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Practical aspects of nutritional support for wound-healing patients

      Abstract

      Nutrition and metabolic support of acutely and chronically ill patients is an emerging branch of medicine that has direct applicability to wound healing. The occurrence of pressure ulcers is associated with malnutrition, as well as specific micronutrient deficiencies. A comprehensive approach is reviewed that involves nutritional assessment, selection of an appropriate route for nutrition support (enteral versus parenteral), prioritizing nitrogen retention over energy balance in stressed patients, micronutrient management, and incorporation of specialized nutritional pharmacologic interventions.
      The issue of nutrition and wound healing applies to several specific scenarios in clinical medicine, such as the critically or chronically ill patient, but is also applicable to all patient populations at risk for skin breakdown. At Mount Sinai Hospital in New York, an integrated approach has evolved between the Metabolic Support and Wound Healing teams to improve quality of life, shorten hospital stay, and decrease morbidity and mortality.
      This collaborative approach is best exemplified in the care of chronically critically ill (CCI) patients in the respiratory step-down unit. The metabolic syndrome found among CCI patients includes (1) adult kwashiorkor-type malnutrition, (2) bone hyperresorption and vitamin D deficiency, (3) hypotestosteronemia in men, and (4) abnormal neuroendocrine function [
      • Nierman D.M
      • Mechanick J.I
      Bone hyperresorption is prevalent in chronically critically ill patients.
      ,
      • Nierman D.M
      • Mechanick J.I
      Hypotestosteronemia in chronically critically ill men.
      ,
      • Nierman D.M
      • Mechanick J.I
      Biochemical response to treatment of bone hyperresorption in chronically critically ill patients.
      ]. Skin breakdown, ulcerations, and wounds are common among CCI patients. The implementation of metabolic support in wound healing not only involves provision of protein and energy, but also manipulation of intermediary metabolism to induce anabolism, use of nutritional pharmacology, and management of metabolic complications.

      Link between nutritional status and wound healing

      In chronically hospitalized patients, the occurrence of pressure ulcers has been associated with nutritional status. The relative risk of developing a pressure ulcer in high-risk, malnourished patients was 2.1 times greater (95% confidence interval) compared with normally nourished patients [
      • Thomas D.R
      • Goode P.S
      • Tarquine P.H
      • Allman R.M
      Hospital-acquired pressure ulcers and risk of death.
      ]. In another study, 65% of severely malnourished nursing home patients had pressure ulcers, whereas no ulcers were detected in the mild to moderately malnourished or normally nourished nursing home patients [
      • Pinchcofsky-Devin G.D
      • Kaminski Jr, M.V
      Correlation of pressure sores and nutritional status.
      ]. Malnutrition is also associated with mortality in nursing home patients [
      • Thomas D.R
      • Verdery R.B
      • Gardner L
      • Kant A
      • Lindsay J
      A prospective study of outcome from protein-energy malnutrition in nursing home residents.
      ]. There are other risk factors that contribute to the development of pressure ulcers in hospitalized patients: immobility, hip fracture, dry skin, decreased dietary intake (especially protein), weight loss, hypoalbuminemia, lymphopenia, poor immune function, low zinc levels, fecal incontinence, diabetes mellitus, and stroke [
      • Thomas D.R
      Improving outcome of pressure ulcers with nutritional interventions a review of the evidence.
      ]. In spinal cord injury patients, those with pressure ulcers had lower serum prealbumin and albumin levels, as well as decreased cellular adhesion molecules, which participate in immunity and wound healing [
      • Cruse J.M
      • Lewis R.E
      • Roe D.L
      • et al.
      Facilitation of immune function, healing of pressure ulcers, and nutritional status in spinal cord injury patients.
      ].
      In a large prospective, randomized, controlled study of 672 critically ill patients treated with high-protein dietary supplements for 15 days, there was a reduction of pressure ulcer risk, compared with controls [
      • Bourdel-Marchasson I
      • Barateau M
      • Rondeau V
      • et al.
      GAGE Group (Groupe Aquitain Geriatrique d'Evaluation)
      A multi-center trial of the effects of oral nutritional supplementation in critically ill older inpatients.
