T

he faces of the chronic wound are many and varied. We are all schooled in the "reason d'etre" for the nonhealing wound. Pressure, poor vascular inflow, infection, concomitant diseases, and poor venous return are well ingrained in our minds as we assess and care for the person with a chronic nonhealing wound. However, we often neglect to uncover the concomitant and subtle nutritional defects that might have prolonged the healing process or contributed to nonhealing.
       This article will take the reader through nutritional assessment and the implications of poor nutrition on the wound healing environment.

Nutritional Assessment and Screening
       The microcellular environment reflects the physiologic environment in which it is found. Hence, if there is an alteration of balance, or an actual loss of available cellular metabolites, a resultant tissue defect may occur. Significantly impaired protein and calorie intake can lead to a depleted total body protein status. This can lead to decreased wound protein content and, ultimately, decreased wound tensile strength. Therefore, a nutritional assessment is important to identify risks for poor nutrition that might result in a poor biochemical environment and inadequate wound healing.
       Ultimately, wound healing is the result of protein processing. This physiologic event (healing) requires the assimilation of protein (e.g., amino acids, peptides, polypeptides) to form a healing matrix. Energy is required for healing to occur. Nutritional assessment helps the observer identify a deficiency in either of these micro- or macroenvironments.
       Lean body mass is reflective of total body protein compartment (i.e., in evaluation, the size and relative density of body protein to body fat).1 The practitioner can get a feel for the person's ultimate total body protein status because total body protein also is reflected in humoral proteins (e.g., circulating proteins that include albumin, globulin, hormones), which should be evaluated as well. The typical nutrition screen, therefore, will look at both of these components to assess the risk.
       There are a number of screening tools to be utilized. The most important, of course, is the visual inspection or observation. The savvy observer will be able to identify subtle visual cues. We have all seen people that appear cachectic or obese. Interestingly enough, it appears that morbid obesity has more of a regrowth impact on wound healing and tensile strength than cachexia. Either of these observations may cue us into evaluating the nutritional status of the person.
       A good verbal health history is paramount to identify poor or undernutritional risk. Nutrition convention tells us that a person who has experienced significant weight loss (10% or greater in 6 months) will be placed at risk for poor wound healing.2 This observer also believes that structured weight loss always will result in total body protein loss. The magnitude of this loss may be inconsequential in wound healing. However, common sense tells us that if we have a person with a chronic nonhealing wound who has also lost weight regardless of the cause of that weight loss, the person will be at risk for further healing stress and poor outcomes unless the nutritional component is stabilized.
       Lean body mass may be assessed through actual or indirect measurement. Direct measurement through the use of a body composition analyzer is useful. Inferring from anthropometrics data is perhaps less costly and more practical. Hence, the person who screens as having some weight loss (or massive weight gain) deserves to have this component assessed. The assessment can be performed by a nutrition professional (dietitian, nurse, physiologist, physician).
       By calculating the ratio of the difference between the lean body compartment and body fat, the person may be compared to a standard. This can be done with total body weight and its relationship to a standard:
% Deficit = 100 - actual weight x 100
Ideal weight
Both of these parameters are subject to various inconsistencies and other influences (e.g., changes, altering of body water, and other concomitant disease states). Total body mass measurement is only an observation and must be utilized as a component or tool in further nutritional evaluation.
       The assessment of humoral or visceral proteins requires some invasion of the body compartment by drawing blood to obtain chemical measurement. The decision to obtain this biochemical data should be balanced with the common sense evaluation of the person's status. Most wounds heal despite nutrition status; hence, the decision to obtain biochemical data should be founded on the observer's key sense of need. This person may have a biochemical nutrition defect. If there is suspicion or a question that there is a biochemical defect, the person's total protein, serum albumin, and total lymphocyte count may give further clues regarding the overall nutritional status. Even more sophisticated biochemical markers may be assessed (transferrin, prealbumin) when a screening assessment has identified increased risk. (See AHCPR Pressure Ulcer Clinical Practice Guidelines).3
       Currently the Subjective Global Assessment (SGA) is the main tool of the nutritionist when performing a dynamic nutritional assessment. The various components of the SGA are fairly self explanatory. Essentially it provides a reproducible template for nutritional evaluation. Further, it offers the healthcare professional an ongoing stable evaluation tool to allow for ongoing assessment as nutrition alterations occur during nutrition therapy. The observer needs to be cautioned, however, as there are many vagaries that adversely affect this biochemical data. These often will not affect the wound healing environment. Influences are not steeped in a true nutrition defect. It is important to realize that regardless of the reason for alterations in these visceral parameters, if they are significantly depressed, wound healing will be affected. Often these parameters are abnormal because of non-nutrition factors. Specifically, acute stress reaction, especially trauma and sepsis, or medication may suddenly deplete these biochemical components. In this situation these acute phase proteins are depleted, although not as a result of patient protein energy malnutrition (PEN) but rather as a result of other protein stresses. The observer must therefore be sensitive to this factor and place these alterations in perspective.

