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Arginine and Glutamine in Wound Healing
- 1. Renee M. Hinojosa NTDT 5340 December 12th, 2011
- 2. Audience will be able to: ◦ Review the medical nutrition therapy for wound healing ◦ Identify the amino acids glutamine and arginine ◦ Recognize glutamine and arginines’ metabolic role in wound healing ◦ Be familiar with the different studies that have been done to establish these roles Pressure Ulcers, Diabetic Ulcers, Skin grafts, and Burns ◦ Discover future outlooks on glutamine and arginine in wound healing
- 4. 20% protein loss within first two weeks of injury Increased energy needs ◦ 25-35 g/kg/d Increased protein needs ◦ 1.5-2.0 g/kg/d Additional vitamins and minerals ◦ Selenium, Vitamin C, Vitamin A, Vitamin E, Zinc
- 5. Most abundant amino acid (AA) in the plasma Conditionally essential Major metabolic fuel for intestinal mucosa and cell proliferation ◦ Fibroblasts, lymphocytes, epithelial cells, macrophages Increases protein synthesis and immunoglobulin a (IgA) Synthesized in muscle
- 6. Conditionally essential Beneficial in improving cardiovascular, reproductive, pulmonary, gastrointestinal, liver and immune functions. Facilitates wound healing, enhances insulin sensitivity, and maintains tissue integrity Precursor for nitric oxide
- 7. Directly ◦ De novo synthesis Citrulline ◦ Synthesized FROM glutamine ◦ Synthesis OF arginine. Glutamine contributes 64% synthesis of arginine. Arginine can be hydrolyzed by hepatic arginase to urea and ornithine which utlimately get converted to glutamine
- 8. Arginine and pressure ulcers ◦ spinal cord injury Observational study Dietitian involved ◦ Mini nutritional assessment ◦ Weekly rounds Oral nutrition supplement ◦ Not exclusively arginine Zinc and Vitamin C Nutrition and Dietetics 2011 Dietitians Associations of Australia
- 9. 2.5-fold greater rate of pressure ulcer healing for those who took supplement ◦ Non-compliance – GI upset, dislike taste; Dietitian recorded monitored weekly intake Wide Age range No exclusion of wounds Limited to one population Stages not specified
- 10. Multicenter, multicountry, randomized, controlled, double blind, parallel group trial ◦ 43 participants ◦ Age: 18-90 years Stage III or Stage IV Pressure Ulcer Excluded Diabetic Ulcers ◦ Also excluded patients on a dietary restrictive diet Not specified
- 11. Standard Nutritional Diets and Wound Care ◦ Locally used protocols Oral Nutrition Supplements ◦ Arginine, Zinc, Vitamin A, Vitamin C, Selenium, Copper, Folic Acid Suggests that healing could be multifactorial Results ◦ Significant differences in the reduction of the ulcers and the difference in PUSH scores Most prominent in 1st weeks
- 12. Both Arginine and Glutamine Observational Study ◦ 16 participants Nutritional Supplement ◦ Arginine, Glutamine, Hydroxy-B-methylbutyrate (HMB) ◦ Energy needs: 20-22% of high quality protein Microalbuminuria – Kidney function ◦ Type II DM
- 13. Two Hypothesis ◦ Reduction in Albuminuria ◦ Arginine protects kidney Results ◦ Supplement decreased microalbuminuria by 47% ◦ 6 months Food ulcers healed after this time Absence of randomization ◦ Role of HMB?
