Prior research suggests potential benefits of vitamin C for critically ill patients, including reduced ICU stays and ventilation times. Animal studies have also shown positive effects. Two randomized controlled trials (RCTs) even indicated decreased sepsis mortality with vitamin C. However, the LOVIT trial unexpectedly showed increased mortality in the vitamin C group compared to placebo. This study hypothesizes that the observed harm was due to the abrupt termination of vitamin C rather than its administration, potentially due to a rebound effect and increased vitamin C consumption in critically ill patients.

Several meta-analyses demonstrate the potential benefits of vitamin C for critically ill patients, including reduced ICU stays and ventilation times, especially in those with severe conditions. Animal studies highlight vitamin C's protective effects against hypotension, lung injury, and improved capillary blood flow in sepsis. The potential benefits of vitamin C for sepsis are well-documented, particularly in relation to pneumonia, a common cause of sepsis, and myocardial dysfunction often associated with sepsis. While two previous RCTs showed decreased sepsis mortality with vitamin C, a re-analysis of one trial revealed a time-dependent effect, with benefits observed only during the vitamin C administration period. This highlights the importance of considering the duration of vitamin C administration in analyzing trial results. Concerns have also been raised regarding potential rebound effects from abruptly stopping high-dose vitamin C.

This secondary analysis used data from the LOVIT trial, a randomized double-blind trial examining the effects of vitamin C on sepsis patients. The researchers extracted survival data from the LOVIT trial's published survival curves for the first 11 days post-randomization. Cox regression analysis, using the `cph` procedure in the `survival` package of R, was employed to model mortality rates in the vitamin C and placebo groups. A two-period Cox regression model was used, dividing the 11-day follow-up into two periods: the 4-day vitamin C administration period and the subsequent 7-day period. The likelihood ratio test compared the fit of a single RR estimate with the two RR estimates from the 2-period Cox regression. The analysis focused on the first 11 days, encompassing the 4-day vitamin C administration and the following week, to assess the impact of abrupt termination.

The analysis included 429 participants in the vitamin C group and 433 in the placebo group. During the 4-day vitamin C administration period, there was no significant difference in mortality between the groups (RR = 0.97, 95% CI: 0.65–1.44). However, in the week following the abrupt cessation of vitamin C, a significant increase in mortality was observed in the vitamin C group (RR = 1.9, 95% CI: 1.2–2.9; p = 0.004). This difference was particularly pronounced in the days immediately following the cessation of vitamin C (days 5-7: RR = 2.28, 95% CI: 1.24–4.2; p = 0.008), suggesting a rapid negative effect. A two-period Cox regression model significantly improved the fit compared to a model assuming a uniform effect over the entire 11-day period, supporting the time-dependent effect of vitamin C termination.

The findings contradict the LOVIT trial's original conclusion that vitamin C administration increased mortality. This analysis demonstrates that the increased mortality observed in the LOVIT trial is not attributable to ongoing vitamin C administration, but rather to its abrupt cessation. This supports the hypothesis of a rebound effect, where the abrupt termination of high-dose vitamin C leads to lower-than-baseline vitamin C levels, potentially exacerbating the negative effects of illness in already critically ill patients. The lack of benefit during the vitamin C administration period might be explained by the short duration of treatment (4 days), potentially insufficient for many patients' ICU stays, or by delayed initiation of treatment. The authors also highlight ethical concerns with the LOVIT trial's design, specifically the failure to address and treat patients with severe vitamin C deficiency.

The abrupt termination of vitamin C, not its administration, explains the increased mortality observed in the vitamin C group of the LOVIT trial. This study underscores the importance of considering the duration of vitamin C administration and potential rebound effects when interpreting trial results. Future research should focus on optimizing vitamin C administration protocols for critically ill patients and address the ethical considerations related to treating vitamin C deficiency.

This analysis relies on data extracted from published survival curves, limiting the precision of the analysis. The authors acknowledge that the lack of benefit during the vitamin C administration period requires further investigation and might be related to treatment duration or initiation timing. The analysis focuses solely on short-term mortality (11 days), and long-term effects may differ.