This action might not be possible to undo. Are you sure you want to continue?
Nutrition and Wound Healing
Meghan Arnold, M.D. Adrian Barbul, M.D.
Summary: The relationship between nutrition and wound healing–-after injury or surgical intervention–-has been recognized for centuries. There is no doubt that adequate carbohydrate, fat, and protein intake is required for healing to take place, but research in the laboratory has suggested that other specific nutritional interventions can have significant beneficial effects on wound healing. Successful translation into the clinical arena, however, has been rare. A review of normal metabolism as it relates to wound healing in normoglycemic and diabetic individuals is presented. This is followed by an assessment of the current literature and the data that support and refute the use of specialized nutritional support in postoperative and wounded patients. The experimental evidence for the use of arginine, glutamine, vitamins, and micronutrient supplementation is described. Most of the experimental evidence in the field supporting the use of specialized nutritional support has not been borne out by clinical investigation. A summary of the clinical implications of the data is presented, with the acknowledgment that each patient’s plan of care must be individualized to optimize the relationship between nutrition and wound healing. (Plast. Reconstr. Surg. 117 (Suppl.): 42S, 2006.)
ound healing and nutrition have an intimate relationship that has been recognized by physicians for hundreds of years. Malnutrition or nutrient deficiencies can have a severe impact on the outcome of traumatic and surgical wounds. Wound failure, as reflected by wound infections and/or delayed healing, significantly contributes to the financial burden imposed on health care systems worldwide. The critical role of nutrition to healing has been recognized since the beginning of medicine as a discipline. Some of the earliest known writings identifying this synergy date to roughly 2300 years ago, when Hippocrates warned of underestimating the vital role that nutrition played in health and human disease.1 In the late 1800s, Coleman, Shaffer, and DuBois investigated the metabolic changes occurring in disease.2 Later, Cuthbertson3 further defined these biochemical responses to injury in studying patients and animals with long bone fractures by demonstrating significant alterations in physiologic electrolyte levels, increased nitrogen turnover, and stimulation of the overall host metabolism.
From the Department of Surgery, Sinai Hospital of Baltimore, and the Johns Hopkins Medical Institutions. Received for publication November 19, 2005; revised April 5, 2006. Copyright ©2006 by the American Society of Plastic Surgeons DOI: 10.1097/01.prs.0000225432.17501.6c
In the 1930s, Ravdin showed the specific relationship between protein malnutrition and the incidence of laparotomy wound dehiscence in dogs.4 – 6 Ravdin concluded that poor nutritional intake or lack of certain essential nutrients significantly altered the body’s ability to heal wounds. Interest has since swung from understanding the basic physiologic mechanisms of wound healing to attempting to modulate or enhance the process. The dynamic and complex cascade of wound healing has proved responsive to the external manipulation of metabolic and nutritional factors, but concrete changes to clinical management have been more elusive.
NUTRITIONAL FACTORS IN WOUND REPAIR
Malnutrition Malnutrition after injury results from multiple factors, including poor nutritional intake to a host’s perturbed metabolic equilibrium. Studies over the past century have shown that changes in energy, carbohydrate, protein, fat, vitamin, and mineral metabolism affect the healing process.7 Loss of protein from protein-calorie malnutrition, the most common form of malnutrition in the world, leads to decreased wound tensile strength, decreased T-cell function, decreased phagocytic activity, and decreased complement and antibody levels, ultimately diminishing the body’s ability to defend the wound against infection. These im-
have shown significantly slower cutaneous wound healing. an increased risk of developing pressure ulcers. reducing caloric intake by 50 percent results in decreased collagen synthesis. therefore.17. Wounds require energy mainly for collagen synthesis. but thermal injuries or large complicated wounds can divert a disproportionate amount of energy to the healing milieu.Volume 117. thus providing amino acids for gluconeogenesis. These discrepant results underscore the importance and preeminence of healing in the posttraumatic response and should not lead clinicians to ignore the need for optimal nutrition.8 –10 In elderly nursing home patients. most wounds heal uneventfully.19 –22 for example. An understanding of normal metabolism is critical when planning a surgical procedure in malnourished patients. for example. are the primary source of energy in the body and. Preoperative food intake. brief nutritional intervention by enteral or parenteral routes can overcome or prevent these impairments in the healing process. These disparities in the overall anabolic or catabolic state between various organs after thermal injury suggest that vital structures are preserved at the expense of others. catecholamine levels. In a society where malnutrition is thought to have been eliminated. Dietary carbohydrates and protein provide approximately 4 kcal of energy per kilogram. and a lower quality of life.28 In other animal models. only modest protein-calorie malnutrition impairs fibroplasia.32 Although the current literature is laden with studies attempting to delineate the exact role that nutrition and nutritional supplements play in the wound-healing process. and granulation tissue formation. resulting in an overall state of catabolism.18 In fact. noted that severe protein-calorie malnutrition and symptomatic specific nutrient deficiencies can impair wound healing by delaying the healing process itself.23 In a separate analysis. The primary goal. and fat.27. A study of orthopedic patients. severe or prolonged protein-calorie malnutrition is necessary to impair the healing responses. Patients undergoing oncologic operations. Albina. may be more important to the wound-healing process than the patient’s overall nutritional status. together with fats.16 The host’s catabolic response to injury is proportional to the severity of the injury. including posttrauma patients and individuals undergoing total hip replacement. malnutrition is also associated with increased mortality.11–14 Malnutrition may predate wounding or may be secondary to the catabolism resulting from the injury itself. and fats provide 9 kcal/kg. As such. simple wounds have little energy impact on overall metabolism. a significant proportion of medical and surgical patients have preexisting malnutrition from decreased nutritional intake. muscle breakdown occurs preferentially to the use of existing fat stores.30 Conversely. matrix protein deposition. Estimates of caloric requirements for a particular wound can be determined knowing that (1) protein synthesis requires 0. Identification of the potential risk imposed by malnutrition is especially important in populations with other risk factors for impaired wound healing.26 In rats. 12 percent of noncancer patients were found to be malnourished at preoperative evaluation. Number 7S • Nutrition and Wound Healing mune compromises correlate clinically with increased wound complication rates and increased wound failure after clean surgical procedures. healing may be prioritized by metabolic activity. found that 42 percent of those studied were malnourished. brief preoperative illness or decreased nutritional intake in the prewounding period has a significant effect on collagen synthesis.15 During this time of increased energy demand.31. One of the critical elements required for healing is energy. Carbohydrates Carbohydrates. should be to provide every patient with optimal nutrition so that this prioritization of wound healing can occur within an ideal host environment. which in turn powers the wound- 43S .25 Although the exact parameters used to define clinical malnutrition may vary. Levenson and others.9 kcal/g and (2) a 3-cm2 1-mm-thick section of granulation tissue contains 10 mg of collagen. but increased liver regeneration. in the wound-healing process. and cellular protein turnover. then. Wounding increases metabolic rates. consequently. loss of total body water.34 Glucose is the major source of fuel used to generate cellular energy in the form of adenosine triphosphate.24 Another cross-sectional study demonstrated that approximately 50 percent of medical and surgical patients in an urban hospital showed evidence of malnutrition. in burned and traumatized animals. In humans. which in the human host is derived from carbohydrates. an assessment of preexisting malnutrition should be performed when evaluating a wound or a patient about to undergo operative intervention. however. often present with preoperative weight loss and malnutrition but generally heal without infection or wound dehiscence.33 however. protein.29 Finally. including those that occur in the setting of significant malnutrition.
Deficiencies in these lipids can occur as early as 2 weeks after their removal from the diet. Total parenteral nutrition is the most common cause of essential fatty acid deficiency. its administration results in rapid onset of essential fatty acid deficiency. which block both lipolysis and essential fatty acid release. leads to elevated insulin levels.51–54 primarily because phospholipids are key constituents of cellular basement membranes while prostaglandins play critical roles in cellular metabolism and inflammation. Although both fatty acids can be synthesized from linoleic acid.40 – 42 Topical application of insulin to infected skin wounds or systemic administration in diabetic mice can improve healing. specifically as it relates to leukocytes. is thought to explain the decreased early inflammatory response and impaired wound healing seen in diabetic patients. although clinical manifestations may not be apparent for 2 to 7 months.44 Hyperglycemia interferes with the cellular transport of ascorbic acid into fibroblasts and leukocytes and decreases leukocyte chemotaxis. but they may be related to a build-up of advanced glycation endproducts in body tissues. but the caloric contribution from glucose is essential in preventing the depletion of other amino acid and protein substrates. This excess may subsequently complicate wound healing.35 Diabetics exhibit a diminished early inflammatory response and inhibition of fibroblast and endothelial cell activity. although it is recognized that the demand for essential fatty acids increases after injury. exhibit increased complication rates compared with their euglycemic counterparts. The alteration in a diabetic’s metabolism after injury or elective surgery can significantly affect wound healing by any of the mechanisms discussed above. an effect that was not corrected by insulin administration at the time of surgery and that extended into the early postoperative period. It is crucial that physicians recognize and anticipate the needs of diabetic patients early.45 Competitive inhibition of ascorbic acid membrane transport may explain this mechanism. triggered by the catecholamine and cortisol surge that occurs after wounding.47 Fats In contrast to carbohydrates.38 Delayed epithelialization of open wounds and decreased collagen accumulation deep within the wound have been reported in models of streptozotocin-induced diabetes. this increased gluconeogenesis can significantly deplete amino acids and protein. in addition to hyperglycemia. the role of fats has not been studied widely. and closure.46. In summary. diabetic patients are more susceptible to infection because of decreased host resistance. Diabetic patients have a significantly impaired ability to heal wounds and. and in the presence of inadequate carbohydrate and fat stores. Deficiencies of dietary essential fatty acids were rarely seen clinically until the introduction of prolonged parenteral feedings that did not contain fat. and wound healing cannot be overemphasized. The importance of controlling serum glucose levels in diabetics around the time of injury. wound remodeling.50 As components or precursors of phospholipids and prostaglandins. As mentioned. The liver.55 This.43 but to achieve normal healing insulin must be started soon after wounding.Plastic and Reconstructive Surgery • June Supplement 2006 healing process. they initiate a prolonged inflammatory phase that results in delayed deposition of matrix components. initiates gluconeogenesis using amino acids from degraded muscle protein.48. Although carbohydrates play an important role in providing the energy essential for optimal healing. In addition. the most important factor affecting wound healing in diabetic patients involves achieving and maintaining normal glucose control. The use of glucose to generate adenosine triphosphate is relatively inefficient. free fatty acid deficiency impairs wound healing in animals and humans.46 This effect of hyperglycemia. the lack of insulin itself seems to impair wound healing. gluconeogenesis is a relatively inefficient pathway for glucose production that can result in the production of excess amounts of glucose. as glucose and ascorbic acid are structurally similar. which can manifest within 10 days of starting an entirely fat-free diet. The mechanisms at work are multifactorial and yet to be clearly delineated. Unchecked.49 Linoleic and arachidonic acid are among the unsaturated fatty acids that must be supplied in the diet to allow for prostaglandin synthesis. in turn. especially in diabetic patients with poor glycemic control. the rate of synthesis is inadequate for basic metabolic needs. The 44S . therefore.35–37 When inflammatory cells eventually arrive at the site of injury. before the encumbering effects of diabetes lay hold to the wound-healing process.56 Additional research has sought to define benefits to wound healing of specific lipid types. little is known about the functions that different sources of carbohydrates play in this process.37 Decreased reendothelialization of microarterial anastomoses has also been demonstrated. operation.39 Work by Weringer and associates using a mouse model demonstrated that.36.
