Lessening Organ dysfunction with VITamin C (LOVIT): protocol for a randomized controlled trial

doi:10.1186/s13063-019-3834-1

. 2020 Jan 8;21(1):42.

doi: 10.1186/s13063-019-3834-1.

Lessening Organ dysfunction with VITamin C (LOVIT): protocol for a randomized controlled trial

Marie-Hélène Masse¹, Julie Ménard¹, Sheila Sprague^{2

3}, Marie-Claude Battista⁴, Deborah J Cook³, Gordon H Guyatt³, Daren K Heyland⁵, Salmaan Kanji⁶, Ruxandra Pinto⁷, Andrew G Day⁸, Dian Cohen⁹, Djillali Annane¹⁰, Shay McGuinness^{11

12}, Rachael Parke^{11

12

13}, Anitra Carr¹⁴, Yaseen Arabi¹⁵, Bharath Kumar Tirupakuzhi Vijayaraghavan¹⁶, Frédérick D'Aragon⁴, Élaine Carbonneau¹, David Maslove¹⁷, Miranda Hunt¹⁷, Bram Rochwerg¹⁸, Tina Millen¹⁹, Michaël Chassé²⁰, Martine Lebrasseur²⁰, Patrick Archambault^{21

22}, Estel Deblois²², Christine Drouin^{23

24}, François Lellouche²⁵, Patricia Lizotte²⁶, Irene Watpool²⁷, Rebecca Porteous²⁷, France Clarke²³, Nicole Marinoff⁷, Émilie Belley-Côté²⁸, Brigitte Bolduc²⁴, Scott Walker²⁹, John Iazzetta³⁰, Neill K J Adhikari^{31

32}, François Lamontagne³³; Canadian Critical Care Trials Group

Affiliations

¹ Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada.
² Division of Orthopaedic Surgery, Department of Surgery, McMaster University, Hamilton, ON, Canada.
³ Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada.
⁴ Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke Sherbrooke and Université de Sherbrooke, Sherbrooke, QC, Canada.
⁵ Department of Critical Care Medicine, Queen's University, Kingston, ON, Canada.
⁶ Departments of Pharmacy and Critical Care, The Ottawa Hospital and Clinical Epidemiology Program, The Ottawa Hospital Research Institute, Ottawa, ON, Canada.
⁷ Department of Critical Care Medicine, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
⁸ Kingston General Health Research Institute, Kingston, ON, Canada.
⁹ No institutional affiliation, No institutional affiliation, Sherbrooke, QC, Canada.
¹⁰ General Intensive Care Unit, Raymond Poincaré Hospital (AP-HP), Lab Inflammation & Infection, U1173 University Paris Saclay-UVSQ/INSERM, Garches, France.
¹¹ Cardiothoracic and Vascular ICU, Auckland City Hospital, Auckland, New Zealand.
¹² Medical Research Institute of New Zealand, Wellington, New Zealand.
¹³ School of Nursing, The University of Auckland, Auckland, New Zealand.
¹⁴ Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand.
¹⁵ College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.
¹⁶ Department of Critical Care Medicine, Apollo Hospitals, Chennai, India.
¹⁷ Department of Critical Care Medicine, Queen's University and Kingston Health Sciences Centre, Kingston, ON, Canada.
¹⁸ Department of Medicine and Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada.
¹⁹ Juravinski Hospital, Hamilton, ON, Canada.
²⁰ Centre de Recherche du Centre Hospitalier Universitaire de Montréal, Montréal, QC, Canada.
²¹ Faculté de Médecine, Université Laval, Québec City, QC, Canada.
²² Département des soins intensifs du Centre intégré de santé et des services sociaux de Chaudière-Appalaches (Secteur Alphonse-Desjardins), Lévis, QC, Canada.
²³ Department of Critical Care Research, St. Joseph's Healthcare, Hamilton, ON, Canada.
²⁴ Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada.
²⁵ Department of Medecine, Université Laval and Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Québec City, QC, Canada.
²⁶ Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec City, QC, Canada.
²⁷ Ottawa Hospital Research Institute, Ottawa, ON, Canada.
²⁸ Division of Cardiology, Department of Medicine, McMaster University, Population Health Research Institute, Hamilton, ON, Canada.
²⁹ Department of Pharmacy, Sunnybrook Health Sciences Centre, Toronto, Canada and Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
³⁰ Department of Pharmacy, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
³¹ Department of Critical Care Medicine, Sunnybrook Health Sciences Centre, Toronto, ON, Canada. neill.adhikari@utoronto.ca.
³² Interdepartmental Division of Critical Care Medicine and Institute for Health Policy, Management, and Evaluation, University of Toronto, Toronto, ON, Canada. neill.adhikari@utoronto.ca.
³³ Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke Sherbrooke and Université de Sherbrooke, Sherbrooke, QC, Canada. francois.lamontagne@usherbrooke.ca.

PMID: 31915072
PMCID: PMC6950903
DOI: 10.1186/s13063-019-3834-1

Lessening Organ dysfunction with VITamin C (LOVIT): protocol for a randomized controlled trial

Marie-Hélène Masse et al. Trials. 2020.