      ]. Eneroth et al [
      • Eneroth M
      • Apelqvist J
      • Larsson J
      • Persson B.M
      Improved wound healing in transtibial amputees receiving supplementary nutrition.
      ] demonstrated the benefit of supplemental nutrition (as high as 2,098 kcal/day on average, for 11 days) on wound healing, but not mortality, in 24 transtibial amputees. Other small studies have demonstrated the benefit of higher-protein intake on pressure ulcer healing, supporting the practice that such patients ought to receive 1.2 to 1.5 g/kg per day protein [
      • Chernoff R.S
      • Milton K.Y
      • Lipschitz D.A
      The effect of a very high-protein liquid formula on decubitus ulcer healing in long-term tube-fed institutionalized patients.
      ,
      • Breslow R.A
      • Hallfrisch J
      • Guy D.G
      • Crawley B
      • Goldberg A.P
      The importance of dietary protein in healing pressure ulcers.
      ]. However, despite the rationality and scientific demonstration that nutritional intervention can improve outcome in malnourished patients, some large studies have not been able to demonstrate this beneficial effect on mortality [
      • Potter J
      • Langhorne P
      • Roberts M
      Routine protein energy supplementation in adults systematic review.
      ] or pressure ulcers [
      • Thomas D.R
      Improving outcome of pressure ulcers with nutritional interventions a review of the evidence.
      ,
      • Mitchell S.L
      • Kiely D.K
      • Lipsitz L.A
      The risk factors and impact on survival of feeding tube placement in nursing home residents with severe cognitive impairment.
      ,
      • Henderson C.T
      • Trumbore L.S
      • Mobarhan S
      • Benya R
      • Miles T.P
      Prolonged tube feeding in long-term care nutritional status and clinical outcomes.
      ,
      • Hartgrink H.H
      • Wille J
      • Konig P
      • Hermans J
      • Breslau P.J
      Pressure sores and tube feeding in patients with a fracture of the hip a randomized clinical trial.
      ].
      Diabetes has long been understood to be an independent risk factor for postoperative wound infection [
      • Gadaleta D
      • Risucci D.A
      • Nelson R.L
      • et al.
      Effects of morbid obesity and diabetes mellitus on risk of coronary artery bypass grafting.
      ]. A prospective study of 2,467 consecutive patients undergoing cardiac surgery demonstrated the efficacy of a perioperative continuous insulin infusion to achieve glycemic control <200 mg/dL and reduce the incidence of deep sternal wound infections [
      • Furnary A.P
      • Zerr K.J
      • Grunkemeier G.L
      • Starr A
      Continuous intravenous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures.
      ]. In fact, a recent study of critically ill patients demonstrated that insulin infusions producing tight glycemic control, <110 mg/dL, was associated with significantly reduced infection rates, morbidity, and mortality [
      • van den Berghe G
      • Wouters P
      • Weekers F
      • et al.
      Intensive insulin therapy in the critically ill patients.
      ].
      Chronic leg ulcers in the elderly have also been associated with diminished serum levels of certain micronutrients, such as vitamins A and E, carotenes, and zinc [
      • Rojas A.I
      • Phillips T.J
      Patients with chronic leg ulcers show diminished levels of vitamins A and E, carotenes, and zinc.
      ]. Zinc deficiency has been associated with impaired wound healing, so it is not surprising that therapeutic zinc may be beneficial for wound healing [
      • Kohn S
      • Kohn D
      • Schiller D
      Effect of zinc supplementation on epidermal Langerhans' cells of elderly patients with decubital ulcers.
      ,
      • Cario E
      • Jung S
      • Harder D'Heureuse J
      • et al.
      Effects of exogenous zinc supplementation on intestinal epithelial repair in vitro.
      ]. However, overzealous zinc treatment can impair wound healing and induce a copper deficiency [
      • Cario E
      • Jung S
      • Harder D'Heureuse J
      • et al.
      Effects of exogenous zinc supplementation on intestinal epithelial repair in vitro.
