Immunonutrition - Back to Science !!! · enterales Produkt validiert. ... Using commercial formulas with high arginine ... Abbott, beginnend am 4. Tag LOW FREE ARGININE DIET:

Erich RothChirurgische Forschungslaboratorien,

Universität Wien

Immunonutrition -Back to Science !!!

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Verehre was du hörst, aber ziehe es in Zweifel

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• Immunologisches Wirkungsspektrum von Makro- und Mikronutrients

• Was ist Immunonutrition?

• Bringen Meta-Analysen Meta-Antworten?



Immunmodulierende Makronutrientsin enteralen Formulierungen

• Glutamin

• Arginin

• Schwefelhältige Aminosäuren

• Glyzin

• verzweigtkettige Aminosäuren

• ω-3 Fettsäuren

• Nukleotide



Redox regulation of genetranscription in inflammation

Inflammation

Oxidants, Cytokines, Environmental stimuli

GSH:GSSG

NF-κB, AP-1activation

vitamin E, C,ß-carotene,NAC,taurine

ROSGLN,glutamate,cysteine, glycine,NACselenium

redox-sensitive kinases +−

Anti-inflammatory/Antioxidant

genes

Pro-inflammatory genesiNOS

Adhesion Molecules



Reduction Potential and Biological Status of Cells

Schafer et al., Free Radic Biol Med, 2001

Proliferating Confluent Differentiating Apoptotic

n 11 2 2 2Ehc/mV for - 237 - 212 - 180 - 168GSSG/2 GSH



Pharmakokinetisches Grundprinzip

Dose-Response von Einzelsubstanzen

Wirksamkeit von Kombinationen



Data from 5 independent experiments*** p < 0.001 vs 0.05 mmol/l GLN** p < 0.05 vs 0.05 mmol/l GLN

Glutamine

B Wessner, E Roth et al, Clin Nutr 2003

11.7 15.9 17.5 16.40

5

10

15

20

0.05 0.3 0.6 2

Glutamine [mmol/l]

Glu

tath

ione

[∆

MCF

] ** ******



0.05 mmol/l GLN

11.5 12.1 13.5 14.2 16.00

5

10

15

20

KO 0.3 1 2 5

added GLY [mmol/l]

Glu

tath

ione

[ ∆ M

CF] *

*

* p < 0.02 vs Ko

Glycine - without Glutamine



+ 2 mmol/l GLN

16.1 12.9 11.2 10.0 3.40

5

10

15

20

KO 0.3 1 2 5added GLY [mmol/l]

Glu

tath

ione

[ ∆ M

CF] * ** **

***

* p < 0.05 vs Ko** p < 0.01 vs Ko*** p < 0.001 vs Ko

Glycine with Glutamine



Intracellular Glutamine

* p < 0.05 vs Ko

9.1 8.0 7.1 4.8 3.70

2

4

6

8

10

12

14

Ko 0.3 1 2 5

added Glycine [mmol/l]

intr

acel

lula

r GLN

[nm

ol/1

06 cel

ls]

2mM GLN + GLY

**



Influence of enteral diets supplemented withkey nutrients on lymphocyte subpopulations in Peyer´s patches of endotoxin-boostered mice

N Manhart, E Roth et al, Clin Nutr 2000; 19: 265

Diet I: GLN (3g/100kcal)

Diet II: GLN (3g/100kcal), ARG (0.5g/100kcal),GLY (1g/100kcal), ω - 3 FA (0.3g/100kcal)

Day 725µg LPS ip.

Day 10sacrified

Feeding period 10 daysControl, diet I or diet II



0

100

200

300

400

500

600

*** °°

µ g/s

mal

lint

estin

e

Control Gln Arg, Gln,Gly, ω -3 FA

Manhart et al.; Clin Nutr 2000; 19:265-269

Small intestinal IgA content



Effect of Different Combinations of DietaryAdditives on Bacterial Translocation and Survival

in Gut-Derived SepsisR Gennari, W Alexander et al., JPEN 1995, 19: 319



• Immunonutrients wirken dosisabhängig

• Kombinationen von Immunonutrientsmüssen sorgfältig auf ihre immun-modulierende Wirkung untersuchtwerden

Schlußfolgerungen - Pharmakokinetik



• Immunonutrition in the critical ill: A systematic review of clinical outcome

(R.J. Beale et al., Crit Care Med 1999; 27: 2799)

• Enteral Nutritional Supplementation with Key Nutrients in Patients with Critical Illness and Cancer

(S.D. Heys et al., Ann Surg 1999; 229: 467)

• Should Immunonutrition become Routine in Critically Ill Patients?

