Vitamin C in sepsis- Answer is elusive

Alpha A. Fowler , Jonathon D. Truwit , R. Duncan Hite et el published results of CITRIS-ALI trial in JAMA on Oct1, 2019.

WHAT

It was a randomized double blind placebo controlled multi Center trial  conducted in 7 medical ICUs in the USA,  comparing placebo to  vitamin-C infusion( 50 milligram/kilogram,  every 6 hours for 96 hours)  in patients with  sepsis and ARDS who were receiving mechanical ventilation.  Purpose of trial was to assess the  effect  of vitamin-C on inflammation and vascular injury.

OUTCOMES

Primary outcomes were change in modified sequential organ failure assessment score(SOFA,   range 0-20),  bio markers of inflammation  C reactive protein  and vascular injury (  thrombomodulin levels).

There were several secondary outcomes including 28 day mortality.

RESULTS

There were no significant differences between vitamin c and placebo groups in the primary outcomes.

In exploratory analysis of 46 specified secondary out comes,  3 secondary outcomes were significantly different  between groups.

  1. At 28 day,  mortality was 46.3%  in the placebo group  versus 29.8% in the vitamin-C group.
  2. Number ventilator free days were 13.1 and vitamin-C group versus 10.6 in placebo.
  3.  Number of ICU  free  days  10.7 in vitamin-C group versus 7.7 in placebo group.

DISCUSSION

Since  early 17 Century,  when James Lind  discovered that   Sailors who  received  citrus fruits  recovered from scurvy,  vitamin-C has been proposed  or thought to be  speed recovery from influenza, common cold,  cancer  etc.

Researchers have been advocating vitamin C as treatment for sepsis,  and recently  a before after trial  of vitamin-C showed promising results  in sepsis.

Physiologically,  vitamin-C  is crucial for endogenous synthesis of catecholamines.   In laboratory,  vitamin-C ameliorate cytokine surges implicated in sepsis induced organ dysfunction.

This trial demonstrated  that there was no difference in  mediators of inflammation and organ dysfunction  when treated with vitamin-C. Furthermore,  vitamin-C was well tolerated  and vitamin C levels improved with the treatment.

In secondary analyses,  28 day of mortality,  ventilator free day  were  better in vitamin-C treated group.  Surprisingly,  other  secondary outcomes,  which are closely linked to mortality  or inflammation  were not different. the finding of reduce mortality was without adjustment for multiple  comparisons.

Mortality benefit seen in secondary analysis  justifies the need for a larger trial,  does not provide a conclusive proof of  its effectiveness.   Hopefully,  such a trial will  look at  mortality benefit  as primary outcome.