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Abstracts

Abstracts

Amino acids

Amino acids (1)

Plasma fluxes of arginine, citrulline, and leucine, and the rate of conversion of labeled citrulline to arginine (Qcit-->arg) were determined in 9 severely burned patients (mean: 56% body surface burn area, mean 10 d postinjury) while they received total parenteral nutrition (TPN) including an L-amino acid mixture that supplied a generous amount of nitrogen (mean: 0.39 +/- 0.02 g.kg-1.d-1).

Leucine kinetics (flux and disappearance into protein synthesis) confirmed the anticipated higher protein turnover in these burn patients compared with healthy control subjects.

The plasma arginine fluxes were correspondingly higher in burn patients than in healthy control subjects.

However, the citrulline flux and rate of conversion of citrulline to arginine were not higher than values obtained in our laboratories in healthy adult subjects

The higher rates of arginine loss from the body after burn injury would need to be balanced by an appropriate exogenous intake of preformed arginine to maintain protein homeostasis and promote recovery from this catabolic condition.

Yu YM et al., Relations among arginine, citrulline, ornithine, and leucine kinetics in adult burn patients. Am J Clin Nutr, 1995 Nov, 62:5, 960-8.

Amino acids (2)

Measured plasma arginine and leucine kinetics and rates of urea production (appearance) in 12 severely burned patients (mean body surface burn area, 48%) during a basal state (low-dose intravenous glucose) and while receiving routine, total parenteral nutrition ([TPN] fed state) including an L-amino acid mixture, supplying a generous level of nitrogen (mean, 0.36 g N.kg-1.d-1).

Yu YM et al., Plasma arginine and leucine kinetics and urea production rates in burn patients. Metabolism, 1995 May, 44:5, 659-66.

Candida infection

Use of an oral prophylactic dose of nystatin in a swish and swallow technique 3 to 4 times daily from the time of hospital admission (mycostatin, Squibb, Princeton, NJ; 5 to 10 ml of 100,000 U/ml). Before excision local wounds were treated with 1,000 U/g of nystatin ointment mixed with silver sulfadiazine to a 1:1 ratio and dressings were changed every 8 hours. After excision, nystatin of 100,000 U/g mixed with a combination of polymyxin B (10,000 U/g) and bacitracin (500 U/g) to a 1:1 ratio, was applied over the autografted and homografted areas. The treated patients were compared to controls who received no candida prophylaxis.

The incidence of candida colonization, infection and sepsis was significantly reduced as compared to the control group.

The incidence of candida wound infection has been significantly reduced and systemic candidiasis has been eradicated by this prophylactic treatment, therefore eliminating the need for toxic and systemic antifungal agents.

Major side effects in 16% of the patients include headache, gastrointestinal upset and skin rashes.

"Candida Infection With and Without Nystatin Prophylaxis. An Eleven-Year Experience With Patients With Burn Injury", Desai, Manu H., MD, et al, Archives of Surgery, February 1992;127:159-162.

Ceruloplasmin levels

Copper (Cu) status is often judged by the plasma level of its chief transport protein, ceruloplasmin (Cp). Only copper deficiency and heredity are known to decrease circulating Cp. Cp is an acute-phase responsive protein in trauma and it is also induced by Cu supplementation. Despite this, plasma concentrations of Cp remain low during the acute recovery from major burn injury. The high provision of vitamin C typically used in burn patients may influence these observations when an indirect oxidase activity assay is used.

Employed a radial immunodiffusion (RID) assay specific for the Cp protein as well as an indirect oxidase assay for Cp in a series of 11 burned children who were supplemented with both Cu and vitamin C, either enterally or parenterally.

Findings confirmed that low Cp is a characteristic of the acute recovery from major burns.

Copper supplementation by either the enteral or parenteral routes is only marginally successful in restoring Cp toward normal levels.

Cunningham JJ et al., Low ceruloplasmin levels during recovery from major burn injury: influence of open wound size and copper supplementation [see comments]. Nutrition, 1996 Feb, 12:2, 83-8.

Clinical nutrition

Multiple guidelines for nutrition services in the postburn period exist. Given that nutrition intervention after burn injury affects outcome, it is appropriate to routinely consider methods for improving current practices.

Effective nutrition therapies for the thermally injured individual are outlined.