      ]. Matrix metalloproteinases are neutral zinc-dependent endopeptidases that degrade extracellular matrix components and participate in wound healing [
      • Agren M.S
      Matrix metalloproteinases (MMPs) are required for re-epithelialization of cutaneous wounds.
      ,
      • Ravanti L
      • Kahari V.M
      Matrix metalloproteinases in wound repair [review].
      ]. During wound healing, matrix metalloproteinases are modulated by insulin, insulinlike growth factors [
      • Huang J.S
      • Mukherjee J.J
      • Chung T
      • Crilly K.S
      • Kiss Z
      Extracellular calcium stimulates DNA synthesis in synergism with zinc, insulin and insulin-like growth factor I in fibroblasts.
      ], zinc availability and calcium availability, as determined by various proteins, such as calprotectin [
      • Isaksen B
      • Fagerhol M.K
      Calprotectin inhibits matrix metalloproteinases by sequestration of zinc.
      ] and calmodulin [
      • Lansdown A.B
      • Sampson B
      • Rowe A
      Sequential changes in trace metal, metallothionein and calmodulin concentrations in healing skin wounds.
      ].
      Vitamin C is required for collagen synthesis and therefore plays a central role in wound healing. Conflicting data exist in the literature regarding the effect of ≥500 mg/day of vitamin C on pressure ulcer healing [
      • Taylor T.V
      • Rimmer S
      • Day B
      • Butcher J
      • Dymock I.W
      Ascorbic acid supplementation in the treatment of pressure-sores.
      ,
      • ter Riet G
      • Kessels A.G
      • Knipschild P.G
      Randomized clinical trial of ascorbic acid in the treatment of pressure ulcers.
      ]. Vitamin A treatment is an effective intervention in patients with impaired wound healing and wound infections, especially while being treated with corticosteroids [
      • Ehrlich H.P
      • Hunt T.K
      Effects of cortisone and vitamin A on wound healing.
      ,
      • Hunt T.K
      Vitamin A and wound healing.
      ]. Vitamin E has unproven benefit in wound healing [
      • Waldorf H
      • Fewkes J
      Wound healing.
      ].

      Clinical practice algorithms

      During the initial evaluation of a patient with wound-healing issues, a nutritional assessment must be performed. Briefly, an unintentional loss of >10% usual body weight in the previous month, and/or a low serum albumin, defines a malnourished condition. Operationally, simple starvation or “marasmus” exists if the patient has lost >10% usual body weight and has a normal serum albumin. In this condition, low carbohydrate intake produces a low-insulin state with decreased energy expenditure and ketone production. Treatment consists of adequate nutrition support: 25 to 35 kcal/kg per day and 1.0 to 1.2 g/kg per day protein by means of oral, gastrostomy or jejunostomy tube, or parenteral routes. Alternatively, the majority of wound-healing patients manifest signs of inflammation, cytokine activation, and hypoalbuminemia, with or without weight loss depending on the extent of anasarca. This condition is termed “kwashiorkor-type” malnutrition and is associated with a higher in-hospital morbidity and mortality rate than patients with marasmus-type malnutrition [
      • McClave S.A
      • Mitoraj T.E
      • Thielmeier K.A
      • Greenburg R.A
      Differentiating subtypes (hypoalbuminemic vs marasmic) of protein-calorie malnutrition incidence and clinical significance in a university hospital setting.
      ]. In kwashiorkor-type malnutrition, cytokines have a plurality of effects on metabolism: (1) activation of the immune-neuroendocrine axis and counterregulatory hormones, (2) induction of lipolysis and muscle proteolysis, and (3) disinhibition of pyruvate dehydrogenase and inappropriately increased carbohydrate oxidation, energy expenditure, and substrate cycling [
      • Chang H.R
      • Bistrian B
      The role of cytokines in the catabolic consequences of infection and injury.
      ]. The net effect of this dysmetabolism is the diminution of body cell mass and resultant visceral organ dysfunction and immune dysfunction. Treatment of kwashiorkor-type malnutrition is supportive: (1) ample protein to optimize nitrogen retention, (2) hypocaloric energy to avoid the refeeding syndrome, hepatopathy, and hyperinsulinemia, (3) correction of micronutrient deficiencies, and (4) nutritional pharmacologic interventions.
