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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. Updated July 2006 . www.criticalcarenutrition.com. Immunonutrition: Cocktail Approach?.
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Pharmaconutrition: Selected Nutrients and Their Influence on Patient OutcomesThe Canadian Clinical Practice Guidelines Daren K. Heyland, MD, FRCPC, MSc Queen’s University, Kingston, Ontario
Updated July 2006 www.criticalcarenutrition.com
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?
endothelial dysfunction activation of coagulation/complement Insult • infection • trauma • I/R • hypoxemic/ • hypotensive Activation of PMN’s elaboration of cytokines, NO, and other mediators generation of OFR (ROS + RNOS) Role of GIT mitochondrial dysfunction oxidative stress = cellular = energetic failure Death organ = failure Pathophysiology of Critical Illness Key nutrient deficiencies (e.g. glutamine, selenium) Arginine
Elective Surgical Patient • cellular immune dysfunction • T-cell • decrease cytokine activation • IL-2, IFN
Elective Surgical Patient arginase arginine expression of zeta chain Taheri Clin Cancer Res 2001 ;7:958
Which Nutrients? Which Patients? Population Nutrients Canadian Clinical Practice Guidelines JPEN 2003;27:355 www.criticalcarenutrition.com
Underlying Rationale for Framework • No scientific rationale for combining nutrients together; need to consider them alone • Empirical evidence that the nutrients have different treatment effects across populations
Which Nutrient for Which Population? Population Nutrients Canadian Clinical Practice Guidelines JPEN 2003;27:355
Underlying PathophysiologyRole of Nitric Oxide Mitaka Shock 2003;19: 305
Optimal NO-Balance cNOS - Microcirculation- Immune augmentation Benefitial Effect of Arginine induced NO formation Arginine / NO availability Harmful cNOS + iNOS - Hemodynamic instability- Immune Suppression- Cytotoxicity- Organe dysfunction Suchner Brit J Nutrition 2001
Effect of Arginine-supplemented diets on Mortality www.criticalcarenutrition.com
Effect of Arginine-supplemented diets on Infectious complications www.criticalcarenutrition.com
Effect of Arginine-supplemented diets in Critically Ill Patients • 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 ...
Potential Beneficial Effects of Glutamine Enhanced Heat Shock Protein GLN Pool Enhanced insulin sensitivity Decreased Free Radical availability (Anti-inflammatory action) NF-B ? Inflammatory Cytokine Attenuation Glutathione Synthesis Glutamine Therapy Reduced Translocation Enteric Bacteria or Endotoxins Maintenance of Intestinal Mucosal Barrier Fuel for Enterocytes Critical Illness Nuclotide Synthesis Preservation of TCA Function Reduction of Infectious complications Maintenance of Lymphocyte Function Fuel for Lymphocytes Anti-catabolic effect Preserved Cellular Energetics- ATP content Preservation of Muscle mass GLN pool
Effect of Glutamine: A Systematic Review of the Literature Infectious Complications www.criticalcarenutrition.com
Effect of Glutamine: A Systematic Review of the Literature Mortality www.criticalcarenutrition.com
Results of subgroup analysis EN vs PN?
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
Mechanisms of Action GLA EPA Arachidonic Acid Borage Oil Fish Oil CyclooxygenaseLipoxygenase DGLA Substitution of AA By EPA Resulting in: Substitution of AA By DGLA resulting in: Decrease in Pro-Inflammatory Eicosanoids (LTB4, TXA2, PGE2) Less Inflammatory Eicosanoids (TXA3, PGE3, LTB5) PGE1 and Less Inflammatory Eicosanoids
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 P=0.02 P=0.03 P=0.17 Gadek Crit Care Med 1999;27:1409
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
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 P=0.04 Pontes -Arruda Crit Care Med 2006:34;2345
Overall Effect on Mortality www.criticalcarenutrition.com
Interpretation of Studies? • treatment effect of antioxidants? • treatment effect of borage oils? • comparison to standard enteral feeding products? How do you interpret the findings?
Rationale for Antioxidants Infection InflammationIschemia OFR CONSUMPTION OFR PRODUCTION Depletion of Antioxidant Enzymes OFR Scavengers Vitamins/Cofactors Impaired - organ function - immune function - mucosal barrier function OXIDATIVE STRESS OFR production > OFR consumption = Complications and Death
Rationale for Antioxidants • 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
Effect of Combined Antioxidant Strategies in the Critically Ill Effect on Mortality
Which Nutrient for Which Population? Population Nutrients Canadian Clinical Practice Guidelines JPEN 2003;27:355
REducing Deaths from OXidative Stress:The REDOXS study antioxidants Factorial 2x2 design glutamine R Concealed Stratified by 1200 ICU patients R placebo Evidence of • site organ failure antioxidants • Shock R placebo placebo
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