Glutamine Therapy: A life-saving therapy?

1. Glutamine Therapy: A life-saving therapy? Daren K. Heyland Professor of Medicine Queen’s University, Kingston, ON Canada

2. ConclusionsNutrition Therapy : Modulating the Inflammatory Response and Improving Patient Outcomes Adjunctive Supportive Care Proactive Primary Therapy

3. What’s new about this paradigm?

4. Case Scenario • Mr KT • 76 per’d diverticulum • Septic shock, ARDS, MODS • Day 1- high NG drainage, distended abdomen • Day 3- trickle feeds • Feeds on and off again for whole first week • No PN, no small bowel feeds, no specialized nutrients

5. Case Scenario Caloric Debt Adequacy of EN Adequacy of EN Prolonged ICU stay, discharged weak and debilitated. Dies on day 43 in hospital from massive PE

7. endothelial dysfunction activation of coagulation Microcirculatory Dysfunction Insult • infection • trauma • I/R • hypoxemic/ • hypotensive elaboration of cytokines, NO, and other mediators Activation of PMN’s generation of OFR (ROS + RNOS) mitochondrial dysfunction Role of GIT oxidative stress = cellular = energetic failure Death organ = failure Pathophysiology of Critical Illness (1) Key nutrient deficiencies (e.g. glutamine, selenium)

8. Loss of Gut Epithelial Integrity Bacteria DISTAL ORGAN INJURY (Lung, Kidneys) INTESTINAL EPITHELIUM SIRS via thoracic duct

9. mtDNA Mitochondrial Function Cell mitochondria Respiratory chain ROS RNS nDNA nucleus Mitochondria are the power house of the cell, generate energy through oxidative phosphorylation (OXPHOS)

10. In Search of the Magic Nutriceutical

11. Glutamine supplementation?

12. Glutamine Glutamine: A conditionally essential amino acid • The most abundant amino acid in the body • Usually considered non essential amino acid • Has many essential metabolic functions • Not usually present in parenteral nutrition products due to manufacturing reasons

13. Glutamine: A conditionally essential amino acid Glutamine levels drop: - following extreme physical exercice - after major surgery - during critical illness Low glutamine levels are associated with: • immune dysfunction • higer mortality in critically ill patients Novak F, Heyland DK, A Avenell et al., Crit Care Med 2002 Oudemans-van Straaten HM, Bosman RJ, Treskes Met al., Intensive Car Med 2001

14. The “Oudemans-van Straaten-Study” “high” “low” => Low plasma glutamine at ICU admission is related to mortality.

15. 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

16. Glutamine-regulated genes in the Pancreatic B cell line

17. Induction HSP-bound protein stabilized for survival and repair Hsp 72 Protein Stress: e.g. HEAT No Induction Aggregation, denaturation, degradation Induction of Heat Shock Protein Leads to Protein Stabilization Paul Wischmeyer

18. IV Glutamine Enhances Serum HSP-70 in Critically Ill Patients with Sepsis/SIRS ALA-GLN treatment leads to significant enhancement of serum HSP-70 with 7 days of treatment ALA-GLN mediated enhancement of HSP-70 correlates with decreased ICU length of stay and time on ventilator * Ziegler Intensive Care Medicine, 31:1079-1086, 2005

19. Mechanism of Glutamine • 3 RCTs of enteral glutamine • Burns patients • Increased plasma glutamine • Improved permeability • Decreased endotoxin levels • Reduced GNB infections • Reduced hospital LOS • Reduced mortality Garrell CCM 2003;31:2444, Zhou JPEN 2003 27;241; Peng Burns 2004;30:135

20. Effect of Glutamine: A Systematic Review of the Literature Infectious Complications Updated Jan 2009, see www.criticalcarenutrition.com

21. Effect of Glutamine: A Systematic Review of the Literature Mortality Updated Jan 2009, see www.criticalcarenutrition.com

22. Antioxidant-supplemented specialized diets?

23. 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

24. 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 Low endogenous levels • Lipid peroxidation and inflammation • Organ failure • Mortality

25. Oxidative Stress Connected to Organ Failure Motoyama Crit Care Med 2003;31:1048

26. Rationale for Antioxidants • 21 patients with septic shock • Exposed plasma from patients to naïve human umbilical vein endothelial cells and quantified degree of oxidative stress by a fluorescent probe (2,7,-dichorodihydrofluorescien diacetate) Huet CCM 2007; 35: 821

27. Rationale for Antioxidants Huet CCM 2007; 35: 821

28. Underlying Pathophysiology of Critical Illness (2) • preserved ATP • Recovery of mt DNA • Regeneration of mito proteins Genetic down regulation Tissue hypoxia Survivors • ↓mt DNA • ↓ ATP, ADP, NADPH • ↓ Resp chain activity • Ultra structural changes cytokine effect ↓ mitochondrial activity Prolonged inflammation Metabolic Shutdown NO Death Endocrine effects

