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Low-dose methylprednisolone treatment in critically ill patients with severe community-acquired pneumonia

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Abstract

Purpose

Severe community-acquired pneumonia (CAP) requiring intensive care unit admission is associated with significant acute and long-term morbidity and mortality. We hypothesized that downregulation of systemic and pulmonary inflammation with prolonged low-dose methylprednisolone treatment would accelerate pneumonia resolution and improve clinical outcomes.

Methods

This double-blind, randomized, placebo-controlled clinical trial recruited adult patients within 72–96 h of hospital presentation. Patients were randomized in 1:1 ratio; an intravenous 40 mg loading bolus was followed by 40 mg/day through day 7 and progressive tapering during the 20-day treatment course. Randomization was stratified by site and need for mechanical ventilation (MV) at the time of randomization. Outcomes included a primary endpoint of 60-day all-cause mortality and secondary endpoints of morbidity and mortality up to 1 year of follow-up.

Results

Between January 2012 and April 2016, 586 patients from 42 Veterans Affairs Medical Centers were randomized, short of the 1420 target sample size because of low recruitment. 584 patients were included in the analysis. There was no significant difference in 60-day mortality between the methylprednisolone and placebo arms (16% vs. 18%; adjusted odds ratio 0.90, 95% CI 0.57–1.40). There were no significant differences in secondary outcomes or complications.

Conclusions

In patients with severe CAP, prolonged low-dose methylprednisolone treatment did not significantly reduce 60-day mortality. Treatment was not associated with increased complications.

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Acknowledgements

We dedicate this work to the memory of Timothy D. Bigby, Principal Investigator at the San Diego VA; his warmth, kindness and professional commitment is missed by all those that had the privilege of working with him. Additional recognition goes to Kelvin K. Lee, PhD, Valerie McGuire, PhD, and Colleen Fitzsimmons (VA Palo Alto Cooperative Studies Program Coordinating Center), Stuart Warren, David Pittman and Jolene Day (VA Albuquerque Cooperative Studies Program Pharmacy Coordinating Center), and Jennifer Ransom, MPH, CCRP (Memphis VA Medical Center Chair’s Office). We also wish to thank the Veterans whose participation made the study possible.

ESCAPe study group members: Khalid Bashir, Octavian Ioachimescu, Theresa Buck, David Johnson, Ali El Solh, Michael Frye, Ralph Panos, Mohammad Shatat, Enoch Gray, Brian Smith, Myron Kung, James Cutrell, Roger Bedimo, Peruvemba Sriram, Charlie Lan, Padmashi Rastogi, John Callaghan, Chadi Hage, Mark Plautz, Takako Schaninger, Richard Greenberg, Lennard Specht, Catherine Sassoon, Juan Guardiola, Julio Ramirez, Muthiah P. Muthiah, Roland Schein, Andreea Antonesu-Turcu, Kathryn Rice, Houssein Youness, Lee Morrow, Ware Kuschner, Lilibeth Pineda, Richard Allen Robbins, Sharon Camhi, Matthew Jankowich, Waseem Ahmed, Thomas Martin, Mitchell Horowitz, John Nord, Mark Elstad, Marcos I. Restrepo, Antonio Anzueto, Timothy Bigby, William Rodriguez-Cintron, Vincent Fan, Pratibha Kaul, Michael Habib, Nitin Seam, Guy Soo Hoo.