may be in their immune modulation of the host rather than in improved wound healing per se. have demonstrated improved immune function. however. the effect of arginine on wound healing in young adult rats was studied. Although arginine is synthesized in adequate quantities to sustain muscle and connective tissue mass. cross-linking. such as platelet-activating factor.67 Arginine and glutamine. in situations of stress or injury. although the clinical relevance of these findings has never been pursued.64 Protein The importance of protein in wound healing has been recognized and researched since the early 1930s. the amino acid requirements of the adult organism would revert to those of the growing infant. have been the most extensively studied amino acids in the wound-healing process.72 The role of arginine in wound healing was first shown in the 1970s using an animal model. severe protein deprivation leads to impaired healing through impaired collagen synthesis and deposition. following injury.36 Arginine also has roles in maintaining positive nitrogen balance. as assessed by woundbreaking strength and collagen synthesis. most patients exhibit combined protein-energy or protein-calorie malnutrition. Arginine is a dibasic amino acid synthesized endogenously from ornithine through citrulline and is a precursor for proline during collagen synthesis.5 g/liter) of arginine. compared with chow-fed controls (Fig. pure protein deficiencies are rarely encountered. It is during these times. and reduced infectious complications after the administration of a diet rich in -3 fatty acids to this specific subset of injured patients.63. Studies of healing burns in humans and guinea pigs. and cysteine in an energydependent and sodium-dependent fashion with substrate specificity. and spatial orientation of collagen fibrils. and T-lymphocyte stimulation and is involved in the metabolic pathways that synthesize urea. there has been a rising interest over the last several decades in the use of individual nutrients to promote wound healing.71.75 In this model.57– 62 are among the most widely investigated. body stores of arginine decrease rapidly.70 Arginine is absorbed from the intestine by a transport system shared with lysine.34 Partial resolution of healing defects in protein-deficient rats was noted with the administration of single sulfur-containing amino acids. in which its synthesis is insufficient to meet the demands of increased protein turnover.. 1). and a notable decrease in wound-breaking strength as well as wound collagen accumulation compared with animals fed a diet containing arginine (Fig.73 Likewise. such as methionine and cysteine. on the other hand. Amino Acids Because wound healing can be impaired by deficiencies in a variety of nutrients. Animals were fed an arginine-deficient diet for 4 to 6 weeks before wounding. however.Volume 117. Animals consuming diets enriched with -3 fatty acids have weaker wounds because of poor quality.69.28. when it was hypothesized that.74 Twenty years ago a micromodel was described that has made it possible to study the human fibroblastic response. 1). interleukin-1.72 Similar findings were observed in parenterally fed rats given an amino acid mixture containing high doses (7. Arginine In the late 1940s and early 1950s. and creatine phosphate. Rose68 classified arginine as one of two semiessential amino acids in mammalian metabolism. nitric oxide. When animals were subjected to the minor trauma of a dorsal skin incision and closure. ornithine. These animals exhibited increased wound-breaking strength. Number 7S • Nutrition and Wound Healing -3 fatty acids. mature or old rats fed diets supplemented with a combination of arginine and glycine had enhanced rates of wound collagen deposition compared with controls. Based on this hypothesis. and increased wound infection rates. that arginine becomes an indispensable amino acid in the process of wound healing and in the maintenance of a positive nitrogen balance. decreased skin and fascial wound-breaking strength. Two studies in healthy human volunteers examined the 45S . they demonstrated increased postoperative weight loss. increased collagen accumulation.72 Subsequent experiments revealed that chow-fed rats that were not arginine-deficient and were then fed a diet containing an additional 1% arginine had enhanced wound healing. therefore. and tumor necrosis factor. an increased mortality rate to approximately 50 percent.65 In the clinical setting. Experimentally. improved survival. collagen accumulation occurs in subcutaneously placed segments (5 to 7 cm long) of polytetrafluoroethylene tubing that can be removed for analysis. growth factor release.57 The true benefit of -3 fatty acids.66. which exhibit anti-inflammatory properties by inhibiting the production of eicosanoids and other mediators. and enhanced immune function.
76 The second study evaluated 30 elderly volunteers (age 70 years) who received 30 g of arginine aspartate or placebo.77 There was no enhanced DNA present in the wounds of the arginine-supplemented group. FxBS. 2). The catheters in this study were analyzed for -amino nitrogen content (assessment of total protein accumulation). 3). or 30 g of arginine hydrochloride (AG HCl. g. 1. 36 young. healthy human volunteers (ages 25 to 35 years) were randomized to one of three groups: (1) 30-g arginine hydrochloride daily supplements (24.8% arginine content) on wound healing in rats.8 g of free arginine). or (3) placebo. formalin-ﬁxed breaking strength. In addition to evaluating the fibroblastic wound response using the catheters. effects of arginine supplementation using this model. Effect of supplemental dietary arginine added to an arginine-free (deﬁned) diet or normal laboratory chow (1. DNA accumulation (index of cellular infiltration). hydroxyproline content of subcutaneously implanted polyvinyl alcohol sponges. (2) 30 g of arginine aspartate (17 g of free arginine). 30 g of arginine aspartate (Arg Asp. Arginine supplementation at both doses significantly increased the amount of hydroxyproline and total protein deposition at the wound site (Fig. this study also examined epithelialization after creation of a split-thickness wound on the upper thigh of each subject.8 g free arginine) per day for 2 weeks. Effect of 2 weeks of arginine supplementation on hydroxyproline accumulation in subcutaneously implanted polytetraﬂuoroethylene catheters in young human volunteers (mean SEM). The supplements were given for 2 weeks. 2.Plastic and Reconstructive Surgery • June Supplement 2006 Fig. 17 g of free arginine) per day. g/100 mg sponge dry weight. 24. Arginine supplementa- Fig. fresh breaking strength of scar. suggesting that the effect of arginine is not mediated by an inflammatory mode of action (Fig. FBS. and hydroxyproline content. In the first study. Groups of 12 volunteers each received a placebo (control). g. after which the polytetrafluoroethylene catheters were removed and the hydroxyproline content (index of reparative collagen synthesis) was determined. 46S . OHP. Statistical comparison by Student’s t test.
In a study by de Luis et al. Nursing home patients with pressure ulcers have been the most recent patient population studied with regard to arginine supplementation.81 Subjects tolerated the arginine supplementation well.. and DNA in subcutaneously implanted polytetraﬂuoroethylene catheters was measured at the end of 2 weeks (mean SEM).79 Despite improvements in markers of collagen biosynthesis. Accumulation of hydroxyproline (OHP). the beneficial effects of supplemental arginine on wound healing are similar to the 47S . 3. but no improvement in immune function was observed.Volume 117. and -hydroxy. glutamine. Patients treated with arginine.83 but other studies found no effect. and preal- bumin. had lower rates of fistula formation and.84 – 86 Several mechanisms have been postulated to explain the positive effect of arginine on wound healing. patients undergoing resection for oral or laryngeal cancer were randomized to receive an enteral dietary supplement containing either fiber or fiber and arginine. total -amino N. First. clinical evidence of improved wound healing has not been reported in most of the studies published to date. however.78. indicating that the predominant effect of arginine is on wound collagen deposition. Effect of arginine on wound-healing parameters in healthy elderly human volunteers. tion had no effect on the rate of epithelialization of the skin defect.80 Postoperative infectious complications were similar in the two groups. as were plasma protein levels of albumin. however.-methylbutyrate.78 Oral arginine supplementation is well tolerated and has been the focus of recent studies of wound healing and medical outcomes. Prior work in volunteers and patients had shown that arginine supplementation increased mitogen-induced lymphocyte proliferation. Controls (n 15) received placebo syrup. transferrin. consequently. Number 7S • Nutrition and Wound Healing Fig. the arginine group (n 30) received 30 g of arginine aspartate. One study sought to determine the tolerance of oral arginine administration and effectiveness in improving mitogeninduced lymphocyte proliferation and interleukin-2 production. two in vitro parameters of immune function.82. shorter hospital stays. A recent randomized trial in healthy volunteers demonstrated improved collagen synthesis after dietary supplementation with arginine.
