Nutrition in Wound Care Management: A Comprehensive Overview

Wound care is a multidisciplinary specialty requiring many physiologic and immunologic processes as well as physical, social, and societal factors working in conjunction to achieve successful wound closure. Most wounds are treated with combinations of antimicrobials, protective barriers, and topical growth agents, including skin and biologic grafts. The role of nutrition in wound healing may be overlooked in the wound care patient. Like the wound care specialty itself, nutrition for these patients is often multifaceted, with many nutritional components playing various roles in the wound healing process. Suboptimal nutrition can alter immune function, collagen synthesis, and wound tensile strength, all of which are essential in the wound healing process.¹ While not all wounds are equal, nutrition is a common denominator in the treatment of all patients with wounds, and what is studied in 1 wound population is often relevant in another.² Due to the complexities of monitoring and measuring both wound healing and dietary intake, randomized, controlled trials of wound care patients are difficult to conduct, and much of the data concerning nutrition in wound care relies on combined supplements. In summary, it appears that some nutrients are necessary only if deficient, whereas others may become conditionally essential and serve a therapeutic role. All of the nutrients discussed should be viewed as a component of a broader, complete diet. This article is a summary of wound healing and the roles of a variety of macronutrients and micronutrients in the process.

The progression of normal wound healing consists of phases that can vary in length, with nutritional elements playing supporting roles throughout the process. The inflammatory phase typically lasts for up to 6 days from initial injury. Following an injury, platelets and coagulation factors will form a fibrin clot over the injury site to achieve hemostasis and a protective barrier. The wound area will also become exudative with increased vascular permeability to deliver neutrophils and macrophages to remove bacteria, leading into the next phase, the proliferative phase, which starts 3-5 days postinjury and can last up to 3 weeks. During this phase, fibroblasts proliferate and angiogenesis and epithelialization occur, with collagen crosslinking and the resulting wound contraction. The remodeling phase starts approximately 2 weeks after injury and can last up to 2 years, during which time collagen maturation and stabilization occur, with a resulting increase in tensile strength and scar formation.^3,4 Chronic wounds are characterized by a prolonged inflammatory response with low levels of growth factors and an increased bioburden on the wound.⁵ Malnutrition is a common contributor to wound chronicity.⁶ Given the prolonged potential for the wound healing process, nutrition should be considered in wound prevention (eg, pressure ulcers in hospitalized patients) and wound preparation (eg, presurgical assessment), as well as in the treatment of acute and chronic wounds.

There are several nutritional risk factors that can lead to the development of impaired wound healing. In its broadest sense, malnutrition includes inadequate intake, overconsumption, and specific nutrient deficits.⁷ Risk factors for malnutrition include poor appetite, inability to feed oneself or requiring assistance to eat, impaired sense of taste and smell, or simply inadequate or excessive intake of calories, protein, fluid, or micronutrients. The elderly are disproportionately burdened with risk of nutritional deficiency due to medical, psychological, physiological, social, and economic difficulties associated with increased age.⁸ Clinical markers of malnutrition include significant weight loss, loss of subcutaneous fat, localized or generalized fluid accumulation, and reduced grip strength.⁹ Extremes in body mass index (BMI, low or high) should increase suspicion for malnutrition.

Unfortunately, diagnostic markers of malnutrition remain elusive, particularly in the critical care setting and the chronic inflammatory state of chronic wound healing.¹ Albumin, prealbumin, transferrin, and retinol binding protein have all been evaluated,¹⁰ but have not been validated for use in critical care or patients with chronic inflammation. In addition to malnutrition, acute or chronic infection, fluid status and fluid shifts, protein-losing states, and hepatic function can result in low albumin levels.¹¹ However, regardless of the cause for low albumin, normalization of values represents an improvement in the metabolic state. In the outpatient evaluation of wound care patients, Legendre et al¹² suggest combining BMI with C-reactive protein, albumin, and prealbumin to assess protein status. One of the most published tools in assessing malnutrition in the elderly is the Mini Nutritional Assessment (MNA) (Nestlé Nutrition Institute, Lausanne, Switzerland)¹³ which has since been shown to be useful across varying demographics.¹⁴ The MNA incorporates food intake and weight loss patterns, mobility, and neuropsychiatric contributors to eating habits, along with current BMI or calf circumference (ie, anthropomorphic measures) to determine risk of malnutrition or malnourished status.

