1. Immunonutrition in the Critically Ill? Role of Arginine-supplemented diets Daren K. Heyland, MD, FRCPC, MSc Professor of Medicine, Queen’s University, Kingston, Ontario

7. JAMA 2001;286:944

10. Outcomes Clinically Important Surrogate Not Clinically Important Mortality QoL Morbidity disease complication s LOS Nutritional weight NB a.a. Physiology Lab animals hypothesis generating

11. Largest Randomized Trial of Immunonutrition  Good Methods  Multicenter RCT  double-blinded  ITT analysis  Heterogeneous group of patients (597)  Elective and urgent surgery (50%)  Trauma (8%)  Medical including septic (42%)  high protein entered formula  enriched with  arginine (10 g/L),  Glutamine  Antioxidants  omega 3 FAs (Stresson®) No other differences in Outcome No subgroup differences Kieft Int Care Med 2005;31:524

12. Updated Analysis: Effect on Mortality www.criticalcarenutrition.com

13. Updated Analysis: Effect on Infectious Complications www.criticalcarenutrition.com

14. Cocktail Approach? Specific nutrients found to have effects on immune system, metabolism, and GI structure and function  Arginine  Glutamine  Omega-3 fatty acids  Nucleic acids  others Rationale for combining substances into products?

15. = Homogenous Patient Populations?

16. Heyland JAMA 2001;286:944 Effect of Immunonutrition: A meta-analysis

17. Elective Surgical Patient cellular immune dysfunction – T-cell decrease cytokine activation –IL-2, IFN

18. Elective Surgical Patient arginase 1 arginine expression of zeta chain Taheri Clin Cancer Res 2001 ;7:958 MYELOID SUPPRESSOR CELLS

19. PGE1 PGE1 + IL-13 PGE2 PGE2 + IL-13 PGE3 PGE3 + IL-13 + Control Effect of Different Types of Oils on Arginase 1 Expression Effect of Different Prostaglandins on Arginase expression in RAW 264.7 cells Arginase expression may be modified by the type of Fatty Acid PGE1 – Borage Oil PGE2 – Corn Oil PGE3 – fish Oil Bansal JPEN 2005 29;S75

20. Elective Surgical Patient Replete arginine levels Inhibit Arginase 1 Restoring Immunocompetence

21. Immunonutrition in Surgical Patients As of 2006

22. Insult infection trauma I/R hypoxemic/ hypotensive Activation of PMN’s = oxidative stress Death organ = failure Pathophysiology of Critical Illness mitochondrial dysfunction Role of GIT Key nutrient deficiencies (e.g. glutamine, selenium) activation of coagulation/complement generation of OFR (ROS + RNOS) endothelial dysfunction elaboration of cytokines, NO, and other mediators cellular = energetic failure

23. Metabolic Effects of Arginine enteral / parenteral supply L-ArginineL-CitrullineL-Ornithine Polyamine Synthesis Putrescine Spermidine Spermine Hormone release GH IGF Insulin Glucagon Prolactin catecholamines Urea Nitrogenous compounds Nitric oxide Nitrite Nitrate Suchner Brit J Nutrition 2001

24. Mitaka Shock 2003;19: 305 Underlying Pathophysiology Role of Nitric Oxide

25. Figert… Ochoa Surg Forum 1998 Arginine Metabolism after Trauma in Mice

26. Rixen Shock 1997;7:17 Underlying Pathophysiology Role of Nitric Oxide

27. cNOS cNOS + iNOS Effect of Arginine induced NO formation Harmful Benefitial Arginine / NO availability Optimal NO-Balance - Hemodynamic instability - Immune Suppression - Cytotoxicity - Organe dysfunction - Microcirculation  - Immune augmentation  Suchner Brit J Nutrition 2001

28. Is it plausible that Arginine- supplemented diets may do harm?  Randomized, double blind, placebo- controlled  Beagles  Parenteral L-arginine (+ NAC) vs placebo  Canine model of E. coli peritonitis Kalil Crit Care Med 2006;34:2719

29. Is it plausible that Arginine- supplemented diets may do harm? Arginine administration associated with: Plasma arginine NO products And worse shock, worse organ injury Increased mortality! Kalil Crit Care Med 2006;34:2719 No effect of NAC

30. Is it plausible that Arginine- supplemented diets may do harm?  3 RCTs  3 different products  All describing excess mortality in patients with infection 1) Bower Crit Care Med 1995;23:436 2) Dent, Crit Care Med 2003;30:A17 3) Bertolini Intesive Care Med 2003;29:834

31. Benefit in Sepsis?  Multicenter RCT  Not blinded  Loose definition of sepsis  181 Critically ill patients with infection and APACHE>10  ?cointerventions  Only assessed ICU mortality  Non ITT P=0.05 Benefit in subgroup APACHE<15 Galban Crit Care Med 2000; 28:643-648

32. Canadian Clinical Practice Guidelines Committee: ARGININE: DISCUSSION Lack of tx effect for mortality and infections.  cost. Possible  mortality in septic pts (3 studies) Heyland DK. Intensive Care Med 2003;17:267-271 VALUES: ValidityEffect sizeConfidence interval HomogeneitySafeFeasibleLow cost But what about...

33. Diets Supplemented with arginine and select other nutrients Recommendation: Based on 3 level 1 studies and 15 level 2 studies, we recommend that diets supplemented with arginine and other select nutrients not be used for critically ill pts. Canadian Clinical Practice Guidelines JPEN 2003;27:355-373

34. Rebuttal

35. Methodological Quality of RCT’s of Arginine-containing diets o 5/22 (23%) concealed randomization o 12/22 (55%) were double-blinded o 10/22 (45%) performed Intention-to-treat analysis

37.  Intention-to-treat  includes all randomized patients  less sensitive but most robust estimate of treatment effect  Efficacy analysis  includes only patients who met the eligibility criteria and actually rec’d feeds  more sensitive than ITT but less valid  Compliance analysis  includes only patients who receive a critical volume of study feeds  highly biased, more likely to misinform Analyzing the Data

38. % Mortality ICU Length of Stay p=0.02 Immunonutrition: Does it make a Impact? Crit Care Med 1998;26:1164

39. IED Control CCM 1998;26:1164 Compliance Analysis Intention-to-treat Analysis

40. Corporate Endorsement! Dear Doctor Nutricia has been closely following the debate over the so-called "immune enhancing diets" or "immunutrition" (IED). Recent publications and studies have questioned the use of IEDs. This month the Canadian Critical Care Clinical Practice Guidelines Committee has published new guidelines for nutrition support in critically ill patients (October 2003); these guidelines clearly advise against the use of IEDs for critically ill patients. The guidelines explicitly state as follows… " According to 2 Level 1 studies and 12 level 2 studies, we recommend that diets supplemented with arginine and other select nutrients not be used for critically ill patients" (1) After full consideration of recent scientific publications and the new evidence based Canadian guidelines, Nutricia has decided, in the best interests of patients and carers, to discontinue the availability of Stresson/Stresson Multi Fibre. Nutricia recommend to you to follow, from now on, the recommendations of the Canadian guidelines. Nutricia Oct 03

41. Arginine diets in ICUs in the world and Australia

42. International Audit of 165 ICUs Total % Patients Ever on EN receiving formula N=2773 Arginine-supplemented formulas 5.3 % (0.0-92.3) Glutamine supplementation 7.2 % (0-100) Fish/Borage oils+AOX (All) 1.4 % (0-40) Fish/Borage oils+AOX (ARDS) 4.1 % (0-100) Polymeric 91.2 % (0-100)