(D.K. Heyland et al., JAMA 2001; 286: 944)

Meta-Analysen - Meta-Antworten



Protein (g/L) 56 37Arginine (g/L) 12.5 (14) 14Glutamine (g/L) 9BCAA (g/L) 20Nucleic acids (g/L) 1.23 1ω - 3 PUFAs (g/L) 1.7 4.5Zinc (mg) 15 26Selenium (µg) 100 100

IMPACT Immun-Aid

R.J. Beale: 13x IMPACT, 2x Immun-Aid... Impact and Immun-Aid are slightly (??)

different in composition.



Decreased mortality and infectious morbidity in adult burn patients given enteral glutamine

supplements: A prospective, controlled, randomized clinical trial

D Garrel et al, Crit Care Med 2003; 31: 2444

Enteral glutamine supplementation in adultburn patients reduces blood infection by a factor of three, prevents bacteremia with P. aeruginosa, and may decrease mortality rate(12 vs 2, p<0.05, intention to treat)( 8 vs 0, p<0.01, per protocol analysis)



Arginine (g/L) 12.5 (14) 5.5Nucleic acids (g/L) 1.23 0ω - 3 PUFAs (g/L) 1.7 4.83ω - 6 : ω - 3 ratio 1.5 : 1 0.86 : 1Osmolarität 375 560Vitamin E 60 250Vitamin C 80 215Selenium (µg/L) 100 50

IMPACT Optimental

D.K. Heyland:... We included studies that compared enteral nutrition withsome combination of arginine, glutamine, nucleotides, ω - 3 fatty acids

LOW FREE ARG



Jedes Immunonutritions-Produkt wurde in der Regel gegen ein anderes normales enterales Produkt validiert.

Es gibt keine Studie, die verschiedene Immunonutritions-Produkte miteinander verglichen hat.



• Beale: ê Infektionenê Beatmungstageê Krankenhausaufenthaltstage

Mortalität

.... The benefits of enteral immunonutrition were most pronounced in surgical patients although they were present in all groups.

.... The reduction in hospital length of stay and infections has resource implications.

Zusammenfassung der Autoren



• Heys: ê Infektionen ( Pneumonie )ê Krankenhausaufenthaltstage

Mortalität

.... Enteral immunonutrition results in a significant reduction in the risk of developing infectious complications and reduces the overall hospital stay in patients with critical illness

.... This data have important implications for the management of such patients.




• Heyland :

.... Using commercial formulas with high argininecontent were associated with a significant reduction in infectious complications and a trend toward a lower mortality rate compared with other immune-enhancing diets.

.... Studies of surgical patients were associated with a significant reduction in infectious complication rates compared with studies of critical ill patients




• Heyland :

.... In studies of critically ill patients, studies with a high quality score were associated with increased mortality and a significant reduction in infectious complication rates compared with studies with a low quality score.

.... Immunonutrition may decrease infectious complication rate but is not associated with an overall mortality advantage.




Stirbt man als kritisch Kranker an derImmunonutrition ?

Kann die Gabe von Immunonutrientsgefährlich sein ?




Immunonutrition bei Sepsis

0

10

20

30

40

50

60

Ster

blic

hkei

t [%

]

'10-15 16-20 21-25 25+APACHE II Score

Reduktion der Sterblichkeit in Abhängigkeit vom APACHE II Score

angereichertkonventionell

C. Galbán et al., Crit Care Med, 2000



A prospective, randomized, double-blind, controlled clinical trial of enteral immunonutrition in the critically ill

(S. Atkinson et al., Crit Care Med 1998; 26: 1164)

Mortalität gesamt 95/197 (48%) 85/193 (44%)APACHE II gesamt 20.1 18.7

IMPACT Kontrolle

Mortalität early enteral group 21/50 (42%) 19/51 (37%)APACHE II early enteral 19.5 18

398 kritisch kranke Patienten



Early enteral administration of a formula (Impact®) supplemented with arginine, nucleotides, and fish oil in intensive care unit patients: Results of a multicenter, prospective, randomized, clinical trial

(R.H. Bower et al., Crit Care Med 1995; 23: 436)

Mortalität gesamt 23/147 (16%) 10/132 (8%)

Mortalität successfull fed 10/100 (10%) 7/100 (7%)Mortalität unsuccessfull fed 13/47 (28%) 3/32 (9%)

APACHE II unsuccesssfull fed (?) 19.2 12.5 p=0.01

IMPACT Kontrolle

326 Intensivpatienten



Effects of an Immune-Enhancing Diet in Critically Injured Patients

(C Mendez et al., J Trauma 1997; 42: 933)

Experimental diet: ARG 6.6g/L + GLN 19.1g/L + high ω - 3 FA

LOW FREE ARGININE DIET !

