The problem of skin ulceration is one common to nearly all healthcare disciplines. Skin ulcers are known to lead to significant morbidity and premature mortality. Moreover, they have also been shown to increase the rates of hospitalization, length of hospital stays, and healthcare-related financial costs . To further complicate the issue, skin ulcers are nearly always multifactorial with both preventable and nonpreventable components. Epidemiologic studies of surgical, trauma, and medical patients in the hospital have found that 12–50% of patients are malnourished [2▪]. The influence of malnutrition on ulcer formation and healing has been well documented, but intervention trials are typically small, heterogeneous, and of poor quality [1,3,4]. This review will highlight the important advances in the area of nutrition for the prevention and treatment of skin ulceration, with special attention to current guidelines and need for further research.
Skin ulcerations can be classified in a variety of ways. The most common way is to first establish the underlying cause of the wound. Causes of skin ulcers include pressure, venous stasis, arterial insufficiency, trauma, diabetic neuropathy, or venom. They are further classified according to the stage or depth of invasion. Wounds are typically described as one that is in stage 1–4, a deep tissue injury, or unstageable. The National Pressure Ulcer Advisory Panel (NPUAP) and European Pressure Ulcer Advisory Panel (EPUAP) have published resources to assist in the staging and characterization of skin ulcers. Monitoring for wound healing is also important and can be done systematically with the Pressure Ulcer Scale for Healing, or PUSH, tool (see Fig. 1) . This tool uses objective wound characteristics and is therefore useful both clinically and for research purposes.
MARKERS AND TOOLS FOR ASSESSING NUTRITIONAL STATUS
Current guidelines recommend universal nutritional screening for all patients with or at risk of developing skin ulceration on initial assessment and with any change in condition . There are many ways to assess nutritional status, each with its own limitation. Because of these limitations, nutritional status should not be assessed using only one measurement tool or marker. In addition, individual clinical context is very important, as acute illnesses can alter nutritional markers considerably.
Anthropomorphic measurements, such as BMI, serial weights, and fat-free mass determination, should be obtained in all patients. These measurements can be affected by the person's fluid status and the accuracy depends on the experience level of the person taking the measurements. Some anthropomorphic measurements require special instruments, which may not be readily available. Others, however, can be useful as quick and simple determinants of skin integrity and risk for ulceration in other areas. For example, assessment of skin elasticity of the forearm was shown in one study to be highly correlated with skin elasticity and pressure ulcer risk in the sacrum and trochanter areas .
Anthropomorphic measurements alone are useful for assessing chronic malnutrition but in the case of acute malnutrition, other parameters must be used to more accurately evaluate nutritional status. Several hematologic markers of protein-calorie malnutrition have been studied for this purpose. Albumin, prealbumin (with or without C-reactive protein), and transferrin are highly correlated with the risk of morbidity and mortality [7▪,8,9]; however, none are specific to nutritional status. In fact, acute inflammation will alter these markers, even in previously well nourished individuals, as they act as acute-phase reactants. Functional tests, such as handgrip strength, assess lean body muscle and may be useful to identify malnourished patients with normal anthropomorphic measurements and acute inflammation .
Nutritional assessment tools
Several screening tools, which incorporate historical, hematologic and anthropomorphic data, have been developed and validated for assessing nutritional status . These include the Subjective Global Assessment (SGA), Malnutrition Universal Screening Tool (MUST), and Mini-Nutritional Assessment (MNA) tool (see Fig. 2, [10–13]). Each has been highly correlated with the risk of malnutrition but is also likely screening for frailty, a condition in which even adequately nourished individuals face adverse outcomes. In older patients, the MNA is more specific than the SGA . These screening tests have also been shown to be useful in the assessment and evaluation of malnutrition in patients with skin ulceration . Many ulcer studies that evaluated the role of nutrition in skin ulceration used one of these tools in the study protocol.
TARGETED NUTRITIONAL THERAPIES
Although discussions on nutritional interventions for skin ulceration typically focus on individual nutrients, most human studies used supplements that contain more than one potentially beneficial nutrient. This makes it more difficult to analyze the impact of each component of the supplement on the measured outcome. For this reason, this discussion will begin by introducing the physiological role and theoretical benefit of individual nutritional components, followed by an update of the literature for these substances, usually in combination, for the prevention and treatment of skin ulceration.
