Protein is composed of approximately 20 amino acids and although protein can be gluconeogenically converted to carbohydrate (that in turn can promote hypertrig-lyceridemia), the desired energy substrates (to drive a-nitrogen into muscle) are dextrose and essential fatty acids and not protein.
Careful repletion of carbohydrate and lipid macronutrients will avoid adverse outcome. For example, overfeeding with carbohydrate is associated with hypercapnia, osmotic dehydration, and nonenzymatic glycosylation leading to immune compromise. The delivery of more than 5 mg/kg/d of dextrose will result in steatosis and the need for exogenous insulin. In addition, deleterious effects of hyperinsulinemia include antinaturetic effects and microalbuminuria.
The omission of long-chain fatty acids in nutrition regimens will lead to essential fatty acid deficiency in as little as 1 d (5 d are cited in the package inserts for intravenous lipid). As much as one third of hepatic phase I (oxidation/reduction) action will fall off if there is no fat in the diet.43
Macronutrients (protein, carbohydrate, and lipids) in turn must always be accompanied by micronutrients (electrolytes, trace elements, and vitamins) and water to promote anabolism. The remainder of this chapter will touch on electrolyte and vitamin micronutrients and will then specifically focus on the faces of trace elements and their relationship to wound healing processes.
Although micronutrients comprise only a small portion of the body's overall nutritional needs, their importance is highlighted by the cellular machinery that carries out wound healing.
Acid/base status must be ascertained to provide the correct salts for needed electrolytes based on serial trends of abnormal blood concentrations and excrements. Chloride, sulfate, and phosphate will provide passive acidification, and acetate, citrate, lactate, and gluconate are the anions of choice for passive alkalinization.
Sodium, potassium, calcium, magnesium, and phosphate will be the most important electrolytes to follow in the wound healing process.
An electrocardiogram is the most sensitive method to measure potassium and calcium status, but whole blood (as well as plasma and serum) concentration complemented by excrement assessment are used clinically. The most difficult electrolyte to measure is likely magnesium, because it is decreased stalwartly by stress or catecholamine shower.
Magnesium (Mg) is a macromineral that is essential for wound repair and is a cofactor for many enzymes that are involved in the process of protein synthesis. The primary role of magnesium is to provide structural stability to ATP, which powers many of the processes used in collagen synthesis, making it a factor essential to wound repair.44,45
Magnesium modulates cellular events involved in inflammation. Severe experimental Mg deficiency in the rat induces after a few days a clinical inflammatory syndrome characterized by polymorphonuclear (PMN) leukocyte and macrophage activation, release of inflammatory cytokines and acute phase proteins, and excessive production of free radicals. An increase in Mg concentration decreases the inflammatory response, and reduction in the extracellular Mg results in cell activation. Because Mg acts as a natural calcium antagonist, the molecular basis for inflammatory response is probably the result of modulation of intracellular calcium concentration. Mg deficiency contributes to an exaggerated response to immune stress, hyperlipemia, atherosclerosis, endothelial dysfunction, thrombosis, hypertension, and free radical damage.46
As with other electrolytes, whole blood (plasma or serum), intracellular stores (i.e., mononuclear leukocyte content), or excretory load will be useful indicators of status integrated with clinical appreciation. In the case of magnesium, urine is the most precise assessment of magnesium status. When sufficient excretion is evident (i.e., greater than 50% of intake), intracellular magnesium concentration is said to be sufficient. Magnesium and zinc are essential elements in all biological systems. They are both essential for enzymatic activity, maintaining three-dimensional structures of proteins, for the synthesis of nucleic acids and proteins, and so forth.
Low phosphate indicators are likely the most important parameters to respect in wound healing, because low 2,3-diphosphoglycerate content in the erythrocyte is very much a part of hemoglobin: oxygen tightening (so-called shift to the left in the hemoglobin:oxygen curve). This is amplified with concurrent clinical happenings, such as hypothermia, alkalemia, and hypocapnia, resulting in poor wound healing.
Overall, electrolyte concentrations must be normalized for favorable wound healing to occur. Serial measurement must guide the clinician to provide adequate but not excessive supplementation via an administration route that will not result in additional morbidity yet will guarantee appropriate needs.