Albumin
       Albumin is the major circulative humoral protein. It is the major oncotic pressure stabilizer in both the cellular and intravascular compartment environment. Therefore, while albumin is the major measurable humoral protein, its serum level can be altered by total body water status. If total body water is increased (nephrotic syndrome, CHF, etc.) serum albumin levels expressed as g/dL are reflective of concentration per unit volume. Concomitantly albumin is a major amino acid storehouse for multiple biochemical synthesis; in acute phase reaction and massive injury, albumin levels may drop precipitously, especially in previously stressed or elderly patients. Again, alterations of its level may not affect total body albumin. In this instance, however, it will reflect a potential impact on wound healing. If there is insufficient circulatory albumin to provide amino acids/peptides for utilization in nonstress-related processes, healing might be affected. Although healing will usually take place, it may be prolonged or there may be diminished wound tensile strength.
       Regardless of the etiology, decreased serum albumin has been confirmed to be related to poor healing outcome and more importantly to poor medical outcome in general.4 As total body protein and, specifically, albumin are acutely depleted, alteration in intracellular fluid occurs. This localized oncotic pressure defect may alter wound healing rates and outcome; pH, tissue oxygenation, volume concentrations of micronutrients, and capillary blood flow are altered, even in instances of normal nutrition stability. Wounds will often heal despite lower than normal levels of albumin. This healing will, however, be impacted. Time to healing or total wound tensile strength will be affected.
       Nutrition assessment is therefore an important methodology in evaluating the patient with poor healing. However, altering the nutrition status may not be reflected in increased time to healing or wound tensile strength.

Wound Healing--Physiology and Nutrition
       It is important to develop a sensitivity to the relationship between total body nutrition and wound nutrition. Each step in the process of healing (inflammation, proliferation, remodeling) is ultimately precursor-dependent upon circulating amino acids, lipids, and carbohydrates. Impaired nutrition can alter not only the modulation of deposition of collagen, fibroblast proliferation, and hydroxyproline content, but also impair immune function and oxygen transport. Growth factor synthesis is also dependent upon adequate nutrient status.
       Protein deficiency can suppress angiogenesis, thereby altering capillary regeneration in the proliferation phase. Malnutrition may alter fibroblast proliferation as well as collagen synthesis, thereby altering the rate and stability of wound healing. Even altered lipid levels, important in membrane stabilization and inflammation, have been shown to adversely affect wound healing. Collagen synthesis requires 1 K Cal/gm of collagen synthesized. Any alteration in the availability of precursor amino acids or energy substrate will affect collagen deposition. Each 500mg of granulation tissue requires 0.5 K Cal/mg for production.
       In wounds where there is excessive lactic acid production (crash injury, low availability of oxygen) the lactate is recycled in the pyruvate cycle and the tissue becomes extremely energy inefficient. Further, in severe stress, status protein becomes the preferred energy source with decreased ability to provide substrate. Decreased protein levels can cause oncotic pressure alterations with a resultant increased local tissue edema.
       Albumin is synthesized in the hepatocytes. The human requires 20 to 30 minutes to synthesize a molecule of albumin. The rate of supply to the tissue is strictly responsive to the synthesis rate. The most common reason for reduction in available protein is nutrient partitioning. In stress states there is significant alteration in the efficiency of energy utilization. Increased energy demands alter the election transfer process, with the by-product being heat. Therefore, there is a drain on the available nutrient leading to net catabolism. This diverts 20 to 30 percent of the available amino acids away from tissue replacement and results in delayed or poor wound healing.

