The primary outcome, fatigue score (assessing the level of "fatigue right now"), was significantly decreased in the vitamin C group compared to the placebo group. The degree of fatigue improved in the vitamin C group 1 day after intervention as well as at 2 hours after intervention. The effect of vitamin C injection was evident in subjects with an initially lower vitamin C level and not in subjects with initially higher levels. Although the pharmacological effect of vitamin C is known to last 4-6 hours (9), our data demonstrate vitamin C injection to be effective a day after intervention as well as at 2 hours after intervention. Previous studies of vitamin C treatment for fatigue have led to disparate results: in some studies, treatment with vitamin C improved fatigue significantly [12, 13]; in others, the treatment proved ineffective [14–18]. One trial showed that regular vitamin C infusion reduced fatigue in inpatients with chronic fatigue syndrome . In a Korean study, vitamin C injection (10 g twice a week) improved fatigue in inpatients with terminal cancer . These trials recruited inpatients with serious diseases, and vitamin C administration was done more than two times. However, the studies were all non-comparative trials. In contrast, randomized controlled trials have reported negative results when vitamin C was administered orally [14–18].
Until recently, oral and intravenous vitamin C were regarded as equivalent, but recent data has shown that the two forms have different pharmacokinetic characteristics (9, 10). Plasma concentrations of vitamin C following oral administration are not dose-dependent, and are instead subject to a plateau. Vitamin C distribution after oral delivery is tightly controlled by intestinal absorption, transport to tissues, and renal reabsorption and excretion [19, 20]. A recent pharmacokinetic study using the depletion-repletion method showed that intravenous administration could achieve 70-fold higher blood levels of vitamin C compared to the highest tolerated oral dose (9). Intravenous administration of vitamin C bypasses the controls described above, and results in high plasma concentrations. Although we did not use a depletion-repletion study design, we measured plasma levels of vitamin C of 267.90 ± 141.83 μg/ml (mean ± SD) two hours after intervention. This level is equivalent to 1521.04 ± 805.25 μmol/L, overlapping the 1000-1500 μmol/L range predicted from the pharmacokinetic model for 10 g intravenous administration .
Our subgroup analysis on the effects on the "fatigue right now" scores indicate that vitamin C injection efficacy is affected by baseline vitamin C levels. Specifically, the subgroup exhibiting an initally lower vitamin C level showed a significant response to vitamin C injection while the subgroup with high baseline levels remained unaffected. We suggest that vitamin C is especially effective in subjects with relatively low baseline levels of vitamin C. Therefore, inconsistent results of previous studies (12, 13, 14-18) may result from route of administration, baseline vitamin C levels of subjects, or both.
Our study has some limitations. First, fatigue measurements were acquired only three times, and plasma vitamin C measurements were made only two times. The association between vitamin C administration and fatigue would have been clearer if we had included more data points in the study. Second, fatigue is a matter of subjective self-assessment. We reduced subjective bias by using a validated measurement tool to assess fatigue , and we detected significant differences in fatigue scores after adjustment of baseline values. These findings confirm the likelihood of wide individual variations in fatigue self-assessment. Third, we found no significant relationship between fatigue and oxidative stress. Our participants were healthy adults, so their oxidative stress and fatigue levels might have been too low to demonstrate a clear relationship. Finally, our participants were 20 to 49 years of age and served as office workers and salespeople. Therefore, generalization to labor workers and elderly (≥ 50 years) workers may be limited. Although it is desirable to perform some screening test such as blood chemistry panel, we excluded subjects having chronic disease by past medical history. The reason why we select the dose of vitamin C 10 g is that we considered efficacy and safety for general population. To avoid unexpected adverse reactions, the least dose for the high dose is ideal and we referred a preceding domestic study.
We suggest that increase in the dosage or frequency of intravenous vitamin C administration may increase the treatment efficacy. Further study is required to determine effective dose ranges of vitamin C for treatment of fatigue, and serial measurements of fatigue should clarify effective dosage windows.