limmunonutrition entérale en réanimation... du concept au concret limmunonutrition entérale en...

L’immunonutrition entérale L’immunonutrition entérale en Réanimation ...en Réanimation ...

Du concept au concretDu concept au concret

G. NitenbergG. Nitenberg DAR et Pathologie InfectieuseDAR et Pathologie Infectieuse

Institut Gustave Roussy - Villejuif - FranceInstitut Gustave Roussy - Villejuif - France

Multiple Organ DysfunctionMultiple Organ Dysfunction Multiple Organ DysfunctionMultiple Organ Dysfunction

LiverLiverLiverLiverinjuryinjuryinjuryinjury

SystemicSystemic InjuryInjurySystemicSystemic InjuryInjury

GutGutGutGut

Gut HypothesisGut HypothesisGut HypothesisGut Hypothesis

1) Hepatocellular1) Hepatocellular1) Hepatocellular1) Hepatocellular2) Macrophage mediated2) Macrophage mediated2) Macrophage mediated2) Macrophage mediated

1) Malnutrition1) Malnutrition1) Malnutrition1) Malnutrition

2) Altered microflora2) Altered microflora2) Altered microflora2) Altered microflora3) Disuse3) Disuse3) Disuse3) Disuse

4) Ischemic injury4) Ischemic injury4) Ischemic injury4) Ischemic injury

AbsorptionAbsorptionAbsorptionAbsorptionTranslocationTranslocationTranslocationTranslocation

ToxinsToxinsToxinsToxinsOrganismsOrganismsOrganismsOrganisms

Cerra FB Critical Care Clinics 1989; 5(2): 289-302Cerra FB Critical Care Clinics 1989; 5(2): 289-302Cerra FB Critical Care Clinics 1989; 5(2): 289-302Cerra FB Critical Care Clinics 1989; 5(2): 289-302

Solutés spéciaux de NE Solutés spéciaux de NE destinés à moduler destinés à moduler la réponse inflammatoire et immunitaire à la la réponse inflammatoire et immunitaire à la chirurgie et aux agressions aiguëschirurgie et aux agressions aiguës glutamine, arginine, acides gras omega-3 etc…glutamine, arginine, acides gras omega-3 etc…

Environ 35 RCT’s d ’ « immunonutrition »Environ 35 RCT’s d ’ « immunonutrition »21 en Réanimation (études en post-op 21 en Réanimation (études en post-op nonnon

généralisables)généralisables)

12 avec Impact 12 avec Impact

2 avec Immun-Aid 2 avec Immun-Aid

7 autres, dont un avec AlitraQ7 autres, dont un avec AlitraQ et un avec Stresson et un avec Stresson

« Effet Immunonutrition » ?« Effet Immunonutrition » ?

units

AlitraQ®

Impact®

Perative®

Stresson®

Manufacturer

Ross Lab. Novartis Abbott Nutricia

Energy kcal/ l 1000 1010 1300 1250 Protein g/ l 52,5 56 66,6 75 Free glutamine g/ l 15,5 0 12,2 13 Arginine g/ l 4,5 12,8 8,1 9 Nucleotides g/ l 0 1,3 0 0 Lipids Saffl ower oil Palm oil Canola oil Vegetable oil MCT* Saffl ower oil Corn oil Fish oil Menhaden oil MCT* n- 3 fatty acids g/ l 0,02 3,3 1,24 1,1 Antioxidants yes yes yes yes

units

AlitraQ®

Impact®

Perative®

Stresson®

Manufacturer

Ross Lab. Novartis Abbott Nutricia

Energy kcal/ l 1000 1010 1300 1250 Protein g/ l 52,5 56 66,6 75 Free glutamine g/ l 15,5 0 12,2 13 Arginine g/ l 4,5 12,8 8,1 9 Nucleotides g/ l 0 1,3 0 0 Lipids Saffl ower oil Palm oil Canola oil Vegetable oil MCT* Saffl ower oil Corn oil Fish oil Menhaden oil MCT* n- 3 fatty acids g/ l 0,02 3,3 1,24 1,1 Antioxidants yes yes yes yes

Polytraumatismes etPolytraumatismes etChirurgie lourdeChirurgie lourde

Kudsk KA et al Ann Surg 1996; 224: 531-43Kudsk KA et al Ann Surg 1996; 224: 531-43Kudsk KA et al Ann Surg 1996; 224: 531-43Kudsk KA et al Ann Surg 1996; 224: 531-43

NE ImmuneNE Immune

NE IsoNE IsoTémoinsTémoins

Inf.Inf.urinairesurinaires

ns

SepsisSepsisSyndromeSyndrome

Suppur.Suppur.Pariét.Pariét.

