Glutamine and Arginine- Benefits and Contraindications in the Clinical Setting

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Glutamine & Arginine:
Benefits and Contraindications
in the Clinical Setting
Amanda Biondo, R.D.
Blake Bartholomew, M.S., R.D.
Brianna Carroll, Dietetic Intern
Objectives
•To understand what glutamine is and its function in
the body
•To understand glutamine’s beneficial effects in
different disease states
•To identify contraindications for glutamine
supplementation

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Disclaimers


We have nothing to disclaim
What is Glutamine?
•Amino acid
•Considered “conditionally essential”
•Accounts for 20% of amino acid pool in the body
•In human skeletal muscle, glutamine account for up
to 60% of the total amino acid pool

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Roles
•Vital fuel for highly proliferating cells such as
fibroblasts, reticuloendothelial cells, malignant cells,
gut epithelial cells
•Aids in removal of excess ammonia
•Immune system modulation
•Regulator of glycogen synthesis
Depletion
•Plasma glutamine is currently the best indicator of glutamine
depletion
•Following operation, injury, systemic infection, other severe
illnesses and exercise there is a rapid fall in the concentration
of glutamine in the circulation and cellular pools
•Glutamine deficiency results in an accelerated net
breakdown of muscle protein, thus contributing to muscle
wasting and negative nitrogen balance
•Associated with atrophy of intestinal mucosa, impairment of
immune function and decreased protein synthesis
•Low plasma and muscle concentrations of glutamine in
critical care patients are correlated with an increase in
mortality

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Simulation of the Additional Mortality
Prediction from an out of Range Plasma
Glutamine Concentration at ICU Admittance
Adopted from Wernerman et al.
Recommended Intake
•Healthy individuals produce 50-80g/day
•Glutamine doses in trials: ~0.3g/kg/day (~0.9g/hour for
70kg patient)
•Critically ill: 0.3-0.5g/kg/day
•However, some studies have shown that providing an
adequate amount of protein will allow the body to
produce glutamine at a faster rate than it can be infused
•Standard enteral formulas contain 2-4g/L, which is
insufficient to normalize plasma glutamine concentration

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Food Sources of Glutamine
•Meat & poultry
•Fish & seafood
•Organ meats
•Dairy
•Eggs
•Cabbage
•Nuts
•Beans & legumes
•Beets, spinach & parsley
Clinical Significance
•Glutamine has been supplemented in cases of:
•Wound healing
•Burns
•GI Disorders
•Cancer
•HIV/AIDS

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Arginine
•“Conditionally” essential amino acid
•Demonstrated importance in immune response and
wound healing
•Plasma levels are usually dependent on dietary
intake
•Used to synthesize nitric oxide, which affects
respiratory, cardiovascular, renal and immunological
function
•Enhances lymphocyte function and may prove useful
in treating inflammatory diseases and AIDS
Food Sources of Arginine
•Red meat
•Seafood
•Eggs
•Nuts
•Spinach & lentils
•Whole grains
•Soy

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Wound Healing
Roles in Wound Healing
•Glutamine
•Main contributor of nitrogen for collagen formation
•Factor in immune response
•Reduction of inflammation and oxidative stress
•Arginine
•Stimulates insulin secretion
•Promotes amino acid transport into cells
•Enhances collagen production and protein synthesis

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Factors of Wound Healing Studied in Regards
to Glutamine and Arginine Supplementation
•Rate of recovery
•Tissue Health
•Exudate Volume
•Presence of infection

Wound Healing
•Research has been conducted in many areas of
wound healing, including pressure ulcers, burns,
post surgical/trauma wounds.

•Animal and human trials have been conducted to
evaluate the efficacy of glutamine and arginine
supplementation for the promotion of wound
healing.

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Burns
•“75% of burn related deaths are caused by infectious
complications, even after surgical intervention and
antibiotic therapy”
•Patients with 20-60% burn surface area
•Supplementation with 0.5gm/kg/day of glutamine
•Incidence of positive blood culture and positive wound
culture were significantly reduced compared to placebo
group
•Length of hospital stay also reduced in supplemented
group
Pressure Ulcers
•Practice Guidelines
•National Pressure Ulcer Advisory Panel, European
Pressure Ulcer Advisory Panel, Pan Pacific Pressure
Injury Alliance nutrition guidelines for pressure ulcer
care
•“Supplement with high protein, arginine and
micronutrients for adults with a pressure ulcer.
Category/stage III or IV or multiple pressure ulcers when
nutritional requirements cannot be met with traditional
high calorie and protein supplements.”