      “If the gastrointestinal tract works, use it.” In a recent study by Lewis et al [
      • Lewis S.J
      • Egger M
      • Sylvester P.A
      • Thomas S
      Early enteral feeding versus “nil by mouth” after gastrointestinal surgery systematic review and meta-analysis of controlled trials.
      ], a systematic review and meta-analysis of 837 patients in 11 randomized, controlled trials showed that enteral feeding within 24 hours after gastrointestinal surgery reduced the mean length of hospital stay and risk of infection. Traditionally, early enteral feedings may be held because of fears of inducing nausea and vomiting, and to protect the anastomosis. These results confirm an earlier study by Schroeder et al [
      • Schroeder D
      • Gillanders L
      • Mahr K
      • Hill G.L
      Effects of immediate postoperative enteral nutrition on body composition, muscle function, and wound healing.
      ], in which early enteral feeds improve wound healing. If the patient can safely tolerate oral feedings, as determined by a speech pathology consultant to exclude aspiration, then a hospital diet incorporating patient preferences, along with appropriate nutritional supplements, should be ordered. A registered dietitian can both provide invaluable input into this prescription and perform calorie counting to assess adequacy. If oral intake is inadequate, then an enteral access device should be placed, preferably as an endoscopically or surgically positioned postpyloric feeding tube.
      Semielemental feeds contain hydrolyzed protein as their nitrogen source and are differentiated from intact protein feeds (protein that has not been hydrolyzed) and elemental feeds (free amino acids as the sole source of nitrogen). Hypoalbuminemia may reflect the severity of active cytokine-mediated inflammation and chronic undernutrition, but it also contributes to gut edema and diarrhea and reflects impairment of proteins necessary for nutrient absorption [
      • Brinson R.R
      • Kolts B.E
      Hypoalbuminemia as an indicator of diarrheal incidence in critically ill patients.
      ,
      • Brinson R.R
      • Kolts B.E
      Diarrhea associated with severe hypoalbuminemia a comparison of a peptide-based chemically defined diet and standard enteral alimentation.
      ,
      • Hwang T.L
      • Lue M.C
      • Nee Y.J
      • Jan Y.Y
      • Chen M.F
      The incidence of diarrhea in patients with hypoalbuminemia due to acute or chronic malnutrition during enteral feeding.
      ]. Semielemental feeds are therefore recommended in those wound-healing patients who also have a serum albumin level <2.5 g/dL [
      • Borlase B.C
      • Bell S.J
      • Lewis E.J
      • et al.
      Tolerance to enteral tube feeding diets in hypoalbuminemic critically ill, geriatric patients.
      ]. In critically ill patients after abdominal surgery, the use of a semielemental, versus an intact protein, enteral feed is associated with better amino acid absorption and insulin responses [
      • Ziegler F
      • Ollivier J.M
      • Cynober L
      • et al.
      Efficiency of enteral nitrogen support in surgical patients small peptides v non-degraded proteins.
      ]. Semielemental feeds are associated with decreased stool output, compared with intact protein feeds, in critically ill patients [
      • Brinson R.R
      • Kolts B.E
      Diarrhea associated with severe hypoalbuminemia a comparison of a peptide-based chemically defined diet and standard enteral alimentation.
      ,
      • Brinson R.R
      • Curtis W.D
      • Singh M
      Diarrhea in the intensive care unit the role of hypoalbuminemia and the response to a chemically defined diet (case reports and review of the literature).
      ]. With early enteral nutrition support after trauma or surgery, diarrhea was found to occur in 50% of patients receiving an elemental diet, 40% with an intact protein diet, but 0% on a semielemental diet [
      • Meredith J.W
      • Ditesheim J.A
      • Zaloga G.P
      Visceral protein levels in trauma patients are greater with peptide diet than with intact protein diet.
      ,
      • Ortiz C
      • Candau P
      • Arock M
      A comparative post-operative study—an enteral solution based on small peptides compared to an enteral solution based on free amino acids.
