Limmunonutrition entérale en Réanimation... Du concept au concret Limmunonutrition entérale en Réanimation... Du concept au concret G. Nitenberg DAR et Pathologie Infectieuse DAR et Pathologie Infectieuse Institut Gustave Roussy - Villejuif - France

Multiple Organ Dysfunction Multiple Organ Dysfunction LiverLiver injuryinjury Systemic Injury InjurySystemic GutGut Gut Hypothesis 1) Hepatocellular 2) Macrophage mediated 1) Malnutrition 2) Altered microflora 3) Disuse 4) Ischemic injury AbsorptionAbsorption TranslocationTranslocation ToxinsToxins OrganismsOrganisms Cerra FB Critical Care Clinics 1989; 5(2):

Solutés spéciaux de NE destinés à moduler la réponse inflammatoire et immunitaire à la chirurgie et aux agressions aiguës Solutés spéciaux de NE destinés à moduler la réponse inflammatoire et immunitaire à la chirurgie et aux agressions aiguës glutamine, arginine, acides gras omega-3 etc… glutamine, arginine, acides gras omega-3 etc… Environ 35 RCTs d « immunonutrition » Environ 35 RCTs d « immunonutrition » 21 en Réanimation (études en post-op non généralisables) 21 en Réanimation (études en post-op non généralisables) 12 avec Impact 12 avec Impact 2 avec Immun-Aid 2 avec Immun-Aid 7 autres, dont un avec AlitraQ et un avec Stresson 7 autres, dont un avec AlitraQ et un avec Stresson « Effet Immunonutrition » ?

Polytraumatismes et Polytraumatismes et Chirurgie lourde

Kudsk KA et al Ann Surg 1996; 224: NE Immune NE Iso Témoins Inf.urinaires nsSepsisSyndrome Suppur.Pariét. Pneum. ns Bacter AbcèsIntra-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

Hospital Stay and Costs Kudsk KA et al 1996 Ann Surg ; 224: Day s Hospital Total in ICU on ventilator stay ns ns p =.03 IEDISO Control ns$ Hospital charges

Impact Impact Control Control Adapted after Braga M et al Arch Surg; : LOS Antibiotics LOS Antibiotics (days) (days) (days) (days) p =.01 p =.001 Adverse effects of EN (%) ns Infect. Complications (%) ITT Eligible ITT Eligible p =.009 p =.02

Immunonutrition préopératoire en Chirurgie cardiaque Tepaske R et al. Lancet 2001; 358:

Réanimation « pur jus »

Atkinson S et al Crit Care Med 1998; 26 : Analyse de survie (Kaplan-Meier) en intention-de-traiter (gauche ; p = 0,36, log-rank) en intention-de-traiter (gauche ; p = 0,36, log-rank) Impact Immunonutrition entérale en réa et survie en nutrition entérale efficace (droite ; p = 0,16, log-rank) en nutrition entérale efficace (droite ; p = 0,16, log-rank)

ITT Impact ITT Impact ITT Control ITT Control Early EN Impact Early EN Impact Early EN Control Early EN Control Hospital Mortality (%) ns Adapted from Atkinson S et al. Crit Care Med; 26: Hospital LOS a p =.03 MV(days) p =.007 p =.03 Days of SIRS

Etude muticentrique prospective, randomisée en réanimation polyvalente Etude muticentrique prospective, randomisée en réanimation polyvalente 181 malades : 181 malades : APACHE II > 10 APACHE II > 10 et septiques et septiques definition microbiologique ou clinique (« sepsis ») definition microbiologique ou clinique (« sepsis ») en majorité pneumonies (n=121) en majorité pneumonies (n=121) Randomisation dans les 36 h après le dg de sepsis Randomisation dans les 36 h après le dg de sepsis immunonutrition entérale (Impact) immunonutrition entérale (Impact ) ou NE témoin non isocalorique non isoazotée (Precitene HP) ou NE témoin non isocalorique non isoazotée (Precitene HP )Immunonutrition: quel est l « Impact » ? Galban C et al. Crit Care Med 2000; 28: 643-8