Theoretical basis for nutritional supplementation to enhance wound healing
The use of various nutrients to aid in chronic wound healing is based on the role of these nutrients in the normal process of acute wound healing . Under ideal conditions, a wound will undergo three phases of wound healing: the inflammatory (4–6 days), proliferative (3 days to 3 weeks), and remodeling (2 weeks to 2 years) phases. During the initial inflammatory phase, there is an influx of inflammatory cells that ‘clean up’ the wound through hemostasis, cytokine signaling, and increased cellular oxidation. Vitamin K and calcium play important roles in fibrin formation during this phase. This stage is also characterized by increased protein, energy, and fluid needs, as well as an increase in the oxidative stress because of production of excess reactive oxygen species (ROS). These ROS are important for the removal of debris and bacteria but if not controlled may lead to the damage of healthy wound tissue. Dietary antioxidants (such as the vitamins C and E) and enzyme cofactors (zinc, copper, iron, and selenium) may play a beneficial role in reducing the impact of ROS. The proliferative phase is characterized by collagen and extracellular matrix protein building. This phase is dependent on adequate availability of amino acids, vitamin C, and iron. In the maintenance phase, magnesium, zinc, and vitamin C are needed to maximize the collagen strength and skin integrity . Unfortunately, chronic wounds do not progress normally through these stages toward skin integrity. For this reason, the role of nutrients in chronic wound states is neither well described nor understood. Most positive nutrition supplementation trials are done in patients with acute wounds, such as burns or surgical wounds. Chronic pressure ulcer trials are often of poor quality and underpowered to detect differences between groups. Trials of higher quality have mostly been negative.
Assessing caloric needs and energy intake during wound care
When assessing the nutritional needs and intake in any patient, the first step is to assess the caloric needs and energy intake since energy deficiency impairs fibroplasia [2▪]. People with wounds and skin ulcers are typically in a nutritionally catabolic state, at high risk of muscle and body fat breakdown to meet increased energy requirements. This is because of the body's reaction to a wound, causing increased energy expenditure and water loss. Typical recommendations for dietary caloric and nutritional intake may be too low for patients with skin ulcers, as the resting energy expenditure (REE) may be higher in these patients . However, whether REE is increased in pressure ulcers remains controversial. In a meta-analysis of five trials , the measured REE was 23.7 + 2.2 kcal/kg/day in persons with a pressure ulcer (n = 92) versus 20.7 + 0.8 in the controls without a pressure ulcer (n = 101), suggesting a small but significant difference. However, 43% of the persons with a pressure ulcer were quadriplegic or paraplegic, perhaps accounting for the difference. Studies of frail, institutionalized elders show conflicting results. In a study of 29 older persons with a pressure ulcer, the measured resting metabolic rate did not differ from hospitalized controls . However, in another study of bedridden elderly women, the 23 patients with stage 3 or 4 pressure ulcers had significantly higher measured and estimated REE than 29 control patients without pressure ulcers . The gold standard for determining REE is through indirect calorimetry. This measurement may not be available in all institutions and as such is not practical for universal use. Estimated REE through predictive equations, such as the Harris–Benedict formula or the Mifflin–St Jeor equation, has been shown to be comparable to the measured REE . Caloric needs can also be estimated according to the individual wound size based on the understanding that protein synthesis requires 0.9 kcal/g and a 3 cm2 × 1 mm granulated wound contains 10 mg of collagen protein [2▪]. Estimating the energy requirement may be useful and should be included in the assessment of nutritional risk and needs in patients with wounds.
Energy can be consumed in many forms, most commonly in the carbohydrate form. This is the energy form that is most readily used by the body; however, as the collagen protein is critically important to wound healing, adequate protein and fat intake should be ensured as well. This may help to ameliorate the breakdown of body energy and protein stores. However, not all energy supplementation is helpful. For example, studies have found mixed results for the use of omega-3 fatty acids for wound healing. In animal studies, diets high in omega-3 fatty acids had increased body weight and immune response; however, they were left with weaker wounds, despite similar levels of collagen [2▪,18]. No studies have yet been done in humans. In addition, care must be taken to avoid hyperglycemia from carbohydrate supplementation, as this can lead to impaired immunity and wound healing .