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Pressure Ulcers
•Study performed to monitor effects of Arginine
supplementation on rate of healing of existing
pressure ulcers.
•9g per day of Arginine for 8 weeks
•Surface area of PU decreased significantly earlier in the
trial for supplemented patients
•Supplemented group showed overall more complete
closure at the end of 8 weeks
•Total staff time spent in wound care and dressing
changes was significantly reduced in the supplemented
group.





Surgical/Trauma Wounds
•Glutamine supplementation in patients with
unhealed wounds 10 days post surgery.
•Supplementation of 19g daily for 14 days
•Supplementation group showed significantly reduced
time to wound closer after 14 days of supplementation.
•Glutamine reduction and reduction in O2 saturation
only noted in the placebo group.

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Surgical/Trauma Wounds
•Animal study of supplementation of arginine and
glutamine for ischemic wounds
•Increased rate of wound healing, with significantly
decreased size on day 10 and day 14.
•Reduction of inflammatory markers.
•Noted, but not statistically significant, increased
collagen accumulation and epithelialization in
supplemented group.

GI Disorders

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Glutamine and the Gut
•The effects of glutamine on the clinical outcome of
critically ill patients was proposed more 30 years ago .
• Although the metabolism is not fully understood several
pathways have been postulated to explain glutamine’s
beneficial effect on the gut .
•Two mechanisms with the greatest amount of literature
behind them are:
•Glutamine improves intestinal integrity
•Regulating intestinal immunity
Improvement of Intestinal
Integrity
•The GI epithelium serves as a barrier from the luminal
contents

•Distribution of the barrier can lead to the diffusion of toxins
such as lipopolysaccharides (LPS), allergens and pathogens
into submucosal regions which induce inflammation and
mucosal injury

•Current information suggest that glutamine is essential for the
maintenance of barrier function in the intestinal epithelium.

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Improvement of Intestinal
Integrity
•Bertrand et al demonstrated that glutamine restores
tight junction in colonic mucosa of patients with
IBS.

•Hughes et al. explored the effect of glutamine on
jejunal cells during TPN administration
Glutamine and Intestinal
Immunity
•Glutamine is one of the most functionally versatile immunonutrients
for regulating intestinal immunity
•It serves as a primary metabolic nutrient for the gut-associated lymphoid
tissue (GALT)
•Reduces the oxidative burden
•Modulates cytokine balance
•Enhances cytoprotective heat shock response

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Reduction in Oxidative
Burden
•Zhou and Li showed that reactive oxygen species are produced in
abnormally high levels in IBD and play a role in the initiation and/or the
propagation of the disease state.
•In turn this lead to the theoretical basis for the use of antioxidants during
IBD conditions
•Glutamine is a precursor to glutathione, and glutamine treatment has been
shown to preserve glutathione stores in ex vivo models
•The jury is still out


Modulates Cytokine Balance
•The immune homeostasis of the intestinal mucosa is a delicate
balance
•Modulation of the gut cytokines profoundly affects the response of
GALT cells to luminal microbes
•Coeffier et al showed that a physiologic dose of Glutamine
effectively decreased the basal production of pro-inflammatory IL-6
and IL-8

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•The heat shock proteins are a group of proteins essential to cellular
survival under stressful conditions.

•Singleton et al presented evidence that glutamine can enhance heat
shock proteins 70 and 72
Enhances Heat Shock Response
What’s the Verdict?

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Contraindications
Acute Liver Failure
•Often admitted with excessively high plasma
glutamine levels
•Over-supplementation of any one amino acid is
contraindicated
•Does not apply to chronic liver failure or acute-on-
chronic liver failure

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Mechanically Ventilated Patients
•Two landmark studies showing contraindications:
•REDOXS
•MetaPlus

•Due to the similar research study results from both studies,
it brings concern about the supplementation of glutamine
REDOXS vs. MetaPlus
Adopted from van Zanten et al.

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Sepsis
•Decreased utilization by the gut during sepsis;
mainly used by the rapidly dividing immune cells
and the liver

•Further enhances the inflammatory response
Head Trauma Patients
•High interstitial concentration of glutamate
•In the intact brain, glutamate is released by the
brain, reabsorbed by nerve endings and metabolized
into glutamine
•Head trauma patients have no change in the net
balance of glutamate or glutamine across the brain
during supplementation

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Continuous Renal Replacement
Therapy
•Amino acids are lost in dialysate during CRRT

•Should be supplemented at a higher rate of
0.5g/kg/day rather than 0.3g/kg/day
Available Products

