Immune Enhancing Nutrition in the Critically Il End of an Era? - Has it ever begun?

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1 Immune Enhancing Nutrition in the Critically Il End of an Era? - Has it ever begun? Prof. Reto Stocker, MD Head Institute for Anesthesiology and Intensive Care Medicine Hirslanden Clinic Zurich, Switzerland

2 AGENDA A Few Basics of Long-Chain-Fatty Acids Clinical Relevance of Long Chain Fatty Acids (LCT) Glutamine and Antioxidants Newer studies and meta-analyses

3 Fatty Acids May Alter Immune and Inflammatory Phenotype Fatty Acids Incorporation into cell membranes Membrane structure and function Fluidity Ion channels Receptors Penetrate into cell Gene expression (eg, inflammatory gene expression via NF-kB) Eicosanoid (and cytokine) production Cell signaling FA, fatty acid; NF-κB, nuclear factor-κb. modified from: Wanten GJA, Calder PC Am J Clin Nutr 2007

4 Eicosanoid Synthesis from Fatty Acids of w6- w9 and w3-family ω-6 FS ω-9 FS ω-3 FS LinoleicAcid C18:2 n6 OleicAcid 18:1w9 a-linolenicacid C18:3 n3 ArachidonicAcid C20:4 n6 20:3w9 Eicosatrienic Acid Eicosapentaenoic Acid C20:5 n3 Lipoxygenase Lipoxygenase Cyclooxygenase Leukotriens Series 4 Prostanoids Series 2 pro-inflammatory pro-thrombotic immune neutral Prostanoids Series 3 Leukotriens Series 5 anti-inflammatory anti-thrombotic

5 AGENDA Basics of Lipids Clinical Relevance of Long Chain Fatty Acids (LCT) LCT in the ICU What should we consider? Newer studies

6 ω-9 Olive Oil: Immunologic Effects compared to ω-6 Fatty Acids Limited to no impact on lymphocyte proliferation or NK cell activity 1,2 Limited to no impact on neutrophil responses 3-5 Prevention of the release of certain chemotactic molecules (eg, ICAM-1) 6 Little effect on eicosanoid production 7 Reduced peroxidation potential 8,9 1. Granato D, et al. JPEN. 2000;24(2): Yaqoob P, et al. Am J Clin Nutr : Cury-Boaventura MF, et al. JPEN. 2008;32(1): Buenestado, et al. JPEN. 2006;30(4): Wanten G, et al. J Lipid Res. 2002;43(4): Yaqoob P, et al. Am J Clin Nutr. 1998;67(1): Harwood JL, Yaqoob P. Eur J Lipid Sci Technol. 2002;104(9-10): Waitzberg DL, et al. JPEN. 2006;30(4): Wanten GJA, Calder PC. Am J Clin Nutr. 2007;85(5):

7 ω-3 Fish Oil: Immunologic Effects compared to ω-6 Fatty Acids In-vitro & Ex-vivo - Decreased production of pro-inflammatory mediators (ie. TNF, IL-1, Il-2, Il-6 ) and adhesion molecules In-vivo - Reduction in natural killer cell activity - Decreased lymphocyte proliferation and activation - Decreased antigen presentation functions - Decreased leukocyte chemotaxis, migration, infiltration - Decreased pro-inflammatory cytokine expression

8 Potential advantages of fish oil in severe hyperinflammation (SIRS / Sepsis) Mediators, Toxines, activated PMNs => Ductus thoracicus SIRS severe Early MODS Mortality Trauma Permeability Motility Integrity moderate (Proinflammatory Cytokines) Shock Laparotomy ICU Therapy Fish IED Oil Bacterial Translocation CARS Infection Late MODS Mortality Immunparalysis

9 Unclear/Disrespected: Individual Pro- and Antiinflammation (Hyper-)Infammation Gender/Genetics Age Comorbidities Concommittant Conditions Time (Hypo-/)Anti-Inflammation

10 Fish Oil (omega-3 PUFA) Whereas the anti-inflammatory properties of PUFA may be beneficial for some chronic inflammatory illnesses, these same anti-inflammatory properties may be detrimental for the response to an infection when an intact immune response is needed to eradicate an invading pathogen Schwerbrock NMJ et al. et al. Fish Oil-Fed MiceHave ImpairedResistance to Influenza Infection. J Nutr 2009; 139: Fish oils lower the host resistance to: - Mycobacterium tuberculosis - Listeria monocytogenes - Salmonella typhimurium - Influenza virus - Fungal infections? - Other Bacteria?