Support for benchmarking these protocols is presented, and the completion of outcomes research in nutrition services for patients with burn injuries is encouraged.

Mayes T et al., Clinical nutrition protocols for continuous quality improvements in the outcomes of patients with burns. J Burn Care Rehabil, 1997 Jul-Aug, 18:4, 365-8; discussion 364.

Dietary fats

Lipids are an integral part of the routine diet of patients and the general public. The physiologic properties of various dietary lipids are reviewed, beginning with those most commonly consumed-the long-chain triglycerides (LCTs) and extending to those with special purposes: the short- and medium-chain triglycerides.

The nutritional dietary management of patients typically includes physical mixtures of lipids. Recently, structured triglycerides (STs), which combine advantages from conventional fats with those of special purposes, have become available. STs are currently developed by interesterifying a mixture of conventional fats and oils, usually with medium-chain triglycerides, to achieve a specific fatty acid profile. This results in a triglyceride containing combinations of short-, medium-, and long-chain fatty acids on a single glycerol backbone. They have unique chemical, physical, or physiologic properties that are not observed by simply blending mixtures of the starting fats and oils.

A number of STs are under intense laboratory and clinical investigation in models of cancer, burns, and immune dysfunction.

Much interest in the fatty acids resides in the sn-2 position on the glycerol molecule. This is because the fatty acid in the sn-2 position of triglycerides is preferentially absorbed as the 2-monoglyceride and serves as the template for reesterification by intestinal cells to re-form triglycerides. The sn-2 fatty acids are also preferentially preserved as components of chylomicrons and very-low-density lipoprotein particles for ultimate incorporation in tissue membranes. Technology is evolving to create STs with a selected fatty acid in this sn-2 position. For instance, incorporating linoleic, arachidonic, or eicosapentaenoic acid at the sn-2 position is being evaluated for the specific objective of modulating serum cholesterol concentrations and essential fatty acid absorption (a review of this work is included).

Bell SJ et al., The new dietary fats in health and disease. J Am Diet Assoc, 1997 Mar, 97:3, 280-6; quiz 287-8.

Enteral nutrition

Enteral nutrition (1)

The method of early enteral nutrition (EEN) in extensively burned patients was started at the Bratislava Burns Department in January 1992. EEN was instituted in all patients with burns exceeding 20% of the BSA who were admitted to the department not later than 6 hours post burn.

The nutrition itself was started with administration of milk, and later on, if good tolerance was observed, the milk was replaced by standard tube feeding formulas. The feeding was adjusted to the actual needs of the individual patients according to nutritional balance calculations and regular control of the patients' weights. During a period of 18 months 20 patients met the criteria for EEN. Twelve of them survived and 8 died due to complications of extensive burns.

The overall tolerance of EEN was very good in both the survivors and nonsurvivors groups of patients. EEN proved to be safe and effective in maintaining nutritional balance of the patients and eliminating particularly the occurrence of Curling's ulcers.

Koller J & Kvalteni K: Early enteral nutrition in severe burns. Acta Chir Plast, 1994, 36:2, 57-60.

Enteral nutrition (2)

"Immune-enhancing" diets (IEDs) are aimed at improving outcomes in patients suffering trauma and infection.

Burned patients (# 50) were randomized to receive either Impact (Sandoz Nutrition, Minneapolis, Minn), an IED enhanced with omega-3 fatty acids, arginine, and RNA, or Replete (Clintec, Deerfield, Ill), our standard high-protein diet.

There were no differences between groups in mortality, length of hospitalization, hospital charges, days of ventilator support, or incidence of complications. Patients with inhalation injuries required more ventilatory support, and had longer lengths of hospitalization and higher costs.

Administration of an IED has no clear advantages over the use of less expensive high-protein enteral nutrition in burn patients.

Saffle JR et al., Randomized trial of immune-enhancing enteral nutrition in burn patients. J Trauma, 1997 May, 42:5, 793-800; discussion 800-2.

Fish oil

Severely ill patients in need of enteral nutrition support must obtain all essential nutrients in at least the amounts recommended for daily intake (RDA) by healthy populations. Until recently essential fatty acids have been entirely omitted from enteral solutions or included only in the form of n-6 PUFAs which are structurally important for cell membranes and play a significant role as precursors (esp. arachidonic acid, AA) of eicosanoids (prostaglandins, thromboxanes, leukotrienes).