. 2020 Jan 8;21(1):42.

doi: 10.1186/s13063-019-3834-1.

Authors

Affiliations

¹ Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada.
² Division of Orthopaedic Surgery, Department of Surgery, McMaster University, Hamilton, ON, Canada.
³ Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada.
⁴ Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke Sherbrooke and Université de Sherbrooke, Sherbrooke, QC, Canada.
⁵ Department of Critical Care Medicine, Queen's University, Kingston, ON, Canada.
⁶ Departments of Pharmacy and Critical Care, The Ottawa Hospital and Clinical Epidemiology Program, The Ottawa Hospital Research Institute, Ottawa, ON, Canada.
⁷ Department of Critical Care Medicine, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
⁸ Kingston General Health Research Institute, Kingston, ON, Canada.
⁹ No institutional affiliation, No institutional affiliation, Sherbrooke, QC, Canada.
¹⁰ General Intensive Care Unit, Raymond Poincaré Hospital (AP-HP), Lab Inflammation & Infection, U1173 University Paris Saclay-UVSQ/INSERM, Garches, France.
¹¹ Cardiothoracic and Vascular ICU, Auckland City Hospital, Auckland, New Zealand.
¹² Medical Research Institute of New Zealand, Wellington, New Zealand.
¹³ School of Nursing, The University of Auckland, Auckland, New Zealand.
¹⁴ Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand.
¹⁵ College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.
¹⁶ Department of Critical Care Medicine, Apollo Hospitals, Chennai, India.
¹⁷ Department of Critical Care Medicine, Queen's University and Kingston Health Sciences Centre, Kingston, ON, Canada.
¹⁸ Department of Medicine and Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada.
¹⁹ Juravinski Hospital, Hamilton, ON, Canada.
²⁰ Centre de Recherche du Centre Hospitalier Universitaire de Montréal, Montréal, QC, Canada.
²¹ Faculté de Médecine, Université Laval, Québec City, QC, Canada.
²² Département des soins intensifs du Centre intégré de santé et des services sociaux de Chaudière-Appalaches (Secteur Alphonse-Desjardins), Lévis, QC, Canada.
²³ Department of Critical Care Research, St. Joseph's Healthcare, Hamilton, ON, Canada.
²⁴ Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada.
²⁵ Department of Medecine, Université Laval and Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Québec City, QC, Canada.
²⁶ Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec City, QC, Canada.
²⁷ Ottawa Hospital Research Institute, Ottawa, ON, Canada.
²⁸ Division of Cardiology, Department of Medicine, McMaster University, Population Health Research Institute, Hamilton, ON, Canada.
²⁹ Department of Pharmacy, Sunnybrook Health Sciences Centre, Toronto, Canada and Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
³⁰ Department of Pharmacy, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
³¹ Department of Critical Care Medicine, Sunnybrook Health Sciences Centre, Toronto, ON, Canada. neill.adhikari@utoronto.ca.
³² Interdepartmental Division of Critical Care Medicine and Institute for Health Policy, Management, and Evaluation, University of Toronto, Toronto, ON, Canada. neill.adhikari@utoronto.ca.
³³ Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke Sherbrooke and Université de Sherbrooke, Sherbrooke, QC, Canada. francois.lamontagne@usherbrooke.ca.

PMID: 31915072
PMCID: PMC6950903
DOI: 10.1186/s13063-019-3834-1

Abstract

Background: Sepsis is a health problem of global importance; treatments focus on controlling infection and supporting failing organs. Recent clinical research suggests that intravenous vitamin C may decrease mortality in sepsis. We have designed a randomized controlled trial (RCT) to ascertain the effect of vitamin C on the composite endpoint of death or persistent organ dysfunction at 28 days in patients with sepsis.

Methods: LOVIT (Lessening Organ dysfunction with VITamin C) is a multicenter, parallel-group, blinded (participants, clinicians, study personnel, Steering Committee members, data analysts), superiority RCT (minimum n = 800). Eligible patients have sepsis as the diagnosis for admission to the intensive care unit (ICU) and are receiving vasopressors. Those admitted to the ICU for more than 24 h are excluded. Eligible patients are randomized to high-dose intravenous vitamin C (50 mg/kg every 6 h for 96 h) or placebo. The primary outcome is a composite of death or persistent organ dysfunction (need for vasopressors, invasive mechanical ventilation, or new and persisting renal replacement therapy) at day 28. Secondary outcomes include persistent organ dysfunction-free days to day 28, mortality and health-related quality of life at 6 months, biomarkers of dysoxia, inflammation, infection, endothelial function, and adverse effects (hemolysis, acute kidney injury, and hypoglycemia). Six subgroup analyses are planned.

Discussion: This RCT will provide evidence of the effect of high-dose intravenous vitamin C on patient-important outcomes in patients with sepsis.

Trial registration: clinicaltrials.gov, NCT03680274, first posted 21 September 2018.

Keywords: biomarkers; randomized controlled trial; sepsis; septic shock; vitamin C.