Veterans affairs medical centers participating in the ESCAPe trial: Participating VAMCs in alphabetical order (ESCAPe site personnel in parenthesis): Asheville, (Khalid Bashir, Whitney Sprinkle, Webster Bazemore, Sujatha Goli, John Lucke, Valerie Allen); Atlanta, (Octavian Ioachimescu, Tiffany Elliott, Amy Anderson, Joanne Allam, Ashish Mehta, Patricia Noren, Vidisha Tanukonda); Bay Pines, (Theresa Buck, David Johnson, Caitlin Butler, James Blankenship, Patricia Ellis, Minhaj Siddiqui, Lynn Anderson); Buffalo, (Ali El-Solh, Lynne Frydrych, Karin Provost, Rachel LaPorta, Philippe Jaoude, Leah Vermont); Charleston, (Michael Frye, Leslie Harrell); Cincinnati, (Ralph Panos, Laura Lach, Dennis McGraw, Nishant Gupta, William Eschenbacher); Cleveland, (Mohammad Shatat, Kimberley Byrne, Frank Jacono, Puja Van Epps); Columbia, (Enoch Gray, Brian Smith, Myron Kung, Joanna Snead, Justin Reynolds, Mohammed Wallam, Shilpa Patel, Stuart Smith, Kathryn Mason, Heather Roth, Rebecca Warner); Dallas, (James Cutrell, Roger Bedimo, John Battaile, Teagan Lampkin, Joyce Ghormley, David Albracht, Cyenthia Willis, Padmashri Rastogi, Holly Wise); Gainesville, (Peruvemba Sriram, Omerea Herring, Daniel Urbine, James Wynne, Ramanjeet Singh, Alice Boyette, Rosie Kizza, Eloise Harman, Michelle Ginsburg); Houston, (Charlie Lan, Sarah Perusich, Daniel Musher, Farrah Kheradmand, Lavannya Pandit, Roberto Casal, Rolando Rumbaut, Amir Sharafkhaneh, Suryakanta Velamuri, Pamela Smithwick, Sherilyn Pillack, Nazanin Zarinkamar, Emily Broussard, Cynthia Boudreaux); Indianapolis, (John Callaghan, Sharon Henson, Casey Stahlheber, Vru Patel, Aliya Noor); Kansas City, (Mark Plautz, Cheryl Perkins, Trenton Nauser, Justine Unruh); Lexington, (Takako Schaninger, Edward Hirshowitz, Hannah Ferrell, Sabrina Broden); Loma Linda, (Lennard Specht, Laura Weaver-Carnahan, James Anholm, Hemad Parekh, Nagamani Dandamudi, Kathleen Ellstrom, Jamie Portillo, Sara Rubio); Long Beach, (Catherine Sassoon, Romena Helal, Yih-Ming Chi, Farhad Mazdisnian, Aliya Asghar, David Stansbury, Gelincik Oraciklar, Lei Zhu); Louisville, (Juan Guardiola, Belica Graf, Rafael Perez, Bogdan Moldoveanu, Julio Ramirez, Jesse Roman, Umair Guahar, Angela Kain, Jinesh Mehta, Ginny Sciortino); Memphis, (Muthiah P. Muthiah, Kathleen Bockhold, Ibrahim Sultan-Ali, Amado Freire, Muhammad Zaman, Veronica Castillo, Margaret Sanders, Lori Sykes); Miami, (Roland Schein, Jacqueline Junco, Lisa Camacho, Cynthia Cely, Michael Hyre, Gregory McGrath, Daniel Coes, Devora Khan); Milwaukee, (Andreea Antonescu-Turcu, Susan Framberg, Mary Ellis, Sharon Pecsi, Christa Kallio); Minneapolis, (Kathryn Rice, Linda Kollman, Dennis Niewoehner, Angela Fabbrini, Debra Condon, Christine Wendt, Erin Wetherbee, Miranda Deconcini, Brandon Doyle, George Sarosi, Ken Kunisaki, Doris Stuber), Oklahoma, (Houssein Youness, Laurel Howard, Jean Keddissi, Ahmed Awab, Ashley Ellis); Omaha, (Lee Morrow, Mary Pote, Kristina Bailey, Daniel Hershberger, Theresa Ramelb); Palo Alto, (Ware Kuschner, Elena Nikolaev, Juliana Barr, Edward Bertaccini, Karen Bratcher, Carlos Brun, Rajinder Chitkara, Jon-Erik Holty, Geoffrey Lighthall, Daphne Ly, Harman Paintal, Craig Zone, Alda Vicencio); Phoenix, (Lilibeth Pineda, Susan Brannan, Clement Singarajah, Pat Jacobs, Lisa Orozco); Pittsburgh, (Sharon Camhi, Marie Berger, Kathryn Hartwig, Charles Atwood, Sarita Kumari, Emily Grum, Mary Van Buskirk, Marcia Homer, Melissa Clark); Providence, (Matthew Jankowich, Sandra Befera, Linda Nici, Sharon Rounds); Reno, (Waseem Ahmed, Anne Inda, Anurag Mehta, Pam Lehman, Andrew Liu, Claudine Aguilera); Salem, (Thomas Martin, Mary Halling, Anil Agarwal, David Boone, Barbara Bowers, Neeraj Gupta, Mitchell Horowitz, Deepa Lala, Mitra Sahebazamani, Tonda Yates); Salt Lake City, (John Nord, Amy Beckstead, Elisabeth Carr, Moises Cortez, Heather Dulin, Mark Elstad, Lydia Rosenthal, Karl Sanders, Lindsay Carpenter, Wade Brown); San Antonio, (Marcos I. Restrepo, Luis Reyes, Antonio Anzueto, Alejandro Arango, Sandra Adams, Anisha Arora, Karla Diaz, Felipe Fernandez, Pamela Foltz, Tim Hernandez, Timothy Houlihan, Stephanie Levine, Adriel Malave, Breion Mallioux, Diego Maselli, Benjamin Michels, Anoop Nambiar, Hector Payan, Jay Peters); San Diego, (Timothy Bigby*, Keith Nicalo, Judd Landsberg, Mark Fuster, Philippe Montgrain, Danielle Beck), San Juan, (William Rodriguez-Cintron, Julia Roig, Damaris Acosta-Miranda, Edwin Alicea, Joan Albors-Sanchez, Jesse Aleman-Ortiz, Felicita Aruz, Onix Cantres-Fonseca, Maria del Mar Torres-Perez, Francisco Del Olmo, Juan Flores, Sandra Galarza-Vargas, Ricardo Hernandez-Castillo, Juancarlos Martinez, Carlos Robles-Arias, Yarilys Rodriguez-Sepulveda); Seattle, (Vincent Fan, Cynthia Lotane, Pauline Shull, Richard Goodman, Cornelia Schneider); Syracuse, (Pratibha Kaul, Autum Bellinger, Girish Trikha, Adnan Abbasi, Bonnie VerHeecke, Mark Chilton); Tucson, (Michael Habib, Tom Vincent, Gina Blackwell, Dena L’Heureux, Wei Shen); Washington DC, (Nitin Seam, Parisa Coffman, Bashar Albarghuthy, Jessica Smith); West Los Angeles, (Guy Soo Hoo, May Luciano).

