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1. Inhaled Volatiles for Status Asthmaticus, Epilepsy, and Difficult Sedation in Adult ICU and PICU: A Systematic Review

Author

Kevin Gorsky, MD, Sean Cuninghame, MD, Kesikan Jayaraj, RN, Marat Slessarev, MD, PhD, FRCPC, Conall Francoeur, MD, Davinia E. Withington, BM, FRCA, MRCP(UK), Jennifer Chen, Brian H. Cuthbertson, MBBS, PhD, Claudio Martin, MD, Martin Chapman, MD, FRCPC, Saptharishi Lalgudi Ganesan, MBBS, MD, DM, FACNS, Nicole McKinnon, MD, PhD, Angela Jerath, MD, MSc, FANZCA, FRCPC, on behalf of the SAVE-ICU Study Investigators, Martin Chapman, Damon Scales, Julie Nardi, Beth Linseman, Phil Lau, Boris Yakubov, Eily Shaw, Francois Carrier, Emmanuel Charbonney, Michaël Chassé, Martin Girard, Antoine Halwagi, Guillaume Plourde, Han Ting Wang, Frédérick D’Aragon, Maxime Tissot-Therrien, François Lamontagne, Dominique Bérard, Yiorgos Alexandros Cavayas, Martin Albert, Francis Bernard, Karim Serri, David Williamson, Virginie Williams, Patricia Martinez Barrios, Sabrina Araujo De Franca, Etienne J. Couture, Adreanne Côté, Mathieu Simon, Pierre-Alexis Lépine, Dave Gleeton, John Basmaji, Marat Slessarev, Ahmed Hegazy, Tracey Bentall, Eileen Campbell, Michelle Stephens, Tim Winterburn, Roupen Hatzakorzian, Kosar Khwaja, Peter Goldberg, Jason Shahin, Jeremy Richard Grushka, Jonathan Hooper, Sherissa Microys, Hilary Meggison, David Leilipovitz, Jessica Haines, Irene Watpool, Rebecca Porteous, Stephanie Dunster, Sylvie Bourbonnais, Ewan Goligher, Lorenzo Del Sorbo, Niall Ferguson, Philip Graham, Michael Long, Tina Yan, Denise Morris, Maria Kobylecky, Hesham Abdelhady, Tina Romagnuolo, Bourke Tillman, Ian Randall, Elizabeth Wilcox, Michael Jacka, Oleksa Rewa, Vincent Lau, Sean Bagshaw, and Nadia Baig

Subjects
Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

OBJECTIVES:. Inhaled volatile anesthetics support management of status asthmaticus (SA), status epilepticus (SE), and difficult sedation (DS). This study aimed to evaluate the effectiveness, safety, and feasibility of using inhaled anesthetics for SA, SE, and DS in adult ICU and PICU patients. DATA SOURCES:. MEDLINE, Cochrane Central Register of Controlled Trials, and Embase. STUDY SELECTION:. Primary literature search that reported the use of inhaled anesthetics in ventilated patients with SA, SE, and DS from 1970 to 2021. DATA EXTRACTION:. Study data points were extracted by two authors independently. Quality assessment was performed using the Joanna Briggs Institute appraisal tool for case studies/series, Newcastle criteria for cohort/case–control studies, and risk-of-bias framework for clinical trials. DATA SYNTHESIS:. Primary outcome was volatile efficacy in improving predefined clinical or physiologic endpoints. Secondary outcomes were adverse events and delivery logistics. From 4281 screened studies, the number of included studies/patients across diagnoses and patient groups were: SA (adult: 38/121, pediatric: 28/142), SE (adult: 18/37, pediatric: 5/10), and DS (adult: 21/355, pediatric: 10/90). Quality of evidence was low, consisting mainly of case reports and series. Clinical and physiologic improvement was seen within 1–2 hours of initiating volatiles, with variable efficacy across diagnoses and patient groups: SA (adult: 89–95%, pediatric: 80–97%), SE (adults: 54–100%, pediatric: 60–100%), and DS (adults: 60–90%, pediatric: 62–90%). Most common adverse events were cardiovascular, that is, hypotension and arrhythmias. Inhaled sedatives were commonly delivered using anesthesia machines for SA/SE and miniature vaporizers for DS. Few (10%) of studies reported required non-ICU personnel, and only 16% had ICU volatile delivery protocol. CONCLUSIONS:. Volatile anesthetics may provide effective treatment in patients with SA, SE, and DS scenarios but the quality of evidence is low. Higher-quality powered prospective studies of the efficacy and safety of using volatile anesthetics to manage SA, SE, and DS patients are required. Education regarding inhaled anesthetics and the protocolization of their use is needed.

Published
2024
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2. Metabolomics Analysis of Mesenchymal Stem Cell (MSC) Therapy in a Phase I Clinical Trial of Septic Shock: An Exploratory Study

Author

Mohammad M. Banoei, Lauralyn A. McIntyre, Duncan J. Stewart, Shirley H. J. Mei, David Courtman, Irene Watpool, John Granton, John Marshall, Claudia dos Santos, Keith R. Walley, Kenny Schlosser, Dean A. Fergusson, Brent W. Winston, on behalf of Canadian Critical Care Trials Group (CCCTG), and on behalf of Canadian Critical Care Translational Biology Group (CCCTBG)

Subjects
biomarker, mesenchymal stem cells, septic shock, clinical trial, metabolomics, cell therapy, Microbiology, QR1-502
Abstract

Sepsis is the result of an uncontrolled host inflammatory response to infection that may lead to septic shock with multiorgan failure and a high mortality rate. There is an urgent need to improve early diagnosis and to find markers identifying those who will develop septic shock and certainly a need to develop targeted treatments to prevent septic shock and its high mortality. Herein, we explore metabolic alterations due to mesenchymal stromal cell (MSC) treatment of septic shock. The clinical findings for this study were already reported; MSC therapy was well-tolerated and safe in patients in this phase I clinical trial. In this exploratory metabolomics study, 9 out of 30 patients received an escalating dose of MSC treatment, while 21 patients were without MSC treatment. Serum metabolomics profiling was performed to detect and characterize metabolite changes due to MSC treatment and to help determine the sample size needed for a phase II clinical trial and to define a metabolomic response to MSC treatment. Serum metabolites were measured using 1H-NMR and HILIC-MS at times 0, 24 and 72 h after MSC infusion. The results demonstrated the significant impact of MSC treatment on serum metabolic changes in a dose- and time-dependent manner compared to non-MSC-treated septic shock patients. This study suggests that plasma metabolomics can be used to assess the response to MSC therapy and that treatment-related metabolomics effects can be used to help determine the sample size needed in a phase II trial. As this study was not powered to detect outcome, how the treatment-induced metabolomic changes described in this study of MSC-treated septic shock patients are related to outcomes of septic shock in the short and long term will need to be explored in a larger adequately powered phase II clinical trial.

Published
2023
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3. The evolution of mean arterial pressure in critically ill patients on vasopressors before and during a trial comparing a specific mean arterial pressure target to usual care

Author

Marie-Hélène Masse, Neill K. J. Adhikari, Xavier Théroux, Marie-Claude Battista, Frédérick D’Aragon, Ruxandra Pinto, Alan Cohen, Michaël Mayette, Charles St-Arnaud, Michelle Kho, Michaël Chassé, Martine Lebrasseur, Irene Watpool, Rebecca Porteous, M. Elizabeth Wilcox, and François Lamontagne

Subjects
Arterial pressure, Control groups, Critical care, Research design, Vasoconstrictor agents, Anesthesiology, RD78.3-87.3
Abstract

Abstract Background In randomized clinical controlled trials, the choice of usual care as the comparator may be associated with better clinician uptake of the study protocol and lead to more generalizable results. However, if care processes evolve to resemble the intervention during the course of a trial, differences between the intervention group and usual care control group may narrow. We evaluated the effect on mean arterial pressure of an unblinded trial comparing a lower mean arterial pressure target to reduce vasopressor exposure, vs. a clinician-selected mean arterial pressure target, in critically ill patients at least 65 years old. Methods For this multicenter observational study using data collected both prospectively and retrospectively, patients were recruited from five of the seven trial sites. We compared the mean arterial pressure of patients receiving vasopressors, who met or would have met trial eligibility criteria, from two periods: [1] at least 1 month before the trial started, and [2] during the trial period and randomized to usual care, or not enrolled in the trial. Results We included 200 patients treated before and 229 after trial initiation. There were no differences in age (mean 74.5 vs. 75.2 years; p = 0.28), baseline Acute Physiology and Chronic Health Evaluation II score (median 26 vs. 26; p = 0.47) or history of chronic hypertension (n = 126 [63.0%] vs. n = 153 [66.8%]; p = 0.41). Mean of the mean arterial pressure was similar between the two periods (72.5 vs. 72.4 mmHg; p = 0.76). Conclusions The initiation of a trial of a prescribed lower mean arterial pressure target, compared to a usual clinician-selected target, was not associated with a change in mean arterial pressure, reflecting stability in the net effect of usual clinician practices over time. Comparing prior and concurrent control groups may alleviate concerns regarding drift in usual practices over the course of a trial or permit quantification of any change.

Published
2022
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4. Intravenous albumin for the prevention of hemodynamic instability during sustained low-efficiency dialysis: a randomized controlled feasibility trial (The SAFER-SLED Study)

Author

Edward G. Clark, Lauralyn McIntyre, Irene Watpool, Jennifer W. Y. Kong, Tim Ramsay, Elham Sabri, Mark Canney, Gregory L. Hundemer, Pierre-Antoine Brown, Manish M. Sood, and Swapnil Hiremath

Subjects
Renal replacement therapy, Albumin, Acute kidney injury, Hypotension, Ultrafiltration, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

Abstract Background Hemodynamic instability is a frequent complication of sustained low-efficiency dialysis (SLED) treatments in the ICU. Intravenous hyperoncotic albumin may prevent hypotension and facilitate ultrafiltration. In this feasibility trial, we sought to determine if a future trial, powered to evaluate clinically relevant outcomes, is feasible. Methods This single-center, blinded, placebo-controlled, randomized feasibility trial included patients with acute kidney injury who started SLED in the ICU. Patients were randomized to receive 25% albumin versus 0.9% saline (control) as 100 mL boluses at the start and midway through SLED, for up to 10 sessions. The recruitment rate and other feasibility outcomes were determined. Secondary exploratory outcomes included ultrafiltration volumes and metrics of hemodynamic instability. Results Sixty patients (271 SLED sessions) were recruited over 10 months. Age and severity of illness were similar between study groups. Most had septic shock and required vasopressor support at baseline. Protocol adherence occurred for 244 sessions (90%); no patients were lost to follow-up; no study-related adverse events were observed; open label albumin use was 9% and 15% in the albumin and saline arms, respectively. Ultrafiltration volumes were not significantly different. Compared to the saline group, the albumin group experienced less hemodynamic instability across all definitions assessed including a smaller absolute decrease in systolic blood pressure (mean difference 10.0 mmHg, 95% confidence interval 5.2–14.8); however, there were significant baseline differences in the groups with respect to vasopressor use prior to SLED sessions (80% vs 61% for albumin and saline groups, respectively). Conclusions The efficacy of using hyperoncotic albumin to prevent hemodynamic instability in critically ill patients receiving SLED remains unclear. A larger trial to evaluate its impact in this setting, including evaluating clinically relevant outcomes, is feasible. Trial registration ClinicalTrials.gov (NCT03665311); First Posted: Sept 11th, 2018. https://clinicaltrials.gov/ct2/show/NCT03665311?term=NCT03665311&draw=2&rank=1

Published
2021
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5. Poly(I:C) enhances mesenchymal stem cell control of myeloid cells from COVID-19 patients

Author

Luciana Souza-Moreira, Yuan Tan, Yan Wang, Jia-Pey Wang, Mahmoud Salkhordeh, Jennifer Virgo, Maria Florian, Aidan B.P. Murray, Irene Watpool, Lauralyn McIntyre, Shane English, Duncan J. Stewart, and Shirley H.J. Mei

Subjects
Immunology, Virology, Stem cells research, Science
Abstract

Summary: Mesenchymal stem cells (MSCs) are being studied for the treatment of COVID-19-associated critical illness, due to their immunomodulatory properties. Here, we hypothesized that viral mimic-priming improves MSCs’ abilities to rebalance the dysregulated immune responses in COVID-19. Transcriptome analysis of poly(I:C)-primed MSCs (pIC-MSCs) showed upregulation of pathways in antiviral and immunomodulatory responses. Together with increased expression of antiviral proteins such as MX1, IFITM3, and OAS1, these changes translated to greater effector functions in regulating monocytes and granulocytes while further enhancing MSCs’ ability to block SARS-CoV-2 pseudovirus entry into epithelial cells. Most importantly, the addition of pIC-MSCs to COVID-19 patient whole blood significantly reduced inflammatory neutrophils and increased M2 monocytes while enhancing their phagocytic effector function. We reveal for the first time that MSCs can be primed by Toll-like receptor 3 agonist to improve their ability to rebalance the dysregulated immune responses seen in severe SARS-CoV-2 infection.

Published
2022
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6. Lessening Organ dysfunction with VITamin C (LOVIT): protocol for a randomized controlled trial

Author

Marie-Hélène Masse, Julie Ménard, Sheila Sprague, Marie-Claude Battista, Deborah J. Cook, Gordon H. Guyatt, Daren K. Heyland, Salmaan Kanji, Ruxandra Pinto, Andrew G. Day, Dian Cohen, Djillali Annane, Shay McGuinness, Rachael Parke, Anitra Carr, Yaseen Arabi, Bharath Kumar Tirupakuzhi Vijayaraghavan, Frédérick D’Aragon, Élaine Carbonneau, David Maslove, Miranda Hunt, Bram Rochwerg, Tina Millen, Michaël Chassé, Martine Lebrasseur, Patrick Archambault, Estel Deblois, Christine Drouin, François Lellouche, Patricia Lizotte, Irene Watpool, Rebecca Porteous, France Clarke, Nicole Marinoff, Émilie Belley-Côté, Brigitte Bolduc, Scott Walker, John Iazzetta, Neill K. J. Adhikari, François Lamontagne, and on behalf of the Canadian Critical Care Trials Group

Subjects
vitamin C, sepsis, septic shock, biomarkers, randomized controlled trial, Medicine (General), R5-920
Abstract

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.

Published
2020
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7. Feasibility of implementing Extubation Advisor, a clinical decision support tool to improve extubation decision-making in the ICU: a mixed-methods observational study

Author

Tim Ramsay, Andrew JE Seely, Karen EA Burns, Aimee J Sarti, Stephanie Sutherland, Rebecca Porteous, Irene Watpool, Christophe L Herry, Nathan B Scales, Caitlin Anstee, and Anna Fazekas

Subjects
Medicine
Abstract

Objectives Although spontaneous breathing trials (SBTs) are standard of care to extubation readiness, no tool exists that optimises prediction and standardises assessment. In this study, we evaluated the feasibility and clinical impressions of Extubation Advisor (EA), a comprehensive clinical extubation decision support (CDS) tool.Design Phase I mixed-methods observational study.Setting Two Canadian intensive care units (ICUs).Participants We included patients on mechanical ventilation for ≥24 hours and clinicians (respiratory therapists and intensivists) responsible for extubation decisions.Interventions Components included a predictive model assessment, feasibility evaluation, questionnaires and interviews with clinicians.Results We enrolled 117 patients, totalling 151 SBTs and 80 extubations. The incidence of extubation failure was 11% in low-risk patients and 21% in high-risk patients stratified by the predictive model; 38% failed extubation when both the model and clinical impression were at high risk. The tool was well rated: 94% and 75% rated the data entry and EA report as average or better, respectively. Interviews (n=15) revealed favourable impressions regarding its user interface and functionality, but unexpectedly, also concerns regarding EA’s potential impact on respiratory therapists’ job security.Conclusions EA implementation was feasible, and users perceived it to have potential to support extubation decision-making. This study helps to understand bedside implementation of CDS tools in a multidisciplinary ICU.Trial registration number NCT02988167.

Published
2021
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8. Saline versus albumin fluid for extracorporeal removal with slow low-efficiency dialysis (SAFER-SLED): study protocol for a pilot trial

Author

Edward G. Clark, Lauralyn McIntyre, Tim Ramsay, Alan Tinmouth, Greg Knoll, Pierre-Antoine Brown, Irene Watpool, Rebecca Porteous, Kaitlyn Montroy, Sophie Harris, Jennifer Kong, and Swapnil Hiremath

Subjects
Albumin, Saline fluid, Acute kidney injury, Dialysis, Low blood pressure, SLED treatment, Medicine (General), R5-920
Abstract

Abstract Background Critically ill patients frequently develop acute kidney injury that necessitates renal replacement therapy (RRT). At some centers, critically ill patients who are hemodynamically unstable and require RRT are treated with slow low-efficiency dialysis (SLED). Unfortunately, hypotension is a frequent complication that occurs during SLED treatments and may limit the recovery of kidney function. Hypotension may also limit the amount of fluid that can be removed by ultrafiltration with SLED. Fluid overload can be exacerbated as a consequence, and fluid overload is associated with increased mortality. Occasionally, intravenous albumin fluid is given to prevent or treat low blood pressure during SLED. The intent of doing so is to increase the colloid oncotic pressure in the circulation to draw in extravascular fluid, increase the blood pressure, and enable more aggressive fluid removal with ultrafiltration. Nonetheless, there is little evidence to support this practice and theoretical reasons why it may not be especially effective at augmenting fluid removal in critically ill patients. At the same time, albumin fluid is expensive. As such, we present a protocol for a study to assess the feasibility of a randomized controlled trial evaluating the use of albumin fluid versus saline in critically ill patients receiving SLED. Methods This study is a single-center, double-blind, and randomized controlled pilot trial with two parallel arms. It involves randomly assigning patients receiving SLED treatment in the ICU to receive either albumin (25%) boluses or normal saline fluid boluses (placebo) to prevent and treat low blood pressure. Discussion The results of this pilot trial will help with planning a larger trial comparing the efficacy of the interventions in achieving fluid removal in critically ill patients with AKI on SLED. They will establish whether enough participants would participate in a larger study and accept the study procedures. Trial registration This trial is registered on ClinicalTrials.gov Identifier NCT03665311, registered on September 11, 2018.