Protein supplementation and wound healing
Protein intake through nutritional supplementation has also been extensively studied, with mixed results. The essential amino acids are most abundantly found in animal sources. With the exception of soy (a complete protein), additional supplementation should be considered in people only consuming vegetable proteins. The conditionally essential amino acids, arginine and glutamine, are labeled such because in periods of acute illness, body stores quickly become depleted and demand for these substances increases. Arginine is important for tissue formation as a substrate for collagen and antioxidation through formation of nitric oxide. It also has similar effects on wound strength as growth hormone and it stimulates T-cell response and function [2▪]. Glutamine is the fuel for cells with rapid turnover, including those responsible for wound healing during the inflammatory and proliferative phases [2▪]. Both arginine and glutamine are commonly used in nutritional supplements for patients with skin ulcerations. Rarely, if ever, have they been studied without the addition of other nutrients and vitamins in the supplement formula. Furthermore, studies of arginine and glutamine have significant variability in quality, sample size and characteristics, dosages, and duration . This makes it difficult to compare the studies to come to a conclusion regarding the true benefit of protein supplementation. This is discussed further in the next section.
The role of antioxidants
Vitamins C, E, and A also have important roles in wound healing. Vitamin C acts as a cofactor for collagen formation and is critical for normal healing. Tissue stores of vitamin C are quickly depleted if dietary intake is inadequate and can lead to the deficiency state, scurvy. Interestingly, studies have shown normal wound healing in patients with early scurvy and no difference in healing rates were seen in those repleted with high-dose vitamin C . Chronic vitamin C deficiency is, however, associated with poor scar and wound integrity and a recent case–control study found lower levels of vitamin C in a group of patients with chronic leg ulcers . True deficiency in developed countries is rare, but frail patients are at high risk of insufficient vitamin C intake . If people with skin ulcers are not getting enough dietary sources of vitamin C, supplementation may be necessary.
Vitamins E or A also have important roles in immune health and wound integrity. Supplementation of these vitamins may improve wound healing, but best data would suggest that this benefit occurs only if a deficiency is present (see Table 1). This occurs commonly in people with malabsorption, but otherwise true vitamin deficiency is rare in developed countries. In addition, there is evidence of potential harm of supplementation, particularly in the presence of liver or kidney dysfunction, and vitamin E has been associated with decreased surgical wound tensile strength . Therefore, routine supplementation with vitamins A or E is not recommended for the prevention or healing of skin ulceration.
Iron, zinc, and copper are three trace elements that also play important roles in wound healing, but supplementation is only recommended if patients are deficient in these nutrients because current evidence does not show a benefit of supplementation in replete individuals . It is also important to remember that zinc and copper compete for binding sites on albumin. For this reason, high-dose supplementation and toxicity of either micronutrient can lead to the deficiency of the other. Signs and symptoms of deficiency and recommended replacement doses can be found in Table 1[21,22].
UPDATE IN EVIDENCE FOR NUTRITIONAL INTERVENTIONS IN THE PREVENTION AND TREATMENT OF ULCERS
Current guidelines  recommend universal screening for malnutrition in patients at risk for or with skin ulceration using anthropomorphic measurements (including serial weights) and appropriate screening tools. In patients at high risk of malnutrition and dehydration, adequacy of caloric, protein, and fluid intake should be assessed. On the basis of the best available evidence, dietary interventions should ideally be under the care of a registered dietician [23▪]. The diet should be well balanced and supplementation with nutrients and vitamins given when deficiency is present (Table 1). Caloric intake is recommended at 30–35 kcal/kg body weight, protein intake at 1.25–1.5 g/kg body weight, and fluid intake of 1 ml/kcal consumed. Evidence for these recommendations are based on the expert consensus as the body of evidence is weak.