Pneum.Pneum.

ns

ns

ns

Bacter.Bacter.

00 55101015152020252530303535404045455050

AbcèsAbcèsIntra-abdo.Intra-abdo.

%%

**

**** ******

* p = 0,05 NEI vs iso* p = 0,05 NEI vs iso ** p = 0,009 NEI vs Témoins** p = 0,009 NEI vs Témoins*** p = 0,02 NEI vs Témoins*** p = 0,02 NEI vs Témoins

* p = 0,05 NEI vs iso* p = 0,05 NEI vs iso ** p = 0,009 NEI vs Témoins** p = 0,009 NEI vs Témoins*** p = 0,02 NEI vs Témoins*** p = 0,02 NEI vs Témoins

ImpactImpact

ControlControl

Adapted after Braga M et al Arch Surg; 1999 134: 428-33Adapted after Braga M et al Arch Surg; 1999 134: 428-33Adapted after Braga M et al Arch Surg; 1999 134: 428-33Adapted after Braga M et al Arch Surg; 1999 134: 428-33

00

55

1010

1515

2020

2525

3030

LOS AntibioticsLOS Antibiotics (days)(days) (days) (days)

p = .01p = .01

p = .001p = .001

Adverse effects Adverse effects of EN (%)of EN (%)

nsns

Infect. Complications (%)Infect. Complications (%)

ITT Eligible ITT Eligible

p = .009p = .009

p = .02p = .02

Réanimation « pur jus »

Atkinson S et al Crit Care Med 1998; 26 : 1164-72Atkinson S et al Crit Care Med 1998; 26 : 1164-72Atkinson S et al Crit Care Med 1998; 26 : 1164-72Atkinson S et al Crit Care Med 1998; 26 : 1164-72

Analyse de survie (Kaplan-Meier) Analyse de survie (Kaplan-Meier) • en “intention-de-traiter” en “intention-de-traiter” (gauche ; p = 0,36, log-rank) (gauche ; p = 0,36, log-rank)

ImpactImpactImpactImpact

Immunonutrition entérale en réa et survieImmunonutrition entérale en réa et survie

• en “nutrition entérale efficace “en “nutrition entérale efficace “ (droite ; p = 0,16, log-rank)(droite ; p = 0,16, log-rank)

00

55

1010

1515

2020

2525

3030

3535

4040

4545

5050

ITT ImpactITT Impact ITT ControlITT Control Early EN ImpactEarly EN Impact Early EN ControlEarly EN Control

HospitalHospitalMortality (%)Mortality (%)

nsns

Adapted from Atkinson S et al. Crit Care Med; 26: 1164-72Adapted from Atkinson S et al. Crit Care Med; 26: 1164-72 Adapted from Atkinson S et al. Crit Care Med; 26: 1164-72Adapted from Atkinson S et al. Crit Care Med; 26: 1164-72

Hospital Hospital LOS LOS aa

p = .03p = .03

MV(days)MV(days)

p = .007p = .007p = .03p = .03

Days of SIRSDays of SIRS

Etude Etude muticentriquemuticentrique prospective, prospective, randomisée en réanimation polyvalenterandomisée en réanimation polyvalente

181 malades :181 malades : APACHE II > 10 APACHE II > 10 et septiqueset septiques

definition microbiologique ou clinique definition microbiologique ou clinique (« sepsis »)(« sepsis »)

en majorité en majorité pneumoniespneumonies (n=121) (n=121)

Randomisation dans les 36 h après le dg de Randomisation dans les 36 h après le dg de sepsis sepsis • immunonutrition entérale (Impactimmunonutrition entérale (Impact))• ou NE témoin ou NE témoin non isocaloriquenon isocalorique non isoazotée non isoazotée

(Precitene HP(Precitene HP) )

Immunonutrition: Immunonutrition: quel est l ’« Impact » ?quel est l ’« Impact » ?