Published
2019
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9. Optimal VAsopressor TitraTION in patients 65 years and older (OVATION-65): protocol and statistical analysis plan for a randomised clinical trial

Author

Sangeeta Mehta, François Lauzier, Emmanuel Charbonney, Michaël Chasse, Marie-Claude Battista, Emilie Belley-Cote, Brian H Cuthbertson, Andreas Laupacis, Alexis F Turgeon, Frédérick D'Aragon, Tina Millen, Laveena Munshi, Sumesh Shah, Alexis Turgeon, David Bellemare, Eve Cloutier, Marjorie Daigle, Stéphanie Grenier, Gabrielle Guilbault, Sydney Miezitis, Rebecca Porteous, Irene Watpool, Karolina Walczak, Frédérick D’Aragon, Charles St-Arnaud, Elaine Carbonneau, Joannie Marchand, Marie-Hélène Masse, Fatna Benettaib, Dounia Boumahni, Marie-Ève Cantin, Ali Ghamraoui, Martine Lebrasseur, Maya Salame, Navjot Kaur, Nicole Marinoff, Guillaume Leblanc, Mary Elizabeth Wilcox, Ruxandra Pinto, Michael Mayette, Marc-André Leclair, Hector Quiroz Martinez, Brian Grondin-Beaudoin, Yannick Poulin, Andrew J E Seely, Édouard Botton, Dian Cohen, Neill K J Adhikari, Neill KJ Adhikari, Lauren Griffith, Scott Halpern, Louise Robert-Petit, Marie-Ève Thibault, François-Michel Boisvert, Lee Hwa Tai, Jean-Luc Parent, Xavier Roucou, Hector Quiroz-Martinez, Line Côté, Marilène Ladouceur, Noémie Turcotte, Andrew Seely, Andre Carlos Amaral, Wael Mohammed, Charles Francoeur, Olivier Costerousse, Isabelle St-Hilaire, and Jeffrey Singh

Subjects
Medicine
Abstract

Introduction Vasodilatory hypotension is common among intensive care unit (ICU) patients; vasopressors are considered standard of care. However, optimal mean arterial pressure (MAP) targets for vasopressor titration are unknown. The objective of the Optimal VAsopressor TitraTION in patients 65 years and older (OVATION-65) trial is to ascertain the effect of permissive hypotension (vasopressor titration to achieve MAP 60–65 mm Hg) versus usual care on biomarkers of organ injury in hypotensive patients aged ≥65 years.Methods and analysis OVATION-65 is an allocation-concealed randomised trial in 7 Canadian hospitals. Eligible patients are ≥65 years of age, in an ICU with vasodilatory hypotension, receiving vasopressors for ≤12 hours to maintain MAP ≥65 mm Hg during or after adequate fluid resuscitation, and expected to receive vasopressors for ≥6 additional hours. Patients are excluded for any of the following: active treatment for spinal cord or acute brain injury; vasopressors given solely for bleeding, ventricular failure or postcardiopulmonary bypass vasoplegia; withdrawal of life-sustaining treatments expected within 48 hours; death perceived as imminent; previous enrolment in OVATION-65; organ transplant within the last year; receiving extracorporeal life support or lack of physician equipoise. Patients are randomised to permissive hypotension versus usual care for up to 28 days. The primary outcome is high-sensitivity troponin T, a biomarker of cardiac injury, on day 3. Secondary outcomes include biomarkers of injury to other organs (brain, liver, intestine, skeletal muscle); lactate (a biomarker of global tissue dysoxia); resource utilisation; adverse events; mortality (90 days and 6 months) and cognitive function (6 months). Assessors of biomarkers, mortality and cognitive function are blinded to allocation.Ethics and dissemination This protocol has been approved at all sites. Consent is obtained from the eligible patient, the substitute decision-maker if the patient is incapable, or in a deferred fashion where permitted. End-of-grant dissemination plans include presentations, publications and social media platforms and discussion forums.Trial registration number NCT03431181.

Published
2020
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10. Economic evaluation alongside the Probiotics to Prevent Severe Pneumonia and Endotracheal Colonization Trial (E-PROSPECT): study protocol

Author

Katie Ross, Dimitra Fleming, John Marshall, Najib Ayas, François Lellouche, Justin Lys, Ryan Zarychanski, Timothy Karachi, Deborah J Cook, Marie-Claude Tremblay, Jeremy Grushka, Dan Deckelbaum, Kosar Khwaja, Tarek Razek, Donald Griesdale, John Muscedere, David Maslove, Roupen Hatzakorzian, Patrick Archambault, Feng Xie, François Lauzier, Heather Smith, David Williamson, Emmanuel Charbonney, John Granton, Alyson Takaoka, Kwadwo Kyeremanteng, Miranda Hunt, Ian Ball, Victoria McCredie, Michaël Chasse, Jennifer LY Tsang, Jordi Mancebo, Peter Dodek, Emilie Belley-Cote, Neala Hoad, Melissa Shears, Mark Soth, Tracy Campbell, Geeta Mehta, Daniel Chen, Shane English, Maureen Meade, John Kim, Jie Meng, Richard Johnston, Jennie Johnstone, Norman Dewhurst, Panagiota Giannakouros, Laura García, John Ma, Dev Jayaraman, Pierre Cardinal, Vincent Issac Lau, John C Marshall, John Basmaji, Deborah Cook, Erick Duan, France Clarke, Mary Copland, Marnie Jakab, Nicole Zytaruk, Christa Connolly, Denise Davis, Catherine Eaton, Tracy Gallinas, Jean Lee-Yoo, Connie Lukinuk, Leia Musielak, Nancy Pavunkovic, Joy Pelayo, Kaitlyn Phillips, Catherine Pracsovics, Julia Raimondo, Vida Stankus, Christine Wallace, Angela Wright, Crystal Young, Katrina Fimiani, Lori Hand, Harjot Jagdey, Lisa Klotz, Alexana Sabev, Nevena Savija, Deanne Cosentino, Diane Lourenco, Julie Misina, Gita Sobhi, Mashari Alghuroba, Alia Khaled, Lauren Locco, Tina Millen, Ryan Vaisler, Maya Biljan, Brittany Marriott, Jan Frieich, Jennifer Hodder, Imrana Khalid, Julie Lee, Yoon Lee, Pragma Roy, Kurtis Salway, Gyan Sandhu, Marlene Santos, Orla Smith, Melissa Wang, Ann Dowbenka, Ann Kosinski, Terri Norrie, Ranjit Parhar, Laura Parsons, Johanna Proceviat, Gitana Ramonas, Mae Yuen, Maria Agda, Victoria Alcuaz, Betty Jean Ashley, Kelsey Brewer, Janice Palmer, Glen Brown, Mara Pavan, Stephen Lapinsky, Laveena Munshi, Maedean Brown, Brittany Giacomino, Alan Kraguljac, Sumesh Shah, Erik Tamberg, Laura Vergeer, Doret Cheng, Gagan Grewal, Anew Han, Holly Leung, Ioanna Mantas, Hilary Roigues, Anew Wyllie, Alexis Turgeon, Danny Barriault, David Bellemare, Anick Boivin, Sarah-Judith Breton, Eve Cloutier, Marjorie Daigle, Charles Delisle-Thibeault, Stéphanie Grenier, Gabrielle Guilbault, Caroline Léger, Catherine Ouellet, Élisabeth Gagne, Julie Gaueau, Claire Grégoire, Véronique Labbé, Ariane Laprise-Rochette, Caroline Ouellet, Mélanie Samson, Marie-David Simoneau, Virginie Turcotte, Tuong-Vi Tran, Lauralyn McIntyre, Joe Pagilarello, Gianni D’Egidio, Mike Hartwick, Jonathon Hooper, Gwynne Jones, Dal Kubelik, Hilary Meggison, Sherissa Microys, Dave Neiliovitz, Guiseppe Pagliarello, Rakesh Patel, Jo Po, Peter Reardon, Erin Rosenberg, Aimee Sarti, Anew Seely, Shelley Acres, Brigette Gomes, Heather Langlois, Liane Leclair, Sydney Miezitis, Kaitlyn Montroy, Rebecca Porteous, Shawna Reddie, Amanda Van Beinum, Allyshia Van Tol, Irene Watpool, Wendy Aikens, Marianne Cox, Anne-Marie Dugal, Susan Fetzer, Kathy Fraser, Jennifer Kuhn, Rob MacLeod, Susanne Richard, Dawn Rose, Sherry Weir, Bill Henderson, Mypinder Sekhon, Denise Foster, Suzie Logie, Judy Yip, Margaret Herridge, s Alberto Goffi, Eyal Golan, Elizabeth Wilcox, Jaimie Archer, Paulina Farias, Brooke Fraser, Cheryl Geen-Smith, Barbara Kosky, Anea Matte, Christina Pugliese, Priscila Robles, Lia Stenyk, Cristian Urrea, Karolina Walczak, Kyung Ae, Jane Ascroft, Fatima Haji, Rajvinder Kaur, Jane Lui, Sophia Mateo, Nga Pham, Tam Pham, Matthew Suen, Jennifer Teng, Gordon Wood, Daniel Ovakim, Fiona Auld, Gayle Camey, Ralph Fleming, Jennifer Good, Mandeep Manhas, Karin Boyd, Jane Dheere, Priscilia Robles, Muhammad Walid, Jill Westlund, Yoan Lamarche, Soazig Leguillan, Karim Serri, Colin Verdant, Yanick Beaulieu, Patrick Bellemare, Philippe Bernard, Marc Giasson, Véronique Brunette, Alexanos Cavayas, Émilie Lévesque, Halina Labikova, Julia Lainer Palacios, Marie-Ève Langlois, Virginie Williams, Thuy Anh Nguyen, Valérie Phaneuf, Frédérick D’Aragon, Charles St-Arnaud, Hector Quiroz, Virginie Bolduc, Elaine Carbonneau, Joannie Marchand, Marie-Hélène Masse, Sylvie Cloutier, Marianne Guay, Line Morin, Jessie Nicolson, Isabelle Paquette, Patricia Roy, France Théberge, Arnold S Kristof, Peter Goldberg, Sheldon Magder, Jason Shahin, Salman Qureshi, Josie Campisi, Vasilica Botan, Anissa Capilnean, Alyssa Corey, Annick Gagné, Jasmine Mian, Kathleen Normandin, Ash Gursahaney, David Hornstein, Robert Salasidis, Patrizia Zanelli, Norine Alam, Tonia Doerksen, Ariane Lessard, Gilbert Matte, Marie-France Robert, Martin Girard, Pierre Aslanian, Sylvain Belisle, François-Martin Carrier, Ané Denault, Jean-Gilles Guimond, Antoine Halwagi, Paul Hébert, Christopher Kolan, Nicholas Robillard, Fatna Benettaib, Dounia Boumahni, Casey Bourdeau Caporuscio, Marie-Ève Cantin, Virginy Côté-Gravel, Ali Ghamraoui, Martine Lebrasseur, Lancelot Legene Courville, Stéphanie Lorio, Maria Trinidad Maid, Nicole Poitras, Romain Rigal, Maya Salame, Valérie Tran, Katie Bacon, Nathalie Boueau, Cecilia Carvajal, Lyne Gauthier, Julie Genon, Karine Jean, Louise Laforest, Antonietta Lembo, Sothun Lim, Jennifer Morrissette, France Pagé, Lucie Pelletier, Marie-Christine Roigue, Jim Kutsiogiannis, Raiyan Chowdhury, Jon Davidow, Curt Johnston, Kim Macala, Sam Marcushamer, Darren Markland, Doug Matheson, Damian Paton-Gay, David Zygun, Nadine Grant, Tayne Hewer, Pat Thompson, Maggie Ge, Janny Hall, Sharon Matenchuk, Osama Loubani, Rick Hall, Robert Green, Diana Gillis, Lisa Julien, Laura Lee Magennis, Tamara Mitterer, Joanna Arsenault, Kim Bruce-Payne, Patti Gallant, Gord Boyd, Christine D’Arsigny, John Over, Jason Erb, Chris Parker, Stephanie Sibley, Tracy Boyd, Ilinca Georgescu, Danielle Muscedere, Cathy Baker, Jennifer Engel, Jennifer Fleming, Lisa Roderick, Shelley Silk, Marcy Spencer, Michelle Tryon, Marcus Blouw, Kendiss Olafson, Bojan Paunovic, Oliver Gutieror, Nicole Marten, Sherri Lynn Wingfield, Marnie Boyle, Halyna Ferens, Debbie Hrabi, Beata Kozak, Chantal MacDonald, Julie Muise, Eileen Campbell, Susie Imerovski, Athena Ovsenek, Rebecca Rondinelli, Teresa Longfield, Amy Moyer, Faith Norris, Janice Sumpton, Karina Teterycz, Brenda Reeve, Karen Bento, Megan Davis, Will Dechert, Krista Gallo, Barbara Longo, Courtney Mullen, Elysia Skrzypek, Laurenne Wierenga, Wesam Abuzaiter, Lynda Amorim, Rosemarie Bauer, Rachel Damota, Thoa Ho, Nicole Macdougall, Mary Thornewell, Lara Pe, Jennifer Visocchi, Auey Bhairo, Halyna Ferenes, Debra Kubin, Dawn-Lee McLaughlin, Maria Valente, Steve Reynolds, Suzette Willems, Tina Sekhon, Sebastien Trop, Alexana Binnie, Ronald Heslegrave, Kim Sharman, Zaynab Panchbhaya, Rakhi Goel, Kim Kozluk, Julianne Labelle, Hina Marsonia, Cecillia Scott, Dave Nagpal, Tracey Bentall, Jessica Sturt-Smith, Michelle Alexander, Tammy Ellis, Mindy Muylaert, Cindy Paczkowski, Wendy Sligl, Sean Bagshaw, Nadia Baig, Lorena McCoshen, Katrina Alexanopoulos, Sherri Bain, Michelle Brandt, Cathy Constable, Kari Douglas, Shaleen Maharaj, Sabrina Travers, Tom Stelfox, Philippe Couillard, Christopher Doig, Ken Parhar, Joshua Booth, Cassidy Codan, Stacy Ruddell, Candice Cameron, Rhonda Edison, Anne Martin, Breanna Mina, Dan Niven, Luc Berthiaume, Jonathan Gaudet, Gina Fleming, Mercedes Carmargo, Beverly Hoekstra, Rita Caporuscio, Rachel Kressner Falvo, Carmelina Maxwell, Karmen Plantic, François Marquis, Han Tin Wang, Francis Toupin, Stephane Ahern, Brian Laufer, Marc Brosseau, Pauline Dul, Johanne Harvey, Lotthida Inthanavong, Danae Tassy, Helen Assayag, Maude Bachand, Marysa Betournay, Karine Daoust, Kristine Goyette, Marceline Quach, Paul Hosek, Bill Plaxton, Catherine Armstrong, Rhonda Barber, William Dechert, Janelle Ellis, Kayla Fisk, Melissa Gabnouri, Emilie Gordon, Rebecca Haegens, Lisa Halford, Brooklynn Hillis, Rebecca Jesso, Jenn McLaren, Elliot McMillan, Mariska Pelkmans, Matthew Rekman, Sylvia Sinkovitis, Monica Truong, Michelle White, Noah Bates, Susan Bryden-Cromwell, Lisa Cha, Colleen Cameron, Aminah Deen, Sheri DiGiovanni, Anders Foss, Esther Lee, Heidi MacGregor, Esther Galbraith, Robyn McArthur, Julie McGregor, Keith Miller, Sharon Morris, Shelley Parker, Candice Smith, Joanna Stoglow, Jennifer Tung, Melissa Vos, Neill Adhikari, Ane Amaral, Ane Carlos, Brian Cuthbertson, Rob Fowler, Damon Scales, Navjot Kaur, Nicole Marinoff, Adic Perez, Jane Wang, Katrina Hatzifilalithis, John Iazzetta, Chrys Kolos, Ingrid Quinton, Paul Lysecki, Joseph Berlingieri, Sameer Shaikh, Steven Skitch, Hala Basheer, Kathy Bruder, Jane Cheng, Kaiser Qureshi, Celeste Thibault, Ying Tung Sia, Mathieu Simon, Pierre-Alexane Bouchard, Patricia Lizotte, Nathalie Chateauvert, Thérèse Grenier, Jean-François Bellemare, Simon Bordeleau, Christine Ouin, Benoît Duhaime, Ann Laberge, Philippe Lachance, Mélanie Constantin, Estel Deblois, Maude Dionne, Lise Lavoie, Isabelle Michel, Alexane Pépin, Sanine Poulin, Sarah Anctil, Amélie Chouinard, Louis-Étienne Marchand, Robin Roy, Roigo Cartin-Ceba, Richard Oeckler, Brenda Anderson, Lavonne Liedl, Laurie Meade, Sueanne Weist, Anna Bartoo, Debbie Bauer, Vince Brickley, Shaun Bridges, Greg Brunn, Jennifer Eickstaedt, Jill Randolph, Sandy Showalter, Melissa Wendling, Robert Taylor, Margaret Cytron, Kim Fowler, Katie Krause, Jackie O’Brien, Marianne Tow, Kaitlin Stassi, 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, and Marjane Villafranca

Subjects
Medicine
Abstract

Introduction Ventilator-associated pneumonia (VAP) is a common healthcare-associated infection in the intensive care unit (ICU). Probiotics are defined as live microorganisms that may confer health benefits when ingested. Prior randomised trials suggest that probiotics may prevent infections such as VAP and Clostridioides difficile–associated diarrhoea (CDAD). PROSPECT (Probiotics to Prevent Severe Pneumonia and Endotracheal Colonization Trial) is a multicentre, double-blinded, randomised controlled trial comparing the efficacy of the probiotic Lactobacillus rhamnosus GG with usual care versus usual care without probiotics in preventing VAP and other clinically important outcomes in critically ill patients admitted to the ICU.Methods and analysis The objective of E-PROSPECT is to determine the incremental cost-effectiveness of L. rhamnosus GG plus usual care versus usual care without probiotics in critically ill patients. E-PROSPECT will be performed from the public healthcare payer’s perspective over a time horizon from ICU admission to hospital discharge.We will determine probabilities of in-ICU and in-hospital events from all patients alongside PROSPECT. We will retrieve unit costs for each resource use item using jurisdiction-specific public databases, supplemented by individual site unit costs if such databases are unavailable. Direct costs will include medications, personnel costs, radiology/laboratory testing, operative/non-operative procedures and per-day hospital ‘hoteling’ costs not otherwise encompassed. The primary outcome is the incremental cost per VAP prevented between the two treatment groups. Other clinical events such as CDAD, antibiotic-associated diarrhoea and in-hospital mortality will be included as secondary outcomes. We will perform pre-specified subgroup analyses (medical/surgical/trauma; age; frailty status; antibiotic use; prevalent vs no prevalent pneumonia) and probabilistic sensitivity analyses for VAP, then generate confidence intervals using the non-parametric bootstrapping approach.Ethics and dissemination Study approval for E-PROSPECT was granted by the Hamilton Integrated Research Ethics Board of McMaster University on 29 July 2019. Informed consent was obtained from the patient or substitute decision-maker in PROSPECT. The findings of this study will be published in peer-reviewed journals.Trial registration number NCT01782755; Pre-results.

