3/9/2016

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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

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