Bad news first
Nutritional interventions targeting patients at risk of developing skin ulcerations have mixed results and have been shown not to be cost-effective [24▪].
The most recent Cochrane review  for nutritional interventions for the prevention and treatment of pressure ulcers included only eight studies. Of all trials of nutritional intervention, these eight were the only ones with sufficient statistical rigor to draw conclusions; however, the heterogeneity in the eight studies precluded the authors from completing a full meta-analysis. Four of the eight studies used mixed nutritional supplements for the prevention of ulcers in hospitalized patients. Only one of the four showed a statistical benefit. This study has several important limitations, including lack of individual randomization, no data on nutrient consumption, and a high incidence of ulcers in the treated group (40%). For the treatment of pressure ulcers, the four studies (two for vitamin C, one for protein, and one for zinc) were markedly different and of poor methodological quality. There was demonstration of a possible benefit for protein supplementation, mixed evidence for vitamin C (the best study being negative), and no benefit for zinc supplementation. Overall, the evidence for vitamin C is weak [19,25]. More recently, the use of supplemental tube feeding for the prevention or healing of pressure ulcers was studied in a large propensity-matched cohort study. Not only did the authors find no benefit of instituting tube feeding in this frail nursing home population, but also there was a potential risk of developing pressure ulcers in the tube-fed group [26▪▪]. This study and the Cochrane review show the dramatic lack of good evidence for nutritional interventions to prevent or treat pressure ulcerations and highlights the fact that much of what is done in clinical practice is based on consensus, not evidence (see Table 2).
Now the good news
Despite the large body of negative studies, there does seem to be evidence for protein supplementation to promote wound healing. In the Cochrane review described above, the single protein trial included was positive for improving wound healing time. In addition, a recent trial was conducted in Japan in which tube-fed patients were given higher than recommended protein and calorie formulas (based on REE calculations). This supplementation resulted in improved wound healing over a 12-week period compared to a group receiving the lower limits of recommended protein and calorie intake [29▪]. This suggests that previous negative trials may have given inadequate support for the catabolic state produced by skin ulcerations. It also supports the use of REE calculations to determine protein-calorie needs. This should become a routine part of nutritional assessments in high-risk patients. Interestingly, oral protein supplements may also benefit nonmalnourished patients with skin ulceration, as evidenced by improved wound healing parameters in a small randomized controlled trial .
Evidence for the conditionally essential amino acids
As stated previously, arginine and glutamine have been extensively studied for their role in wound healing. The evidence for arginine is slightly more promising as studies of glutamine supplementation have been disappointing and surprisingly negative given its important physiologic role in wound healing [1,2▪,4]. There is evidence of benefit in burn and trauma victims, so although routine glutamine supplementation for all types of skin ulcers is not currently recommended, use in selected individuals is warranted. In fact, the most recent trial, which utilized glutamine in a mixed nutritional supplement for nonhealing trauma wounds, found that this glutamine-based supplement shortened the time to wound closure over placebo [31▪▪]. Use caution when supplementing glutamine in patients with liver or kidney disease as increasing circulating glutamine can lead to excess ammonia levels.
The evidence for arginine, although stronger than glutamine, is limited to a few, small, heterogeneous studies. Support for arginine supplementation comes from several animal and healthy human studies that showed improved healing of induced wounds in these models [2▪]. The most important study historically for the use of arginine in patients with pressure ulceration was a small randomized controlled trial by Desneves et al., which demonstrated improved ulcer healing using the PUSH tool. Since then, additional studies of variable quality have been published. The most recent study lacks a true control [28▪], causing an inability to make solid conclusions. Another recent study is a small prospective cohort study of hospitalized patients in Japan, which included patients with enteral tube-feeding who were supplemented with a formulation containing arginine, as well as carbohydrates, zinc, and copper. The authors demonstrated that supplementing arginine improved wound healing parameters and time during the 3-month study period . Although several studies support the use of arginine for pressure ulcer healing, the study quality is overall poor and mixed formulations make it difficult to make firm conclusions regarding the exact substance leading to the improved outcomes. In addition, arginine is utilized in the urea cycle, so its use may be contraindicated in patients with liver disease.