Published
2020
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11. The Effect of an Accelerated Renal Replacement Therapy Initiation Is Not Modified by Baseline Risk

Author

Federico Angriman, Bruno L. Ferreyro, Natalia Angeloni, Bruno R. da Costa, Ron Wald, Sean M. Bagshaw, Neill K.J. Adhikari, Rinaldo Bellomo, Didier Dreyfuss, Bin Du, Martin P. Gallagher, Stéphane Gaudry, François Lamontagne, Michael Joannidis, Kathleen D. Liu, Daniel F. McAuley, Shay P. McGuinness, Alistair D. Nichol, Marlies Ostermann, Paul M. Palevsky, Haibo Qiu, Ville Pettilä, Antoine G. Schneider, Orla M. Smith, Suvi T. Vaara, Matthew Weir, Glenn M. Eastwood, Leah Peck, Helen Young, Peter Kruger, Gordon Laurie, Emma Saylor, Jason Meyer, Ellen Venz, Krista Wetzig, Craig French, Forbes McGain, John Mulder, Gerard Fennessy, Sathyajith Koottayi, Samantha Bates, Miriam Towns, Rebecca Morgan, Anna Tippett, Andrew Udy, Chris Mason, Elisa Licari, Dashiell Gantner, Jason McClure, Alistair Nichol, Phoebe McCracken, Jasmin Board, Emma Martin, Shirley Vallance, Meredith Young, Chelsey Vladic, Steve McGloughlin, David Gattas, Heidi Buhr, Jennifer Coles, Debra Hutch, James Wun, Louise Cole, Christina Whitehead, Julie Lowrey, Kristy Masters, Rebecca Gresham, Victoria Campbell, David Gutierrez, Jane Brailsford, Loretta Forbes, Lauren Murray, Teena Maguire, Martina NiChonghaile, Neil Orford, Allison Bone, Tania Elderkin, Tania Salerno, Tim Chimunda, Jason Fletcher, Emma Broadfield, Sanjay Porwal, Cameron Knott, Catherine Boschert, Julie Smith, Angus Richardson, Dianne Hill, Graeme Duke, Peter Oziemski, Santiago Cegarra, Peter Chan, Deborah Welsh, Stephanie Hunter, Owen Roodenburg, John Dyett, Nicos Kokotsis, Max Moser, Yang Yang, Laven Padayachee, Joseph Vetro, Himangsu Gangopadhyay, Melissa Kaufman, Angaj Ghosh, Simone Said, Alpesh Patel, Shailesh Bihari, Elisha Matheson, Xia Jin, Tapaswi Shrestha, Kate Schwartz, Rosalba Cross, Winston Cheung, Helen Wong, Mark Kol, Asim Shah, Amanda Y. Wang, Zoltan Endre, Celia Bradford, Pierre Janin, Simon Finfer, Naomi Diel, Jonathan Gatward, Naomi Hammond, Anthony Delaney, Frances Bass, Elizabeth Yarad, Hergen Buscher, Claire Reynolds, Nerilee Baker, Romuald Bellmann, Andreas Peer, Julia Hasslacher, Paul Koglberger, Sebastian Klein, Klemens Zotter, Anna Brandtner, Armin Finkenstedt, Adelheid Ditlbacher, Frank Hartig, Dietmar Fries, Mirjam Bachler, Bettina Schenk, Martin Wagner, Philipp Eller, Thomas Staudinger, Esther Tiller, Peter Schellongowski, Andja Bojic, Eric A. Hoste, Stephanie Bracke, Luc De Crop, Daisy Vermeiren, Fernando Thome, Bianca Chiella, Lucia Fendt, Veronica Antunes, Frédérick D'Aragon, Charles St-Arnaud, Michael Mayette, Élaine Carbonnaeu, Joannie Marchand, Marie-Hélène Masse, Marilène Ladouceur, Alexis F. Turgeon, François Lauzier, David Bellemare, Charles Langis Francoeur, Guillaume LeBlanc, Gabrielle Guilbault, Stéphanie Grenier, Eve Cloutier, Annick Boivin, Charles Delisle-Thibault, Panagiota Giannakouros, Olivier Costerousse, Jean-François Cailhier, François-Martin Carrier, Ali Ghamraoui, Martine Lebrasseur, Fatna Benettaib, Maya Salamé, Dounia Boumahni, Ying Tung Sia, Jean-François Naud, Isabelle Roy, Henry T. Stelfox, Stacey Ruddell, Braden J. Manns, Shelley Duggan, Dominic Carney, Jennifer Barchard, Richard P. Whitlock, Emilie Belley-Cote, Nevena Savija, Alexandra Sabev, Troy Campbell, Thais Creary, Kelson Devereaux, Shira Brodutch, Claudio Rigatto, Bojan Paunovic, Owen Mooney, Anna Glybina, Oksana Harasemiw, Michelle Di Nella, John Harmon, Navdeep Mehta, Louis Lakatos, Nicole Haslam, Francois Lellouche, Mathieu Simon, Ying Tung, Patricia Lizotte, Pierre-Alexandre Bourchard, Bram Rochwerg, Tim Karachi, Tina Millen, John Muscedere, David Maslove, J. Gordon Boyd, Stephanie Sibley, John Drover, Miranda Hunt, Ilinca Georgescu, Randy Wax, Ilan Lenga, Kavita Sridhar, Andrew Steele, Kelly Fusco, Taneera Ghate, Michael Tolibas, Holly Robinson, Matthew A. Weir, Ravi Taneja, Ian M. Ball, Amit Garg, Eileen Campbell, Athena Ovsenek, Sean van Diepen, Nadia Baig, Sheldon Magder, Han Yao, Ahsan Alam, Josie Campisi, Erika MacIntyre, Ella Rokosh, Kimberly Scherr, Stephen Lapinsky, Sangeeta Mehta, Sumesh Shah, Daniel J. Niven, Michael Russell, Kym Jim, Gillian Brown, Kerry Oxtoby, Adam Hall, Luc Benoit, Colleen Sokolowski, Bhanu Prasad, Jag Rao, Shelley Giebel, Demetrios J. Kutsogiannis, Patricia Thompson, Tayne Thompson, Robert Cirone, Kanthi Kavikondala, Mark Soth, France Clarke, Alyson Takaoka, David Mazer, Karen Burns, Jan Friedrich, David Klein, Gyan Sandhu, Marlene Santos, Imrana Khalid, Jennifer Hodder, Peter Dodek, Najib Ayas, Victoria Alcuaz, Gabriel Suen, Oleksa Rewa, Gurmeet Singh, Sean Norris, Neil Gibson, Castro Arias, Aysha Shami, Celine Pelletier, Alireza Zahirieh, Andre Amaral, Nicole Marinoff, Navjot Kaur, Adic Perez, Jane Wang, Gregory Haljan, Christopher Condin, Lauralyn McIntyre, Brigette Gomes, Rebecca Porteous, Irene Watpool, Swapnil Hiremath, Edward Clark, Margaret S. Herridge, Felicity Backhouse, M. Elizabeth Wilcox, Karolina Walczak, Vincent Ki, Asheer Sharman, Martin Romano, R.T. Noel Gibney, Adam S. Romanovsky, Lorena McCoshen, Gordon Wood, Daniel Ovakim, Fiona Auld, Gayle Carney, Meili Duan, Xiaojun Ji, Dongchen Guo, Zhili Qi, Jin Lin, Meng Zhang, Lei Dong, Jingfeng Liu, Pei Liu, Deyuan Zhi, Guoqiang Bai, Yu Qiu, Ziqi Yang, Jing Bai, Zhuang Liu, Haizhou Zhuang, Haiman Wang, Jian Li, Mengya Zhao, Xiao Zhou, Xianqing Shi, Baning Ye, Manli Liu, Jing Wu, Yongjian Fu, Dali Long, Yu Pan, Jinlong Wang, Huaxian Mei, Songsong Zhang, Mingxiang Wen, Enyu Yang, Sijie Mu, Jianquan Li, Tingting Hu, Bingyu Qin, Min Li, Cunzhen Wang, Xin Dong, Kaiwu Wang, Haibo Wang, Jianxu Yang, Chuanyao Wang, Dongxin Wang, Nan Li, Zhui Yu, Song Xu, Lan Yao, Guo Hou, Zhou Liu, Liping Lu, Yingtao Lian, Chunting Wang, Jichen Zhang, Ruiqi Ding, Guoqing Qi, Qizhi Wang, Peng Wang, Zhaoli Meng, Man Chen, Xiaobo Hu, Xiandi He, Shibing Zhao, Lele Hang, Rui Li, Suhui Qin, Kun Lu, Shijuan Dun, Cheng Liu, Qi Zhou, Zhenzhen Chen, Jing Mei, Minwei Zhang, Hao Xu, Jincan Lin, Qindong Shi, Lijuan Fu, Qinjing Zeng, Hongye Ma, Jinqi Yan, Lan Gao, Hongjuan Liu, Lei Zhang, Hao Li, Xiaona He, Jingqun Fan, Litao Guo, Yu Liu, Xue Wang, Jingjing Sun, Zhongmin Liu, Juan Yang, Lili Ding, Lulu Sheng, Xingang Liu, Jie Yan, Quihui Wang, Yifeng Wang, Dan Zhao, Shuangping Zhao, Chenghuan Hu, Jing Li, Fuxing Deng, Haibo Qui, Yi Yang, Min Mo, Chun Pan, Changde Wu, Yingzi Huang, Lili Huang, Airan Liu, Anna-Maija Korhonen, Sanna Törnblom, Sari Sutinen, Leena Pettilä, Jonna Heinonen, Eliria Lappi, Taria Suhonen, Sari Karlsson, Sanna Hoppu, Ville Jalkanen, Anne Kuitunen, Markus Levoranta, Jaakko Långsjö, Sanna Ristimäki, Kaisa Malila, Anna Wootten, Simo Varila, Mikko J Järvisalo, Outi Inkinen, Satu Kentala, Keijo Leivo, Paivi Haltia, Jean-Damien Ricard, Jonathan Messika, Abirami Tiagarajah, Malo Emery, Aline Dechanet, Coralie Gernez, Damien Roux, Laurent Martin-Lefevre, Maud Fiancette, Isabelle Vinatier, Jean Claude Lacherade, Gwenhaël Colin, Christine Lebert, Marie-Ange Azais, Aihem Yehia, Caroline Pouplet, Matthieu Henry- Lagarrigue, Amélie Seguin, Laura Crosby, Julien Maizel, Dimitri Titeca-Beauport, Alain Combes, Ania Nieszkowska, Paul Masi, Alexandre Demoule, Julien Mayaux, Martin Dres, Elise Morawiec, Maxens Decalvele, Suela Demiri, Morgane Faure, Clémence Marios, Maxime Mallet, Marie Amélie Ordon, Laura Morizot, Marie Cantien, François Pousset, Florent Poirson, Yves Cohen, Laurent Argaud, Martin Cour, Laurent Bitker, Marie Simon, Romain Hernu, Thomas Baudry, Sylvie De La Salle, Adrien Robine, Nicholas Sedillot, Xavier Tchenio, Camille Bouisse, Sylvie Roux, Fabienne Tamion, Steven Grangé, Dorothée Carpentier, Guillaume Chevrel, Luis Ensenyat-Martin, Sophie Marque, Jean-Pierre Quenot, Pascal Andreu, Auguste Dargent, Audrey Large, Nicolas Chudeau, Mickael Landais, Benoit Derrien, Jean Christophe Callahan, Christophe Guitton, Charlène Le Moal, Alain Robert, Karim Asehnoune, Raphaël Cinotti, Nicolas Grillot, Dominique Demeure, Christophe Vinsonneau, Imen Rahmani, Mehdi Marzouk, Thibault Dekeyser, Caroline Sejourne, Mélanie Verlay, Fabienne Thevenin, Lucie Delecolle, Didier Thevenin, Bertrand Souweine, Elisabeth Coupez, Mireille Adda, Jean-Pierre Eraldi, Antoine Marchalot, Nicolas De Prost, Armand Mekontso Dessap, Keyvan Razazi, Ferhat Meziani, Julie Boisrame-Helms, Raphael Clere-Jehl, Xavier Delabranche, Christine Kummerlen, Hamid Merdji, Alexandra Monnier, Yannick Rabouel, Hassene Rahmani, Hayat Allam, Samir Chenaf, Vincenta Franja, Bertrand Pons, Michel Carles, Frédéric Martino, Régine Richard, Benjamin Zuber, Guillaume Lacave, Karim Lakhal, Bertrand Rozec, Hoa Dang Van, Éric Boulet, Fouad Fadel, Cedric Cleophax, Nicolas Dufour, Caroline Grant, Marie Thuong, Jean Reignier, Emmanuel Canet, Laurent Nicolet, Thierry Boulain, Mai-Anh Nay, Dalila Benzekri, François Barbier, Anne Bretagnol, Toufik Kamel, Armelle Mathonnet, Grégoire Muller, Marie Skarzynski, Julie Rossi, Amandine Pradet, Sandra Dos Santos, Aurore Guery, Lucie Muller, Luis Felix, Julien Bohé, Guillaume Thiéry, Nadia Aissaoui, Damien Vimpere, Morgane Commeureuc, Jean-Luc Diehl, Emmanuel Guerot, Orfeas Liangos, Monika Wittig, Alexander Zarbock, Mira Küllmar, Thomas van Waegeningh, Nadine Rosenow, Kathy Brickell, Peter Doran, Patrick T. Murray, Giovanni Landoni, Rosalba Lembo, Alberto Zangrillo, Giacomo Monti, Margherita Tozzi, Matteo Marzaroli, Gaetano Lombardi, Gianluca Paternoster, Michelangelo Vitiello, Shay McGuinness, Rachael Parke, Magdalena Butler, Eileen Gilder, Keri-Anne Cowdrey, Samantha Wallace, Jane Hallion, Melissa Woolett, Philippa Neal, Karina Duffy, Stephanie Long, Colin McArthur, Catherine Simmonds, Yan Chen, Rachael McConnochie, Lynette Newby, David Knight, Seton Henderson, Jan Mehrtens, Stacey Morgan, Anna Morris, Kymbalee Vander Hayden, Tara Burke, Matthew Bailey, Ross Freebairn, Lesley Chadwick, Penelope Park, Christine Rolls, Liz Thomas, Ulrike Buehner, Erin Williams, Jonathan Albrett, Simon Kirkham, Carolyn Jackson, Troy Browne, Jennifer Goodson, David Jackson, James Houghton, Owen Callender, Vicki Higson, Owen Keet, Clive Dominy, Paul Young, Anna Hunt, Harriet Judd, Cassie Lawrence, Shaanti Olatunji, Yvonne Robertson, Charlotte Latimer-Bell, Deborah Hendry, Agnes Mckay-Vucago, Nina Beehre, Eden Lesona, Leanlove Navarra, Chelsea Robinson, Ryan Jang, Andrea Junge, Bridget Lambert, Michel Thibault, Philippe Eckert, Sébastien Kissling, Erietta Polychronopoulos, Elettra Poli, Marco Altarelli, Madeleine Schnorf, Samia Abed Mallaird, Claudia Heidegger, Aurelie Perret, Philippe Montillier, Frederic Sangla, Seigenthaller Neils, Aude De Watteville, Mandeep-Kaur Phull, Aparna George, Nauman Hussain, Tatiana Pogreban, Steve Lobaz, Alison Daniels, Mishell Cunningham, Deborah Kerr, Alice Nicholson, Pradeep Shanmugasundaram, Judith Abrams, Katarina Manso, Geraldine Hambrook, Elizabeth McKerrow, Juvy Salva, Stephen Foulkes, Matthew Wise, Matt Morgan, Jenny Brooks, Jade Cole, Tracy Michelle Davies, Helen Hill, Emma Thomas, Marcela Vizcaychipi, Behrad Baharlo, Jaime Carungcong, Patricia Costa, Laura Martins, Ritoo Kapoor, Tracy Hazelton, Angela Moon, Janine Musselwhite, Ben Shelley, Philip McCall, Gill Arbane, Aneta Bociek, Martina Marotti, Rosario Lim, Sara Campos, Neus Grau Novellas, Armando Cennamo, Andrew Slack, Duncan Wyncoll, Luigi Camporota, Simon Sparkes, Rosalinde Tilley, Austin Rattray, Gayle Moreland, Jane Duffy, Elizabeth McGonigal, Philip Hopkins, Clare Finney, John Smith, Harriet Noble, Hayley Watson, Claire-Louise Harris, Emma Clarey, Eleanor Corcoran, James Beck, Clare Howcroft, Nora Youngs, Elizabeth Wilby, Bethan Ogg, Adam Wolverson, Sandra Lee, Susie Butler, Maryanne Okubanjo, Julia Hindle, Ingeborg Welters, Karen Williams, Emily Johnson, Julie Patrick-Heselton, David Shaw, Victoria Waugh, Richard Stewart, Esther Mwaura, Lynn Wren, Louise Mew, Sara-Beth Sutherland, Jane Adderley, Jim Ruddy, Margaret Harkins, Callum Kaye, Teresa Scott, Wendy Mitchell, Felicity Anderson, Fiona Willox, Vijay Jagannathan, Michele Clark, Sarah Purv, Andrew Sharman, Megan Meredith, Lucy Ryan, Louise Conner, Cecilia Peters, Dan Harvey, Ashraf Roshdy, Amy Collins, Malcolm Sim, Steven Henderson, Nigel Chee, Sally Pitts, Katie Bowman, Maria Dilawershah, Luke Vamplew, Elizabeth Howe, Paula Rogers, Clara Hernandez, Clara Prendergast, Jane Benton, Alex Rosenberg, Lui G. Forni, Alice Grant, Paula Carvelli, Ajay Raithatha, Sarah Bird, Max Richardson, Matthew Needham, Claire Hirst, Jonathan Ball, Susannah Leaver, Luisa Howlett, Carlos Castro Delgado, Sarah Farnell-Ward, Helen Farrah, Geraldine Gray, Gipsy Joseph, Francesca Robinson, Ascanio Tridente, Clare Harrop, Karen Shuker, Derek McLaughlan, Judith Ramsey, Sharon Meehan, Bernd Oliver Rose, Rosie Reece-Anthony, Babita Gurung, Tony Whitehouse, Catherine Snelson, Tonny Veenith, Andy Johnston, Lauren Cooper, Ron Carrera, Karen Ellis, Emma Fellows, Samanth Harkett, Colin Bergin, Elaine Spruce, Liesl Despy, Stephanie Goundry, Natalie Dooley, Tracy Mason, Amy Clark, Gemma Dignam, Geraldine Ward, Ben Attwood, Penny Parsons, Sophie Mason, Michael Margarson, Jenny Lord, Philip McGlone, Luke E. Hodgson, Indra Chadbourn, Raquel Gomez, Jordi Margalef, Rinus Pretorius, Alexandra Hamshere, Joseph Carter, Hazel Cahill, Lia Grainger, Kate Howard, Greg Forshaw, Zoe Guy, Kianoush B. Kashani, Robert C. Albright, Amy Amsbaugh, Anita Stoltenberg, Alexander S. Niven, Matthew Lynch, AnnMarie O'Mara, Syed Naeem, Sairah Sharif, Joyce McKenney Goulart, Ashita Tolwani, Claretha Lyas, Laura Latta, Azra Bihorac, Haleh Hashemighouchani, Philip Efron, Matthew Ruppert, Julie Cupka, Sean Kiley, Joshua Carson, Peggy White, George Omalay, Sherry Brown, Laura Velez, Alina Marceron, Javier A. Neyra, Juan Carlos Aycinena, Madona Elias, Victor M. Ortiz-Soriano, Caroline Hauschild, and Robert Dorfman

Subjects
Renal Replacement Therapy, Pulmonary and Respiratory Medicine, Critical Illness, Medicine and Health Sciences, Humans, Acute Kidney Injury
Published
2022

12. Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit

Author

François, Lamontagne, Marie-Hélène, Masse, Julie, Menard, Sheila, Sprague, Ruxandra, Pinto, Daren K, Heyland, Deborah J, Cook, Marie-Claude, Battista, Andrew G, Day, Gordon H, Guyatt, Salmaan, Kanji, Rachael, Parke, Shay P, McGuinness, Bharath-Kumar, Tirupakuzhi Vijayaraghavan, Djillali, Annane, Dian, Cohen, Yaseen M, Arabi, Brigitte, Bolduc, Nicole, Marinoff, Bram, Rochwerg, Tina, Millen, Maureen O, Meade, Lori, Hand, Irene, Watpool, Rebecca, Porteous, Paul J, Young, Frederick, D'Aragon, Emilie P, Belley-Cote, Elaine, Carbonneau, France, Clarke, David M, Maslove, Miranda, Hunt, Michaël, Chassé, Martine, Lebrasseur, François, Lauzier, Sangeeta, Mehta, Hector, Quiroz-Martinez, Oleksa G, Rewa, Emmanuel, Charbonney, Andrew J E, Seely, Demetrios J, Kutsogiannis, Remi, LeBlanc, Armand, Mekontso-Dessap, Tina S, Mele, Alexis F, Turgeon, Gordon, Wood, Sandeep S, Kohli, Jason, Shahin, Pawel, Twardowski, Neill K J, Adhikari, Francis, Malenfant, Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Lotte and John Hecht Memorial Foundation, LJHMF, The trial was funded by the Lotte and John Hecht Memorial Foundation. Nova Biomedical Canada provided glucometers, testing strips, and control solutions (StatStrip Express) to trial sites that requested them. Without input from the funder, the authors were responsible for the design, planning, and coordination of the trial and for the analysis of the data, all the authors made the decision to submit the manuscript for publication. Site investigators, research personnel, or trained delegates assessed the eligibility of potential patients, and research personnel collected the data. Informed consent was provided by the patients or their legal representatives, and after approval by local authorities, consent could be obtained by telephone or patients could be enrolled with deferred consent, followed by informed consent as soon as reasonably possible.

