A Clinical Approach to Nutrition and Wound Healing a Patient’S Diet Matters

THE DIABETIC FOOT

A Clinical Approach to Nutrition and Wound Healing A patient’s diet matters.

BY JAMES MCGUIRE DPM, LPT, LPED., ALEX SHELTZER, BS

utrition plays a vital supplement, arginine, has been hy- To simply ignore the role of nutrition role in living a healthy pothesized to enhance wound heal- in wound healing would be to ne- lifestyle; however, it is ing through its formation of collagen glect a powerful tool that can be used often overlooked in the and increased nitric oxide produc- to our advantage. 87 management of chronic tion.4 Numerous other nutrients have Definitive data on the effects Nwounds and diabetic wounds in par- been shown to be essential for heal- of nutritional supplementation on ticular. Unaddressed malnutrition is a significant risk factor for delayed wound closure and post-operative To simply ignore the role of nutrition in complications. How many of us real- ly take the time to include nutrition wound healing would be to neglect a powerful tool in our patient assessment and pre-operative protocols? Because of the that can be used to our advantage. prevalence of diabetes, complications of glycosylation—such as delayed wound healing, impaired growth fac- ing of acute and chronic wounds. wound closure has been scarce, but tor production, altered cell migration, Dietary management is an inte- the burden of chronic ulceration and impaired collagen synthesis—are gral aspect of inpatient hospital care. management has prompted a need well known.1 HbA1c levels have been However, nutritional status is not for new studies. It is generally ac- shown to be an important biomarker routinely evaluated during the clini- cepted that vitamin and mineral sup- in predicting wound-healing rate in cal assessment of outpatient chronic plementation is helpful in patients diabetic patients. In an examination wounds or surgical candidates. The with known vitamin deficiency; how- of 71 studies that evaluated the asso- annual cost of chronic wound ever, the effects of superfluous sup- ciation between diabetic foot ulcers care in the U.S. is conser- plementation with these nutrients, (DFUs) and more than 100 indepen- vatively believed to be recommended by many “pseudo ex- dent variables… age, gender, diabe- $31.7 bil- perts”, has not been demonstrated in tes duration, body mass index, lion.5 controlled studies. HbA1C and neuropathy were most predictive.2 Vitamin A Other nutritional Vitamin A supplemen- deficiencies are less tation has been recom- common and often mended during con- overlooked. Vitamin comitant corticoste- D plays an import- roid use, due to its ant role in wound role in collagen healing, and supple- production mentation has been and en- shown to decrease hanc- ulcer size and inflamma- ing growth tory biomarkers.3 Another common Continued on page 88

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Nutrition (from page 87) supplement for any clinician who width in patients with diabetic foot treats wounds. ulcers.13 Individuals who abuse alco- factors such as transforming growth hol are at high risk for zinc deficien- factor-beta (TGF-beta) and insu- Vitamin D cy, and zinc supplementation should lin-like growth factor-1 (IGF-1), all Similarly, vitamin D has an ex- be considered if they present with a suppressed during steroid use.6 De- tensive array of effects on glucose non-healing wound. Diabetics are at spite the pro-collagen effect of vita- homeostasis, inflammatory cell mi- high risk for developing hypomagne- min A supplementation with concur- gration, and angiogenesis. Tiwari, et semia that can subsequently lead to rent corticosteroid use, there is little al. found that vitamin D deficiency neuropathy and platelet dysfunction, information about universal applicability of vitamin A supplementation on wound healing. Certain metals are essential co-factors for enzymes that

