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Arginine: Friend or Foe

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Presentation on theme: "Arginine: Friend or Foe"— 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 GM065914 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 Intestinal Lumen Citrulline Citrulline Protein Breakdown
Glutamine Citrulline Arginine Protein Breakdown

7 Arginine Nitric Oxide T cell Proliferation Other

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

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

16 Plasma Nitric oxide Metabolites in Mice
Control Primary Sepsis Trauma Trauma/septic 25 50 75 p=0.02 p<0.01 m M Nitrates Human 160 140 120 100 Nitric Oxide Metab. uM 80 60 40 20 Control LPS Trauma Trauma+LPS Bansal et. al. in Preparation

17 Arginase 1 is increased after Trauma

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

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


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 The Heyland meta-analysis looked at studies where the products had supplemental arginine as well as fish oil. This shows you how the immune restoring diets faired when compared to standard enteral diets in both elective surgery and critically ill patients. There’s a couple of take away points I want to leave you with here. #1, this data shows a clear indication for the use of high arginine diets in elective surgery and trauma patients. #2, this data has increased our awareness for the need to further study the application of these diets in septic patients. #3, if we are to meaningfully discuss and study the use of immune restoring diets in our patients we must drop the concept of ‘critical illness diet’ and talk specifically about surgery, trauma, and sepsis. Given what we know about arginine metabolism, critical illness is no longer a very useful term in discussing patient populations and the best diet to put them on.

27 Trauma/Surgery Hemolytic Diseases Sickle Cell Anemia Arginine Deficiency Cancer Transfusions 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 The Benefit or Harm of Arginine depends on How we use it
Thank you ASPEN

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