      ]. In critically ill and nursing home patients, improved visceral protein stores (albumin, transferrin, and retinol-binding protein) are induced with semielemental diets, compared with intact protein or elemental diets [
      • Ziegler F
      • Ollivier J.M
      • Cynober L
      • et al.
      Efficiency of enteral nitrogen support in surgical patients small peptides v non-degraded proteins.
      ,
      • Meredith J.W
      • Ditesheim J.A
      • Zaloga G.P
      Visceral protein levels in trauma patients are greater with peptide diet than with intact protein diet.
      ,
      • Feller A
      • Rudman D
      • Caindec N
      Comparison of nutritional efficacy of Peptamin and Vivonex TEN elemental diets in elderly tube fed subjects.
      ]. Moreover, a shorter hospital stay has been associated with semielemental feeds, compared with intact protein feeds, in trauma patients [
      • Meredith J.W
      • Ditesheim J.A
      • Zaloga G.P
      Visceral protein levels in trauma patients are greater with peptide diet than with intact protein diet.
      ].
      Several metabolic complications can result from enteral nutrition support. Tube feeding syndrome is a hypertonic dehydration state produced by overfeeding protein [
      • Pardoe E.M
      Tube feeding syndrome revisited.
      ]. If there is inadequate free water administered as flushes (to meet the increased obligate renal free water excretion that accompanies urea formation and excretion), then the patient becomes hypernatremic. Treatment is simply to avoid hypertonic feeds and administer ample free water. Diarrhea can also induce a hypertonic dehydration and is typically osmotic, or the result of occult sorbitol in medications, although secretory causes, such as Clostridium difficile enterocolitis and bacterial overgrowth, are quite common. Diarrhea can markedly impair wound healing because of bacterial contamination, difficulty maintaining a clean dressing, malabsorption, and gastrointestinal protein losses. Empiric therapy consists of (1) reverting to a semielemental or dilute elemental feeding (for example, two-thirds strength Vivonex [Novartis, Basel, Switzerland] or FAA [free amino acids; Nestlé Clinical Nutrition, Glendale, CA]), (2) adding 10 mL kaolin-pectin (Kaopectate; Pfizer, New York, NY) and/or bismuth salicylate (Pepto-Bismol; Procter & Gamble, Cincinnati, OH) to each 500-mL bag of feeds, (3) taking cholestramine, 1 packet, 2 to 4 times daily, and (4) using opioids, such as deiodinized tincture of opium or diphenoxylate HCl (Lomotil; Pfizer), octreotide, or pre-/probiotics.
      Abnormal gut flora result from overgrowth of various enteric pathogens, such as C difficile, and produces disturbances of colonic salt and water resorption, nutrient absorption, and gas formation. Beneficial colonic anaerobic microflora salvage energy by means of bacterial fermentation of undigested carbohydrate and protein into short-chain fatty acids, which are trophic to colonocyte physiology. Beneficial genera include Bifidobacterium and Lactobacillus. Prebiotics are inulin and oligofructosaccharides, which serve to provide substrates for probiotic organisms. A 15-g/day dose of oligofructosaccharide or inulin leads to Bifidobacterium becoming the dominant genus in feces [
      • Gibson G.R
      • Beatty E.R
      • Wang X
      • Cummings J.H
      Selective stimulation of bifidobacteria in the human colon by oligofructose and inulin.
      ]. Lactobacillus GG (Culturelle; ConAgra Foods, Omaha, NE) treatment has been used successfully for the management of recurrent C difficile colitis [
      • Biller J.A
      • Katz A.J
      • Flores A.F
      • Buie T.M
      • Gorbach S.L
      Treatment of recurrent Clostridium difficile colitis with Lactobacillus GG.
      ].
      In situations where patients are not able to meet the metabolic demands of wound healing with enteral feedings alone, parenteral nutrition support is initiated. Animal studies have indicated superiority of enteral nutrition over parenteral nutrition regarding wound-breaking strength, wound collagen accumulation, and type 1 (but not type 3) gene expression. However, these results have not been confirmed in humans [
      • Kiyama T
      • Witte M.B
      • Thornton F.J
      • Barbul A
      The route of nutrition support affects the early phase of wound healing.