Vitamin B Complex play critical roles in cellular and immune function. While vitamin B complex has not traditionally been associated with wound healing, a 2015 paper was prevalent and more severe in both well-known contributors to foot showed that vitamin B supplemen- diabetics with foot ulcers, likely ex- ulceration. A well-controlled 2018 tation has anti-diabetic effects and plained by its association with elevat- study demonstrated that a 12-week improves wound closure in dia- ed inflammatory cytokine markers.11 regimen of magnesium supplemen- betic rat models.7 This is likely ex- A recent 2017 paper showed a tation in diabetics with foot wounds plained by the fact that diabetes significant reduction of ulcer length, significantly decreased ulcer size depletes folate, vitamin B6, and vi- width, depth, and erythema in pa- compared to placebo.14 Additionally, 88 tamin B12 levels, and supplemen- tients with diabetic foot ulcers follow- the study group demonstrated en- tation can enhance healing, and in ing high dose vitamin D supplemen- hanced glucose metabolism and de- some cases improve symptoms of tation.12 Countless physicians have creased inflammatory markers such diabetic neuropathy.8 encountered the challenges present- as high-sensitivity C-reactive protein. ed by non-healing wounds, and their Vitamin C association with vitamin D deficien- Copper Possibly the most well-studied cy is undeniable. Dr. Caroline Fife, Copper is an essential nutrient and understood nutrient in the con- a wound care specialist, notes that needed for host defense mecha- text of wound healing is vitamin C. many patients that she tests are se- nisms, red and white cell matura- Numerous studies have provided verely vitamin D-deficient, including tion, iron transport, cholesterol and convincing evidence that vitamin C those already on supplements. She re- glucose metabolism, and wound enhances wound healing regardless cently presented a patient with a stub- closure; however, its main utilization in wound care is as an adjunct to wound dressings because of its Possibly the most well-studied and understood nutrient antifungal and antimicrobial properties.15,16 Iron and selenium supple- in the context of wound healing is vitamin C. mentation have been studied, but results are either inconclusive as in the case of selenium, or even indic- of deficiency. A recent 2018 study born non-healing wound dehiscence ative of being detrimental to wound demonstrated that high-dose vitamin following surgery. The wound almost healing.17,18 C supplementation in addition to completely closed after three weeks mesenchymal stem cells drastically of high dose vitamin D supplementa- Amino Acids improves wound closure in diabetic tion.12 This scenario is not unique and Certain amino acids, such as ar- mice compared to either component vitamin D levels must be considered ginine and glutamine, are essential in isolation.9 Another study showed for patients with chronic wounds or for normal wound closure and sup- that vitamin C had a pleiotropic ef- ulcerations. plementation, with these amino acids fect on genes that promoted fibro- essential in cases of malnutrition.19 blast proliferation and histological- Zinc Supplementation above the recom- ly showed enhanced wound matrix Certain metals are essential mended maximum daily allowance deposition and organization through co-factors for enzymes that play crit- has not proven to improve wound its favorable genetic impact.10 Vita- ical roles in cellular and immune healing. Arginine is a precursor of min C is a co-factor for collagen syn- function. Zinc, for example, is re- nitric oxide that has a potent vasodi- thesis, has anti-inflammatory char- quired for cell growth, membrane latory effect, increasing blood flow to acteristics, and stimulates fibroblast repair, and immune cell migration. the distal extremities. Arginine is also proliferation. This profile of effects Zinc supplementation has been involved in the synthesis of collagen causes vitamin C to be an enticing shown to reduce ulcer length and Continued on page 90