11 Newer Data

12 RiceTW. et al. Enteral Omega-3 FattyAcid, γ-linolenicacid, and AntioxidantSupplementationin Acute Lung Injury(OMEGA study) JAMA 2011;306: Randomized, double-blind, placebo-controlled, multicenter trial: 272 adults within 48 hours of developing ALI requiring mechanical ventilation Enteral supplement of n-3 PUFAs, γ-linolenic acid, and AOXs twice per day compared with an isocaloric control Study stopped early for futility after 143 and 129 patients were enrolled

13 From: Enteral Omega-3 Fatty Acid, γ-linolenic Acid, and Antioxidant Supplementation in Acute Lung Injury Rice et. Al. JAMA. 2011;306(14): doi: /jama Figure Legend: Omega-3 (n-3) supplement (docosahexaenoic acid and eicosapentaenoic acid), omega-6 γ-linolenic acid, and antioxidants. Solid lines: survival curves; dashed lines: proportion of patients breathing without assistance at each period. Areas above solid lines: proportion of patients who have died in each group at each period; areas below the dashed lines: proportion of patients alive and free of mechanical ventilation in each group at each period. Areas between the solid and dashed lines indicate percentages alive and still receiving mechanical ventilation in each group at each period. Copyright 2014 American Medical Date of download: 11/12/2014 Association. All rights reserved.

14 Rice et. Al. JAMA. 2011;306(14): doi: /jama

15 Study restriction All patients suffered from undernutrition. 5 x more protein in the control group!!! Rice et al, JAMA 2011

16 MetaPlus Study JAMA. 2014;312: doi: /jama

17 Design, Setting, and Participants Randomized, double-blind, multicenter trial, 6-month follow-up period 301 adult patients, expected to be ventilated for > 72 h and to require EN for > 72 h - Immune-modulating nutritient enriched high-protein diet (IMHP; n = 152) vs. high-protein diet (n = 149), initiated within 48 hours of ICU admission and continued during the ICU stay for a maximum of 28 days - intention-to-treat analysis in predefined medical, surgical, and trauma subpopulations

18 6- Months-Mortality New infections a, No (%) Total Group Medical patients Surgical patients Trauma patients IMHP HP P IMHP HP P Value Value IMHP HP P Value IMHP HP P Valu e (n=152) (n=149) (n=54) (n=55) (n=81) (n=75) (n=55) (n=54) 80 (53) 78 (52).96 b 21 (39) 26 (47).38 b 50 (62) 38 (51).16 b 32 (58) 36 (67).36 b Mortality, No (%) e ICU 30 (20) 29 (20).95 b 17 (32) 12 (22).25 b 11 (14) 16 (22).20 b 5 (9) 6 (11).73 b Hospital 38 (25) 33 (23).56 b 23 (43) 16 (29).14 b 13 (17) 16 (22).39 b 6 (11) 6 (11).97 b 28 days 31 (20) 25 (17).42 b 19 (35) 13 (24).19 b 11 (14) 12 (16).67 b 4 (7) 2 (4).68 b 6 months 53 (35) 42 (29).21 b 29 (54) 19 (35).04 b 22 (28) 21 (29).90 b 8 (15) 9 (17).76 b Total numbers Number of events (deaths) DF Coefficient SE P Value Hazard Ratio 95% CI Treatment IMHP HP Van Zanten ARH et al., JAMA 2014