Member of committees and CSP 574 organizational structure of the trial: Planning Committee: Gianfranco Umberto Meduri, MD (Principal Proponent: Memphis VA Medical Center); Antonio Anzueto, MD (University of Texas Health Science Center); Mark Holodniy, MD (VA Palo Alto Health Care System); Philip Lavori, PhD (Stanford Comprehensive Cancer Center); Linda Nichols, PhD (Memphis VA Medical Center); Lori Nielsen (VA Palo Alto Cooperative Studies Program Coordinating Center); Mei-Chiung Shih, PhD (VA Palo Alto Cooperative Studies Program Coordinating Center); Anthony F. Suffredini, MD (National Institutes of Health Clinical Center); Derek C. Angus, MD, MPH (University of Pittsburgh School of Medicine); Thomas M. File, Jr., MD, MSc (Northeastern Ohio Universities College of Medicine); Kelvin K. Lee, PhD (VA Palo Alto Cooperative Studies Program Coordinating Center); Paul Marik, MD (East Virginia Medical School); Dennis E. Niewoehner, MD (Minneapolis VA Healthcare System); Mike Sather, PhD (VA CSP Clinical Research Pharmacy Coordinating Center, Albuquerque, NM); Mark W. Smith, PhD (VA Health Economics Resource Center); Stuart R. Warren, JD, PharmD (VA CSP Clinical Research Pharmacy Coordinating Center, Albuquerque, NM).

Study chairman’s office: Gianfranco Umberto Meduri, MD (Memphis VA Medical Center); Lisa Bridges, RN, MS, ACNP-BC (Memphis VA Medical Center); Jennifer Ransom, MPH (Memphis VA Medical Center).

Executive committee: Gianfranco Umberto Meduri, MD (Memphis VA Medical Center); Lisa Bridges, RN, MS, ACNP-BC (Memphis VA Medical Center); Ali El-Solh, MD (VA Western New York Health Care System); Nitin Seam, MD (National Institutes of Health Clinical Center); Antonio Anzueto, MD (University of Texas Health Science Center); Anthony F. Suffredini, MD (National Institutes of Health Clinical Center); Reba Umberger, MS, RN, CCRN, PhD (University of Tennessee Health Science Center); W. Andrew Bell, PharmD (Memphis VA Medical Center, Renown Health, Reno, NV); Anne Davis-Karim, PharmD and Stuart R. Warren, JD, (ex officio) (VA CSP Clinical Research Pharmacy Coordinating Center); Thomas J. Martin, MD (Salem VA Medical Center); Mei-Chiung Shih, PhD, Colleen Fitzsimmons, BS, Kelvin Lee, PhD, (ex officio), Julia Lin, PhD, (ex officio), Valerie McGuire, PhD, (ex officio), Lori Nielsen, BA, (ex officio) (VA CSP Palo Alto Coordinating Center).

