Effect of Vitamin C, Thiamine, and Hydrocortisone on Ventilator- and Vasopressor-Free Days in Patients With Sepsis
Authors: Jonathan E. 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 A. Levine, Roger J. Lewis, Chris J. Lindsell, Jessica S. Marlin, Anna McGlothlin, Brooks L. Moore, Katherine L. Nugent, Samuel Nwosu, Carmen C. Polito, Todd W. Rice, Erin P. Ricketts, Caroline C. Rudolph, Fred Sanfilippo, Kert Viele, Greg S. Martin, David W. Wright, Katherine L. Nugent, Christine Spainhour, Carmen C. Polito, Brooks L. Moore, Lovie Negrin, Akram Khan, Bory Kea, Olivia Krol, Ebaad Haq, Vincent Pinkert, Kelly Nguyen, Samuel M. Brown, Joseph Bledsoe, Ithan Peltan, Darrin Applegate, Brent Armbruster, Quinn Montgomery, Katie Brown, Austin Daw, Michelle N. Gong, Michael Aboodi, Jen T. Chen, Aluko Hope, Swarna Gummadi, Brenda Lopez, Jeremiah S. Hinson, David N. Hager, Erin P. Ricketts, Casey M. Clements, Ognjen Gajic, Rahul Kashyap, Derek Vanmeter, Laurence W. Busse, Mary McBride, Adit Ginde, Marc Moss, Lani Finck, Michelle Howell, Jeffrey McKeehan, Carrie Higgins, Jonathan Clare, Breana McBryde, Aaron Barksdale, Dan Kalin, Derek Kruse, Katlyn Hilz, Nida Qadir, Steven Y. Chang, Rebecca Beutler, Andrea Tam, Estelle S. Harris, Scott T. Youngquist, Elizabeth A. Middleton, Ervin Davidov, Amber Plante, Justin Belsky, Jonathan Siner, Charles Wira, Carolyn Brokowski, Jay Steingrub, Howard Smithline, Sherell Thornton-Thompson, Alpha A. Fowler, Stephen Miller, Kyle Narron, Michael A. Puskarich, Matthew E. Prekker, Audrey Hendrickson, James Quinn, Jennifer Wilson, Joseph Levitt, Rosen Mann, Anita Visweswaran, Nina Gentile, Nathaniel Marchetti, Hannah Reimer, Faheem Guirgis, Lisa Jones, Lauren Black, Morgan Henson, Nuala J. Meyer, John C. Greenwood, Caroline Ittner, Emanuel Rivers, Namita Jayaprakash, Jayna Gardner-Gray, Gina Hurst, Jacqueline Pflaum, Anja Kathrin Jaehne, Jasreen Gill, Aaron 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 Haukoos, Ivor Douglas, Stacy Trent, Carolynn Lyle, Alicia Cupelo, Stephanie Gravitz, Terra Hiller, Judy Oakes, Frank LoVecchio, Pedro Quiroga, Shiloh Danley, Mary Mulrow, Amanda Encinas, Andrew Goodwin, Gregory Hall, Abigail Grady, Matthew Exline, Thomas Terndrup, Sonal Pannu, Emily Robart, Sarah Karow, D. Clark Files, Lane Smith, Kevin Gibbs, Lori Flores, Stephen M. Pastores, David J. Shaz, Natalie Kostelecky, Chad Case, Elizabeth Wilkins, David F. Gaieski, Michael Baram, Daniel Schwegler, Nicole Renzi, Jarrod M. Mosier, Cameron Hypes, Elizabeth S. Campbell, Michael H. Hooper, Joshua Sill, Kate Mitchell, Kristin Hudock, Michael Lyons, Kari Gorder, Yousef Ahmad, Autumn Studer, Jacqueline Davis, Matthew Barrett, Jason Nomura, Jennifer Knox, Pauline Park, Ivan Co, Jakob McSparron, Robert Hyzy, Kelli McDonough, Sinan Hanna, Wesley H. Self, Matthew W. Semler, Margaret Hays, Raquel Bartz, Alexander Limkakeng, Katherine Sweeney, Rachael Woodburn, Munish Goyal, Akram Zaaqoq, Theresa Moriarty, John Oropello, Ziya Zhang
Journal: JAMA (2021)

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.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.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.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.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.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.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.ClinicalTrials.gov Identifier: NCT03509350.