Does vitamin C supplementation promote pressure ulcer healing?

EVIDENCE-BASED REPORT CARD FROM THE CENTER FOR CLINICAL INVESTIGATION SECTION EDITOR: Mikel Gray, PhD, CUNP, CCCN, FAAN

Does Vitamin C Supplementation Promote Pressure Ulcer Healing? Mikel Gray, PhD, CUNP, CCCN, FAAN, and JoAnne D. Whitney, PhD, RN, CWCN

INTRODUCTION

Tissue Repair and Regeneration

This Evidence-Based Report Card explores whether vitamin C supplementation promotes pressure ulcer healing and under what clinical circumstances it may be indicated. Vitamin C is a water-soluble organic substance essential to humans and a relatively small number of animal species that lack the enzyme gulonolactone oxidase necessary for its biosynthesis.1, 2 The term vitamin C is used to describe both ascorbic and dehydroascorbic acid. Ascorbic acid is the enolic form of vitamin C, and its primary chemical source, whether consumed within the diet or taken as a dietary supplement. Ascorbic acid is a stable, odorless whitish powder that is soluble in water. Dehydroascorbic acid (DHA) contains two fewer hydrogen ions than ascorbic acid. It is formed when ascorbic acid is dissolved in water, but readily converts to ascorbic acid according to metabolic needs. DHA also may be transformed into a number of other compounds when the pH of the solute is alkaline, or in the presence of copper or iron. Unfortunately, these chemical products lack the beneficial actions of ascorbic acid or DHA. Vitamin C absorption is an energy-requiring process that is enhanced by conversion from ascorbic acid to DHA. DHA is rapidly transported into the intestinal epithelium, where much is converted back to ascorbic acid before being distributed to cells throughout the body. Physiologic functions associated with vitamin C arise from its ability to act as a reducing agent.1, 2 Reducing agents are critical to life because they balance the potentially harmful byproducts produced in oxidative reactions within the body. Ascorbic acid carries two hydrogen atoms that can be donated to a variety of metabolic reactions within the human body, leading to its conversion to DHA. DHA is converted back to ascorbic acid in vivo, in the presence of glutathione and nicotinamide adenine dinucleotide phosphate dependent reductases, allowing it to once again act as a reducing agent. Because of this ability to regenerate itself, vitamin C is critical for and beneficial to multiple physiologic processes in the human (Table).

In addition to the multiple functions outlined in Table, vitamin C also influences tissue repair and regeneration within the body.3 Probably the most critical role, based on current knowledge, is contribution of vitamin C to the synthesis of connective tissue and, in particular, collagen. It acts as a cofactor with iron for enzymes involved during the hydroxylation of proline and lysine in the production of collagen and also during cross-linking of mature collagen. Both of these are critical to the proliferative and remodeling phases of wound healing. Ascorbic acid also promotes fibroblast formation, upregulates collagen gene expression and cellular procollagen secretion, and enhances the biosynthesis of other substances important to wound repair and regeneration including elastin, fibronectin, proteoglycans, and elastin-associated fibrillin. In addition, the level of vitamin C within leukocytes is important for phagocytic functions relevant to bacterial control in wounds.

Nutritional Assessment and Vitamin C Unfortunately, no reliable tests for vitamin C deficiency have been developed, and nutritional assessment of adequate stores relies primarily on measurement of serum or leukocyte levels.1 Measurement of serum vitamin C reflects dietary intake of ascorbic acid, but measuring leukocyte levels provides a better reflection of tissue levels and total body stores. While urine or salivary ascorbic acid levels can be measured, they have not proved to reliably reflect either body stores or vitamin C deficiency. The normal range for serum vitamin C is 23-84 mg/dl. Values falling between 11.4 and 23 mg/dl reflect vitamin C deficiency, and values less than 11.4 reflect a serious deficiency that places the individual at risk for scurvy. The normal range for mixed leukocyte vitamin C levels are 114-301 mg/108 cells and the normal range for mononuclear leukocytes is 142-250 mg/108. The total body pool for vitamin C is 500-1500 mg (10-22 mg/ kg), but no reliable test for measuring this value exists for the clinical setting.

