Quality of the evidence
We identified one trial that examined the therapeutic effect of vitamin C on the mortality of people with tetanus (Jahan 1984). In this 2013 update, no new trials were identified. The Jahan 1984 trial reported a highly significant benefit associated with intravenous vitamin C on the case fatality rate of tetanus patients. The methods used in the Jahan trial were, however, unsatisfactory and superficially described. Here we will consider whether potential biases could explain the differences reported in the case fatality rate between the vitamin C and control arms.
Jahan 1984 did not state an explicit case definition for tetanus. Although this is a shortcoming in the report, it does not seem reasonable to assume that tetanus was improperly diagnosed in an infectious diseases hospital in a country that had a high incidence of this disease (currently the incidence is lower). Furthermore, the trial author described in a personal letter that the diagnosis was by a "physician specialised in infectious diseases".
Selection bias operates when there are systematic differences between comparison groups at baseline. Adequate randomisation with allocation concealment guards against it. No data were presented by Jahan 1984 to allow us to judge whether the allocation process resulted in balanced allocation between treatment groups for prognostic factors. This trial was not randomised and there is a risk of selection bias (the ward a patient was allocated to determined whether they received vitamin C, and there might have been a systematic difference in the allocation to the wards). However, it is highly unlikely that potential baseline differences could lead to such great difference in mortality between the study arms as reported for the younger patients.
Performance bias operates when there are systematic differences in the care provided apart from the intervention being evaluated. Jahan 1984 stated that both vitamin C and control arms received "conventional antitetanus therapy which included antitetanus serum, sedatives, antibiotics and muscle relaxant etc.", so the administration of vitamin C was the only systematic difference between the trial arms. However, the vitamin C and control patients were treated in different wards, which is unsatisfactory because aspects of treatment could be somewhat different between the two wards. Placebo was not used in Jahan 1984, however, a recent meta-analysis showed that, in trials examining various topics, placebo arms did not differ from no-treatment arms if the outcome was binary; e.g. mortality (Hrobjartsson 2010). Thus, the care providers may have been aware of which arm the patients had been enrolled into, but it is highly unlikely that such knowledge would have altered treatment to such an extent that it could explain the difference in mortality between the study arms as reported for the younger patients in Jahan 1984.
Attrition bias operates when there are large numbers of people who withdraw from the study or when the rates of withdrawal are different between treatment arms. Attrition bias is unlikely in Jahan 1984, since all patients allocated were followed up and analysed. Furthermore, in a personal letter, the trial author confirmed that all patients were followed up "until they were discharged as fit persons or died".
Detection bias operates when there are systematic differences in the ways outcomes were assessed between treatment groups and is more likely to occur when there is no blinded outcome assessment and when the outcome is subjective. It is unlikely, however, that detection bias is operating in Jahan 1984 since the outcome was mortality which is not a subjective outcome. There is minimal possibility of bias in detecting mortality in a hospital.
Consequently, although the methods of the Jahan 1984 trial are poorly described and the trial was poorly conducted, the biases discussed above cannot explain the reported findings. There seems to be no basis to assume attrition bias or detection bias in the trial. Possibly there has been selection bias and performance bias to some degree, but this cannot explain the reported difference in outcomes among the younger participants. Glasziou 2007 argued that rate ratios beyond 10 are highly likely to reflect real treatment effects, even if confounding factors may contribute to the size of the observed effect. In the younger patients of the Jahan trial, the entire 95% CI and not just the point estimate is beyond the ratio of 10. In the older patients of the Jahan trial, the upper limit of the 95% CI is close to the control group level, and therefore the results are not robust to the possibility of selection and performance biases. Nevertheless, the findings in the older patients are consistent with the findings in the younger patients.
Finally, the existence of a single positive study might be explained by publication bias, meaning that researchers tend to report studies with 'positive' results but not those with 'negative' results. With this reasoning, it is possible that Jahan 1984 was published just because vitamin C appeared beneficial (but simply by chance), whereas several trials might remain unpublished because of their negative results. Publication bias may explain findings that are close to statistical significance, but it is not a reasonable explanation for highly statistically significant findings such as those of the younger patients in the Jahan 1984 trial. Furthermore, it would seem incomprehensible that publication bias would generate the highly significant heterogeneity over the age groups. Therefore we do not consider that publication bias is relevant in this case.
