S 72

Post injury

FIGURE 8.13 Burn patients receiving high-dose vitamin C (VC) vs. control (CTRL) demonstrated improved oxygenation (see text).

significant advance in the treatment of fluid resuscitation of thermal injury. One may conclude that vitamin C may prove extremely useful as an adjunctive therapy for the management of the burn shock period as well as for minimizing the progression of the severity of the burn wound in the early hours after injury.

In a similar fashion, Nathens et al. evaluated the efficacy of a combination of tocopherol (vitamin E) and vitamin C in a prospective randomized trial on critically ill surgical trauma patients.28 In this study, 595 patients were enrolled. Those randomized to antioxidant supplementation received tocopherol (1000 IU) every 8 h per gastric tube and 1000 mg of ascorbic acid every 8 h intravenously for the period of time in the ICU or for 28 d. Measured outcomes included pulmonary morbidity, multiple organ system failure, duration of mechanical ventilation, length of intensive care stay, and mortality. Based on this treatment, pulmonary morbidity was significantly decreased, as was duration of mechanical ventilation and ICU stay.

While the above studies concerned patients with wounds, outcomes measured were primarily systemic endpoints rather than wound healing endpoints. However, as suggested elsewhere in this chapter and in this book (Chapter 1), one might anticipate improved wound healing either from the decrease in total metabolic stress or from a direct effect on the wound. Tanaka's studies clearly indicate decreased edema, which results in improved vascular density and decreased perfusion distances. Nathens' study would perhaps have an indirect influence on wound healing; pulmonary function was improved, allowing better tissue oxygenation and less total metabolic stress, leaving a metabolic reserve for improved wound healing.

Ascorbic acid appears to have very few toxic side effects. This is not surprising in view of the rate-limiting mechanisms of gastrointestinal absorption and the linearity in urinary excretion as described above. It would appear that it is impossible for the toxicity of vitamin c body to store significant quantities of vitamin C, thus minimizing adverse systemic effects.1-410-27-31 These limitations in intestinal absorption are one of the arguments against high-dose oral vitamin C. It will result only in bathing the gastrointestinal tract with large quantities of ascorbate, but it will not increase plasma or tissue levels.90

Side effects of ascorbic acid have been reported in people taking ascorbic acid at 3 g/d. Complaints at this dose level include nausea, abdominal cramping, bloating, and diarrhea.131 The upper limit of oral intake is, therefore, set at 2 g/d.132 Nonetheless, some proponents of high-dose vitamin C intake for antioxidant value advocate 4 to 6 g/d of oral intake and anecdotally, these large doses seem to be tolerated.

One of the breakdown products of vitamin C is oxalate. In normal circumstances, oxalate accounts for 35 to 50% of the oxalate excretion by the body every day. However, this pathway of metabolic excretion is limited; therefore, large doses of vitamin C should not cause excessive oxaluria. In studies of normal people with no history of renal stones or kidney disease, increased vitamin C consumption did not increase kidney stone formation.31 However, in patients with renal failure or known oxalate renal stone history, caution should be used, and vitamin C should be limited to 200 mg/d.30,31

In a similar fashion, because uric acid and ascorbic acid are both reabsorbed in the proximal tubule, there is concern that high-dose ascorbate intake could decrease renal absorption of uric acid, leading to gout. However, it appears that, because the tubular reabsorption of ascorbic acid is a saturable process, this concern is not valid. Studies have demonstrated in normal individuals that intakes of 4 to 12 g of ascorbic acid per day did not increase serum uric acid levels or urine uric acid or uric acid clearance.3191 Even in individuals with a history of gout, it is doubtful that large doses of ascorbate decrease uric acid excretion, although it would be prudent to be cautious in such individuals.

Because ascorbic acid facilitates absorption of nonheme iron by changing the redox state of the iron, there has been concern that elevated vitamin C intake could result in excessive iron storage. However, optimal promotion of iron absorption is induced with iron intakes of 25 to 50 mg per meal, suggesting that larger intakes would not result in excessive iron accumulation.13192 Cook et al. demonstrated that even 2 g/d of ascorbate taken in divided doses with meals did not induce increased iron stores over 18 months of observation in otherwise healthy individuals.93 Nonetheless, caution should be used in patients with iron overload or in susceptible patients, such as those with sickle cell disease, sideroblastic anemia, thalassemia major, or those needing frequent blood transfusions.