- 14. Prospective Study Healthy adults - skin transplantation ◦ Reconstructive Surgery Mechanisms of Arginine ◦ Compared healing Surgical wounds and normal skin Inducible Nitric Oxide ◦ Activated by arginine
- 15. Cells observed after supplementation ◦ PMNs and Marcrophages Increased NO levels and wound tensile strength Arginine was increased in all wounds Not increased in non-surgical wounds ◦ Fibroblasts Increase in NO More specific ◦ Arginine 2
- 16. Double Blind Control Study Skin Graft ◦ 35 subjects Intravenous Arginine Wound healing evaluated at donor site ◦ Angiogenesis ◦ Reepithilialization ◦ Neutrophil influx Plasma arginine AA concentrations measured Burns 37 (2011)
- 17. Two groups comparable ◦ Age, nutritional status, metabolic and inflammatory state No differences found in arginine group or placebo Conclusion ◦ Arginine does not improve angiogenesis, reepethilialization or neutrophil influx
- 18. Arginine and Glutamine ◦ No effect on pressure ulcers in elderly Randomized control study Dietitian involved in assessment ◦ 26% were at risk for malnutrition Nutritional supplement ◦ Agrinine Did not increase NO in this population Did not enhance lympocyte proliferation Lack of other vitamins and minerals Did not provide immune benefit
- 19. Randomized, controlled double blind clinical trial Burn patients ◦ 30-75% total surface area burned Glutamine Supplementation – enteral nutrition and oral supplementation ◦ Glutamine granules and glycine Nutrition ◦ All patients receiving the same amount of nitrogen and energy Did not specify grams or kcals/kg
- 20. Immune function improved in glutamine groups Hospital stay ◦ 9 days shorter fro supplemented group Results ◦ Glutamine supplementation improves immune function and facilitates wound healing
- 21. Arginine studied more than Glutamine ◦ Individalization Mixed results Bigger study groups needed for generalization ◦ Nutritional supplements Had more benefit Vitamins, minerals, antioxidants Most subjects were not malnourished in all studies Wound healing ◦ Multifactorial More studies needed ◦ Individualizing both amino acids
- 22. Questions?
- 23. Peng, X., H. Yan, Z. You, P. Wang, and S. Wang. "Glutamine Granule- supplemented Enteral Nutrition Maintains Immunological Function in Severely Burned Patients." Burns 32.5 (2006): 589-93. Stechmiller, Joyce K., Bobbi Langkamp-Henken, Beverly Childress, Kelli A. Herlinger-Garcia, Jan Hudgens, Lili Tian, Susan S. Percival, and Ruby Steely. "Arginine Supplementation Does Not Enhance Serum Nitiric Oxide Levels in Elderly Nursing Home Residents With Pressure Ulcers." 4 Apr. 2006. Web. 2 Dec. 2011. <http://www.ncbi.nlm.nih.gov/pubmed/15788738>. Debats, I.B.J.G., T.G.A.M. Wolfs, J.P.M. Cleutjens, and C.J. Peutz- Kootstra. "Role of Arginine in Superficial Wound Healing in Man." Web. 12 Dec. 2011. <http://www.ncbi.nlm.nih.gov/pubmed/19638312>. atti, Patrizio, Leonardo Masselli, Annalisa Pipicelli, and Annabel Barber. "Effect of a Nutritional Supplement Used for Diabeic Foot Ulcers on Microalbuminuria." Mediterranian Journal of Nutrition Metabolism 9 (2011).
Editor's Notes
- 20% protein loss within first two weeks of injury Increased energy needs 25-35 g/kg/d Increased protein needs 1.5-2.0 g/kg/d depending on the severity of the injury Long-standing DM with a high rate of gluconeogenesis is in itself a catabolic condition, these subjects have a high rate of protein loss. Additional vitamins and minerals Selenium, Vitamin C, Vitamin A, Vitamin E, Zinc
- Most abundant AA in the plasma Conditionally essential Initially classified as non-essential since it can be synthesized de novo , it is now considered conditionally essential in catabolic states. Major metabolic fuel for intestinal mucosa and cell proliferation Fibroblasts, lymphocytes, epithelial cells, macrophages Increases protein synthesis and immunoglobulin a (IgA) This contributes to maintain intestinal barrier Synthesized in muscle From nonessential amino acids and gucose, with much of the nitrogen coming from glucose.
- Conditionally essential It is synthesized from glutamine, glutamate and proline via the intestinal renal axis Beneficial in improving cardiovascular, reproductive, pulmonary, gastrointestinal, liver and immune functions. Facilitates wound healing, enhances insulin sensitivity, and maintains tissue integrity Precursor for nitric oxide nitrous oxide synthase 2 (NOS2) gene transfer reversed impaired wound repair in NOS2 deficient mice Precursor derived from L-arginine NO has cytostatic, chemotactic, and vasodilatory effects during early wound repair, regulates proliferation and differentiation of several cell types, modulates collagen deposition and angiogenesis, and affects wound contraction.