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Conflict of interest statement

The authors declare that they have no competing interests.

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References

1. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) JAMA. 2016;315(8):801–810. doi: 10.1001/jama.2016.0287. - DOI - PMC - PubMed
1. Fleischmann C, Scherag A, Adhikari NK, Hartog CS, Tsaganos T, Schlattmann P, Angus DC, Reinhart K. International Forum of Acute Care Trialists: Assessment of Global Incidence and Mortality of Hospital-treated Sepsis. Current Estimates and Limitations. Am J Respir Crit Care Med. 2016;193(3):259–272. doi: 10.1164/rccm.201504-0781OC. - DOI - PubMed
1. Herridge MS, Chu LM, Matte A, Tomlinson G, Chan L, Thomas C, Friedrich JO, Mehta S, Lamontagne F, Levasseur M, et al. The RECOVER Program: disability risk groups and 1-year outcome after 7 or more days of mechanical ventilation. Am J Respir Crit Care Med. 2016;194(7):831–844. doi: 10.1164/rccm.201512-2343OC. - DOI - PubMed
1. Garland A, Olafson K, Ramsey CD, Yogendran M, Fransoo R. A population-based observational study of intensive care unit-related outcomes. With emphasis on post-hospital outcomes. Ann Am Thorac Soc. 2015;12(2):202–208. doi: 10.1513/AnnalsATS.201405-201CME. - DOI - PubMed
1. Dugani S, Veillard J, Kissoon N. Reducing the global burden of sepsis. CMAJ. 2017;189(1):E2–E3. doi: 10.1503/cmaj.160798. - DOI - PMC - PubMed

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[1] Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) JAMA. 2016;315(8):801–810. doi: 10.1001/jama.2016.0287. - DOI - PMC - PubMed

[2] Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) JAMA. 2016;315(8):801–810. doi: 10.1001/jama.2016.0287. - DOI - PMC - PubMed

[3] Fleischmann C, Scherag A, Adhikari NK, Hartog CS, Tsaganos T, Schlattmann P, Angus DC, Reinhart K. International Forum of Acute Care Trialists: Assessment of Global Incidence and Mortality of Hospital-treated Sepsis. Current Estimates and Limitations. Am J Respir Crit Care Med. 2016;193(3):259–272. doi: 10.1164/rccm.201504-0781OC. - DOI - PubMed

[4] Fleischmann C, Scherag A, Adhikari NK, Hartog CS, Tsaganos T, Schlattmann P, Angus DC, Reinhart K. International Forum of Acute Care Trialists: Assessment of Global Incidence and Mortality of Hospital-treated Sepsis. Current Estimates and Limitations. Am J Respir Crit Care Med. 2016;193(3):259–272. doi: 10.1164/rccm.201504-0781OC. - DOI - PubMed

[5] Herridge MS, Chu LM, Matte A, Tomlinson G, Chan L, Thomas C, Friedrich JO, Mehta S, Lamontagne F, Levasseur M, et al. The RECOVER Program: disability risk groups and 1-year outcome after 7 or more days of mechanical ventilation. Am J Respir Crit Care Med. 2016;194(7):831–844. doi: 10.1164/rccm.201512-2343OC. - DOI - PubMed

[6] Herridge MS, Chu LM, Matte A, Tomlinson G, Chan L, Thomas C, Friedrich JO, Mehta S, Lamontagne F, Levasseur M, et al. The RECOVER Program: disability risk groups and 1-year outcome after 7 or more days of mechanical ventilation. Am J Respir Crit Care Med. 2016;194(7):831–844. doi: 10.1164/rccm.201512-2343OC. - DOI - PubMed

[7] Garland A, Olafson K, Ramsey CD, Yogendran M, Fransoo R. A population-based observational study of intensive care unit-related outcomes. With emphasis on post-hospital outcomes. Ann Am Thorac Soc. 2015;12(2):202–208. doi: 10.1513/AnnalsATS.201405-201CME. - DOI - PubMed

[8] Garland A, Olafson K, Ramsey CD, Yogendran M, Fransoo R. A population-based observational study of intensive care unit-related outcomes. With emphasis on post-hospital outcomes. Ann Am Thorac Soc. 2015;12(2):202–208. doi: 10.1513/AnnalsATS.201405-201CME. - DOI - PubMed

[9] Dugani S, Veillard J, Kissoon N. Reducing the global burden of sepsis. CMAJ. 2017;189(1):E2–E3. doi: 10.1503/cmaj.160798. - DOI - PMC - PubMed

[10] Dugani S, Veillard J, Kissoon N. Reducing the global burden of sepsis. CMAJ. 2017;189(1):E2–E3. doi: 10.1503/cmaj.160798. - DOI - PMC - PubMed

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Lessening Organ dysfunction with VITamin C (LOVIT): protocol for a randomized controlled trial

Affiliations

Lessening Organ dysfunction with VITamin C (LOVIT): protocol for a randomized controlled trial

Authors

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Abstract

Conflict of interest statement

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Abstract

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