Precitene HP Impact Pts with bacteremia, % > 1 Nosoc Inf LOS, days.41 MV days.90 Mortality, % 10<Apache II< Galban C et al. Crit Care Med 2000; 28: 643-8

Comparative effects of early EN with Stresson or Nutrison in the critically ill Multicenter single-blind PRCT in 15 spanish ICUs Multicenter single-blind PRCT in 15 spanish ICUs 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 infections² incidence of nosocomial infections² ICU and hospital LOS ICU and hospital LOS mortality at 6 month follow-up mortality at 6 month follow-up Multicenter single-blind PRCT in 15 spanish ICUs Multicenter single-blind PRCT in 15 spanish ICUs 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 infections² incidence of nosocomial infections² ICU and hospital LOS ICU and hospital LOS mortality at 6 month follow-up mortality at 6 month follow-up Adapted from Caparros T et al JPEN 2001; 25:

Comparative effects of early EN with Stresson or Nutrison: clinical outcome Adapted from Caparros T et al JPEN 2001; 25: Stresson (n=105) Nutrison (n=85) ICU Hospital Mortality (%) 6 m. ICU Hosp. LOS (days)

Comparative effects of early EN with Stresson or Nutrison: infection rates * Adapted from Caparros T et al JPEN 2001; 25: * Number of episodes per 1000 days of ICU LOS or MV Overall Pneumonia Bacteremia CRS UTI Stresson Nutrison p <.001

IMMUNONUTRITION

Heyland DK et al JAMA 2001; 286 : Effect of Immunonutrition: Pooled Results Pooled Effect Size Pooled Effect Size Pooled Effect Size Pooled Effect Size Hospital Stay (17 trials) Hospital Stay (17 trials) Infectious Complications (18 trials) Infectious Complications (18 trials) 0,1 0,5 5 RR (IC 95%) RR (IC 95%) 0,1 0,5 5 RR (IC 95%) RR (IC 95%) Mortality (22 trials) Mortality (22 trials) 0,1 0,5 5 RR (IC 95%) RR (IC 95%) 0,1 0,5 5 RR (IC 95%) RR (IC 95%)

RR (IC 95%) 0,005 0,01 0,05 0,1 0, RR (IC 95%) 0,005 0,01 0,05 0,1 0, Favors Immunonutrition Favors Immunonutrition Favors Standard Diet Favors Standard Diet Brown, 1994 Moore, 1994 Bower, 1995 Kudsk, 1996 Engel, 1997 Mendez, 1997 Rodrigo, 1997 Galban, 2000 Brown, 1994 Moore, 1994 Bower, 1995 Kudsk, 1996 Engel, 1997 Mendez, 1997 Rodrigo, 1997 Galban, 2000 Heyland DK et al JAMA 2001; 286 : Effect of Immunonutrition on Infections (ICU)

RR (IC 95%) 0,005 0,01 0,05 0,1 0, RR (IC 95%) 0,005 0,01 0,05 0,1 0, Favors Immunonutrition Favors Immunonutrition Favors Standard Diet Favors Standard Diet Cerra, 1990 Gottschlich, 1990 Brown, 1994 Moore, 1994 Bower, 1995 Kudsk, 1996 Engel, 1997 Mendez, 1997 Rodrigo, 1997 Weimann, 1998 Atkinson, 1998 Galban, 2000 Cerra, 1990 Gottschlich, 1990 Brown, 1994 Moore, 1994 Bower, 1995 Kudsk, 1996 Engel, 1997 Mendez, 1997 Rodrigo, 1997 Weimann, 1998 Atkinson, 1998 Galban, 2000 Heyland DK et al JAMA 2001; 286 : Effect of Immunonutrition on Mortality (ICU)

Heyland DK et al JAMA 2001; 286 : Effect of Immunonutrition on Hospital LOS (ICU) Effect Size (95% CI) – Favors Immunonutrition Favors Immunonutrition Favors Standard Diet Favors Standard Diet Cerra, 1990 Moore, 1994 Bower, 1995 Kudsk, 1996 Mendez, 1997 Weinmann, 1998 Atkinson, 1998 Cerra, 1990 Moore, 1994 Bower, 1995 Kudsk, 1996 Mendez, 1997 Weinmann, 1998 Atkinson, 1998