- Dierectly De novo synthesis Glutamine directly contributes to arginine de-novo synthesis through an intestine kidney pathway Citrulline Synthesized from glutamine Synthesis of arginine Citrulline, synthesized from glutamine, directly through glutamate and proline in the mitochondria of enterocytes, is released from the small intestine, escapes the liver and is extracted primarily by the kidney in which it is used for synthesis of arginine. glutamine contributes 64% to the synthesis of arginine from citrulline under postabsorptive conditions
- Use of an arginine-enriched oral supplement in the healing of pressure ulcers in patients with spinal cord injuries: An observational study Observational Study 34 patients involved Average age 49 Dietitian in charge of all nutritional assessments BMI, weight history, clinical factors impacting nutritional status (bowel regimen, appetite, dentition, level of spinal chord injury and its impact on self feeding, diet history Supplement compliance and overall dietary intake. This study had no significant differences in age, baseline pressure ulcer scale for healing (PUSH) score, prevalence of under nutrition, gender, or type of spinal chord injury. Majority of patients were well nourished 3 of the 4 patients that were malnourished improved nutritional status throughout the study. Patients prescribed two 237 ml tetra packs per day of specialized wound healing supplement containing 9g of protein 500mg Vitamin C 30 mg Zinc
- 2.5-fold greater rate of PU healing for those who took the supplement While the study was not a randomized controlled trial, it examined the healing of PU in normal clinical practice and therefore presents a realistic picture of the likely benefit of nutritional intervention Good Study Wide age range Dietitian assessed patients Wound patients included – diabetics, osteomyelitis, and recovering surgery. Bad Study Could have compared the groups in one taking a supplement having extra protein vitamin C and zinc and another group with added arginine. Limited to one population Melbourn Victoria All stages of pressure ulcer taken into consideration Could have skewed numbers; patiens with lower pressure ulcers could have cured faster Prior intake of nutritional supplements (Ensure etc…) were not taken into consideration…patients could have already been taking supplement at home which could have also skewed results.
- Specific nutritional Support accelerates pressure ulcer healing and reduces wound care intensity in non-malnourished patients. Multicenter, multicountry, randomized, controlled, double blind, parallel group trial Czech Republic, Belgium, The Netherlands, Curacao Age: 18-90 years Stage III or Stage IV Pressure Ulcer Revised by the European Pressure Ulcer Advisory Panel Classification system Excluded Diabetic Ulcers Also excluded were malnourished patients, those on pallative care, those using corticosteroids, and those on a dietary restrictive diet No protein, no CHO???
- Standard Nutritional Diets and Wound Care Locally used protocols Oral Nutrition Supplements Arginine, Zinc, Vitamin A, Vitamin C, Selenium, Copper, Folic Acid Results Significant differences in the reduction of the ulcers and the difference in PUSH Conclusion: Present study showed that pressure ulcer healing can be accelerated in non-malnoursihed patients by providing a specific oral nutrition supplement enriched in Arginine, zinc, and antioxidants. This suggests that the benefits of this supplement reach beyond restoring caloric and protein deficiencies. Supplementation is also likely to improve the quality of life of patietns and sace cost by decreasing wound care. Good Study Broad range of patients: Can be generalized to different countries Limited to stage III and stage IV ulcers therefore, no bias to smaller pressure ulcers was present Wide age range can also generalize that it works for everyone Patients were excluded if they were taking supplement 2 weeks prior to admission to the hospital. Bad Study Exclusion of diabetic ulcers – sometimes the most prevalent Also not exclusive to arginine (glutamine not present) Small sample considering so many countries involved No dietitian monitored intake No specific details given as to what was the “standard nutritional protocol” followed
- Both Arginine and glutamine Most recent study found that takes both of these amino acids into consideration Observational study 16 participants Average age of 63 years All patients suffered from nephropathy, rentinopathy and neuropathy Patients at a slightly overweight BMI (Normal) 25 Nephropathic diabetic who develops a foot ulcer usually is protein malnourished, even at a normal BMI. Average duration of DM in these patients was 11 years Nutritional Supplement Arginine, glutamine, HMB – two doses Individual Caloric needs supplying 20-22% of high quality protein per day Microalbuminuria – Kidney Function Type II DM Microalbuminuria is a hallmark of renal involvement in DM Condition defined as the passage of protein in the urine. Precursor of proteinuria and early mortality.