A summary of the best available evidence for nutritional interventions in skin ulcerations can be found in Table 2.
In conclusion, it has been well established that weight loss, protein-calorie malnutrition, and dehydration are the risk factors for pressure ulcers. There is also good evidence that pressure ulcers lead to a catabolic energy state, predisposing an individual to increased inflammation and cachexia. As this ‘chicken–egg’ relationship can lead to a complicated cycle of events, trying to understand the role of nutritional supplementation in the prevention and management of skin ulceration can be challenging. There is mixed evidence for most nutritional interventions, with most studies being of poor quality with variable study designs, lack of control groups, small sample sizes, and short study lengths. Long-term randomized trials of individual nutrients and clinically relevant endpoints are needed to definitively show the benefit of additional nutritional supplementation over dietary interventions. Until those studies become available, best evidence suggests the importance of screening for malnutrition, calculating REE and caloric needs, and monitoring the dietary intake of essential nutrients.
The author wishes to acknowledge Dr David R. Thomas for his contribution in reviewing and commenting on an early draft.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 111).
1. Dorner B, Posthauer ME, Thomas D. The role of nutrition in pressure ulcer prevention and treatment: National Pressure Ulcer Advisory Panel white paper. Adv Skin Wound Care 2009; 22:212–221.
2▪. Williams JZ, Barbul A. Nutrition and wound healing. Crit Care Nurs Clin North Am 2012; 24:179–200.
This review highlights the energy requirements in perioperative, burn, and other acutely ill patients. It also reviews the individual nutritional components with some evidence to support their use for specific wound types.
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7▪. Tsutsumi R, Tsutsumi YM, Horikawa YT, et al. Decline in anthropometric evaluation predicts a poor prognosis in geriatric patients. Asia Pac J Clin Nutr 2012; 21:44–51.
This study assessed the albumin levels and body composition (triceps skinfold thickness and arm circumference) to determine the nutritional status in a population of hospitalized patients. The authors were able to show that both albumin and measurements of body compositions predicted pressure ulcers and mortality. However, the use of albumin suggests that severity and acuity of illness, not nutritional status, is predictive of adverse outcomes. Interestingly, the body composition measurements more acurately predicted poor prognosis than albumin levels.
8. Barbosa-Silva MC. Subjective and objective nutritional assessment methods: what do they really assess? Curr Opin Clin Nutr Metab Care 2008; 11:248–254.
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14. Langkamp-Henken B, Hudgens J, Stechmiller JK, Herrlinger-Garcia KA. Mini nutritional assessment and screening scores are associated with nutritional indicators in elderly people with pressure ulcers. J Am Diet Assoc 2005; 105:1590–1596.
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16. Dambach B, Salle A, Marteau C, et al. Energy requirements are not greater in elderly patients suffering from pressure ulcers. J Am Geriatr Soc 2005; 53:478–482.
17. Sergi G, Coin A, Mulone S, et al. Resting energy expenditure and body composition in bedridden institutionalized elderly women with advanced-stage pressure sores. J Gerontol A Biol Sci Med Sci 2007; 62:317–322.
18. Doley J. Nutrition management of pressure ulcers. Nutr Clin Pract 2010; 25:50–60.
19. Collins N. Adding vitamin C to the wound management mix. Adv Skin Wound Care 2004; 17:109–112.
20. Lazareth I, Hubert S, Michon-Pasturel U, Priollet P. Vitamin C deficiency and leg ulcers. A case control study. J Mal Vasc 2007; 32:96–99.
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23▪. Baldwin C, Weekes CE. Dietary advice with or without oral nutritional supplements for disease-related malnutrition
in adults. Cochrane Database Syst Rev 2011; CD002008.
This intervention review assessed the effects of dietary advice, with or without oral nutritional supplements in 45 randomized controlled trials. No differences were seen for mortality; however, significant benefit on weight and anthropomorphic measurements were seen for the groups including dietary advice.
24▪. Pham B, Stern A, Chen W, et al. Preventing pressure ulcers in long-term care: a cost-effectiveness analysis. Arch Intern Med 2011; 171:1839–1847.