Why these differences between surgical and critically ill patients ? simple vs complex and versatile immunosuppression (anti-cytokines etc) simple vs complex and versatile immunosuppression (anti-cytokines etc) early death masks the true risk of infection in the ICU (censoring data +++) early death masks the true risk of infection in the ICU (censoring data +++) insufficient risk stratification in studies insufficient risk stratification in studies different risk of complications/death in the ICU populations (Pneumonia +++) different risk of complications/death in the ICU populations (Pneumonia +++) Surgical = low-risk ICU ?? simple vs complex and versatile immunosuppression (anti-cytokines etc) simple vs complex and versatile immunosuppression (anti-cytokines etc) early death masks the true risk of infection in the ICU (censoring data +++) early death masks the true risk of infection in the ICU (censoring data +++) insufficient risk stratification in studies insufficient risk stratification in studies different risk of complications/death in the ICU populations (Pneumonia +++) different risk of complications/death in the ICU populations (Pneumonia +++) Surgical = low-risk ICU ??

Immun-aid Other Trauma Non trauma Not infected at baseline Infected included Low quality score High quality score Overall Effect (n=13) Immunonutrition: Potion or Poison ? Risk ratio (log scale) Immunonutrition Immunonutrition BeneficalBenefical HarmfulHarmful p=0.08 p=0.4 p=0.5 p= Mortality

Impact or Immun-aid Other Trauma Non trauma Not infected at baseline Infected included Low quality score High quality score Overall Effect (n=10) Immunonutrition: Potion or Poison ? Risk ratio (log scale) Immunonutrition Immunonutrition BeneficalBenefical HarmfulHarmful p=0.2 p=0.6 p=0.6 p= Infectious Complications

Mais tout ce qui brille nest pas dor ! Parmi les études incluses: Parmi les études incluses: 8 études randomisées non aveugles 8 études randomisées non aveugles 6 études avec témoin non isoazoté 6 études avec témoin non isoazoté score de qualité variant de 5 à 11 (max=14) ! score de qualité variant de 5 à 11 (max=14) ! aucune étude dans la méta-analyse: aucune étude dans la méta-analyse: avec diète monosupplémentée avec diète monosupplémentée avec nutrition orale avec nutrition orale publiée sous forme dabstract publiée sous forme dabstract seule limmunonutrition entérale est évaluée seule limmunonutrition entérale est évaluée hétérogénéité significative entre les études hétérogénéité significative entre les études une avalanche …indigeste de statistiques superflues une avalanche …indigeste de statistiques superflues Parmi les études incluses: Parmi les études incluses: 8 études randomisées non aveugles 8 études randomisées non aveugles 6 études avec témoin non isoazoté 6 études avec témoin non isoazoté score de qualité variant de 5 à 11 (max=14) ! score de qualité variant de 5 à 11 (max=14) ! aucune étude dans la méta-analyse: aucune étude dans la méta-analyse: avec diète monosupplémentée avec diète monosupplémentée avec nutrition orale avec nutrition orale publiée sous forme dabstract publiée sous forme dabstract seule limmunonutrition entérale est évaluée seule limmunonutrition entérale est évaluée hétérogénéité significative entre les études hétérogénéité significative entre les études une avalanche …indigeste de statistiques superflues une avalanche …indigeste de statistiques superflues

ITT 0.05 ns Statistics are for doctors what street lamps are for drunks: they serve more as a crutch than as a source of illumination !

Immune –enhancing diets: any benefit ? Probable benefit (burns, head injury, …) Probable benefit (burns, head injury, …) Expected benefit (major surgery, trauma) Expected benefit (major surgery, trauma) No expected benefit No expected benefit resuming po oral intake within 5 days resuming po oral intake within 5 days in ICU for surveillance in ICU for surveillance sepsis sepsis Incomplete/inadequate resuscitation Incomplete/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 benefit No expected benefit resuming po oral intake within 5 days resuming po oral intake within 5 days in ICU for surveillance in ICU for surveillance sepsis sepsis Incomplete/inadequate resuscitation Incomplete/inadequate resuscitation No definite, proven, benefit +++ No definite, proven, benefit +++

Les inconnues tenaces... Intérêt de l association NE + NP (immunomodulatrices ?), pendant la période dinstabilité 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 dadministration joue telle un rôle majeur ? EN EFFET... Intérêt de l association NE + NP (immunomodulatrices ?), pendant la période dinstabilité 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 dadministration joue telle un rôle majeur ? EN EFFET...