Data and Safety Monitoring Committee: Robert Danner, MD (National Institutes of Health Clinical Center); Matthew Goetz, MD (VA Greater Los Angeles Healthcare System); Joan Hilton, ScD (University of California San Francisco); John Kellum, MD (University of Pittsburgh School of Medicine); David Looney, MD, PhD (University of California San Diego); Colin Wu, PhD (National Heart Lung and Blood Institute); Richard ZuWallack, MD (Saint Francis Hospital and Medical Center).

Clinical Evaluation Committee: Ali El-Solh, MD (VA Western New York Health Care System); Nitin Seam, MD (National Institutes of Health Clinical Center); Marcos I. Restrepo, MD (South Texas Veterans Health Care System); Antonio Anzueto, MD (University of Texas Health Science Center); Octavian Ioachimescu, MD (Atlanta VA Health Care System); Charlie Lan, MD (Michael E. DeBakey VA Medical Center).

VA Palo Alto CSP Coordinating Center: Mei-Chiung Shih, PhD, Ying Lu, PhD, Kelvin Lee, PhD, Valerie McGuire, PhD, Julia Lin, PhD, Lan Zhao, Colleen Fitzsimmons, Lori Nielsen, Parinaz Lajevardi, MPH, Aileen Baylosis, Elizabeth Smith, Lauren Uyeda, Ania Ray, Jennifer Cockroft, Martha Forrester, Aaron Alsleben, Anita Kelly, Nigel Gladhart.

VA Albuquerque CSP Clinical Research Pharmacy Coordinating Center: Stuart Warren, JD, PharmD, Anne Davis-Karim, PharmD, Alexandra Scrymgeour, PharmD, Jolene Day, and David Pittman.

The CSP Site Monitoring, Auditing and Review Team (SMART); Mary Mills, RN, CCRA, Tasha Anderson, RN, BSN, Mariette Coyle, RN, MSN, Barbara Curtis, Michelle Prehoda, Clair Haakenson, Darlene Kreuger.

Funding

This study was conducted with support from the VA Cooperative Studies Program. However, the views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs or any US governmental agency. Role of the sponsor: The VA Cooperative Studies program was involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation of the manuscript. The data from the 42 sites were maintained by the VA Cooperative Studies Program Coordinating Center in Palo Alto, CA, where Mei-Chiung Shih, PhD, performed all statistical analyses with assistance from Lan Zhao, MS, and Lauren Uyeda, MA. Funding was provided by Department of Veterans Affairs, Cooperative Studies Program (Grant no. CSP #2009).