Mikel Gray, PhD, CUNP, CCCN, FAAN, is Director of the WOCN Center for Clinical Investigation (CCI) and a Nurse Practitioner and Professor, Department of Urology and School of Nursing, University of Virginia, Charlottesville. JoAnne D. Whitney, PhD, RN, CWCN, is Professor, Department of Biobehavioral Nursing and Health Systems, University of Washington School of Nursing, Seattle, Washington. Reprint requests: Mikel Gray, PhD, CUNP, CCCN, FAAN, University of Virginia, Department of Urology, PO Box 800422, Charlottesville, VA 22908; e-mail: mg5k@ virginia.edu. J WOCN 2003;30:245-9. Copyright © 2003 by the Wound, Ostomy and Continence Nurses Society. 1071-5754/2003/ $30.00 + 0 doi:10.1067/mjw.2003. 140

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246 Gray and Whitney Table. Biologic functions of vitamin C1, 2 Function

Probably the most critical role, based on current knowledge, is contribution of vitamin C to the synthesis of connective tissue and, in particular, collagen.

Biologic significance

Acts as direct antioxidant

Scavenges photolytic free oxygen radicals in the eye; protects neutrophils from reactive oxygen species generated during phagocytosis; reduces oxidative damage to spermatogenic DNA in human semen; reduces intracellular DNA damage from reactive oxygen species; reduces mutagenic damage to gastric epithelium in patients with gastritis; diminishes DNA damage when lymphocytes are exposed to bleomycin

Interacts with other antioxidants

Regenerates itself when DHA ascorbic contributes two hydrogen atoms to reduce an oxidative agent; restores active form of glutathione diminishing risk for cataracts in the eye; restores biologically beneficial (antioxidant) form of vitamin E (tocopherol); acts in synergy with flavonoids to reduce cellular mutation (in vitro evidence only)

Influences neurotransmitter synthesis and neuron function

Contributes molecule needed for synthesis of dopamine and norepinephrine in the central nervous system; influences activity of glutamatergic and dopaminergic neurons

Reduces mixed function oxidases

Promotes synthesis of corticosteroids; promotes hepatic cytochrome P450 enzyme production needed for cholesterol conversion to bile acids and may lower serum cholesterol levels

Influences iron and copper absorption

Reduces iron to a ferrous state needed for transfer and storage pathways; enhances absorption of iron (the magnitude and relevance of this action remains controversial); inhibits intestinal absorption of copper and ceruloplasmin oxidase; inhibits ceruloplasmin oxidase bound copper in the cell

Promotes carnitine synthesis

Promotes serum levels of carnitine, essential for transport of long-chain fatty acids, especially important for cardiac and skeletal muscle activity

Anticlotting action

Promotes biosynthesis of prostacyclin and other prostaglandins

Influences immune function

Promotes neutrophil chemotaxis, lymphocyte proliferation, and natural killer cell bioactivity; influences immune system modulators including histamine, serum complement, prostaglandins, B- and T-cell cyclic nucleotides

ADMINISTRATION, DOSAGE, AND SIDE EFFECTS Like all vitamins, the recommended dose for ascorbic acid varies according to the reason for administration.1, 2 The minimum requirement for ascorbic acid (necessary to avoid scurvy) is 510mg/day. The recommended daily allowance (RDA) is the average intake sufficient to meet nutrient requirements of at least 97%-98% of the population at large.4 In the United States, the RDA for vitamin C is 60 mg/day for adult women and men; this value is two standard deviations above the dietary intake needed to maintain a total body pool of ascorbic acid between 900 and 1500 mg. This recommendation must be tailored for special

groups. An additional 10 mg/day is recommended for pregnant women, and lactating mothers should consume an additional 30-35 mg/day. Because of the added oxidative stress created by cigarette smoke, the RDA for smokers is 100 mg/day. Unfortunately, there is insufficient evidence to determine whether these special recommendations should include healthy elders. For the healthy adult living in the United States, about 95107 mg of ascorbic acid are consumed in the diet.1 The principal dietary sources include fruits, vegetables, potatoes, tomatoes, and tomato juice. In addition, approximately 35%-44% of adults take a daily vitamin supplement containing vitamin C.2 Higher doses of vitamin C may be consumed in an effort to achieve therapeutic benefits beyond