Houdijk APV et al. Lancet 1998; 352 : AlitraQ NE témoin % Pneumonies Sepsis Bactériémies p<0,02 p< 0,005 p<0,02 Inf. urinaires ns DS à l'hôpital (j) ns

Griffiths RD et al Griffiths RD et al Nutrition 1997; 13 (4): Nutrition 1997; 13 (4): P = 0,049 Glutamine Standard TPN Controls

Glutamine reduces Gram-negative bacteremia in severely burned patients Glutamine reduces Gram-negative bacteremia in severely burned patients Wischmeyer PE et al Crit Care Med 2001; 29: Wischmeyer PE et al Crit Care Med 2001; 29: Improved clinical outcome in ICU patients receiving alanyl-glutamine supplemented TPN Improved clinical outcome in ICU patients receiving alanyl-glutamine supplemented TPN Déchelotte P et al Clin Nutr 2002 (abstr.) Glutamine reduces Gram-negative bacteremia in severely burned patients Glutamine reduces Gram-negative bacteremia in severely burned patients Wischmeyer PE et al Crit Care Med 2001; 29: Wischmeyer PE et al Crit Care Med 2001; 29: Improved clinical outcome in ICU patients receiving alanyl-glutamine supplemented TPN Improved clinical outcome in ICU patients receiving alanyl-glutamine supplemented TPN Déchelotte P et al Clin Nutr 2002 (abstr.)

OKG improves wound healing in severe burn patients Control OKG Last Gaft Healing Time ** Days * p < 0.05 vs Controls * p < 0.05 vs Controls Coudray-Lucas C et al. Crit Care Med 2000; 28:

Excess of Lipids in TPN depress immunity and the reduction of their global amounts seems benefic Excess of Lipids in TPN depress immunity and the reduction of their global amounts seems benefic Linoleic acid, via LTB4 and PGE2 synthesis, have inflammatory and immunodepressive effects, and so should be reduced Linoleic acid, via LTB4 and PGE2 synthesis, have inflammatory and immunodepressive effects, and so should be reduced Fish Oil supplementation has rapid anti-inflammatory effects and is potentially interesting. Fish Oil supplementation has rapid anti-inflammatory effects and is potentially interesting. In ICU patients

EN supplemented with EPA, GLA and antioxidants in ARDS patients Control EPA + GLA Gadek JE et al Crit care Med 1999; 27: MV (days) p<.03 Mortality Mortality (%) (%) (%) (%)ns p<.02ns LOS (days) LOS (days) in ICU Hospital in ICU Hospital p<.02 New OF (n)

Metabolic and hormonal effects of Arginine Enteral/Parenteral supply L-arginine L-Citrulline L-Ornithine Urea Polyamine Synthesis Putrescine Spermidine Spermine Polyamine Synthesis Putrescine Spermidine Spermine Hormone release GH IGF Insulin/Glucagon Prolactin Hormone release GH IGF Insulin/Glucagon Prolactin Nitrogenous Compounds NO Nitrites Nitrates Nitrogenous Compounds NO Nitrites Nitrates Suchner U et al. Br J Nutr 2002; 87 (Supplt 1): S

Is arginine supply the key point ? Risk ratio (log scale) Immune Nutrition Immune Nutrition BeneficalBenefical HarmfulHarmful Mortality Arg + Arg - Rate of infections Arg + Arg - Arg - Hospital LOS Arg + Arg - Arg - p=0.06p=0.06 p=0.01p=0.01 p=0.008p=0.008 Infections, Critically ill Surgical Surgical p=0.002p=0.002 Hospital LOS, Critically Ill Hospital LOS, Critically Ill Surgical Surgical ns ns

Arginine, n-3 fatty acids Arginine, n-3 fatty acids in sepsis Arginine, n-3 fatty acids Arginine, n-3 fatty acids in sepsis Friends or Foes ? or Foes ?