Applicability of the evidence
The Jahan 1984 trial is methodologically unsatisfactory and caution is required in the interpretation of the results. There are no other trials with humans giving independent direct support to the findings. Nevertheless, in western countries tetanus patients are treated in ICUs, and four randomised trials with critically ill patients found that vitamin C alone or with vitamin E reduced the duration of mechanical ventilation or the length of ICU stay or both (Tanaka 2000; Nathens 2002; Papoulidis 2011; Bjorndahl 2012).
In the Jahan 1984 trial, vitamin C was used over and above treatments that are still used for treating tetanus patients. In this respect, the trial is not outdated.
When considering extrapolation of the findings of vitamin C trials, one issue of particular importance is the level of dietary vitamin C intake. A different outcome between the vitamin C and control arms may result from a particularly low dietary intake in the control arm ('marginal vitamin C deficiency') or from the high dose supplementation in the vitamin C arm. In the former case, a small dosage of supplement may produce a similar effect, whereas in the latter case the high dose is necessary. As reference levels: scurvy may be caused by vitamin C intake of less than 10 mg/day, whereas the mean vitamin C intake, for example, in the USA is about 100 mg/day (IOM 2000).
If the biological basis for the results in Jahan 1984 was the treatment of marginal deficiency, this would not provide an explanation for the significant heterogeneity between the age groups, as the dose is so high that it would cure marginal deficiency in both age groups. Thus, it is possible that the high dose, 1 g/day, was essential for the results. The benefit of vitamin C was significantly greater for the younger patients (1 to 12 years), who weigh on average less than the older patients (13 to 30 years). Thus the heterogeneity might have resulted from dose dependency because the dose per weight was higher in the younger patients. However, there are other differences between the younger and older patients, and some of them might explain the heterogeneity as well.
In the Jahan 1984 trial, vitamin C was administered intravenously which increases plasma level substantially more than oral administration (Padayatty 2004). Therefore, the same dose of vitamin C as tablets might not have similar effects.
Safety of vitamin C
In the Jahan 1984 report, no adverse effects related to the intravenous 1 g/day vitamin C administration were mentioned.
Two large-scale trials with 8171 female health professionals and 14,641 male physicians found no adverse effects of 0.5 g/day of vitamin C when administered for 8 to 9 years indicating long term safety of such a dosage level (Cook 2007; Sesso 2008).
There is also evidence that high dose vitamin C is usually safe when administered intravenously. A matched case control study of cancer patients found that 10 g/day vitamin C by intravenous infusion for 10 days and orally thereafter was associated with a longer survival time which indicates the absence of harmful effects with such a dosage (Cameron 1976). Large doses of vitamin C have been administered intravenously for numerous patients without adverse effects (Padayatty 2006; Padayatty 2010). In a pharmacokinetic study, no adverse effects were reported with the administration of up to 100 g of vitamin C intravenously to healthy people (Padayatty 2004). A case report described the use of intravenous vitamin C doses at levels up to 28 g/day for a six-year-old boy with tetanus (Klenner 1954).
Cathcart 1981 stated that patients with severe infections can take over 30 g/day of vitamin C orally without suffering from diarrhoea, whereas healthy people can take only 4 to 10 g/day. This difference in tolerable doses may be caused by the changes in vitamin C metabolism because of severe infections (Chakrabarti 1955; Hemilä 2006). Thus, it is possible that the range of safe doses extends to higher levels in people who have severe infections compared with healthy people.
There are few reports of severe harm caused by high-dose vitamin C administration. Furthermore, the death of a 68-year-old African American man was not attributed to the intravenous injection of 80 grams of vitamin C on two consecutive days per se, but to his coincident glucose-6-phosphate dehydrogenase deficiency (G6PD) (Campbell 1975). Such unfortunate events do not have public health importance, although they discourage use of large vitamin C doses to G6PD patients.
Consequently, there seems to be no concern about the safety of the intravenous dosage level, 1 g/day, used in Jahan 1984.