19 Van Zanten ARH et al., JAMA 2014

20 Edmunds E et al. The effects of different IV fat emulsions on clinical outcomes in critically ill patients. Crit Care Med 2014;42: OBJECTIVE: To examine effects of different IV fat emulsions on clinical outcomes in critically ill patients. DESIGN: Secondary analysis of data from a prospective multicenter study. SETTING: An international sample of ICUs. PATIENTS: 451 adults with ICU-stay > 72 hours, MV within 48 hours, receiving TPN 5 days, without change IV fat emulsion during data collection for up to 12 days, until death, or discharge from the ICU, whichever came first. Clinical outcomes were recorded at 60 days following ICU admission MAIN RESULTS: 70 pat. (15.5%) in lipid-free group, 223 (49.5%) in soybean oil group, 65 (14.4%) in the MCT group, 74 (16.4%) in olive oil group, and 19 (4.9%) in fish oil group. - Compared to lipid-free PN, patients with FO had faster time to ICU discharge alive (hazard ratio, 1.84; 95% CI, ; p = 0.05). - When compared with soybean oil, patients with olive oil or fish oil had a shorter time to termination of MV alive (HR, 1.43; 95% CI, ; p = 0.02 and HR, 1.67; 95% CI, ; p = 0.05) and a shorter time to ICU discharge alive (HR 1.76; 95% CI, ; p < and HR, 2.40; 95% CI, ; p = 0.001).

21 Hall TC et al. A Randomized Controlled Trial Investigating the Effects of Parenteral Fish Oil on Survival Outcomes in Critically Ill Patients With Sepsis: A Pilot Study. JPEN 2015;39: Intervention: 60 Patients, parenteral ω-3 (Omegaven; as independent drug, not as a nutrition supplement) vs. standard medical care; 30% (control), 33% (intervention) received artificial nutrition only RESULTS: Significant in new organ dysfunction (Δ-SOFA 2.2 ± 2.2 vs. 1.0 ± 1.5, P =.005) max-sofa (10.1 ± 4.2 vs. 8.1 ± 3.2, P =.041), max. CRP (186.7 ± 78 vs ± 62.6, P =.019) in patients with ω-3 No significant reduction in LOS between cohorts Significant in mortality (P =.042) with ω-3 and less severe sepsis CONCLUSION: Treatment of critically ill septic patients with parenteral ω-3 was safe and associated with a significant reduction in organ dysfunction. It may be associated with a reduction in mortality in patients with less severe sepsis 21

22 Hall TC et al. A Randomized Controlled Trial Investigating the Effects of Parenteral Fish Oil on Survival Outcomes in Critically Ill Patients With Sepsis: A Pilot Study. JPEN 2015;39: Intervention: 60 Patients, parenteral ω-3 (Omegaven; as independent drug, not as a nutrition supplement) vs. standard medical care; 30% (control), 33% (intervention) received artificial nutrition only RESULTS: Significant in new organ dysfunction (Δ-SOFA 2.2 ± 2.2 vs. 1.0 ± 1.5, P =.005) max-sofa (10.1 ± 4.2 vs. 8.1 ± 3.2, P =.041), max. CRP (186.7 ± 78 vs ± 62.6, P =.019) in patients with ω-3 No significant reduction in LOS between cohorts Significant in mortality (P =.042) with ω-3 and less severe sepsis CONCLUSION: Treatment of critically ill septic patients with parenteral ω-3 was safe and associated with a significant reduction in organ dysfunction. It may be associated with a reduction in mortality in patients with less severe sepsis 22