Subjects
Adult, Intensive Care Units, [SDV]Life Sciences [q-bio], Multiple Organ Failure, Sepsis, Quality of Life, Humans, Hypoglycemic Agents, Vasoconstrictor Agents, Ascorbic Acid, Vitamins, General Medicine
Abstract

International audience; BACKGROUND Studies that have evaluated the use of intravenous vitamin C in adults with sepsis who were receiving vasopressor therapy in the intensive care unit (ICU) have shown mixed results with respect to the risk of death and organ dysfunction. METHODS In this randomized, placebo-controlled trial, we assigned adults who had been in the ICU for no longer than 24 hours, who had proven or suspected infection as the main diagnosis, and who were receiving a vasopressor to receive an infusion of either vitamin C (at a dose of 50 mg per kilogram of body weight) or matched placebo administered every 6 hours for up to 96 hours. The primary outcome was a composite of death or persistent organ dysfunction (defined by the use of vasopressors, invasive mechanical ventilation, or new renal-replacement therapy) on day 28. RESULTS A total of 872 patients underwent randomization (435 to the vitamin C group and 437 to the control group). The primary outcome occurred in 191 of 429 patients (44.5%) in the vitamin C group and in 167 of 434 patients (38.5%) in the control group (risk ratio, 1.21; 95% confidence interval [CI], 1.04 to 1.40; P = 0.01). At 28 days, death had occurred in 152 of 429 patients (35.4%) in the vitamin C group and in 137 of 434 patients (31.6%) in the placebo group (risk ratio, 1.17; 95% CI, 0.98 to 1.40) and persistent organ dysfunction in 39 of 429 patients (9.1%) and 30 of 434 patients (6.9%), respectively (risk ratio, 1.30; 95% CI, 0.83 to 2.05). Findings were similar in the two groups regarding organ-dysfunction scores, biomarkers, 6-month survival, health-related quality of life, stage 3 acute kidney injury, and hypoglycemic episodes. In the vitamin C group, one patient had a severe hypoglycemic episode and another had a serious anaphylaxis event. CONCLUSIONS In adults with sepsis receiving vasopressor therapy in the ICU, those who received intravenous vitamin C had a higher risk of death or persistent organ dysfunction at 28 days than those who received placebo. (Funded by the Lotte and John Hecht Memorial Foundation; LOVIT ClinicalTrials.gov number, NCT03680274.).

Published
2022

13. Monitoring and auditing protocol adherence, data integrity and ethical conduct of a randomized clinical trial: A case study

Author

Alyson Takaoka, Nicole Zytaruk, Megan Davis, Andrea Matte, Jennie Johnstone, François Lauzier, John Marshall, Neill Adhikari, France J. Clarke, Bram Rochwerg, François Lamontagne, Lori Hand, Irene Watpool, Rebecca K. Porteous, Marie-Hélène Masse, Frédérick D'Aragon, Daniel Niven, Diane Heels-Ansdell, Erick Duan, Joanna Dionne, Shane English, Charles St-Arnaud, Tina Millen, and Deborah J. Cook

Subjects
Canada, Informed Consent, Humans, Multicenter Studies as Topic, Patient Safety, Critical Care and Intensive Care Medicine
Abstract

To categorize, quantify and interpret findings documented in feedback letters of monitoring or auditing visits for an investigator-initiated, peer-review funded multicenter randomized trial testing probiotics for critically ill patients.In 37 Canadian centers, monitoring and auditing visits were performed by 3 trained individuals; findings were reported in feedback letters. At trial termination, we performed duplicate content analysis on letters, categorizing observations first into unique findings, followed by 10 pre-determined trial quality management domains. We further classified each observation into a) missing operational records, b) errors in process, and potential threats to c) data integrity, d) patient privacy or e) safety.Across 37 monitoring or auditing visits, 75 unique findings were categorized into 10 domains. Most frequently, observations were in domains of training documentation (180/566 [32%]) and the informed consent process (133/566 [23%]). Most observations were missing operational records (438/566 [77%]) rather than errors in process (128/566 [23%]). Of 75 findings, 13 (62/566 observations [11%]) posed a potential threat to data integrity, 1 (1/566 observation [0.18%]) to patient privacy, and 9 (49/566 observations [8.7%]) to patient safety.Monitoring and auditing findings predominantly concerned missing documentation with minimal threats to data integrity, patient privacy or safety.PROSPECT (Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial): NCT02462590.

