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Effect of Vitamin C, Thiamine, and Hydrocortisone on Ventilator- and Vasopressor-Free Days in Patients With Sepsis

2021; American Medical Association; Volume: 325; Issue: 8 Linguagem: Inglês

10.1001/jama.2020.24505

1538-3598

Jonathan Sevransky, Richard E. Rothman, David N. Hager, Gordon R. Bernard, Samuel M. Brown, Timothy G. Buchman, Laurence W. Busse, Craig M. Coopersmith, Christine DeWilde, E. Wesley Ely, Lindsay M. Eyzaguirre, Alpha A. Fowler, David F. Gaieski, Michelle N. Gong, Alex Hall, Jeremiah S. Hinson, Michael H. Hooper, Gabor D. Kelen, Akram Khan, Mark Levine, Roger Lewis, Christopher J. Lindsell, Jessica S. Marlin, Anna McGlothlin, Brooks Moore, K. Nugent, Samuel Nwosu, Carmen Polito, Todd W. Rice, Erin P. Ricketts, Caroline C. Rudolph, Fred Sanfilippo, Kert Viele, Greg S. Martin, David W. Wright, K. Nugent, Christine Spainhour, Carmen Polito, Brooks Moore, Lovie Negrin, Akram Khan, Bory Kea, Olivia Krol, Ebaad Haq, Vincent Pinkert, Kelly Nguyen, Samuel M. Brown, Joseph Bledsoe, Ithan D. Peltan, Darrin Applegate, Brent Armbruster, Quinn Montgomery, Samuel M. Brown, Austin Daw, Michelle N. Gong, Michael S. Aboodi, Jen T. Chen, Aluko A. Hope, Swarna Gummadi, Brenda López, Jeremiah S. Hinson, David N. Hager, Erin P. Ricketts, Casey M. Clements, Ognjen Gajic, Rahul Kashyap, Derek Vanmeter, Laurence W. Busse, Mary L. McBride, Adit A. Ginde, Marc Moss, Lani Finck, Michelle Howell, Jeffrey McKeehan, Carrie Higgins, Jonathan Clare, Breana McBryde, Aaron Barksdale, Dan Kalin, Derek A. Kruse, Katlyn Hilz, Nida Qadir, Steven Y. Chang, Rebecca M. Beutler, Andrea Tam, Estelle S. Harris, Scott T. Youngquist, Elizabeth A. Middleton, Ervin Davidov, Amber E. Plante, Justin Belsky, Jonathan Siner, Charles Wira, Carolyn Brokowski, Jay S. Steingrub, Howard Smithline, Sherell Thornton‐Thompson, Alpha A. Fowler, Stephen T. Miller, Kyle Narron, Michael A. Puskarich, Matthew E. Prekker, Audrey Hendrickson, James Quinn, Jennifer G. Wilson, Joseph E. Levitt, Rosen Mann, Anita Visweswaran, Nina T. Gentile, Nathaniel Marchetti, Hannah Reimer, Faheem W. Guirgis, Lisa Jones, Lauren Page Black, Morgan Henson, Nuala J. Meyer, John C. Greenwood, C.A.G. Ittner, Emanuel P. Rivers, Namita Jayaprakash, Jayna Gardner-Gray, Gina Hurst, Jacqueline Pflaum, Anja Kathrin Jaehne, Jasreen Gill, Aaron M. Cook, David R. Janz, Derek Vonderhaar, Connie Romaine, R. Gentry Wilkerson, Michael T. McCurdy, Dana Beach, Kyra Lasko, Richard Gill, Katherine Price, Lisa Dickson, Abhijit Duggal, Sharon E. Mace, R. Duncan Hite, Andrei Hastings, Jason S. Haukoos, Ivor S. Douglas, Stacy A. Trent, Carolynn Lyle, Alicia Cupelo, Stephanie Gravitz, T. Hiller, Judy Oakes, Frank LoVecchio, Pedro Quiroga, Shiloh Danley, Mary Mulrow, Amanda Encinas, Andrew J. Goodwin, Gregory E. Hall, Abigail Grady, Matthew C. Exline, Thomas E. Terndrup, Sonal Pannu, Emily Robart, Sarah Karow, D. Clark Files, Lane M. Smith, Kevin W. Gibbs, Lori Flores, Stephen M. Pastores, David Shaz, Natalie Kostelecky, Catherine M. Case, Elizabeth A. Wilkins, David F. Gaieski, Michael Baram, Daniel Schwegler, Nicole Renzi, Jarrod Mosier, Cameron Hypes, Elizabeth Salvagio Campbell, Michael H. Hooper, Joshua Sill, Kate M. Mitchell, Kristin Hudock, Michael J. Lyons, Kari Gorder, Ahmad Yousef, Autumn Studer, Jacqueline Davis, Matthew J. Barrett, Jason T. Nomura, Jennifer J. Knox, Pauline Park, Ivan Co, Jakob I. McSparron, Robert C. Hyzy, Kelli McDonough, Sinan Hanna, Wesley H. Self, Matthew W. Semler, Margaret Hays, Raquel R. Bartz, Alexander T. Limkakeng, Katherine Sweeney, Rachael Woodburn, Munish Goyal, Akram Zaaqoq, Theresa Moriarty, John M. Oropello, Ziya Zhang,