Carbohydrates, fats, proteins, and fluids. Overall, nutrition in wound healing must provide adequate support for an increased energy demand during the wound healing process. Caloric needs during wound healing are estimated at 30-35 kcal/kg,¹⁵ or up to 40 kcal/kg if the patient is underweight, but may need to be individualized based on age, comorbidities, body weight, activity level, stage of the healing process, and  the severity, size, and number of wounds. Also, the composition of the calories needs to be evaluated with carbohydrates, proteins, and fats, as each play a role in the wound healing process. Protein-calorie malnutrition (PCM) is a form of malnutrition with decreased calories and decreased protein content of diet, leading to deficient lean body mass (LBM).⁶ It is sometimes found in critically ill patients due to hypermetabolic/hypercatabolic responses, but it can also be found in nonhospitalized patients due to behavioral eating habits. The hypermetabolic response results in glycogen depletion with cortisol production resulting in protein catabolism, amino acid mobilization, and the production of hepatic glucose. Additionally, inflammatory and immune responses are activated with increased production of interleukins 1 through 6; tumor necrosis factor alpha (TNFα); C-reactive protein, fibrinogen, and protein S; and decreased production of albumin and prealbumin.³ Altogether, these changes result in anorexia, malaise, cachexia, and impaired use of nutrients. In wound healing, inadequate protein stores result in increased skin fragility, decreased immune function with poor healing, and decreased reserve capacity with longer recuperation after illness.¹⁶

Carbohydrates. Carbohydrates stimulate insulin production, which is helpful in the anabolic processes of wound healing, particularly during the proliferative phase. However, hyperglycemia can reduce granulocyte function and increase infectious complications.¹⁷ Also, diabetic neuropathy can propagate wound formation if the patient does not take care to protect the wound in the area of reduced pain sensation. Apart from diabetes mellitus, steroid use, antibiotics, fluid supplementation with dextrose, and physiologic stress with increased cortisol production can also contribute to hyperglycemia.

Fats. Adequate fat intake in the patient with an acute or chronic wound can supply additional energy to the wound healing process, as well as structural functions including axonal myelination and lipid bilayers in cell and organelle membranes during tissue growth. Dietary fats can produce ATP via beta-oxidation, thereby addressing other energy-requiring processes to spare protein for wound healing. Fat intake is also important in the role of absorbing fat-soluble micronutrients, including vitamin A, omega-3, and omega-6 fatty acids. Omega-6 fatty acids are an important precursor to production of prostaglandins, thromboxane, and leukotrienes in the inflammatory response, resulting in platelet aggregation and inflammatory vasoconstriction.¹⁸ Omega-3 fatty acids, on the other hand, dampen inflammatory responses and result in vasodilation through cytokine release.¹⁹ Omega-3 fatty acid supplementation was shown to have a detrimental effect on wound healing with decreased wound tensile strength²⁰; however, it was also shown to decrease progression of pressure ulcers when supplemented in combination with omega-6 fatty acids in fish oil.²¹ Though the overall effect of essential fatty acids on wound healing is still unclear, supplements during the inflammatory phase in a 1:1 ratio of omega-6 to omega-3 have been proposed as beneficial.¹⁸ More information is needed on when to supplement fatty acids, what types of fatty acids are needed and in what ratio, as many trials thus far have been confounded due to a multisupplement approach.

