1. Pharmaconutrition: Selected Nutrients and Their Influence on Patient Outcomes The Canadian Clinical Practice Guidelines Daren K. Heyland, MD, FRCPC, MSc Queen’s University, Kingston, Ontario

2. www.criticalcarenutrition.com Updated July 2006

3. Immunonutrition: 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 Individual effect on clinical outcomes?

4. 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 Arginine

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

6. Elective Surgical Patient arginase arginine expression of zeta chain Taheri Clin Cancer Res 2001 ;7:958

7. =

8. 1.18 (0.88,1.58)

9. Elective Surgery Critically Ill GeneralSepticTraumaBurnsAcute Lung Injury Arginine Glutamine Omega 3 FFA Antioxidants Population Nutrients Which Nutrients? Which Patients? Canadian Clinical Practice Guidelines JPEN 2003;27:355 www.criticalcarenutrition.com

10. Underlying Rationale for Framework oNo scientific rationale for combining nutrients together; need to consider them alone oEmpirical evidence that the nutrients have different treatment effects across populations

11. Elective Surgery Critically Ill GeneralSepticTraumaBurnsAcute Lung Injury ArginineBenefitNo benefitHarmNo benefit GlutaminePossible Benefit PN Beneficial (? receiving EN) …EN Possibly Beneficial … Omega 3 FFA ……………Possible Benefit Antioxidants…Possible Benefit ………… Population Nutrients Which Nutrient for Which Population? Canadian Clinical Practice Guidelines JPEN 2003;27:355

12. Arginine-supplemented diets?

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

14. 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

15. Effect of Arginine- supplemented diets on Mortality www.criticalcarenutrition.com

16. Effect of Arginine-supplemented diets on Infectious complications

17. Possible  mortality in septic pts. Crit Care Med 1995;23:436 Dent, Crit Care Med 2003 Bertolini Int Care Med 2003;29:834  cost. Lack of treatment effect. But what about... Effect of Arginine-supplemented diets in Critically Ill Patients

18. Glutamine supplementation?

19. Potential Beneficial Effects of Glutamine Fuel for Enterocytes Lymphocytes NuclotideSynthesis Maintenance of Intestinal Mucosal Barrier Maintenance of LymphocyteFunction Preservation of TCA Function Decreased Free Radical availability (Anti-inflammatory action) GlutathioneSynthesis GLNpool Glutamine Therapy Enhanced Heat Shock Protein Shock Protein Anti-catabolic effect Preservation of Muscle mass ReducedTranslocation Enteric Bacteria or Endotoxins Reduction of Infectious complications Inflammatory Cytokine Inflammatory CytokineAttenuation NF-  B NF-  B? Preserved Cellular Energetics- ATP content GLNPool Critical Illness Enhanced insulin sensitivity

20. Effect of Glutamine: A Systematic Review of the Literature www.criticalcarenutrition.com Infectious Complications

21. Effect of Glutamine: A Systematic Review of the Literature www.criticalcarenutrition.com Mortality

22. Results of subgroup analysis EN vs PN? MortalityInfection EN0.80 (0.45-1.43) P=0.46 0.83 (0.64-1.08) P=0.16 PN0.67 (0.48-0.92) P=0.01 0.75(0.54-1.04) P=0.08

23. Benefit of Parenteral Glutamine in Patients on EN?

24. Fish Oil supplemented diets?

25. Mechanisms of Action Mediator formation depends on the phospholipid fatty acid content of arachidonic acid (AA) in inflammatory cell membranes It is possible to modulate the content of AA in inflammatory cell membranes by changing lipid composition of the diet

26. Borage Oil DGLA PGE 1 and Less Inflammatory Eicosanoids Substitution of AA By DGLA resulting in: Fish Oil GLAEPA Less Inflammatory Eicosanoids (TXA 3, PGE 3, LTB 5 ) Substitution of AA By EPA Resulting in: Arachidonic Acid Cyclooxygenase Lipoxygenase Pro-Inflammatory Eicosanoids (LTB 4, TXA 2, PGE 2 ) Decrease in X Mechanisms of Action

27. Borage Oil DGLA PGE 1 and Less Inflammatory Eicosanoids Substitution of AA By DGLA resulting in: Fish Oil GLAEPA Less Inflammatory Eicosanoids (TXA 3, PGE 3, LTB 5 ) Substitution of AA By EPA Resulting in: Arachidonic Acid Cyclooxygenase Lipoxygenase Pro-Inflammatory Eicosanoids (LTB 4, TXA 2, PGE 2 ) Decrease in Mechanisms of Action

28. Effect of Fish Oils/Borage Oils and antioxidants in Critically Ill with ALI RCT of 146 critically ill patients with ALI and BAL+ for WBCs Double-blinded; ITT Experimental: Oxepa® Control: high fat diet Groups well matched at baseline Gadek Crit Care Med 1999;27:1409 P=0.03 P=0.17 P=0.02

29. Effect of Fish Oils/Borage Oils and antioxidants in Critically Ill with ALI RCT of 100 critically ill patients with ALI Single center unblinded; not ITT Experimental: Oxepa® Control: high fat diet Oxepa associated with improved oxygenation and lung compliance Singer Crit Care Med 2006:34;1033

30. Effect of Fish Oils/Borage Oils and antioxidants in Critically Ill with ALI RCT of 165 critically ill patients with ARDS secondary to sepsis Double-blinded; not ITT Experimental: Oxepa® Control: high fat diet Oxepa associated with: improved oxygenation More Vent free days More ICU free days Fewer new organ failures Pontes -Arruda Crit Care Med 2006:34;2345 P=0.04

31. Overall Effect on Mortality www.criticalcarenutrition.com

32. treatment effect of antioxidants? treatment effect of borage oils? comparison to standard enteral feeding products? Interpretation of Studies? How do you interpret the findings?

33. Antioxidant-supplemented specialized diets?

34. OFR CONSUMPTION OFR PRODUCTION Depletion of Antioxidant Enzymes OFR Scavengers Vitamins/Cofactors Infection Inflammation Ischemia OFR production > OFR consumption = Impaired - organ function - immune function - mucosal barrier function Complications and Death OXIDATIVE STRESS Rationale for Antioxidants

35. Endogenous antioxidant defense mechanisms Enzymes (superoxide dismutase, catalase, glutathione perioxidase, glutathione reductase including their cofactors Zn and Selenium) Sulfhydryl group donors (glutathione) Vitamins E, C, and B-carotene Rationale for Antioxidants

37. Effect of Combined Antioxidant Strategies in the Critically Ill Effect on Mortality

38. Elective Surgery Critically Ill GeneralSepticTraumaBurnsAcute Lung Injury ArginineBenefitNo benefitHarmNo benefit GlutaminePossible Benefit PN Beneficial (? receiving EN) …EN Possibly Beneficial … Omega 3 FFA ……………Possible Benefit Antioxidants…Possible Benefit ………… Population Nutrients Which Nutrient for Which Population? Canadian Clinical Practice Guidelines JPEN 2003;27:355

39. 1200 ICU patients Evidence of organ failure R glutamine placebo Concealed Stratified by  site R R antioxidants placebo Factorial 2x2 design placebo antioxidants  Shock REducing Deaths from OXidative Stress: The REDOXS study

40. Critical Care Nutrition Web Site www.criticalcarenutrition.com – web based clinical practice guidelines – summaries of evidence – online survey of current practice – benchmarking (other sites and the clinical practice guidelines) – tools (protocols, etc) – research related news