Published
2022

14. Evolution Over Time of Ventilatory Management and Outcome of Patients With Neurologic Disease

Author

Tejerina E. E., Pelosi P., Robba C., Penuelas O., Muriel A., Barrios D., Frutos-Vivar F., Raymondos K., Du B., Thille A. W., Rios F., Gonzalez M., Del-Sorbo L., Marin M. D. C., Valle Pinheiro B., Soares M. A., Nin N., Maggiore S. M., Bersten A., Amin P., Cakar N., Young Suh G., Abroug F., Jibaja M., Matamis D., Ali Zeggwagh A., Sutherasan Y., Anzueto A., Esteban A, Fernando Ríos, Damian Violi, Marisol Rodríguez-Goñi, Roger Lamoglie, Fernando Villarejo, Norberto Tiribelli, Santiago Ilutovich, Matías Brizuela, Mariana Monllau, Fernando Saldarini, Silvina Borello, Alberto Marino, Mauricio Vinzio, Karina Bonasegla, Julián Hernández, María Belén Yapur, María Eugenia González, Sebastián E Mare, Judith Sagardía, Marco Bezzi, Cecilia Pereyra, Julian Strati, Daniel Vargas, Claudia Diaz, Pablo Gómez, Marcelo Palavecino, Graciela Elizabeth, Aguilera García, M Eugenia, Luis Pablo Cardonnet, Lisandro Betttini, Hernán Nuñez, Lucas Vallejo, Fernando Fernández, Jorge Arroyo, Daniel Duarte, Gerardo Filippa, Cayetano Galetti, Hernan Nunia, Fernando Lambert, Elisa Estenssoro, Marina Busico, Javier Horacio Álvarez, Alejandro Raimondi, Gustavo Badariotti, Martín Lugaro, Fernando Lipovestky, Alan Javier Zazu, Hugo Capponcelli, Patricia Vogl, Cristina Orlandi, Alejandro Gómez, Gustavo Jannello, Alejandro Risso, Leticia Rapetti, Guillermo Chiappero, Juan Domingo Fernández, Rodrigo E Gómez-Paz, Marcos Juan Zec, Pascual Valdez, Jorgelina Guyon, Ariel Chena, Sergio Lasdica, Martin Deheza, Schimdt Alejandra, Francisco Criado, Norma Beatriz Márquez, Pablo Desmery, José Luis Scapellato, Gonzalo Javier Ríos, Cristian Casabella, Jasmin Board, Andrew Davies, Andrew Bersten, Elisha Matheson, Amy Waters, John Santamaria, Jennifer Holmes, Cartan Costello, Manoj K Saxena, John Myburgh, Ellen Kinkel, Forbes McGain, Claire Cattigan, Allison Bone, Ian Seppelt, Leonie Weisbrodt, Cheryl Cuzner, Christopher MacIsaac, Deborah Barge, Tania Caf, Cameron Knott, Graeme Duke, Imogen Mitchell, Helen Rodgers, Rachel Whyte, Elisha Fulton, Alistair Nichol, Hergen Buscher, Priya Nair, Claire Reynolds, Simon J G Hockley, Ian Moore, Katherine Davidson, David Milliss, Raju Pusapati, Helen Wong, Jason Fletcher, Julie Smith, Paul Goldrick, Dianne Stephens, Jane Thomas, Anders Aneman, Sutrisno Gunawan, Tom Cowlam, George Lukas, Rick McAllister, Minka Springham, Joanne Sutton, Jeff Presneill, Tony Sutherland, Dianne Hill, Howard Connor, Jenny Dennett, Tim Coles, Freddy Sandy, Sando Chavarria, Marcelo Choque, Ronald Pairumani, Juan Guerra, Marco Antônio Soares Reis, José Carlos Versiani, Eduardo Fonseca Sad, Maria Aparecida Braga, Dinalva Aparecida Gomes, Fernando Antônio Botoni, Maurício Meireles Góes, Frederico Costa Val Barros, Rogério de Castro Pereira, Hugo Urbano, Valéria de Carvalho Magela, Aline Camile Yehia, Bruno Bonaccorsi Fernandino, Marco Antônio Ribeiro Leão, Rovílson Lara, Rubens Altair Amaral de Pádua, Janine Dias Alves, Aloísio Marques do Nascimento, Bruno do Valle Pinheiro, Carlos Alberto Studart Gomes, Marcelo Alcântara Holanda, Frederico Rodrigues Anselmo, Niall Ferguson, Neill Adhikari, Robert Fowler, Cheromi Sittambalam, Mehar-Un-Nisa Raja, Nicole Marinoff, Lauralyn McIntryre, Shawna Reddie, Laura Jones, Irene Watpool, Jeffrey Singh, Madison Dennis, Andrea Matte, Marc Lipkus, Ryan Albert, Andrew Steel, Emily Stern, Michael Miletin, Antonio Raso, Robyn Klages, Jan Friedrich, Orla Smith, Laura Wilson, Deborah Cook, Mark Bailey, Sangeeta Mehta, Stephen Lapinsky, Hannah Mathers, Cheryl Ethier, Stephanie Lubchansky, Samer Haj-Bakri, Dietrich Henzler, Lisa Julien, Luis Soto-Román, Juan Carlos Maurelia, César Antonio Maquilon, Luis Soto-Germani, Bin Du, Yan Kang, Bo Wang, Fachun Zhou, Fang Xu, Haibo Qiu, Yi Yang, Qingyuan Zhan, Bing Sun, Zhenjie Hu, Bin Yu, Xi Zhu, Yu Bai, Gang Li, Yi Li, Geng Zhang, Jianbiao Meng, Xiaobo Huang, Hong Pu, Daxing Yu, Chuanyun Qian, Wei Zhang, Yongjie Yin, Debiao Song, Yunxuan Yue, Zhengxuan Lv, Chengmin Yu, Qunmei Yao, Xue Wang, Yuan Xu, Wei He, Mian Chen, Zhihua Hu, Dongpo Jiang, Jian Huang, Wei Yu, Juanxian Gu, Yangong Chao, Zhixiang Li, Zhicheng Zhang, Wanxia Li, Zhenyang He, Jianguo Li, Chang Liu, Tiehe Qin, Shouhong Wang, Feng Li, Jun Jin, Jianhong Fu, Hongyang Xu, Hongyuan Lin, Jianying Guo, Yalin Liu, Jinghua Wang, Maoqin Li, Jiaqiong Li, Lei Chen, Qing Song, Liang Pan, Xianyao Wan, Jiuzhi Zhang, Weihai Yao, Yuhong Guo, Pang Wing Yan, Kelly Choy, Kwan Ming Chit, Patricia Leung, Chau Chin Man, Marco González, Ricardo Buitrago, Marcela Granados, Guillermo Ortiz, Cesar Enciso, Mario Gómez, Bladimir Alejandro Gil, Juan Pablo Sedano, Luis Fernando Castro Castro, Carlo Alberto Acosta, Marco Gonzalez, Francisco Molina, Camilo Pizarro, Mario Villabon, Carmelo Dueñas, Carlos Andrés Díaz, Nelson Fonseca, Rubén Camargo, Juan David Uribe, Hans-Henrik Bülow, Simona Beniczky, Jens Brushoj, Mikkel Præst, Birgitte Viebaek, Sine Wichman, Anette Mortensen, Susanne Andi Iversen, Bo Broberg, Edgard Luna, Manuel Jibaja, Leonardo Pazmiño, Katty Trelles, Fabricio Picoita, Gustavo Paredes, Vanesa Ramírez, Guillermo Falconí, Cristian Cevallos, Boris Villamagua, Marco Escobar, Freddy Sánchez, Miguel Llano, Miguel Lazcano, Ramiro Puetate, José Miguel Guerrero, Mijail Játiva, Myriam Montalvo, Franklin Villegas, Luis González Zambrano, Ronnie Mantilla, Gina Quinde, Andrea Gimenez, Luis Gonzalez Mosquera, Henry Caballero, María Fernanda García, Marcelo Ochoa, Soraya Puertas, Jackeline Coello, Mario Acosta, Medhat Soliman, Arnaud W Thille, Achille Kouatchet, Alain Mercat, Laurent Brochard, François Collet, Guillaume Marcotte, Pascal Beuret, Jean-Christophe M Richard, Gaëtan Bedunaeu, Pierre-Gildas Guitard, Fabien Soulis, Frédéric Bellec, Philippe Berger, Dorothée Carpentier, Benoit Veber, Salem Ould Zein, Géraldine Dessertaine, C Canevet, Fabien Grelon, Konstantinos Raymondos, Rolf Dembinski, Rolf Rossaint, Steffen Weber-Carstens, Christian Putensen, Maximillian Ragaller, Michael Quintel, Winfried Schubert, Thomas Bein, Heinrich Paulus, Walter Brandt, Lutz Pfeiffer, Silke Frenzel, Thoralf Kerner, P Kruska, Leila Eckholt, Joachim Hartung, Harald Fritz, Monika Holler, Johannes Busch, Andreas Viehöfer, Jens Buettner, Jörn Schlechtweg, Achim Lunkeit, Roland Schneider, Maria Wussow, Nils Marquardt, Christian Frenkel, Falk Hildebrandt, Tumbass Volker, Thomas Lipp, Cezar Mihailescu, Thomas Moellhoff, Thomas Steinke, Oliver Franke, Marcus Ruecker, Markus Schappacher, Steffen Appel, Heinz Kerger, Andreas Schwartz, Jan Dittmann, Jörg Haberkorn, Wolfgang Baier, Walter Seyde, Dimitros Matamis, Eleni Antoniadou, Pertsas Evangelos, Maria Giannakou, Zoltan Szentkereszty, Zsolt Molnar, Pravin Amin, Farhad N Kapadia, Nagarajan Ramakrishnan, Deepak Govil, Anitha Shenoy, Umesh G, Samir Sahu, Sheila Nainan Myatra, Subhash Kumar Todi, Sanjay Dhanuka, Mayur Patel, P Samaddar, Dhruva Chaudhry, Vivek Joshi, Srinivas Samavedam, Ankur Devendra Bhavsar, Prachee Sathe, Sujoy Mukherjee, Salvatore Maurizio Maggiore, Francesco Idone, Federica Antonicelli, Paolo Navalesi, Rosanna Vaschetto, Arianna Boggero, Rosalba Tufano, Michele Iannuzzi, Edoardo De Robertis, Romano Tetamo, Andrea Neville Cracchiolo, Antonio Braschi, Francesco Mojoli, Ilaria Curro', Mirko Belliato, Chiara Verga, Marta Ferrari, Erika Mannelli, Valerio Mangani, Giorgio Tulli, Francesca Frigieri, Armando Pedulla', Monica Rocco, Giorgia Citterio, Di Russo, Gaetano Perchiazzi, Loredana Pitagora, Antonio Pesenti, Michela Bombino, Davide Chiumello, Federica Tallarini, Serena Azzari, Antonina Pigna, Ivano Aprile, Marco Adversi, Antonio Corcione, Marianna Esposito, Annunziata Mattei, Vito Marco Ranieri, Rosario Urbino, Ilaria Maria Mastromauro, Antonino Giarratano, Maurizio Raineri Santi, Ambrogio Sansone, Younsuck Koh, Moo Suk Park, Je Hyeong Kim, Kyung Chan Kim, Hye Sook Choi, Yun Seong Kim, Jin Hwa Lee, Myung-Goo Lee, Won-Yeon Lee, Jin Young An, Gee Young Suh, Ki-Suck Jung, Asisclo J Villagómez Ortiz, César Cruz Lozano, Zalatiel Maycotte Luna, José Francisco López Baca, José Elizalde, Guillermo Cueto Robledo, Mario Alonso Treviño Salinas, Ricardo Martinez Zubieta, Claudia Olvera-Guzman, Marco Montes De Oca, Silvio A Ñamendys-Silva, José Salvador Martínez Cano, Jose Angel Baltazar Torres, Gustavo Morales Muñoz, Antonio Villa Delgado, Javier Ladape Martinez, Amine Ali Zeggwagh, Tarek Dendane, Abderrahim Azzouzi, Ahmed Sbihi, Wajdi Maazouzi, Mourad Amor, Charki Haimeur, Michael A Kuiper, Matty Koopmans, Uli Strauch, Dennis Bergmans, Serge Heines, Sylvia den Boer, Bas M Kors, Peter van der Voort, Paul J Dennesen, Bert Beishuizen, Ingrid van den Hul, Erna Alberts, Harry P P M Gelissen, Eduard Bootsma, Auke Reidinga, Kim Heus, Diane Mackle, Paul Young, Rachael Parke, Eileen Gilder, Jodi Brown, Lynette Newby, Catherine Simmonds, Jan Mehrtens, Seton Henderson, Tony Williams, Judi Tai, Chantal Hogan, Mary La Pine, John Durning, Sheree Gare, Troy Browne, Shirley Nelson, Jennifer Goodson, Julio Osorio, Chabu Coronado, Rollin Roldán Mori, Rosa Luz López Martínez, Adam Mikstacki, Barbara Tamowicz, Rui Moreno, Eduardo Almeida, Joana Silvestre, Heloisa Castro, Irene Aragão, Susana Alves Ferreira, Nelson Barros, Filomena Faria, Carlos André Correia Casado, Fausto Fialho Moura, Paulo Marcal, Ricardo Matos, Edward Nicolayenko, Mikhail Kirov, Andrey Yaroshetskiy, Andrei Piontek, Valery Subbotin, Yaseen Arabi, Olivia Dulfo, Chafrina Marie Olay, Edgardo E Tabhan, Nicolas Nin, Alfonso Muñoz, César Aragón, Ana Villagrá, Ainhoa Rosselló, Joan Maria Raurich, María Garitacelaya, Miguel Ángel González-Gallego, Francisco Ortuño, Miguel Fernández-Vivas, David Freire, Francisco Guerrero, Francisco Manzano, Juan Carlos, Alfredo Padrón, Pedro Rosa, Rafael Morales, Liliana Caipe, Maurizio Bottiroli, José María Nicolás, Marta Ugalde, Javier Ruiz, Lucia Capilla, Guillermo Muñiz, Jesús Sánchez-Ruiz, Javier Cebrián, Begoña Balerdi, Elena Parreño, Alvaro van Bommel, César Pérez-Calvo, Irene Dot, Javier Blanco, Raquel Manzanedo, José J Blanco, Daniel Fontaneda, Raúl González, Javier Díaz Domínguez, Alfonso Moreno, Antonio Reyes, Ian Carrasco, Itziar Mintegui, Rosa Sebastián, Javier García-Alonso, Carolina Lorencio, Josep Maria Sirvent, Patricia Jimeno, Miguel León, Pedro Galdos, Nuria Alonso, Julia López-Díaz, María Victoria de la Torre, Jorge Vidal Hernández, Nicolás Zamboschi, Francisco Lucena, Gemma Rialp, Raquel Montoiro, Victoria Goñi, María Ángeles Pena, Antonio Maestre, Marc Fabra, Jacinto Baena, Eva Benveniste, Susana Temprano, Jesús Sánchez, Carmen Campos, Sara Cabañes, María Elena Pérez-Losada, José Claudio Leo, Enrique Piacentini, María Del Carmen de la Torre, Laura Álvarez-Montero, Fernando Sánchez, Antonio Viñuales, Bernabé Álvarez, Javier Castañeda, Ángela Alonso, María Isabel Ruiz, Pedro Jesús Domínguez, Marcos Delgado, Eugenio Palazón, Antonio García-Jiménez, Rosa Álvaro, Clara Laplaza Eva Regidor, Enrique Maraví, José María Quiroga, Amalia Martínez de la Gandara, Cecilia Carbayo, María Luisa Navarrete, Manuel Valledor, Raquel Yano, José María Gutiérrez, Javier González-Robledo, Amparo Ferrandiz, Alberto Belenguer, Lidón Mateu, Laura Sayagues, María José Tolón, Nieves Franco, Elena Gallego, Félix Lacoma, Patricia Albert, Vicente Arraez, Mar Gobernado, Susana Moradillo, Carolina Gímenez-Esparza, Teresa Sánchez de Dios, Carlos Marian Crespo, Cecilia Hermosa, Federico Gordo, Genis Carrasco, María Ángeles Alonso, Alejandro Algora, Raúl de Pablo, Sofía García, Ana Carolina Caballero, José María Montón, Teresa Mut, Eva Manteiga, Alejandro de la Serna, Ana Esther Trujillo, Rafael Blancas, Inmaculada Vallverdú, José Manuel Serrano, Miquel Ferrer, Juan Diego Jiménez, Carlos Gallego, Dolores Vila, Luis Marina, Valentín Parra, Juan Ramón Cortés, Chen Chin-Ming, Ai-Chin Cheng, Fekri Abroug, Besbes Mohamed, Imed Chouchene, Mounir Bouaziz, Stambouli Neji, Islem Ouanes, Ayed Samia, Nahit Cakar, Ismail Kati, Ali Aydım Altunkan, Remzi Iscimen, Zafer Dogan, Bilge Çetin, Tayfun Adanir, Sabriye Guvenc, Unase Büyükkoçak, Antonio Anzueto, Ashley Ellis, Gary Kinasewitz, Allan Walkey, Phil Alkana, Gregory A Schmidt, Susan Gillen, Kathleen Lilli, Jennifer Twombley, Denice Wells, Larry Welder, Alejandro Arroliga, Alfredo Vasquez-Sandoval, Vincent John Scott, Craig Cernosek, Christopher Spradley, Dimple Tejwani, Sindhaghatta Venkatram, Gilda Diaz-Fuentes, Amber Monson, Anthony Saleh, Madhav Gudi, George Liziamma, Mohamed A Saad, Crissie De Spirito, Bryan Beatty, Samir Vermani, Crissie Despirito, Zaza Cohen, Amee Patrawalla, Samir Abdelhadi, Rupesh Vakil, Steven Y Chang, Brian Sherman, Rosanna Del Giudice, John Oropell, Timothy D Girard, Cayce Strength, Joyce Okahashi, Leanne Boehm, Matthew Kirchner, Erwin J Oei, Sebastian Circo, Nelson Medina, Mohammed Al-Jagbeer, V J Cardenas Jr, Smyth Smith, Shelby Sutton, Marcela Canola-Mazo, Tim Houlihan, Yogeet Kaur, Travis Parry, Craig A Piquette, Kerry Canady, Rahul Nanchal, Dana K Soetaert, Maria Del Mar Torres-Perez, Carlos Robles-Arias, William Rodriguez-Cintron, Mark Tidswell, Jennifer Germain, Lori-Ann Kozikowski, Erin Braden, Geneva Tatem, Javier Hurtado, Alberto Deicas, Daniel Weiss, Marta Beron, Román Garrido, Cristina Santos, Mario Cancela, Raúl Lombardi, Pedro Alzugaray, Jorge Gerez, Silvia Mareque, Graciela Franca, Oscar Cluzet, Edgardo Nuñez, Julio Pontet, Sergio Cáceres, Elias Caragna, Alberto Soler, Frank Torres, Gastón Pittini, Gabriel D Empaire, Stevens Salva, Fernando Pérez, Clara Pacheco, Zoraida Parra, Ingrid Von der Osten, Luis Williams, José Salinas, Do Danh Quynh, Pham Thi Van Anh, Nguyen Huu Hoang, Nghuyen Ba Tuan, RS: NUTRIM - R2 - Liver and digestive health, MUMC+: MA Arts Assistenten IC (9), Intensive Care, MUMC+: MA Medische Staf IC (9), Tejerina E.E., Pelosi P., Robba C., Penuelas O., Muriel A., Barrios D., Frutos-Vivar F., Raymondos K., Du B., Thille A.W., Rios F., Gonzalez M., Del-Sorbo L., Marin M.D.C., Valle Pinheiro B., Soares M.A., Nin N., Maggiore S.M., Bersten A., Amin P., Cakar N., Young Suh G., Abroug F., Jibaja M., Matamis D., Ali Zeggwagh A., Sutherasan Y., Anzueto A., Esteban A, and Fernando Ríos, Damian Violi, Marisol Rodríguez-Goñi, Roger Lamoglie, Fernando Villarejo, Norberto Tiribelli, Santiago Ilutovich, Matías Brizuela, Mariana Monllau, Fernando Saldarini, Silvina Borello, Alberto Marino, Norberto Tiribelli, Mauricio Vinzio, Karina Bonasegla, Julián Hernández, María Belén Yapur, María Eugenia González, Sebastián E Mare, Judith Sagardía, Marco Bezzi, Cecilia Pereyra, Julian Strati, Daniel Vargas, Claudia Diaz, Pablo Gómez, Marcelo Palavecino, Graciela Elizabeth, Aguilera García, M Eugenia, Luis Pablo Cardonnet, Lisandro Betttini, Hernán Nuñez, Lucas Vallejo, Fernando Fernández, Jorge Arroyo, Daniel Duarte, Gerardo Filippa, Cayetano Galetti, Hernan Nunia, Fernando Lambert, Elisa Estenssoro, Marina Busico, Fernando Villarejo, Javier Horacio Álvarez, Alejandro Raimondi, Gustavo Badariotti, Martín Lugaro, Fernando Lipovestky, Alan Javier Zazu, Hugo Capponcelli, Patricia Vogl, Cristina Orlandi, Alejandro Gómez, Gustavo Jannello, Alejandro Risso, Leticia Rapetti, Guillermo Chiappero, Juan Domingo Fernández, Rodrigo E Gómez-Paz, Marcos Juan Zec, Pascual Valdez, Jorgelina Guyon, Ariel Chena, Sergio Lasdica, Martin Deheza, Schimdt Alejandra, Francisco Criado, Norma Beatriz Márquez, Pablo Desmery, José Luis Scapellato, Gonzalo Javier Ríos, Cristian Casabella, Jasmin Board, Andrew Davies, Andrew Bersten, Elisha Matheson, Amy Waters, John Santamaria, Jennifer Holmes, Cartan Costello, Manoj K Saxena, John Myburgh, Ellen Kinkel, Forbes McGain, Claire Cattigan, Allison Bone, Ian Seppelt, Leonie Weisbrodt, Cheryl Cuzner, Christopher MacIsaac, Deborah Barge, Tania Caf, Cameron Knott, Graeme Duke, Imogen Mitchell, Helen Rodgers, Rachel Whyte, Elisha Fulton, Jasmin Board, Andrew Davies, Alistair Nichol, Hergen Buscher, Priya Nair, Claire Reynolds, Simon J G Hockley, Ian Moore, Katherine Davidson, David Milliss, Raju Pusapati, Helen Wong, Jason Fletcher, Julie Smith, Paul Goldrick, Dianne Stephens, Jane Thomas, Anders Aneman, Sutrisno Gunawan, Tom Cowlam, George Lukas, Rick McAllister, Minka Springham, Joanne Sutton, Jeff Presneill, Tony Sutherland, Dianne Hill, Howard Connor, Jenny Dennett, Tim Coles, Freddy Sandy, Sando Chavarria, Marcelo Choque, Ronald Pairumani, Juan Guerra, Marco Antônio Soares Reis, José Carlos Versiani, Eduardo Fonseca Sad, Maria Aparecida Braga, Dinalva Aparecida Gomes, Fernando Antônio Botoni, Maurício Meireles Góes, Frederico Costa Val Barros, Rogério de Castro Pereira, Hugo Urbano, Valéria de Carvalho Magela, Aline Camile Yehia, Bruno Bonaccorsi Fernandino, Marco Antônio Ribeiro Leão, Rovílson Lara, Rovílson Lara, Rubens Altair Amaral de Pádua, Janine Dias Alves, Aloísio Marques do Nascimento, Bruno do Valle Pinheiro, Carlos Alberto Studart Gomes, Marcelo Alcântara Holanda, Frederico Rodrigues Anselmo, Niall Ferguson, Neill Adhikari, Robert Fowler, Cheromi Sittambalam, Mehar-Un-Nisa Raja, Nicole Marinoff, Lauralyn McIntryre, Shawna Reddie, Laura Jones, Irene Watpool, Jeffrey Singh, Madison Dennis, Andrea Matte, Marc Lipkus, Ryan Albert, Andrew Steel, Emily Stern, Michael Miletin, Antonio Raso, Robyn Klages, Jan Friedrich, Orla Smith, Laura Wilson, Deborah Cook, Mark Bailey, Sangeeta Mehta, Stephen Lapinsky, Hannah Mathers, Cheryl Ethier, Stephanie Lubchansky, Samer Haj-Bakri, Dietrich Henzler, Lisa Julien, Luis Soto-Román, Juan Carlos Maurelia, César Antonio Maquilon, Luis Soto-Germani, Bin Du, Yan Kang, Bo Wang, Fachun Zhou, Fang Xu, Haibo Qiu, Yi Yang, Qingyuan Zhan, Bing Sun, Zhenjie Hu, Bin Yu, Xi Zhu, Yu Bai, Gang Li, Yi Li, Geng Zhang, Jianbiao Meng, Xiaobo Huang, Hong Pu, Bin Du, Daxing Yu, Chuanyun Qian, Wei Zhang, Yongjie Yin, Debiao Song, Yunxuan Yue, Zhengxuan Lv, Chengmin Yu, Qunmei Yao, Xue Wang, Yuan Xu, Wei He, Mian Chen, Zhihua Hu, Dongpo Jiang, Jian Huang, Wei Yu, Juanxian Gu, Yangong Chao, Zhixiang Li, Zhicheng Zhang, Wanxia Li, Zhenyang He, Jianguo Li, Chang Liu, Tiehe Qin, Shouhong Wang, Feng Li, Jun Jin, Jianhong Fu, Hongyang Xu, Hongyuan Lin, Jianying Guo, Yalin Liu, Jinghua Wang, Maoqin Li, Jiaqiong Li, Lei Chen, Qing Song, Liang Pan, Xianyao Wan, Jiuzhi Zhang, Weihai Yao, Yuhong Guo, Pang Wing Yan, Kelly Choy, Kwan Ming Chit, Patricia Leung, Chau Chin Man, Marco González, Ricardo Buitrago, Marcela Granados, Guillermo Ortiz, Cesar Enciso, Mario Gómez, Bladimir Alejandro Gil, Juan Pablo Sedano, Luis Fernando Castro Castro, Carlo Alberto Acosta, Marco Gonzalez, Francisco Molina, Camilo Pizarro, Mario Villabon, Carmelo Dueñas, Carlos Andrés Díaz, Nelson Fonseca, Rubén Camargo, Juan David Uribe, Hans-Henrik Bülow, Simona Beniczky, Jens Brushoj, Mikkel Præst, Birgitte Viebaek, Sine Wichman, Anette Mortensen, Susanne Andi Iversen, Bo Broberg, Edgard Luna, Manuel Jibaja, Leonardo Pazmiño, Katty Trelles, Fabricio Picoita, Gustavo Paredes, Vanesa Ramírez, Guillermo Falconí, Cristian Cevallos, Boris Villamagua, Marco Escobar, Freddy Sánchez, Miguel Llano, Miguel Lazcano, Ramiro Puetate, José Miguel Guerrero, Mijail Játiva, Myriam Montalvo, Franklin Villegas, Luis González Zambrano, Ronnie Mantilla, Gina Quinde, Andrea Gimenez, Luis Gonzalez Mosquera, Henry Caballero, María Fernanda García, Marcelo Ochoa, Soraya Puertas, Jackeline Coello, Mario Acosta, Medhat Soliman, Arnaud W Thille, Achille Kouatchet, Alain Mercat, Laurent Brochard, François Collet, Guillaume Marcotte, Pascal Beuret, Jean-Christophe M Richard, Gaëtan Bedunaeu, Pierre-Gildas Guitard, Fabien Soulis, Frédéric Bellec, Philippe Berger, Dorothée Carpentier, Benoit Veber, Salem Ould Zein, Géraldine Dessertaine, C Canevet, Fabien Grelon, Konstantinos Raymondos, Rolf Dembinski, Rolf Rossaint, Steffen Weber-Carstens, Christian Putensen, Maximillian Ragaller, Michael Quintel, Winfried Schubert, Thomas Bein, Heinrich Paulus, Walter Brandt, Lutz Pfeiffer, Silke Frenzel, Thoralf Kerner, P Kruska, Leila Eckholt, Joachim Hartung, Harald Fritz, Monika Holler, Johannes Busch, Andreas Viehöfer, Jens Buettner, Jörn Schlechtweg, Achim Lunkeit, Roland Schneider, Maria Wussow, Nils Marquardt, Christian Frenkel, Falk Hildebrandt, Tumbass Volker, Thomas Lipp, Cezar Mihailescu, Thomas Moellhoff, Thomas Steinke, Oliver Franke, Marcus Ruecker, Markus Schappacher, Steffen Appel, Heinz Kerger, Andreas Schwartz, Jan Dittmann, Jörg Haberkorn, Wolfgang Baier, Walter Seyde, Dimitros Matamis, Eleni Antoniadou, Pertsas Evangelos, Maria Giannakou, Zoltan Szentkereszty, Zsolt Molnar, Pravin Amin, Farhad N Kapadia, Nagarajan Ramakrishnan, Deepak Govil, Anitha Shenoy, Umesh G, Samir Sahu, Sheila Nainan Myatra, Subhash Kumar Todi, Sanjay Dhanuka, Mayur Patel, P Samaddar, Dhruva Chaudhry, Vivek Joshi, Srinivas Samavedam, Ankur Devendra Bhavsar, Prachee Sathe, Sujoy Mukherjee, Salvatore Maurizio Maggiore, Francesco Idone, Federica Antonicelli, Paolo Navalesi, Rosanna Vaschetto, Arianna Boggero, Rosalba Tufano, Michele Iannuzzi, Edoardo De Robertis, Romano Tetamo, Andrea Neville Cracchiolo, Antonio Braschi, Francesco Mojoli, Ilaria Curro', Mirko Belliato, Chiara Verga, Marta Ferrari, Erika Mannelli, Valerio Mangani, Giorgio Tulli, Francesca Frigieri, Armando Pedulla', Monica Rocco, Giorgia Citterio, Di Russo, Gaetano Perchiazzi, Loredana Pitagora, Antonio Pesenti, Michela Bombino, Davide Chiumello, Federica Tallarini, Serena Azzari, Antonina Pigna, Ivano Aprile, Marco Adversi, Antonio Corcione, Marianna Esposito, Annunziata Mattei, Vito Marco Ranieri, Rosario Urbino, Ilaria Maria Mastromauro, Antonino Giarratano, Maurizio Raineri Santi, Ambrogio Sansone, Younsuck Koh, Moo Suk Park, Je Hyeong Kim, Kyung Chan Kim, Hye Sook Choi, Yun Seong Kim, Jin Hwa Lee, Myung-Goo Lee, Won-Yeon Lee, Jin Young An, Gee Young Suh, Ki-Suck Jung, Asisclo J Villagómez Ortiz, César Cruz Lozano, Zalatiel Maycotte Luna, José Francisco López Baca, José Elizalde, Guillermo Cueto Robledo, Mario Alonso Treviño Salinas, Ricardo Martinez Zubieta, Claudia Olvera-Guzman, Marco Montes De Oca, Silvio A Ñamendys-Silva, José Salvador Martínez Cano, Jose Angel Baltazar Torres, Gustavo Morales Muñoz, Antonio Villa Delgado, Javier Ladape Martinez, Amine Ali Zeggwagh, Tarek Dendane, Abderrahim Azzouzi, Ahmed Sbihi, Wajdi Maazouzi, Mourad Amor, Charki Haimeur, Michael A Kuiper, Matty Koopmans, Uli Strauch, Dennis Bergmans, Serge Heines, Sylvia den Boer, Bas M Kors, Peter van der Voort, Paul J Dennesen, Bert Beishuizen, Ingrid van den Hul, Erna Alberts, Harry P P M Gelissen, Eduard Bootsma, Auke Reidinga, Jasmin Board, Andrew Davies, Kim Heus, Diane Mackle, Paul Young, Rachael Parke, Eileen Gilder, Jodi Brown, Lynette Newby, Catherine Simmonds, Jan Mehrtens, Seton Henderson, Tony Williams, Judi Tai, Chantal Hogan, Mary La Pine, John Durning, Sheree Gare, Troy Browne, Shirley Nelson, Jennifer Goodson, Julio Osorio, Chabu Coronado, Rollin Roldán Mori, Rosa Luz López Martínez, Adam Mikstacki, Barbara Tamowicz, Rui Moreno, Eduardo Almeida, Joana Silvestre, Heloisa Castro, Irene Aragão, Susana Alves Ferreira, Nelson Barros, Filomena Faria, Carlos André Correia Casado, Fausto Fialho Moura, Paulo Marcal, Ricardo Matos, Edward Nicolayenko, Mikhail Kirov, Andrey Yaroshetskiy, Andrei Piontek, Valery Subbotin, Yaseen Arabi, Olivia Dulfo, Chafrina Marie Olay, Edgardo E Tabhan, Nicolas Nin, Alfonso Muñoz, César Aragón, Ana Villagrá, Ainhoa Rosselló, Joan Maria Raurich, María Garitacelaya, Miguel Ángel González-Gallego, Francisco Ortuño, Miguel Fernández-Vivas, David Freire, Francisco Guerrero, Francisco Manzano, Juan Carlos, Alfredo Padrón, Pedro Rosa, Rafael Morales, Liliana Caipe, Maurizio Bottiroli, José María Nicolás, Marta Ugalde, Javier Ruiz, Lucia Capilla, Guillermo Muñiz, Jesús Sánchez-Ruiz, Javier Cebrián, Begoña Balerdi, Elena Parreño, Alvaro van Bommel, César Pérez-Calvo, Irene Dot, Javier Blanco, Raquel Manzanedo, José J Blanco, Daniel Fontaneda, Raúl González, Javier Díaz Domínguez, Alfonso Moreno, Antonio Reyes, Ian Carrasco, Itziar Mintegui, Rosa Sebastián, Javier García-Alonso, Carolina Lorencio, Josep Maria Sirvent, Patricia Jimeno, Miguel León, Pedro Galdos, Nuria Alonso, Julia López-Díaz, María Victoria de la Torre, Jorge Vidal Hernández, Nicolás Zamboschi, Francisco Lucena, Gemma Rialp, Raquel Montoiro, Victoria Goñi, María Ángeles Pena, Antonio Maestre, Marc Fabra, Jacinto Baena, Eva Benveniste, Susana Temprano, Jesús Sánchez, Carmen Campos, Sara Cabañes, María Elena Pérez-Losada, José Claudio Leo, Enrique Piacentini, María Del Carmen de la Torre, Laura Álvarez-Montero, Fernando Sánchez, Antonio Viñuales, Bernabé Álvarez, Javier Castañeda, Ángela Alonso, María Isabel Ruiz, Pedro Jesús Domínguez, Marcos Delgado, Eugenio Palazón, Antonio García-Jiménez, Rosa Álvaro, Clara Laplaza Eva Regidor, Enrique Maraví, José María Quiroga, Amalia Martínez de la Gandara, Cecilia Carbayo, María Luisa Navarrete, Manuel Valledor, Raquel Yano, José María Gutiérrez, Javier González-Robledo, Amparo Ferrandiz, Alberto Belenguer, Lidón Mateu, Laura Sayagues, María José Tolón, Nieves Franco, Elena Gallego, Félix Lacoma, Patricia Albert, Vicente Arraez, Mar Gobernado, Susana Moradillo, Carolina Gímenez-Esparza, Teresa Sánchez de Dios, Carlos Marian Crespo, Cecilia Hermosa, Federico Gordo, Genis Carrasco, María Ángeles Alonso, Alejandro Algora, Raúl de Pablo, Sofía García, Ana Carolina Caballero, José María Montón, Teresa Mut, Eva Manteiga, Alejandro de la Serna, Ana Esther Trujillo, Rafael Blancas, Inmaculada Vallverdú, José Manuel Serrano, Miquel Ferrer, Juan Diego Jiménez, Carlos Gallego, Dolores Vila, Luis Marina, Valentín Parra, Juan Ramón Cortés, Chen Chin-Ming, Ai-Chin Cheng, Fekri Abroug, Besbes Mohamed, Imed Chouchene, Mounir Bouaziz, Stambouli Neji, Islem Ouanes, Ayed Samia, Nahit Cakar, Ismail Kati, Ali Aydım Altunkan, Remzi Iscimen, Zafer Dogan, Bilge Çetin, Tayfun Adanir, Sabriye Guvenc, Unase Büyükkoçak, Antonio Anzueto, Ashley Ellis, Gary Kinasewitz, Allan Walkey, Phil Alkana, Gregory A Schmidt, Susan Gillen, Kathleen Lilli, Jennifer Twombley, Denice Wells, Larry Welder, Alejandro Arroliga, Alfredo Vasquez-Sandoval, Vincent John Scott, Craig Cernosek, Christopher Spradley, Dimple Tejwani, Sindhaghatta Venkatram, Gilda Diaz-Fuentes, Amber Monson, Anthony Saleh, Madhav Gudi, George Liziamma, Mohamed A Saad, Crissie De Spirito, Bryan Beatty, Samir Vermani, Crissie Despirito, Zaza Cohen, Amee Patrawalla, Samir Abdelhadi, Rupesh Vakil, Steven Y Chang, Brian Sherman, Rosanna Del Giudice, John Oropell, Timothy D Girard, Cayce Strength, Joyce Okahashi, Leanne Boehm, Matthew Kirchner, Ashley Ellis, Gary Kinasewitz, Erwin J Oei, Sebastian Circo, Nelson Medina, Mohammed Al-Jagbeer, V J Cardenas Jr, Smyth Smith, Shelby Sutton, Marcela Canola-Mazo, Tim Houlihan, Yogeet Kaur, Travis Parry, Craig A Piquette, Kerry Canady, Rahul Nanchal, Dana K Soetaert, Maria Del Mar Torres-Perez, Carlos Robles-Arias, William Rodriguez-Cintron, Mark Tidswell, Jennifer Germain, Lori-Ann Kozikowski, Erin Braden, Geneva Tatem, Javier Hurtado, Alberto Deicas, Daniel Weiss, Marta Beron, Román Garrido, Cristina Santos, Mario Cancela, Raúl Lombardi, Pedro Alzugaray, Jorge Gerez, Silvia Mareque, Graciela Franca, Oscar Cluzet, Edgardo Nuñez, Julio Pontet, Sergio Cáceres, Elias Caragna, Alberto Soler, Frank Torres, Gastón Pittini, Gabriel D Empaire, Stevens Salva, Fernando Pérez, Clara Pacheco, Zoraida Parra, Ingrid Von der Osten, Luis Williams, José Salinas, Do Danh Quynh, Pham Thi Van Anh, Nguyen Huu Hoang, Nghuyen Ba Tuan

