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

J Rynne; M Mosavie; Marie-Hélène Masse; Julie Ménard; Marie-Claude Battista; David M Maslove; Lorenzo Del Sorbo; Charles St-Arnaud; Frederick DAragon; Alison Fox-Robichaud; Emmanuel Charbonney; Neill K J Adhikari; François Lamontagne; M Shankar-Hari; LOVIT Investigators, the Canadian Critical Care Trials Group

doi:10.1007/s00134-024-07733-9

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

Intensive Care Med. 2025 Jan 7. doi: 10.1007/s00134-024-07733-9. Online ahead of print.

Authors

J Rynne¹, M Mosavie¹, Marie-Hélène Masse², Julie Ménard², Marie-Claude Battista³, David M Maslove^{4

5}, Lorenzo Del Sorbo⁶, Charles St-Arnaud^{2

3}, Frederick DAragon^{2

3}, Alison Fox-Robichaud⁷, Emmanuel Charbonney⁸, Neill K J Adhikari^#^{9

10}, François Lamontagne^#^{11

12}, M Shankar-Hari^#^{13

14}; LOVIT Investigators, the Canadian Critical Care Trials Group

Collaborators

LOVIT Investigators, the Canadian Critical Care Trials Group:
Michaël Chassé, Pierre Aslanian, Sylvain Bélisle, Jean-François Cailhier, François Martin Carrier, André Denault, Martin Girard, Jean-Gilles Guimond, Antoine Halwagi, Paul Hébert, Christophe Kolan, Caroline Ouellet, Nicholas Robillard, Fatna Benettaib, Dounia Boumahni, Martine Lebrasseur, Maya Salamé, Marie-Ève Cantin, Patrick Archambault, Christine Drouin, Estel Duquet-Deblois, Monia Noël-Hunter, Jean-Nicolas Dubé, Marie-Josée Bériault, Marco Chacon, David Claveau, Jean-François Naud, Élise Rodrigue, Danielle Tapss, Guylaine Toupin, Han Ting Wang, Marc Brosseau, Brian Laufer, François Marquis, Francis Toupin, Danaë Tassy, Vincent Cheung, Sam-Ang Toun, Frédérick D'Aragon, Dominique Bérard, Brian Grondin-Beaudoin, Marc-André Leclair, Olivier Lesur, Michaël Mayette, Yannick Poulin, Hector Quiroz Martinez, Elaine Carbonneau, Julie Bélisle, Marie-Pier Bouchard, Line Côté, Marylène Ladouceur, Joannie Marchand, Alexandra Naisby, Louise Robert-Petit, Marie-Ève Thibault, Martin Albert, Francis Bernard, Alexandros Cavayas, Karim Serri, David Williamson, Virginie Williams, Julia Lainer Palacios, François Lauzier, Charles Francoeur, Guillaume Leblanc, Maude St-Onge, Alexis Turgeon, David Bellemare, Marie-Claude Boulanger, Eve Cloutier, Gabrielle Guilbault, Frédérique Thibeault, Emilie Belley-Côté, Maureen Meade, Richard Whitlock, Lori Hand, Leah Hayward, Courtney Mullen, Nevena Savija, François Lellouche, Mathieu Simon, Ying Tung Sia, Patricia Lizotte, Bram Rochwerg, Tina Millen, David Maslove, J Gordon Boyd, John Drover, John Muscedere, Stephanie Sibley, Tracy Boyd, Miranda Hunt, Tina Mele, Tracey Bentall, Chadia ElKhatib, Jason Shahin, Kosar Khwaja, Josie Campisi, Norine Alam, Raham Rahgoshai, Sangeeta Mehta, Michael Detsky, Sumesh Shah, Sonny Kohli, Fulan Cui, Vikas Khera, David McConachie, Sachdeep Rehsia, Dalisha Bharti, Adic Perez, Demetrios James Kutsogiannis, Raiyan Chowdhury, Jon Davidow, Curtis Johnston, Michael Kim, Kimberley Macala, Sam Marcushamer, Darren Markland, Doug Matheson, Arabesque Parker, Damian Paton-Gay, Tayne Hewer, Patrica Thompson, Deborah Cook, Waleed Al-Hazzani, Erick Duan, Tania Ligori, Mark Soth, France Clarke, Mary Copland, Karlo Matic, Neill K J Adhikari, Andre Amaral, Brian H Cuthbertson, Robert A Fowler, Dominique Piquette, Damon C Scales, Bourke Tillmann, Hannah Wunsch, Nicole Marinoff, Maneesha Kamra, Navjot Kaur, Deeptha Murali, Thivya Sabananthan, Thuva Sugumaran, Andrew Seely, Shane English, Hilary Meggison, Sherissa Microys, Scott Millington, Aimee Sarti, Jessica Haines, Sydney Miezitis, Rebecca Porteous, Irene Watpool, Eddy Fan, John Granton, Hesham Abdelhady, Tina Romagnuolo, Oleksa Rewa, Sean Bagshaw, Michael Meier, Wendy Sligl, Nadia Baig, Gordon Wood, Daniel Ovakim, Fiona Auld, Gayle Carney, Deborah Parfett, Rémi Leblanc, Matthieu Poirier, Theophile Theriault, Maryse Williston, Jackie Caissie Collette, Melanie Carriere, Melissa Daigle, Bernise Gaudet, Karine Morin, Lola Ouellette-Bernier, Julie Poitras, Melanie Robichaud, Joanne Rockburn, Armand Mekontso Dessap, Romain Arrestier, François Bagate, Ines Bendib, Brice Benelli, Enora Berti, Astrid Bertier, Pedro Cavaleiro, Nicolas Prost, Segolene Gendreau, Otto Hartman, Anne-Fleur Haudebourg, Julien Lopinto, Paul Masi, Gaël Michaud, Keyvan Razazi, Samuel Tuffet, Aline Alves, Luiza Nait Chabane, Fariza Ouali, Rachida Ouedraogo, Djillali Annane, Lilia Abdeladim, Rania Bounab, Nicholas Heming, Virginie Maxime, Pierre Moine, Isabelle Bossard, Segolene Jourdier, Siline Mahiou, Hayette Tessa, Shay McGuinness, Jonathan Ball, Immanuel Hennessy, Maurice Hogan, Magdalena Butler, Keri-Anne Cowdrey, Eileen Gilder, Rachael Parke, Samantha Ryan, Melissa Woollett, Andrew Poll, Kerry Benson-Cooper, Jonathan Chen, Kirk Freeman, David Harley, Dave Harvey, Craig Hourigan, Kylie Julian, Stephen Lo, Colin McArthur, Stuart Miller, Chris Pointer, Rex Anthony Smith, Laura Tincknell, Rachael McConnochie, Catherine Simmonds, Geoffrey Shaw, Toby Betteridge, Brandon Burke, David Closey, Rosalind Crombie, Neil Davidson, Louise Henderson, Seton Henderson, Louise Hitchings, David Knight, Christine Quigley, Jay Ritzema Carter, Jessica Roberts, Katherine Townend, Tara Doyle, Jan Mehrtens, Stacey Morgan, Anna Morris, Kymbalee Heyden, Pawel Twardowski, Martin Dvoracek, Markus Renner, David Silverman, Myles Smith, Katherine Monica Stephens, Hansjörg Albert Waibel, Stefan Wiebe, Mark Woolley, Amie Eden, Dawn France, Ulrike Buehner, Katallah Kramer, Erin Williams, Troy Browne, Owen Callender, Jonathan Chen, Susanne Farrell, Vicky Higson, David Jackson, Owen Keet, Jennifer Goodson, Robert Martynoga, Kelly Byrne, Amelia Butler, Kara Trask, Gay Mans, Jonathan Termaat, Paul Young, Colin Barnes, Ben Barry, Kim Grayson, James Moore, Alex Psirides, Shawn Sturland, Kate Tietjens, Bob Ure, Laurence Walker, Jason Wright, April Aguilar-Dano, Kirsha Delaney, Cassie Lawrence, Mildred Lesona, Alexandra Millington, Leanlove Navarra, Shaanti Olatunji, Raulle Sol Cruz, Rhoze Sol Cruz, Chelsea Young, Andrew Day, Deborah J Cook, Gordon H Guyatt, Sheila Sprague, Dian Cohen, Daren K Heyland, Neill K J Adhikari, Ruxandra Pinto, Salmaan Kanji, Djillali Annane, Bharath Kumar Tirupakuzhi Vijayaraghavan, Shay McGuinness, Rachael Parke, Yaseen Arabi

