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Original ArticleFree Preview

Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit

List of authors.
  • François Lamontagne, M.D.,
  • Marie-Hélène Masse, M.Sc.,
  • Julie Menard, Ph.D.,
  • Sheila Sprague, Ph.D.,
  • Ruxandra Pinto, Ph.D.,
  • Daren K. Heyland, M.D.,
  • Deborah J Cook, M.D.,
  • Marie-Claude Battista, Ph.D.,
  • Andrew G. Day, M.Sc.,
  • Gordon H. Guyatt, M.D.,
  • Salmaan Kanji, Pharm.D.,
  • Rachael Parke, R.N., M.H.Sc., Ph.D.,
  • Shay P. McGuinness, M.B., Ch.B.,
  • Bharath-Kumar Tirupakuzhi Vijayaraghavan, M.D.,
  • Djillali Annane, M.D., Ph.D.,
  • Dian Cohen, B.A.,
  • Yaseen M. Arabi, M.D.,
  • Brigitte Bolduc, M.Sc.,
  • Nicole Marinoff, R.N.,
  • Bram Rochwerg, M.D.,
  • Tina Millen, R.R.T.,
  • Maureen O. Meade, M.D.,
  • Lori Hand, B.Sc.,
  • Irene Watpool, R.N., B.Sc.N.,
  • Rebecca Porteous, B.N.Sc.,
  • Paul J. Young, M.B., Ch.B., Ph.D.,
  • Frederick D’Aragon, M.D.,
  • Emilie P. Belley-Cote, M.D., Ph.D.,
  • Elaine Carbonneau, R.N.,
  • France Clarke, R.R.T.,
  • David M. Maslove, M.D.,
  • Miranda Hunt, B.A.,
  • Michaël Chassé, M.D., Ph.D.,
  • Martine Lebrasseur, R.N.,
  • François Lauzier, M.D.,
  • Sangeeta Mehta, M.D.,
  • Hector Quiroz-Martinez, M.D.,
  • Oleksa G. Rewa, M.D.,
  • Emmanuel Charbonney, M.D., Ph.D.,
  • Andrew J.E. Seely, M.D., Ph.D.,
  • Demetrios J. Kutsogiannis, M.D., M.H.S.,
  • Remi LeBlanc, M.D.,
  • Armand Mekontso-Dessap, M.D., Ph.D.,
  • Tina S. Mele, M.D., Ph.D.,
  • Alexis F. Turgeon, M.D.,
  • Gordon Wood, M.D.,
  • Sandeep S. Kohli, M.D.,
  • Jason Shahin, M.D.C.M.,
  • Pawel Twardowski, M.D., Ph.D.,
  • and Neill K.J. Adhikari, M.D.C.M.
  • for the LOVIT Investigators and the Canadian Critical Care Trials Group*

Abstract

Background

Studies that have evaluated the use of intravenous vitamin C in adults with sepsis who were receiving vasopressor therapy in the intensive care unit (ICU) have shown mixed results with respect to the risk of death and organ dysfunction.

Methods

Download a PDF of the Research Summary.

In this randomized, placebo-controlled trial, we assigned adults who had been in the ICU for no longer than 24 hours, who had proven or suspected infection as the main diagnosis, and who were receiving a vasopressor to receive an infusion of either vitamin C (at a dose of 50 mg per kilogram of body weight) or matched placebo administered every 6 hours for up to 96 hours. The primary outcome was a composite of death or persistent organ dysfunction (defined by the use of vasopressors, invasive mechanical ventilation, or new renal-replacement therapy) on day 28.

Results

A total of 872 patients underwent randomization (435 to the vitamin C group and 437 to the control group). The primary outcome occurred in 191 of 429 patients (44.5%) in the vitamin C group and in 167 of 434 patients (38.5%) in the control group (risk ratio, 1.21; 95% confidence interval [CI], 1.04 to 1.40; P=0.01). At 28 days, death had occurred in 152 of 429 patients (35.4%) in the vitamin C group and in 137 of 434 patients (31.6%) in the placebo group (risk ratio, 1.17; 95% CI, 0.98 to 1.40) and persistent organ dysfunction in 39 of 429 patients (9.1%) and 30 of 434 patients (6.9%), respectively (risk ratio, 1.30; 95% CI, 0.83 to 2.05). Findings were similar in the two groups regarding organ-dysfunction scores, biomarkers, 6-month survival, health-related quality of life, stage 3 acute kidney injury, and hypoglycemic episodes. In the vitamin C group, one patient had a severe hypoglycemic episode and another had a serious anaphylaxis event.

Conclusions

In adults with sepsis receiving vasopressor therapy in the ICU, those who received intravenous vitamin C had a higher risk of death or persistent organ dysfunction at 28 days than those who received placebo. (Funded by the Lotte and John Hecht Memorial Foundation; LOVIT ClinicalTrials.gov number, NCT03680274.)

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Funding and Disclosures

Supported by the Lotte and John Hecht Memorial Foundation. Nova Biomedical Canada provided glucometers, testing strips, and control solutions (StatStrip Express) to trial sites that requested them. Vitamin C that was used at trial sites in Canada and New Zealand was purchased from Mylan.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Drs. Lamontagne and Adhikari contributed equally to this article.

This article was published on June 15, 2022, at NEJM.org.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

We thank the trial patients and their caregivers; the health care providers, research and laboratory staff members, and trial and data coordinators; the staff members at the Unité de Recherche Clinique et Épidémiologique of the Centre de Recherche du CHU de Sherbrooke for providing support in the conduct of the trial; Louise Robert Petit for her work with biologic specimens and supplies; Marie-Pier Domingue for her assistance in the preparation of earlier versions of the figures; Anitra Carr for her insights regarding the potential underlying mechanisms of the effects of vitamin C in previous studies; members of the Canadian Critical Care Trials Group for their input on methodologic issues, including Ron Wald for his review of the manuscript; and the members of the data and safety monitoring board (Andreas Laupacis, Lauren Griffith, and Scott Halpern); and the broader Code C community, whose support proved essential to the success of this trial.

