Role of Vitamins in Wound Healing
Wound healing is a complex process and the body’s innate response to trauma.1 It occurs in 3 phases:
- Inflammation begins at the time of injury and continues for 4 to 6 days. Macrophages migrate to the wound, remove the necrotic tissue and bacteria, and secrete growth factors.2,3 Bleeding is controlled.
- Proliferation begins on the third or fourth day after injury and continues for 2 weeks. Fibroblasts and epithelial cells proliferate. Collagen synthesis, deposition, and cross-linking provide integrity and strength to the wound. Epithelialization occurs within 5 to 15 days, depending on the size and depth of the wound.2
- Maturation begins in the second or third week after injury and may continue for up to 2 years. Collagen stabilization, which increases the tensile strength of the wound, occurs throughout this phase, and fibroblasts decrease in number.2,4
For the healing process to be successful, the body must be well nourished.3 Adequate nutrients help promote new tissue formation, suppress oxidation of tissue, improve wound function, maintain immune competence, and decrease the risk of infection.5-7 Malnutrition can delay proper healing, which may lead to infections and keloid scarring at the wound site.1,5
The goal during injury and the wound healing process is to provide patients with the necessary nutrition support to maintain body cell mass, limit weight loss, prevent complications, and promote healing.5 It is well known that protein, glucose, and fatty acids are required for optimal wound healing. Vitamins, too, play an important role and will be the focus of this article.
Evidence of vitamin alterations during injury
More and more data suggest that major trauma, such as burns, produces abundant free radicals and impairs endogenous free-radical scavenging mechanisms.8 Unfortunately, under these stressful conditions, the body quickly consumes its supply of antioxidants.9
A number of studies have reported dramatic decreases in plasma vitamin levels of burn victims. Pintaudi and colleagues measured plasma beta-carotene, vitamin A, and vitamin E in burn patients involving 10%, 20%, and 40% total body surface area (TBSA) burns, from 24 hours up to 30 days post burn injury. All patients received enteral nutrition and supplemental vitamin C. Vitamin A, vitamin E, and beta-carotene all showed a marked decline that was related to the severity of injury. The levels of beta-carotene remained low in all patients at the end of 30 days. Vitamin A concentrations showed some recovery, but even in the 10% TBSA burn patients, plasma levels were below healthy control levels. Vitamin E concentration recovered in the 10% and 20% TBSA burn patients, and 75% resumption was observed in those with 40% TBSA.9
High-dose (66 mg/kg/h) administration of vitamin C (as ascorbic acid) has been shown to significantly reduce resuscitation fluid volume requirements, body weight gain, and wound edema in adult patients with burns over >=30% total body surface area versus therapy without vitamin C.10 The reduction in fluid volume was associated with significantly fewer days on mechanical ventilation (12.1 days vs 21.3 days, P = .03) and improved early respiratory function.10 It should be noted that data on burns may not apply to nonburn wounds.
Extremely low or undetectable concentrations of vitamin C have also been documented following trauma and infection, most likely due to increased vitamin C turnover, redistribution following stress, or depletion prior to injury.11 In critically ill adult patients and those with severe surgical infection, supplementation with 300 mg/d of vitamin C for 2 days did not improve plasma concentrations; concentrations only began approaching normal after 2 days of 1000 mg/d supplementation. Normal plasma levels were reached after 5 or 6 days of 3000 mg/d supplementation, indicating a severe depletion of vitamin C following trauma and infection.
Key vitamins in wound healing
Vitamin C (ascorbic acid)
The roles of vitamin C in wound healing include:
- Increasing collagen synthesis and cross-linking3– Vitamin C is a necessary electron donor in the hydroxylation of proline and lysine in collagen synthesis.12,13 If collagen is not produced correctly, the wound takes longer to heal and is more prone to open5,12 ; in fact, dehiscence is 8 times more common in patients with vitamin C deficiency.4,14
- Enhancing neutrophil function3 helps avoid infection.