23 Grau-Carmona T et al. Influence of n-3 polyunsaturated fatty acids enriched lipid emulsions on nosocomial infections and clinical outcomes in critically ill patients: ICU lipids study. Crit Care Med 2015;43:31-9 OBJECTIVE: To investigate the effects of n-3 fatty acids on prevalence of nosocomial infections and clinical outcomes in medical and surgical critically ill patients. DESIGN: Prospective, multicenter, randomized, comparative, double-blind study SETTING: 17 Spanish ICUs during 4 years SUBJECTS: 159 medical and surgical intensive care patients with APACHE II score 13 (0-71), expected to require total parenteral nutrition for at least 5 days. INTERVENTIONS: TPN with a lipid emulsion containing 10% fish oil vs. a fish oil-free lipid emulsion. MEASUREMENTS AND MAIN RESULTS: Significant reduction in patients with nosocomial infections in the fish oil-receiving group (21.0% vs 37.2%, p = 0.035) and the predicted time free of infection was prolonged (21 ± 2 vs 16 ± 2 d, p = 0.03). No significant differences in ICU, hospital, and 6-month mortality. CONCLUSIONS: Administration of n-3 PUFA s reduced the risk of nosocomial infections and increased the predicted time free of infections in critically ill medical and surgical patients. Administration was safe and well tolerated 23

24 Grau-Carmona T et al. Influence of n-3 polyunsaturated fatty acids enriched lipid emulsions on nosocomial infections and clinical outcomes in critically ill patients: ICU lipids study. Crit Care Med 2015;43:31-9 OBJECTIVE: To investigate the effects of n-3 fatty acids on prevalence of nosocomial infections and clinical outcomes in medical and surgical critically ill patients. DESIGN: Prospective, multicenter, randomized, comparative, double-blind study SETTING: 17 Spanish ICUs during 4 years SUBJECTS: 159 medical and surgical intensive care patients with APACHE II score 13 (0-71), expected to require total parenteral nutrition for at least 5 days. INTERVENTIONS: TPN with a lipid emulsion containing 10% fish oil vs. a fish oil-free lipid emulsion. MEASUREMENTS AND MAIN RESULTS: Significant reduction in patients with nosocomial infections in the fish oil-receiving group (21.0% vs 37.2%, p = 0.035) and the predicted time free of infection was prolonged (21 ± 2 vs 16 ± 2 d, p = 0.03). No significant differences in ICU, hospital, and 6-month mortality. CONCLUSIONS: Administration of n-3 PUFA s reduced the risk of nosocomial infections and increased the predicted time free of infections in critically ill medical and surgical patients. Administration was safe and well tolerated 24

25 Manzarenes W. Langlois P, Dhaliwal R, Lemier M, Heyland D.K. Intravenous fish oil lipid emulsions in critically ill patients: an updated systematic review and meta-analysis. Critical Care 2015;19:167 Infections

26 Manzarenes W. Langlois P, Dhaliwal R, Lemier M, Heyland D.K. Intravenous fish oil lipid emulsions in critically ill patients: an updated systematic review and meta-analysis. Critical Care 2015;19:167 Mortality

27 Manzarenes W. Langlois P, Dhaliwal R, Lemier M, Heyland D.K. Intravenous fish oil lipid emulsions in critically ill patients: an updated systematic review and meta-analysis. Critical Care 2015;19:167 Mechanical Ventilation

28 Manzarenes W. Langlois P, Dhaliwal R, Lemier M, Heyland D.K. Intravenous fish oil lipid emulsions in critically ill patients: an updated systematic review and meta-analysis. Critical Care 2015;19:167 LOHS

29 Manzarenes W. Langlois P, Dhaliwal R, Lemier M, Heyland D.K. Intravenous fish oil lipid emulsions in critically ill patients: an updated systematic review and meta-analysis. Critical Care 2015;19:167 ICU-LOS

30 Manzarenes W. Langlois P, Dhaliwal R, Lemier M, Heyland D.K. Intravenous fish oil lipid emulsions in critically ill patients: an updated systematic review and meta-analysis. Critical Care 2015;19:167 Conclusions According to the current literature, there is inadequate evidence to give a strong recommendation on the routine use of FO-containing Lipid Emulsions in PN and/or as a pharmaconutrient strategy in enterally fed critically ill patients