Galban C et al. Crit Care Med 2000; 28: 643-8Galban C et al. Crit Care Med 2000; 28: 643-8Galban C et al. Crit Care Med 2000; 28: 643-8Galban C et al. Crit Care Med 2000; 28: 643-8

Precitene HP

Impact

0

5

10

15

20

25

30

35

Pts

wit

hb

acte

rem

ia,

%

> 1

Nosoc I

nf

.01.01

.01.01

LO

S,

days

.41.41

MV

days

.90.90

Mort

ality

, %

Mort

ality

, %

10

<A

pach

e I

I<1

5

.05.05 .02.02

Galban C et al. Galban C et al. Crit Care Med 2000; 28: 643-8Crit Care Med 2000; 28: 643-8Galban C et al. Galban C et al. Crit Care Med 2000; 28: 643-8Crit Care Med 2000; 28: 643-8

Comparative effects of early EN with Comparative effects of early EN with Stresson or Nutrison in the critically ill Stresson or Nutrison in the critically ill

Multicenter single-blind PRCT in 15 spanish Multicenter single-blind PRCT in 15 spanish ICUsICUs

220 patients enrolled to receive:220 patients enrolled to receive: Nutrison ( 62,5 g protein/l – no MCT, no fiber )Nutrison ( 62,5 g protein/l – no MCT, no fiber ) or Streson ( 75 g protein/l + arginine, MCT and fiber)or Streson ( 75 g protein/l + arginine, MCT and fiber)

Primary end-points:Primary end-points: incidence of nosocomial infections²incidence of nosocomial infections² ICU and hospital LOSICU and hospital LOS mortality at 6 month follow-upmortality at 6 month follow-up

Multicenter single-blind PRCT in 15 spanish Multicenter single-blind PRCT in 15 spanish ICUsICUs

220 patients enrolled to receive:220 patients enrolled to receive: Nutrison ( 62,5 g protein/l – no MCT, no fiber )Nutrison ( 62,5 g protein/l – no MCT, no fiber ) or Streson ( 75 g protein/l + arginine, MCT and fiber)or Streson ( 75 g protein/l + arginine, MCT and fiber)

Primary end-points:Primary end-points: incidence of nosocomial infections²incidence of nosocomial infections² ICU and hospital LOSICU and hospital LOS mortality at 6 month follow-upmortality at 6 month follow-up

Adapted from Caparros T et al JPEN 2001; 25: 299-309Adapted from Caparros T et al JPEN 2001; 25: 299-309

Comparative effects of early EN with Comparative effects of early EN with Stresson or Nutrison: clinical outcomeStresson or Nutrison: clinical outcomeComparative effects of early EN with Comparative effects of early EN with

Stresson or Nutrison: clinical outcomeStresson or Nutrison: clinical outcome


Stresson (n=105)Stresson (n=105)Nutrison (n=85)Nutrison (n=85)

00

55

1010

1515

2020

2525

3030

3535

ICU HospitalICU Hospital

Mortality (%)Mortality (%)

6 m. 6 m. ICU Hosp.ICU Hosp.

LOS (days)LOS (days)

Comparative effects of early EN with Comparative effects of early EN with Stresson or Nutrison: infection rates *Stresson or Nutrison: infection rates *Comparative effects of early EN with Comparative effects of early EN with

Stresson or Nutrison: infection rates *Stresson or Nutrison: infection rates *


* Number of episodes per 1000 days of ICU LOS or MV* Number of episodes per 1000 days of ICU LOS or MV

0

5

10

15

20

25

30

35

40

Overall Pneumonia Bacteremia CRS UTI

StressonStresson

NutrisonNutrison

p < .001p < .001

IMMUNOIMMUNONUTRITIONNUTRITION

Heyland DK et al JAMA 2001; 286 : 944-53Heyland DK et al JAMA 2001; 286 : 944-53

Effect of Immunonutrition: Pooled ResultsEffect of Immunonutrition: Pooled Results

- 2 - 1 1 - 2 - 1 1 Pooled Effect Size Pooled Effect Size

- 2 - 1 1 - 2 - 1 1 Pooled Effect Size Pooled Effect Size

Hospital Stay(17 trials)

Hospital Stay(17 trials)

Infectious Complications

(18 trials)


(18 trials)

0,1 0,50,1 0,5 5 5 RR (IC 95%) RR (IC 95%)

0,1 0,50,1 0,5 5 5 RR (IC 95%) RR (IC 95%)