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Nutrition (from page 88) wound healing remains unclear, 12 weeks of probiotic supplementa- there is even less certainty regard- tion demonstrated decreased length, and the release of insulin-like growth ing the impact of glutamine. Gluta- width, and depth of diabetic foot ul- factor (IGF-1), essential for epitheli- mine is abundant in plasma and an cers compared to a placebo group.33 alization. Despite these demonstrat- important inflammatory mediator. It This could be explained by the di- ed positives, little research has been also induces production of certain rect antimicrobial effects of probi- done to prove the impact of arginine cytoprotective heat shock proteins otics as well as their impact on the patient’s antioxidant status. While this study’s findings were promising, the impact of probiotics on insulin Certain amino acids, such as arginine and metabolism and lipid profiles has glutamine, are essential for normal wound closure been inconclusive.33-35 Despite the growing interest in and supplementation, with these amino acids nutrient supplementation as an adjunct to wound closure protocols, essential in cases of malnutrition. the fundamental building blocks of carbohydrates, proteins, fats, and fluids must be present as a base- supplementation on wound healing. that help decrease infection rates.28 line. Before any nutrient supple- In rat models, arginine supplementa- Kesici, et al. showed that well-nour- mentation should be considered, a tion increased collagen deposition in ished rats showed no difference in clinician must first ensure that their subcutaneous tissues and amplified hydroxyproline deposition, a strong patients are sufficiently nourished wound breaking strengths.20 marker for collagen synthesis and with basic macronutrients. Calo- 90 This phenomenon could be ex- subsequent wound closure after rie restriction has severe impact on plained specifically by the impact of glutamine supplementation was ad- wound closure as calorie deficits nitric oxide, as nitric oxide knock- ministered. The authors deduced can prompt cortisol production, out rat models had no difference in that glutamine supplementation in which leads to subsequent protein wound breaking strengths or colla- healthy subjects does not accelerate catabolism and increased inflamma- gen deposition after arginine sup- wound healing.29 tory responses.36 plementation.21 (a knockout rat is a Conversely, Jalilimanesh, et al. rat whose DNA has been genetically found improved wound contraction Proteins engineered so that it does not ex- and expedited complete wound clo- Proteins are required for col- press particular proteins.) Howev- sure of second-degree burns follow- lagen synthesis, inflammatory cell er, arginine supplementation does ing glutamine supplementation.31 formation, and wound contraction. increase protein balance of skin wounds despite inhibition of nitric oxide synthase.22 As promising as ani- mal studies have been, these benefits Calorie restriction has severe impact on wound have not been shown in human mod- closure as calorie deficits can prompt els, and all wounds examined were acute as opposed to chronic. Several cortisol production which leads to subsequent protein studies have shown the benefits of catabolism and increased inflammatory responses. a nutritional cocktail that contained arginine on pressure ulcer healing; however, it is difficult to attribute this solely to arginine.23-26 Studies on amino acid supplementa- Proteins are active throughout each Leigh, et al. showed that pres- tion are promising and further stud- phase of wound healing and must sure ulcers did not respond to argi- ies are indicated. be present in ample quantities to nine in a dose-dependent manner, ensure competent matrix deposition as there was no change in pres- Probiotics and maintenance of oncotic pressure ulcer healing when comparing The extensive utilization of sure. Breslow, et al. observed that 4.5g and 9g supplements.27 With no probiotics has also led to specula- patients with pressure ulcers who known human studies investigating tions regarding their role in diabetic consumed the most amount of pro- the effect of arginine supplementa- wound healing. Probiotics have been teins and calories healed the most tion on healing of chronic wounds theorized to improve immune func- efficiently and did not gain a signif- it is debatable whether arginine sup- tion and metabolic control, and to icant amount of weight, suggesting plementation has any positive effect abolish pathogenic microbes.32 These that energy is being preferentially on the healing of chronic wounds in properties make probiotics an ap- utilized for ulcer healing and not humans.27 pealing supplement for aiding dia- being stored.37 While the role of arginine in betic wound closure. An analysis of Continued on page 91

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Nutrition (from page 90) index utilizes a scoring system that quantifies factors such as BMI, Fat Intake weight loss, and mobility. The MNA Adequate fat intake is neces- has been reported to have a 96% sary as fats serve as the vehicle for sensitivity, 98% specificity, and a fat-soluble vitamins A, D, E, and 97% positive predictive value for K. Specific fats such as omega-6 predicting under-nutrition, and is a fatty acids are precursors to pros- practical tool for clinicians.39 taglandins and leukotrienes, while Other similar tools exist such also having a robust impact on in- as the Malnutrition Screening Tool, flammatory cell proliferation and and the Malnutrition Universal migration.38 Many older patients Screening Tool, but the MNA seems have little interest in drinking and to have the broadest applicabili- are in a state of constant dehydra- ty currently. While these assess- tion. While not directly contribut- ments are useful, there are certain ing to caloric nourishment, fluid demographics that may still be at