31 Final Conclusions on Lipids With respect to the fact that inflammation per se is indispensable for immune response, for infection control, for wound healing and that individual response of critically ill ICU patients is unpredictable...based on new literature it is questionable if every ICU patient should receive higher amounts omega-3 Fatty acids or if it is not sufficient/ advantageous in cases without obvious hyperinflammation just to reduce overall omega-6 FA administration i.e. by replacement with omega-9 FA

32 AGENDA Some Basics of Lipids Clinical Relevance of Lipid Emulsions Antioxidants Glutamine

33 Functions of Antioxidants Neutralize free radicals Reduce inflammation at adequate doses Stimulate immune function Alter gene expression Co-factor for certain biological reactions Required by mitochondria to generate ATP

34 Antioxidants: Enzymes OXYGEN MOLECULE O 2 2 H 2 O + O 2 Antioxidant SUPEROXIDE RADICAL Supoeroxide Dismutase e - Comments 2 H + O 2 SUPEROXIDE Co-factor of glutathione peroxidase e Cave: pro-oxidant - DISMUTASE effects at high doses? (FE, CU, ZN) CATALASE (HEME PROTEIN) HYDROGEN PEROXIDE Catalase Glutathione Peroxidase HYDROXYL RADICAL & ION SCAVENGERS H 2 O 2 Major intracellular antioxidant e - - Treatment of acetaminophen PEROXIDASE overdose OH + OH 2 H + e - Fe (II) Fe (III) H 2 O 2 GLUTATHION (Se) 2 GSH reduced GSSG oxidized NADP GLUTATHION REDUCTASE (Riboflavin) H + NADPH WATER 2 H 2 O 2 H 2 O

35

36 Selenium

37 Glutathionperoxidase (GSH-Px) Leopold Flohé GBF, The Boss s Hobby- Glutathione Peroxidases, identical subunits Every subunit needs a selenium atom to allow for its enzymatic activity Task: Protection of the cell from free radicals

38 Possible Reasons for low Selenium Levels in Critically Ill Low nutritive selenium level Increased consumption due to oxidative stress Catabolism (Postaggression Metabolism) Redistribution within body compartments Increased renal losses GI-losses Losses via drainages Reduced supplementation (i.e. TPN) negative Selenium Balance

39 Selenium Content of Soil: Regional Differences

40 Main Problems Clinical Studies ConsiderableDifferencesin Study Design Study location (Soil Content of Selenium) Dose Bolus-No Bolus Early-Late Duration May explain some differences between trials and impair value of metaanalyses

41 Intravenous Loading Dose versus no Loading Lose In 5 aggregated studies, parenteral selenium supplementation with a bolus showed a trend toward reduction in mortality (RR = 0.81, 95% CI 0.65 to 1.02, P = 0.07; test for heterogeneity P = 0.40, I 2 = 1%). Parenteral selenium without loading dose did not show effect on mortality Berger MM, Soguel L, Shenkin A, Revelly JP, Pinget C, Baines M, Chiólero R: Influence of early antioxidant supplements on clinical evolution and organ function in critically ill cardiac surgery, major trauma, and subarachnoid hemorrhage patients. Crit Care 2008, 12:R101 Valenta J, Brodska H, Drabek T, Hendl J, Kazda A: High-dose selenium substitution in sepsis: a prospective, randomized clinical trial. Intensive Care Med 2011, 37: Manzanares W, Biestro A, Torre MH, Galusso F, Facchín G, Hardy G: High dose selenium reduces ventilator associated pneumonia and illness severity in critically ill patients with systemic inflammation. Intensive Care Med 2011, 37: Zimmermann T, Albrecht S, Kühne H, Vogelsang U, Grützmann R, Kopprasch S: Selensubstitution bei Sepsispatienten. Medizinische Klinik 1997, 92:3-4. Angstwurm MW, Engelmann L, Zimmermann T, Lehmann C, Spes CH, Abel P, Strauss R, Meier-Hellmann A, Insel R, Radke J, Schüttler J, Gärtner R: Selenium in Intensive Care (SIC): results of a prospective randomized, placebo-controlled, multiple-center study in patients with severe systemic inflammatory response syndrome, sepsis, and septic shock. Crit Care Med 2007, 35:

