Immunonutrition - Back to Science!!!

Transkript

1 Immunonutrition - Back to Science!!! Erich Roth Chirurgische Forschungslaboratorien, Universität Wien

2 Aus evolutionsbiologischen Gründen soll das Gehirn die Wahrheit nicht erkennen. Konrad Lorenz: Die Rückseite des Spiegels Verehre was du hörst, aber ziehe es in Zweifel Nahuatl / Alt Mexiko

3 Immunologisches Wirkungsspektrum von Makro- und Mikronutrients Was ist Immunonutrition? Bringen Meta-Analysen Meta-Antworten?

4 Immunmodulierende Makronutrients in enteralen Formulierungen Glutamin Arginin Schwefelhältige Aminosäuren Glyzin verzweigtkettige Aminosäuren w-3 Fettsäuren Nukleotide

5 Redox regulation of gene transcription in inflammation Oxidants, Cytokines, Environmental stimuli GLN, glutamate, cysteine, glycine, NAC selenium - GSH:GSSG ROS redox-sensitive kinases + NF-kB, AP-1 vitamin E, C, ß-carotene, NAC, taurine activation Anti-inflammatory/ Antioxidant genes Inflammation Pro-inflammatory genes inos Adhesion Molecules

6 Reduction Potential and Biological Status of Cells Proliferating Confluent Differentiating Apoptotic n E hc /mv for GSSG/2 GSH Schafer et al., Free Radic Biol Med, 2001

7 Pharmakokinetisches Grundprinzip Dose-Response von Einzelsubstanzen Wirksamkeit von Kombinationen

8 Glutamine Glutathione [D MCF] *** ** *** Glutamine [mmol/l] B Wessner, E Roth et al, Clin Nutr 2003 Data from 5 independent experiments *** p < vs 0.05 mmol/l GLN ** p < 0.05 vs 0.05 mmol/l GLN

9 Glycine - without Glutamine Glutathione [D MCF] mmol/l GLN * * KO added GLY [mmol/l] * p < 0.02 vs Ko

10 Glycine with Glutamine Glutathione [D MCF] mmol/l GLN * ** ** *** KO added GLY [mmol/l] * p < 0.05 vs Ko ** p < 0.01 vs Ko *** p < vs Ko

11 Intracellular Glutamine intracellular GLN [nmol/10 6 cells] Ko added Glycine [mmol/l] 2mM GLN + GLY * * * p < 0.05 vs Ko

12 Influence of enteral diets supplemented with key 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: Diet II: GLN (3g/100kcal) GLN (3g/100kcal), ARG (0.5g/100kcal), GLY (1g/100kcal), w - 3 FA (0.3g/100kcal) Feeding period 10 days Control, diet I or diet II Day 7 25µg LPS ip. Day 10 sacrified

13 Small intestinal IgA content µg/small intestine *** 0 Control Gln Arg, Gln, Gly, w -3 FA Manhart et al.; Clin Nutr 2000; 19:

14 Effect of Different Combinations of Dietary Additives on Bacterial Translocation and Survival in Gut-Derived Sepsis R Gennari, W Alexander et al., JPEN 1995, 19: 319

15 Schlußfolgerungen - Pharmakokinetik Immunonutrients wirken dosisabhängig Kombinationen von Immunonutrients müssen sorgfältig auf ihre immunmodulierende Wirkung untersucht werden

16 Meta-Analysen - Meta-Antworten 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)

17 R.J. Beale: 13x IMPACT, 2x Immun-Aid... Impact and Immun-Aid are slightly (??) different in composition. IMPACT Immun-Aid Protein (g/l) Arginine (g/l) 12.5 (14) 14 Glutamine (g/l) 9 BCAA (g/l) 20 Nucleic acids (g/l) w - 3 PUFAs (g/l) Zinc (mg) Selenium (µg)

18 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 adult burn 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)

19 D.K. Heyland:... We included studies that compared enteral nutrition with some combination of arginine, glutamine, nucleotides, w - 3 fatty acids IMPACT Optimental Arginine (g/l) 12.5 (14) 5.5 Nucleic acids (g/l) w - 3 PUFAs (g/l) w - 6 : w - 3 ratio 1.5 : : 1 Osmolarität Vitamin E Vitamin C Selenium (µg/l) LOW FREE ARG

20 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.

21 Zusammenfassung der Autoren Beale: Œ Infektionen Œ Beatmungstage Œ 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.

22 Zusammenfassung der Autoren Heys: Œ Infektionen ( Pneumonie ) Œ 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.

23 Zusammenfassung der Autoren Heyland :... Using commercial formulas with high arginine content were associated with a significant reduction in infectious complications and a trend toward a lower mortality rate compared with other immuneenhancing diets.... Studies of surgical patients were associated with a significant reduction in infectious complication rates compared with studies of critical ill patients

24 Heyland : Zusammenfassung der Autoren... 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.

25 Zusammenfassung der Autoren Stirbt man als kritisch Kranker an der Immunonutrition? Kann die Gabe von Immunonutrients gefährlich sein?