- Two Hypothesis The reduction in microalbuminuria, the blend increased collagen deposition helped the reconstruction of the capillary basement in the kidney Arginine may have exerted a renoprotective effect demonstrated in different models of renal failure Anti inflammatory of arginine in muscle Results Supplement decreased microalbuminuria by 47% 6 months Foot ulcers healed but authors thought it would have had more of an improvement in microalbuminuria had the patients continued to take the supplement . Weakness of the study Absence of randomization Does not include any other wounds Does not focus on one amino acid What role does HMB play in wound healing 6 months is not a long time to fully see the effects this supplementation has on albuminuria but it did show that giving the supplement did help in healing wounds.
- Prospective Study Healthy adults – Skin Transplantation Reconstructive surgery Excluded if patients had kidney or liver failure, pregnant, use of steroids or had DM Mechanisms of Arginine Compared healing Surgical wounds and normal skin Study provides insight in the mechanisms of arginine by showing expression of arginine metabolites and arginine metabolizing enzymes at different time prints during normal healing of surgical wounds compared with normal skin. Inducible nitric Oxide – derived from L-arginine NO has cytostatic, chemotactic, and vasodilatory effects during early wound repair, regulates proliferation and differentiation of several cell types, modulates collagen deposition and angiogenesis, and affects wound contraction. In the present study, iNOS was observed in macrophages, PMNs (Neutrophils), fibroblasts, epithelial and endothelial cells upon wounding. In contrast, these cells did not express iNOS in normal skin, indicating wounding activates arginine metabolism. All of these cells have specific functions during the complex process of healing and nitric oxide has been implicated as a mediator.
- In summary, the finding support that arginine supplementation activates the cells most involved in wound healing In the future, arginine 2 over arginine 1 might be considered as a supplement
- Neutrophil influx was assessed to evaluate the essential inflammatory phase of wound healing. Neutrophils generate NO Angiogenesis (new blood vessels from old blood vessels)– mediated through NO, through the induction of vascular endothelial growth factor.
- Despite a significantly increased plasma arginine levels after supplementation, there was no benefit from supplementational arginine. Arginine supplementation might only affect wound healing when there is a depletion
- Arginine and Glutamine No effect on pressure ulcers in elderly Randomized control study Dietitian involved in assessment 26% were at risk for malnutrition None malnourished Nutritional supplement Agrinine Did not increase NO in this population Possible that arginine was metabolized via arginase and not via NO synthase NO synthase is also down-regualted with age Did not enhance lymphocyte proliferation Lack of other vitamins and minerals
- Randomized, controlled double blind clinical trial Burn patients Divided into two groups Both groups given same amount of nitrogen and energy Vitamins and minerals? 14 days 48 patients with severe burns 30-75% of surface area burned Glutamine supplementation Glutamine granules and glycine were provided All solutions packed the same way Neither the provider nor the patient knew if they were getting glutamine or not. Nutrition All patients receiving the same amount of protein
- Patients receiving glutamine did better in maintaining immunologic function, blocking sepsis, accelerating wound repair, and reducing hospital stay 9 days shorter The study showed that is is possible to increase plasma concentrations of glutamines by providing glutamine granules via nutrition support, and could benefit burn patients Limitations Some of these granules were given through enteral nutrition Not known if other vitamins and minerals were aiding the healing process. What diets were being followed in hospital Were all patients given the same amount of vitamins and minerals as would be given in a premixed enteral formula? Burns 30-70% big gap Wound have been better to separate wounds in stages
- Arginine is being more observed than glutamine. Studies that did individualize these amino acids had mixed conclusions Nutritional supplement's enhanced with other vitamins minerals and antioxidants had more benefit More studies are needed to determine if arginine and glutamine can be individually given to benefit Further studies could evaluate the healing effects of single nutrients (arginine or glutamine).