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the maintenance of an adequate body pool and avoidance of scurvy. Therapeutic doses vary from 200 mg to four grams per day in an effort to increase the total body pool of ascorbic acid beyond 1500 mg. While higher doses have been shown to increase serum levels, they have not been shown to significantly increase leukocyte levels.2 Adverse effects have been associated with higher vitamin C intake; these effects tend to be dose-related and are typically associated with daily intakes of 3 grams or more.1,2 Gastrointestinal side effects, including nausea, abdominal cramp, and diarrhea, may occur when excess ascorbic acid passes through the stomach and bowel. Urinary excretion of oxalate and uric acid are increased by high dose vitamin C consumption, but there is no clear evidence that this necessarily leads to an increased risk for urinary stone formation. Similarly, theoretic possibilities for lowered vitamin B12 levels and excessive iron and copper absorption have been postulated, but studies have not identified adverse effects in the clinical setting. While the antioxidant properties of ascorbic acid have been shown to reduce DNA damage,1, 2 higher serum levels of vitamin C have been associated with increased DNA damage in certain circumstances.5 Nevertheless, subsequent studies have not associated vitamin C supplementation with an increased risk for cancer or other clinically relevant adverse effects.1, 2, 5

Vitamin C Deficiency and Pressure Ulceration Adverse consequences of vitamin C deficiency initially arose among eighteenth-century sailors who experienced signs and symptoms of scurvy when their diets contained insufficient fruits and vegetables needed to meet minimum requirements for ascorbic acid consumption.1 The compromised healing observed in vitamin C deficiency is related to reduced formation of mature and adequately crossed-linked collagen fibers, without which wounds are vulnerable to breakdown and reoccurrence. Hypotheses have arisen that vitamin C supplementation may promote pressure ulcer healing, from research into the relationship between nutritional status and pressure ulcer healing and from research focusing on the role of vitamin C in collagen deposition and maturation.6 Malnutrition has been found to increase the individual’s susceptibility to pressure ulceration6-10 and to compromise subsequent wound healing,7, 11 but multiple dietary substances, including protein, amino acids (arginine), calorie and vitamin deficiencies have been found to play a role. Nevertheless, several studies have specifically associated vitamin C deficiency and pressure ulcer risk. Goode and colleagues12 compared vitamin A, C, and E levels in a group of 21 elders admitted to an ortho-

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pedic inpatient unit for femoral bone fractures. On average, the leukocyte levels of vitamin C were found to be about 50% lower among the 10 subjects who developed pressure ulcers, when compared to the 11 subjects who remained ulcer free. Selvaag and associates13 found similar results when they examined serum concentrations of multiple vitamins (including vitamin C) in 11 elder hospitalized patients with pressure ulcers. These results were then compared to 11 age-matched controls. Serum ascorbic acid concentrations were significantly less (again about 50% lower) among patients with a pressure ulcer as compared to those who were ulcer free. This Evidence-Based Report Card explores whether vitamin C supplementation promotes pressure ulcer healing and under what clinical circumstances it may be indicated.

METHODS A systematic literature review was undertaken using key words “vitamin C,” “ascorbic acid,” “pressure ulcer,” “pressure sore,” and “decubitus ulcer”. MEDLINE, and CINAHL databases were searched from 1966 to May 1, 2003. In addition, the Cochrane Database for Systematic Reviews, Cochrane Central Register for Controlled Trials, ACP Journal Club, and Database for Abstracts for Reviews of Effects were also searched. Research reports were limited to English language articles or abstracts reporting experimental or quasi-experimental studies using human subjects. Case studies and single-subject experiments were excluded from the review. Evidence concerning vitamin C supplementation for other chronic wounds, including radiation, vascular ulcerations, or burn wounds, was also excluded.

