Adjunctive Supportive Care Proactive Primary Therapy Nutrition therapy that modulates the underlying disease process

Adjunctive Supportive Care Proactive Primary Therapy Nutrition therapy impacts clinical outcomes

Adjunctive Supportive Care Proactive Primary Therapy Timeliness of administration of nutritional therapy matters!

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

Fish Oil supplemented diets?

Copyright ©2007 The American Society for Nutrition Mechanisms by which fatty acids can affect immune cell function Wanten, G. J. et al. Am J Clin Nutr 2007;85:

21 patients with sepsis requiring TPN Randomized to recieve PN with an n-3 or n- 6 lipid emulsion for 5 days Dose: 350 ml og s 10% n-3 lipid emulsion (Omegevan) Am J Respir Crit Care Med 2003; 167: 1321

TPN with N-3 vs n-6 FAs in severe sepsis. Monocyte membrane FA composition: arachidonic, EPA, DHA Mayer K, Am J Respir Crit Care med 2003; 167: 1321 N- 3 group N- 6 group

TPN with N-3 vs n-6 FAs in severe sepsis. Ex vivo monocyte cytokine release in response to LPS Mayer AJRCCM 2003; 167: 1321 N- 3 group N- 6 group

25 Patients with SIRS or sepsis receiving PN Randomized to 50:50 MCT/soybean emulsion or lipid emulsion with 50% MCT, 40% soy, and 10% Fish oil x 5 days Dose of fish oils: –rec’d 6.4 gms/day –.09 g/kg/d Barbosa Critical Care 2010;14:R5

Fish oil group resulted in: Greater attenuation of IL-1B, IL-6, and TNF Improved Pa02/FiO2 ration by day 6 No difference in vent days, ICU stay Tendency to reduced hospital stay (22 vs 55 days, p=0.08) and fewer deaths 31% vs 40% (p=ns). Greater treatment effect with higher dose? ? treatment effect if control group not receiving any lipids?

Retrospective study of 194 patients with intraabdominal infection leading to sepsis Control group rec’d standard PN with soybean/olive oil (80%/20%). Treatment group had 10% FO (omegaven) infused on top of standard PN over mins No effect with fish oils on CRP, organ failure or any clinical outcomes Dose of fish oils: rec’d 0.12 g/kg/d over 1 hr! (infusion >0.05 g/kg/hr may be harmful!) Wohlmuth JPEN 2010

There appears to be a dose- response curve with IV FO Pittet Intensive Care Med 2010;36: However, in this small study of healthy volunteers, no correlation with biological effect

Fish Oil optimal Dose Determination Study The FOILED Study Phase 2 dose finding study Mechanically ven’t patients with sepsis with high IL-6 level receiving EN (NO PN lipids) Open label use 10% Fish Oil (Omegaven) to 3 groups: –Group 1: standard care only, no FO –Group 2: 0.20 kg/day of IBW –Group 3: 0.50 kg/day of IBW Outcomes: –Safety- SOFA scores, complications, bleeding –Systemic inflammation: IL-6 and IL-10 –Immunity: LPS ex-vivo stimulation of TNF and IL-6 –Clinical outcomes

What about enteral fish oils? (Product enhanced with fish oils +borage oils + antioxidants)

Borage Oil GLA DGLA PGE 1 and eicosanoids that are less inflammatory Replacing AA with DGLA results in Fish Oil EPA Eicosanoids that are less inflammatory (TXA 3, PGE 3, LTB 5 ) Replacing AA with EPA results in Cyclooxygenase Lipoxygenase Arachidonic Acid Decreased proinflammatory eicosanoids (LTB 4, TXA 2, PGE 2 ) EPA + GLA Modulate Inflammation

Effect of Enteral 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 Gadek Crit Care Med 1999;27:1409 After 3-4 days Reduction in AA and increase in EPA in lung and alveolar macrophage Decrease in neutrophils recovered in BAL fluid Improved oxygenation

Effect of Enteral 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 Gadek Crit Care Med 1999;27:1409 P=0.03 P=0.17 P=0.02

Overall Effect on Mortality

Diets Supplemented with fish oils, borage oils, and antioxidants Recommendation: Based on 1 level 1 studies and 4 level 2 studies, we recommend the use of enteral formula with fish oils, borage oils, and antioxidants in patients with ALI/ARDS. Canadian Clinical Practice Guidelines JPEN 2003;27: Updated 2009;

 Multicenter, Randomized, Double-blinded trial (14 Clinical Sites – Brazil)  200 Patients in the early stages of sepsis (no organ failures; within 36 hrs from onset of sepsis)  Fish oil/borage oil/antioxidant vs standard polymeric  Primary Outcome: Evolution to more severe forms of sepsis (severe sepsis or septic shock)  Secondary Outcome: 28 day all-cause mortality, organ failure development, hyper/hypoglycemic events, insulin use, hospital stay, ICU stay Investigating Nutritional Therapy with EPA, GLA and Antioxidants Role in SEPsis Treatment (INTERSEPT) Pontes-Arruda Crit Care 2011;15:R144

Mostly due to reduced Cardio- resp failures

Variable Study (n=53) Control (n=53) P Value Use of mechanical ventilation, n (%) Invasive10 (18.9%)18 (34%) Non-invasive5 (9.4%)6 (11.3%)NS Number of days using mechanical ventilation* 7 (4-12)15 (9-21).0033 Number of ICU days*7 (4-12)13 (9-18)<.0001 Number of hospital days*9 (6-14)19 (13-24)<.0001 SECONDARY OUTCOMES No Difference in survival between the groups?