Subjects
Male, medicine.medical_treatment, pulmonary complications, RESPIRATORY-DISTRESS-SYNDROME, Critical Care and Intensive Care Medicine, CASE-FATALITY, 0302 clinical medicine, Risk Factors, Brain Injuries, Traumatic, Multicenter Studies as Topic, Hospital Mortality, Prospective Studies, Simplified Acute Physiology Score, Stroke, POPULATION, Age Factors, ANEURYSMAL SUBARACHNOID HEMORRHAGE, Middle Aged, Hemorrhagic Stroke, Intensive Care Units, Observational Studies as Topic, Anesthesia, Breathing, Female, medicine.symptom, Ventilator Weaning, Cohort study, Adult, TRAUMATIC BRAIN-INJURY, Pressure support ventilation, mechanical ventilation, prognosis factors, ACUTE LUNG INJURY, 03 medical and health sciences, medicine, Humans, Aged, Ischemic Stroke, Mechanical ventilation, Noninvasive Ventilation, business.industry, MORTALITY, neurologic patients, Organ dysfunction, 030208 emergency & critical care medicine, Length of Stay, medicine.disease, TRENDS, Respiration, Artificial, 030228 respiratory system, Etiology, NEUROCRITICAL CARE, Nervous System Diseases, Tracheotomy, business
Abstract

OBJECTIVES: To describe the changes in ventilator management over time in patients with neurologic disease at ICU admission and to estimate factors associated with 28-day hospital mortality. DESIGN: Secondary analysis of three prospective, observational, multicenter studies. SETTING: Cohort studies conducted in 2004, 2010, and 2016. PATIENTS: Adult patients who received mechanical ventilation for more than 12 hours. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among the 20,929 patients enrolled, we included 4,152 (20%) mechanically ventilated patients due to different neurologic diseases. Hemorrhagic stroke and brain trauma were the most common pathologies associated with the need for mechanical ventilation. Although volume-cycled ventilation remained the preferred ventilation mode, there was a significant (p < 0.001) increment in the use of pressure support ventilation. The proportion of patients receiving a protective lung ventilation strategy was increased over time: 47% in 2004, 63% in 2010, and 65% in 2016 (p < 0.001), as well as the duration of protective ventilation strategies: 406 days per 1,000 mechanical ventilation days in 2004, 523 days per 1,000 mechanical ventilation days in 2010, and 585 days per 1,000 mechanical ventilation days in 2016 (p < 0.001). There were no differences in the length of stay in the ICU, mortality in the ICU, and mortality in hospital from 2004 to 2016. Independent risk factors for 28-day mortality were age greater than 75 years, Simplified Acute Physiology Score II greater than 50, the occurrence of organ dysfunction within first 48 hours after brain injury, and specific neurologic diseases such as hemorrhagic stroke, ischemic stroke, and brain trauma. CONCLUSIONS: More lung-protective ventilatory strategies have been implemented over years in neurologic patients with no effect on pulmonary complications or on survival. We found several prognostic factors on mortality such as advanced age, the severity of the disease, organ dysfunctions, and the etiology of neurologic disease.

Published
2021

15. Poly(I:C) enhances mesenchymal stem cell control of myeloid cells from COVID-19 patients

Author

Luciana Souza-Moreira, Yuan Tan, Yan Wang, Jia-Pey Wang, Mahmoud Salkhordeh, Jennifer Virgo, Maria Florian, Aidan B.P. Murray, Irene Watpool, Lauralyn McIntyre, Shane English, Duncan J. Stewart, and Shirley H.J. Mei

Subjects
Multidisciplinary
Abstract

Mesenchymal stem cells (MSCs) are being studied for the treatment of COVID-19-associated critical illness, due to their immunomodulatory properties. Here, we hypothesized that viral mimic-priming improves MSCs' abilities to rebalance the dysregulated immune responses in COVID-19. Transcriptome analysis of poly(I:C)-primed MSCs (pIC-MSCs) showed upregulation of pathways in antiviral and immunomodulatory responses. Together with increased expression of antiviral proteins such as MX1, IFITM3, and OAS1, these changes translated to greater effector functions in regulating monocytes and granulocytes while further enhancing MSCs' ability to block SARS-CoV-2 pseudovirus entry into epithelial cells. Most importantly, the addition of pIC-MSCs to COVID-19 patient whole blood significantly reduced inflammatory neutrophils and increased M2 monocytes while enhancing their phagocytic effector function. We reveal for the first time that MSCs can be primed by Toll-like receptor 3 agonist to improve their ability to rebalance the dysregulated immune responses seen in severe SARS-CoV-2 infection.

Published
2021

16. Feasibility of implementing

Author

Aimee J, Sarti, Katina, Zheng, Christophe L, Herry, Stephanie, Sutherland, Nathan B, Scales, Irene, Watpool, Rebecca, Porteous, Michael, Hickey, Caitlin, Anstee, Anna, Fazekas, Tim, Ramsay, Karen Ea, Burns, and Andrew Je, Seely

Subjects
Canada, Intensive Care, Decision Support Systems, Clinical, Respiration, Artificial, Intensive Care Units, Airway Extubation, respiratory physiology, Feasibility Studies, Humans, Ventilator Weaning, adult intensive & critical care, qualitative research
Abstract

Objectives Although spontaneous breathing trials (SBTs) are standard of care to extubation readiness, no tool exists that optimises prediction and standardises assessment. In this study, we evaluated the feasibility and clinical impressions of Extubation Advisor (EA), a comprehensive clinical extubation decision support (CDS) tool. Design Phase I mixed-methods observational study. Setting Two Canadian intensive care units (ICUs). Participants We included patients on mechanical ventilation for ≥24 hours and clinicians (respiratory therapists and intensivists) responsible for extubation decisions. Interventions Components included a predictive model assessment, feasibility evaluation, questionnaires and interviews with clinicians. Results We enrolled 117 patients, totalling 151 SBTs and 80 extubations. The incidence of extubation failure was 11% in low-risk patients and 21% in high-risk patients stratified by the predictive model; 38% failed extubation when both the model and clinical impression were at high risk. The tool was well rated: 94% and 75% rated the data entry and EA report as average or better, respectively. Interviews (n=15) revealed favourable impressions regarding its user interface and functionality, but unexpectedly, also concerns regarding EA’s potential impact on respiratory therapists’ job security. Conclusions EA implementation was feasible, and users perceived it to have potential to support extubation decision-making. This study helps to understand bedside implementation of CDS tools in a multidisciplinary ICU. Trial registration number NCT02988167.

Published
2021

17. Feasibility of implementing Extubation Advisor, a clinical decision support tool to improve extubation decision-making in the ICU: a mixed-methods observational study

Author

Andrew J.E. Seely, Karen E. A. Burns, Aimee Sarti, Anna Fazekas, Tim Ramsay, Irene Watpool, C. Anstee, Stephanie Sutherland, Michael Hickey, Christophe L. Herry, Rebecca Porteous, Nathan B. Scales, and Katina Zheng

Subjects
Mechanical ventilation, medicine.medical_specialty, Decision support system, business.industry, medicine.medical_treatment, Psychological intervention, General Medicine, Clinical decision support system, Multidisciplinary approach, Intensive care, Emergency medicine, medicine, Medicine, Observational study, business, Qualitative research
Abstract

ObjectivesAlthough spontaneous breathing trials (SBTs) are standard of care to extubation readiness, no tool exists that optimises prediction and standardises assessment. In this study, we evaluated the feasibility and clinical impressions of Extubation Advisor (EA), a comprehensive clinical extubation decision support (CDS) tool.DesignPhase I mixed-methods observational study.SettingTwo Canadian intensive care units (ICUs).ParticipantsWe included patients on mechanical ventilation for ≥24 hours and clinicians (respiratory therapists and intensivists) responsible for extubation decisions.InterventionsComponents included a predictive model assessment, feasibility evaluation, questionnaires and interviews with clinicians.ResultsWe enrolled 117 patients, totalling 151 SBTs and 80 extubations. The incidence of extubation failure was 11% in low-risk patients and 21% in high-risk patients stratified by the predictive model; 38% failed extubation when both the model and clinical impression were at high risk. The tool was well rated: 94% and 75% rated the data entry and EA report as average or better, respectively. Interviews (n=15) revealed favourable impressions regarding its user interface and functionality, but unexpectedly, also concerns regarding EA’s potential impact on respiratory therapists’ job security.ConclusionsEA implementation was feasible, and users perceived it to have potential to support extubation decision-making. This study helps to understand bedside implementation of CDS tools in a multidisciplinary ICU.Trial registration numberNCT02988167.

Published
2021

18. Vancomycin Population Pharmacokinetics in Critically Ill Adults During Sustained Low-Efficiency Dialysis

Author

Sheryl A. Zelenitsky, Swapnil Hiremath, Irene Watpool, Salmaan Kanji, Rakesh Patel, Jiao Xie, Guijun Zhang, Rebecca Porteous, and Jason A. Roberts

Subjects
Male, 0301 basic medicine, Critical Illness, 030106 microbiology, Population, Context (language use), Microbial Sensitivity Tests, Loading dose, Mass Spectrometry, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Vancomycin, Humans, Medicine, Pharmacology (medical), Prospective Studies, 030212 general & internal medicine, Dosing, education, Serum Albumin, Aged, Aged, 80 and over, Pharmacology, education.field_of_study, medicine.diagnostic_test, business.industry, Acute Kidney Injury, Middle Aged, Anti-Bacterial Agents, Therapeutic drug monitoring, Anesthesia, Pharmacodynamics, Female, business, Monte Carlo Method, Hybrid Renal Replacement Therapy, Chromatography, Liquid, medicine.drug
Abstract

Sustained low-efficiency dialysis (SLED) is a hybrid form of dialysis that is increasingly used in critically ill patients with kidney injury and hemodynamic instability. Antimicrobial dosing for patients receiving SLED is informed by pharmacokinetic studies that describe the drug clearance. Studies available to assist in the dosing of vancomycin in the context of SLED are lacking. The objective of this prospective observational study was to describe the population pharmacokinetics of vancomycin in critically ill patients receiving SLED, and use simulation studies to propose dosing strategies. Serial serum samples were obtained from 31 critically ill patients prescribed vancomycin while receiving SLED. Vancomycin concentrations were quantified in plasma using a validated liquid chromatography mass spectrometry/mass spectrometry method. A population pharmacokinetic model was developed, and Monte Carlo simulation was used to determine the probability of target attainment at different doses. From a total of 335 serum samples from 31 patients receiving 52 sessions of SLED therapy, a two-compartment linear model with zero-order input was developed. The mean (standard deviation) clearance of vancomycin on and off SLED was 5.97 (4.04) and 2.40 (1.46) L/h, respectively. Using pharmacodynamic targets for efficacy (area under the concentration–time curve from time zero to 24 h [AUC24]/minimum inhibitory concentration [MIC] ≥ 400) and safety (AUC24 ≥ 700), a loading dose of 2400 mg followed by daily doses of 1600 mg is recommended. Subsequent dosing should be informed by therapeutic drug monitoring of vancomycin levels. In critically ill patients receiving SLED, vancomycin clearance is highly variable with a narrow therapeutic window. Empiric dosing is proposed but subsequent dosing should be guided by drug levels.

Published
2019

19. Saline versus albumin fluid for extracorporeal removal with slow low-efficiency dialysis (SAFER-SLED): study protocol for a pilot trial

Author

Irene Watpool, Kaitlyn Montroy, Tim Ramsay, Sophie Harris, Pierre-Antoine Brown, Jennifer Kong, Edward G. Clark, Alan Tinmouth, Rebecca Porteous, Lauralyn McIntyre, Greg Knoll, and Swapnil Hiremath

Subjects
Oncotic pressure, medicine.medical_treatment, Medicine (miscellaneous), Renal function, law.invention, Study Protocol, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Low blood pressure, medicine, 030212 general & internal medicine, Renal replacement therapy, Saline, Dialysis, lcsh:R5-920, business.industry, Albumin, Acute kidney injury, medicine.disease, SLED treatment, Blood pressure, Anesthesia, Saline fluid, Hypotension, business, lcsh:Medicine (General), 030217 neurology & neurosurgery
Abstract

Background Critically ill patients frequently develop acute kidney injury that necessitates renal replacement therapy (RRT). At some centers, critically ill patients who are hemodynamically unstable and require RRT are treated with slow low-efficiency dialysis (SLED). Unfortunately, hypotension is a frequent complication that occurs during SLED treatments and may limit the recovery of kidney function. Hypotension may also limit the amount of fluid that can be removed by ultrafiltration with SLED. Fluid overload can be exacerbated as a consequence, and fluid overload is associated with increased mortality. Occasionally, intravenous albumin fluid is given to prevent or treat low blood pressure during SLED. The intent of doing so is to increase the colloid oncotic pressure in the circulation to draw in extravascular fluid, increase the blood pressure, and enable more aggressive fluid removal with ultrafiltration. Nonetheless, there is little evidence to support this practice and theoretical reasons why it may not be especially effective at augmenting fluid removal in critically ill patients. At the same time, albumin fluid is expensive. As such, we present a protocol for a study to assess the feasibility of a randomized controlled trial evaluating the use of albumin fluid versus saline in critically ill patients receiving SLED. Methods This study is a single-center, double-blind, and randomized controlled pilot trial with two parallel arms. It involves randomly assigning patients receiving SLED treatment in the ICU to receive either albumin (25%) boluses or normal saline fluid boluses (placebo) to prevent and treat low blood pressure. Discussion The results of this pilot trial will help with planning a larger trial comparing the efficacy of the interventions in achieving fluid removal in critically ill patients with AKI on SLED. They will establish whether enough participants would participate in a larger study and accept the study procedures. Trial registration This trial is registered on ClinicalTrials.gov Identifier NCT03665311, registered on September 11, 2018. Electronic supplementary material The online version of this article (10.1186/s40814-019-0460-3) contains supplementary material, which is available to authorized users.

Published
2019

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

Author

Patricia Lizotte, Brigitte Bolduc, Martine Lebrasseur, Michaël Chassé, Deborah J. Cook, Nicole Marinoff, Élaine Carbonneau, Shay McGuinness, Marie-Claude Battista, Estel Deblois, John Iazzetta, Christine Drouin, Emilie P. Belley-Côté, Miranda Hunt, Francois Lamontagne, Dian Cohen, Marie-Hélène Masse, Tina Millen, Scott E. Walker, Andrew G. Day, François Lellouche, David M. Maslove, Irene Watpool, Patrick Archambault, Julie Ménard, Sheila Sprague, Salmaan Kanji, Gordon H. Guyatt, Djillali Annane, Ruxandra Pinto, Daren K. Heyland, Bram Rochwerg, Rebecca Porteous, Neill K. J. Adhikari, Frédérick D’Aragon, Yaseen M. Arabi, Rachael Parke, Bharath Kumar Tirupakuzhi Vijayaraghavan, Anitra C. Carr, Infection et inflammation (2I), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, medicine.medical_treatment, vitamin C, Medicine (miscellaneous), Ascorbic Acid, Antioxidants, law.invention, sepsis, Study Protocol, 0302 clinical medicine, Randomized controlled trial, law, Vasoconstrictor Agents, Pharmacology (medical), Hospital Mortality, 030212 general & internal medicine, lcsh:R5-920, Acute kidney injury, Acute Kidney Injury, Middle Aged, Intensive care unit, 3. Good health, Intensive Care Units, Treatment Outcome, Administration, Intravenous, Drug Therapy, Combination, Female, medicine.symptom, lcsh:Medicine (General), Adult, medicine.medical_specialty, Multiple Organ Failure, Hemolysis, Sepsis, 03 medical and health sciences, Internal medicine, medicine, Humans, Renal replacement therapy, Adverse effect, Dose-Response Relationship, Drug, business.industry, Septic shock, Organ dysfunction, biomarkers, 030208 emergency & critical care medicine, medicine.disease, Hypoglycemia, Clinical Trials, Phase III as Topic, randomized controlled trial, Quality of Life, septic shock, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business
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.

Published
2020

21. Cellular Immunotherapy for Septic Shock. A Phase I Clinical Trial

Author

Keith R. Walley, Irene Watpool, Claudia C. dos Santos, Shirley H. J. Mei, John Marshall, Brent W. Winston, Dean Fergusson, Kenny Schlosser, Duncan J. Stewart, David W. Courtman, Lauralyn McIntyre, and John Granton

Subjects
Adult, Male, 0301 basic medicine, Pulmonary and Respiratory Medicine, Stromal cell, Phases of clinical research, Inflammation, Mesenchymal Stem Cell Transplantation, Critical Care and Intensive Care Medicine, Risk Assessment, Young Adult, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, Confidence Intervals, medicine, Humans, Infusions, Intravenous, Aged, business.industry, Septic shock, Mesenchymal stem cell, Age Factors, Middle Aged, Tissue repair, Allografts, medicine.disease, Shock, Septic, Survival Rate, Treatment Outcome, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Immunology, Female, Immunotherapy, Bone marrow, Cellular immunotherapy, medicine.symptom, business, Follow-Up Studies
Abstract

In septic animal models mesenchymal stem (stromal) cells (MSCs) modulate inflammation, enhance tissue repair and pathogen clearance, and reduce death.To conduct a phase I dose escalation trial of MSCs in septic shock with the primary objective of examining the safety and tolerability of MSCs.We enrolled nine participants within 24 hours of admission to the ICU. A control cohort of 21 participants was enrolled before starting the MSC interventional cohort to characterize expected adverse events (AEs) and to serve as a comparator for the intervention cohort. Three separate MSC dose cohorts, with three participants per cohort, received a single intravenous dose of 0.3, 1.0, and 3.0 × 10Ages of participants in the interventional versus observational cohorts were median of 71 (range, 38-91) and 61 (range, 23-95). Acute Physiology and Chronic Health Evaluation scores were median of 25 (range, 11-28) and 26 (range, 17-32). MSC doses ranged from 19 to 250 million cells. There were no prespecified MSC infusion-associated or serious unexpected AEs, nor any safety or efficacy signals for the expected AEs or the measured cytokines between the interventional and observational cohorts.The infusion of freshly cultured allogenic bone marrow-derived MSCs, up to a dose of 3 million cells/kg (250 million cells), into participants with septic shock seems safe. Clinical trial registered with www.clinicaltrials.gov (NCT02421484).

Published
2018

22. Results of the cellular immuno-therapy for covid-19 related acute respiratory distress syndrome (circa-phase i trial

Author

Shane W. English, Sarwat T. Khan, Duncan J. Stewart, Josee Champagne, David W. Courtman, M. Jamieson, Manoj M. Lalu, Bernard Thébaud, S. Hodgins, Dean Fergusson, Irene Watpool, and M. Sobh

Subjects
Cancer Research, Transplantation, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Immunology, Cell Biology, Acute respiratory distress, Article, Oncology, Immuno therapy, Immunology and Allergy, Medicine, business, Genetics (clinical)
Published
2021

23. Manufacturing freshly cultured umbilical cord-derivedmesenchymal stromal cells (UC-MSCS) for a phase 1, multiple-dose clinical trial for COVID-19-induced acute respiratory distress syndrome (ARDS)

Author

S. Hodgins, Shane W. English, Duncan J. Stewart, Josee Champagne, Irene Watpool, Dean Fergusson, M. Sobh, David W. Courtman, M. Jamieson, Manoj M. Lalu, Bernard Thébaud, and Sarwat T. Khan

Subjects
Cancer Research, Transplantation, Cord, Cumulative dose, business.industry, Immunology, Mesenchymal stem cell, Cell Biology, Umbilical cord, Dosage form, Cryopreservation, Andrology, medicine.anatomical_structure, Oncology, medicine, Immunology and Allergy, CD90, business, Cell bank, Genetics (clinical)
Abstract

Background & Aim: The Cellular Immuno-Therapy for COVID-19 related ARDS (CIRCA-19) was a phase 1, single site, dose escalation trial using a 3+3+3 design to determine the safety and maximum feasible tolerated dose of intravenously delivered, freshly cultured UC-MSCs. Nine patients, each receiving repeated unit doses of UC-MSCs over 3 consecutive days, were enrolled into 3 dose panels: Panel 1: 25×106 cells/dose (cumulative dose: 75×106 MSCs);Panel 2: 50×106 cells/dose (cumulative dose: 150×106 MSCs);Panel 3: up to 90×106 cells/dose (cumulative dose: 270×106 MSCs). Methods, Results & Conclusion: UC-MSCs were isolated from cords of healthy term pregnancies delivered by C-section. Cords were mechanically and enzymatically digested, and UC-MSCs were propagated in xeno-free conditions for 2 weeks prior to cryopreservation in a cord specific cell bank. One fully validated cell bank was used in CIRCA-19 that was free of adventitious agents (HBV, HCV, HSV1/2, Parvo B19 and Retroviruses), had high viability (>95%) and MSC identity with positive expression (>95%) of CD73, CD90 and CD105 and negative expression ( 45%;DBT = 22h) and enhanced IDO expression (ΔΔCq?>18) when treated with IFN-γ. For the final product, UC-MSCs were thawed, plated and cultured for 24 to 120 h before harvesting to produce a batch of the final drug product formulated as 2.5×106 fresh UC-MSCs/mL suspended in PlasmaLyte A containing 5% Human Albumin, to be infused within 48h. Batches were tested for viability, endotoxin level, ACE-2 expression, tissue factor activity, sterility and mycoplasma. Sixteen batches of UC-MSCs were produced for a total of 41 cell doses (16 doses of 25M;13 doses of 50M;12 doses of 90M cells each). Twenty-seven of the 41 doses (9 doses of 25M, 50M and 90M cells each) were used to treat trial participants. The remaining doses were used for stability studies. All drug products had high viability (> 95%), endotoxin levels of 35;GAPHD Cq: 15±2;no detectable levels by western blotting) and had tissue factor activity levels between 250-310pM. UC-MSC drug product was stable for up to 96h (>80% viability) and had?>90% viability up to 48h in all 3 dose panels. This study demonstrates the feasibility of manufacture and delivery of a multi-dose fresh cell product in an emergent ICU setting.

Published
2021

24. Whole transcriptome RNA sequencing analysis on mesenchymal stem cells preconditioned by inflammatory stimuli

Author

J. Virgo, Lauralyn McIntyre, Y. Tan, Shirley H. J. Mei, M. Salkhordeh, L. Souza-Moreira, J. Wang, Irene Watpool, and Duncan J. Stewart

Subjects
Cancer Research, Transplantation, Cell type, Immunology, Mesenchymal stem cell, Cell, Cell Biology, Biology, Cell biology, Cell therapy, Transcriptome, medicine.anatomical_structure, Oncology, Downregulation and upregulation, Gene expression, medicine, Immunology and Allergy, Gene, Genetics (clinical)
Abstract

Background & Aim Mesenchymal stem cells are a promising cell type in the field of cell therapy, and the number of clinical trials utilizing different tissue sources derived MSCs continues to grow. To date, various cell preconditioning strategies have been used to boost MSC's existing immunomodulatory functions and include exposure to environmental stimuli or small molecules. However, the exact molecular mechanism by which preconditioning enhances MSCs potency, particularly with inflammatory stimuli, is still not well understood. Herein we performed whole-transcriptome RNA sequencing (RNAseq) on cytomix preconditioned MSCs (to mimic the acute inflammatory microenvironment) to specifically examine MSC molecular pathways involved by this preconditioning strategy. Methods, Results & Conclusion Human bone marrow MSCs were used between passages 3-6, and MSCs with or without cytomix preconditioning were collected for whole transcriptome RNAseq (Qiagen). Analysis of the transcriptome profile showed a robust separation of gene expression profiles for cytomix-preconditioned versus non-preconditioned MSCs. Differential expression analysis (DESEq2) revealed 1,020 upregulated genes (FDR 1) and 413 downregulated genes (FDR In summary, our preliminary analysis on the whole transcriptome of inflammatory stimuli-preconditioned MSCs showed upregulation of genes coding for secreted proteins associated with functions in immune responses. Further experiments will be performed to confirm the relationships between genes coding for secreted proteins identified in this study with MSC's immunomodulatory functions.

Published
2020

25. Piperacillin Population Pharmacokinetics in Critically Ill Adults During Sustained Low-Efficiency Dialysis

Author

Jiao Xie, Jason A. Roberts, Abdulaziz S. Alobaid, Rakesh Patel, Sheryl A. Zelenitsky, Swapnil Hiremath, Rebecca Porteous, Guijun Zhang, Irene Watpool, and Salmaan Kanji

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, Tazobactam, medicine.medical_treatment, Critical Illness, 030106 microbiology, Microbial Sensitivity Tests, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Renal Dialysis, Intensive care, Medicine, Humans, Pharmacology (medical), Renal replacement therapy, Prospective Studies, Prospective cohort study, Intensive care medicine, Dialysis, Aged, Piperacillin, business.industry, 030208 emergency & critical care medicine, Middle Aged, Anti-Bacterial Agents, Renal Replacement Therapy, Intensive Care Units, Piperacillin, Tazobactam Drug Combination, Piperacillin/tazobactam, Female, business, medicine.drug
Abstract

Sustained low-efficiency dialysis (SLED), is increasingly being used in intensive care units (ICUs) but studies informing drug dosing for such patients is lacking.To describe the population pharmacokinetics (PKs) of piperacillin/tazobactam in critically ill adults receiving SLED and to provide dosing recommendations.This prospective population PK study was conducted in adult ICU patients prescribed piperacillin/tazobactam while receiving SLED; 321 blood samples were obtained from 34 participants during and between approximately 50 SLED treatments for quantification of piperacillin and tazobactam concentrations in plasma. A population PK model was developed. Monte Carlo simulation was used to determine the probability of target attainment and pathogen-specific fractional target attainment at different doses.From a 2-compartment linear model with zero-order input, the mean (SD) clearance of piperacillin on SLED and off SLED were 4.81 (8.48) and 1.42 (1.54) L/h, respectively. Tazobactam concentrations were not sufficient for analysis. For the target of 50% fTMIC (unbound concentrations of drug are above the minimum inhibitory concentration for50% of the dosing interval), 3-g of piperacillin infused over 0.5 hours every 8 hours was appropriate for susceptible organisms with MIC ≤16 mg/L. For life-threatening infections where the target of 100% fTMIC is preferred, a 9-g dose administered as a continuous infusion every 24 hours was appropriate for susceptible organisms with MIC ≤32 mg/L.In critically ill patients receiving SLED, piperacillin doses need to be guided by the frequency of SLED treatments and susceptibility of the known or suspected pathogen.

Published
2018

26. The association between platelet transfusions and bleeding in critically ill patients with thrombocytopenia

Author

Donald M. Arnold, Francois Lauzier, Martin Albert, David Williamson, Na Li, Ryan Zarychanski, Chip Doig, Lauralyn McIntyre, Andreas Freitag, Mark Crowther, Lois Saunders, France Clarke, Rinaldo Bellomo, Ismael Qushmaq, Renato D. Lopes, Diane Heels‐Ansdell, Kathryn Webert, Deborah Cook, Rick Hall, Graeme Rocker, Lisa Julien, Debbie Wright, Caroline Roy, Judy Theriault, Susan Pleasance, Maureen Meade, Lori Hand, Christine Wynne, Mark Duffett, Michelle Kho, Nicole Zytaruk, John Granton, Andrea Matte, Paulina Farias, Leslie Chu, Nancy Brockest, Stephanie Go, Margaret McGrath‐Chong, Madison Dennis, Marc Lipkus, Emily Stern, Ryan Albert, Stephan Langevin, Alexis F Turgeon, Marie‐Claude Tremblay, Martine Blais, Maxime Beauparlant, Julie Asselin, Chantal Gagne, Marie Thibodeau, Germain Poirier, Sandrine Spearson, Isabelle Neas, Joe Pagliarello, Paul Hébert, Irene Watpool, Tracy McArdle, Claude Gaudert, Paule Marchand, Carson Davidson, Mary‐Jo Lewis, Erin Murphy, Julia Foxall, Yoanna Skrobik, Johanne Harvey, Stefania Chitu, Virginie Williams, Carole Sirois, Carole Nadon, Stephanie Dolle, Audrey‐Anne Gosselin, Patrice Deroy, Geeta Mehta, Sumesh Shah, Cheryl Ethier, Sam Tirgari, Lindsay Steinberg, Rod McDonald, Vidhya Sivanantham, Kristofer Bandayrel, Friederike Quittnat Pelletier, Marnie Kramer‐Kile, Maedean Brown, Scott Kim, Rob Fowler, Nicole Marinoff, Karen Code, Boris Bojilov, Derek Parsotam, John Marshall, Orla Smith, Beth Fry, Kerri Porretta, Yoon Lee, Jeanna Morrissey, Victoria Wen, John Muscedere, Miranda Hunt, Susan Fleury, Nicole Godfrey, Sharlene Hammond, Elizabeth Mann, Monica Myers, Amber Robinson, Donald Griesdale, Dean Chittock, Vinay Dhingra, Denise Foster, Maureen Gardner, Susan Logie, Roger Autio, Dara Davies, Pia Ganz, Laurie Smith, Peter Dodek, Victoria Alcuaz, Betty Jean Ashley, Sheilagh Mans, Niall Ferguson, James Stevenson, Joel Elman, Timothy Karachi, Tina Millen, Andrea Tkaczyk, Mike Jacka, Marleen Irwin, Carmen Chan, Leeca Sonnema, Kelly Marsh, Jennifer Maurer, Tamara Kreidl, Candice Varden, Carey Kinjerski, Christopher Doig, Stacy Ruddell, Linda Knox, Crystal Wilson, Kevin Champagne, Gordon Wood, Fiona Auld, Leslie Atkins, Bojan Paunovic, Nicole Marten, Kym Wiebe, Ellen McDonald, Sean Keenan, Steven Reynolds, Miroslav Svetik, Mary Van Osch, Jim Kutsogiannis, Patrica Thompson, Norine Whalen, Francois Lellouche, Marie‐Claude Ferland, Patrick Dussault, Caroline Jacob, Marie‐Eve Morneau, Nancy Laberge, Kosar Khwaja, Laura Banici, Lena Havell, Olivier Lesur, Francois Lamontagne, Sandra Proulx, Gerald Hollinger, Vasanti Shende, Vanessa Belcastro, Bill Plaxton, Anders Foss, Jonathan Eisenstat, Tammy Doerle, Michael Sharpe, Mona Madady, Jamie Cooper, Andrew Davies, Shirley Vallance, Cindy Weatherburn, Jasmin Board, Victoria Bennett, Simon Finfer, Naresh Ramakrishnan, Simon Bird, Julie Potter, Anne O’Connor, Susan Ankers, Jack Cade, Deborah Barge, Tania Caf, Belinda Howe, Glenn Eastwood, Leah Peck, Donna Goldsmith, Kim O’Sullivan, David Ernest, Sam Radford, Ann Whitfield, Anthony Cross, Suzanne Eliott, Jaspreet Sidhu, Inga Mercer, Angela Hamilton, John Botha, Jodi Vuat, Sharon Allsop, Nina Fowler, Tim Crozier, Jonathan Barrett, Chris Wright, Pauline Galt, Carly Culhane, Rebecca Ioannidis, Sue Burton, Marnie Reily, Cyveen Weeraratna, Ian Seppelt, Leonie Weisbrodt, Robyn Bond, Nepean Hospital, Justine Rivett, Stephanie O’Connor, Alex Poole, Clive Woolfe, Dorrilyn Rajbhandari, Caitlin Rees, John Edington, Jason Fletcher, Julie Smith, Catherine Boschert, Graham Reece, Treena Sara, Kiran Nand, Andrew Bersten, Alex Gallus, Elisha Matheson, Margie O’Callaghan, Neil Orford, Tania Elderkin, Melissa Fraser, Allison Bone, Tania Salerno, Anne Kinmonth, Subhash Arora, Bridget O’Bree, Katherine Shepherd, Alan –Quinn, Martin Sterba, Bronwyn Ruth Johnson, Renee Xu, Francisco Hill, Rajaram Ramadoss, Josette Wood, Marcelo Garcia da Rocha, Andréa Kramer, Martha Hädrich, Nilton Brandao, Cassiano Teixeira, Cíntia Roehrig, Juliana Zeni, Suzana Alves da Silva, Rubens Costa Filho, Renato Correa, Alves Moreira, Plínio N. Gomes, Rodrigo Biondi, Otavio Berwanger, Edson Romano, Anna Maria Buehler, Helio Penna Guimarães, Adriano Truffa, Rosana Nakamura, Lillian Mazza Barbosa, Jean Brennick, Sawsan Bassi, Mohammed Alsultan, Yaseen Arabi, Riette Brits, Jamal Alhashemi, Sanaa Shalabi, Yasser Mandourah, Nadeem Shaikh, Manal Al‐Hazmi, M. Ali Al‐Azem, Trevor Wyngaard, Barbara Smithson, Nicholas E Vlahakis, Laurie Meade, Michael Cox, Jackie O’Brien, Catherine Krause, Joseph Nates, Sajid Haque, Deidre Mooring, Rose Erfe, Paula Nickerson, Tony Sherry, John Smith, Barnaby Sanderson, Josephine Ng, John Brooks, Ling Lim, and Katie Lei

Subjects
medicine.medical_specialty, Anemia, Population, thrombocytopenia, 030204 cardiovascular system & hematology, law.invention, 03 medical and health sciences, 0302 clinical medicine, law, Internal medicine, medicine, Platelet, education, transfusion, education.field_of_study, business.industry, Hazard ratio, Original Articles, Hematology, medicine.disease, mortality, Intensive care unit, Thrombosis, 3. Good health, critical care, Platelet transfusion, 030228 respiratory system, Online‐only Articles, platelets, Original Article, Medical emergency, hemorrhage, business, Cohort study
Abstract

Background Platelet transfusions are commonly used to treat critically ill patients with thrombocytopenia. Whether platelet transfusions are associated with a reduction in the risk of major bleeding is unknown. Patients/Methods Observational cohort study nested in a previous multicenter, randomized thromboprophylaxis trial in the intensive care unit (ICU). The objective was to evaluate the association between platelet transfusions and adjudicated major bleeding events. Platelet transfusion episodes were reviewed for timing of administration, product type, and dose. Major bleeding with and without platelet transfusions was adjusted for severity of thrombocytopenia, use of anti‐platelet agents, surgery and other covariates. Secondary outcomes were thrombosis, death in ICU and platelet count increment. Results Among 2,256 patients, 71 (3.1%) received 190 platelet transfusions. Of those, 121 (63.7%) were administered to 54 non‐bleeding, thrombocytopenic patients. Adjusted rates of major bleeding were not statistically different with or without the administration of platelet transfusions (hazard ratio for transfused patients 0.85; 95% confidence interval, 0.42‐1.72). We did not find a significant association between platelet transfusion use and thrombosis or death in ICU in adjusted analyses. Thrombocytopenia, anemia, major or minor bleeding and use of anticoagulants were associated with platelet transfusion administration. The median post‐transfusion platelet count increment was 20×109/L at 3.5 hours post‐transfusion. Conclusions Rates of major bleeding were not different for patients who did and did not receive platelet transfusions. Inferences were limited by the small number of transfused patients. Clinical trials are needed to better investigate the potential hemostatic benefit and potential harms of platelet transfusions for this high‐risk population.