      ]. One paradigm uses trophic enteral feeds with parenteral nutrition so that, together, they fully meet the metabolic demands of the patient. Formulation of parenteral nutrition has been the subject of much controversy [
      • Mechanick J.I
      Parenteral nutrition formulation an integral part of the endocrinologist's metabolic support consultation service.
      ]. For patients experiencing metabolic stress and manifesting signs of kwashiorkor-type malnutrition, a hyperproteic-hypocaloric approach has several advantages. High rates of amino acid infusion (up to 1.5 g/kg per day) are prescribed to meet the huge protein losses generated by wounds. Care must be taken not to create a hyperammonemic or severely azotemic state. Relatively low amounts of nonprotein calories (<20 to 25 total kcal/kg per day) in critically ill patients avoid the risk of overfeeding, without sacrificing benefit with regard to nitrogen balance [
      • Patino J.F
      • de Pimiento S.E
      • Vergara A
      • Savino P
      • Rodriguez M
      • Escallon J
      Hypocaloric support in the critically ill.
      ,
      • Muller T.F
      • Muller A
      • Bachem M.G
      • Lange H
      Immediate metabolic effects of different nutritional regimens in critically ill medical patients.
      ,
      • Frankenfield D.C
      • Smith J.S
      • Cooney R.N
      Accelerated nitrogen loss after traumatic injury is not attenuated by achievement of energy balance.
      ]. Regardless of the route of nutrient administration, tight glycemic control with subcutaneous and/or intravenous insulin should be achieved, as needed.
      Micronutrient support of wound healing is accomplished by means of enteral and/or parenteral routes, as reviewed in Table 1. Although certain nutrients play important roles in wound-healing physiology, the value of supplementing patients who are not deficient remains unproved.
      Table 1Micronutrition and nutritional pharmacology in wound healing
      NutrientDose
      Arginine
      In addition to standard amounts in parenteral nutrition trace elements and multivitamins.
      PO: 1–3 g/day
      Ascorbic acid
      In addition to standard amounts in parenteral nutrition trace elements and multivitamins.
      IV in PN: 100–200 mg/day; PO: 500–1,000 mg/day
      Cyanocobalamin
      In addition to standard amounts in parenteral nutrition trace elements and multivitamins.
      IV in PN: 25 μg/day; SC 1,000 μg/1–4 wk; PO: 250–1,000 μg/day
      GlutaminePO: 0.3–0.57 g/kg/day as 10–15-g doses
      Growth hormoneSC: 0.03–0.1 mg/kg/day
      Lactobacillus GGPO: 1 capsule bid–tid
      MolybdenumIV in PN: 25 μg/day
      Multivitamin
      In addition to standard amounts in parenteral nutrition trace elements and multivitamins.
      IV in PN: 10 mL/day; PO: 1–2 qd
      OligofructosaccharidePO: 1 capsule bid–tid
      OxandrolonePO: 2.5–5.0 mg bid–qid
      Pyridoxime
      In addition to standard amounts in parenteral nutrition trace elements and multivitamins.
      IV in PN: 25 mg/day; PO: 25–50 mg/day
      Selenium
      In addition to standard amounts in parenteral nutrition trace elements and multivitamins.
      IV in PN: 50–200 μg/day
      Testosterone enanthateIM: 50–200 mg/wk; transdermal 2.5–5.0 mg/day
      Thiamine
      In addition to standard amounts in parenteral nutrition trace elements and multivitamins.
      IV in PN: 25–100 mg/day; PO: 100 mg/day
      Vitamin A
      In addition to standard amounts in parenteral nutrition trace elements and multivitamins.
      PO: 5–10,000 U qd–bid
      Zinc
      In addition to standard amounts in parenteral nutrition trace elements and multivitamins.
      IV in PN: 5–10 mg/day; PO: 50–100 mg (elemental zinc)/day
      IM = intramuscularly; IV = intravenously; PN = parenteral nutrition; PO = orally; SC = subcutaneously.
      * In addition to standard amounts in parenteral nutrition trace elements and multivitamins.