Increased ARDS in exp. Diet (45 vs 19%)Identical overall mortality



Early enteral immunonutrition in patients with severe sepsis(G. Bertolini et al., Intensive Care Med 2003; 29: 834)

Patienten:237 eingeschlossen, 39 mit schwerer Sepsis oder septischem Schockdavon 21 PN und 18 EN

Ernährung:Perative, Abbott, beginnend am 4. Tag

LOW FREE ARGININE DIET: 6.8g/L



Early enteral immunonutrition in patients with severe sepsis

(G. Bertolini et al., Intensive Care Med 2003; 29: 834)

Resultate:u Primärer Endpunkt Gesamtstudie: 28 Tage Mortalität

EN (n=18) PN (n=21)8 (44%) 5 (24%) p= 0.179 (chi square)

p= 0.196 (Fischer)

u Primärer Endpunkt Subgruppe SS: ICU MortalitätEN (n=18) PN (n=21)8 (44%) 3 (14%) p= 0.039 (chi square)

p= 0.072 (Fischer)



Consensus statements

1. Leitlinien der DGEMAkt Ernährungsmedizin 2003:28: S42

2. Consensus statement der SEMICYUC, SpanienClin Nutr 2003; 22:221

3. Canadian Crit Care Clinical Practice Guidelines CommitteeJPEN 2003; 27: 355



• Bei Patienten mit leichter Sepsis (APACHE II < 15) ist die Immunonutrition der enteralen Standardernährung überlegen.

• Traumapatienten sollen mit Immunonutrition ernährt werden.

• Beim kritisch Kranken (keine elektiv operierten, keine Trauma-, keine Verbrennungspatienten) konnte ein Vorteil einer Immunonutrition (Impact) lediglich in einer Subgruppe, die mehr als 2500ml Sondennahrung in 72h erhalten hat, gezeigt werden. Diese sollte eine Immunonutrition erhalten.

Leitlinien der DGEM



Pharmaconutrition group• Lower incidence in abdominal abscesses (p=0.005)

• Nosocomial pneumonia (p=0.007)

• Nosocomial bacteremia (p=0.0002)

• Reduction on mechanical ventilation (p=0.009)

• Reduction of ICU and Hospital length of stay(p=0.0001)

• No effect on mortality

Consensus Statement der SEMICYUC, Spanien



Conclusions:• Considering the beneficial effects and the absence

of detrimental ones, the use of diets enriched withpharmaconutrients could be recommended in ICU patients requiring enteral feeding.

• Nevertheless, more investigation is needed in thisfield in order to find the more appropriate populationof patients that can be beneficed with this nutritionaltherapy.

Consensus Statement der SEMICYUC, Spanien



Canadian Guidelines



• Out of 14 studies: no effect on mortality

• Subgroup analysis: High quality studies vs lowquality studies, showed that in the higherquality studies, diets supplemented witharginine and other nutrients had no effect on mortality

• Whereas, in lower quality studies, dietssupplemented with Arg and other nutrients hada trend toward reduction in mortality

Canadian Guidelines



•No differences in infectious complications (?)

•Reduction in hospital length of stay

•Trend towards a reduction of ICU length of stay

•Trend toward a reduction of mechanicalventilation

Canadian Guidelines



Canadian Guidelines



• The committee noted the lack of a treatment effectwith respect to mortality and infection (?) in dietssupplemented with Arg and other nutrients.

• Given the potential harm (increased mortality) associated with the use of diets supplemented withArg and other nutrients in septic patients(Literaturangabe) and the increased costs thecommittee decided to recommend against their usein critically ill patients.

Canadian Guidelines



Editorial:

Does immunonutrition in patients with sepsisdo more harm than good?