Affiliations

¹ Centre for Inflammation Research, Institute For Regeneration and Repair, University of Edinburgh, Edinburgh, Scotland, UK.
² Centre de Recherche du Centre Hospitalier, Universitaire de Sherbrooke, Sherbrooke, Canada.
³ Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Canada.
⁴ Department of Critical Care Medicine, Queen's University, Kingston, Canada.
⁵ Kingston Health Sciences Center, Kingston, Canada.
⁶ Interdepartmental Division of Critical Care Medicine, Toronto General Hospital, Toronto, Canada.
⁷ Department of Medicine, McMaster University, Hamilton, Canada.
⁸ Centre Hospitalier de L'Université de Montréal, University of Montreal, Montreal, Canada.
⁹ Department of Critical Care Medicine, Sunnybrook Health Sciences Centre, Toronto, Canada. [email protected].
¹⁰ Interdepartmental Division of Critical Care Medicine and Institute for Health Policy, Management, and Evaluation, University of Toronto, Toronto, Canada. [email protected].
¹¹ Centre de Recherche du Centre Hospitalier, Universitaire de Sherbrooke, Sherbrooke, Canada. [email protected].
¹² Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Canada. [email protected].
¹³ Centre for Inflammation Research, Institute For Regeneration and Repair, University of Edinburgh, Edinburgh, Scotland, UK. [email protected].
¹⁴ Intensive Care Unit, Royal Infirmary of Edinburgh, Edinburgh, Scotland, UK. [email protected].

^# Contributed equally.

PMID: 39774855
DOI: 10.1007/s00134-024-07733-9

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.

Associated data

ClinicalTrials.gov/NCT03680274