Timing of Feeding SUPPLEMENT “Early Full” Fast ramp up “Early Trophic” (10 ml/hr) N-3 + Antioxidants (Module delivered as bolus bid) Control Standard EN (480 cal/ 20 g pro) n = 250 EDEN-OMEGA: Factorial Trial Design NIH NHLBI

OMEGA: 60-Day Mortality P=0.05 P=0.14 JAMA on line Oct 2011

OMEGA: Plasma Eicosapentaenoic Acid (EPA) Levels (%)

Problems with OMEGA Hard to attribute excess mortality to FO when the EPA levels were half of what Gadek achieved, what would the biological mechanism for harm be? Multpile tests of significance and baseline imbalances in patients disadvantaging FO group. More likely, problem with delivery and utilization in the context of bolus fed patients who were semi starved (fat used for fuel!) Improved outcomes in control group may be due to 20 grams extra/day of protein Because of different study design, difficult to combine with other studies of continuous administration in moderately well fed patients Bottom Line: Continue with FO/AOX continuously administered in optimally fed ICU patients Cook, Heyland JAMA Oct 2011

Glutamine supplementation?

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 Increased Autophagy Increased Autophagy Preserved Cellular Energetics- ATP content GLNPool Critical Illness Enhanced insulin sensitivity

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

High Dose Low Dose Effect on Mortality Novak CCM 2002;30:2022

Results of Phase I Dosing Study 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 ParenterallyEnterally Glutamine/day0.35 gms/kg30 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

 RCT 368 heterogeneous critically ill patients  Double-blind  Enteral nutrition supplemented glutamine: 20 grams/L  Control: Glycine 20g/L  Well matched groups  Glutamine group rec’d average 19 g/day of glutamine Hall Intensive Care Med 2003;29:1710 Inadequate Dose and Wrong Patient Population? No differences noted

CCM 2002;30:2032 No difference in outcome for patients who stayed 9 days The longer you stay, the greater duration of exposure, the greater the benefit

Canadian Critical Care Nutrition Clinical Practice Guidelines “If using parental nutrition, we strongly recommend supplementing with parenteral glutamine.” “Enteral Glutamine should be considered for Burns and Trauma Patients.” “There are insufficient data to support the routine use of enteral glutamine in other critically ill patients.” Benefit of Parenteral Glutamine in Patients on EN? JPEN 2003;27:355 see for current versionwww.criticalcarenutrition.com

Admitted to ICU ? PN Glu SeGlu + SeNone Andrews BMJ 2011:342

10 centres in Scotland 502 Patients expected to be in ICU for at least 48h and required PN meet at least half their requirements Randomized 2.6 days after admission to ICU Trial PN isocaloric and isonitrogenous, given for up to 7 days unless died or stopped PN » Glutamine 20g/d » Selenium 500μg/d » Both » Neither Main Outcomes: – New infections – Mortality (ICU/HDU and at 6 months) Prespecifed analysis of people having ≥ 5 Median duration of study PN was 4-5 days The SIGNET Trial - Design

The SIGNET Trial – RESULTS Effect of Glutamine No significant differences Confirmed infections within 14 days Mortality No significant differences

The SIGNET Trial – RESULTS Effect of Selenium No significant differences Confirmed infections within 14 days P=0.12P=0.02 Mortality

Right patient population? – Only about half getting PN at time of randomization Timing of intervention? – Started too late (2.6 days plus time to get PN running) Inadequate exposure to intervention? – Too small of dose – Too short of duration (4-5 days) The SIGNET Trial – Questions!

Multicenter trial in Spain 127 patients with APACHE II score >12 and requiring PN for 5–9 days Standard PN vs. Supplemented with 0.5 g/kg/d of Ala-Gln dipeptide Enrolled patients rec’d only 5-6 days of PN Grau CCM 2011; 39

P=0.10P=0.03 Grau CCM 2011; 39

Scandinavian Glutamine Trial: a Pragmatic Clinical Multi-Centre RCT of ICU patients 413 Patients given nutrition by EN and/or PN route Within 72 hrs of ICU admission supplemented as IV L-Ala-Glutamine, g/kg/day administered separate from PN (Placebo was saline in identical bottles.) Primary endpoint SOFA; infections not recorded All included patients were considered as intention-to-treat (ITT) patients. Patients given supplementation for > 3 days (68%) were considered as predetermined per protocol (PP) patients. No effect on SOFA

jw -10 Scandinavian Glutamine Trial (prel results)

Updated Meta-Analysis Effect on Mortality According to control group mortality highest to lowest April 2011

Updated Meta-Analysis Effect on Infection April 2011

Updated Meta-Analysis Effect on Hospital LOS April 2011

Antioxidant supplementation?