Mortality(22 trials)Mortality(22 trials)

0,1 0,50,1 0,5 5 5 RR (IC 95%) RR (IC 95%)

0,1 0,50,1 0,5 5 5 RR (IC 95%) RR (IC 95%)

RR (IC 95%) RR (IC 95%) 0,0050,005 0,010,01 0,05 0,1 0,50,05 0,1 0,5 5 10 50 100 5 10 50 100 RR (IC 95%) RR (IC 95%) 0,0050,005 0,010,01 0,05 0,1 0,50,05 0,1 0,5 5 10 50 100 5 10 50 100

Favors Immunonutrition


Favors Standard Diet


Brown, 1994Brown, 1994

Moore, 1994Moore, 1994

Bower, 1995Bower, 1995

Kudsk, 1996Kudsk, 1996

Engel, 1997Engel, 1997

Mendez, 1997Mendez, 1997

Rodrigo, 1997Rodrigo, 1997

Galban, 2000Galban, 2000










Effect of Immunonutrition on Infections (ICU) Effect of Immunonutrition on Infections (ICU)

RR (IC 95%) RR (IC 95%) 0,0050,005 0,010,01 0,05 0,1 0,50,05 0,1 0,5 5 10 50 100 5 10 50 100 RR (IC 95%) RR (IC 95%) 0,0050,005 0,010,01 0,05 0,1 0,50,05 0,1 0,5 5 10 50 100 5 10 50 100





Cerra, 1990Cerra, 1990

Gottschlich, 1990Gottschlich, 1990








Weimann, 1998Weimann, 1998

Atkinson, 1998Atkinson, 1998



Gottschlich, 1990Gottschlich, 1990








Weimann, 1998Weimann, 1998




Effect of Immunonutrition on Mortality (ICU)Effect of Immunonutrition on Mortality (ICU)


Effect of Immunonutrition on Hospital LOS (ICU)Effect of Immunonutrition on Hospital LOS (ICU)

Effect Size (95% CI) Effect Size (95% CI) – 4 - 3 - 2 - 1 1 2 3– 4 - 3 - 2 - 1 1 2 3Effect Size (95% CI) Effect Size (95% CI) – 4 - 3 - 2 - 1 1 2 3– 4 - 3 - 2 - 1 1 2 3










Weinmann, 1998Weinmann, 1998







Weinmann, 1998Weinmann, 1998


Why these differences Why these differences between surgical and between surgical and critically ill patients ?critically ill patients ?

simple vs complex and versatile simple vs complex and versatile immunosuppression (anti-cytokines etc)immunosuppression (anti-cytokines etc)

early death masks the true risk of early death masks the true risk of infection in the ICU (censoring data +++)infection in the ICU (censoring data +++)

insufficient risk stratification in studies insufficient risk stratification in studies different risk of complications/death in different risk of complications/death in

the ICU populations (Pneumonia +++)the ICU populations (Pneumonia +++)

Surgical = low-risk ICU ??Surgical = low-risk ICU ??

simple vs complex and versatile simple vs complex and versatile immunosuppression (anti-cytokines etc)immunosuppression (anti-cytokines etc)

early death masks the true risk of early death masks the true risk of infection in the ICU (censoring data +++)infection in the ICU (censoring data +++)

insufficient risk stratification in studies insufficient risk stratification in studies different risk of complications/death in different risk of complications/death in

the ICU populations (Pneumonia +++)the ICU populations (Pneumonia +++)

Surgical = low-risk ICU ??Surgical = low-risk ICU ??

Immun-aidImmun-aid

OtherOther

TraumaTraumaNon traumaNon trauma

Not infected at baselineNot infected at baselineInfected includedInfected included

Low quality Low quality scorescoreHigh quality scoreHigh quality score

Overall Effect Overall Effect (n=13)(n=13)

Immunonutrition: Potion or Poison ?Immunonutrition: Potion or Poison ?