This Canadian study used a validated Mankov model to stimulate the benefits of various pressure ulcer prevention strategies for nursing home residents. The authors found that oral nutritional supplements have a small beneficial effect with the NNT of 333 to prevent one pressure ulcer. This was not a cost-effective strategy when analyzed using their cost model, even when adjusting for QALY gained.
25. Ellinger S, Stehle P. Efficacy of vitamin supplementation in situations with wound healing disorders: results from clinical intervention studies. Curr Opin Clin Nutr Metab Care 2009; 12:588–595.
26▪▪. Teno JM, Gozalo P, Mitchell SL, et al. Feeding tubes and the prevention or healing of pressure ulcers. Arch Intern Med 2012; 172:697–701.
This is a well designed, large, propensity-matched, cohort study of nursing home patients with cognitive impairment designed to assess the benefit of feeding tube insertion on prevention of stage 2 or higher ulcers and healing of stage 2 or higher pressure ulcers. In more than 18 000 residents studied using information gathered from the minimum data set over an 8-year period, the authors found no benefit for either outcome and a potential risk of increased development of pressure ulcers in the tube-fed group. The exact mechanism of this increase in unclear, but postulated to be because of other unmeasured factors such as restraint use or tube-feeding formula-induced diarrhea.
27. Desneves KJ, Todorovic BE, Cassar A, Crowe TC. Treatment with supplementary arginine, vitamin C and zinc in patients with pressure ulcers: a randomised controlled trial. Clin Nutr 2005; 24:979–987.
28▪. Leigh B, Desneves K, Rafferty J, et al. The effect of different doses of an arginine-containing supplement on the healing of pressure ulcers. J Wound Care 2012; 21:150–156.
This randomized trial compared different doses of arginine to historical controls. The authors were unable to show a dose–response effect on the primary outcome of pressure ulcer healing rate. The lack of a true control group makes it impossible to draw firm conclusions on the benefit of either arginine dose on wound healing. Previous positive studies of arginine-containing oral nutritional supplements also suffer from similar limitations.
29▪. Ohura T, Nakajo T, Okada S, et al. Evaluation of effects of nutrition intervention on healing of pressure ulcers and nutritional states (randomized controlled trial). Wound Repair Regen 2011; 19:330–336.
This article assesses the impact of administering high-protein supplements at doses exceeding recommended caloric intake. The authors chose tube-fed patients because they had greater control over their consumption. The authors randomized participants to receive the feeding formula based on the calculated REE using the Harris–Benedict equation or weight (control group). Over 12 weeks, the authors show improved wound healing in the intervention group. Although these were not acutely ill patients, they also showed improvements in prealbumin and copper levels in the intervention group. Baseline nutritional stauts was not discussed and it is questionable whether or not extrapolation can be made to other populations.
30. van Anholt RD, Sobotka L, Meijer EP, et al. Specific nutritional support accelerates pressure ulcer healing and reduces wound care intensity in nonmalnourished patients. Nutrition 2010; 26:867–872.
31▪▪. Blass SC, Goost H, Tolba RH, et al. Time to wound closure in trauma patients with disorders in wound healing is shortened by supplements containing antioxidant micronutrients and glutamine: a PRCT. Clin Nutr 2012; 31:469–475.
This recent, small, double-blind, randomized controlled trial enrolled 20 patients with traumatic or surgical wound with disordered healing to receive 14 days of a supplement containing glutamine, ascorbic acid, alpha-tocopherol, beta-carotene, selenium, and zinc twice daily. Various markers of nutritional status were obtained, along with the parameters of wound healing. Baseline parameters of microcirculation were not equal between groups and wound measurements are not reliably reproducible, which may have affected the healing time results independent of nutritional supplementation. Despite the positive effects of supplementation in this study, the limitations of this study make it difficult to make definitive conclusions and recommendations on glutamine supplementation to improve wound healing.
32. Yatabe J, Saito F, Ishida I, et al. Lower plasma arginine in enteral tube-fed patients with pressure ulcer and improved pressure ulcer healing after arginine supplementation by Arginaid Water. J Nutr Health Aging 2011; 15:282–286.