QUESTION 1 Does vitamin C supplementation promote pressure ulcer healing? Two randomized clinical trials were identified that evaluated the effects of vitamin C on pressure ulcer healing. Taylor and colleagues14 completed a prospective, double-blind clinical trial in which 20 subjects with pressure ulcers were randomized to receive either 500 mg of ascorbic acid twice daily or a placebo in addition to routine therapies. Few details concerning routine therapy for pressure ulcer management are provided in this research report, but the authors do note that subjects were maintained on standard hospital mattresses, their diets were not otherwise manipulated, and all received “similar local therapy to the wound area” (p. 544). Wound healing was assessed as changes in wound area; weekly evaluations included a qualitative assessment completed by the principal investigator, wound area tracings completed independently by a physical therapist, and a weekly photographic assessment. The original wound area portrayed graphically appeared similar

Gastrointestinal side effects, including nausea, abdominal cramps, and diarrhea, may occur when excess ascorbic acid passes through the stomach and bowel.

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KEY POINTS • There is a significant paucity of rigorous evidence concerning the efficacy of vitamin C as a complementary therapy for promoting pressure ulcer healing.The available evidence suggests that vitamin C may be beneficial for patients with a preexisting deficiency, but high-dose vitamin C is not effective for patients without such a deficit. (Level of Evidence: 2) • Of the 2 randomized trials that were identified, the study by Taylor and coworkers14 has several weaknesses including: 1) small sample size (N = 20); 2) inadequate description of primary therapies for pressure ulcer treatment; 3) inadequate data collection period (4 weeks); and 4) failure to correct for vitamin C deficiency in the control group. While the study by ter Reit and associates15 overcomes many of these weaknesses, it also suffers from significant methodologic weaknesses, including a second intervention (high- versus low-hertz frequency ultrasound) and diminishing the number of patients managed by high-dose vitamin C therapy without the potentially confounding effects of concomitant ultrasound treatment to no more than 22 patients. Recommendations for Clinical Practice

Based on these results, neither ascorbic acid nor ultrasound appear to improve wound healing in patients with pressure ulcers.

• Vitamin C status should be evaluated as part of a nutritional assessment in patients with pressure ulcers. Serum or leukocyte vitamin C levels may be obtained to quantitatively estimate total body vitamin C stores. • Particular attention is warranted in those patients at high risk for nutritional deficiency (older individuals, those with cognitive deficits, chronic health conditions, trauma, or reduced resources/access to adequate nutrition). • In patients with documented vitamin C deficiency, or a very high index of suspicion for general nutritional deficiency, supplement with vitamin C to correct deficiency according to USDA daily recommended allowances.

among the groups, with slightly smaller pressure ulcers among treatment subjects. Ascorbic acid levels were quantified as mixed leukocyte concentrations and measured biweekly. Subjects treated with ascorbic acid were found to have significantly higher levels of leukocyte ascorbic acid and a higher percentage of reduction in pressure ulcer area at 1 month (42.7% mean reduction vs. 84% mean reduction) compared to subjects receiving placebo. Approximately 20 years later, ter Reit and associates15 partially replicated the study reported by Taylor’s group,14 but they substituted 20 mg of ascorbic acid rather than placebo to answer criticisms that delayed wound healing in the control group may represent a significant deficiency of vitamin C, rather than a therapeutic benefit gained from supplementation with 1 gram/day in 2 divided doses. In addition to this change in ascorbic acid dosing, data collection was extended from 4 to 12 weeks. Eighty-eight patients from 11 hospitals and 1 long-term care facility were randomized and an intent to treat analysis was completed. Both vitamin C supplementation and ultrasound therapy were described as complementary management. Subjects lay on waterbeds, and flotation pads were used if they were able to sit up for parts of the day.

Topical wound care was described as daily cleansing or rinsing with sterile saline or chlorhexidine. Enzymatic and surgical débridements were performed “as needed” and wounds were covered with paraffin and hydrophilic gauze. Of note, this study also evaluated the effects of ultrasound on pressure ulcer healing rates, and subjects were randomized into one of four (rather than one of 2 groups) for treatment and analysis. Group 1 received high-hertz frequency ultrasound and high-dose vitamin C; patients in group 2 received high-dose vitamin C and sham ultrasound; subjects in group 3 received low- hertz frequency ultrasound and low-dose vitamin C; group 4 was comprised of subjects receiving low-dose vitamin C and sham ultrasound. Ascorbic acid levels, quantified as serum rather than leukocyte concentration, were measured at weeks 2, 6, and 12. Color photographs and computerized analysis were used to measure wound surface area and calculate ulcer reduction in cm per week. The photographs also provided documentation for a semiquantitative assessment of wound healing based on global visual assessment. A 10-point scale was used to determine global healing, where a score of 1 indicates a “bad” appearance and a score of 10 indicates an excellent appearance. Evaluation of wound heal-

