1. 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

2. 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?

3. Canadian CPGs
Heyland et al JPEN 2003

4. 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

5. A Systematic Review of the Literature
Effect of Glutamine:
A Systematic Review of the Literature
Mortality

6. A Systematic Review of the Literature
Effect of Glutamine:
A Systematic Review of the Literature
Infectious Complications

7. 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

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

9. 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

10. 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

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

12. 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

13. Enteral Study Supplement
EN REDOXS © Formula

14. Parenteral Study Supplements (Dipeptiven and Selenium)+

15. 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