J Intensive Care. 2020 (Feb 7); 8: 15 ~ FULL TEXT
Harri Hemilδ & Elizabeth Chalker
Department of Public Health,
University of Helsinki,
POB 41, FI-00014 Helsinki, Finland.
BACKGROUND: Our recent meta-analysis indicated that vitamin C may shorten the length of ICU stay and the duration of mechanical ventilation. Here we analyze modification of the vitamin C effect on ventilation time, by the control group ventilation time (which we used as a proxy for severity of disease in the patients of each trial).
METHODS: We searched MEDLINE, Scopus, and the Cochrane Central Register of Controlled Trials and reference lists of relevant publications. We included controlled trials in which the administration of vitamin C was the only difference between the study groups. We did not limit our search to randomized trials and did not require placebo control. We included all doses and all durations of vitamin C administration. One author extracted study characteristics and outcomes from the trial reports and entered the data in a spreadsheet. Both authors checked the data entered against the original reports. We used meta-regression to examine whether the vitamin C effect on ventilation time depends on the duration of ventilation in the control group.
RESULTS: We identified nine potentially eligible trials, eight of which were included in the meta-analysis. We pooled the results of the eight trials, including 685 patients in total, and found that vitamin C shortened the length of mechanical ventilation on average by 14% (P = 0.00001). However, there was significant heterogeneity in the effect of vitamin C between the trials. Heterogeneity was fully explained by the ventilation time in the untreated control group. Vitamin C was most beneficial for patients with the longest ventilation, corresponding to the most severely ill patients. In five trials including 471 patients requiring ventilation for over 10 h, a dosage of 1-6 g/day of vitamin C shortened ventilation time on average by 25% (P < 0.0001).
CONCLUSIONS: We found strong evidence that vitamin C shortens the duration of mechanical ventilation, but the magnitude of the effect seems to depend on the duration of ventilation in the untreated control group. The level of baseline illness severity should be considered in further research. Different doses should be compared directly in future trials.
KEYWORDS: Antioxidants; Artificial respiration; Burns; Cardiac surgical procedures; Critical care; Dietary supplements; Meta-analysis; Oxidative stress; Sepsis; Systematic review
From the FULL TEXT Article:
In controlled trials, vitamin C has improved endothelial function, lowered blood pressure, increased left ventricular ejection fraction, decreased the incidence of atrial fibrillation, decreased bronchoconstriction, prevented pain, shortened the duration of colds, and decreased the incidence of colds in physically stressed people, and it may also have beneficial effects against pneumonia, see reference .
The average person, in good health, maintains normal plasma vitamin C levels with a daily intake of about 0.1 g/day. However, much higher doses, in the order of grams per day, are needed for critically ill patients to reach normal plasma vitamin C levels . Without supplementation, plasma vitamin C levels are particularly low in critically ill patients , indicating that the body may have a greater need for vitamin C when under severe stress such as illness requiring intensive care. It seems evident that there are gradual changes in vitamin C metabolism according to the severity of disease, in that the sicker a patient is, the greater the consumption of vitamin C. This further suggests that the sicker a patient is, the more they are likely to benefit from additional vitamin C.
Given this background, we previously examined whether vitamin C administration has an effect on practical outcomes such as the length of ICU stay, without looking at specific medical conditions. From the results of 12 trials with 1766 patients, we calculated that vitamin C reduced the length of ICU stay on average by 7.8% (P < 0.001) .
We also found that in trials in which the control groups were ventilated for 24 h or more, vitamin C shortened the duration of mechanical ventilation by 18% (P = 0.001) . However, vitamin C did not have an effect on the duration of mechanical ventilation in trials in which control groups were ventilated for less than 24 h, i.e., trials in patients with less severe illness.
In this study, we hypothesize that there is a continuous relationship between disease severity and the beneficial effect of vitamin C administration. We used meta-regression to analyze the gradual relationship between the effect of vitamin C in the treatment group and the duration of mechanical ventilation in untreated patients of the control group, which we used as a proxy for the severity of the disease.
There is significant variation in the severity of disease in patients who are mechanically ventilated. One measure of severity is the mechanical ventilation time required by the patient, which we used as a proxy for severity. In this study, we found that the duration of ventilation in the untreated control group explained most of the variation in the reported effects of vitamin C on the mechanical ventilation time. In the standard meta-analysis, there is high-level heterogeneity with I2 = 83% (Fig. 3), whereas in the meta-regression of the vitamin C effect by the control group duration of ventilation, the residual heterogeneity is small with I2 = 12% (Fig. 4).
Some of the included trials examined elective surgical patients. These patients are not usually critically ill; however, as a result of their surgery, they are routinely ventilated in the ICU for a period of time. In the meta-regression, such patients are located on the left-hand side of Fig. 4 which means that the analysis takes into account the low level of illness severity. In contrast, the inclusion of patients with less severe disease in the standard meta-analysis decreases the average effect of vitamin C, so that the greater effect on the sicker patients is masked (Fig. 3).