111.70 Both pathways have been shown to deplete the wound environment of extracellular arginine.78 Second.87– 89 In a study exploring this observation. one involving nitric oxide synthases and the other by arginase. arginine supplementation in doses that have been shown to improve wound healing also increases plasma insulin-like growth factor. hypophysectomized and normal pituitary-bearing animals were divided into two groups–-one receiving growth hormone and one receiving placebo–-with half the animals in each group also supplemented with 1% dietary arginine.100 Arginine is catabolized in wounds through two separate pathways.110 Gluconeogenesis involves the shuttling of alanine and glutamine to the liver for conversion to glucose. as evidenced by decreased woundbreaking strength in animals treated with monoclonal antibodies against all T lymphocytes.69 Arginine supplementation may play an especially important role in the wound healing of diabetic patients.Plastic and Reconstructive Surgery • June Supplement 2006 effects seen with growth hormone.94 The exact mechanisms are not fully understood.112 Finally.95–97 Third.109. thus emphasizing its essential nature in wound healing. glutamine has a crucial role in stimulating the inflammatory immune response occurring early in wound healing.g. Inhibitors of nitric oxide have been shown to significantly impair the healing of cutaneous incisional wounds and colonic anastomoses in rodents.. This abnormal response is characterized by delayed neutrophil chemotaxis and impaired phagocytosis and leads to decreased concentrations of nitric oxide and growth factors as well as inadequate collagen synthesis. but it is thought that one manner in which arginine may enhance wound healing is by stimulating the host’s T-cell response.108 Glutamine is also an important precursor for the synthesis of nucleotides in cells. again regardless of the administration of growth hormone. a highly reactive radical that may play a critical role in wound healing. in rats. an impairment that is remedied by adenoviral transfer of the iNOS gene into the wound bed. which is used peripherally as fuel for certain aspects of wound healing. As previously described. it accounts for approximately 20 percent of the total circulating free amino acid pool and 60 percent of the free intracellular amino acid pool.105 48S . have demonstrated that arginine supplementation leads to greater wound-breaking strength resulting from increased levels of hydroxyproline and collagen. T lymphocytes can be detected immunohistochemically in distinctive patterns throughout the various phases of wound healing. arginine had no effect on these wound-healing parameters.77 The inducible isoform of nitric oxide synthase. Animal models of diabetes. In addition.91–93 T lymphocytes are known to be essential for normal wound healing. arginine-supplemented animals demonstrated increased wound-breaking strength and collagen accumulation. the effects of arginine on wound healing require an intact hypothalamopituitary axis. Glutamine is also an energy source for lymphocytes and is essential for lymphocyte proliferation. This result suggests that. which.105. In the hypophysectomized animals.106 In addition to being a major respiratory fuel source.70 Supranormal collagen deposition has been observed after transfection of iNOS DNA into wounds. diabetic patients exhibit an impaired inflammatory response to injury. however.99 In vitro studies have noted increased collagen synthesis in cultured dermal fibroblasts exposed to exogenous nitric oxide. arginine has been identified as a unique substrate for the generation of nitric oxide. whether growth hormone was given or not.73. glutamine serves as a nitrogen donor for the synthesis of amino acids and amino sugars.104 Glutamine Glutamine is the most abundant amino acid in the body.98. the intact. when considered collectively.102 Functional loss of the iNOS gene abrogates the beneficial effect of arginine in wound healing. This finding suggests that the iNOS pathway is at least partially responsible for the enhancement of wound healing observed with the administration of arginine. which in turn increases fibroplasia. After wounding.107. is most active in response to inflammatory stimuli (e.101 while mice lacking the iNOS gene experience delayed closures of excisional wounds.90 In humans. T lymphocytes interact within the dynamics of each phase of healing to accomplish a specific task. including fibroblasts and macrophages. leads to normal repair of the wound. supplemental arginine has a unique effect on T-cell function by stimulating T-cell responses and reducing the inhibitory effect of injury and wounding on T-cell function. wounding) and generates more nitric oxide than the constitutive isoforms. iNOS. specific T-cell types have modulating roles on different stages of cutaneous healing. Furthermore. the peripheral mediator of growth hormone activity.103. whereas wild-type mice fed arginine-supplemented diets exhibit improved incisional wound healing as assessed by breaking strength and collagen deposition.
During the time that Osler was describing the symptoms of scurvy.Volume 117. increased macrophage influx and activation. it is not surprising that there is a rapid fall in plasma and muscle glutamine levels after injury.129 –132 As alluded to earlier. The administration of vitamin A. and significant hemorrhage. decreased angiogenesis. Scurvy has as its central element a failure in collagen synthesis and cross-linking. This increased response is thought to occur by an enhanced lysosomal membrane lability. improved protein synthesis.114 Although efficacy of supplemental glutamine administration has been shown in some clinical situations.” After resuming a diet supplemented with 1 g of ascorbic acid per day.36 In vitro studies have shown increased collagen synthesis of fibroblast cell cultures in the presence of vitamin A. Vitamin C deficiency is well known because of its historical significance in relation to scurvy (scorbutus).115 it has not proved to have any noticeable effect on wound healing specifically. More generalized symptoms include weakness.117–119 Vitamins The vitamins most closely associated with wound healing are vitamin C (ascorbic acid) and vitamin A.133.128 Finally. joints. In major burn victims. however.113. Crandon consumed a diet lacking vitamin C. the clinical spectrum of its administration varies widely. cyclophosphamide.123 In animal models. also can correct the impaired wound healing of patients on long-term steroid therapy. Ehrlich and Hunt126 subsequently described the benefits of supplemental vitamin A on wound healing in nondeficient humans and animals by showing that vitamin A can reverse the anti-inflammatory effects of corticosteroids on wound healing. and radiation. and stimulation of collagen synthesis. There also is no evidence that excess vitamin C is toxic. After 3 months on this diet.116 Most of glutamine’s benefit appears to involve improvements in gut permeability. there is no evidence to suggest that massive doses of ascorbic acid provide any substantial benefit to wound healing.34 McCollum and Davis initially discovered vitamin A in the early 1900s. Since that time it has been shown to be beneficial to the wound-healing process by stimulating epithelialization and collagen deposition by fibroblasts.127.134 These mechanisms still are not well understood. while working as a surgical resident. fatigue. the underlying defect in collagen was not understood. as well an impairment of neutrophil function and complement activity. noting that it had virtually disappeared as a clinical entity. a skin incision healed normally and a biopsy sample 10 days after the injury was normal. vitamin A increases the inflammatory response in wounds. in addition to impairing wound healing. the wounds of burned guinea pigs bore histologic resemblance to those of scorbutic unburned animals. owing in large part to the work of Lind. peritoneum. 49S . If wound infection does occur in the setting of vitamin C deficiency. and depression. These early histologic descriptions are consistent with the findings now known to be associated with vitamin C deficiency: minimal collagen deposition. the requirement may be as much as 2 g per day to restore urine and tissue levels to normal. and a final biopsy sample showed increased collagen and capillary formation. a second incision healed poorly. it is apt to be more severe. In the late 1800s.124 Vitamin C deficiency. Number 7S • Nutrition and Wound Healing Given the abundant roles of glutamine in the cells involved in wound healing. has been associated with an increased susceptibility to wound infection. topically or systemically. Osler120 categorized and eloquently described the manifestations of this condition. tumor formation. and adrenal glands. normalization of serum levels. These changes were prevented when supplemental vitamin C was given. Although the dose needed in different settings may vary. but it is clear vitamin A plays in important role in wound healing.121 The symptoms of scurvy reflect this impaired synthesis of collagen and connective tissue and include bleeding into the gingiva. Brandaleone and Papper125 were the first to demonstrate that wound healing was impaired by vitamin A deficiency. Although the recommended dietary allowance for vitamin C is 60 mg/d. Crandon and colleagues122 first revealed the significance of this “intracellular substance” (collagen) and the temporal aspects of vitamin C deficiency. and decreased hospital length of stay. The earliest accounts of this deficiency were in sailors and field armies who consumed a diet lacking in fresh fruits and vegetables and who subsequently developed scurvy. pericardium. In 1940. and a 10-day biopsy sample revealed a lack of “intracellular substance. healing improved. skin. After 6 months on this diet. vitamin A has been used to restore the impaired wound healing caused by diabetes. These effects are thought to be attributable to impaired collagen synthesis and a subsequent inability to wall off bacteria and localize infection.