Risk ratio (log scale)Risk ratio (log scale)Risk ratio (log scale)Risk ratio (log scale)

Immunonutrition Immunonutrition Immunonutrition Immunonutrition BeneficalBeneficalBeneficalBenefical HarmfulHarmfulHarmfulHarmful

.2 .4 .6 .8 .2 .4 .6 .8

11

p=0.0p=0.088

p=0.4p=0.4

p=0.5p=0.5

p=0.0p=0.044

22 44

Mortality Mortality

Impact or Immun-aidImpact or Immun-aid

OtherOther

TraumaTraumaNon traumaNon trauma

Not infected at baselineNot infected at baselineInfected includedInfected included

Low quality Low quality scorescoreHigh quality scoreHigh quality score

Overall Effect Overall Effect (n=10)(n=10)

Immunonutrition: Potion or Poison ?Immunonutrition: Potion or Poison ?


Immunonutrition Immunonutrition Immunonutrition Immunonutrition BeneficalBeneficalBeneficalBenefical HarmfulHarmfulHarmfulHarmful

.2 .4 .6 .8 .2 .4 .6 .8

11

p=0.2p=0.2

p=0.6p=0.6

p=0.6p=0.6

p=0.2p=0.2

22 44Infectious Complications


ITTITT

0.050.05

ns

Statistics are for doctors Statistics are for doctors what street lamps are for drunks: what street lamps are for drunks: they serve more as a crutch they serve more as a crutch than as a source of illumination !than as a source of illumination !

Immune –enhancing diets: any Immune –enhancing diets: any benefit ?benefit ?

Immune –enhancing diets: any Immune –enhancing diets: any benefit ?benefit ?

Probable benefit (burns, head injury, …)Probable benefit (burns, head injury, …)

Expected benefit (major surgery, trauma)Expected benefit (major surgery, trauma)

No expected benefitNo expected benefit resuming po oral intake within 5 daysresuming po oral intake within 5 days in ICU for surveillancein ICU for surveillance sepsissepsis Incomplete/inadequate resuscitationIncomplete/inadequate resuscitation

No definite, proven, benefit +++No definite, proven, benefit +++

Probable benefit (burns, head injury, …)Probable benefit (burns, head injury, …)

Expected benefit (major surgery, trauma)Expected benefit (major surgery, trauma)

No expected benefitNo expected benefit resuming po oral intake within 5 daysresuming po oral intake within 5 days in ICU for surveillancein ICU for surveillance sepsissepsis Incomplete/inadequate resuscitationIncomplete/inadequate resuscitation

No definite, proven, benefit +++No definite, proven, benefit +++

Les inconnues tenaces...

Les inconnues tenaces...

Intérêt de l ’association NE + NP (immunomodulatrices ?), pendant la période d’instabilité hémodynamique initiale ??

Sur quels critères choisir entre les différents solutés nutritifs immunomodulateurs disponibles ou à venir ? Tout paraît si bon !

Lequel ou lesquels des alicaments est

responsable des effets observés ?

La voie d’administration joue t’elle un rôle majeur ?

EN EFFET ...

Intérêt de l ’association NE + NP (immunomodulatrices ?), pendant la période d’instabilité hémodynamique initiale ??

Sur quels critères choisir entre les différents solutés nutritifs immunomodulateurs disponibles ou à venir ? Tout paraît si bon !

Lequel ou lesquels des alicaments est

responsable des effets observés ?

La voie d’administration joue t’elle un rôle majeur ?

EN EFFET ...

Houdijk APV et al. Lancet 1998; 352 : 772-6Houdijk APV et al. Lancet 1998; 352 : 772-6Houdijk APV et al. Lancet 1998; 352 : 772-6Houdijk APV et al. Lancet 1998; 352 : 772-6

AlitraQ

NE témoin

0

5

10

15

20

25

30

35

40

45%

Pneumonies Sepsis

Bactériémies

p<0,02

p< 0,005

p<0,02

Inf. urinaires

ns

DS àl'hôpital (j)

ns

Griffiths RD et al Griffiths RD et al Nutrition 1997; 13 (4): 295-302Nutrition 1997; 13 (4): 295-302 Griffiths RD et al Griffiths RD et al Nutrition 1997; 13 (4): 295-302Nutrition 1997; 13 (4): 295-302

P = P = 0,0490,049 GlutamineGlutamine

Standard TPNStandard TPN

ControlsControls

Glutamine reduces Gram-negative Glutamine reduces Gram-negative bacteremia in severely burned patientsbacteremia in severely burned patients Wischmeyer PE et al Crit Care Med 2001; 29: 2075-80Wischmeyer PE et al Crit Care Med 2001; 29: 2075-80

Improved clinical outcome in ICU patients Improved clinical outcome in ICU patients receiving alanyl-glutamine supplemented receiving alanyl-glutamine supplemented TPNTPN

Déchelotte P et al Clin Nutr 2002 (abstr.)Déchelotte P et al Clin Nutr 2002 (abstr.)

