1. Immunonutrition By Dr Noha Elsharnouby Associate professor of anesthesia and ICU Ain shams university

2. objectives Nutritional importance Immunonutrition Glutamine Arginine Omega 3 fatty acid Evidence

4. Critical Illness Heterogeneous patients Extreme physiological stress/organ failure Acute phase response: TNF, IL-6, IL-1β Immuno-suppression: monocytes, MØ, NK cells, T and B lymphocytes Insulin resistance: hyperglycaemia Protein loss and fat gain in muscle Impaired gut function

5. Consequences of malnutrition Increased morbidity and mortality Prolonged hospital stay Impaired tissue function and wound healing Defective muscle function, reduced respiratory and cardiac function Immuno-suppression, increased risk of infection lose around 2%/day muscle protein

6. Magnitude of the problem McWhirter and Pennington 1994: >40% of hospitalized patients malnourished on admission Recent Scottish data 35% Estimated cost to hospitals: ?????????? Many ICU patients malnourished or at risk on ICU admission

7. Immunonutrition and the Immune System A complex and interactive biological system that coordinates the detection, destruction and elimination of any foreign material or organism entering the body.  Oxidants: cytokines, NFkB, genes, inflam n  Nutrients: glutamine, FFAs, protein  Antioxidants: Glutathione, oxidant defence  Anti-inflammatory molecules: attenuation

8. Immuno/Pharmaconutrition Potential to modulate the activity of the immune system by interventions with specific nutrients in amounts above those normally encountered in the diet’ ‘Disease-modulating’ nutrients Attenuate metabolic response, and prevent oxidant stress Favourably modulate immune response Shift protein synthesis from acute phase to constitutive proteins

9. Nutrients most often studied: Arginine - improve immune function. Glutamine –aiding in immune function. Branched chain amino acid’s – support immune cell functions. Transforming growth factor B – down regulate inflammation Omega 3 fatty acids – decrease inflammatory response, modulate immune response. Probiotics- to alter gut environment Nucleotides-DNA/RNA precursors deficiency suppresses cell-mediated immunity

10. Glutamine Most abundant amino acids in the body Non-essential amino acid – ‘conditionally essential’ in sepsis/major trauma primary fuel for enterocytes, lymphocytes and neutrophils; also involved in signal transduction and gene expression precursor to DNA synthesis massive release from skeletal muscle during critical illness BUT Levels drop after injury, exercise and stress. Very low in critical illness first 72 hours Glutamine deficiency at onset of critical illness/sepsis correlated with increased mortality Supplementation 0.2-0.57 gm/kg/day (20 gm/day) for at least 5 days, iv dose 0.13-0.57g/kg

12. Beneficial effects of glutamine supplementation Metabloic – protein precurssor – gluconeogensis precursor Ammoniagenesis(kidney) Immunologic –– Attenuation of cytokine expression in SIRS Preservation of tissue reduces villus atrophy in animals and humans Enterocytes replication function in stress states – Preserves ATP in sepsis and inflammatory response – Preserves mitochondrial function Antioxidant – Enhanced glutathione synthetase – Attenuates iNOS in sepsis and inflammatory response – Reduction in oxidant stress

13. Glutamine Modest reduction in mortality/infections Improvement in morbidity and mortality in burns and trauma patients reduced pneumonia and bacteraemia in two studies - multiple trauma, sepsis is not given in standard TPN parenteral supplementation appears to be beneficial in patients requiring TPN for many days

14. PROBIOTICS Non pathogenic bacteria which when administered in adequate amounts confer a health benefit on the host, stimulate SIGA, and mucous production Bioecological control: Supply viable beneficial bacteria, or a substrate which enhances specific beneficial bacteria, instead of trying to eliminate the pathogen improve mucosal barrier function enhance T-cell and macrophage function reduce production of TNF

15. Arginine 1980’s – Arginine incorporated into so called “Immune Enhancing Diets”. Mediated by l-arginine –nitric oxide pathway ‘Conditionally essential’ amino acid derived from glutamine and citrulline For protein synthesis, cell division, NO, urea cycle, creatine phosphate (ATP), stimulates hormone release Enteral dose controversial from 12 to 16gm Deficiency: Immune suppression, ↓ TH2 cell function, free radical formation – Abnormal microperfusion – Abnormal wound healing

16. Arginine Glutamine Arginine Citrulline Intestinal Lumen Citrulline Protein Breakdown Arginine is synthesized primarily in the kidney from gut-derived citrulline via the urea cycle, which also detoxifies ammonia and facilitates excretion of nitrogen.

17. PUFAs Arachidonic Acid Omega-6 FA Omega-3 FA fish oils: Eicosapentanoic acid (EPA) and Docosahexanoic acid (DHA):

18. Dietary Lipids Ratios in diet ω-6:ω-3 1:1,optimum 5:1 Current Western diet 16.7:1 Current UK PN Soybean oil base 7:1 (LCT) New PN (‘SMOF’) 2.5:1 (LCT/MCT) Membrane composition depends on diet AA, DHA and EPA are present in inflammatory cell membrane phospholipids Hydrolysis of FAs by phospholipase to mediators Reversing proinflammatory cytokines

19. Mechanisms of Action ω-3s EPA/DHA are incorporated quickly into cell membrane: inhibit ω-6 activity Promote synthesis of low activity PGs and LTs Decrease expression of adhesion molecules Inhibits monocyte production of pro- inflammatory cytokines, increases lymphocyte apoptosis Dose 0.1-0.2 gm/kg/day of omega 3 FA

20. Borage Oil DGLA PGE 1 and fewer Inflammatory Eicosanoids Substitution of AA By DGLA resulting in: Fish Oil GLAEPA Fewer Inflammatory Eicosanoids (TXA 3, PGE 3, LTB 5 ) Substitution of AA By EPA Resulting in: Arachidonic Acid Cyclooxygenase Lipoxygenase Pro-Inflammatory Eicosanoids (LTB 4, TXA 2, PGE 2 ) Decrease in X Mechanisms of Action

21. Omega 3 FA reverse immunosuppression Decrease coagulation capacity Patients with ARDS fed with, EPA and antioxidants had a reduction in pulmonary neutrophils – Improvement in oxygenation – Decrease in ventilator days – Decrease in ICU and hospital days Gadek, Singer, Pontes-Arruda (sepsis)

22. Nulceotides Important substrate for cell replication, maturation, and differentiation in the immune system, lymphocytes, NK, enterocytes, and macrophage Substrate for protein synthesis and cell metabolism and energy( coenzyme NAD, FAD, and ATP) Implicated in IL-2 and macrophage receptor synthesis

23. Antioxidants Glutathione, Vitamins A, C and E Zinc, copper, manganese, iron, selenium Oxidative stress in critically ill patients contributes to organ damage / malignant inflammation

24. Which Nutrient for Which Population? Canadian Clinical Practice Guidelines JPEN 2003;27:355

25. Immunonutrition- the future? The right nutrient or combination Correct dose The appropriate timing The right patient and circumstance The appropriate assessment of efficacy Balance between harm and benefit of the immune response ?? Nutrient-gene interactions

26. Summary Immunonutrition is beneficial for the patient Studies are still controversial except for some indications may improve morbidity and mortality The right composition for the right case Must be tailored to patient needs