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