Protein. Protein plays an essential role in all stages of wound healing. Protein supplies are essential to collagen synthesis, angiogenesis, fibroblast proliferation, immune function, tissue remodeling, wound contraction, and skin structural proteins.²² Leukocytes, monocytes, lymphocytes, and macrophages require protein for their formation and function in mounting an immune response. Protein deficiency results in impaired fibroblast proliferation and collagen synthesis during the proliferative phase of healing.^4,5 One key role of protein is the maintenance of oncotic pressure, particularly in venous insufficiency wounds, where excess extraluminal pressure due to peripheral edema will exacerbate wound formation and slow wound healing. Also, as mentioned with fat intake, overall protein and calorie malnutrition may shunt protein reserves away from wound healing processes into other required functions, thereby slowing wound healing. The presence of a wound increases protein demand by up to 250% and caloric demand by up to 50% to maintain adequate LBM stores.²³ Additionally, large quantities of protein can be lost through wound exudate.²⁴ Depletion of 10% of LBM is associated with impaired immunity and risk of infection, losses of 20% of LBM decreases the rate of wound closure with thinning of the skin, and losses of 30% of LBM will halt healing and predispose the patient to new wound formation.²⁵ Greater losses often result in death. Ensuring adequate protein stores and protein intake is vital; however, oversupplementation may not promote additional protein synthesis with the risk of increased oncotic pressure resulting in dehydration.²⁶

Fluids. Apart from calories, another factor of malnutrition to consider in wound healing is fluid intake. The function of fluid in wound healing is to maintain skin turgor and promote tissue perfusion and oxygenation.⁴ Water serves as a diluent for glucose, waste removal, and micronutrients¹⁵; to this end, risk factors for dehydration should be evaluated in the wound patient including fever, diarrhea, vomiting, diuresis, fistulae, wound drainage, and poor intake. The goal for fluid intake in patients with wounds is approximately 1ml/kcal/day,⁴ but should be adjusted for insensible losses or comorbid renal or cardiac disease.¹⁵ It is also important to encourage intake of water vs other fluids: one common social factor that can often lead to malnutrition and alter physiologic demand is alcohol abuse. Chronic alcohol consumption impairs the antioxidant defense and induces chronic oxidative stress.²⁷ The micronutrient zinc was noted to be decreased in male alcoholics with decreased plasma levels and increased urinary excretion.²⁸ Alcohol abuse can also propagate zinc deficiency, whereby zinc levels in the liver and serum have been found to be depleted in alcoholic cirrhotic patients.²⁹ Selenium was also noted to be affected by alcohol consumption, as the liver is the primary storage site for this micronutrient, and plasma selenium concentrations were significantly lower in patients with alcoholic cirrhosis.³⁰ Of note, selenium levels improved in these patients following supplementation.³¹ Also, narcotic use (prescription or recreational) often results in constipation, nausea, and anorexia, which can discourage oral intake and thus exacerbate nutritional deficiencies.²

Amino acids. Micronutrients must also be considered in the evaluation of the wound care patient including amino acids, vitamins, and minerals. Amino acids have also been implicated in the role of wound healing, in particular arginine and glutamine. Arginine is a conditionally essential amino acid, normally synthesized in the kidney and liver from citrulline.³² Supplementation of arginine may be required in states of increased demand, including patients with sepsis, trauma, and wounds.^33,34 The role of arginine in wound healing is diverse. Arginine is a precursor for nitric oxide, which is essential in the inflammatory process of wound healing,³⁵ but it is also used in the production of collagen.³⁶ Arginine is also a precursor of proline, which is necessary for the synthesis of collagen. Arginine supplementation was observed to increase collagen deposition in wounds.³⁷ Additionally, arginine supplementation was observed to increase lymphocyte mitogenesis. Together with ornithine, arginine also stimulates production of growth hormone and activation of T cells.^32,33 The recommendations for supplementation of arginine in patients with pressure wounds or stasis wounds was found to be 4.5 g/day,³⁸ but this can only be followed in the setting of adequate protein intake; otherwise, supplementation is of no value.

Glutamine, like arginine, is also conditionally essential and can be manufactured endogenously; but with increased demand and metabolic stress, supplementation may become necessary. Glutamine’s roles in the body are many, including metabolic, enzymatic, antioxidant, immunologic, and transport. In the process of wound healing, glutamine likewise has many roles to play.³⁹ Glutamine decreases infectious complications and protects against inflammatory injury by inducing the expression of heat shock proteins.⁴⁰ Metabolically, it increases insulin sensitivity and serves as an energy source by production of nicotinamide adenine dinucleotide phosphate (NADPH) or by breakdown to glutamate and alpha-ketoglutarate to be used in the Krebs cycle. It is a precursor for glutathione, an antioxidant necessary for stabilization of cell membranes, transporting amino acids across membranes, and a cofactor for enzymatic reactions.⁴¹ Ardawi⁴² found that neutrophils may preferentially use glutamine as an energy source more so than glucose. The role of glutamine as an energy source and in the production of necessary amino acids and nucleic acids suggests a key function in neutrophil biology. Additionally, glutamine appears to have a role in leukocyte apoptosis, superoxide production, antigen processing, and phagocytosis,^40,42 all with implications on the inflammatory phase of wound healing.