42 Selenium high Dose versus lower Dose 4 trials [16,59,67,69] using doses > 500 μg/d showed a trend towards a lower mortality (RR = 0.80, 95% CI 0.63 to 1.02, P = 0.07) and infections. Doses < 500 μg/d had no effect on mortality (RR = 0.94, 95% CI 0.67 to 1.33, P = 0.75) Manzanares W, Biestro A, Torre MH, Galusso F, Facchín G, Hardy G: High dose selenium reduces ventilator associated pneumonia and illness severity in critically ill patients with systemic inflammation. Intensive Care Med 2011, 37: Zimmermann T, Albrecht S, Kühne H, Vogelsang U, Grützmann R, Kopprasch S: Selensubstitution bei Sepsispatienten. Medizinische Klinik 1997, 92:3-4 Angstwurm MW, Engelmann L, Zimmermann T, Lehmann C, Spes CH, Abel P, Strauss R, Meier-Hellmann A, Insel R, Radke J, Schüttler J, Gärtner R: Selenium in Intensive Care (SIC): results of a prospective randomized, placebo-controlled, multiple-center study in patients with severe systemic inflammatory response syndrome, sepsis, and septic shock. Crit Care Med 2007, 35: Forceville X, Laviolle B, Annane D, Vitoux D, Bleichner G, Korach JM, Cantais E, Georges H, Soubirou JL, Combes A, BellissantE: Effects of high doses of selenium, as sodium selenite, in septic shock: a placebo-controlled, randomized, double-blind, phase II study. Crit Care 2007, 11:R73 2 trials [17,64] using doses equal to 500 μg/d showed a trend towards a lower infections (RR = 0.86, 95% CI 0.71 to 1.05, P = 0.13) Doses lower than 500 μg/d had no effect on infections (RR = 0.87, 95% CI 0.64 to 1.19, P = 0.39). The test for subgroup differences was not significant Andrews PJ, Avenell A, Noble DW, Campbell MK, Croal BL, Simpson WG, Vale LD, Battison CG, Jenkinson DJ, Cook JA, Scottish Intensive care Glutamine or selenium Evaluative Trial Trials Group: Randomised trial of glutamine, selenium, or both, to supplement parenteral nutrition for critically ill patients. BMJ 2011, 17:d1542 Berger MM, Recmond MJ, Shenkin A, Rey F, Wardle C, Cayeux C, Schindler C, Chioléro RL: Influence of selenium supplements on the post-traumatic alterations of the thyroid axis: a placebo-controlled trial. Intensive Care Med 2001, 27:91-100

43 A Meta - Analysis Manzanares W. et al. Pharmaconutrition with antioxidant micronutrients in the critically ill: The time has come! Nutrition 2013;29:

44 Effects of Antioxidant Strategies on Mortality (n = 20) Manzanares W. et al. Pharmaconutrition with antioxidant micronutrients in the critically ill: The time has come! Nutrition 2013;29:

45 Effect of Combined Antioxidant Therapy on Ventilation Days (n = 4) Manzanares W. et al. Pharmaconutrition with antioxidant micronutrients in the critically ill: The time has come! Nutrition 2013;29:

46 Results of Subgroup Analyses Examining the Effect of Parenteral Selenium Supplementation on Mortality Manzanares W. et al. Pharmaconutrition with antioxidant micronutrients in the critically ill: The time has come! Nutrition 2013;29:

47 Results of Subgroup Analyses Examinating the Effects of Parenteral Selenium Supplementation on Infections Manzanares W. et al. Pharmaconutrition with antioxidant micronutrients in the critically ill: The time has come! Nutrition 2013;29:

