| Title | Sepsis subtypes and differential treatment response to vitamin C: biological sub-study of the LOVIT trial. |
| Publication Type | Journal Article |
| Year of Publication | 2025 |
| Authors | Rynne J, Mosavie M, Masse M-H, Ménard J, Battista M-C, Maslove DM, Del Sorbo L, St-Arnaud C, DAragon F, Fox-Robichaud A, Charbonney E, Adhikari NKJ, Lamontagne F, Shankar-Hari M |
| Corporate Authors | LOVIT Investigators, the Canadian Critical Care Trials Group |
| Journal | Intensive Care Med |
| Volume | 51 |
| Issue | 1 |
| Pagination | 82-93 |
| Date Published | 2025 Jan |
| ISSN | 1432-1238 |
| Keywords | Aged, Ascorbic Acid, Biomarkers, Female, Humans, Male, Middle Aged, Sepsis, Treatment Outcome, Vitamins |
| 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. |
| DOI | 10.1007/s00134-024-07733-9 |
| Alternate Journal | Intensive Care Med |
| PubMed ID | 39774855 |
| PubMed Central ID | 6970225 |