Glutamine supplementation is controversial. In critical situations such as trauma, burns, and sepsis, glutamine has been shown to improve gut function, decrease septic complications, and improve insulin sensitivity.⁴³ However, in the case of chronic wounds where the chronic inflammatory state is not present, the role of glutamine supplementation is less clear. In states of chronic malnutrition, however, its role in supplementation may be augmented due to intestinal mucosal atrophy, and overall muscle mass decrease leading to decreased glutamine stores, both leading to increased requirement of exogenous glutamine.² Like arginine, most studies regarding glutamine supplementation are confounded by the use of combination supplements.⁴⁴ According to Molnar et al,² even without randomized, controlled trials of isolated glutamine, supplementation is relatively safe in select patients with malnutrition, and the benefits of glutamine supplementation appear to be many. However, the researchers reiterate that glutamine and arginine should never be considered a substitute in the correction of PCM, and that without overall adequate protein intake supplementation is of no value.

Vitamins. The role of vitamins in wound healing has been evaluated more extensively, particularly given the cofactor role of many vitamins in enzymatic processes related to wound healing. Vitamin A (retinoic acid) has been shown to be beneficial in wound healing regardless of deficiency status, with deficiency showing impairment in wound closure. Vitamin A has been used topically in management of dermatologic conditions due to its ability to stimulate epithelial growth, fibroblasts, and ground substance.² It has also been shown to have an anti-inflammatory effect in open wounds, increasing the number of monocytes and macrophages at the wound site early in the inflammatory phase and facilitating epithelial cell differentiation.⁴⁵ Studies have shown that vitamin A functions as a hormone, altering the activity of epithelial cells, melanocytes, fibroblasts, and endothelial cells through its action on the family of retinoic acid receptors.⁴⁶ Deficiency of vitamin A results in altered B cell and T cell function and antibody production during the inflammatory phase and impaired collagen synthesis in the remodeling phase.^3,4 Vitamin A has shown a particular role for the management of chronic wounds in patients on corticosteroids for inflammatory diseases,⁴⁷ such as rheumatoid arthritis, where supplementation counteracts the negative effects of corticosteroids on wound healing⁴⁸ by decreasing transforming growth factor beta (TGFβ) and insulinlike growth factor-1 (IGF-1) within the wound.⁴⁹ The current recommendation for vitamin A supplementation in wound healing can range from 10,000 to 15,000 IU/day⁵⁰ up to 25,000 IU/day²; however, treatment must be administered in a short course of 10-14 days to prevent acute toxicity. Also, patients with deficiency of the retinol-binding protein due to liver malfunction or protein malnutrition may require a lower dose.

Vitamin C (ascorbic acid) deficiency brings to mind images of scurvy and loose-toothed sailors; however, vitamin C deficiency may not be readily apparent in the wound-healing patient.⁵¹ The role of vitamin C in wound healing is believed to be due to an influence on collagen formation, immunomodulation, and antioxidant functions. Deficiency results in impaired immune response during the inflammatory phase with increased capillary fragility and reduced collagen tensile strength and synthesis during the proliferative and remodeling phases,^4,5 with risk of wound dehiscence. Supplementation in the deficient patient is clearly beneficial; however, the evidence supporting the use of vitamin C alone in the nondeficient patient has been inconclusive. A review of multiple trials looking at the impact of supplementation on wound healing noted, “convincing evidence only exists for a protein and energy rich ONS (oral nutrient supplement) providing at least 500 mg of vitamin C, 17 mg of zinc, and 3gm of L-arginine in pressure ulcer therapy.”⁵² However, recommendations exist for 500-1,000 mg of vitamin C daily in divided doses for wound healing, and up to 1-2 g/day in severe wounds, such as extensive burns.⁵³

Vitamin D is a fairly new player to join the wound care supplementation repertoire; however, vitamin D deficiency has been shown to have increased incidence in patients with venous ulcers and pressure ulcers,^54,55 and recent studies have identified vitamin D receptors in a variety of tissues where their presence was previously unknown. Cathelicidin, an antimicrobial peptide induced by vitamin D, promotes wound healing.⁵⁶ These researchers concluded that vitamin D and its receptor signaling regulates structural integrity and transport functions of epithelial barriers with implications for wound healing.