However, in the absence of n-3 PUFAs, these eicosanoids may produce exaggerated effects in acute stress responses causing immunosuppression, platelet aggregation and excessive or chronic inflammation. n-3 PUFAs act as precursors of complementary eicosanoids which counteract the exaggerated responses of AA-derived eicosanoids.

Therefore, n-3 PUFAs should be part of any optimally balanced diet and must be included also in enteral solutions.

Since the transformation of the n-3 parent fatty acid, alpha-linolenic acid, to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) is slow and unreliable, it is necessary to provide them as preformed nutrients as they occur in fish oil.

The British Nutrition Foundation recommends a daily intake of EPA and DHA in amounts corresponding to the intake of 3 to 4 g standardized fish oil. The requirements can also be covered by the weekly consumption of 2 to 3 portions of fatty fish.

Preliminary clinical trials have shown certain beneficial effects of fish oil intakes in diseases associated with inflammatory reactions such as rheumatoid arthritis or inflammatory bowel disease, in conditions with impaired immune competence such as burns, post-operative situations and cyclosporine treatment after renal transplants, and in conditions with enhanced platelet aggregation such as after coronary angioplasty.

While these findings must be verified in strictly controlled trials, the intake of fish oil n-3 PUFAs in a balanced ratio to n-6 PUFAs can be recommended for all patients including those in need of enteral nutrition support.

Gerster H: The use of n-3 PUFAs (fish oil) in enteral nutrition. Int J Vitam Nutr Res, 1995, 65:1, 3-20.

Glutamine

Immune suppression after a major injury such as a burn may lead to sepsis and increased mortality. Found (in culture media) a significant decrease in glutamine concentration resulted in an equally significant decrease in the rate of proliferation of human lymphocytes and of phagocytosis by mouse macrophages.

In burn patients blood glutamine levels were decreased 58% compared to controls and in some cases 80%.

Reduction in glutamine may contribute to the impaired immune function after a major burn injury or other immunosuppressive conditions such as severe trauma, major surgery or sepsis. Glutamine may benefit burn patients.

"Does Glutamine Contribute to Immunosuppression After Major Burns?", Parry-Billings, Mark et al, The Lancet, September 1, 1990;336:523-525.

Hypoalbumenemia

Physiologic hypoalbuminemia, defined as a plasma albumin (pl-ALB) of 1.0 to 2.5 g/dL, is a component of the injury response. A consensus on the need for albumin supplementation in this setting is lacking.

Profound physiologic hypoalbuminemia (pl-ALB of 1.0-2.5 g/dL) does not have adverse effects on pulmonary or gut function, wound healing, or outcome in severely burned children, perhaps because of a compensatory increase in acute-phase proteins reflected in plasma globulin.

Sheridan RL et al., Physiologic hypoalbuminemia is well tolerated by severely burned children. J Trauma, 1997 Sep, 43:3, 448-52.

Length of care

The optimal amount and type of fat in the nutrition support of burned patients have not been determined. The aim of this study was to test low-fat nutritional solutions, with or without fish oil, on protein metabolism, morbidity, and length of care in severely burned adults.

Compared with controls, patients on low-fat support had fewer cases of pneumonia: 3/24 vs 7/13, better respiratory and nutrition status, and shorter time to healing: 1.2 vs 1.8 days/% burned area.

Low-fat nutrition support decreases infectious morbidity and shortens length of stay in burn patients. Fish oil does not seem to add clinical benefit to low-fat solutions. In addition, nutrition intervention modulates cortisol-binding globulin and the concentration of free circulating cortisol after a severe stress.

Garrel DR et al., Improved clinical status and length of care with low-fat nutrition support in burn patients. JPEN J Parenter Enteral Nutr, 1995 Nov-Dec, 19:6, 482-91.

Nitric oxide

Human burn injury is associated with an inflammatory response and related hyperdynamic cardiovascular profile. Increased production of nitric oxide (NO), a potent endogenous vasodilator, has been reported in patients with inflammatory states, including sepsis, but not after trauma other than burns. Studied plasma levels of the stable byproducts of NO, nitrite (NO2-) and nitrate (NO3-), in burn patients.

For each comparison between the groups, NO2-/NO3- plasma levels were higher in those patients with burns than in the control group.