Adequate fat intake is necessary as fats serve as the vehicle for fat-soluble vitamins A, D, E, and K.

intake is still vital and serves to nutritional risk regarding wound maintain skin turgor and promote healing. For example, impoverished tissue oxygenation. Fluids must be individuals are often calorically sufficiently restored, particularly nourished but may still be deficient in the setting of a draining wound in certain nutrients which may in- such as venous stasis or lymphatic terfere with wound closure. Thor- wound. Before nutrient supplemen- ough clinical assessment and the tation should even be considered, a proper utilization of lab values are clinician must first ensure that their imperative to ensure malnourish- patients are sufficiently nourished ment does not go untreated, as its with basic macronutrients. impact on chronic wounds can be devastating. Biochemical Lab Values Not all nutritional supplemen- Biochemical lab values have tation is benign and can be det- been historically used to predict nu- rimental if utilized when not in- tritional status. Albumin and pre-al- dicated. Omega-3 fatty acids were bumin are widely used by physi- previously thought to be benefi- cians to assess malnourishment. cial for wound healing because of These values can be affected by fac- their anti-inflammatory properties. tors such as hydration, medications, However, studies have shown that congestive heart failure, and liver omega-3 fatty acids reduce long- disease, and may not always give term wound strength. Initial analy- the entire picture. To aid in evalu- sis demonstrated improved epithe- ating laboratory data, the medical lialization during the early phases community has begun shifting to- of healing, but the benefits quickly wards the utilization of indices for faded as the wound bed became nutritional assessments. weaker than the placebo during the maturation phase.40 Mini Nutritional Assessment There is controversy regarding One widely used tool is the the effect of vitamin E as well. Be- Mini Nutritional Assessment (MNA) cause it inhibits the absorption of which was originally designed for vitamin A, it is contraindicated in elderly individuals in the United vitamin A deficiency. Because of States but has been proven to be the vasodilatory effect of increased effective in any demographic. This Continued on page 92 www.podiatrym.com NOVEMBER/DECEMBER 2019 | PODIATRY MANAGEMENT THE DIABETIC FOOT