DK Heyland, A Samis; Intensive Care Med 2003; 29:669

Literaturangabe



Lest we throw out the baby with the bath water …

Most likely the culprit is arginine, a nutrientcommon to all the specialized diets included in themeta-analysis. There are no randomized studies of arginine supplementation in critically ill patients. However, arginine supplementation is capable of promoting an increase in NO production, which mayhave an adverse effect on critically ill patients withsepsis (Literaturangabe)

DK Heyland, A Samis; Intensive Care Med 2003; 29:669



Immune-modulating actions of arginine in thecritícally ill

U Suchner, DK Heyland, K Peter; Br J Nutr 2002; 87:S121

Literaturangabe



•Erhöhte Mortalität und Infektionsrate mit experimentellen Diäten, die einen niedrigen Arginin-Gehalt haben

•Erhöhter Anteil an ω - 3 Fettsäuren erhöht die Mortalität

• Immunonutritions-Produkte mit Nukleotidenbringen einen Vorteil

Mögliche Aussagen auf Grund der vorliegenden Studien (E. Roth)



•Diese Schlußfolgerungen sind der gleiche Nonsens wie die Schlußfolgerung, dass Arginin beim septischen Patienten („leichte“ Sepsis, schwere Sepsis, septischer Schock?) kontraindiziert ist



• Jede Aussage der vorliegenden Originalstudien über „Immunonutrition“ bezieht sich nur auf jenes Präparat, das in der speziellen Studie eingesetzt wurde.

• Alle Präparate beinhalten verschiedene Nutropharmazeutika.



•Unterschiedlich zusammengesetzte Immunonutritions-Produkte müssen miteinander in einem experimentellen Ansatz, nicht aber mittels einer Meta-Analyse verglichen werden.



•Arginin als Vorstufe von NO bewirkt eine Vasodilatation

•NO + Superoxidradikal führen zu Peroxynitritbildung

Negative Arginin-Daten



•Argininanaloga, um die „negative“ Arginin-wirkung zu verringern, haben sich beim septischen Patienten nicht durchgesetzt und sind vom Markt verschwunden

•Arg reduziert die Glukoseintoleranz

•Arg verbessert die Endothelfunktion

Positive Arginin-Daten



•Arg verbessert die Mikrozirkulation der Leber

•Arg verbessert den portalen Leberfluß

•Arg verringert die Akkumulation von Neutrophilen in der Lunge

•Arg verbessert die Wundheilung

Positive Arginin-Daten



•30 % des zugeführten Glutamins werden in Arg umgewandelt

•Alle enteralen Ernährungsprodukte enthalten Arg in gebundener Form

•Arg ist Teil parenteraler Ernährungslösungen

Arginin in der klinischen Ernährung



• Hypodynamischer septischer Schock

- hier hat man wohl andere Probleme als die Ernährungstherapie und die Immunonutrition

Kontraindikation für Arginin



Immune-paralysis

Hyper-inflammation

Imm

uner

eact

ion Sepsis

TNFIL-1

IL-6IL-8

IL-10

IL-13IL-4

TGF-β

HLA-DR LPS inducedTNF-α release

GLNω - 3 FS ?GLN ?

ω - 3 FSGLYARG ?

Two-Phase-Model of sepsis:different therapeutical interventions



Gender differences in Sepsis: Genetically determined?

Schroder J et al. Shock 2000; 14: 307-311

Men (133) Women (68)

Genotype

TNFB1/TNFB1

TNFB1/TNFB2

TNFB2/TNFB2

% mortality

42

47

33

33

5372 *

* Significantly different fromother genotypes, same sex



Do all cytokine genotypes respond toimmuno-nutrients in the same way?

Are some genotypes more responsiveto immuno-nutrients than others?

or



Influence of HLA characteristics on the abilityof fish oil to suppress TNF production

• 158 healthy males given6g/d fish oil for 12weeks.

• TNF-α production fromLPS stimulated PBMCsmeasured

• HLA characteristics ofpatients identified

0

10

20

30

40

50

60

HLA DR15 DR3 DR4

Percentage of each HLAtype showing a fall in TNF

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• weg von der Editorial – Wissenschaft

• weg von falsch angesetzten Meta-Analysen

• hin zu soliden Originalstudien mit dementsprechenden Patientenzahlen

• Industrie: im Wettbewerb die wissenschaftstheoretischen Grundprinzipien nicht vergessen

Klinische Ernährung



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Immunonutrition - Back to Science !!! · enterales Produkt validiert. ... Using commercial formulas with high arginine ... Abbott, beginnend am 4. Tag LOW FREE ARGININE DIET: