Effect of Probiotics on Incident Ventilator-Associated Pneumonia in Critically Ill Patients
Jennie Johnstone(University of Toronto), Maureen O. Meade(McMaster University), François Lauzier(Université Laval), John C. Marshall(University of Toronto), Erick Duan(McMaster University), Joanna C. Dionne(McMaster University), Yaseen M. Arabi(King Saud bin Abdulaziz University for Health Sciences), Diane Heels‐Ansdell(McMaster University), Lehana Thabane(McMaster University), Daphnée Lamarche(McMaster University), Michael G. Surette(McMaster University), Nicole Zytaruk(McMaster University), Sangeeta Mehta(University of Toronto), Peter Dodek(University of British Columbia), Lauralyn McIntyre(University of Ottawa), Shane English(University of Ottawa), Bram Rochwerg(McMaster University), Tim Karachi(McMaster University), William R. Henderson(University of British Columbia), Gordon Wood(University of Victoria), Daniel Ovakim(University of Victoria), Margaret S. Herridge(University of Toronto), John Granton(University of Toronto), M. Elizabeth Wilcox(University of Toronto), Alberto Goffi(University of Toronto), Henry T. Stelfox(University of Calgary), Daniel J. Niven(University of Calgary), John Muscedere(Queen's University), François Lamontagne(Université de Sherbrooke), Frédérick D’Aragon(Université de Sherbrooke), Charles St.-Arnaud(Université de Sherbrooke), Ian Ball(Western University), Dave Nagpal(Western University), Martin Girard(Université de Montréal), Pierre Aslanian(Université de Montréal), Emmanuel Charbonney(Université de Montréal), David Williamson(Université de Montréal), Wendy Sligl(University of Alberta), Jan O. Friedrich(University of Toronto), Neill K. J. Adhikari(University of Toronto), François Marquis(Université de Montréal), Patrick Archambault(Université Laval), Kosar Khwaja(McGill University), Arnold S. Kristof(McGill University), James Kutsogiannis(University of Alberta), Ryan Zarychanski(University of Manitoba), Bojan Paunovic(University of Manitoba), Brenda Reeve(McMaster University), François Lellouche(Université Laval), Paul Hosek(McMaster University), Jennifer Tsang(McMaster University), Alexandra Binnie(University of Toronto), Sébastien Trop(Université de Montréal), Osama Loubani(Dalhousie University), Richard Hall(Dalhousie University), Robert Cirone(University of Toronto), Steve Reynolds(University of British Columbia), Paul Lysecki(McMaster University), Eyal Golan(University of Toronto), Rodrigo Cartin‐Ceba(Mayo Clinic), Robert W. Taylor(Mercy Hospital), Deborah Cook(McMaster University), Prevention of Severe Pneumonia and Endotracheal Colonization Trial (PROSPECT) Investigators and the Canadian Critical Care Trials Group, Christine Wallace, Gita Sobhi, Jennie Johnstone(University of Toronto), François Lauzier(Université Laval), Deborah Cook(McMaster University), Erick Duan(McMaster University), Joanna C. Dionne(McMaster University), Bram Rochwerg(McMaster University), John Centoanti, Simon Oczkowski, Daphne Lamarche(McMaster University), Michael G. Surette(McMaster University), Dawn M. E. Bowdish, Andreas Laupacis, Robin Roberts, Christian Brun‐Buisson, Steve Reynolds(University of British Columbia), Sue Willems, Tina Sekhon, Peter Dodek(University of British Columbia), Najib Ayas, Maria