Nutrition (from page 91) References kauskas D, Ward S, Wayne JS, Brophy DF, 1 Brem H, Tomic-Canic M. Cellular and Fowler AA 3rd, Yager DR, Natarajan R. nitric oxide with arginine supple- molecular basis of wound healing in diabe- Vitamin C promotes wound healing through mentation in a septic patient, it tes. J Clin Invest. 2007 May;117(5):1219-22. novel pleiotropic mechanisms. Int Wound doi: 10.1172/JCI32169. Review. J. 2016 Aug;13(4):572-84. doi: 10.1111/ may lead to increased risk of septic 2 Christman AL, Selvin E, Margolis DJ, iwj.12484. shock. Even nutraceuticals are not Lazarus GS, Garza LA. Hemoglobin A1c 11 Tiwari S, Pratyush DD, Gupta completely benign, and despite the predicts healing rate in diabetic wounds. J SK, Singh SK. Vitamin D deficiency is utility of nutritional supplementa- Invest Dermatol, 131 (2011), pp. 2121-2127. associated with inflammatory cytokine concentrations in patients with diabetic foot infection. Br J Nutr. 2014 Dec 28;112(12):1938-43. doi: 10.1017/ Undiagnosed nutritional deficiencies are S0007114514003018. likely responsible for the chronicity of a surprisingly 12 Fife, Caroline. Wound Whisperer: Shhhh… My Secret Treatment for a Surgical high number of non-healing wounds. Wound Dehiscence. 2019 April. https:// carolinefifemd.com/2019/04/15/wound- whisperer-shhhh-my-secret-treatment-for-a- surgical-wound-dehiscence/. Accessed May tion in non-healing wounds, they 3 Razzaghi R, Pourbagheri H, 5, 2019. should not be given aimlessly. Momen-Heravi M, Bahmani F, Shadi J, 13 Momen-Heravi M, Barahimi E, Raz- The keys to nutritional manage- Soleimani Z, Asemi Z. The effects of vita- zaghi R, Bahmani F, Gilasi HR, Asemi Z. ment of wound patients in a clini- min D supplementation on wound heal- The effects of zinc supplementation on cal environment are identification ing and metabolic status in patients with wound healing and metabolic status in pa- and knowledge. 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Appropriate use of Duangpatra J, Buppajarntham S, De- effects of arginine: a pituitary mechanism of charatanachart P, Mutirangura A, Patumraj action. Am J Clin Nutr. 1983 May;37(5):786- nutritional supplements should be S. High dose oral vitamin C and mesen- 94. doi: 10.1093/ajcn/37.5.786. a mainstay in any clinical setting chymal stem cells aid wound healing in 21 Shi HP, Efron DT, Most D, Tantry US, where wounds are commonplace, a diabetic mouse model. J Wound Care. Barbul A. Supplemental dietary arginine en- and podiatric wound care specialists 2018 May 2;27(5):334-339. doi: 10.12968/ hances wound healing in normal but not in- have the opportunity to be at the jowc.2018.27.5.334. ducible nitric oxide synthase knockout mice. forefront of this advancement. PM 10 Mohammed BM, Fisher BJ, Kras- Continued on page 94