The substantial benefit observed in the Tanaka  trial seems to be explained by the particularly long mechanical ventilation in the untreated control patients (which reflects the greater illness severity), rather than the particularly high vitamin C dosage of 90 g/day in that trial. All the other trials used 6 g/day or less, but there is no evidence that the benefit was less than in the Tanaka trial when taking into account the ventilation time in the untreated control group (Fig. 4). There are a few reports of deaths caused by intravenous vitamin C in doses of 80 to 224 g/day [32, 33]. Therefore, the interpretation that the benefit in the Tanaka trial may be caused by the type of patients and not by the very high vitamin C dose is important for planning further trials.
Our previous analysis of the length of ICU stay also found that the effect of vitamin C appeared greater for the sicker patients. The length of ICU stay was reduced by 10.1% (P = 0.0001) in patients who required an ICU stay of 3 days or longer, but by just 5.7% (P = 0.03) in those who needed only 12 days in the ICU .
There are also other findings that are consistent with vitamin C having a greater effect on patients with more severe medical conditions. A meta-analysis of vitamin C effect on exercise-induced bronchoconstriction found that vitamin C halved FEV1 decline caused by exercise . The constant relative effect indicates that the absolute effect was greatest for patients who had the greatest bronchoconstriction in the exercise test. Finally, a trial with common cold patients indicated that the bronchodilatory effect of vitamin C was most beneficial for those with the greatest bronchial hypersensitivity to histamine [35, 36].
There is much evidence indicating that vitamins C and E have an interaction in vitro and in vivo , and three trials have examined the effect of the combination of vitamins C and E on the duration of mechanical ventilation . The reported effects from the three trials are largely consistent with the meta-regression model based on the eight trials using vitamin C alone (Fig. 5), though the confidence interval of the Nathens et al. trial does not cross the regression line. Thus, the statistically significant benefit observed in each of these three trials might be explained by the long ventilation time in the control groups, indicating greater severity of illness in the patients, rather than by the addition of vitamin E to the intervention. To test the possible additional benefit of vitamin E over vitamin C would require 2 Χ 2 factorial trials.
Although our meta-regression analysis by the ventilation time in the control group explains the heterogeneity in the published trials, it seems evident that other variables influence the effects of vitamin C. For example, there are indications that treatment effects can differ between less and more developed countries. Panagiotou et al. identified several studies that reported greater treatment effects in less developed countries than in more developed countries . Although methodological variations may explain some of the differences, there can also be genuine treatment differences between substantially different cultures, since wealth is strongly correlated with life-style factors including nutrition and with differences in hospital treatments. Previously, vitamin C was found to prevent post-operative atrial fibrillation in non-US trials, but not in US-based trials , which may also indicate that the effects of vitamin C can depend on cultural context. Thus, although the fit of the meta-regression line in Fig. 4 is good, the findings should not be extrapolated directly to other contexts.
Two recent meta-analyses concluded that vitamin C is not beneficial for critically ill patients [44, 45], whereas a third concluded that vitamin C was beneficial for sepsis patients . However, all three meta-analyses included studies that administered vitamin C in combination with numerous other substances, such as vitamins A, B, and E, selenium, and zinc . Such trials do not test the specific effect of vitamin C. The other substances can have negative or positive effects, and they can also modify the effect of vitamin C. The three meta-analyses also had statistical shortcomings . Our current meta-analysis was restricted to trials that tested vitamin C alone. A fourth recent meta-analysis concluded that vitamin C shortens ventilation time in cardiac surgery patients ; however, the study was shown to contain several substantial statistical errors .
In systematic reviews, one potential concern is publication bias, in that negative trials may remain unpublished. However, publication bias cannot realistically generate the close association shown in Fig. 4. To explain this association by publication bias would require that positive studies with less ill patients remain unpublished, and negative studies with severely ill patients also remain unpublished. Five trials did not use an explicit placebo [1215, 17], but we do not consider that the lack of placebo undermines the validity of those trials, since ICU patients receive numerous treatments and it is unlikely that one additional tablet or infusion would cause a substantial placebo effect for ventilated patients. The lack of a placebo may cause bias in research on subjective outcomes, but less so on objective outcomes . Thus, it is unlikely to bias studies with outcomes such as the duration of mechanical ventilation.
It may not be worthwhile to carry out further research on the effects of vitamin C on mechanical ventilation for patient groups that require on average less than 10 h of ventilation. The level of sickness severity should be taken into account in future studies, for example, by evaluating prognostic scores at the start of the trial. Our analysis did not find differences between oral and intravenous vitamin C, but oral administration is rarely an option for the sickest patients, for whom the effects of vitamin C appear greatest. Our analysis is not informative about the optimal dosage of vitamin C. Future trials should directly compare different dosage levels.