Abstract

Background Sepsis and septic shock are common causes of ICU admission with devastating outcomes. Adjunctive therapies are urgently needed, and the use of high dose of vitamin B1 and C have recently gained interest. However, on the basis of a perceived possible synergic effect, most trials have never tested the combination of thiamine and ascorbic acid, with a separate assessment of the effect of each individual component. In this context, while the association of thiamine and ascorbic acid was not found to improve survival rates, potentially harmful effects were found when administering ascorbic acid alone. We have conducted a retrospective cohort study, comparing ICU mortality of septic shock patients receiving standard treatment, thiamine alone or a combination of thiamine and ascorbic acid.

Results A total of 1800 patients were included, 1260 receiving standard care, 436 receiving only thiamine and 104 patients receiving a thiamine / ascorbic acid combination. Using doubly robust estimation of the treatment effect, combining propensity score weighting and variables adjustment, we found thiamine alone to be associated with a decrease in ICU mortality compared to the use of a thiamine / ascorbic acid combination (Hazar Ratio equal to 0.60, 95% Confidence Interval [0.36;0.99], p=0.048).

Conclusions In septic shock patients, administration of thiamine is associated with improved ICU mortality when used alone rather than when associated with ascorbic acid. This result strengthens the evidence showing a lack of effectiveness of the ascorbic acid / thiamine combination reported in recent randomized controlled trials. Furthermore, it argues in favor of the need for further trials investigating the effect of thiamine in septic ICU patients as an adjunctive therapy.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

D.L. is supported by two young researcher grants from the Geneva University Hospitals (PRD 5-2020-I and PRD 4-2021-II) and by a grant from the Ernst and Lucie Schmidheiny Foundation.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethics committee/IRB of Commission Cantonal d ethique de la Recherche de Geneve, Suisse, gave ethical approval for this work

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Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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Yes

Data Availability

The datasets used and or analyzed during the current study are available from the corresponding author on reasonable request.

List of AbbreviationsATTAverage Treatment effect on the TreatedHAT therapycombination of hydrocortisone, ascorbic acid and thiamine HR: Hazard RatioICUIntensive Care UnitRCT(s)Randomized Controlled Trial(s)