Daren K. Heyland Professor of Medicine Queen’s University, Kingston, ON Canada

Conclusions Nutrition Therapy : Modulating the Inflammatory Response and Improving Patient Outcomes Adjunctive Supportive Care Proactive Primary Therapy

What’s new about this paradigm? Old Nutrition Support New Nutrition Therapy Emphasis on metabolic and nutritional effects Emphasis on clinical outcomes Minimize substrate lossAchieve pharmacological effect Heterogeneous patientsHomogeneous Patients Focus on nutritionFocus on nutrients Small single centerLarge multicenter Weak methodsStrong methods

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

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

To what extent did nutrition therapy (or lack thereof) play a role in this patient’s demise?

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

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

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

Mito Function In Search of the Magic Nutriceutical

Glutamine supplementation?

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 Glutamine

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 Glutamine: A conditionally essential amino acid

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

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

Glutamine-regulated genes in the Pancreatic B cell line

Induction of Heat Shock Protein Leads to Protein Stabilization Induction Hsp 72 Protein HSP-bound protein stabilized for survival and repair NoInduction Aggregation, denaturation, degradation Stress: e.g. HEAT Paul Wischmeyer

* 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: , 2005

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 ;241; Peng Burns 2004;30:135

Effect of Glutamine: A Systematic Review of the Literature Infectious Complications Updated Jan 2009, see

Effect of Glutamine: A Systematic Review of the Literature Hospital Length of Stay Updated Jan 2009, see

Effect of Glutamine: A Systematic Review of the Literature Updated Jan 2009, see Mortality

Antioxidant-supplemented specialized diets?

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

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 Low endogenous levels  Lipid peroxidation and inflammation  Organ failure  Mortality

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

Non-survivors associated with : –Higher APACHE III scores –Higher degree of oxidative stress LPP SH TAC –Higher levels of inflammation (NOx) –Higher levels of leukocyte activation (myeloperoxidase, PMN elastase) Rationale for Antioxidants Alonso de Vega CCM 2002; 30: 1782

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) Rationale for Antioxidants Huet CCM 2007; 35: 821

Rationale for Antioxidants Huet CCM 2007; 35: 821

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

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

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

Heyland JPEN 2007;31:109

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

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

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

Randomized, Prospective Trial of Antioxidant Supplementation in Critically Ill Surgical Patients Nathens Ann Surg 2002;236:814  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 controls treated

Largest Randomized Trial of Antioxidants  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 p=0.11

Effect of Combined Antioxidant Strategies in the Critically Ill Effect on Mortality Updated Jan 2009, see

Biological Plausibility! Inflammation/oxidative stressMitochondrial dysfunctionOrgan dysfunction Antioxidants

Pharmaconutrients Impact Outcomes! Glutamine Antioxidants Fish/Borage Oils Plus AOX Effect on Mortality Arginine

What’s new about this paradigm? Old Nutrition Support New Nutrition Therapy Emphasis on metabolic and nutritional effects Emphasis on clinical outcomes Minimize substrate lossAchieve pharmacological effect Heterogeneous patientsHomogeneous Patients Focus on nutritionFocus on nutrients Small single centerLarge multicenter Weak methodsStrong methods

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

The Research Protocol 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? The Question(s)

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

GroupEnteral Supplement Parenteral Supplement ( Glutamine AOX) (Glutamine AOX) AGlutamine + AOX+Glutamine + Selenium BPlacebo + AOX+Placebo + Selenium CGlutamine + Placebo+Glutamine + Placebo DPlacebo + Placebo+Placebo + Placebo Combined Entered and Parental Nutrients

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 Vit C 1500 mg Vit E 500 mg B-carotene 10 mg Zinc 20mg Selenium 300ug Glutamine 30 gms

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

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

The Research Protocol 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? The Question

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

The Research Protocol Intervention Group NDose of Dipeptides (glutamine) Parenterally* (gm/kg/day) Enterally^ (gm/day) AOX (.35) (15)½ can 47.5 (.35)42 (30)full can 57.5 (.35)42 (30) full can + 500ug IV Selenium

The Research Protocol Outcomes Primary: ∆SOFA Secondary (groups 2-5); Plasma levels of Se, Zn, and vitamins TBARS Glutathione Mitochondrial function (ratio)

Control N = 30 Group 2 N =7 Group 3 N= 7 Group 4 N= 7 Group 5 N=7 All N=58 Age (Mean) Female (%)11 (37%)2(29%)1(14%)2(29%)3(43%)19(33%) APACHE II score (Mean) Etiology of shock Cardiogenic (%) Septic (%) Hypovolemic (%) 6 (86%) 1(14%) 3 (43%) 4 (57%) 3 (43%) 4 (57%) 1(14%) 5(71%) 1(14%) 13(46%) 14(50%) 1(4%) ICU days (Median) day mortality (%)9(30%)3(43%)2(29%)3(43%)1(14%)18(31%) Baseline Characteristics

4 vs 5: p=0.17 Effect on SOFA

Effect on TBARS

Effect on Glutathione

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

Inferences 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

REDOXS: A New Paradigm! Nutrients dissociated from nutrition Focus on single nutrient administration Rigorous, large scale, multicenter trial of nutrition related intervention powered to look at mortality sick homogenous population Preceded by: –standardization of nutrition support thru the development and implementation of CPGs –a dosing optimizing study Funded by CIHR

REDOXS Study A new way of thinking!

Conclusions Nutrition Therapy : Modulating the Inflammatory Response and Improving Patient Outcomes Adjunctive Supportive Care Proactive Primary Therapy

To what extent did nutrition therapy (or lack thereof) play a role in this patient’s demise?

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

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