Agda, Victoria Alcuaz, Betty-Jean Ashley, Kelsey Brewer, Janice L. Palmer, Glen Brown, Mara Pavan, William R. Henderson(University of British Columbia), Donald Greisdale, Mypinder S. Sekhon, Denise Foster, Suzie Logie, Judy Yip, Gordon Wood(University of Victoria), Daniel Ovakim(University of Victoria), F. C. Auld, Gayle Carney, R.Y. Declan FLEMING, Jennifer Good, Mandeep Manhas, Karin Boyd, Jane Dheere, Tom Stelfox, Philippe Couillard, Christopher J. Doig, Ken Kuljit S. Parhar, Joshua Booth, Cassidy Codan, Stacy Ruddell, C. Blake Cameron, Rhonda Edison, Anne Martin, Breanna Mina, Daniel J. Niven(University of Calgary), Luc Berthiaume, Jonathan Gaudet, Jim Kutsiogiannis, Raiyan Chowdhury, Jon Davidow, Curt Johnston, Richard Johnston, Kim Macala, Sam Marcushamer, D. Markland, Doug Matheson, Damian Payton-Gay, David Zygun, Tayne Hewer, Pat Thompson, Maggie Ge, Janny Hall, Sharon Matenchuk, Wendy Sligl(University of Alberta), Sean M. Bagshaw, Nadia Baig, Lorena McCoshen, Katrina Alexandropoulos, Sherri Bain, Michelle Brandt, Cathy Constable, K. Douglas, Shaleen Maharaj, Sabrina Travers, Ryan Zarychanski(University of Manitoba), Bojan Paunovic(University of Manitoba), Justin Lys, Nicole Marten, Audrey Bhairo, Halyna Ferenes, Beata Kozak, Debra Verrier, Dawn-Lee McLaughlin, Maria Valente, Marcus Blouw, Kendiss Olafson, Heather Smith, Oliver Gutieror, Sherri Lynn Wingfield, M A Boyle, Debbie Hrabi, Chantal MacDonald, Brenda Reeve(McMaster University), Karen Bento, Megan Davis, William Dechert, Barbara Longo, Courtney Mullen, Elysia Skrzpek, Laurenne Wierenga, Wesam Abuzaiter, Lynda Amorim, Rosemarie Bauer, Rachel Damota, Hoang Ho, Nicole Macdougall, Mary Thornewell, Lara Tran, Jennifer Visocchi, Paul Hosek(McMaster University), Bill Plaxton, Catherine Armstong, Janelle Ellis, Kayla Fisk, Melissa Gabnouri, Emilie Gordon, Rebecca Haegens, Lisa Halford, Brooklyn Hillis, Rebecca Jesso, Jennifer McLaren, Elliot McMillan, Mariska Pelkmans, Matthew Rekman, Sylvia Sinkovitis, Monica Truong, Michelle C. White, Noah Bates, Susan Bryden-Cromwell, Colleen Cameron, A. Gamal El Deen, Sheri DiGiovanni, Anders Foss, E. H. Lee, Heidi MacGregor, Esther Galbraith, Robyn McArthur, J. Mcgregor, Keith R. Miller, Sharon Morris, Shelley Parker, Candice A. Smith, Joanna Stoglow, Jennifer Tung, Melissa Vos, Maureen O. Meade(McMaster University), Emilie P. Belley‐Côté, Lori Hand, Lisa Klotz, Alexandra Sabev, Nevena Savija, Paige Guyatt, Deanna Cosentino, Diane Lourenco, Julie Misina, Paul Lysecki(McMaster University), Joseph Berlingieri, Sameer Shaikh, Steven Skitch, Tracy Campbell, Hala Basheer, Kathy Bruder, Jane Cheng, Kaiser Qureshi, C. A. González Infantino, Timothy Karachi(McMaster University), Mashari Alghuroba, Alia Khaled, Tina Millen, Ryan Vaisler, Maya Biljan, Deane Cosentino, Brittany Marriott, John Muscedere(Queen's University), Gordon Boyd, Christine D`Arsigny, John Drover, Jason Erb, David M. Maslove, Chris M. Parker, Stephanie Sibley, Tracy Boyd, Ilinca Georgescu, Miranda Hunt, D. Muscedere, Cathy Baker, Jennifer Engel, Jennifer Fleming, Lisa Roderick, Shelley Silk, Marcy Spencer, Michelle Tryon, Dave Nagpal(Western University), Ian Ball(Western University), Michael D. Sharpe, Karen J. Bosma, Tracey Bentall, Jessica Sturt-Smith, M. Yvonne Alexander, T.M. Ellis, Mindy Muylaert, Cindy Paczkowski, Eileen Campbell, Susie Imervoski, Athena Ovsenek, Rebecca Rondinelli, Teresa Longfield, Amy Moyer, F. H. Norris, Janice Sumpton, Karina Teterycz, Sangeeta Mehta(University of Toronto), Stephen E. Lapinsky, Laveena Munshi, Maedean Brown, Brittany Giacomino, Marnie Jakab, Alan Kraguiljac, Sumesh Shah, E. Tamberg, Doret Cheng, Gagan Grewal, Andrew Han, Holly Leung, Ioanna Mantas, Hilary Rodrigues, Andew Wyllie, Jennifer Tsang(McMaster University), Mercedes Carmargo, Beverly Richter, Rita Caporuscio, Rachel Kressner Falvo, Dimitra Fleming, Carmelina Maxwell, Karmen Plantic, Lauralyn McIntyre(University of Ottawa), Giuseppe Pagliarello, Gianni D`Egidio, Shane English(University of Ottawa), Mike Hartwick, Jonathan C. Hooper, D. Kubelik, Kwadwo Kyeremanteng, Hilary Meggison, David Neilipovitz, Rakesh Patel, Joseph Po, Erin Rosenberg, Brigette Gomes, Lianne Leclair, Rebecca Porteous, Shawna Reddie, Irene Watpool, Marianne Cox, Kathy Fraser, Jennifer Kuhn, Rob MacLeod, Susanne Richard, Dawn Rose, Sherry Weir, Pierre Cardinal, Gwynne Jones, John S. Kim, Sherissa Microys, Aimee Sarti, Andrew Seely, Shelley Acres, Sydney Mietitis, Kaitlyn Montroy, Amanda van Beinum, Wendy Aikens, Anne-Marie Dugal, Susan Fetzer, Mark Soth, Waleed Alhazanni, France Clarke, Mary Copland, Neala Hoad, M. Sheers, Alyson Takaoka, Nicole Zytaruk(McMaster University), Christa Connolly, Denise Davis, Catherine Torrington Eaton, Tracy Gallinas, Jean Lee-Yoo, Connie Lukinuk, Leia Musielak, Nancy Pavunkovic, Joy Pelayo, Kaitlyn Phillips, Catherine Pracsovics, Julia Raimondo, Vida Stankus, Angela Wright, Crystal Young, Rob Cirrone, Kanthi Kavikondala, Axelle Pellerin, Laura Tomat, Jeff Carter, J. Jani, Brendan Yaets, John C. Marshall(University of Toronto), Jan O. Friedrich(University of Toronto), Jennifer Hodder, Imrana Khalid, Julie Lee, Yoon Lee, Kurtis D. Salway, Gyan Sandhu, Marlene Santos, Orla Smith, Melissa Wang, Norman Dewhurst, Ann Dowbenka, Ann Kosinski, Laura Parsons, J Proceviat, Gitana Ramonas, Mae Yuen, Neill K. J. Adhikari(University of Toronto), Andre Amaral, Brian H. Cuthbertson, Rob Fowler, Damon C. Scales, Navjot Kaur, Nicole Marinoff, Adic Pérez, Jane Wang, Katrina Hatzifilalithis, John Iazzetta, Chrys Kolos, Ingrid Quinton, Margaret Herridge(University of Toronto), Eyal Golan(University of Toronto), John Granton(University of Toronto), Jaimie Archer, Daniel Tzu-Hsuan Chen, Brooke Fraser, Cheryl Geen-Smith, Andrea Matté, Priscilla Robles, Cristian Urrea, Jane Ascroft, Fatima Haji, Jie Ming, Matthew Suen, Muhammad Walid, Jill M. Westlund, Alberto Goffi(University of Toronto), Victoria McCredie, Elizabeth Wilcox, Paulina Farías, Barbara Kosky, Christina Pugliese, Lia Stenyk, Karolina Walczak, Kyung Ae, Rajvinder Kaur, Jane Lui, Sophia Mateo, Nga Pham, Tam Thi Pham, Sébastien Trop(Université de Montréal), Alexandra Binnie(University of Toronto), Ronald J. Heslegrave, Zaynab Panchbhaya, Kim Sharman, Rakhi Goel, Kim Kozluk, Julianne Labelle, Hina Marsonia, Cecillia Scott, Martin Girard(Université de Montréal), P. Aslanian(Université de Montréal), Sylvain Bélisle, François Martin Carrier, Michaël Chassé, André Denault, Jean‐Gilles Guimond, Antoine Halwagi, Paul L. Hebert, Christopher