127. VII. zinc.139 The primary role of magnesium is to provide structural stability to adenosine triphosphate.15 While two studies in animal models have suggested a beneficial effect of vitamin E supplementation on wound healing. It is difficult to associate deficits in specific minerals and trace elements to impairments in wound healing. primarily by protection against destruction by oxidation.138 The fat-soluble vitamin A and the water-soluble vitamin C are the predominant vitamins at work in the wound-healing process. as shown by the reversal of wound-healing impairment imposed by vitamin E after administration of vitamin A in the first days after wounding. retinyl esters.149 Zinc is the most well-known element in wound healing and has been used empirically in dermatologic conditions for centuries. and for the optimal functioning of lysyl oxidase. impaired healing has been noted secondary to decreased copper stores in patients with Wilson’s disease and in animals after the administration of penicillamine. The remaining fat-soluble vitamins.15 Micronutrients Micronutrients are essential components of cellular function and can be divided into organic compounds. such as the vitamins already discussed. and K.141 The liberation of free radicals from inflammatory cascades in necrotic tissue. which is known to occur in chronic wounds. thus making it a factor essential to wound repair. vitamin E may have a role in decreasing excess scar formation. D. is involved in DNA synthesis. tissue colonized with microbial flora. which did not include supplemental minerals and trace elements. therefore. E. IX. Large doses of corticosteroids can also deplete hepatic stores of vitamin A.145 supplementation in humans has not been shown to have a beneficial effect on wound healing. ischemic tissue.139 Of the numerous trace elements present in the body. Decreased serum levels of vitamin A.139 Experimentally. however. retinol-binding protein.Plastic and Reconstructive Surgery • June Supplement 2006 Serious injury or stress leads to increased vitamin A requirements. copper. Larger doses of vitamin A do not improve further wound healing. vitamin E may reduce injury to the wound by scavenging excess free radicals. an enzyme that catalyzes the cross-linking of collagen and strengthens the collagen framework. fractures. and iron have the closest relationship to wound healing. either of which could impair healing. protein synthe- 50S .148.15. Some authors have suggested that. which may have an indirect role in wound healing through its influence on host resistance. Zinc is a cofactor for both RNA and DNA polymerase and. Copper is a required cofactor for cytochrome oxidase. and prolonged excessive intake can be toxic. the cytosolic antioxidant superoxide dismutase.147 Vitamin K is required for the carboxylation of glutamate in clotting factors II. Clinicians became more aware of deficiencies of these elements after the introduction of long-term parenteral nutritional solutions. The other water-soluble vitamin is vitamin B complex. and chronic wounds can result in depletion of free radical scavengers such as vitamin E. similar to those of steroids. which powers many of the processes used in collagen synthesis. and inorganic compounds or trace elements. and elective surgery.34 Magnesium is essential for wound repair and functions as a cofactor for many enzymes involved in protein and collagen synthesis. rather they serve as cofactors or part of an enzyme that is essential to healing and homeostasis. In these patients it is not known if their relative lack of vitamin E is due to consumption of vitamin E in its antioxidant capacity or overall vitamin E deficiency.139 Vitamin E possesses anti-inflammatory properties.144. it is often easier to prevent these deficiencies than to diagnose them clinically. Most of these minerals and trace elements do not influence wound healing directly. may lead to hematoma formation within a wound. which can impair healing and predispose to infection. As such.143 This process is believed to be at work in patients with chronic lower extremity wounds. and X and contributes little to direct wound healing.142. they are relied on heavily by the cellular machinery that carries out wound healing. Although these nutrients comprise only a small portion of the body’s overall nutritional needs.138.000 IU/d (five times the recommended daily dose) have been advocated and used without any significant side effects. in chronic wounds of the lower extremity. Vitamin E maintains and stabilizes cellular membrane integrity. It is this hemostatic capacity of vitamin K that most influences wound healing. doses of vitamin A of 25.36. because micronutrient deficiencies almost always are accompanied by other coexisting metabolic or nutritional disturbances.146.140 Vitamin E also has been shown to affect various host immune functions.135–137 In the severely injured. As an antioxidant. do not contribute significantly to wound healing. and -carotene have been noted after burns. Its absence or deficiency.
In the clinical environment. (3) peritonitis increases metabolism 20 percent to 40 percent. Sepsis. prealbumin. The immune system is tied to overall host nutrition and specific nutritional entities. This value can then be used to guide nutritional care.Volume 117. whether present as local bacterial colonization of the wound site or as a systemic inflammatory response. Kinney157 outlined the metabolic adjustments experienced after injury as follows: (1) uncomplicated intra-abdominal surgery increases the metabolic rate approximately 10 percent. the sine qua non of linear nutritional status measurements over time has been serial weight measurements.150 In zinc deficiency. normal albumin and total lymphocyte levels corre- OTHER FACTORS AFFECTING WOUND HEALING Infection The complex cascade of events that comprise the body’s response to tissue injury with the purpose of restoring cutaneous integrity occurs in the presence of various environmental factors. to delayed wound healing. and cellular proliferation. however. In contrast to other deficiencies of trace elements. Iron is also a component of the oxygen transport system and can affect wound healing in this capacity. retinol-binding protein and transferrin levels. functioning immune system is vital to preventing and 51S . iron deficiency is common and can result from blood loss.15. fibroblast proliferation and collagen synthesis are decreased. and respiratory minute volume. such as arginine and its related metabolic pathways. Serum albumin levels and total lymphocyte count also are useful nutritional prognosticators. is one of the most formidable obstacles to successful wound healing. urinary nitrogen. (4) third-degree burns increase metabolism 50 percent to 100 percent. No studies have shown improvement in wound healing after the administration of zinc to patients who are not already zinc deficient. with normal breathing. anergy-delayed hypersensitivity. an intact. Zinc levels can be depleted in settings of severe stress151 and in patients receiving long-term steroids. Other markers predictive of nutritional state include serum albumin.128 clearing wound infection. the current recommended daily allowance for zinc is 15 mg. total lymphocyte count. In a study of nutritional status as a predictor of wound healing after amputation. ultimately. but only in settings of severe iron-deficiency anemia.156 Evaluation of Overall Nutritional State Clinicians must be aware of nutritional disturbances in wounded patients before these nutritional deficits can be corrected. One of the least expensive and practical ways to estimate simple caloric requirements of seriously ill patients is respiratory minute volume. (2) uncomplicated injuries. iron deficiency is easily detected and treated.158 Body water also can influence the anthropometric measurements used to estimate body fat from skin-fold thickness and predetermined nomograms. the respiratory minute volume gives a close correlation to the patient’s metabolic rate. infection.34 Both cellular and humoral immune functions are impaired in zinc deficiency. Experimentally.154. Zinc deficiency impairs the crucial roles each of these processes play in wound healing and leads. it is crucial that nutritional status be optimized to provide increased substrate availability to meet the demands of tissue repair and immune function and to prevent wounds from succumbing to infection and delayed healing. These defects are readily reversed with repletion of zinc to normal levels. it is recommended that patients receive vitamin A and zinc supplementation to improve wound healing152 . Total body water increases at approximately the same rate that body protein decreases. and (5) fever increases metabolism 10 percent for each 1ºC above normothermia. Historically. such as femoral fracture. severe iron deficiency can result in impaired collagen production. or an underlying hematopoietic disorder.155 In addition to appropriate antibiotic therapy. resulting in an increased susceptibility to wound infection and a resultant increased probability of delayed healing. Number 7S • Nutrition and Wound Healing sis. The severity of the deficit must be assessed and the caloric requirements for healing to ensue should be estimated. Any of these factors can impair the wound-healing process if they are not effectively managed or prevented. and as a result. if the presence of abnormal amounts of body water is not taken into account. the crucial inoculum of microorganisms that significantly inhibits healing is 105 colony-forming units per square centimeter of wound surface or gram of tissue. malnutrition.153 Iron is required for the hydroxylation of proline and lysine. In critically ill patients.15 In these settings. This commonly used marker for malnutrition can be misleading. In the absence of metabolic acidosis or alkalosis. increase metabolism about 20 percent. leading to decreased wound strength and delayed epithelialization.
but the data are conflicting. Total enteral nutrition maintains local and systemic immune responses. sepsis.168 Specific feeding regimens. but there is growing experimental evidence that it is superior to total parenteral nutrition as a feeding modality. total enteral nutrition seems to exert a greater influence over the early cellular.9 These values can be misinterpreted. or infection are present and not taken into account. Total parenteral nutrition has been shown to reduce postoperative complications when administered to severely malnourished patients for at least 7 days preoperatively. Total enteral nutrition has associated risks as well. The exact route of administration. A depressed hypersensitivity reaction to intradermally injected antigens has also been established as an indicator of nutritional status.160 –163 Total parenteral nutrition has many associated risks. 52S . There seems to be ample evidence that nutritional repletion before planned elective operations in malnourished patients significantly reduces these complications. inflammatory phase of wound healing than total parenteral nutrition. may be important. it should then be raised to 200 to 225:1 as the body shifts to a period of positive nitrogen balance. however.138 Patients who are malnourished before injury have increased rates of wound infection and exhibit delayed wound healing. In patients who are malnourished. carbohydrate. should be tailored to individual patients. The substrates for wound-healing energy are protein. fat. In these studies. improves protein metabolism and survival. mean SEM) and hydroxyproline content ( g/100 mg sponge. and preserves gut integrity. Studies evaluating the route of nutrition and wound healing in rats showed that total enteral nutrition particularly influences the early stages of wound healing. Specifically.159 Feeding Wound healing has been described repeatedly in this article as a complex series of cellular and biochemical events that are dependent on energy availability. thereby decreasing bacterial translocation. however. This cellular phase is exquisitely sensitive to nutrient availability. This beneficial influence seems to disappear during the period of maximal fibroplasias. amino acids. mean SEM) of the sponge granulomas in enterally [total enteral nutrition (open square)] and parenterally [total parenteral nutrition (striped square)] fed animals. if factors such as liver dysfunction. 4.Plastic and Reconstructive Surgery • June Supplement 2006 lated with increased rates of healing. 4). which occurs 5 to 10 days after injury.164 –167 As already alluded to. not the least of which is infection. ultimately affecting wound repair. and micronutrients. total enteral nutrition significantly increased collagen deposition and wound-breaking strength when measured within 5 days after wounding when compared with total parenteral nutrition (Fig. Wound-breaking strength (g. it has been recommended that the calorie-to-nitrogen ratio be 120 to 150:1 during the early weeks of wound healing after severe injury. however. The influence total enteral nutrition has on systemic immune function contributes to the function and number of inflammatory cells present during early healing. preoperative repletion should be Fig. whether enteral or parenteral.