48 Glutamine and Antioxidants in ICU Patients Heyland D et al. New Engl J Med 2013; 368:

49 Antioxidants in ICU Patients Heyland D et al. New Engl J Med 2013; 368:

50 Antioxidants in ICU Patients Selenium dose to low (?), to slow, no bolus => no effect, no harm Heyland D et al. New Engl J Med 2013; 368:

51 Another Meta-Analysis Parenteral selenium treatment significantly reduced allcause mortality in critically ill patients with sepsis (relative risk [RR] 0.83, 95% CI , p=0.04, I(2)=0%). Subgroup analyses demonstrated that following administration schedule are associated with a lower mortality risk - Longer duration (RR 0.77, 95% CI , p=0.01, I(2)=0%), - Loading boluses (RR 0.73, 95% CI , p=0.01, I(2)=0%) - High-dose selenium treatment (RR 0.77, 95% CI , p=0.04, I(2)=0%) There was no evidence of adverse events. Ting-Shuo H, Effect of Parenteral Selenium Supplementation in Critically Ill Patients: A Systematic Review and Meta-Analysis PLoS One. 2013;8: e54431.

52 Conclusions Antioxidants may decrease mortality and shorten mechanical ventilation and may be associated with a trend towards reduced infections in critically ill Treatment effect may be greatest in patients with low serum level, greater severity of illness, higher dose and may also depend on the type of intervention and/or the method of administration Upper dose limit has not been identified yet but most probably exists

53 AGENDA Some Basics of Lipids Clinical Relevance of Lipid Emulsions Antioxidants Glutamine

54 Numerous studies and meta-analyses showing beneficial effects of glutamine supplementation The beneficial trials consistently administered larger doses of glutamine (typically >0.5 g/kg/day) and most gave it intravenously

55

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57 Safety Aspects Increased ammonia levels in two patients receiving GLN supplementation, partly related to acute renal failure and liver dysfunction. - Authors commented that a high nitrogen load from any protein source could have contributed to raised levels - They suggested it may be prudent to monitor ammonia concentrations in patients on GLN supplementation with severe renal or liver dysfunction Wischmeyer PE, et al. Glutamine administrationreduces Gram-negative bacteraemia in severely burned patients: a prospective, randomised, double-blindtrial versus isonitrogenous control. Crit Care Med 2001; 29:

58 An Important Cautious Note Critically ill patients presenting with severe appearances of SIRS, sepsis and organ failure apparently may present with increased glutamine plasma levels - Increased plasma levels of glutamine relate to an impaired outcome Rodas P et al. Clin Scie 2012; 122:

59 Additional Information In 776 patients without impaired renal function at enrollment, a slight trend to reduced mortality was seen in the GLN and AOX groups compared to placebo

60 Critical Appraisal Results have to be considered in the light of a very special shock patient group, treated with very high doses of glutamine and anti-oxidants within less than 24 hours after onset of cardio-vascular instability. - Such a patient group has never been evaluated in a clinical trial on glutamine and anti -oxidants before and cannot be compared with the huge body of evidence which is available on other patient groups being critically ill as well but not in shock and organ failure!

61 Conclusion Currently a combined enteral and parenteral supply of high doses of glutamine cannot be recommended in patients presenting with severe shock and multiple organ failure as the substrate may not be conditionally essential anymore in that particular clinical setting The use of high dose glutamine administration -even provided by combined enteral/parenteral supply -should be continued to be evaluated in other patient groups but in randomised controlled trials (RCTs) only and under tight control of plasma glutamine and ammonia levels

62 A Kind of Summary

63 63

64 Glutamine 64

65 Glutamine 65

66 Omega-3 FA 66

67 Omega-3 FA 67

68 Arginine 68

69 Arginine 69

70 Selenium and Trace Elements, Antioxidant Cocktails 70

71 Final Conclusions The end of immunonutrition may have not come (yet) but Provision maybe has to be individualized as one size does not fit all 71

72 If you cannot convince them - confuse them!

73 THANK YOU!