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