Modulation of the systemic immune response by immunonutrients Systemic invasion of bacteria Systemic immune response Systemic invasion of bacteria Systemic immune response Cell defense function Degranulation Phagocytosis Cytotoxicity Lymphopoiesis Cell defense function Degranulation Phagocytosis Cytotoxicity Lymphopoiesis SIRS Microcirculation Ventilation Endothelial permeability Platelet aggregation SIRS Microcirculation Ventilation Endothelial permeability Platelet aggregation Mediators Eicosanoids Cytokines NO Mediators Eicosanoids Cytokines NO Immune Nutrients Adapted from Suchner et al Proc Nutr Soc 2000; 59:

Systemic inflammatory and anti-inflammatory responses after Insult RC. Bone Crit. Care Med CARSCARS Localanti-inflammatoryresponse Systemic spillover of anti-inflammatorymediators SIRSSIRS Localpro-inflammatoryresponse pro-inflammatorymediators Initial sepsis MARSMARS

Consequences of unbalanced NO availability Optimal NO Balance c NOS + i NOS c NOS Arginine / NO availability Arginine / NO availability Efects of Arginine induced NO formation HarmafulBeneficial Efects of Arginine induced NO formation HarmafulBeneficial Microcirculation Immune response Microbial killing Cytoprotection Hemodynamic instability Immune suppresion Cytotoxicity Organ dysfunction Hemodynamic instability Immune suppresion Cytotoxicity Organ dysfunction Suchner U et al. Br J Nutr 2002; 87 (Supplt 1): S

« Nous sommes tous égaux… mais certains sont plus égaux que dautres » Coluche ( freely adapted from « Animals farm », G. Orwell)

« Relooking » of immune nutrients at the beginning of the 3rd millenium Arginine Arginine Glutamine Glutamine OKG OKG Glutathione and sulfur amino acids Glutathione and sulfur amino acids Taurine Taurine Omega-3 fatty acids Omega-3 fatty acids Various antioxidants Various antioxidants Prebiotics / Probiotics Prebiotics / Probiotics … … Arginine Arginine Glutamine Glutamine OKG OKG Glutathione and sulfur amino acids Glutathione and sulfur amino acids Taurine Taurine Omega-3 fatty acids Omega-3 fatty acids Various antioxidants Various antioxidants Prebiotics / Probiotics Prebiotics / Probiotics … …

Enteral Formulas Cysteine content / 1000 kcal 0 0,2 0,4 0,6 0,8 1 1,2 1,4 Peptamen Alitraq VHP Perative Traumacal Impact Critical HN g

Early EN supply of Fiber and Lactobacilli vs standard PN after major 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 Lactobacilli (LL) Fiber-containing EN with living Lactobacilli (LL) Fiber-containing EN with heat-killed Lact. (KL) Fiber-containing EN with heat-killed Lact. (KL) Main endpoints Main endpoints infection rates infection rates duration of antibiotic therapy duration of antibiotic therapy length of hospital stay length of hospital stay side-effects of nutrition side-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 Lactobacilli (LL) Fiber-containing EN with living Lactobacilli (LL) Fiber-containing EN with heat-killed Lact. (KL) Fiber-containing EN with heat-killed Lact. (KL) Main endpoints Main endpoints infection rates infection rates duration of antibiotic therapy duration of antibiotic therapy length of hospital stay length of hospital stay side-effects of nutrition side-effects of nutrition Rayes N et al. Nutrition 2002; 18:

Early EN supply of Fiber and Lactobacilli vs standard PN after major abdominal surgery Rayes N et al. Nutrition 2002; 18: Pts Pneumonia (n) (n) Pts Pneumonia (n) (n) infected HospitalDuration of antibiotic therpy (d) HospitalDuration of antibiotic therpy (d) LOS Controls (n=30) F + LL (n=30) F + KL (n=30) p =.04 p =.01

Berger MM et al Am J Clin Nutr 1998; 68 : Eléments-traces et pneumopathies après brûlures étendues et profondes

EFFICACITE CLINIQUE Hypothèses séduisantes Hypothèses séduisantes Données expérimentales convaincantes Données expérimentales convaincantes