29. Mitochondrial Dysfunction is a Time-Dependent Phenonmenon Hypoxia Accelerates Nitric Oxide Inhibition of Complex 1 Activity 1% O2 21% O2 Nitration of Complex 1 in Macrophages activated with LPS and IFN Frost Am J Physio Regul Interg Comp Physio 2005;288:394

30. Mitochondrial Damage mtDNA Potentially Irreversible by 48 hours Cell mitochondria Respiratory chain ROS RNS nDNA nucleus LPS exposure leads to GSH depletion and oxidation of mtDNA within 6-24 hours Levy Shock 2004;21:110 Suliman CV research 2004;279

31. Heyland JPEN 2007;31:109

32. Effect of Antioxidants on Mitochondrial Function Heyland JPEN 2007;31:109

33. Smallest Randomized Trial of Selenium in Sepsis • Single center RCT • double-blinded • ITT analysis • 40 patients with severe sepsis • Mean APACHE II 18 • Primary endpoint: need for RRT • standard nutrition plus 474 ug x 3 days, 316 ug x 3 days; 31.6 ug thereafter vs 31.6 ug/day in control Mishra Clinical Nutrition 2007;26:41-50

34. Smallest Randomized Trial of Selenium in Sepsis Effect on SOFA scores • Increased selenium levels • Increased GSH-Px activity • No difference in • RRT (5 vs 7 patients) • mortality (44% vs 50%) • Other clinical outcomes *p=<0.006 * * Mishra Clinical Nutrition 2007;26:41-50

35. Randomized, Prospective Trial of AntioxidantSupplementation in Critically Ill Surgical Patients controls • Surgical ICU patients, mostly trauma • 770 randomized; 595 analysed • alpha-tocopherol 1,000 IU (20 mL) q8h per naso- or orogastric tube and 1,000 mg ascorbic acid IV q8h or placebo • Tendency to less pulmonary morbidity and shorter duration of vent days treated Nathens Ann Surg 2002;236:814

36. Largest Randomized Trial of Antioxidants p=0.11 • Multicenter RCT in Germany • double-blinded • non-ITT analysis • 249 patients with severe sepsis • standard nutrition plus 1000 ug bolus followed by 1000 ug/day or placebo x14 days • Greater treatment effect observed in those patients with: • supra normal levels vs normal levels of selenium • Higher APACHE III • More than 3 organ failures Crit Care Med 2007;135:1

37. Effect of Combined Antioxidant Strategies in the Critically Ill Effect on Mortality Updated Jan 2009, see www.criticalcarenutrition.com

38. Biological Plausibility! Antioxidants Antioxidants Antioxidants Inflammation/oxidative stress Mitochondrial dysfunction Organ dysfunction

39. Pharmaconutrients Impact Outcomes! Effect on Mortality Antioxidants Glutamine Arginine Fish/Borage Oils Plus AOX 10 .01 0.1 1 100 www.criticalcarenutrition.com

40. What’s new about this paradigm?

41. REducing Deaths from OXidative Stress:The REDOXS study A multicenter randomized trial of glutamine and antioxidant supplementation in critical illness

42. The Research Protocol The Question(s) In critically ill patients with a clinical evidence of acute multi organ dysfunction fed enterally • What is the effect of glutamine supplementation compared to placebo • What is the effect of antioxidant supplementation compared to placebo …on 28 day mortality?

43. 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

44. Combined Entered and Parental Nutrients Group Enteral Supplement Parenteral Supplement (Glutamine AOX) (Glutamine AOX) A Glutamine + AOX + Glutamine + Selenium B Placebo + AOX + Placebo + Selenium C Glutamine + Placebo + Glutamine + Placebo D Placebo + Placebo + Placebo + Placebo

45. Glutamine Dipeptides • Free L-glutamine has limited solubility and stability • Synthetic dipeptides (ala-gln, gly-gln) overcome these difficulties • 8.5 gms of dipeptide=6 gms of glutamine Glutamine 30 gms Vit C 1500 mg Vit E 500 mg B-carotene 10 mg Zinc 20mg Selenium 300ug

46. Optimal Dose? • High vs Low dose: • observations of meta-analysis • Providing experimental nutrients in addition to standard enteral diets

47. Optimizing the Dose of Glutamine Dipeptidesand Antioxidants in Critically ill Patients: A phase 1 dose finding study of glutamine and antioxidant supplementation in critical illness JPEN 2007

48. The Research Protocol The Question In critically ill patients with a clinical evidence of hypoperfusion... • What is the maximal tolerable dose (MTD) of glutamine dipeptides and antioxidants as judged by its effect on multiorgan dysfunction? Safety

49. The Research Protocol The Design • Single Center • Open-label • Dose-ranging study • Prospective controls Patients • Critically Ill patients in shock

50. The Research Protocol Intervention