- Increasing angiogenesis3 supplies new skin tissues with nutrients. In the absence of vitamin C and correctly synthesized collagen, capillaries become weak and break, since collagen also plays a role in the synthesis of blood vessels.
Studies have documented that vitamin C enhances wound healing in patients who are deficient in this micronutrient; however, supplementation in nondeficient individuals remains controversial.3 Levenson and Demetriou recommend 1 g/d to 2 g/d vitamin C supplementation in adult wounded patients until c o nvalescence is almost complete.3,15 They argue that since the body does not store vitamin C to a great extent, its loss can be substantial during stress and injury. In addition, they note that ingestion of these high doses is not associated with adverse effects.
Vitamin A (retinol)
Numerous studies conducted in animals have demonstrated the positive role of vitamin A in wound healing. Supplemental vitamin A in various animal models has been shown to:
- Promote the early inflammatory reaction to injury15
- Increase peripheral blood monocyte count and influx of monocytes/macrophages into the wound site following injury15
- Increase the number of antibody-producing cells and antibody production15
- Increase collagen content15
- Increase angiogenesis15
In vitro, vitamin A can also accelerate fibroblast maturation and multiplication, increase fibroblast layer collagen content, and increase the number of fibroblast receptors for epidermal growth factor.15
While it is known that vitamin A deficiency delays wound healing, there is little or no data that the effect of supplementation in nondeficiency states heals wounds.3 Some physicians believe that supplemental vitamin A is needed, since injury can result in deficient concentrations of this vitamin. Levenson and Demetriou propose 25,000 IU/d vitamin A orally in patients with severe injury.15 Their rationale for recommendation is that the amount of vitamin A required for wound healing is much greater than the amount needed to prevent deficiency. In addition, 10,000 IU/d intravenously has been recommended for moderately to severely injured patients or for malnourished individuals before and after elective surgery.3 The authors did not specify length of therapy. It should be noted that high doses of vitamin A can be toxic, since this vitamin is stored in the body.3 Symptoms include nausea, vomiting, headache, dizziness in acute toxicity, gingivitis, alopecia, and peeling skin in chronic toxicity.16 For this reason, exercise caution and observe patients for symptoms of toxicity when administering high doses of this vitamin. Serum concentrations can be high, normal, or even low in patients who have symptoms of toxicity.
Other vitamins and wound healing
Vitamin E (tocopherol)
Vitamin E is an antioxidant and free-radical scavenger that helps prevent the oxidation of cell membrane polyunsaturated phospholipids,12,17 offsetting the oxidative changes that occur with injury. It is known that in burn victims, serum concentrations of vitamin E are reduced because of its consumption by oxygen radical release and subsequent systemic inflammation.12
Although vitamin E is thought to facilitate wound healing by enhancing the immune response,1 it has anti-inflammatory properties, inhibits collagen synthesis, and decreases tensile strength of wounds.3,18 For these reasons, vitamin E supplementation should not exceed the current recommended daily allowance of 15 mg/d orally and 10 IU/d in total parenteral nutrition.3 Until studies demonstrate optimal doses of vitamin E supplementation for patients with injury, high doses should be avoided.3,18
Vitamin B complex
Thiamine, riboflavin, pyridoxine, folic acid, and pantothenate are necessary as cofactors for cellular development; they also promote enzyme activity involved in the metabolism of proteins, carbohydrates, and fats.14 More specifically, thiamine, riboflavin, and pyridoxine contribute to wound healing by functioning in antibody and leukocyte cell formation, and folic acid facilitates the development and maturation of blood cells.5,14
Studies have indicated that severe injury or acute serious illness decreases the amount of B-complex vitamins in the body, suggesting increased requirements during periods of stress.14 Unfortunately, studies have not been conducted to establish the amounts of vitamin B complex necessary during injury.
