Nutrition, Anabolism, and the Wound Healing Process: An Overview

Robert H. Demling, MD

Disclosures

ePlasty. 2009;9:65-94. 

In This Article

Nutritional Support: The Process

Macronutrient Distribution

Once the assessment is complete and the nutrient needs in terms of calories and protein intake are made, macro- and micronutrients are provided. Macronutrients include carbohydrate, fat and protein. In the presence of a large traumatic wound or a burn, the stress response has been activated requiring an increase in calories for energy and protein for protein synthesis. The breakdown for feeding a catabolic state is described as follows.

Approximately 55% to 60% of total calories should be delivered as complex carbohydrates instead of simple sugars. Each gram of carbohydrate generates 3.3 kcal. Excess carbohydrates will lead to hyperglycemia, a major complication resulting in impeded healing and immune dysfunction. Maximum glucose utilization is considered to be 7 μg/kg/min.[48,57]

Approximately 20% to 25% of calories should be provided by fat, but not more than 2 g/kg/day. Values in excess will likely not be cleared from serum. Triglyceride levels should be kept below 250 mg/dL. Fat provides 10 kcal/g.

Because normal protein preservation in LBM is not maintained with a wound stress response, approximately 20% to 25% of total calories need to be provided as protein. Inadequate intake will not prevent protein use for calories, as LBM becomes the source.

Carbohydrates and Wound Healing

As described, calories are needed to supply the energy needed to heal and carbohydrates are the key source of energy through lactate use. Skin cells are dependent on glucose for energy. In patients with diabetes, careful control of glucose intake, with adequate insulin, is essential to optimizing healing rate.

Carbohydrates have also been shown to be important for a wound unrelated to energy production. These carbohydrate factors include structural lubricant, transport, immunologic, hormonal, and enzymatic functions. Carbohydrates are a key component of glucoproteins, which is a key element in the healing wound used for its structure and communicative properties. Carbohydrates have also been found to be a key factor in the activity of the enzymes hexokinase and citrate synthase used for wound-repair reactions.[69–72]

Cell adhesion, migration, and proliferation is regulated by cell-surface carbohydrates including B-4-glycosylated carbohydrate chains.[72] Glucose is also used for inflammatory cell activity leading to the removal of bacteria and of necrotic material (Table 12).[73]

Lactate is a metabolic byproduct of glucose. This 2-carbon compound appears to have many important wound healing effects. The increase in wound lactate is required for the release of macrophage angiogenesis factor. Lactate stimulates collagen synthesis by fibroblasts and is an important activator of the genetic expression of many healing pathways in addition to its role as an energy source.[74,75]

Fats and Wound Healing

Fats are unique in that they function both as a source of energy and also as signaling molecules. It is important to recognize that the composition of cell membrane basically reflects dietary fatty acid consumption. Cell membrane composition affects cell-function-influencing enzyme absorption such as protein kinase C and a variety of genes. White adipose tissue is a source of proinflammatory fat metabolism and is one of the key regulators of wound inflammation and healing.[76–84]

Fats are broken down into free fatty acids and then packaged into chylomicron absorption and transportation to the body for energy or storage. The essential fatty acids must be consumed in the diet. Polyunsaturated fatty acids are used for cell membrane production while saturated fatty acids are often used for fuel.[77–80] The oxidative stress typical in the inflamed wound can lead to membrane alteration by a process called lipid peroxidation, which can alter wound cell function. In addition, circulating by-products can have a negative affect by stimulating wound cell death or apoptosis, while other lipid by-products such as leptins protect the cell.[77–80]

It is clear, however, that adequate fat, whether consumed or obtained from the fat depot by lipase activity, is essential to wound healing of both acute and chronic wounds. The first role is to provide adequate energy to the wound. The second role is to provide the substrate for the many roles of fat by-products, especially the components of free fatty acids on wound cell function, wound inflammation, and wound cell proliferation. At present, it would appear that a dietary intake containing high levels of monosaturated fatty acids and omega-3 polysaturated fatty acids is ideal. Lipid components are responsible for tissue growth and wound remodeling including collagen and extracellular matrix production.[84–91]

