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Randomized Controlled Trial
. 2025 Jan;51(1):82-93.
doi: 10.1007/s00134-024-07733-9. Epub 2025 Jan 7.

Sepsis subtypes and differential treatment response to vitamin C: biological sub-study of the LOVIT trial

J Rynne  1 , M Mosavie  1 , Marie-Hélène Masse  2 , Julie Ménard  2 , Marie-Claude Battista  3 , David M Maslove  4   5 , Lorenzo Del Sorbo  6 , Charles St-Arnaud  2   3 , Frederick DAragon  2   3 , Alison Fox-Robichaud  7 , Emmanuel Charbonney  8 , Neill K J Adhikari #  9   10 , François Lamontagne #  11   12 , M Shankar-Hari #  13   14 ; LOVIT Investigators, the Canadian Critical Care Trials Group
Collaborators, Affiliations
Randomized Controlled Trial

Sepsis subtypes and differential treatment response to vitamin C: biological sub-study of the LOVIT trial

J Rynne et al. Intensive Care Med. 2025 Jan.

Abstract

Purpose: We hypothesised that the biological heterogeneity of sepsis may highlight sepsis subtypes with differences in response to intravenous vitamin C treatment in the Lessening Organ Dysfunction with VITamin C (LOVIT) trial. Our aims were to identify sepsis subtypes and to test whether sepsis subtypes have differences in treatment effect to vitamin C and describe putative biological effects of vitamin C treatment.

Methods: We measured biomarkers of inflammation, at baseline and at 7 days post-randomisation, in 457/863 (53.0%) of participants with plasma samples in the LOVIT trial. We used agglomerative hierarchical clustering on log10-transformed baseline data of 26 biomarkers to identify sepsis subtypes. We analysed differences in vitamin C treatment effect with regression models incorporating robust standard errors to report odds ratio and 95% confidence intervals (OR(95% CI)). All analyses were completed blinded to treatment allocation.

Results: Our cohort included 233/429 (54.3%) allocated to vitamin C and 224/434 (51.6%) allocated to placebo. A three-subtype model best explained the variance in our data. Subtype-2 had the highest, and subtype-3 had the lowest levels of inflammatory response. In paired longitudinal samples, vitamin C did not have discernible anti-inflammatory effects, with anti-inflammatory effects related to time since randomisation and concomitant hydrocortisone treatment. The treatment effect estimates (OR (95% CI)) for subtype-1, subtype-2 and subtype-3 were 1.04 (0.63-1.73), 1.33 (0.53-3.36) and 1.95 (0.85-4.49), respectively (test of heterogeneity p = 0.002).

Conclusion: We report three sepsis subtypes based on inflammatory response profile. No subtype benefitted from vitamin C treatment in the LOVIT trial, with heterogeneity of treatment effect in the magnitude of harm.

Trial registration: Funded by the Lotte and John Hecht Memorial Foundation; LOVIT ClinicalTrials.gov number, NCT03680274.

Keywords: Ascorbic acid; Cluster analysis; Cytokines; Precision medicine; Sepsis; Subphenotype; Subtype.

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Conflict of interest statement

Declarations. Conflicts of interest: MS-H declares that he has done advisory board activity either directly or indirectly through International Sepsis Forum for Biotest, Endpoint Health, Janssen, Pfizer and Santersus, with payments going into the unrestricted institutional research funds or to the International Sepsis Forum. MSH reports receiving grant from the Chief Scientists Office, Scotland, for time‐critical precision medicine in adult critically ill patients (TRAITS Programme— https://traits-trial.ed.ac.uk ).

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