The story of vitamin C in sepsis is fascinating. There was a great deal of controversy around what became known as the Marik protocol (after Prof. Paul Marik). The protocol included the use of vitamin C, thiamine and hydrocortisone to treat sepsis. It was initially reported as before/after study with quite remarkable success rates. Some even claimed 100% survival rates for patients with sepsis. It sounded unbelievable and subsequent studies suggested that it was. The initial enthusiasm was certainly tempered, but did not entirely diminish. In part this was due to a commonly held belief that the treatments were unlikely to cause harm. This has led to a number of clinicians persisting with the use of the Marik protocol.
This week we have the publication of the #LOVITrial randomised controlled trial in the NEJM that addresses the question of Vitamin C use in sepsis. The abstract is below, but as we always say, please read the full paper yourself before making up your mind.
What kind of study is this?
As this is an intervention it’s good to see it designed as a randomised controlled trial. It’s also placebo controlled and masked which are further refinements of the RCT design.
Who was studied?
Patients were recruited from 35 ICUs in North America. They were >18 with a presumed diagnosis of sepsis and had to be on a vasopressor. In total 872 patients were enrolled into the trial. The groups were pretty similar at baseline.
Tell me about the interventions.
Patients were randomised in a 1:1 ratio and received either placebo or an infusion of 50mg/Kg of Vitamin C every 6-hours for 96-hours (or until they left the ICU). 96.7% of patients received at least 90% of the regime.
What about the outcomes?
The principal outcome was death or persistent organ dysfunction at 28 days. There were the usual smorgasbord of secondary outcomes as is typical in these sort of trials. This allowed a number of pre-specified secondary analyses (again typical for these sorts of trials).
What did they find?
In terms of the primary outcome 191/429 patients (44.5%) in the Vitamin C group died or had persistent organ failure as compared to 38.5% in the placebo group. This was statistically significant (p=0.01) and is clearly clinically significant too.
If we just look at deaths then a similar trend is found. 35.4% in the Vitamin C group and 31.6% (not statistically significant RR 1.17 95% CI 0.98-1.40).
So what does this mean?
It’s yet another study that challenges the assertion that Vitamin C works in sepsis. I suspect that we may hear similar defences as we have in the past. These generally consisted of 1. The treatment was given too late and 2. You need the whole package (the hydrocortisone and thiamine) to make it work. These are reasonable questions but the well designed studies in this area have not suggested any real signal to support these arguments.
What has been interesting is how a relatively low quality single centre study led to so much activity in refuting it. Some are critical of this, and I can see that argument, but I also like the idea of science being self correcting. It’s also worth reflecting on how positive data findings can be disseminated through the press and other non-academic publications which lead to real changes in practice.
What should we do?
There appears to be little evidence to support the routine use of Vitamin C in sepsis patients on the ICU. It’s use should be restricted to those with known Vit C deficiency and possibly within the context of future trials.
François Lamontagne, M.D., Marie-Hélène Masse, M.Sc., Julie Menard, Ph.D., Sheila Sprague, Ph.D., et al., for the LOVIT Investigators and the Canadian Critical Care Trials Group* Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit. DOI: 10.1056/NEJMoa2200644 https://www.nejm.org/doi/full/10.1056/NEJMoa2200644?query=featured_home
Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock. Chest. June 2017:1229-1238. doi:10.1016/j.chest.2016.11.036
Simon Carley, “JC: The Vitamins trial. Hydrocortisone, Vit C and Thiamine (Marik protocol – or not?) in sepsis. St Emlyn’s,” in St.Emlyn’s, January 17, 2020, https://www.stemlynsblog.org/jc-the-vitamins-trial-hydrocortisone-vit-c-and-thiamine-marik-protocol-or-not-in-sepsis-st-emlyns/.
Dan Horner, “JC: Vitamin SCepTiC?,” in St.Emlyn’s, April 3, 2017, https://www.stemlynsblog.org/vitamin-sceptic/.
Simon Carley, “JC: Effect of Ascorbic Acid, Corticosteroids, and Thiamine on Organ Injury in Septic Shock. The ACTS Randomized Clinical Trial St Emlyn’s,” in St.Emlyn’s, August 23, 2020, https://www.stemlynsblog.org/jc-effect-of-ascorbic-acid-corticosteroids-and-thiamine-on-organ-injury-in-septic-shock-the-acts-randomized-clinical-trial-st-emlyns/.
Simon Carley, “JC: Critical Care Reviews day 2. #CCR20. St Emlyn’s,” in St.Emlyn’s, January 17, 2020, https://www.stemlynsblog.org/jc-critical-care-reviews-day-2-ccr20-st-emlyns/.