      Glutamine is a conditionally essential amino acid and may promote nitrogen balance [
      • Hammarqvist F
      • Wernerman J
      • Ali R
      • von der Decken A
      • Vinnars E
      Addition of glutamine to total parenteral nutrition after elective abdominal surgery spares free glutamine in muscle, counteracts the fall in muscle protein synthesis, and improves nitrogen balance.
      ], gut absorptive function [
      • Byrne T.A
      • Morrissey T.B
      • Nattakom T.V
      • Ziegler T.R
      • Wilmore D.W
      Growth hormone, glutamine, and a modified diet enhance nutrient absorption in patients with severe short bowel syndrome.
      ], and immune function [
      • Newsholme E.A
      • Crabtree B
      • Ardawi M.S
      Glutamine metabolism in lymphocytes its biochemical, physiological and clinical importance.
      ]. Arginine is also a conditionally essential amino acid that improves wound healing and immune function [
      • Nijveldt R.J
      • Prins H.A
      • Siroen M.P
      • Rauwerda J.A
      • Teerlink T
      • van Leeuwen P.A
      Low arginine plasma levels in patients after thoracoabdominal aortic surgery.
      ,
      • Langkamp-Henken B
      • Herrlinger-Garcia K.A
      • Stechmiller J.K
      • Nickerson-Troy J.A
      • Lewis B
      • Moffatt L
      Arginine supplementation is well tolerated but does not enhance mitogen-induced lymphocyte proliferation in elderly nursing home residents with pressure ulcers.
      ,
      • Efron D
      • Barbul A
      Role of arginine in immunonutrition.
      ]. Ornithine α-ketoglutarate is a precursor of glutamine, arginine, proline, and α-ketoisocaproate, and can regulate protein metabolism, influence secretion of insulin and growth hormone, and improve wound healing [
      • Coudray-Lucas C
      • Le Bever H
      • Cynober L
      • De Bandt J.P
      • Carsin H
      Ornithine alpha-ketoglutarate improves wound healing in severe burn patients a prospective randomized double-blind trial versus isonitrogenous controls.
      ]. If attempts at improving nitrogen retention are unsatisfactory, anabolic agents [
      • Demling R.H
      • DeSanti L
      Involuntary weight loss and the nonhealing wound the role of anabolic agents.
      ], such as intramuscular or transdermal testosterone enanthate [
      • Nierman D.M
      • Mechanick J.I
      Hypotestosteronemia in chronically critically ill men.
      ], oral oxandrolone [
      • Mendenhall C.L
      • Moritz T.E
      • Roselle G.A
      • et al.
      A study of oral nutritional support with oxandrolone in malnourished patients with alcoholic hepatitis results of a Department of Veterans Affairs cooperative study.
      ,
      • Demling R
      • De Santi L
      Closure of the “non-healing wound” corresponds with correction of weight loss using the anabolic agent oxandrolone.
      ,
      • Demling R.H
      • Orgill D.P
      The anticatabolic and wound healing effects of the testosterone analog oxandrolone after severe burn injury.
      ], or subcutaneous growth hormone [
      • Manson J.M
      • Smith R.J
      • Wilmore D.W
      Growth hormone stimulates protein synthesis during hypocaloric parenteral nutrition role of hormonal-substrate environment.
      ,
      • Wilmore D.W
      Postoperative protein sparing.
      ] can be considered, but their benefit regarding wound healing also remains unproved. It should be noted that systemic growth hormone therapy has been associated with a worse outcome among critically ill patients compared with controls [
      • Takala J
      • Ruokonen E
      • Webster N.R
      • et al.
      Increased mortality associated with growth hormone treatment in critically ill adults.
      ]. Even topical essential fatty acids, insulin, and zinc, in addition to the commercially available growth factors, have demonstrated efficacy in wound healing in preliminary studies [
      • Greenway S.E
      • Filler L.E
      • Greenway F.L
      Topical insulin in wound healing a randomised, double-blind, placebo-controlled trial.
      ,
      • Declair V
      The usefulness of topical application of essential fatty acids (EFA) to prevent pressure ulcers.
      ].

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