L’immunonutrition entérale L’immunonutrition entérale en Réanimation ... en Réanimation ... Du concept au concret Du concept au concret G. Nitenberg G. Nitenberg DAR et Pathologie Infectieuse DAR et Pathologie Infectieuse Institut Gustave Roussy - Villejuif - France Institut Gustave Roussy - Villejuif - France
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Limmunonutrition entérale en Réanimation... Du concept au concret Limmunonutrition entérale en Réanimation... Du concept au concret G. Nitenberg DAR et.
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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
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
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 (%)
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
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: 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 *
Adapted from Caparros T et al JPEN 2001; 25: 299-309Adapted from Caparros T et al JPEN 2001; 25: 299-309
* 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
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 +++)
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 +++)
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, …)
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, …)
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
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
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