In a subgroup of five burned patients who became septic during the study period, NO2-/NO3- plasma levels were slightly higher than in the non-infected patients (177 +/- 131 vs. 83 +/- 48 micromoles/L, NS).

Human burn injury is associated with an increase in NO production. In this small-size study, NO production was not proportional to burn area, and seemed to be further enhanced in septic patients.

Preiser JC et al., Nitric oxide production is increased in patients after burn injury. J Trauma, 1996 Mar, 40:3, 368-71.

Nutritional items

Contents:
Nutrition and Burn Patients (2)
Nutritional Immunomodulation
Nutritional Support (1)
Nutritional support (2)
Nutritional support (3)
Nutrition - Vitamin A

Nutrition and Burn Patients [1]

According to this study, burn patients experience improved healing and fewer infections when given supplements of glutamine, arginine, and the omega-3 fatty acids. Glutamine is very important in muscle metabolism and is the preferred energy source for cells of the intestinal mucosa. Arginine is a nonessential amino acid which is a precursor to nitric oxide, and a secretagogue for insulin, glucagon, prolactin, catecholamines, corticosterone, somatostatin and growth hormone. Omega-3 fatty acids alter phospholipid composition of cell membranes and the quantity of eicosanoids synthesized. In addition to these three agents, burn patients benefit from a diet high in protein, low in fat, linoleic-acid restricted and enriched with histidine, cysteine, vitamin A, zinc, and vitamin C.

De-Souza, Daurea Abadia and Greene, Lewis Joel: Pharmacological Nutrition After Burn Injury, Journal of Nutrition, 1998;128:797-803.

Nutrition and Burn Patients [2]

Energy expenditure of burn patients increases depending on burn size reaching a maximum of 2-2.25 times the normal resting metabolic rate in patients having over 50% total burn area. Protein requirements are still debatable for burn patients but they may lose over 200 gm/d of protein during the first weeks after injury. Between 1.4-2.5 gm/kg/d have been recommended.

In a recent survey of burn care dieticians and physicians, it was found that 85% routinely prescribed a multivitamin preparation while 75% prescribed supplemental vitamin C, 14% folic acid, 10% vitamin A, 9% vitamin B1 and 24% zinc. Moderate dosages of vitamin C should be used (less than 1 gm/d). Zinc should be given at 220 mg of zinc sulfate, daily or on alternate days.

A balanced hospital diet of 1500 cal/d will provide the recommended daily allowances of most micronutrients. For those on parenteral nutrition iron 10-15 mg/wk, and vitamin K 10 mg/wk, zinc 2-5 mg/d and vitamin C 250-1000 mg/d is recommended. Special consideration is given to those with renal and hepatic disorders. The understanding of micronutrient supplementation for stress patients is still in its infancy.

"Nutrition Considerations For The Burned Patient", Pasulka, Patrick S., MD and Wachtel, Thomas L., MD, Surgical Clinics of North America/Burns, February 1987;67(1):109-131.

Nutritional Immunomodulation

In a guinea pig model enteral feeding immediately after a burn injury decreases the metabolic response by preventing the loss of the GI barrier with subsequent entrance of intestinal endotoxins and bacteria. IV or crystalline amino acid therapy instead of intact protein does not prevent intestinal atrophy or a hypermetabolic response. Optimal burn diets should include 20% of energy from whey protein, 2% from arginine, .5% from cysteine and .5% from histidine. Fats should be 15% of the nonprotein calories with 50% from fish oil (omega-3 fatty acids) and 50% from safflower (linoleic acid). In a prospective clinical study in humans the administration of this new diet was found to reduce infection, shorten hospital stay and reduce death when compared with other standard diets. The Shriners Burn diet was used and developed at the Shriners Burn Institute in Cincinnati, Ohio.

"Nutritional Immunomodulation in Burn Patients", Alexander, J. Wesley, MD, Sc.D and Gottschlich, Michelle M., Ph.D., RD, Critical Care Medicine, February 1990;18(2):S149-S153.

Nutritional Support (1)

Metabolic rate is markedly increased in burn patients. This metabolic demand includes increased rates of glucose production and utilization, along with protein catabolism and anabolism; and a decreased rate of lipid metabolism. These alterations can affect other physiologic parameters such as immune function.