Author information

Authors and Affiliations

  1. Pulmonary, Critical Care and Sleep Medicine Services, Memphis VA Medical Center, Memphis, USA

    G. Umberto Meduri & Lisa Bridges

  2. University of Tennessee Health Science Center, Memphis, USA

    G. Umberto Meduri, Lisa Bridges & Reba Umberger

  3. VA Cooperative Studies Program Coordinating Center, Palo Alto, USA

    Mei-Chiung Shih, Julia Lin, Lan Zhao, Lauren Uyeda & Lori Nielsen

  4. Department of Biomedical Data Sciences, Stanford University, Stanford, USA

    Mei-Chiung Shih

  5. Salem VA Health Care System, Salem, USA

    Thomas J. Martin

  6. Virginia Tech Carilion School of Medicine, Roanoke, USA

    Thomas J. Martin

  7. Edward Via Virginia College of Osteopathic Medicine, Blacksburg, USA

    Thomas J. Martin

  8. VA Western New York Health Care System, Buffalo, USA

    Ali El-Solh

  9. University at Buffalo, Buffalo, USA

    Ali El-Solh

  10. National Institutes of Health Clinical Center, Bethesda, USA

    Nitin Seam & Anthony Suffredini

  11. VA Cooperative Studies Program Pharmacy Coordinating Center, Albuquerque, USA

    Anne Davis-Karim

  12. South Texas Veterans Health San Antonio, San Antonio, USA

    Antonio Anzueto & Marcos I. Restrepo

  13. University of Texas Health Science Center, Houston, USA

    Antonio Anzueto & Marcos I. Restrepo

  14. Malcom Randall VA Medical Center, Gainesville, USA

    Peruvemba Sriram

  15. Michael E Debakey VA Medical Center, Houston, USA

    Charlie Lan

  16. Robley Rex VA Medical Center, Louisville, USA

    Juan J. Guardiola

  17. University of Louisville, Louisville, USA

    Juan J. Guardiola

  18. Bay Pines VA Healthcare Center, Bay Pines, USA

    Teresa Buck & David P. Johnson

  19. Renown Health, Reno, NV, USA

    W. Andrew Bell

  20. Office of Research and Development, Department of Veterans Affairs, Baltimore, USA

    Grant D. Huang

Authors
  1. G. Umberto Meduri
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  2. Mei-Chiung Shih
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  3. Lisa Bridges
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  4. Thomas J. Martin
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  5. Ali El-Solh
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  6. Nitin Seam
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  7. Anne Davis-Karim
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  8. Reba Umberger
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  9. Antonio Anzueto
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  10. Peruvemba Sriram
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  11. Charlie Lan
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  12. Marcos I. Restrepo
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  13. Juan J. Guardiola
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  14. Teresa Buck
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  15. David P. Johnson
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  16. Anthony Suffredini
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  18. Julia Lin
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  19. Lan Zhao
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  20. Lauren Uyeda
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Consortia

the ESCAPe Study Group

  • Khalid Bashir
  • , Octavian Ioachimescu
  • , Theresa Buck
  • , David Johnson
  • , Ali El Solh
  • , Michael Frye
  • , Ralph Panos
  • , Mohammad Shatat
  • , Enoch Gray
  • , Brian Smith
  • , Myron Kung
  • , James Cutrell
  • , Roger Bedimo
  • , Peruvemba Sriram
  • , Charlie Lan
  • , Padmashi Rastogi
  • , John Callaghan
  • , Chadi Hage
  • , Mark Plautz
  • , Takako Schaninger
  • , Richard Greenberg
  • , Lennard Specht
  • , Catherine Sassoon
  • , Juan Guardiola
  • , Julio Ramirez
  • , Muthiah P Muthiah
  • , Roland Schein
  • , Andreea Antonesu-Turcu
  • , Kathryn Rice
  • , Houssein Youness
  • , Lee Morrow
  • , Ware Kuschner
  • , Lilibeth Pineda
  • , Richard Allen Robbins
  • , Sharon Camhi
  • , Matthew Jankowich
  • , Waseem Ahmed
  • , Thomas Martin
  • , Mitchell Horowitz
  • , John Nord
  • , Mark Elstad
  • , Marcos I Restrepo
  • , Antonio Anzueto
  • , Timothy Bigby
  • , William Rodriguez-Cintron
  • , Vincent Fan
  • , Pratibha Kaul
  • , Michael Habib
  • , Nitin Seam
  •  & Guy Soo Hoo

Contributions

GUM and M-CS had full access to all the data in the study and take responsibility for the integrity of the data and accuracy of the analyses. Study concept and design: GUM, M-CS, LB, NS, AD-K, MIR, AS, WAB, JL, and GDH. Acquisition of the data: TJM, AE-S, AA, PS, CL, MIR, JJG, TB, and DPJ. Analysis and interpretation of data: GUM and M-CS. Drafting of the manuscript: GUM and M-CS. Critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: M-CS, LZ, and LU. Obtaining funding: GUM and M-CS. Administrative, technical, or material support: GUM, M-CS, LB, JL, and LN.

Corresponding author

Correspondence to G. Umberto Meduri.

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The members of the ESCAPe study group are listed in the Acknowledgements section.

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Meduri, G.U., Shih, MC., Bridges, L. et al. Low-dose methylprednisolone treatment in critically ill patients with severe community-acquired pneumonia. Intensive Care Med 48, 1009–1023 (2022). https://doi.org/10.1007/s00134-022-06684-3

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