170. Although glutamine and arginine have been shown to have beneficial effects on wound healing in animal models and in healthy volunteers. is to determine whether. enteral nutritional support is generally preferred. and a variety of commercial nutrition products are available for use in specialized patient populations. wound healing remains enigmatic. gastrostomy. the physician should be able to recognize patients who may be expected to have wound-healing difficulties and offer early intervention to avoid wound failure. are best reserved for those with preexisting deficiency states.171 While the only absolute contraindication to enteral feeding is complete intestinal obstruction. total parenteral nutrition should be initiated early. when. such that depletion exerts an inhibitory effect and nutritional supplementation has a positive effect. or gastrojejunal tubes. its nutritive value is substantially less than that of central prepa- SUMMARY The relationship between host nutrition and wound healing has been the subject of study and experimentation for centuries. on the other hand. many questions remain about the specific type of supplementation that should be used. as conventional methods.173 Serum protein markers are the best way to assess the adequacy of nutritional supplementation. Beyond the basic understanding that general nutritional support is critical for optimal wound healing. may not be accurate in critically ill patients. arginine) should be included.D. and how nutritional supplementation is needed. rations and its use is generally only indicated for less than 7 days. Although the benefits of perioperative nutritional support are apparent. In patients who are not likely to take nutrition orally. the decreased activation of gut-associated lymphoid tissue. then. serum albumin 2. such as daily weight. If intestinal function is maintained in a patient. We cannot. Supplemental vitamin C appears to have beneficial effects in burn healing. and substrates that are turned over rapidly (e. While albumin is commonly used as a preoperative marker of nutritional. elective operations should be delayed until the patient is satisfactorily supplemented. Adrian Barbul. 7 to 10 days) should be monitored weekly in patients receiving enteral or parenteral nutritional support. Number 7S • Nutrition and Wound Healing accomplished by the route that exposes the patient to the least risk. Preoperative nutritional support is generally recommended for patients with moderate (10 to 20 percent weight loss.5 g/dl) to severe malnutrition ( 20 percent weight loss. severe diarrhea) must be considered. whereas vitamin A is best reserved for those patients who have required long-term corticosteroid therapy. jejunostomy. as it is associated with the maintenance of gut mucosal barrier function.edu 53S .2 g/dl to 2. acute inflammatory bowel disease.172 Parenteral nutritional support is often used as the sole source of caloric intake in hospitalized patients.Volume 117. and lower costs of administration than parenteral nutrition. but there are some instances in which its use is best as a supplement to enteral feeding.. acute pancreatitis. 21215 abarbul@jhmi. Belvedere Avenue Baltimore. 3 to 5 days) and transferrin (half-life. nasoenteric. the risk complications and increased cost need to be considered as well.g.. Despite the many years of study and substantial knowledge base of the specific processes and factors involved. its half-life of 18 to 21 days precludes its use as an effective daily indicator of improvements in nutritional status. CLINICAL IMPLICATIONS The clinical significance of nutrition and wound healing involves individual patients with unique needs. Because even brief periods of malnutrition can have significant negative effects on wound healing. There are few concrete answers. nutritional deficiencies must be recognized early and repletion initiated as soon as possible. Within this paradigm.g. their clinical significance has yet to be proven. Nutrition profoundly influences the process of wound healing. high-output intestinal fistulas. Although peripheral parenteral nutrition may be easier to implement because it does not require central venous access. a variety of relative contraindications (e. The goal of the physician.5 g/dl)169 and who can tolerate waiting at least 7 days for an elective operation. serum albumin 3. Zinc and iron supplementation. therefore. Enteral nutritional support may be achieved via nasogastric. Md. 2401 W. There is still much to learn about the wound-specific nutritional interventions that are available to improve wound healing. recommend their general use in severely injured or postsurgical patients. M. The nutritional supplement should be as specific as possible to the patient’s perceived nutritional deficiency. Prealbumin (half-life. and if possible.
J. A.. and W. Kelso. P. In J. D. 17. III. Nutrition 11 (2 Suppl. 28. Goodson. Nutrition and Metabolism in the Surgical Patient. 2005. E. and Dudrick. 2005. St. Diabetes Res. The mechanism of delayed wound healing in the presence of hypoproteinemia. J. C. 1991. 118: 21. K. 1999. The systemic response to injury. Nutrition in wound healing. 18: 367. Crowley.. L. 1991.. G. B. Haydock. 35. 9-33. Food Nutr. Principles of Surgery. Tamai.A. 3. Nakao.. J. J.. J. In S. L.).. Pp. D. Metabolism in fever and in clinical infections. and Aulick. S.. uraemia and malnutrition. G. West. 44: 1435. 1988. Effect of severe burn on liver regeneration. I. Schwartz.. Effects of immediate postoperative enteral nutrition on body composition. Am.. T. Oates. R.N. Pathol.. T. F.. Pinchcofsky-Devin. New York: Scientific American. J. J. A. and Peterkofsky. R. H.. Akerlind. Endocrinology and Metabolism. Lin. 33. 1983. I.Plastic and Reconstructive Surgery • June Supplement 2006 REFERENCES 1. Meakins (Eds. 1986. D.. 29. 1989. 75: 135. Jr. Levenson. J.. D. 99: 74. 1994. 22. 19. Yue. R. Nutrition in wound healing. Jensen. Louis.. J. McLennan.N. K. Clin.1958.. In I. 1942.. 1984. S. Mo. Flinn. and Lindsay. S. Weringer. Prog. K.. S.. Warnold. M. J. H. W. Low Extrem. J..). J. 21. 1939. E.. 1938. Shires.. 1987. and Bistrian. (Am. 1992. S. G. Thompson.). A specific decrease in collagen synthesis in acutely fasted. S. W. E. Surg. R.. S. 12: 133. Wilmore. E. Y. 67: 3. and Frank.. E. I. Moreland. DuBois. V. 41. Ann. Jensen.. D.. Abnormalities of granulation tissue and collagen formation in experimental diabetes. 38. Br. 260: 3955.E. L. 74: 320. Effect of thermal burns on wound healing. Pirani. Crowley. S.). 36: 500.). New York: Appleton and Co. J.. B. 2001. Am. Granja-Mena. L. Goova. Parenter. J.E. Obstet. 217: 253. 2-deoxyglucose-induced 54S . Springfield: Charles C Thomas.. 3-51. 42. Tamai. B. J. S. Surg. Metabolic response to critical illness... Schroeder. Thomas..): 217. Fahey. M. A.P. Goode. 1985. and Bergan. 31. Gardner. 4. (Am. P. 25. D. Microvascular anastomoses in diabetes: An experimental study. Johnston. A. Br.. 20. The influence of a brief preoperative illness on postoperative healing. R. Surg. Forum 9: 493.. muscle function. J.) 64: 1263. 34: 435. Surg. M. J. 36. T. G. Chem. M. C. M. 34. J. Spanheimer. Casey. and A. and Page.. 1986. Arch. I. Lopez-Sarmiento. 423– 442. J. 1996.. I. Pp. Bone Joint Surg. 146: 357. 36: 509. I. N. and Glinos. I. 1996.. and Demetriou. F. T. J. G. V. A. 199: 299. 27. R. 4: 147. J. J. J. 23. W. J. Soc. 42: 50. D. K. Dermatol... 1994.A. Parenter. Impact of nutritional state on quality of life in surgical patients. Biol.. S. Nutritional status: Importance in predicting wound-healing after amputation. Barbul. Zalonga (Ed. and Schmitter.. Parenter. Goodson. Relat. Pp. Weringer. I. W. and Arquilla. A. Br. 16.. D. R. Brown. 1938. 1975.. Plast. A. G. and Lundholm. 8. Cohen. Surg. Nutrition and wound healing... Windsor.. Seifter. J. Wound collagen accumulation in obese hyperglycemic mice. and Hornqvist. Levenson. Nutrition in orthopaedic surgery.M.. D. In G. vitamin C-supplemented. P. Effect of hypoproteinemia on wound disruption. 1994.. J. Daly. J. A. 15: 400. Preston. Tarquine. E. The role of nutrition in the management of lower extremity wounds. J. S. and Allman.. Scientific American Surgery. Correlation of pressure sores and nutritional status. 24. and Waterman.. M. 9. Upjohn. Enteral Nutr. R. J. S. 39. In L. Pp. Wound healing in normal and diabetic Chinese hamsters. et al. Correlation of immune and nutritional status with wound complications in patients undergoing vascular operations. 30. guinea pigs. Knight. J. 15: 376. Daley. Kriss. Enteral Nutr. 11. 1995. and Calvano.. and Hopf. Diabet. and Arquilla. Surgery 93: 822. 40. Nutritional assessment. R. Levenson.. Barr. T. Surg. Advanced glycation endproducts: Role in pathology of diabetic complications.1957. Surg. Trauma 17: 436. and Hill. Cuthbertson. Baltimore: Williams & Wilkins. Fliegelman. Philadelphia: Saunders. G.. Braash. 248-273. J. Soc. Ahmed.N. Ravdin. L. Clinical significance of preoperative nutritional status in 215 noncancer patients. 1981. J. Bone Joint Surg.. Wounds 4: 12. The Biochemical Response to Injury. The Genuine Works of Hippocrates. In D. 1987. T. G. M. C. O.. Cheung. Kislinger. 1987. K. 1984. Effects of insulin on wound healing in diabetic mice. Ravdin. J. Boston: Little..P. Res. J. Barker (Ed. 10. Hippocrates. R. and Arquilla. M. Arch. New York: McGraw-Hill.) 66: 71. Enteral Nutr. and Hunt. S. J.) 99: 101. G. 2... 12. B. B. 1960. DeLee.P.: Mosby. W. The effect of antisera to insulin. Spencer. Albina. and Joyce. 15. Lindblad (Eds.. J.. D. (Copenh. Metabolic factors. J. Rhoads. J.E. P. 26. L. L. Dickhaut.. Am. Blockade of receptor for advanced glycation end-products restores effective wound healing in diabetic mice. 18. A. and Hill. Thomas. C.1954. H. Acta Endocrinol. and Kaminski. 3: 221. E.. 32. Smith. 1980. Cuthbertson. and wound healing. The effect of thermal burns on wound healing. L. and Panzer. Levenson. L. Rhoads. E. J.. Int. Y. J. Gynecol.. J. Gillanders. M. K. A. L. Surg. 1982. Nutrition in Critical Care. Wound Healing: Biochemical & Clinical Aspects.. D. L. H. Galloway (Eds. 1977.. Wilmore. 7. Enteral Nutr. Effects of environmental temperature and femoral fracture on wound healing in rats. H. et al.. 1982. Kant. Orthop. Yao. Geriatr. Pawlowski. E. Kay. and Frank. J. 1994. Jensen. J. J. Sci. Clin. Surg.. Parenter.. 13. and Purtill. Verdery. M. Ann. V. Use of lyophile plasma in correction of hypoproteinemia and prevention of wound disruption. Diabetologia 21: 394. Diabetes 35: 491. Kelso.. E. W.P. and Hill.. P. L. L. Swanson. D. Harken. Clin. G. A prospective study of outcome from proteinenergy malnutrition in nursing home residents.). 159: 513. and Levenson. Lowry. Systemic responses to injury and the healing wound. S. E. 37. R. Med.... J. Thompson. J. E. J. 1: 263. J.. Surg. Wound healing response in surgical patients: Recent food intake is more important than nutritional status. J. H. 1986. W. Permerth. K. Hospital-acquired pressure ulcers and risk of death. Holcroft. A. Diegelmann. J. J. Nutrition in relation to trauma and surgery. Geriatr. Pract.. Nutritional status and wound healing in lower extremity amputations. Hunt. Rettura. Li. C.. 6. A. L. Weringer. Fischer (Ed. F. and J. P. Bessey. and Chavez-Estrella. Mahr..N. 205: 250. Ann. III.. J. A. V. D.E. 5. Fischer. A. Larsson. and Steer. 1922. 14. W. Improved wound healing response in surgical patients receiving intravenous nutrition.. Patel.