Glutamine reduces Gram-negative Glutamine reduces Gram-negative bacteremia in severely burned patientsbacteremia in severely burned patients Wischmeyer PE et al Crit Care Med 2001; 29: 2075-80Wischmeyer PE et al Crit Care Med 2001; 29: 2075-80

Improved clinical outcome in ICU patients Improved clinical outcome in ICU patients receiving alanyl-glutamine supplemented receiving alanyl-glutamine supplemented TPNTPN

Déchelotte P et al Clin Nutr 2002 (abstr.)Déchelotte P et al Clin Nutr 2002 (abstr.)

OKG improves wound healing in severe burn

patients

OKG improves wound healing in severe burn

patients

00

2020

4040

6060

8080

100100

ControlControl

OKGOKG

Last GaftLast GaftHealing TimeHealing Time

****

DaysDays

** p < 0.05 p < 0.05 vs Controlsvs Controls** p < 0.05 p < 0.05 vs Controlsvs Controls

Coudray-Lucas C et al. Crit Care Med 2000; 28: 1772-6Coudray-Lucas C et al. Crit Care Med 2000; 28: 1772-6Coudray-Lucas C et al. Crit Care Med 2000; 28: 1772-6Coudray-Lucas C et al. Crit Care Med 2000; 28: 1772-6

Excess of Lipids in TPN depress immunity and Excess of Lipids in TPN depress immunity and the reduction of their global amounts seems the reduction of their global amounts seems beneficbenefic

Linoleic acid, via LTB4 and PGE2 synthesis, Linoleic acid, via LTB4 and PGE2 synthesis,

have inflammatory and immunodepressive have inflammatory and immunodepressive effects, and so should be reducedeffects, and so should be reduced

Fish Oil supplementation has rapid anti-Fish Oil supplementation has rapid anti-inflammatory effects and is potentially inflammatory effects and is potentially interesting.interesting.

In ICU patientsIn ICU patients

EN supplemented with EPA, GLA and antioxidants in ARDS

patients

ControControll

EPA + GLAEPA + GLA

Gadek JE et al Crit care Med 1999; 27: 1409-20Gadek JE et al Crit care Med 1999; 27: 1409-20Gadek JE et al Crit care Med 1999; 27: 1409-20Gadek JE et al Crit care Med 1999; 27: 1409-20

00

55

1010

1515

2020

2525

3030

3535

MV MV (days)(days)

p<.03p<.03

MortalityMortality

((%%))

nsns

p<.02p<.02

nsns

LOS (days)LOS (days)

in ICU Hospitalin ICU Hospital

p<.02p<.02

New OFNew OF(n)(n)

Metabolic and hormonal effects of Metabolic and hormonal effects of ArginineArginine

Enteral/Parenteral supplyEnteral/Parenteral supply

L-arginineL-arginine L-CitrullineL-CitrullineL-OrnithineL-Ornithine

UreaUrea

PolyamineSynthesis

PutrescineSpermidineSpermine

PolyamineSynthesis

PutrescineSpermidineSpermine

Hormone release

GHIGFInsulin/GlucagonProlactin

Hormone release

GHIGFInsulin/GlucagonProlactin

NitrogenousCompounds

NONitritesNitrates

NitrogenousCompounds

NONitritesNitrates

Suchner U et al. Br J Nutr 2002; 87 (Supplt 1): S 121-32 Suchner U et al. Br J Nutr 2002; 87 (Supplt 1): S 121-32

Is arginine supply the key Is arginine supply the key point ?point ?


