibrium

of the [plasma] and [dial]

ONLY SMALL MOLECULES

CROSS THE MBNE

Pdialysat = P blood

Cd < Csang

<30 000 Da

>30 000 Da<65 000 Da

>65000 Da

DIFFUSION


substitution

FILTRATION RATE

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

DEFINITIONSBELLOMO 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)


Access

Return

P

R

I

S

M

A

S

Effluent

Therapy options

SCUFSlow Continuous

Ultrafiltration

Maximum Pt. Fluid removal rate = 2000 ml/h


Access

Return

P

R

I

S

M

A

Replacement

S

Effluent

Therapy options

CVVHContinuous

Veno-Venous

Hemofiltration

Maximum Pt. Fluid removal rate = 1000 ml/h


Access

Dialysate

Return

P

R

I

S

M

A

S

Effluent

Therapy Options

CVVHDContinuous

Veno-Venous

Hemodialysis

  • Maximum Pt. fluid removal rate = 1000 ml/h


Access

Dialysate

Return

P

R

I

S

M

A

S

Effluent

Therapyoptions

CVVHDFContinuous

Veno-Venous

Hemodiafiltration

  • Replacement

Maximum Pt. Fluid removal rate = 1000 ml/h




Clinical indications
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

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 9241
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 in vivo experimental studies
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.


From mateo et al ajr ccm 1996 abst

Mean Arterial Pressure (%)

Aortic Blood Flow Velocity (%)

*

110

110

*

*

*

*

*

100

100

90

90

80

80

70

70

HAD + LPS

HAD + LPS

LPS

60

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)


From mateo et al ajr ccm 1996 abst1

6000

5000

4000

LPS

LPS + HAD

3000

2000

1000

0

0

10

60

120

180

0

30

60

120

180

From Mateo et al AJR&CCM 1996 (Abst)

(E.U / ML)

EDTX levels

10000

TNF-levels

( U.I / ML)

8000

LPS

6000

*

LPS + HAD

* p < 0,05

4000

3000

2000

*

*

1000

*

*

*

0

TIME (min)

TIME (min)


From mateo et al aj r ccm 1996 abst

1

8

0

% of KCl

1

6

0

*

1

4

0

1

2

0

1

0

0

C

o

n

t

r

o

l

8

0

E

D

T

X

*

6

0

E

D

T

X

+

H

A

D

4

0

*

2

0

0

1

10-9M 10-8M 10-7M 10-6M 10-5M

From Mateo et al AJ R&CCM 1996 (Abst)

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


Extensive activation of inflammatory responses
Extensive activation of inflammatory responses PERITONITIS (

  • vasoactive

  • cardiodepressant

mediators

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 ?


Convective elimination of cytokines
CONVECTIVE ELIMINATION OF CYTOKINES PERITONITIS (

  • 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 cytokines1
CONVECTIVE ELIMINATION OF CYTOKINES PERITONITIS (

  • 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 hemofiltration
Elimination of inflammatory mediators by hemofiltration PERITONITIS (

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


High volume hf in severe sepsis p honor et al hop st pierre in press ccm
High volume HF in severe sepsis PERITONITIS ((P Honoré et al . Hop St Pierre) (in press CCM)

  • 20 Ptsin 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
How to limit adverse effects ? PERITONITIS (

  • 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
CONTROL STUDIES PERITONITIS (

  • Substances involved ?

  • Mechanisms of the inflammatory reaction ?

  • Before or after renal failure appearance?

  • End-points : mortality ? Organ failure ? Cost/benefit ?

    design?????


Perspectives
PERSPECTIVES PERITONITIS (

Materials

  • Enhanced adsorption

  • Definitions of cut-offs for specific molecules

  • Selective or non-selective removal

  • Anticoagulation coating systems


Facteur d presseur myocardique l ultrafiltrat des animaux septiques provoque

in vivo PERITONITIS (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

"Facteur Dépresseur Myocardique"L'ultrafiltrat des animaux septiques provoque :


Systemic reaction PERITONITIS (

SIRS (pro-inflammatory)

CARS (anti-inflammatory)

MARS (mixed)

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

  • predominates

  • 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

predominates


Hemodiafiltration PERITONITIS (

The use of hemodialysis, hemofiltration and ultrafiltration


Dialysis PERITONITIS (

The use of diffusion (dialysis fluid) to achieve clerance


Slow Continuous Ultrafiltration PERITONITIS (

The removal of plasma water (ultrafiltrate)

using pressures


Hemofiltration PERITONITIS (

Use of convection (solute drag)

to remove small and middle molecules


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