Vitamin K
Vitamin K is necessary for blood clotting, where it is a cofactor in the synthesis of prothrombin and factors VII, IX, and X; it is also required for the synthesis of calcium-binding protein.15,19 The role of vitamin K in wound healing involves the prevention of hemorrhage and hematoma formation, which directly impair wound healing.7,14 Deficiency of vitamin K can result in wound infection and dehiscence due to prolonged bleeding times and lack of proper clotting.5 NPO plus broad-spectrum antimicrobials may lead to vitamin K deficiency. Daily requirement is 80 µg for males and 65 µg for females,14 though needs vary depending on the use of anticoagulant therapy.
Vitamin D
Vitamin D is necessary for calcium homeostasis, normal bone growth, and healing of fractures.5,14 A strong relationship between this vitamin and wound healing, however, does not exist at this time.
Summary
Wound healing is a complex process, requiring a multitude of nutrients. Since injury and stress can reduce or even deplete the body’s stores of several important vitamins, supplementation of these micronutrients is imperative to promote successful healing and avoid complications that will delay recovery. Studies use serum (plasma) concentrations, which are difficult to directly correlate with body stores. Recommendations for supplemental dosing of some vitamins have been made based on clinical experience; however, optimal doses for wound healing have yet to be determined in controlled, randomized clinical trials.
References:
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2. George S,Bugwadia N.Nutrition and wound healing. Medsurg Nurs. 1996;5:272-275.
3. Scholl D,Langkamp-Henken B.Nutrient recommendations for wound healing. J Intraven Nurs. 2001;24:124- 132.
4. Young ME.Malnutrition and wound healing. Heart Lung. 1988;17:60-67.
5. Brylinsky CM.Nutrition and wound healing: an overview. Ostomy Wound Manage. 1995;41:14-16,18,20-22,25-26.
6. Ehrlichman RJ, Seckel BR,Bryan DJ,Moschella CJ.Common complications of wound healing:prevention and management. Surg Clin North Am. 1991;71:1323-1351.
7. Telfer NR, Moy RL. Drug and nutrient aspects of wound healing. Dermatol Clin. 1993;11:729-737.
8. Horton JW. Free radicals and lipid peroxidation mediated injury in burn trauma: the role of antioxidant therapy. Toxicology. 2003;189:75-88.
9. Pintaudi AM, Tesoriere L,D'Arpa N,et al. Oxidative stress after moderate to extensive burning in humans. Free Rad Res . 2000;33:139-146.
10. Tanaka H,Matsuda T, Miyagantani Y, Yukioka T, Matsuda H,Shimazaki S.Reduction of resuscitation fluid volumes in severely burned patients using ascorbic acid administration: a randomized, prospective study. Arch Surg. 2000;135:326-331.
11. Long CL,Maull KI,Krishnan RS,et al.Ascorbic acid dynamics in the seriously ill and injured. J Surg Res. 2003;109:144-148.
12. Meyer NA,Muller MJ,Herndon DN.Nutrient support of the healing wound. New Horiz. 1994;2:202-214.
13. Anderson TW. New horizons for vitamin C. Nutr Today. 1977;12:6-13.
14. Trujillo EB.Effects of nutritional status on wound healing. J Vasc Nurs. 1993;11:12-18.
15. Levenson SM, Demetriou AA.Metabolic factors.In:Cohen IK,Diegelmann RF, Lindblad WJ,eds. Wound Healing:Biochemical and Clinical Aspects. Philadelphia,Pa:WB Saunders Co; 1992:248-273.
16. Ross, V. Micronutrient recommendations for wound healing. Support Line. 2002;4:3-9.
17. Hinder RA,Stein HJ.Oxygen-derived free radicals. Arch Surg. 1991;126:104-105.
18. Ehrlich HP, Tarver H,Hunt TK.Inhibitory effects of vitamin E on collagen synthesis and wound repair. Ann Surg. 1972;175:235-240.
19. Gallop PM,Lian JB,Hauschka PV. Carboxylated calcium-binding proteins and vitamin K. N Engl J Med. 1980;302:1460-1466.
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