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ing was completed at baseline and weeks 1, 2, 4, 6, 8, 10, and 12. Unlike Taylor’s group, ter Reit and associates15 found no statistical differences between velocity of wound closure (0.21cm2/week vs. 0.27cm2/week) or global appearance (0.45 vs. 0.72 points per week). Based on these results, they concluded that neither ascorbic acid nor ultrasound improved wound healing in patients with pressure ulcers. No meta-analysis was located that quantitatively reviewed pooled evidence concerning the effect of vitamin C as a complementary therapy for healing a pressure ulcer, although Issue 6 of the Cochrane Wound Group listed the use of vitamin C as “ripe for review” (page 2).16 A systematic review was identified that focused on the efficacy of vitamin C as a complementary therapy for pressure ulcer management. This review used a methodology adapted by the American College of Physicians (ACP) Journal Club based on topics where only a very small number of clinical trials are available to answer a relevant clinical question. They also identified two randomized trials (Taylor et al.14 and ter Reit et al.15) and concluded that vitamin C is not an effective complementary therapy for healing pressure ulcers. REFERENCES 1. Jacob RA.Vitamin C. In: Shils ME, Olson JA, Shike M, Ross AC. Modern Nutrition in Health & Disease, 10th ed. Baltimore: Williams & Wilkins, 1999, pp. 467-83. 2. Food and Nutrition Board. Dietary References for Vitamins E, C, selenium and carotenoids. Washington, DC, National Academy Press, 2000, pp. 95185. 3. Ronchetti IP, Quaglino D, Bergaminni G. Ascorbic acid and connective tissue. Subcell Biochem 1996;25:249-64.

Gray and Whitney 249 4. Food and Nutrition Board. Introduction to dietary reference intakes. Washington, DC, National Academy Press, 2000, pp. 17-26. 5. Halliwell B. Vitamin C: poison, prophylactic or panacea? Trends Biochem Sci 1999;24(7):255-9. 6. Breslow R. Nutritional Status and dietary intake of patients with pressure ulcers: a review of research literature 1943-1981. Decubitus 1991;4:16-21. 7. Albina JE. Nutrition and Wound healing. J Parenter Enteral Nutr 1994;18:367-76. 8. Breslow RA, Bergstrom N. Nutritional prediction of pressure ulcers. J Amer Diet Assoc 1994;94:1301-4. 9. Ek AC, Onosson M, Larsson J, von Schenk H, Bjurulf P. The development and healing of pressure sores related to the nutritional state. Clin Nutr 1991;10:24550. 10. Pinchofsky-Devin, GD, Kaminski MV. Correlation of pressure sores with nutritional status. J Amer Geriatr Soc 1986;34:435-40. 11. Stotts NA. Nutritional assessment and support. In: Bryant RA (editor). Acute and Chronic Wounds: Nursing Management, 2nd edition, St. Louis: Mosby, 2000, pp. 41-50. 12. Goode HF, Burns E,Walker BE.Vitamin C depletion in elderly patients with femoral neck fracture. Br Med J 1992;305:925-7. 13. Selvaag E, Bohmer T, Benkestock K. Reduced serum concentrations of riboflavin and ascorbic acid, and blood thiamine pyrophosphate and pyridoxal-5-phosphate in geriatric patients with and without pressure sores. J Nutr Health Aging 2002; 6:75-7. 14. Taylor TV, Rimmer S, Day B, Butcher J, Dymock IW. Ascorbic acid supplement in the treatment of pressure sores. Lancet 1974;2:544-6. 15. Reit GT, Kessels AGH, Knipschild PG. Randomized clinical trial of ascorbic acid in the treatment of pressure ulcers. J Clin Epidemiol 1995;48:1453-60. 16. Anonymous. Cochrane wounds: newsletter of the Cochrane wounds group. Issue 6, October 2002.