Vitamin C: abrupt termination may increase mortality of sepsis patients

The recent LOVIT trial of vitamin C for sepsis patients found that mortality was increased in patients randomized to the vitamin C group. In a re-analysis we show that mortality was increased only after the 4-day vitamin C administration was terminated, but not during the vitamin C administration.
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In animal models of sepsis, vitamin C prevented hypotension and lung injury, improved capillary blood flow, and prolonged survival. Two randomized trials reported that vitamin C significantly decreased mortality for patients with sepsis (Zabet 2016; CITRIS-ALI 2019). In the CITRIS-ALI trial, there was significant time-dependent modification of the vitamin C effect, with decreased mortality during the 4-days of vitamin administration, but not after vitamin C was stopped (Hemilä 2020). We also used the quantile treatment effect approach to estimate the effect of vitamin C in the CITRIS-ALI trial and found that, for example, the proportion of patients alive after 5 days in the placebo group was the same as that after 13 days in the vitamin C group, also demonstrating the benefit of vitamin C (Hemilä 2022).

The recent LOVIT 2022 trial, including 862 participants, further examined the potential effects of vitamin C on sepsis patients. Unexpectedly, those in the vitamin C group had 1.17 times the risk of dying within 28 days than those in the placebo group. The LOVIT authors concluded that “those who received intravenous vitamin C had a higher risk of death or persistent organ dysfunction at 28 days than those who received placebo”.

However, in the LOVIT trial vitamin C administration was just 4 days, whereas the median length of ICU stay was 6 days, that is, 2 days longer than the vitamin C administration. In addition, 25% of patients stayed in ICU for more than 12 days, that is more than 8 days after vitamin C was stopped. Given that the effects of vitamin C administration are likely to be short-lasting, we investigated whether the survival difference between the vitamin C and placebo groups was modified by the duration of vitamin C administration.

We found that there was no difference between the vitamin C and placebo groups during the 4-day vitamin C administration, indicating that vitamin C itself was not harmful. Immediately after the termination of vitamin C, on days 5 to 7, there was a 2.3-fold increase in mortality in the vitamin C group when compared to the placebo group, see Figure below. This indicates that it was the termination of vitamin C which caused the harm to the vitamin C group. Hence the conclusion of the LOVIT trial authors that the “receiving” of vitamin C explained the observed harm seems unjustified. Further research on the role of vitamin C for critically ill patients is needed and should not be discouraged by the increased mortality caused by the abrupt termination of vitamin C in the LOVIT trial.

There has been significant bias against vitamin C for many years. However there is a substantial body of evidence that vitamin C can be beneficial in certain circumstances, such as leading to shorter ICU stay and ventilation time, increasing low LVEF levels, and decreasing the risk of AF. Given its low-cost, ready availability and safety, it seems obvious that further research is warranted.

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