It can be seen that fat and its derived lipid products are an extremely diverse class of molecules, which includes fatty acids and all their metabolic derivatives. Fats are a major source of energy in addition to its role as various signaling molecules.[80–91]

Protein and Wound Healing

It is well recognized that protein is required for wound healing and a protein deficiency retards healing in both acute and chronic wounds.[57,59,63,87–97] This fact is particularly evident in chronic pressure ulcers and acute burn injury. Dipeptides and polypeptides have been shown to have a wound healing activity. Several amino acids, such as leucine, glutamine, and arginine, all have anabolic activity. It has been shown that there is a greater protein accretion with orally fed protein, which becomes a hydrolysate than parenteral protein, which consists of total breakdown into amino acids.

The renewal of the skin involves 2 components: cell proliferation, mostly fibroblasts and protein synthesis, mainly collagen from the fibroblasts. Both components require protein substrates.[89,93] After injury, both metabolic processes are accelerated to repair the wound. In a severely injured patient, with a wound, the metabolic process for healing must occur in the presence of a hypermetabolic catabolic state.[47,48,57,59–62] This state will cause a protein malnutrition very rapidly if a high protein intake is not rapidly initiated. However, an injured man can use only a certain amount of protein. Also, severely burned adults can assimilate only 1.5 g/kg/day into the LBM, additional protein will only be used as a fuel source, unless anabolic activity is increased.

It has been found that in a major injury, skin is in a negative protein status identical to the net whole-body loss of protein.[90–92] Use of an anabolic stimulus like insulin and provision of an adequate amino acid supply can control this deleterious process.[89–93] Modulation of anabolic factors will not only improve the whole-body protein balance but will also increase the skin protein metabolism.[89–93] Positive skin-protein synthesis will accelerate the wound healing process.

Glutamine

Glutamine is the most abundant amino acid in the body and accounts for 60% of the intracellular amino acid pool.[98] This amino acid is considered to be conditionally essential as a deficiency can occur rapidly after injury. Glutamine is used as an energy source after the stress response as it is released from cells to undergo glucose conversion in the liver for use as energy.[98,99] In addition, glutamine is the primary fuel source for rapidly dividing cells like epithelial cells during healing.

Glutamine has potent antioxidant activity, being a component of the intracellular glutathione system. It also has direct immunological function by stimulating lymphocyte proliferation through its use as energy. Glutamine has anticatabolic and anabolic properties also and is the rate-limiting agent for new protein synthesis (Table 13).

Because of its many roles in the wound, it is of particular concern when there is a rapid fall in both intracellular and extracellular glutamine levels, to a deficiency state, in the presence of a major wound. Replacement using a glutamine dose of 0.3 to 0.4 g/kg/day is commonly performed after a major burn.[100,101] Of interest is that glutamine delivery at this level has been shown to increase survival after major burns.[100,101] Glutamine supplementation in and of itself has not been shown to dramatically impact the wound. However, it does appear to decrease wound infection and it does improve healing in experimental studies.[102–104] Glutamine intake of 2 g or more does increase HGH release, which has potent anabolic activity. In general, it is clear that glutamine does assist in restoration and maintenance of LBM and that property in and of itself will improve healing.

Excess glutamine provision is deleterious. Since this amino acid has 2 nitrogens and is metabolized into ammonia, excess will increase the risk of increased ammonia levels and azotemia. This process is more prominent in the elderly population where added glutamine exceeds the metabolic pathways for glutamine use and excess is, therefore, metabolized.

Zinc

Zinc is a cofactor for RNA and DNA polymerase and is, therefore, involved with DNA synthesis, protein synthesis, and cell proliferation. Zinc is a key cofactor for matrix metalloproteinase activity and is also involved in immune function and collagen synthesis. Zinc is also a cofactor for superoxide dismutase, an antioxidant (Table 14). After wounding, there is a redistribution of body zinc with wound levels increasing and levels in normal skin decreasing.