With regards to carbohydrate metabolism, burn patients have elevated glucose and insulin levels. Burn patients need large quantities of calories and protein to achieve positive nitrogen balance. Burn patients have been shown to have elevated blood and tissue concentrations of thromboxane and prostaglandin E. These metabolites may be immunosuppressive and cause vasoconstriction. Since burn patients are immunosuppressed and have decreased perfusion of the burn wound, prevention of the synthesis of these metabolites by dietary manipulation may be of benefit.

Replacing the omega-6 fatty acids (which can be from the standard vegetable oils and animal oils) with omega-3 fatty acids (fish oil) may help avoid post burn immunosuppression.

Dietary composition should be 20% of the calories as protein, 50% as carbohydrate and the remainder as fat. Arginine supplementation in animal models is shown to improve lymphocyte blastogenesis. It is desirable to increase the amount of arginine in the diet of burn patients. Glutamine is a fuel of choice for gastrointestinal mucosa. Branch chain amino acids may have some benefit in burn patients. The documentation at present is still not overwhelming. Vitamin supplementation is probably indicated in burn patients.

The exact requirement of burn patients has not been determined. It seems appropriate to add a multivitamin or its equivalent to the diet of burn patients. They may also benefit from the addition of 500 mgs of ascorbic acid and 10,000 I.U. of vitamin A (and half these doses in children).

"Nutritional Support of the Burned Patient", Waymack, J. Paul, MD and Herndon, David N., MD, World Journal of Surgery, 1992;16:80-86.

Nutrition support (2)

Sepsis, shock, multiple trauma, and burns are often associated with altered metabolism characterized by severe catabolism, wasting of the lean body mass, immune dysfunction, and compromised wound healing.

Nutrition support is one of the mainstays in the management of these critically ill patients and is aimed at minimizing these complications.

Review article.

Barton RG: Nutrition support in critical illness [see comments]. Nutr Clin Pract, 1994 Aug, 9:4, 127-39.

Nutritional support (3)

Nutritional support of the burn patient is essential to optimize host immune defenses and to promote prompt wound healing. The interdependent relationship between metabolism, nutrition, and infection is discussed, followed by an extensive description of the various means of determining the appropriate type, form, and amount of nutritional support to provide to patients of various ages and with differing burn sizes. A concise discussion of the role of various growth factors and micronutrients completes this article.

Deitch EA: Nutritional support of the burn patient. Crit Care Clin, 1995 Jul, 11:3, 735-50.

Nutrition - Vitamin A

In a guinea pig model (30% burned body surface area) vitamin A was needed following burn injury somewhere between one and 10 times the RDA (10 - 100,000 I.U). Though difficult to extrapolate to humans about 3 liters per day of 20,000 I.U. per liter which would provide a maximal subtoxic therapeutic dose.

"Effect of Vitamin A and Enteral Formulae For Burned Guinea-Pigs", Kuroiwa, K., et al, Burns, 1990;16(4):265-272.


Scars

The state of excessive fibroblastic proliferation for wound healing results in hypertrophic and keloid scars. It has been well established that some of the trace elements (such as zinc) are essential in wound healing, and there are appreciable changes in trace elements in various disease states.

The levels of zinc (Zn), copper (Cu), manganese (Mn), and selenium (Se) in serum, normal skin and scar of 40 keloid and hypertrophic scar patients were assessed. There was a significant increase of manganese (Mn) level in skin of burn, trauma, and surgical incision patients compared to controls.

Furthermore, the zinc, copper, and selenium contents of the skin in incision patients were decreased significantly when compared to other groups.

No significant changes occurred regarding serum levels of zinc, copper, manganese, and selenium in the different groups.

No relationships between the hypertrophic and keloid scar to trace elements were found; however, because of the limited numbers of patients, a definite conclusion could not be drawn.

Bang RL & Dashti H: Keloid and hypertrophic scars: trace element alteration. Nutrition, 1995 Sep-Oct, 11:5 Suppl, 527-31.

Severe burns

Postburn hypermetabolism can lead rapidly to deleterious consequences if adequate nutrition support is not provided. Several predictive formulas are used currently for estimation of the nutrition needs of both adult and pediatric patients with burn injuries. Adequacy of enteral or parenteral or both deliveries of nutrients must be interpreted in light of injury-induced effects on nutrition parameters.

Rodriguez DJ: Nutrition in patients with severe burns: state of the art. J Burn Care Rehabil, 1996 Jan-Feb, 17:1, 62-70.