Glucose-6-phosphate deficiency is a genetic disease that leads to hemolytic crises when the individual is exposed to oxidative stress. Hemolyis may be precipitated with intakes of oral doses of 6 g of vitamin C, with lower doses given by intravenous administration.194

As discussed above, Tanaka et al. examined the safety of continuous large-dose administration (66 mg/kg/h x 24 continuous hours; = 4.6 gm/h in a 70 kg man) of vitamin C to 20 healthy adult volunteers.87 These studies revealed no abnormalities in liver function, kidney function, or the blood clotting system for 7 d after administration of this dose in healthy volunteers. This would suggest that even in extremely high doses given for short time periods, vitamin C has minimal adverse effects.

Vitamin C in doses of greater than 250 mg per day may cause false positive blood stool tests.131 This must be considered in routine tests for occult blood. In a similar fashion, because ascorbate is excreted in the urine, it may interfere with urinary sugar tests.

Finally, certain adverse side effects that have been attributed to vitamin C must be mentioned only to indicate that they have not been proven to be true. It does not appear that vitamin C can cause hypoglycemia, rebound scurvy, infertility, mutagenesis, or destruction of vitamin B12.1,31

recommendations for vitamin c to support wound healing

The combined effect of ascorbic acid on collagen synthesis, antioxidant status, and immunomodulation make it an appropriate supplement for wound repair protocols. Research provides evidence for the use of low doses of vitamin C in vitamin C deficient individuals, but many practitioners believe larger doses of ascorbic acid in nondeficient individuals are indicated for optimal wound repair. In light of the discussion above, one must also decide if vitamin C is to be provided as an enzymatic cofactor or as an antioxidant.

While the literature is controversial, the authors suggest that to support collagen synthesis and immune function in otherwise healthy individuals with small wounds, such as pressure ulcers or elective small to moderate surgery, doses of 500 to 1000 mg should be given daily in two divided doses. Those with larger injury, such as large body surface area burns and multiple traumas, should be given doses of 1 to 2 g/d.

Proper doses to optimize antioxidant effect remain to be determined. The studies of Tanaka suggest 66 mg/kg/h intravenously for patients with large body surface area burns.84-87,89 For multiple trauma patients Nathens et al. suggest an intake of only 1000 mg/d in three divided doses, as well as vitamin E.28 Inadequate data exist to recommend doses to optimize the antioxidant effect in patients with smaller wounds and less metabolic stress. The low risk of toxicity suggests the liberal use of vitamin C.

future directions

Much of the controversy in the literature on vitamin C in wound healing revolves around the measured endpoints for optimal nutrition. Some studies measure plasma levels, some measure tissue levels, and others measure clinical parameters of vitamin C nutriture. In addition, some look at clinical parameters of collagen synthesis, immune competence, or free radical metabolism. Future studies should concentrate on functional assays of vitamin C deficiency. Serum and tissue levels are of uncertain value, even in healthy individuals, and will continue to be problematic when used to assess nutrition in the critically ill. Development of biochemical assays of collagen metabolism, immune function, and free radical metabolism that could be obtained as a clinical test rather than a laboratory research project would be invaluable to help in the healing of our wound patients.

Although the role of ascorbate in collagen metabolism has long been understood and extensively studied, further research on the other enzymatic cofactor functions and on its role in general protein synthesis must be better understood. The effect that these systems have on wound healing must also be elucidated.

Much of the future research in vitamin C will revolve around its use as a free radical scavenger. Its role in protecting against disease as well as in treating injury must be further understood, and proper safe intakes at these pharmacologic levels of ascorbate must be determined in a variety of clinical situations. The interaction of ascorbate and other antioxidants, such as glutathione and vitamin E, must be better understood to allow for the determination of proper clinical doses of vitamin C.

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