26 Immunonutrition bei Sepsis Reduktion der Sterblichkeit in Abhängigkeit vom APACHE II Score 60 Sterblichkeit [%] angereichert konventionell 0 ' APACHE II Score C. Galbán et al., Crit Care Med, 2000

27 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) IMPACT Kontrolle Mortalität gesamt 95/197 (48%) 85/193 (44%) APACHE II gesamt Mortalität early enteral group 21/50 (42%) 19/51 (37%) APACHE II early enteral kritisch kranke Patienten

28 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) IMPACT Kontrolle 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 (?) p= Intensivpatienten

29 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 w - 3 FA LOW FREE ARGININE DIET! Increased ARDS in exp. Diet (45 vs 19%) Identical overall mortality

30 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 Schock davon 21 PN und 18 EN Ernährung: Perative, Abbott, beginnend am 4. Tag LOW FREE ARGININE DIET: 6.8g/L

31 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= (chi square) p= (Fischer) u Primärer Endpunkt Subgruppe SS: ICU Mortalität EN (n=18) PN (n=21) 8 (44%) 3 (14%) p= (chi square) p= (Fischer)

32 Consensus statements 1. Leitlinien der DGEM Akt Ernährungsmedizin 2003:28: S42 2. Consensus statement der SEMICYUC, Spanien Clin Nutr 2003; 22: Canadian Crit Care Clinical Practice Guidelines Committee JPEN 2003; 27: 355

33 Leitlinien der DGEM 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.

34 Consensus Statement der SEMICYUC, Spanien 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

35 Consensus Statement der SEMICYUC, Spanien Conclusions: Considering the beneficial effects and the absence of detrimental ones, the use of diets enriched with pharmaconutrients could be recommended in ICU patients requiring enteral feeding. Nevertheless, more investigation is needed in this field in order to find the more appropriate population of patients that can be beneficed with this nutritional therapy.

36 Canadian Guidelines

37 Canadian Guidelines Out of 14 studies: no effect on mortality Subgroup analysis: High quality studies vs low quality studies, showed that in the higher quality studies, diets supplemented with arginine and other nutrients had no effect on mortality Whereas, in lower quality studies, diets supplemented with Arg and other nutrients had a trend toward reduction in mortality

38 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 mechanical ventilation

39 Canadian Guidelines

40 Canadian Guidelines The committee noted the lack of a treatment effect with respect to mortality and infection (?) in diets supplemented with Arg and other nutrients. Given the potential harm (increased mortality) associated with the use of diets supplemented with Arg and other nutrients in septic patients (Literaturangabe) and the increased costs the committee decided to recommend against their use in critically ill patients.

41 Literaturangabe Editorial: Does immunonutrition in patients with sepsis do more harm than good? DK Heyland, A Samis; Intensive Care Med 2003; 29:669

42 Lest we throw out the baby with the bath water Most likely the culprit is arginine, a nutrient common to all the specialized diets included in the meta-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 may have an adverse effect on critically ill patients with sepsis (Literaturangabe) DK Heyland, A Samis; Intensive Care Med 2003; 29:669

43 Literaturangabe Immune-modulating actions of arginine in the critícally ill U Suchner, DK Heyland, K Peter; Br J Nutr 2002; 87:S121

44 Mögliche Aussagen auf Grund der vorliegenden Studien (E. Roth) Erhöhte Mortalität und Infektionsrate mit experimentellen Diäten, die einen niedrigen Arginin-Gehalt haben Erhöhter Anteil an w - 3 Fettsäuren erhöht die Mortalität Immunonutritions-Produkte mit Nukleotiden bringen einen Vorteil

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

46 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.

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

48 Negative Arginin-Daten Arginin als Vorstufe von NO bewirkt eine Vasodilatation NO + Superoxidradikal führen zu Peroxynitritbildung

49 Positive Arginin-Daten Argininanaloga, um die negative Argininwirkung zu verringern, haben sich beim septischen Patienten nicht durchgesetzt und sind vom Markt verschwunden Arg reduziert die Glukoseintoleranz Arg verbessert die Endothelfunktion

50 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

51 Arginin in der klinischen Ernährung 30 % des zugeführten Glutamins werden in Arg umgewandelt Alle enteralen Ernährungsprodukte enthalten Arg in gebundener Form Arg ist Teil parenteraler Ernährungslösungen

52 Kontraindikation für Arginin Hypodynamischer septischer Schock - hier hat man wohl andere Probleme als die Ernährungstherapie und die Immunonutrition

53 Two-Phase-Model of sepsis: different therapeutical interventions GLN w - 3 FS GLY w - 3 FS? GLN? Immuneparalysis Hyperinflammation Immunereaction ARG? Sepsis IL-6 IL-1 TNF IL-8 HLA-DR IL-10 TGF-b IL-13 LPS induced TNF-a release IL-4

54 Gender differences in Sepsis: Genetically determined? Schroder J et al. Shock 2000; 14: Men (133) Women (68) Genotype % mortality TNFB1/TNFB1 TNFB1/TNFB TNFB2/TNFB2 72 * 53 * Significantly different from other genotypes, same sex

55 Do all cytokine genotypes respond to immuno-nutrients in the same way? or Are some genotypes more responsive to immuno-nutrients than others?

56 Influence of HLA characteristics on the ability of fish oil to suppress TNF production 158 healthy males given 6g/d fish oil for 12 weeks. TNF-a production from LPS stimulated PBMCs measured HLA characteristics of patients identified Grimble et al Percentage of each HLA type showing a fall in TNF HLA DR15 DR3 DR4

57 Klinische Ernährung 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