R. H. Essential fatty acid deficiency in an infant receiving prolonged parenteral alimentation. 11: 419. 1974. T. C. 1990. The impairment of transport of amino acid by monosaccharides. 66.. J. H. 17: 519. Goodson. C. J. 63. M. Goodson... 77. Sci.. 1989. Barbul. Arginine physiology and its implication for wound healing. Ann. B.P. A. J.. M.. Lewis. H. E.. 79. Parenter. and Hinton. Amino acid requirements of man. J. 49. A. G. T. S. 139: 4186. B. B. Mann. Localio. A. Differential effects of three enteral dietary regimens on selected outcome variables in burn patients. 59. G. Ann. R.. Y. D. Effects of malnutrition and hyperalimentation on wound healing. 38: 328. 1977. Surg. and Barbul. 1975. O’Neill. A. 1975. C. 76: 115. M. and starvation on wound healing in normal mice. N. S.. E.. J. The importance of lipid type in the diet after burn injury.. 258: 243. Kremer. Rose. 64. Pediatr. Shi.. 1989. A. and Chen. Parenter. T. Ann. Endres. Fishel. Trocki.. H. Surgery 114: 155. A. D. Singleton. A.. Z. Lipid Res. Immunol. 1975. J. G. 15: 505. Br. Prickett. K. Number 7S • Nutrition and Wound Healing hyperglycemia. W. Efron. Pecoraro. A. J.. J. 67.. Alexander. R. Am. J. 56: 127. 1987. J. 76. and Moffatt. H. A. Acad. Most. Surg. 2004. P. N. D. N. Barbul. D. M. D. 1978. Physiol. et al. Jenkins. Intern. Effects of dietary enrichment with eicosapentaenoic acid upon autoimmune nephritis in female NZB X NZW/F1 mice. 14: 225. Simopoulos. Invest. 2002. Robin. Proc. and Walsh.. 70.. A. Detrimental effects of an omega-3 fatty acid-enriched diet on wound healing. and DenBesten. 60... J. Nordenstrom. J.. A. 1947. M. J. J. 50. Williams. Sperling.. Ascorbic acid metabolism in diabetes mellitus. 48. J. 53.. D. V. Connor. and Austen. Arginine stimulates wound healing and immune function in elderly human beings. 46. Eckart. Ann. and Fromm.. R. Caldwell. W. R. 1): E459. 80. Wene. G. J. M. Cuellar. 72. 51. The effects of N-3 polyunsaturated fatty acids on the generation of platelet-activating factor-acether by human monocytes. Arginine metabolism in wounds. Wasserkrug. The development of essential fatty acid deficiency in healthy men fed fat-free diets intravenously and orally... Riella. and Hung. J. 2: 179. M. L. and Othersen. 22: 298. S. et al. de Luis. Experimental wound healing in essential fatty acid deficiency. K. Rose. Herrlinger-Garcia. J. Med. G. R. H.. I. D. Morgan. Wolfram. and Efron. S. Surg. Intern. S. 65. 236: 369. W. J. Parenter. Enteral Nutr. J. Nickerson-Troy.. J. 1983.. 81: 894. L. E. A. 1981.P... Rev.. 43. D. G. Izaola. Gynecol. 74. A. W. Surgery 108: 331... Annu. Wells. The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells.. J. and Jonsson. and Jeejeebhoy. Omega-3 fatty acids in health and disease and in growth and development.. Kelley. R. Supplemental dietary arginine enhances wound healing in normal but not inducible nitric oxide synthase knockout mice. P. E. J. and Newton. 1978. Free fatty acid mobilization and oxidation during total parenteral nutrition in trauma and infection. Douglas. and Shaw. 58. 24: 280. Barbul. J. T... Biol. P. 1987. G. J. Clin.. J. Acad. et al. et al. L. O. 78.. Seifter. U. Randomized clinical trial with an enteral arginineenhanced formula in early postsurgical head and neck cancer patients. M... 81. Studies of wound healing in experimental diabetes mellitus.. 582. H. K. 47. Ghorbani. crossover study. D.. Wasserkrug.E. Factors influencing essential fatty acid requirement in total parenteral nutrition (TPN). W.. Nutr. Saito. 1982. Development of a new miniature method for the study of wound healing in human subjects. 204: 1.. Regan. Role of essential fatty acids in cutaneous wound healing in rats. Clin. Nutr. R. Gynecol. H. A.N. and Barbul.. H. Witte. Hulsey. L.. 20: 641. Arginine supplementation is well tolerated but does not enhance mitogen-induced lymphocyte proliferation in elderly nursing home residents with pressure ulcers. 146: 33. Mann.. A. Chem. and Aller. D. 1993. Efron. Neblett. 54. Fed.. K. Baker. H. 1978. and Griminger. Diabetes 30: 407. Nutr.. S. Pediatr. Stechmiller. K. R. 58: 1505.. Essential fatty acid deficiency in human adults during total parenteral nutrition. 1972. T. 106: 497. Ann. Lewis. P. N. S. Med. 2000..E. Fed. controlled. E. 1993. 1949. T. L. III. J. Sci. J. N. W. J.. W. Ann. K. and Rudek. The incorporation of sulfur amino acids into the proteins of regenerating wound tissue. Mills. 68. Res. Obstet. 71. 45. S. 86.. 57. Res.N. Arginine: An essential amino acid for injured rats. Metabolic effects of total parenteral nutrition. Irvin. Terroba. Prog..E. J. 33: 251. Surg. Holt. B. The membrane transport of ascorbic acid. Jr. C. Arginine enhances wound healing and lymphocyte immune responses in humans. W.. P. 1983. J. Rettura.P. J. Obstet. Surg. 1948. Ann. and Scribner. Surg. R. Parenter. Surg. 22: 221. M. 55. Askanazi. 1981. Langkamp-Henken.N. H. 2: 634. J.. H. K. 1987. et al. W. C. M. E. 1990. P.. Robinson. R. 114: 1697. Proc. C. J. B. J. and Hunt. 62. Y. M.. 52. Surgery 128: 374. T. Enteral Nutr. Clin.. 1988. T. C.. S. Tantry. 198: 725.. Surg. Lee. Warden. Carpentier. 212: 705. Surg.. D. M. Surg. B. Med.. Eur. Greig. Shimazu. Biological chemistry of wound healing: I. 61. 83: 786. M.P. 26: 133. 56.. and Steinberg. Jonsson. 1955. V.. et al. A. Science 86: 298. 44. and Barbul. H.. Levenson. 2000. 1985. F. T. J.... Metabolic response to sepsis and trauma. Am. N. H. D. 1984. Jubiz.E. 73. S. K. and Barbul. Improvement of nitrogen retention by arginine and glycine supplementation and its relation to collagen synthesis in traumatized mature and aged rats. M. Caffrey. M.N.. 1982. K. 69.. 75... A. Intravenous hyperalimentation with high arginine levels improves wound healing and immune function. A. J. J.. Hanam. Enteral Nutr. J. 2003. J. Abumrad. Michalek. O. 1986. Gladden. Nutr.. B. 320: 265. 1991. Albina. III.. Chyun. Broviac. Gottschlich. and Zollner. Res. 33: 394. Effect of dl-methionine on healing of wounds in protein-depleted animals. E.. 54: 438.. W. Y. Fish-oil fatty acid supplementation in active rheumatoid arthritis: A doubleblinded. H.. Barbul. D. P. Wound Repair Regen. 254 (4 Pt. Albina. L.. Hurson.Volume 117. 1983. J. Foot Surg. and Meng. J. B.. 55S . A. B.. Kirk.. Walther. Williamson.. Surgery 84: 224. J. W. The effect of topical insulin on infected cutaneous ulcerations in diabetic and nondiabetic mice. 8: 546. Jr. Kylander. Arthritis Rheum.. Effect of a specialized amino acid mixture on human collagen deposition. T. J. Lazarou. R. Engl. 1980. The nutritive significance of the amino acids and certain related compounds. Enteral Nutr. 498: 248. and Ogle.