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)

Heyland JPEN 2007;31:109

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

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

N-Acetylcysteine Treatment to Prevent the Progression of Multisystem Organ Failure: A prospective, randomized, placebo-controlled study 100 patients admitted to ICU with MODS Randomized to NAC (150 mg/kg bolus followed by 12 mg/hr) vs placebo No difference in clinical outcomes Median time to treatment 24 hrs P=0.05 % mortality

What do the clinical studies show?

Influence of early antioxidant supplements on clinical evolution and organ function in critically ill cardiac surgery, major trauma and subarachnoid hemorrhage patients. CRP levels daily in the Control groups Significant reduction with AOX in Cardiac and Trauma but not SAH Berger Crit Care 2008  RCT  200 patients  IV supplements for 5 days after admission (Se 270 mcg, Zn 30 mg, Vit C 1.1 g, Vit B1 100 mg) with a double loading dose on days 1 and 2 (AOX group), or placebo.  No affect on clinical outcomes

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

Treatment Stratgy For Sepsis?  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

Phase II study building on previous dosing work 35 Patients with SIRS and APACHE II >15 Randomized within 24 hrs of admission Received either placebo or IV Se as a bolus-loading dose of 2,000 ug followed by continuous infusion of 1,600 ug/ day for 10 days.

Confirms observation of SIGNET trial and Berger study in burns Mechanism related to: increase neutrophil and macrophage function? reversible inhibition of NF-kB binding to DNA induction of apoptosis and cytotoxicity in activated pro- inflammatory cells a direct virucidal or bactericidal effect No serous adverse events noted

Randomized, open-label, single-centre clinical trial 150 patients with SIRS/sepsis and a SOFA score of >5. Patients in the Se group received 1,000 ug on day followed by 500 ug/day on days 2–14. Administered daily over 30 mins. Patients in both groups received a standard Se dose (75 ug/day).

Greater treatment effect in sicker patients! P=0.10

o16 RCTs oSingle nutrients (selenium) and combination strategies (selenium, copper, zinc, Vit A, C, & E, and NAC) oAdministered various routes (IV/parenteral, enteral and oral) oPatients: oCritically ill surgical, trauma, head injured oSIRS, Pancreatitis, Pancreatic necrosis oBurns oMedical oSepsis, Septic Shock Supplementation with Antioxidants in the Critically Ill: A meta-analysis Heyland Int Care Med 2005:31;327;updated 2011

Effect of Combined Antioxidant Strategies in the Critically Ill Effect on Mortality Updated April 2011

Effect of Combined Antioxidant Strategies in the Critically Ill Effect on Infection Updated April 2011

Biological Plausibility! Inflammation/oxidative stress Mitochondrial + Microvascular dysfunction Organ dysfunction Antioxidants

Supplemental Antioxidant Nutrients Recommendation: Based on 3 level 1 studies and 13 level 2 studies, the use of supplemental vitamins and trace elements should be considered. Canadian Clinical Practice Guidelines JPEN 2003;27: Updated 2009;

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

enteral / parenteral supply L-ArginineL-CitrullineL-Ornithine Polyamine Synthesis Putrescine Spermidine Spermine Hormone release GH IGF Insulin Glucagon Prolactin catecholamines Urea Nitrogenous compounds Nitric oxide Nitrite Nitrate Suchner Brit J Nutrition 2001

Figert… Ochoa Surg Forum 1998 Arginine Metabolism after Trauma in Mice

cNOS cNOS + iNOS Effect of Arginine induced NO formation Harmful Benefitial Arginine / NO availability Optimal NO-Balance - Hemodynamic instability - Immune Suppression - Cytotoxicity - Organe dysfunction - Microcirculation  - Immune augmentation  Suchner Brit J Nutrition 2001

Overall Effect on Mortality (2009)

Overall Effect on Infection (2009)

Diets Supplemented with arginine and select other nutrients Recommendation: Based on 4 level 1 studies and 18 level 2 studies, we recommend that diets supplemented with arginine and other select nutrients not be used for critically ill pts. Canadian Clinical Practice Guidelines JPEN 2003;27: Updated 2009;

= Critically Ill patient not the same as Elective Surgery patient!

Heyland JAMA 2001;286:944

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

Summary Nutrients/Nutritional strategies –Modulate underlying pathphysiological processes –Improve clinical outcomes, particularly in sickest patients –Disease processes and treatment effects are time dependent

ICU length of stay Nutrition Therapy for Critically ill Patients of the Future Pare n t e r a l Pharmaconutrition Enteral Pharmaconutrition Assement of nutritional risk Measurement of biomarker to determine which pharmaconutrient 1. enteral nutrition ? parenteral nutrition Set of tools to monitor response to nutrition/nutrient therapy

Questions?