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Arginine: Friend or Foe Juan B. Ochoa, MD, FACS Professor of Surgery and Critical Care Medical Director Division of Trauma Surgery University of Pittsburgh.

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Presentation on theme: "Arginine: Friend or Foe Juan B. Ochoa, MD, FACS Professor of Surgery and Critical Care Medical Director Division of Trauma Surgery University of Pittsburgh."— Presentation transcript:

1 Arginine: Friend or Foe Juan B. Ochoa, MD, FACS Professor of Surgery and Critical Care Medical Director Division of Trauma Surgery University of Pittsburgh

2 Disclosures University of Pittsburgh Financial Support NIH – K , RO1 GM Pittsburgh Society Foundation Nutrition Companies Ross, Novartis, Nestle Patent Arginase and Immunity

3 Objectives Review the metabolism of arginine Demonstrate how disease alters the expression of the metabolic pathways. –Trauma –Sepsis Determine possible biological roles –In health –In disease Evaluate the clinical role of arginine supplementation.

4 Arginine Supplementation  Biologically active Metabolite Physiological Change Benefit

5 Arginine Supplementation  Biologically active Metabolite Pathological Change Detriment

6 Arginine Glutamine Arginine Citrulline Intestinal Lumen Citrulline Protein Breakdown

7 Arginine Nitric Oxide T cell ProliferationOther

8 Arginine - Vasodilation Nitric oxide Generated by a –CONSTITUTIVE ENZYME Very small quantities Substrate Dependent –The more arginine, the more vasodilation Better Organ Perfusion –More tolerance to low flow states - SHOCK

9 Effect of Arginine on Microcirculation after Open Heart Surgery Tepaske - Lancet 2001 Circulating NOx was Increased

10 The effect of Arginine infusion on Nitric oxide Production in ischemic flaps P<0.05 P< Pigs - Vascularized Pedicle Ischemic Flaps. Arginine given DURING the creation of the Flap Nitric oxide production measured by chemiluminescence – microdialysis Flap viability using vital dyes

11 Arginine and Immunity 1980’s – Arginine incorporated into so called –“Immune Enhancing Diets” Other Nutrients added –Omega 3 Fatty acids –Nucleotides “Boost” the Immune System

12 Arginine and Immunity Friend or Foe? Benefit: “Enhanced” immunity “better” fights against infection Harm: “Enhanced” immunity may produce “Self Injury”

13 What is the Evidence? Harm vs. Benefit Under Resting conditions –Arginine is NOT used by the immune System NO mechanism of arginine transport into the cell. Enzymes that metabolize arginine NOT expressed. –Therefore there is NO EVIDENCE that arginine Is an “IMMUNE ENHANCER” –Dr. Bobbi Langkamp-Henken

14 Arginine Myeloid cell CATs Arginine and Immunity iNOS Nitric Oxide Arginase Ornithine

15 Myeloid cell iNOS Nitric Oxide Arginase Ornithine Sepsis Trauma Endotoxin, IL-1 TNF, IFN, IL-2 Catecholamines, IL-4 IL-13, IL-10, TGF B

16 Plasma Nitric oxide Metabolites in Mice ControlLPSTraumaTrauma+LPS Nitric Oxide Metab. uM Bansal et. al. in Preparation ControlPrimary SepsisTraumaTrauma/septic p=0.02 p<0.01 m M Nitrates Human

17 Arginase 1 is increased after Trauma ARG 1

18 Does Trauma induce Myeloid Suppressor Cells? Myeloid cells exhibit chemotaxis to T cell zones in NON-traumatized mice. Makarenkova et. al. in preparation A= ControlB= 12 Hr. Trauma

19 Effect of Myeloid Suppressor cells on Amino Acid Levels MSC express high levels of Arginase Amino acid levels measured by HPLC Progressive depletion of Arginine Accumulation of Ornithine

20 P<0.05 Arginine and Citrulline Plasma Levels Ochoa et. Al. Ann Surg 1991

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22 Relationship between plasma arginine and leucine after trauma and sepsis.

23 Arginine Deficiency after Trauma Caused by Increased Arginase –Note: arginase expression may be modulated by omega 3 fatty acids Is difficult to overcome with arginine replacement alone –High doses of arginine Arginine homeostasis is restored by a combination of –Arginine –Omega 3 Fatty Acids –Nucleotides?

24 No Clear Evidence of Arginine Deficiency in Sepsis

25 What about Clinical Evidence of Benefit or Harm?

26 Meta-analysis- Immune Enhancing Diets and Infectious Complications Heyland D. JAMA 2001;(286)8: Taken as a whole indiscriminate use of IEDs is NOT indicated. IEDs ONLY work on disease processes where there is arginine DEFICIENCY

27 Arginine Deficiency Trauma/Surgery Sickle Cell Anemia Hemolytic Diseases TransfusionsCancer Chronic Infections Hypertension of Pregnancy

28 Conclusions Arginine is Not an Immune Enhancer Arginine is metabolized in a completely different way in health and disease Changes in arginine metabolism occur principally in the immune system Trauma activates Myeloid cells to produce arginase –Arginase depletes arginine & generates ornithine Sepsis appears NOT to be associated with arginine deficiency

29 Conclusions Clinical Evidence –Surgery is benefited by the use of arginine, omega 3 fatty acids, and nucleotides –Ideally used 5 days preoperatively Overall > 20 clinical Studies – ↓ 40% in infection rates – Significant savings –Trauma Patients appear to benefit also Modest number of patients

30 Conclusions Medical Critically Ill Patients are NOT benefited. –No clear evidence of Harm Sepsis Patients Controversial evidence –Some studies show Harm –Some studies show benefit Arginine-containing diets SHOULD NOT be used in these Patients

31 Thank you ASPEN The Benefit or Harm of Arginine depends on How we use it


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