Minerals. Along with vitamins, minerals represent another essential micronutrient in the role of enzyme structural factors and metalloenzymes. Zinc, selenium, and iron have been postulated as beneficial in wound healing, and more than 200 zinc-containing enzymes, including superoxide dismutase, are involved in wound healing. They function as antioxidants and modulate cell replication, nucleic acid metabolism, tissue repair, and growth.⁵⁷ Decreased zinc levels result in decreased cytotoxicity of natural killer cells, impaired phagocytosis in macrophages and neutrophils, and decreased number of granulocytes. Also with zinc deficiency, B-cell precursors and mature B-cells are reduced.⁵⁸ Zinc deficiency affects all phases of wound healing. In the inflammatory phase, there is decreased immunity and increased susceptibility to infections. In the proliferative phase, there is impaired collagen synthesis and tensile strength. Finally, in the remodeling phase, there is a dampening of fibroblast proliferation, collagen synthesis, and epithelialization.^4,5 However, excess zinc supplementation can interfere with the absorption of other cations, specifically iron and copper.²⁹ Therefore, supplementation should be avoided unless deficiency is present. The most common causes of zinc deficiency include diarrhea, malabsorption, and hypermetabolic states including stress, sepsis, and burns.²⁶ A review by Lansdown et al⁵⁹ looked at enteral vs topical zinc in wound healing, and found topical zinc applied to surgical wounds consistently augmented wound healing.⁵⁹ Recommendations for zinc supplementation in the zinc-deficient patient range from 40 mg/day²⁶ up to 220 mg⁶⁰ 2 times per day for 10-14 days.

Selenium is strongly involved in antioxidant functions, and a large randomized, controlled trial investigating the effect of high dose intravenous supplements found increased cutaneous concentrations of selenium.⁶¹ Normalization of plasma glutathione peroxidase level, a marker of antioxidant status, was improved, and patients were noted to have a decreased graft requirement. However, graft requirement is a less objective measure, and the IV preparations included copper and zinc, so the use of selenium in wound healing is still unclear, but appears beneficial.

Iron was previously postulated as beneficial in wound healing, due to its status as a cofactor in collagen synthesis. In wound healing, iron deficiency results in impaired T cell and phagocyte function in the inflammatory phase and decreased tensile strength and collagen synthesis in the proliferative phase.^4,5 However, iron supplementation has been shown to prolong inflammation,⁶² and no evidence exists that iron supplementation benefits wound healing. Patients with iron deficiency anemia, which is known to inhibit wound healing due to decreased oxygen transport to proliferating tissues, may benefit from iron supplementation; however, more data is required to establish treatment guidelines.

In conclusion, there are several roles for optimizing macronutrients and micronutrients in the management of patients with wounds; however, available data does not seem to support robust use. The data supports evaluating the patients’ nutritional status and ensuring sufficient calories from a balanced diet of carbohydrates, fats, and protein, and supplementing protein, fluid, and vitamins A and C as needed. Deficiencies in arginine, glutamine, and zinc should also be considered, and the data supports supplementing these in deficiency states. More data is needed to evaluate the role of supplementing vitamin D, selenium, iron, and essential fatty acids in the wound care patient.

Affiliation: Eastern Virginia Medical School, Norfolk, VA

Correspondence:
Nancy M. Khardori, MD, PhD
Professor, Department of Internal Medicine
Director, Division of Infectious Diseases
Eastern Virginia Medical Schoola
825 Fairfax Ave, Suite #572
Norfolk, VA 23507
khardonm@evms.edu

Disclosure: The authors disclose no financial or other conflicts of interest.