The REDOXS© Study REducing Deaths from OXidative Stress PART 1 of 4 REDOXS Training The REDOXS© Study REducing Deaths from OXidative Stress PART 1 of 4 Sponsor Dr. Daren Heyland, MD, FRCPC Project Leader Rupinder Dhaliwal, BASc, RD October 2007

Research Questions In critically ill patients with severe organ dysfunction, what is the effect of: 1) Glutamine supplementation compared to placebo on 28-day mortality? 2) Antioxidant supplementation compared to placebo on 28-day mortality?

Canadian CPGs Heyland et al JPEN 2003

Potential Beneficial Effects of Glutamine Enhanced Heat Shock Protein Enhanced insulin sensitivity Decreased Free Radical availability (Anti-inflammatory action) Inflammatory Cytokine Attenuation NF-B ? Glutamine Therapy Glutathione Synthesis Reduced Translocation Enteric Bacteria or Endotoxins Reduction of Infectious complications Maintenance of Intestinal Mucosal Barrier Lymphocyte Function Fuel for Enterocytes Lymphocytes Nuclotide Synthesis Critical Illness GLN pool GLN Pool Preservation of TCA Function Anti-catabolic effect Preservation of Muscle mass Preserved Cellular Energetics- ATP content

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

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

Inflammation Ischemia REDOXS Training Rationale for Antioxidants Infection Inflammation Ischemia OFR CONSUMPTION OFR PRODUCTION Depletion of Antioxidant Enzymes OFR Scavengers Vitamins/Cofactors There has been increasing interest.awareness between the imbalance between oxygen free radical generation and endogenous antioxidant capacity associated with critical illness. Where ROS production is greater the consumption, this leads to conditions of oxidative stress which has adverse sequelae on the host. Impaired - organ function - immune function - mucosal barrier function OXIDATIVE STRESS OFR production > OFR consumption = Complications and Death October 2007 7

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

Pharmaconutrition A New Emerging Paradigm Old Immunonutrition New Pharmaconutrients Nutrition Nutrients Combined nutrients Single nutrients Heterogeneous populations Homogenous Patients Weak methods Rigorous Small single center Large multicenter Heyland Int Care Med 2005;31:501

Inferences High dose appears safe High dose associated with Parenterally Enterally Glutamine/day 0.35 gms/kg 30 gms Antioxidants per day 500 mcg Selenium Vit C 1500 mg Vit E 500 mg B carotene 10 mg Zinc 20 mg Se 300 ug High dose appears safe High dose associated with no worsening of SOFA Scores greater resolution of oxidative stress greater preservation of glutathione Improved mitochondrial function Heyland JPEN Mar 2007

R R R REDOXS© Study Design Factorial 2x2 design antioxidants glutamine 1200 ICU patients R Evidence of placebo organ failure antioxidants placebo R placebo

Parenteral Supplement Study Groups Enteral Supplement Parenteral Supplement GLN +AOX Glutamine + AOX Dipeptiven + Selenium AOX AOX only Placebo + Selenium GLN Glutamine only Dipeptiven + Placebo Placebo Placebo + Placebo SC blinded Pharmacist unblinded

Enteral Study Supplement EN REDOXS © Formula

Parenteral Study Supplements (Dipeptiven and Selenium) +

Enteral Nutrition ENTERAL REDOXS formula PARENTERAL REDOXS formula (but will be in a normal saline type bag) Jevity and ENTERAL REDOXS being “Y”-ed in using Y connector