Immune Nutrition Immune Nutrition Immune Nutrition Immune Nutrition BeneficalBeneficalBeneficalBenefical HarmfulHarmfulHarmfulHarmful

0.10.10.10.1 1111 10101010

Mortality Arg +Mortality Arg +Mortality Arg +Mortality Arg +Arg -Arg -Arg -Arg -

Rate of infections Arg +Rate of infections Arg +Rate of infections Arg +Rate of infections Arg +

Arg -Arg - Arg -Arg -

Hospital LOS Arg +Hospital LOS Arg +Hospital LOS Arg +Hospital LOS Arg + Arg -Arg -

p=0.0p=0.066p=0.0p=0.066

p=0.0p=0.011p=0.0p=0.011

p=0.00p=0.0088p=0.00p=0.0088

Infections, Critically illInfections, Critically illInfections, Critically illInfections, Critically ill

SurgicalSurgical SurgicalSurgical p=0.002p=0.002p=0.002p=0.002

Hospital LOS,Hospital LOS, Critically IllCritically Ill Hospital LOS,Hospital LOS, Critically IllCritically Ill

SurgicalSurgical SurgicalSurgical nsns nsns

Arginine, n-3 fatty Arginine, n-3 fatty acids acids

in sepsisin sepsis

Arginine, n-3 fatty Arginine, n-3 fatty acids acids

in sepsisin sepsis

Friends Friends

or Foes ?or Foes ?Friends Friends

or Foes ?or Foes ?

Modulation of the systemic Modulation of the systemic immune response by immune response by

immunonutrients immunonutrients Systemic invasion of bacteria

Systemic immune response

Systemic invasion of bacteria

Systemic immune response

Cell defense functionDegranulationPhagocytosisCytotoxicityLymphopoiesis

Cell defense functionDegranulationPhagocytosisCytotoxicityLymphopoiesis

SIRSMicrocirculationVentilationEndothelial permeabilityPlatelet aggregation

SIRSMicrocirculationVentilationEndothelial permeabilityPlatelet aggregation

Mediators

EicosanoidsCytokines

NO

Mediators

EicosanoidsCytokines

NO

Immune Immune NutrientsNutrients

Adapted from Suchner et al Proc Nutr Soc 2000; 59: 553-63Adapted from Suchner et al Proc Nutr Soc 2000; 59: 553-63

Systemic inflammatory and Systemic inflammatory and anti-inflammatory responses after anti-inflammatory responses after

InsultInsult

Systemic inflammatory and Systemic inflammatory and anti-inflammatory responses after anti-inflammatory responses after

InsultInsult

RC. Bone Crit. Care Med. 1996RC. Bone Crit. Care Med. 1996

CARSCARSCARSCARS

Local Local anti-inflammatory anti-inflammatory

responseresponse

Systemic spillover ofSystemic spillover ofanti-inflammatoryanti-inflammatory

mediatorsmediators

SIRSSIRSSIRSSIRS

Local Local pro-inflammatory pro-inflammatory

responseresponse

Systemic spillover ofSystemic spillover ofpro-inflammatorypro-inflammatory

mediatorsmediators

Initial sepsisInitial sepsis

MARSMARSMARSMARS

Consequences of unbalanced NO Consequences of unbalanced NO availabilityavailability

Optimal NO Balance

Optimal NO Balance

c NOS + i NOSc NOS + i NOS

c NOSc NOS

Arginine / NOavailabilityArginine / NOavailability

Efe

cts

of

Arg

inin

e

ind

uced

NO

form

ati

on

H

arm

afu

lB

en

efi

cia

l

Efe

cts

of

Arg

inin

e

ind

uced

NO

form

ati

on

H

arm

afu

lB

en

efi

cia

lMicrocirculationImmune responseMicrobial killingCytoprotection

Hemodynamic instabilityImmune suppresionCytotoxicityOrgan dysfunction

Hemodynamic instabilityImmune suppresionCytotoxicityOrgan dysfunction

Suchner U et al. Br J Nutr 2002; 87 (Supplt 1): S 121-32 Suchner U et al. Br J Nutr 2002; 87 (Supplt 1): S 121-32

« Nous sommes tous égaux…« Nous sommes tous égaux…mais certains sont plus égaux que mais certains sont plus égaux que

d’autres »d’autres »

« Nous sommes tous égaux…« Nous sommes tous égaux…mais certains sont plus égaux que mais certains sont plus égaux que

d’autres »d’autres »

Coluche ( freely adapted from « Animals farm », G. Coluche ( freely adapted from « Animals farm », G. Orwell)Orwell)Coluche ( freely adapted from « Animals farm », G. Coluche ( freely adapted from « Animals farm », G. Orwell)Orwell)