G. 86. 29: 228. Gross. A.. Ma. Enteral Nutr 4: 446.): 1. Noree. 121: 1270. 1994. Krebs. Rettura. Ann. Breslin.. Parenter. J. Newsholme. 1968. et al. E. A. D. U. R. Bergstrom. 1981. Eur. 15: 437. Wound Care 12 (1 Suppl. 123: 481.... Expression and function of inducible nitric oxide synthase during rat colon anastomotic healing. T. Thymic stimulatory actions of arginine. 93. L. A. 101.. Immuno-inflammatory cell dynamics during cutaneous wound healing. H.. F... 212: 835. Surg. E. and Ardawi. 206: 25. New York: Academic.. In J. 1987. Tong.. and Souba. 1987. Acad. 116: 821. Glutamine and the regulation of DNA replication and cell multiplication in fibroblasts. J. 1980. J. J. W. Jiang. Nutr. Roth. 73: 4110. Surg. Biophys. Biochem. 106. Ann. Enzymology. 1999. and Regulation. 165: 262. Jorgensen. J. and Wang. Rettura.. H. G. D. Burns 31: 342. J. G. R. Sisto. L-Arginine supplementation enhances diabetic wound healing: Involvement of the nitric oxide synthase and arginase pathways. A.. E. Z. Thom. C. F. Mini Rev. Sisto.N. Palacios (Eds. Moore. 110. The effect of supplemental enteral glutamine on plasma levels. Nutrition and Metabolism in the Surgical Patient. 36: 693. and Efron. gut function. 4): 531. M. T. Pines. Surgery 102: 300. J. M. B. 88. Tantry... R. 1974. H. Levenson. Beschorner. Involuntary weight loss and the nonhealing wound: The role of anabolic agents. Edington.. Kudsk. Growth Factors and Other Aspects of Wound Healing: Biological and Clinical Implications. L. L. K. Ronnenberg. S. and DeSanti. Surg. R. 1976. 2005. K... 100. Steulten. double-blind. C. et al. Lymphocyte participation in wound healing: Morphologic assessment using monoclonal antibodies... M..Plastic and Reconstructive Surgery • June Supplement 2006 82.A. and Andreassen. 115. trauma... Surg.. Muhlbacher. 112. Surg. S. Biochem. Appl. 1980. Tildon. Askanazi. 195 (Pt. J.. Wound healing and thymotropic effects of arginine: A pituitary mechanism of action. J. J. E. F. R. (Copenh. Intern. Fischer (Ed. Barbul. S. Metabolic disorders in severe abdominal sepsis: Glutamine deficiency in skeletal muscle. and Efron. Sun. 158: 2375. Wasserkrug. 192: 78. Invest. N. et al.. Z. Cell Physiol. J. New York: Alan R. 99.. 90. T. M. Parenter. G. Oral arginine supplementation does not affect lymphocyte proliferation during endotoxin-induced inflammation in rats. R. Trauma. 1982. B. and Barbul. R. 161–175. S. Bode.. M.. Gastrointest. Thornton. 84. D. Funovics. In A. Surg. L.P. 1988.. 113. A.. Natl.. Hartman..). Clinical benefits of an immune-enhancing diet for early postinjury enteral feeding. Tantry. Wang. J. 37: 607. P. T. G. L. G. 116. 102.. A. H. 85. L.. A. and Efron. J. J. J.. 105. 1984. Yamasaki. Liss. McClosky. 83.. and Engstrom. L. 1999. Peng. Curi.... X. and Barbul.. 103. L. Thornton. 1981. and Newsholme. K. Barbul. Clin.. S.. K. B. E.. et al. H.. A. Barbul. Glutamine metabolism in lymphocytes of the rat. Inhibition of nitric oxide synthesis in wounds: Pharmacology and effect on accumulation of collagen in wounds in mice.. and Barbul. M. Proc. 1983. and Wilmore. P. 91. Nutr. Witte.. et al. A. Fishel. 2002. A.. H.). E. Physiol.. 111. and Yong. Chem. Acta Endocrinol. Agaiby. J. A. Influence of biosynthetic human growth hormone on biomechanical properties of rat skin incisional wounds. Sci. 1980. 1988. H.. Zhou. Growth of human diploid fibroblasts in the absence of glucose utilization. X. 208: 512. Effects of recombinant human growth hormone on donor-site healing in severely burned children. G. and Barbul. J. 1988. 1983. R. Y. Hartman. Platell. and McCulloch. Clinical and protein metabolic efficacy of glutamine granules-supplemented enteral nutrition in severely burned patients.. 1993. S... 1992. M. Abcouwer. L. Caldwell. Ann. M. D. 1999. et al. High arginine levels in intravenous hyperalimentation abrogate post-traumatic immune suppression. P. Ann. U. Demling. M. 101: 967. 37: 786. Yoshimura. Barbul. P. T. S.)... Ann.. Anat. Barrow. Thornton.N. J. Glutamine metabolism in the animal body. 2004. Seifter. W. R. Schaffer. Boston: Little.. Ozand. 109. S. 96. Med. R. 87.. Benfell. R. Significance of T-lymphocytes in wound healing. Cellular and physiological effects of arginine. Hall. Ronnenberg.. Schaffer. Reynolds. 353-384. et al. E. 107. M. Young. 1991. controlled study. Surg. Nutr. Dietary arginine supplementation does not enhance lymphocyte proliferation or interleukin-2 production in young and aged rats... E.. H. Arginine stimulates lymphocyte immune response in healthy human beings. Furst.. 1: 25. Barbul. 1998.. T. Kowalewski. Daly. Hunt (Eds. Commun. L. Klingel. D. L. 1991. 95. R. J. W.. W.. A. F. Immune and metabolic effects of arginine in the surgical patient. C.. M. Ardawi. Newsholme. W. Wasserkrug. sepsis and burns. Muscle and plasma amino acids following injury: Influence of intercurrent infection. Effects of glutamine infusion on colonic anastomotic strength in the rat. Carpentier. M.. Michelsen.. 4: 823. Y.... Thornton. Pp. In J. 98. Res. Zetterberg. D. H. E. U. and Seifter. 1999. You. and Rutan. J. L. et al. A. Effect of growth hormone and an anabolic steroid on hydroxyproline in healing dermal wounds in rats. D. Nitric oxide.. Scand. A. J. M.. J. K.. Kunkel. E. and outcome in 56S . et al. H. 1998.. M. 246: 654. Wasserkrug. Levenson.. R. Barbul. G. 97.. Wang.. 1990. Acta Chir. M. B. and Prior. Glutamine as a metabolic intermediate. P. an autocrine regulator of wound fibroblast synthetic function.. 154: 623. S.E. Am. Wasserkrug.. and Cornblath. L.E.. E. Broemeling. 104. Tao.. R. Intracellular free amino acid concentration in human muscle tissue. Res. R.P. E. Gross. Glutamine: Metabolism.. 36: 620. A. Clin. 114.. Metabolism 51: 1269. Barbul.. 108: 365. 108. Challoner. Y. K. F. Meydani. J.. 92. A. A. A... 1997.. A. A role for muscle in the immune system and its importance in surgery. and Efron. Med. Surgery 90: 244. N.. J. P. Peterson. R.. Ziegler. O. and T. Reversal of impaired wound repair in iNOS-deficient mice by topical adenoviral-mediated iNOS gene transfer. J.. R. G. A. Mora and R. P. D. B. 89. N. Barbul. Surg. 3: 592. Yan. Schaffer. 117. R. and Dyson. Witte. A. J. A. 94. Efron. S. 1996. P. Role of T cell-dependent immune system in wound healing. M. Enhanced collagen accumulation following direct transfection of the inducible nitric oxide synthase gene in cutaneous wounds.. Efron. A.. McCauley. F. Clinical and metabolic efficacy of glutamine-supplemented parenteral nutrition after bone marrow transplantation: A randomized. Moore. Zielke. and Vinnars. J. J. Nutrition 4: 261.. A..) 59: 53. J. Enteral Nutr. E. Wasserkrug. S.. J.. Immunostimulatory effects of arginine in normal and injured rats. J. A. K. Herndon. L. Immunol. J.. L. H. 1980. 1998. Adv. J. Sevdalian. Torre. J. 118.. H. 212: 424. H. F. C. Res. Nutr.S. Pp. Brown. and Prior. C. Clin. Thornton.. and Efron. Barbul.. Wasserkrug.