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Nutrition (from page 92) sure ulcers. J Wound Care. 2012 Mar;21(3):150-6. doi: 10.12968/ jowc.2012.21.3.150. Surgery. 2000 Aug;128(2):374-8. doi: 10.1067/msy.2000.107372. 28 Chow O, Barbul A. Immunonutrition: Role in Wound Heal- 22 Zhang XJ, Chinkes DL, Wolfe RR. The anabolic effect of argi- ing and Tissue Regeneration. Adv Wound Care (New Rochelle). nine on proteins in skin wound and muscle is independent of nitric 2014;3(1):46-53. Doi:10.1089/wound.2012.0415. oxide production. Clin Nutr. 2008 Aug;27(4):649-56. doi: 10.1016/j. 29 Kesici U, Kesici S, Ulusoy H, Yucesan F, Turkmen AU, Besir clnu.2008.01.006. A, Tuna V. Effects of glutamine on wound healing. Int Wound J. 23 Benati G, Delvecchio S, Cilla D, Pedone V. Impact on pressure 2015 Jun;12(3):280-4. doi: 10.1111/iwj.12098. ulcer healing of an arginine-enriched nutritional solution in patients 30 Jalilimanesh M, Mozaffari-Khosravi H, Azhdari M. The Effect with severe cognitive impairment.Arch Gerontol Geriatr Suppl. of Oral L-glutamine on the Healing of Second-degree Burns in Mice. 2001;7:43-7. Wounds. 2011 Mar;23(3):53-8. 24 Frías Soriano L, Lage Vázquez MA, Maristany CP, Xandri 31 Oelschlaeger TA. Mechanisms of probiotic actions—a review. Graupera JM, Wouters-Wesseling W, Wagenaar L. The effective- Int J Med Microbiol. 2010;300(1):57-62. ness of oral nutritional supplementation in the healing of pres- 32 Mohseni S, Bayani M, Bahmani F, Tajabadi-Ebrahimi M, sure ulcers. J Wound Care. 2004 Sep;13(8):319-22. doi: 10.12968/ Bayani MA, Jafari P, Asemi Z The beneficial effects of probiotic ad- jowc.2004.13.8.26654. ministration on wound healing and metabolic status in patients with 25 Heyman H, Van De Looverbosch DE, Meijer EP, Schols JM. diabetic foot ulcer: a randomized, double-blind, placebo-controlled Benefits of an oral nutritional supplement on pressure ulcer healing trial. Diabetes Metab Res Rev. 2017. in long-term care residents. J Wound Care. 2008 Nov;17(11):476-8, 33 Ivey KL, Hodgson JM, Kerr DA, Lewis JR, Thompson PL, 480. doi: 10.12968/jowc.2008.17.11.31475. Prince RL. The effects of probiotic bacteria on glycaemic control in 26 Cereda E, Gini A, Pedrolli C, Vanotti A. Disease-specific, overweight men and women: a randomised controlled trial. Eur J versus standard, nutritional support for the treatment of pressure Clin Nutr. 2014;68(4):447-452. ulcers in institutionalized older adults: a randomized controlled trial. 34 Naruszewicz M, Johansson ML, Zapolska-Downar D, Bukow- J Am Geriatr Soc. 2009 Aug;57(8):1395-402. doi: 10.1111/j.1532- ska H. Effect of Lactobacillus plantarum 299v on cardiovascular dis- 5415.2009.02351.x. ease risk factors in smokers. Am J Clin Nutr. 2002;76(6):1249-1255. 94 27 Leigh B, Desneves K, Rafferty J, Pearce L, King S, Wood- 35 Hunt ND, Li GD, Zhu M, Miller M, Levette A, Chachich ME, ward MC, Brown D, Martin R, Crowe TC. The effect of different Spangler EL, Allard JS, Hyun DH, Ingram DK, de Cabo R. Effect of doses of an arginine-containing supplement on the healing of pres- calorie restriction and refeeding on skin wound healing in the rat. Age (Dordr). 2012 Dec;34(6):1453-8. doi: 10.1007/s11357-011-9321-6. 36 Breslow RA, Hallfrisch J, Guy DG, Crawley B, Goldberg AP. The importance of dietary protein in healing pressure ulcers. J Am Geriatr Soc. 1993 Apr;41(4):357-62. 37 Silva JR, Burger B, Kühl CMC, Candreva T, Dos Anjos MBP, Rodrigues HG. Wound Healing and Omega-6 Fatty Acids: From In- flammation to Repair. Mediators Inflamm.2018;2018:2503950. doi: 10.1155/2018/2503950. 38 Kaiser MJ, Bauer JM, Ramsch C, Uter W, Guigoz Y, Ceder- holm T, Thomas DR, Anthony P, Charlton KE, Maggio M, Tsai AC, Grathwohl D, Vellas B, Sieber CC. Validation of the Mini Nutritional Assessment short-form (MNA-SF): a practical tool for identification of nutritional status. J Nutr Health Aging. 2009 Nov;13(9):782-8. 39 Albina JE, Gladden P, Walsh WR. Detrimental effects of an omega-3 fatty acid-enriched diet on wound healing. JPEN J Parenter Enteral Nutr. 1993 Nov-Dec;17(6):519-21. doi: 10.1177/ 0148607193 017006519.

Dr. McGuire has been a Clinical Professor at the Temple University School of Podiatric Medicine for the past 27 years. He also serves as director of the Foot and Ankle Institute’s Leonard Abrams Center for Advanced Wound Healing where he has worked since 1999. He has been a founding member of both the APWH, the APWCA, and the Council for Medical Educa- tion and Testing. He is very involved in research with several active research trials and numerous papers in the area of wound healing, off-loading, diabetic foot care, and biomechanics of the foot and ankle. Alex Sheltzer is currently a 4th year stu- dent at Temple University School of Podiatric Medicine. He graduated with a BS in Biology from Tufts University in 2015. His interests include diabetic wound care, sports medicine, and biomechanics.

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