« Relooking » of immune nutrients « Relooking » of immune nutrients at the beginning of the 3rd at the beginning of the 3rd

milleniummillenium

« Relooking » of immune nutrients « Relooking » of immune nutrients at the beginning of the 3rd at the beginning of the 3rd

milleniummillenium

ArginineArginine GlutamineGlutamine OKGOKG Glutathione and sulfur amino acidsGlutathione and sulfur amino acids TaurineTaurine Omega-3 fatty acidsOmega-3 fatty acids Various antioxidantsVarious antioxidants Prebiotics / ProbioticsPrebiotics / Probiotics … …

ArginineArginine GlutamineGlutamine OKGOKG Glutathione and sulfur amino acidsGlutathione and sulfur amino acids TaurineTaurine Omega-3 fatty acidsOmega-3 fatty acids Various antioxidantsVarious antioxidants Prebiotics / ProbioticsPrebiotics / Probiotics … …

Enteral FormulasEnteral FormulasCysteine content / 1000 kcalCysteine content / 1000 kcal

0

0,2

0,4

0,6

0,8

1

1,2

1,4

Peptamen AlitraqVHP

Perative Traumacal

Impact Critical HN

g

Early EN supply of Fiber and Early EN supply of Fiber and Lactobacilli Lactobacilli vs standard PN after vs standard PN after

major abdominal surgerymajor abdominal surgery

Early EN supply of Fiber and Early EN supply of Fiber and Lactobacilli Lactobacilli vs standard PN after vs standard PN after

major abdominal surgerymajor abdominal surgery PRCT in 3 groups of patients:PRCT in 3 groups of patients:

Standard PN of fiber-free EN (C)Standard PN of fiber-free EN (C) Fiber-containing EN with living Fiber-containing EN with living LactobacilliLactobacilli

(LL)(LL) Fiber-containing EN with heat-killed Fiber-containing EN with heat-killed Lact.Lact.

(KL)(KL) Main endpointsMain endpoints

infection ratesinfection rates duration of antibiotic therapyduration of antibiotic therapy length of hospital staylength of hospital stay side-effects of nutritionside-effects of nutrition

PRCT in 3 groups of patients:PRCT in 3 groups of patients: Standard PN of fiber-free EN (C)Standard PN of fiber-free EN (C) Fiber-containing EN with living Fiber-containing EN with living LactobacilliLactobacilli

(LL)(LL) Fiber-containing EN with heat-killed Fiber-containing EN with heat-killed Lact.Lact.

(KL)(KL) Main endpointsMain endpoints

infection ratesinfection rates duration of antibiotic therapyduration of antibiotic therapy length of hospital staylength of hospital stay side-effects of nutritionside-effects of nutrition

Rayes N et al. Nutrition 2002; 18: 609-15Rayes N et al. Nutrition 2002; 18: 609-15

Early EN supply of Fiber and Early EN supply of Fiber and Lactobacilli Lactobacilli vs standard PN after major abdominal vs standard PN after major abdominal

surgerysurgery

Early EN supply of Fiber and Early EN supply of Fiber and Lactobacilli Lactobacilli vs standard PN after major abdominal vs standard PN after major abdominal

surgerysurgery

Rayes N et al. Nutrition 2002; 18: 609-15Rayes N et al. Nutrition 2002; 18: 609-15

00

22

44

66

88

1010

1212

1414

1616

Pts Pneumonia (n) (n)Pts Pneumonia (n) (n)infectedinfected

Hospital Duration of antibiotic therpy (d)

Hospital Duration of antibiotic therpy (d)LOSLOS

Controls (n=30)Controls (n=30)

F + LL (n=30)F + LL (n=30)

F + KL (n=30)F + KL (n=30)

p = .04p = .01

1515 3 3 1515 3 3

Berger MM et al Am J Clin Nutr 1998; 68 : 365-71Berger MM et al Am J Clin Nutr 1998; 68 : 365-71Berger MM et al Am J Clin Nutr 1998; 68 : 365-71Berger MM et al Am J Clin Nutr 1998; 68 : 365-71

Eléments-traces et pneumopathies Eléments-traces et pneumopathies après brûlures étendues et profondesaprès brûlures étendues et profondes

EEFFFFIICCAACCIITTE E CCLLIINNIIQQUUEE

Hypothèses Hypothèses séduisantesséduisantes

Données expérimentales Données expérimentales convaincantesconvaincantes

limmunonutrition entérale en réanimation... du concept au concret limmunonutrition entérale en...

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