Jetten. Streat. Flaring. and DeBiasse. Acad. double-blind.. A. 15 (4 Pt. E. Dermatol. Soc. R. Coll. C. In W. 1968. J. 129. M. 1986. The interrelationship of thyroid hormones. D.. E.. D.. Ann. F. Ann. Friis-Moller. Demetriou.. M. 119. 155. Number 7S • Nutrition and Wound Healing severe burns: A randomized. G. 2): 817. Packer. Rettura. 1982. Nutritional support in the management of critically ill patients in surgical intensive care. Forum 31: 224. H. Baxter. World J. 141. 1978. 635– 642. H. K. K. M. 120. Sci. Kambosos.) 104: 275. Am. 144.P. S. and Wan Winkle.. 156. Chim. Crit. Surg. Hallbook. Goodson. 143. Levenson. Geever. Seifter.. 200: 271. A randomized controlled trial of preoperative intravenous nutrition in patients with stomach cancer. Free Radic. Kinney and K. Med. Pp. Prasad. Proc.). Seifter. Osler. Stevens. 211: 269. Schwarze. B. Philadelphia: Saunders. 286 –363. Med. Modulation of cell growth by retinoids and their possible mechanisms of action. O. Gruber. Laenger.. J. Depletion of reduced glutathione. Surg. Vitamin A assay in burned patients. T. Rettura. 52: 583. Adv. A. J. Williams. H. 152. Nutrient Modulation of the Immune Response. Raahave. Ann. V. The effect of topical tretinoin on tissue strength and skin components in a murine incisional wound model.. 1984. R. 138.. 139. A. Experimental human scurvy. Am. L. 167: 324. Seifter. Glutamine attenuates post-traumatic glutathione depletion in human muscle.. D. New Jersey: Chirurgecom Inc. V. N. Stratford. Smale. Bjerre-Jepsen. B. Surg. G. 1981. E. R. Aslam.P. In T. 114: 791.... Padawer. (Lond. 1980. and Wong. Supplemental vitamin A prevents the acute radiation-induced defect in wound healing.N. A. Rivers. Weinzweig.1994.. D. and Rosato. Heatley. Hristopoulos. G. and Barbul. T. N. L. 1979. Zeppa (Eds. and Dill. A. E. K. A. K. and R. Acad. Demling. D. 1995. Moody. Surgery 129: 467. 131. Clin. 1975. Br... Surgery 98: 931. A. B.. 142. Seifter. 7: 160. et al. 1940. J.. Fed. 63: 667. J. H.. Acad. A. A. J. L. Surg. Pp. Waldorf. 1984. 132. Kinney. 1993. K. M. G. M. F. O. D. Soc. Safety of high-level vitamin C ingestion.. and Levenson. G. S. Crandon. Moresi. New York: Appleton-Century-Crofts. 10: 77.. Res. 133. 223: 353. 1997. 134. R. P. and Hunt. The infective dose of aerobic and anaerobic bacteria in postoperative wound sepsis. Care Clin. 1892. 124. The effect of the local and oral administration of cod liver oil on the rate of wound healing in vitamin A-deficient and normal rats. Exp. E... 2005. S. 1997. W. Ann. Enteral Nutr. 171: 279.). 140. Levenson. Cunningham-Rundles (Ed. 153. 1970. Annu. Rai.. 122. M. Supplemental vitamin A prevents the tumor-induced defect in wound healing. Zinc in growth and development and spectrum of human zinc deficiency. H. controlled clinical trial. and Lewis. Green.. 157. 150. 154. and Hammarqvist. Fundamentals of Wound Management. C. E. J. 123. J. 200: 494. Babyatsky. Impaired wound healing due to cyclophosphamide alleviated by supplemental vitamin A. Wound healing and nutrition. S.. 121. Surg. G. and Seifter. Ascorbic acid.. J. J. Levenson. E. 147. H. Interactions among antioxidants in health and disease: Vitamin E and its redox cycle. 1980. 498: 445. 57S . Prasad. Endocrinol.. J. A.. R. 11: 194.. S. and Walton. 3): 65. Nutr. Philadelphia: Saunders.. A. 393– 410. H. 16: 899. vitamin E and antioxidant defence enzymes in a healing cutaneous wound. B.. 126.. 121: 924. S. 1972. Lund. 2003. Lateef. J. Topical pretreatment of diabetic rats with all-trans retinoic acid improves healing of subsequently induced abrasion wounds.N. M. and Heggers. Ehrlich. Pp. 118: 87. 137. Impaired wound healing in streptozotocin diabetes: Prevention by supplemental vitamin A. E. Rasik. stimulates wound healing in genetically diabetic mice. 145. Shaw. and Lanner.. R. Surg 167: 12S. Stratford. 1990. Engl. Muehlberger. J. J. D. Drucker. S. and Hill. T. Ballinger. S. J. I. R. Dudrick. 125.. Y.. Wernerman.. 26: 93... J. Christou. and Fewkes. C. Wound healing in sepsis and trauma. C. Clin. Proc. Orgill. 1986. H. P.. U. F. 223–235. M. Robson. Levenson. W. 151.. In J. Parenter. 149. Surg. Torre. E. 2001. New York: Marcel Dekker.. 1985.. M.Volume 117. A. M. 1990.. J. Clin. H. M. J. M. Micronutrients in critical illness..): 186S. Shock 8: 391. Surg.. Care Med. Hunt. Ramsden. J. M. Current concepts and approaches to wound healing. riboflavin and nicotinic acid in relation to acute burns in man. N. Ann. Pp. Dermatol. and Demling. 161. J. and Varani. 1987. Reduction of operative morbidity and mortality by combined preoperative and postoperative nutritional support. Perioperative nutritional support: Immunologic defects. J. Levenson. J. 1977. Rev. Arch. Brandaleone. The biochemical functions of ascorbic acid. G. L. Seifter. S. Rettura. S. Vitamin A and wound healing. and Levenson... Surg. G.. Am. Levenson. Am. 194: 42. 192: 604. J. Rettura. Deodato. Wound healing.. Demetriou... Surg. Nimni. 2003. Res. a hydrophilic vitamin E-like antioxidant. T. Shukla. 135. E. S. Thornton... New York: Appleton and Co. 159.. and Seifter. E. J. 1976. Youssef. W.. Crit. C. Ann. J. Energy requirements of the surgical patient. 1975. Med. M. 127. et al. M. The reclosure of postoperative incisional abscesses based on bacterial quantification of the wound. K. 136. R. Mullen. Jeejeebhoy (Eds. 55: 583.).. Nutr. In S. Prince. 2005. Surg. Matthews. Ann. Nutrition. Effects of cortisone and vitamin A on wound healing.. Vitamin A and retinoic acid: Induced fibroblast differentiation in vitro. Rooyackers. H. 128.. J. Serum-zinc and healing of venous leg ulcers. 1988. 1977. 6: 365. J. S. Fundamentals of Wound Management in Surgery. and Papper. A. Mechanism of inhibition of collagen crosslinking by penicillamine. Diabetes 54: 855. P.. G. A. et al. vitamin A and their binding proteins following acute stress. 1967. C.E. R. Parenter. Buzby. B. Penicillamine and wound healing in young guinea pigs. 158. Acta. Enteral Nutr. and Seifter. and Courtemanche. Surg.. 70 (Suppl. Trauma 15: 419. H. Lancet 2: 780. Schaffer. 1988. Surg. S. and Patnaik. and Levenson. J.... S. 130.) 8: 109. J.. Ann. Gruber. M. Collins. (Oxf. Englard.. A. 1987. 7: 377. Changes in the serum concentrations of thyroxine-binding prealbumin and retinol-binding protein following burn injury. Acquired zinc deficiency and immune dysfunction in sickle cell anemia. F.. 146. Hunt and J. Dermatol. 1941. thiamine. Sci. Immunologic reactions in chronic wounds. W. Surg. Lund. I..E. 1992. Burr. et al. 27: 241.. 160. M. 11: 651. and Hunt. S.... Biol. 14 (5 Suppl. Arch. The Principles and Practice of Medicine. 1947. W. Rettura. ascorbic acid. V. Manual of Surgical Nutrition. N. Nutrition and Metabolism in Patient Care. G. Thiis-Knudsen. 1988. 1995. F.. F. 148.. Abatan.. 43: 134. B. Dunphy (Eds.). T.. and Rasmussen. E. E. D. Raxofelast. Proc. Galeano. 1986..
K. Pp. 2000. Dervenis. A. B. J. Pp. M. E. T.. Enteral nutrition is superior to parenteral nutrition in severe acute pancreatitis: Results of a randomized prospective trial. F. 165.. Thornton. and remote organ responses to intraperitoneal bacterial challenge. et al. M. Nutrition. Teh. and Barbul.Plastic and Reconstructive Surgery • June Supplement 2006 162. N. Nutr. and Prielipp. R. R. 1996. Surg. R. Kehagias. Zaloga.). K. Nutritional support in the critically ill. 1977... M. J. The route of nutrition support affects the early phase of wound healing.. J. L. Trauma 23: 605. Ann. Contrasting effects of identical nutrients given parenterally or enterally after 70% hepatectomy.: Mosby. 10: 415. coli peritonitis in normal rats. St. R. 84: 1665. Fluids and Electrolytes in the Surgical Patient. 172. Surg. 2001. H.. Saito.. Total parenteral nutrition increases mortality after hemorrhage. 1994. Perioperative total parenteral nutrition in patients with gastrointestinal cancer. R. G. Pestana. 223: 84.. J. J. 1344 –1348. F. A. Am.. Annu. 169. 163. F. B. Res. 2003. J. John. E. 127–149. E. 23: 31. J. Carpenter. Black. Kalfarentzos. Keating... 164.. and Ashley. Route of nutritional supply influences local. Surg. 173. B.N. Enteral Nutr. 22: 276. Res. Care Med. Holter. L. 30: 497. 19: 54. 1998. 167: 135. C. Howard. In J... systemic. and Gogos.. Fukushima. Hepatobiliary Pancreat. 58S .. Lin.E.. C. 1991. J. D. Nutrition in the perioperative patient. Bacterial translocation and its prevention in acute pancreatitis. Delany. and Stremple. Kiyama. Surg. Parenter. and Fischer. T... Enteral and parenteral feeding influences mortality after hemoglobin-E. C.. Current Surgical Therapy. Stone. J. 1983. Kudsk. 2003. and Hatzitheoklitos. 171. T. 168. 1981. F. J.. Kokkinis. Knowles. Witte. A. J. 166. Rev. P. M. Julian. K.. G. Surg. 23: 263. Surg. Philadelphia: Lippincott Williams & Wilkins. Smailis. G. Mo. Mead. 1997. K. et al.. Louis. 170.. J. Br.P. A. 167. C. Crit. J. J. Thompson. H. and Sheldon. W. The effects of perioperative hyperalimentation on complications in patients with carcinoma and weight loss. Cameron (Ed..
This action might not be possible to undo. Are you sure you want to continue?
We've moved you to where you read on your other device.
Get the full title to continue reading from where you left off, or restart the preview.