Nutrition Repletion
       The catabolic patient is at risk for poor or delayed wound healing. Logic would therefore follow that correction of this catabolic state would not only improve overall health but also provide available substrate to correct the wound healing process. On the surface, it appears that this logic is straightforward. While there is some evidence to support this concept, the vast majority of data is confusing.
       The provision of nutrient repletion can be provided in various forms. Ideally an appropriate oral diet is the most efficacious repletion available. The nutrition assessment should calculate a prediction of overall protein and calorie needs based upon either ideal or actual body mass needs.
       Unfortunately it is often difficult to predict with accuracy the actual calorie needs of a person in any given circumstance. By convention the calorie needs are predicted upon either the actual or ideal body weight. Obese people provide the most difficult management problem in this situation. Their lean body mass may be depleted or normal with the increased fat stores creating an abnormal elevation of weight. This situation will call for further expertise regarding selection of caloric needs. The stress state will also alter the calorie requirement; hence, a stress or metabolic activity factor must be utilized to adjust the calorie need prediction.
       The actual energy requirement can be obtained through the use of indirect calorimetry, which measures the actual energy requirement at a given moment in time. Indirect calorimetry is costly and cumbersome. For the most part it is useful only in the research setting or critical care practice.

Protein Requirement
       Protein needs are assessed by the total body mass and the amount of stress to which the person is subjected. The normal protein requirement is 0.8g of protein per kilogram per 24-hour period.5 This number is altered by the amount of stress the person is undergoing. This can be increased from 1.5 to 2.1gm/kg or more. Ongoing protein assessment is achieved by measuring nitrogen balance.
       Nitrogen balance studies require normal renal function. When a person has impaired renal function, the renal excretion of nitrogen is altered. Therefore, urine urea nitrogen cannot be utilized.

Micronutrients
       There is significant controversy in the requirements and effect of micronutrients. There is little frank data to support the quantity and type of most micronutrients required. In this author's opinion, physiologic common sense states that replacement of circulating electrolytes is always necessary. The daily requirements of Na2, CL-, K+, and Mg- must always be met. It is the amount of the other micronutrients and vitamins that are controversial.

Zinc
       Zinc is an essential component of numerous RNA and DNA polymerizes. It is a required cofactor for over 100 metabolic steps. Cellular proliferation and synthesis require adequate levels of zinc. There is some data that supports increased healing of venous ulcers with zinc supplementation in patients with low pretreatment screen zinc levels.6 However, some other data is not as supportive.7,8 Serum zinc levels may not correlate with microcellular involvement zinc availability. It does seem logical to supplement zinc to people with chronic wounds. Unfortunately, there is no research to guide the required amount.

Vitamin A
       The mechanism of vitamin A and its relationship to wound healing is unknown. It does appear that vitamin A supplementation does affect wound healing.9 Vitamin supplementation increases wound collagen content and increases the breaking strength of anastomosis. There even may be a beneficial effect of vitamin A supplementation in patients taking glucocorticoids.
       Vitamin A may effectively enhance collagen deposition either topically or systemically. It has been suggested that 25,000u of vitamin A be given to patients at risk.10 Again, as in the case of zinc, no recommendation can be made as to dosage or timing of supplementation.

Vitamin C
       The presence of scurvy is a clear-cut wound-related vitamin deficiency. Scurvy is perhaps the most well-documented wound-related vitamin deficiency state.11 Vitamin C is required for proline cross-linking, and therefore is an essential component of healing. Unfortunately the amounts of intake above the daily minimal requirements needed to enhance human healing are not evident from animal research models.
       Wounds in vitamin C-deficient patients have decreased angiogenesis, very little collagen deposition, and decreased and retarded tensile strength.
       A significant number of elderly people have low plasma and leukocyte ascorbate concentrations. It appears that pre-existing vitamin C deficiency data may predispose patients, especially the elderly, to vitamin C-deficient wound healing delay. Hence, vitamin C supplementation in the patients with chronic nonhealing wounds should be considered.

Vitamin E
       There is significant controversy surrounding the systemic supplementation of vitamin E in the patient with the chronic nonhealing wound. The clinical relevance remains to be shown.

Arginine
       The amino acid, arginine, deserves special mention. There are data that suggest that arginine supplementation promotes wound healing. It appears that ornithine (the metabolite of arginine) can be converted into proline directly by wounds. This, in turn, may promote increased collagen synthesis. Elderly patients placed on arginine supplementation have shown increased hydroxyproline content.12,13 It therefore appears that arginine supplementation may be beneficial.

Nutrition Supplementation and Support
       The vast majority of people with chronic wounds can be treated in the ambulatory setting. In fact, in most cases, these patients have no difficulty orally ingesting nutrients. A nutrition screen should be performed in all of these patients. When a screen identifies a possible nutrition defect, a full assessment should be performed, which should identify potential risk factors, and a nutrition intervention plan should be derived. Often the professional dietitian can devise this plan, provide a sample intervention menu, and follow up on calorie counts. In situations where the person has impairment of oral intake, the provision of nutrition via the enteral or parenteral route is necessary as an adjunct to good wound care.