Trace elements

Because Cu, Se, and Zn are involved in immune and antioxidative defense mechanisms and tissue repair, deficiencies might aggravate complications classically observed with burns. After measuring massive cutaneous trace element losses in 10 burn patients, this study determined whether large intravenous intakes of Cu, Zn, and Se can modify serum trace element levels and recovery after major burns.

The patients were divided into two groups of 5 and received either standard (group 1, control) or greatly increased (group 2, treatment: 4.5 mg Cu, 190 micrograms Se, and 40 mg Zn/day) trace element intakes. Energy and protein intake and wound treatment were similar in both groups.

The treatment group was characterized by improved Cu, Se, and Zn status (increase in serum levels and various protein indicators), a much larger leukocyte increase between D4 and D14 (mainly neutrophils), and shorter hospital stay (45 days) compared with the untreated group (57 days). Grafting requirements were more extensive in group 1.

Although severity of injury and wound treatment were similar in the groups, the duration of hospitalization was lower in the treated group. Further studies are required to determine whether this is related to trace element supplementation.

Berger MM et al., Influence of large intakes of trace elements on recovery after major burns. Nutrition, 1994 Jul-Aug, 10:4, 327-34; discussion 352.

Vitamin E & Wound Healing

Vitamin E and Wound Healing

In a double-blind, randomized trial assessing topical vitamin E or a steroid on scar formation in burn patients, no beneficial effect with vitamin E was seen. Therefore, vitamin E's benefit on surgical wound healing has not been demonstrated. The author states that for most people, the use of vitamin E to improve the results of wound healing would be considered supplemental and not essential from a nutritional perspective. The author notes that vitamin E's role in wound healing is very complex. It is noted that systemic vitamin E will inhibit the inflammatory response, inhibit collagen synthesis, and thereby decrease wound tensile strength.

Robert J., M.D.: Vitamin E and Wound Healing, Havlik, Plastic and Reconstructive Surgery, December, 1997;1901-1902.

Antioxidants and Burn Injuries

Antioxidants and Burn Injuries

Oral supplementation with certain antioxidants may help to recover immune function after suppression due to burn injury, according to this study. After incidence of burn injury, rats were given supplements of allopurinol, desferrioxamine, PEG-catalase, N-acetylcysteine, or vitamin C for 7 days. Researchers then measured the contact hypersensitivity response and host-versus-graft-reaction in vivo. Allopurinol and PEG-catalase effected the most improvement, while desferrioxamine, N-acetylcysteine, and vitamin C effected slight improvement.

Cetinkale O, Senel O, Bulan R: The effect of antioxidant therapy on cell-mediated immunity following burn injury in an animal model, Burns 1999 Mar;25(2):113-8

Vitamin C and Burn Injuries

Vitamin C and Burn Injuries

Supplementation with vitamin C may reduce swelling that often follows major burn injuries, according to this animal study. Rats with full thickness burn injuries covering 10% of the body, or a sham burn, were given either vitamin C or saline either 5 min before the burn or 30 min after the burn. Burned rats given the vitamin C exhibited a more stable interstitial fluid hydrostatic pressure and less swelling than rats given saline.

Tanaka H, et al: High dose vitamin C counteracts the negative interstitial fluid hydrostatic pressure and early edema generation in thermally injured rats., Burns 1999 Nov;25(7):569-74

Vitamins and Sunburn

Vitamins and Sunburn

Supplementing with vitamins C and E may reduce sunburn reactivity and may therefore protect against UV-induced skin damage, according to this double-blind, placebo-controlled study. Researchers gave 10 subjects either placebo or combination of vitamin C (2 g) and vitamin E (1000 IU) for 8 days. UV tolerance was then measured as the threshold UV dose for causing sunburn, and by measuring the cutaneous blood flow of irradiated versus non-irradiated skin. The results indicated that vitamin C and E combination significantly raised the threshold UV dose for sunburn and decreased the cutaneous blood flow, compared to placebo. Vitamins C and E therefore reduce the sunburn reaction.


Eberlein-Konig B, Placzek M, Przybilla B: Protective effect against sunburn of combined systemic ascorbic acid (vitamin C) and d-alpha-tocopherol (vitamin E), J Am Acad Dermatol 1998 Jan;38(1):45-8