Kolan, Jordi Mancebo, Nicholas Robillard, Fatna Benettaib, Dounia Boumahni, Casey Bourdeau Caporuscio, M Cantin, Virginy Côté-Gravel, Ali Ghamraoui, Martine Lebrasseur, Lancelot Legendre Courville, S. Lorio, Maria Trinidad Madrid, Nicole Poitras, Romain Rigal, Maya Salamé, V.K. Tran, Katie Bacon, Nathalie Boudreau, Cecilia Carvajal, Lyne Gauthier, Julie Gendron, Karine Jean, Louise Laforest, Antonietta Lembo, S. H. Lim, Jennifer J.D. Morrissette, France Pagé, L Pelletier, Marie-Christine Rodrigue, Patrick Archambault(Université Laval), Jean-François Bellemare, Simon Bordeleau, Christine Drouin, Benoit Duhaime, Ann Laberge, Philippe Lechance, Estel Deblois, Maude Dionne, Lise Lavoie, Isabelle Michel, A. Pépin, S. Poulin, Sarah Anctil, Louis-Étienne Marchand, Robin Roy, François Lamontagne(Université de Sherbrooke), Charles St-Arnaud(Université de Sherbrooke), Frédérick D’Aragon(Université de Sherbrooke), Héctor Quiroz, Dominique Bérard, Marc-André Leclair, Virginie Bolduc, Élaine Carbonneau, Joannie Marchand, Marie-Hélène Masse, Sylvie Cloutier, M Guay, Line Morin, J. T. Nicolson, Isabelle Paquette, France Théberge, Emmanuel Charbonney(Université de Montréal), Yoan Lamarche, Soazig LeGuillan, Karim Serri, Colin Verdant, Yanick Beaulieu, Patrick Bellemare, Philippe Rico, Françis Bernard, Marc Giasson, Véronique Brunette, Alexandros Cavayas, Émilie Lévesque, Halina Labikova, Julia Palacios, Marie-Ève Langlois, Virginie Williams, Thùy Anh Nguyễn, Valérie Phaneuf, David Williamson(Université de Montréal), François Marquis(Université de Montréal), Han Tin Wang, Francis Toupin, Stéphane P. Ahern, Brian Laufer, Marc Brosseau, Pauline Dul, Johanne Harvey, Lotthida Inthanavong, Danaë Tassy, Helen Assayag, M. Bachand, Marysa Bétournay, Karine Daoust, Kristine Goyette, Ariane Lessard, Marceline Quach, Alexis F. Turgeon, Danny Barriault, David Bellemare, Anick Boivin, S. Breton, Ève Cloutier, Marjorie Daigle, Charles Delisle-Thibeault, Panagiota Giannakouros, Stéphanie Grenier, Gabrielle Guilbault, Caroline Léger, Catherine Ouellet, Marie-Claude Trembley, Julie Gaudreau, Claire Grégoire, Véronique Labbé, Ariane Laprise-Rochette, Caroline Ouellet, Mélanie Samson, Marie-David Simoneau, Virginie Tourcotte, Tuong-Vi Tran, François Lellouche(Université Laval), Ying Tung Sia, Mathieu Simon, Pierre-Alexandre Bouchard, Patricia Lizotte, Nathalie Châteauvert, T Grenier, Kosar Khwaja(McGill University), Dan Deckelbaum, Jeremy Grushka, Ash Gursahaney, David Hornstein, Dev Jayaraman, Tarek Razek, Robert Salasidis, Patrizia Zanelli, Norine Alam, Laura García, Tonia Doerksen, Gilbert Matte, Marie‐France Robert, Arnold S. Kristof(McGill University), Peter Goldberg, Roupen Hatzakorzian, Sheldon Magder, Jason Shahin, Salman Qureshi, Josie Campisi, Vasilica Botan, Anissa Capilnean, A. E. Corey, Annick Gagné, J N Mian, Kathleen Normandin, Osama Loubani(Dalhousie University), Rick Hall(Dalhousie University), Robert Green, Diana Gillis, Lisa Julien, Laura Magennis, Tamara Mitterer, Joanna Arsenault, Kim Bruce-Payne, Patti Gallant, Rodrigo Cartin‐Ceba(Mayo Clinic), Richard A. Oeckler, Brenda J. Anderson, Lavonne M. Liedl, Laurie Meade, Sueanne Weist, Anna Bartoo, Debbie Bauer, Vince Brickley, S. Louis Bridges, G.J. Brunn, Jennifer E. Eickstaedt, Jill