Enteral and Parenteral Nutrition
       Enteral nutrition, the provision of total calories, protein, and substrate into the GI tract, is the preferred route of interventional nutrition. Providing nutrition directly into the GI tract is more efficacious. Continued maintenance of the GI tract brush border helps to maintain the stability of humoral immunity. Further, enteral products are usually less problematic to manipulate and systemic complications occur less often. The management of enteral feeding often requires direct intervention into the GI tract via a naso-enteral, gastrostomy, or jejunostomy catheter. All of these require a direct intervention and cause increased overall morbidity. However, the morbidity is usually less problematic than that associated with parenteral nutrition. Enteral nutrition products for the most part are formulated and prepackaged at the factory. Therefore, nutrients can be added but not removed.
       There is a small group of people that cannot be fed enterally due to failure of the GI tract. In these instances parenteral (central vein or peripheral) nutrition should be provided. This is a complex task and should be managed by a team well versed in its provision. Parenteral nutrition can be more finely tuned for the person's needs; however, it does carry with it significant morbidity and mortality.
       Parenteral nutrition requires fairly aggressive monitoring and management. The potential for significant complications while people are being fed parenterally requires a specific expertise in its provision. People requiring parenteral nutrition are usually sicker than the general aggregate of chronic wound patients. Because of this, a nutrition team should be utilized to monitor and maintain this nutrition intervention.

Other Nutrients
       Free radicals and antioxidants. Oxygen-free radicals are highly reactive molecules produced at the cellular level as the result of cellular metabolism. Free radical levels increase with inflammation and in all phases of the wound healing process. These free radicals, when present in high concentrations, can damage cellular membranes and wreak havoc with tissue repair. Free radicals actually can help in the healing environment by helping release cytokines, promote leukocyte adherence, and kill certain types of bacteria. However, in excess, these free radicals can be released causing further inflammation and the release of iron into the wound resulting in prolonged cellular damage and delayed healing. Malnourished individuals will have higher cellular levels of oxygen-free radicals; therefore, a good wound healing plan may include the oral or parenteral ingestion of antioxidant vitamins.
       Antioxidants exist in both the cytosol and lipid environment. Vitamins C, E, A, beta-carotene, taurine, glutathione, and pyruvate all act as antioxidants. The enzymes responsible for free radical destruction (glutathione peroxidase, superoxide dismutase, and catalase) depend upon adequate amounts of trace metal cofactors from the diet (selenium, zinc, copper, magnesium). Vitamin E functions in the lipid-laden cellular membrane as a major antioxidant.
       People with chronic wounds can generate excessive oxygen-free radicals that consume various parts of the antioxidant defense network faster than repletion. This depletion leads to loss of glutathione, vitamins E and C, Zinc, copper, and selenium. This results in further cellular damage and further impairs wound healing.
       The use of systemic and topical antioxidants carries great scientific weight.9 Unfortunately, the amounts and types of these trace metals and vitamins to administer are unknown. Suffice it to say that antioxidant supplementation should aid in wound healing. This needs to be tempered with the knowledge that in some cases Vitamin E, iron, beta carotene, though helpmates, can fast become toxic at the cellular level.

Summation and Outcome Implications
       A chronic wound develops for a myriad of reasons. The nutritional stability of the person plays a significant role in the development and ultimate healing of tissue injury. It is obvious that the macro- and micronutrition environment affect the healing of wounds. Essentially all functions of wound healing are related to this nutritional environment. Proteins (amino acid, peptides, dipeptides) provide the matrix for collagen synthesis and hydroxyproline deposition. The complexities of the wound healing process are regulated by enzymes and trace metals, all of which are provided by nutrition-related processes. A failure anywhere in this system can ultimately affect the healing process.
       The healthcare practitioner is obligated to evaluate and monitor the nutritional status of all people presenting with chronic wounds. Often manipulation of the nutrition environment, along with appropriate wound management, may lead to successful healthy outcomes.

Excerpted and adapted with permission from HMP Communications. Zagoren AJ. Nutritional assessment and intervention in the person with a chronic wound. In: Krasner DL, Rodeheaver GT, Sibbald RG (eds). Chronic Wound Care: A Clinical Source Book for Healthcare Professionals, Third Edition. Wayne, PA: HMP Communications, 2001:117-26. Copyright © 2001 HMP Communications.