Vitamin A increases the inflammatory response in wounds that is thought to occur by an enhanced lysosomal membrane lability, increased macrophage influx and activation, and stimulation of collagen synthesis. In vitro studies have shown an increased presence of epidermal growth factor receptors and increased collagen synthesis of fibroblast cell cultures in the presence of vitamin A.47,48
Serious injury or stress leads to increased vitamin A requirements. Large doses of corticosteroids also deplete hepatic stores of vitamin A. Decreased serum levels of vitamin A, retinol binding protein, retinyl esters, and P-carotene have been noted after burns, fractures, and elective surgery. The clinician must be ever mindful, however, of the disease states (i.e., acute or chronic renal failure) associated with hyper-vitamosis A to avoid the toxicities of vitamin A overload (i.e., osteolytic effects).49-51 In the severely injured, doses of vitamin A of 25,000 IU/d (five times the recommended daily dose) have been advocated and used without any significant side effects. Larger doses of vitamin A do not improve further wound healing, and prolonged excessive intake can be toxic.52 It is generally appreciated that zinc and other nutrients, such as a vitamin A derivative, are needed to avoid age-related macular degeneration. Several chronic diseases also associated with alterations in zinc status are bronchial asthma, rheumatoid arthritis, and Alzheimer's disease.
Vitamin E, or tocopherol, maintains and stabilizes cellular membrane integrity, primarily by protection against destruction by oxidation.53 Vitamin E also possesses anti-inflammatory properties similar to those of steroids, as shown by the reversal of wound healing impairment imposed by vitamin E after administration of vitamin A in the first days after wounding.54 Vitamin E also has been shown to affect various host immune functions. As an antioxidant, it has been proposed that vitamin E could reduce injury to the wound by squelching excessive free radicals. The liberation of free radicals from inflamed tissue cascades in necrotic tissue, tissue colonized with microbial flora, ischemic tissue, and chronic wounds can result in the depletion of free radical scavengers such as vitamin E.55,56
Vitamin K is known as the antihemorrhage vitamin and is required for the carboxylation of glutamate in clotting factors II, VII, IX, and X. Vitamin K contributes little to wound healing, but its absence or deficiency leads to decreased coagulation, which consequently affects the initial phases of healing. Vitamins A and E antagonize the homeostatic properties of vitamin K.
Formation of hematomas within the wound can impair healing and predispose to wound infection. The enteral absorption of fat-soluble vitamins (vitamins A, D, E, and K) requires the action of lipid and bile acids. These are absorbed via the jejunal/ileal parenchyma.
Cyanocobalamin (B12) and folic acid (B9), as well as copper and calcium, are inherently associated with hematological homeostasis. Pyridoxine (B6) is intimately aligned with protein supplementation. Vitamins B1 (important for the treatment of lactic acidemia), B2, and B3 (thiamine, riboflavin, and niacin, respectively) are similarly dosed as per caloric supplementation. Vitamin C or ascorbic acid decreases capillary fragility and provides antioxidant action to promote collagen synthesis.
Vitamins provide the coenzymatic machinery in the work of healing wounds. In addition to the superior free radical squelching of the sulfurated amino acids (i.e., acetylcysteine, cysteine, serine, threonine), much has been written about the antiox-idant actions of vitamins A, C, and E. Daily supplementation of fat- and water-soluble vitamins will be required for optimum wound healing to occur.
Trace element and vitamin (and other indirect reflections of) status can be measured in plasma, serum or whole blood, and excrements. Again, pragmatic supplementation designed to avoid deficiencies or excesses will be a mandate. The clinician must be ever vigilant for signs and symptoms of deficiency or excess. It will be particularly difficult to associate deficits in trace elements (Table 10.3) to impairment in wound healing, because deficiencies of micronutrients are almost always accompanied by coexisting metabolic or other nutritional disturbances. Most of the trace elements do not influence wound healing directly; rather, they serve as cofactors or part of an enzyme that is essential to healing and homeostasis. Clinicians became more aware of deficiencies of these elements after the introduction of long-term parenteral nutrition solutions that did not include supplemental trace elements. It is often easier to prevent these deficiencies than to diagnose them clinically.
Copper, zinc, and iron have the closest relationship to wound healing. Copper is a required cofactor for cytochrome oxidase and the cytosolic antioxidant superoxide dismutase. Lysyl oxidase is a key copper enzyme used in the development of connective tissue, where it catalyzes the cross-linking of collagen and strengthens the collagen framework.57
Zinc is a cofactor for RNA and DNA polymerase and, consequently, is involved in DNA synthesis, protein synthesis, and cellular proliferation. Zinc deficiency
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