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Juven
•Supports tissue building in elderly in 2 weeks
•Helps maintain lean body mass (LBM) in cancer
cachexia patients in 4 weeks
•Recommended intake: 2 packets/day
•Administered orally or as a modular via feeding tube
•Active ingredients:
•Revigor (CaHMB, calcium B-hydroxy-B-methylbutyrate)
•Arginine
•Glutamine

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Preface

Glutamine, like any other nutritional supplement,
should be considered on an individualized basis
References
• Mueller C, McClave S, Kuhn JM. The A.S.P.E.N. Adult Nutrition Support Core Curriculum. Silver Spring, MD: American Society for Parenteral and Enteral Nutrition;
2012.
• Hoffer LJ. Human Protein and Amino Acid Requirements. Journal of Parenteral and Enteral Nutrition 2016.
• Smith RJ, Wilmore DW. Glutamine Nutrition and Requirements. Journal of Parenteral and Enteral Nutrition 1990;14(4 Suppl).
• Wernerman J. Glutamine supplementation. Ann Intensive Care Annals of Intensive Care 2011;1(1):25.
• Ellinger S. Micronurients, Arginine and Glutamine: Does Supplementation Provide an Efficient Tool for Prevention and treatment of Different Kinds of
wounds. Advances in Wound Care. 2016;2(11):691-707.
• Posthauer M, Banks M, Dorner B, Schols J. The Role of Nutrition for Pressure Ulcer Management. Advances in Skin & Wound Care. 2015;28(4):175-188.
doi:10.1097/01.asw.0000461911.31139.62.
• Gu ndogdu R, Temel H, Bozk rl B, Ersoy E, Yazgan A, Y ld r m Z. The Mixture of Arginine, Glutamine, and  -hydroxy- -methyl Butyrate
Enhances the Healing of Ischemic Wounds in Rats. Journal of Parenteral and Enteral Nutrition. 2016. doi:10.1177/0148607115625221.
• Pattanshetti V, Powar R, Godhi A, Metgud S. Enteral glutamine supplementation reducing infectious morbidity in burns patients: a randomised controlled trial.
Indian Journal of Surgery. 2009;71(4):193-197. doi:10.1007/s12262-009-0056-x.
• van Anholt R, Sobotka L, Meijer E et al. Specific nutritional support accelerates pressure ulcer healing and reduces wound care intensity in non-malnourished
patients. Nutrition. 2010;26(9):867-872. doi:10.1016/j.nut.2010.05.009.
• Balda, M.S., Fallon, M.B., Van Itallie, C.M., Anderson, J.M. 1992. “Structure, Regulation, and Pathophysiology of Tight Junctions in the Gastrointestinal
Tract.” The Yale journal of Biology and Medicine 65: 725-735
• Rao, R., & Samak, G. (2012). Role of Glutamine in Protection of Intestinal Epithelial Tight Junctions. Journal of Epithelial Biology & Pharmacology,5(Suppl 1-M7),
47–54. http://doi.org/10.2174/1875044301205010047
• Li N, Lewis P, Samuelson D, Liboni K, Neu J. Glutamine regulates Caco-2 cell tight junction proteins. Am J Physiol Gastrointes Liver Physiol. 2004; 287(3):
G726-33.
• Zhu H. Li YR. Oxidative stress and redox signaling mechanism of inflammatory bowel disease: updated experimental and clinical evidence. Exp Biol Med
(Maywood). 2012
• Ziegler TR, Ogden LG, Singleton KD, et al. Parental glutamine increases serum heat shock protein 70 in critically ill patients. Intensive Care Med. 2005:31 :
1079-86
• Rajendram R, Preedy V, Patel V. Glutamine in clinical nutrition. (Nutrition and Health).Springer 2014
• Holecek M. Side Effects of Long-Term Glutamine Supplementation. Journal of Parenteral and Enteral Nutrition 2012;37(5):607–616.
• Wernerman J. Glutamine supplementation to critically ill patients? Critical Care Crit Care 2014;18(2):214.
• Straaten HMO-V, Zanten ARV. Glutamine supplementation in the critically ill: friend or foe? Critical Care Crit Care 2014;18(3):143.
• Wischmeyer P. Glutamine Supplementation in Parenteral Nutrition and Intensive Care Unit Patients: Are We Throwing the Baby Out With the Bathwater?
Journal of Parenteral and Enteral Nutrition 2015;39(8):893–897.
• Zanten ARHV, Hofman Z, Heyland DK. Consequences of the REDOXS and METAPLUS Trials: The End of an Era of Glutamine and Antioxidant
Supplementation for Critically Ill Patients? Journal of Parenteral and Enteral Nutrition 2015;39(8):890–892.