Vitamin K Research Studies

Importance Sepsis is a common syndrome with substantial morbidity and mortality. A combination of vitamin C, thiamine, and corticosteroids has been proposed as a potential treatment for patients with sepsis. Objective To determine whether a combination of vitamin C, thiamine, and hydrocortisone every 6 hours increases ventilator- and vasopressor-free days compared with placebo in patients with sepsis. Design, Setting, and Participants Multicenter, randomized, double-blind, adaptive-sample-size, placebo-controlled trial conducted in adult patients with sepsis-induced respiratory and/or cardiovascular dysfunction. Participants were enrolled in the emergency departments or intensive care units at 43 hospitals in the United States between August 2018 and July 2019. After enrollment of 501 participants, funding was withheld, leading to an administrative termination of the trial. All study-related follow-up was completed by January 2020. Interventions Participants were randomized to receive intravenous vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) every 6 hours (n = 252) or matching placebo (n = 249) for 96 hours or until discharge from the intensive care unit or death. Participants could be treated with open-label corticosteroids by the clinical team, with study hydrocortisone or matching placebo withheld if the total daily dose was greater or equal to the equivalent of 200 mg of hydrocortisone. Main Outcomes and Measures The primary outcome was the number of consecutive ventilator- and vasopressor-free days in the first 30 days following the day of randomization. The key secondary outcome was 30-day mortality. Results Among 501 participants randomized (median age, 62 [interquartile range {IQR}, 50-70] years; 46% female; 30% Black; median Acute Physiology and Chronic Health Evaluation II score, 27 [IQR, 20.8-33.0]; median Sequential Organ Failure Assessment score, 9 [IQR, 7-12]), all completed the trial. Open-label corticosteroids were prescribed to 33% and 32% of the intervention and control groups, respectively. Ventilator- and vasopressor-free days were a median of 25 days (IQR, 0-29 days) in the intervention group and 26 days (IQR, 0-28 days) in the placebo group, with a median difference of −1 day (95% CI, −4 to 2 days; P = .85). Thirty-day mortality was 22% in the intervention group and 24% in the placebo group. Conclusions and Relevance Among critically ill patients with sepsis, treatment with vitamin C, thiamine, and hydrocortisone, compared with placebo, did not significantly increase ventilator- and vasopressor-free days within 30 days. However, the trial was terminated early for administrative reasons and may have been underpowered to detect a clinically important difference. Trial Registration ClinicalTrials.gov Identifier:NCT03509350