Bergerson, Sandy Showalter, Erin Stern, Melissa Manley, Robert Taylor(Mercy Hospital), Margaret Cryton, K. T. Fowler, Katie Krause, Jackie O`Brien, Marianne Tow, John Ma, Kaitlin MS Moore, Yaseen M. Arabi(King Saud bin Abdulaziz University for Health Sciences), Abdulaziz Al‐Dawood, Haytham Tlayjeh, Alaaeldien Ghanem, Ahmad Hassanien, Mohamed Hegazy, Ashraf El Sharkawi, Felwa Bin Humaid, Hala Alanizi, Nadyah Alanizy, Njoud Al Bogami, Mohammed Muhaidib, Jawaher Gramish, Randa Alsomali, Nora Devera, M.C. Muñoz Villafranca
Cited by 218Open Access
Abstract
Importance: Growing interest in microbial dysbiosis during critical illness has raised questions about the therapeutic potential of microbiome modification with probiotics. Prior randomized trials in this population suggest that probiotics reduce infection, particularly ventilator-associated pneumonia (VAP), although probiotic-associated infections have also been reported. Objective: To evaluate the effect of Lactobacillus rhamnosus GG on preventing VAP, additional infections, and other clinically important outcomes in the intensive care unit (ICU). Design, Setting, and Participants: Randomized placebo-controlled trial in 44 ICUs in Canada, the United States, and Saudi Arabia enrolling adults predicted to require mechanical ventilation for at least 72 hours. A total of 2653 patients were enrolled from October 2013 to March 2019 (final follow-up, October 2020). Interventions: Enteral L rhamnosus GG (1 × 1010 colony-forming units) (n = 1321) or placebo (n = 1332) twice daily in the ICU. Main Outcomes and Measures: The primary outcome was VAP determined by duplicate blinded central adjudication. Secondary outcomes were other ICU-acquired infections including Clostridioides difficile infection, diarrhea, antimicrobial use, ICU and hospital length of stay, and mortality. Results: Among 2653 randomized patients (mean age, 59.8 years [SD], 16.5 years), 2650 (99.9%) completed the trial (mean age, 59.8 years [SD], 16.5 years; 1063 women [40.1%.] with a mean Acute Physiology and Chronic Health Evaluation II score of 22.0 (SD, 7.8) and received the study product for a median of 9 days (IQR, 5-15 days). VAP developed among 289 of 1318 patients (21.9%) receiving probiotics vs 284 of 1332 controls (21.3%; hazard ratio [HR], 1.03 (95% CI, 0.87-1.22; P = .73, absolute difference, 0.6%, 95% CI, -2.5% to 3.7%). None of the 20 prespecified secondary outcomes, including other ICU-acquired infections, diarrhea, antimicrobial use, mortality, or length of stay showed a significant difference. Fifteen patients (1.1%) receiving probiotics vs 1 (0.1%) in the control group experienced the adverse event of L rhamnosus in a sterile site or the sole or predominant organism in a nonsterile site (odds ratio, 14.02; 95% CI, 1.79-109.58; P < .001). Conclusions and Relevance: Among critically ill patients requiring mechanical ventilation, administration of the probiotic L rhamnosus GG compared with placebo, resulted in no significant difference in the development of ventilator-associated pneumonia. These findings do not support the use of L rhamnosus GG in critically ill patients. Trial Registration: ClinicalTrials.gov Identifier: NCT02462590.
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