The hypermetabolic state leads to a marked increase in urinary loss of zinc, and a risk for a zinc deficiency state has adverse effects on the healing process including a decrease in epithelial rate, wound strength, and decreased collagen strength. Restoration of the expected zinc deficiency state is usually performed by oral provision of zinc sulfate 220 mg tid.[105,106–109]

There are data that would indicate that correction of a zinc deficiency is beneficial while zinc supplementation over and above replacement has no added benefit in wound healing. However, zinc supplementation is a common approach to managing wounds.

Arginine

Arginine is another conditionally essential amino acid whose level decreases after major trauma and wounds.[97,110–112] Arginine has been shown to stimulate immune function and is used for a variety of components of healing including a proline precursor. Its role in wound healing itself has not been clearly defined, although large doses have been shown to increase tissue collagen content. High doses also stimulate the release of HGH. It has recently been shown that the healing effect is not due to nitric oxide synthesis.[97,104,111–113]

Other Micronutrient Support

Micronutrients are required for cofactors in energy production and protein synthesis. Since energy demands are increased, cofactor needs are also increased.[105–109,114–138] The various micronutrients and their roles and estimated requirements are presented for the presence of a large wound. The key vitamins for energy are the B complex and vitamin C, water-soluble vitamins that need to be replaced daily[105,114–122] (Table 15).

The micronutrients involved in energy production are described. Vitamin B complex is a prominent factor. Zinc is very prominent as it is a cofactor for a large number of enzymes involved in DNA synthesis and is protein synthesis.[105,107,114]

The micronutrients required for anabolic and anticatabolic activity and protein synthesis are described in Table 16 *. These elements have properties considered to be directly involved with protein synthesis and as cell protectors through potent antioxidant properties. Oxidants are a major source of cell toxicity with wound inflammation, and antioxidant activity is essential for the wound healing process to continue. Vitamin C and glutathione, products of glutamine, are water-soluble antioxidants. (Table 17) Other vitamins and minerals with antioxidants activity are described in Table 16.

There are now well-recognized micronutrients that are necessary for anabolic activity and that can actually improve net protein synthesis (Table 17). These components include the amino acids glutamine and arginine already described. A variety of vitamins and microminerals are also involved in this process.

Increased anabolic and wound healing benefits have also been shown for the conditionally essential amino acids, glutamine, and arginine. Both of these amino acids characteristically decrease with activation of the stress response leading to a deficiency state well recognized to impede protein synthesis and overall anabolism.*. Replacement therapy has been shown in both circumstances to increase net anabolism.

The trace elements that have clear healing properties include zinc, copper, and selenium. Copper is a key factor for overall homeostasis. It is necessary for a cofactor for antioxidant activity to control oxidant stress, assisting in energy formation in the respiratory chain at cytochrome c. In addition, copper is used for collagen and elastin cross-linking. By 10 days after severe injury serum, copper levels are decreased. It is probably an increase in the acute-phase protein ceruloplasmin that leaks into the tissues taking copper with it. Copper replacement therapy is often performed after major wounds like burns. Typically, 1 to 2 mg of copper is provided.[105,114]

Manganese is associated with various enzymes in the Krebs Cycle and is also involved with protein metabolism. It also activates lipoprotein lipase and also protein synthesis. Manganese, Mn, is also a cofactor for the antioxidant superoxide dismutase and also for metalloproteinase activity in the wound. A deficiency state after severe trauma or in the presence of a large burn is yet to be documented. Maintenance dosing is 0.3 to 0.5 mg daily.

Selenium is required for the glutathione system to work, glutathione being the major intracellular antioxidant. Management of the wound-inflammation-induced oxidant stress is a key component of cell protection during the healing process. Selenium is excreted in increased amounts in the urine after major injury.[108]

Muscle contains almost half the total body selenium. Myositis coupled with myocardiopathy is seen clinically with selenium deficiency. Replacement is common after burns and severe trauma including wounds, at a daily dose of 100 to 150 mg.

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