Author Affiliations

From the Departments of Medicine (F. Lamontagne, M.-C.B., H.Q.M.) and Anesthesiology (F.D.), Université de Sherbrooke, the Department of Pharmacy (B.B.), Centre de Recherche du CHU de Sherbrooke, Centre Intégré Universitaire de Santé et de Services Sociaux de l’Estrie–Centre Hospitalier Universitaire de Sherbrooke (F. Lamontagne, M.-H.M., J.M., F.D., E. Carbonneau), and Bishop’s University (D.C.), Sherbrooke, QC, the Division of Orthopaedic Surgery, Department of Surgery (S.S.), the Department of Medicine (D.J.C., G.H.G., B.R., T.M., M.O.M., E.P.B.-C., S.S.K.), the Department of Health Research Methods, Evidence, and Impact (D.J.C., G.H.G., B.R., M.O.M., L.H., E.P.B.-C., F.C.), and the Population Health Research Institute (E.P.B.-C.), McMaster University, the Department of Critical Care, St. Joseph’s Healthcare Hamilton (D.J.C.), the Intensive Care Unit, Juravinski Hospital (T.M.), and Respiratory Therapy, Hamilton Health Sciences (L.H.), Hamilton, ON, the Department of Critical Care Medicine, Sunnybrook Health Sciences Centre (R. Pinto, N.M., N.K.J.A.), the Interdepartmental Division of Critical Care Medicine, University of Toronto (S.M., N.K.J.A.), and Sinai Health System (S.M.), Toronto, the Departments of Critical Care Medicine (D.K.H., D.M.M., M.H.), Public Health Sciences (A.G.D.), and Medicine (D.M.M.), Queen’s University, and Kingston Health Sciences Centre (A.G.D., D.M.M.), Kingston, ON, the Department of Pharmacy, Ottawa Hospital (S.K.), Ottawa Hospital Research Institute (S.K., I.W., R. Porteous), and the Department of Surgery, University of Ottawa (A.J.E.S.), Ottawa, ON, the Massawippi Valley Foundation, Ayer’s Cliff, QC (D.C.), the Department of Medicine, Université de Montréal (M.C.), the Centre Hospitalier de l’Université de Montréal (M.C., M.L., E. Charbonney), the Centre de Recherche de l’Hôpital du Sacré-Coeur de Montréal (E. Charbonney), and the Departments of Medicine and Critical Care, McGill University Health Centre (J.S.), Montreal, QC, the Department of Medicine (F. Lauzier) and the Division of Critical Care Medicine, Department of Anesthesiology and Critical Care (F. Lauzier, A.F.T.), Université Laval, the Critical Care Medicine Service (F. Lauzier, A.F.T.), and the Research Center (F. Lauzier, A.F.T.), CHU de Québec–Université Laval, Quebec, QC, the Department of Critical Care Medicine, University of Alberta, Edmonton (O.G.R., D.J.K.), the Division of Intensive Care, Department of Medicine, CHU Dr. Georges L. Dumont, Moncton, NB (R.L.), the Department of Surgery, Schulich School of Medicine and Dentistry, Western University, London, ON (T.S.M.), the Division of Intensive Care Medicine, Island Health Authority, Victoria, BC (G.W.), and the Department of Medicine, Halton Healthcare, Oakville, ON (S.S.K.) — all in Canada; the Cardiothoracic and Vascular Intensive Care Unit, Auckland City Hospital (R. Parke, S.P.M.), and the School of Nursing, University of Auckland (R. Parke), Auckland, the Medical Research Institute of New Zealand, Newtown (R. Parke, S.P.M., P.J.Y.), the Intensive Care Unit, Wellington Hospital, Wellington (P.J.Y.), and the Department of Surgical Sciences, University of Otago, Dunedin (P.T.) — all in New Zealand; the Department of Critical Care Medicine, Apollo Hospitals, Chennai, and George Institute for Global Health, New Delhi — both in India (B.K.T.V.); the Department of Intensive Care Medicine, Raymond-Poincaré Hospital (Assistance Publique–Hôpitaux de Paris [AP-HP]), and Fédération Hospitalo-Universitaire SEPSIS, Garches (D.A.), Institut National de la Santé et de la Recherche Médicale, University Paris-Saclay Campus UVSQ, Versailles (D.A.), and Service de Médecine Intensive Réanimation, AP-HP, Hôpitaux Universitaires Henri-Mondor, Groupe de Recherche Clinique CARMAS, and Institut Mondor de Recherche Biomédicale, Université Paris Est Créteil, Créteil (A.M.-D.) — all in France; the College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, and the Department of Intensive Care, King Abdulaziz Medical City, Ministry of National Guard Health Affairs — all in Riyadh, Saudi Arabia (Y.M.A.); and the Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, VIC, Australia (R. Parke, S.P.M., P.J.Y.).

Dr. Lamontagne can be contacted at or at the Department of Medicine, Université de Sherbrooke, 3001 12th Ave. N., Sherbrooke, Quebec J1H 5N4, Canada. Dr. Adhikari can be contacted at or at the Department of Critical Care Medicine, Sunnybrook Health Sciences Centre, 2075 Bayview Ave., Room D1.08, Toronto M4N 3M5, Canada.

A complete list of the LOVIT investigators is provided in the Supplementary Appendix, available at NEJM.org.

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