Published
2017

27. Physicians declining patient enrollment in a critical care trial: a case study in thromboprophylaxis

Author

Diane Heels-Ansdell, R. Costa Filho, Manal Al-Hazmi, S. Alves da Silva, Ellen McDonald, Andreas Freitag, Nicole Zytaruk, Margaret S. Herridge, G. Hollinger, F Clarke, Neill K. J. Adhikari, Deborah J. Cook, Irene Watpool, Shirley Vallance, Tim M. Crozier, John F. Cade, Tim Karachi, T. McArdle, Nilton Brandao, G. Pagliarello, Protect Investigators, Niall D. Ferguson, Yaseen M. Arabi, W. Plaxton, Sean P. Keenan, and Y. Mandourah

Subjects
Dalteparin, Pilot phase, medicine.medical_specialty, Critical Care, Critical Care and Intensive Care Medicine, law.invention, Morbid obesity, Double-Blind Method, Fibrinolytic Agents, Randomized controlled trial, law, Informed consent, Physicians, Anesthesiology, medicine, Humans, Prospective Studies, Practice Patterns, Physicians', Refusal to Participate, Informed Consent, Heparin, business.industry, Patient Selection, Thrombosis, Odds ratio, Confidence interval, Intensive Care Units, Epidural catheter, Family medicine, Emergency medicine, Patient Participation, business
Abstract

To analyze the frequency, rationale and determinants of attending physicians requesting that their eligible patients not be approached for participation in a thromboprophylaxis trial. Research personnel in 67 centers prospectively documented eligible non-randomized patients due to physicians declining to allow their patients to be approached. In 67 centers, 3,764 patients were enrolled, but 1,460 eligible patients had no consent encounter. For 218 (14.9 %) of these, attending physicians requested that their patients not be approached. The most common reasons included a high risk of bleeding (31.2 %) related to fear of heparin bioaccumulation in renal failure, the presence of an epidural catheter, peri-operative status or other factors; specific preferences for thromboprophylaxis (12.4 %); morbid obesity (9.6 %); uncertain prognosis (6.4 %); general discomfort with research (3.7 %) and unclear reasons (17.0 %). Physicians were more likely to decline when approached by less experienced research personnel; considering those with >10 years of experience as the reference category, the odds ratios (OR) for physician refusals to personnel without trial experience was 10.47 [95 % confidence interval (CI) 2.19–50.02] and those with less than 10 years experience was 1.72 (95 % CI 0.61–4.84). Physicians in open rather than closed units were more likely to decline (OR 4.26; 95 % CI 1.27–14.34). Refusals decreased each year of enrollment compared to the pilot phase. Tracking, analyzing, interpreting and reporting the rates and reasons for physicians declining to allow their patients to be approached for enrollment provides insights into clinicians’ concerns and attitudes to trials. This information can encourage physician communication and education, and potentially enhance efficient recruitment.

Published
2013

28. A pilot prospective study of the vascular repair response following red cell transfusion in critically ill patients

Author

T. McArdle, Karim Abou-Nassar, Irene Watpool, David S. Allan, Alan Tinmouth, Grace Christou, Yuhua Li, Laura Labonté, and Lauralyn McIntyre

Subjects
medicine.medical_specialty, Critically ill, business.industry, medicine.medical_treatment, Hematology, Surgery, Red cell transfusion, Cytokine, Internal medicine, Intensive care, Cohort, medicine, Population study, Progenitor cell, Prospective cohort study, business
Abstract

Summary Background Red blood cell transfusion has been associated with adverse outcomes including infection, delayed recovery and increased mortality in some patient populations. Circulating cells that yield endothelial-like vascular progenitor cell (VPC) clusters are correlated with vascular repair and recovery after ischaemic injury. The impact of red cell transfusion on VPC clusters and vascular repair remains uncertain. Study design We prospectively enrolled patients admitted to intensive care requiring red cell transfusion and subjects at low likelihood of requiring red cell transfusion. Levels of VPC clusters and plasma levels of angiogenic cytokines were compared. A total of 17 patients were recruited and had blood samples collected at time of enrolment and at 24–48 h, 48–72 h and 1 week following transfusion. Results We could not discern differences in the number of VPC clusters between transfused patients (n = 6) and non-transfused subjects (n = 11) at baseline or throughout the study period. VPC cluster levels demonstrated wide variance and were highest at 24-h post-enrolment in the entire cohort. Furthermore, levels of all 16 cytokines analysed were not significantly different between transfused and non-transfused patients and we did not observe a correlation between cytokine concentrations and levels of circulating VPC-cluster forming cells in the overall study population. Conclusions Our data suggest that assessment of vascular repair responses after red blood cell transfusion in critically ill patients is challenging. Although our study did not allow us to discern an influence of red cell transfusion on VPC cluster levels or angiogenic cytokines, new methods evaluating vascular repair mechanisms may be required.

Published
2013

29. [Untitled]

Author

France Clarke, Denise Foster, Ann Laberge, Nicole O’Callaghan, Patrica Thompson, Laurie Meade, Lisa Julien, Queen Elizabeth, Irene Watpool, Betty Jean Ashley, and Nicole Marinoff

Subjects
medicine.medical_specialty, business.industry, Family medicine, Medicine, Audit, Critical Care and Intensive Care Medicine, business
Published
2012

30. Cellular immunotherapy for septic shock (CISS): a phase I trial

Author

Claudia C. dos Santos, Irene Watpool, John Granton, Duncan J. Stewart, Dean Fergusson, Brent W. Winston, Lauralyn McIntyre, John Marshall, Shirley H. J. Mei, David W. Courtman, and Keith R. Walley

Subjects
Cancer Research, Transplantation, Septic shock, business.industry, Immunology, Cell Biology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, Oncology, medicine, Immunology and Allergy, 030212 general & internal medicine, Cellular immunotherapy, business, Genetics (clinical)
Published
2017

31. High-frequency oscillation in adults: A utilization review*

Author

Francois Lamontagne, Deborah J. Cook, Jan O. Friedrich, Maureen O. Meade, Abdel Bashir, Sangeeta Mehta, Andreas Freitag, Neill K. J. Adhikari, Lori Hand, Irene Watpool, Niall D. Ferguson, Qi Zhou, John Granton, and Kasia Czarnecka

Subjects
Male, medicine.medical_treatment, Acute Lung Injury, High-Frequency Ventilation, Hemodynamics, Lung injury, Critical Care and Intensive Care Medicine, Humans, Medicine, Intubation, Hospital Mortality, Academic Medical Centers, Respiratory Distress Syndrome, business.industry, Respiration, Oxygenation, Middle Aged, Confidence interval, Treatment Outcome, Respiratory failure, Quartile, Anesthesia, Female, business, Complication
Abstract

Objectives High-frequency oscillation is used for adults with acute lung injury/acute respiratory distress syndrome. Given the uncertain benefits, our objective was to describe contemporary patient selection, high-frequency oscillation utilization, and outcomes. Design Utilization review. Setting Ten academic centers (Ontario, Canada; January 1, 2005-January 31, 2007). Patients We included 190 consecutive adults treated with high-frequency oscillation and retrospectively abstracted data on patient demographics, gas exchange, hemodynamics, settings during conventional ventilation and high-frequency oscillation, adjunctive therapies, and outcomes. We used logistic regression to explore associations with oxygenation response and hemodynamic and ventilatory complications (2 hrs after high-frequency oscillation initiation) and mortality. Continuous data are reported as mean (sd) or median (quartile 1, quartile 3). Interventions None. Measurements and main results Patients (60.0% male; mean age, 52; sd 17) had predominantly acute lung injury/acute respiratory distress syndrome (89.8%) and were severely ill (mean Acute Physiology and Chronic Health Evaluation II score, 28; sd, 9) and hypoxemic (mean Pao2/Fio2, 80; sd, 42). High-frequency oscillation was started a median of 2 (1, 8) days after intubation and continued for a median of 3 (2, 7) days. During high-frequency oscillation, adjunctive treatments (neuromuscular blockade, 75.6%; recruitment maneuvers, 49.5%; nitric oxide, 34.0%; steroids, 63.1%) and new barotrauma or chest tube placement (23.5%) were common. Ten patients (5.3%) had technical complications; five required a new ventilator. Reasons for stopping high-frequency oscillation included death or withdrawal of life support (39.1%), significant improvement in respiratory failure (37.6%), and inadequate improvement (23.3%). One hundred and twenty-eight of 189 patients died in hospital. Most (62.5%) had a positive oxygenation response after 2 hrs of high-frequency oscillation (mean absolute increase in PaO₂/FiO₂, 22 [SD, 54]; 95% confidence interval of mean 14-31). A minority had lower PaO₂/FiO₂ (32.5%) or a hemodynamic (27.5%) or ventilatory (30.5%) complication. Older age, Acute Physiology and Chronic Health Evaluation II score, and Paco2 before high-frequency oscillation were independently associated with mortality. Conclusions Most patients treated with high-frequency oscillation have acute respiratory distress syndrome and severe hypoxemia that modestly improves 2 hrs after high-frequency oscillation application. However, oxygenation worsens in some patients, complications are common, and mortality is high.

Published
2011

32. Effects of inflammatory cytokines on the immune-modulatory properties of Mesenchymal Stem Cell

Author

Duncan J. Stewart, Shirley H. J. Mei, Lauralyn McIntyre, M. Salkhordeh, L. Souza-Moreira, Kenny Schlosser, Y. Tan, J. Wang, and Irene Watpool

Subjects
0301 basic medicine, Cancer Research, Transplantation, business.industry, Immunology, Mesenchymal stem cell, Cell Biology, Proinflammatory cytokine, 03 medical and health sciences, 030104 developmental biology, Immune system, Oncology, Immunology and Allergy, Medicine, business, Genetics (clinical)
Published
2018

33. Serial assessment of systemic levels of proinflammatory cytokines in septic shock patients treated with allogeneic mesenchymal stem cells

Author

Keith R. Walley, John Marshall, Duncan J. Stewart, John Granton, J. Wang, Irene Watpool, Lauralyn McIntyre, Claudia C. dos Santos, Kenny Schlosser, Brent W. Winston, and Shirley H. J. Mei

Subjects
Cancer Research, Transplantation, Pathology, medicine.medical_specialty, business.industry, Septic shock, Immunology, Mesenchymal stem cell, Cell Biology, medicine.disease, Proinflammatory cytokine, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, Oncology, Immunology and Allergy, Medicine, 030212 general & internal medicine, business, Genetics (clinical)
Published
2017

34. Vasopressin versus epinephrine for inhospital cardiac arrest: a randomised controlled trial

Author

Lyall Higginson, Katherine L. Vandemheen, Anthony S.L. Tang, George A. Wells, Ian G. Stiell, Brian N. Weitzman, Catherine M. Clement, Irene Watpool, Terry P. Klassen, Erica Battram, Jonathan Dreyer, Sharon Mason, and Paul C. Hébert

Subjects
Vasopressin, Resuscitation, Chemotherapy, business.industry, medicine.medical_treatment, Neurological function, Infarction, General Medicine, medicine.disease, law.invention, Pharmacotherapy, Epinephrine, Randomized controlled trial, law, Anesthesia, medicine, business, medicine.drug
Abstract

Summary Background Survival rates for cardiac arrest patients, both in and out of hospital, are poor. Results of a previous study suggest better outcomes for patients treated with vasopressin than for those given epinephrine, in the out-of-hospital setting. Our aim was to compare the effectiveness and safety of these drugs for the treatment of in-patient cardiac arrest. Methods We did a triple-blind randomised trial in the emergency departments, critical care units, and wards of three Canadian teaching hospitals. We assigned adults who had cardiac arrest and required drug therapy to receive one dose of vasopressin 40 U or epinephrine 1 mg intravenously, as the initial vasopressor. Patients who failed to respond to the study intervention were given epinephrine as a rescue medication. The primary outcomes were survival to hospital discharge, survival to 1 h, and neurological function. Preplanned subgroup assessments included patients with myocardial ischaemia or infarction, initial cardiac rhythm, and age. Findings We assigned 104 patients to vasopressin and 96 to epinephrine. For patients receiving vasopressin or epinephrine survival did not differ for hospital discharge (12 [12%] vs 13 [14%], respectively; p=0·67; 95% CI for absolute increase in survival –11·8% to 7·8%) or for 1 h survival (40 [39%] vs 34 [35%]; p=0·66; –10·9% to 17·0%); survivors had closely similar median mini-mental state examination scores (36 [range 19–38] vs 35 [20–40]; p=0·75) and median cerebral performance category scores (1 vs 1). Interpretation We failed to detect any survival advantage for vasopressin over epinephrine. We cannot recommend the routine use of vasopressin for inhospital cardiac arrest patients, and disagree with American Heart Association guidelines, which recommend vasopressin as alternative therapy for cardiac arrest.

Published
2001

35. Enrolling Critically Ill Patients Into Multiple Studies: A Case Study Of A Thromboprophylaxis Trial

Author

France Clarke, Ellen McDonald, Orla Smith, Nicole Zytaruk, Diane Heels-Ansdell, Irene Watpool, Tracy McArdle, Andrea Matte, Shirley Vallance, Simon Finfer, Pauline Galt, Tim Crozier, Robert Fowler, Yaseen Arabi, Clive Woolfe, Neil Orford, Richard Hall, Neill Adhikari, Marie Claude Ferland, John Marshall, Denise Foster, Paulina Farias, Deborah J. Cook, and Maureen Meade

Subjects
medicine.medical_specialty, Pediatrics, Critically ill, business.industry, medicine, Intensive care medicine, business
Published
2012

36. [Untitled]

Author

Lois Saunders, France Clarke, Lori Hand, Marnie Jakab, Irene Watpool, Jennifer Good, and Diane Heels-Ansdell

Subjects
medicine.medical_specialty, business.industry, Internal medicine, Medicine, Critical Care and Intensive Care Medicine, business
Published
2015

37. Title: Standardized Documentation To Understand Reasons For Missed Blood Draws For Translational Analyses Within A Pilot Randomized Controlled Trial

Author

Lisa Julien, Nicole Kraus, Wendy Janz, Agnieszka Grabowski-Comeau, Claude Gaudert, Deborah Wright, Irene Watpool, Lauralyn McIntyre, Christine Brean, Karen O'Hara-Banack, Tracy McArdle, and Caroline Roy

Subjects
medicine.medical_specialty, Documentation, Randomized controlled trial, business.industry, law, Alternative medicine, Physical therapy, Medicine, business, law.invention, Blood drawing
Published
2010

38. Establishing a master cell bank of bone marrow-derived mesenchymal stem cells for the cellular immunotherapy for septic shock trial (CISS)

Author

M. Salkhordeh, S. Hodgins, Irene Watpool, David W. Courtman, David S. Allan, Duncan J. Stewart, Shirley H. J. Mei, S. Khan, J. Wang, Lauralyn McIntyre, and Amanda van Beinum

Subjects
Cancer Research, Transplantation, Pathology, medicine.medical_specialty, Septic shock, business.industry, Immunology, Mesenchymal stem cell, Cell Biology, medicine.disease, medicine.anatomical_structure, Oncology, medicine, Immunology and Allergy, Cellular immunotherapy, Bone marrow, business, Cell bank, Genetics (clinical)
Published
2015

39. Regulatory environment for the development of an allogeneic mesenchymal stromal cell product for use in clinical trials

Author

David W. Courtman, Lauralyn McIntyre, Dean Fergusson, Duncan J. Stewart, Shirley H. J. Mei, Amanda van Beinum, David S. Allan, and Irene Watpool

Subjects
Cancer Research, Transplantation, Stromal cell, business.industry, Immunology, Mesenchymal stem cell, Cell Biology, Clinical trial, Oncology, Cancer research, Immunology and Allergy, Medicine, Product (category theory), business, Genetics (clinical)
Published
2015

40. Isolation and large-scale expansion of bone marrow-derived mesenchymal stem cells with serum-free media under GMP-compliance

Author

David S. Allan, Lauralyn McIntyre, Irene Watpool, M. Salkhordeh, F. Xue, J. Zhang, David W. Courtman, Duncan J. Stewart, and S.H. Mei

Subjects
Cancer Research, Transplantation, medicine.medical_specialty, business.industry, health care facilities, manpower, and services, education, Immunology, Cell Biology, Clinical epidemiology, humanities, medicine.anatomical_structure, Oncology, health services administration, Family medicine, medicine, Immunology and Allergy, Bone marrow, General hospital, business, health care economics and organizations, Genetics (clinical), Serum free media
Abstract

390 ISOLATION AND LARGE-SCALE EXPANSION OF BONE MARROW-DERIVED MESENCHYMAL STEM CELLS WITH SERUM-FREE MEDIA UNDER GMP-COMPLIANCE SH Mei, M Salkhordeh, F Xue, J Zhang, I Watpool, D Allan, L McIntyre, DW Courtman, DJ Stewart Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada, Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada, Critical Care, Ottawa General Hospital, Ottawa, Ontario, Canada

Published
2014

41. [Untitled]

Author

Orla Smith, Irene Watpool, Craig Dale, D Heels-Ansdell, T. McArdle, R Farrell, F Clarke, E McDonald, C Davidson, Marilyn Steinberg, Deborah J. Cook, R Ward, and L Hand

Subjects
medicine.medical_specialty, business.industry, 030208 emergency & critical care medicine, Critical Care and Intensive Care Medicine, Data science, Motion (physics), Radiology report, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, Multicenter study, medicine, Medical physics, business
Published
2005

42. Anti-Xa Levels in Critically Ill Patients Receiving Dalteparin for Thromboprophylaxis

Author

Tracy McCardle, Mark Crowther, Deborah J. Cook, Carson Davidson, Julia Foxall, Christine Wynne, Kim Bouwers, Andrea McNeill, Lauren Griffith, Susan Pleasance, Ellen McDonald, Geneviève Larouche, Nicole Zytaruk, Mark Duffett, Johanne Harvey, Anik Rioux, Irene Watpool, Craig Dale, Mary Jo, and Louise Provost

Subjects
medicine.medical_specialty, medicine.drug_class, business.industry, Critically ill, Immunology, Low molecular weight heparin, Renal function, Cell Biology, Hematology, Biochemistry, Group B, Surgery, Increased risk, Anesthesia, Orthopedic surgery, medicine, In patient, Neurosurgery, business
Abstract

Rationale: Despite the efficacy and safety of low molecular weight heparin (LWMH) compared to unfractionated (UFH) in many patients, LMWH may bioaccumulate in patients with renal insufficiency which could cause an increased risk of bleeding. If LMWH thromboprophylaxis is safe in ICU patients with renal insufficiency, this could reduce the risk of DVT and HIT. Since the extent to which LMWH bioaccumulates in critically ill patients in prophylactic rather than therapeutic doses is unclear, our objective was to measure peak and trough anti-Xa levels during a multicenter randomized pilot trial of LMWH vs UFH for thromboprophylaxis in the medical-surgical ICU setting. Methods: We included 128 patients ≥18 years with an expected ICU stay ≥72h. We excluded patients with trauma, orthopedic, cardiac, or neurosurgery, severe hypertension, DVT, PE or hemorrhage within 3 mos, INR >2ULN, PTT >2ULN, platelets Results: No differences were found in the 2 groups (median anti-Xa levels) as shown below. Conclusions: We did not observe LWMH or UFH bioaccumulation when administered in prophylactic doses in these critically ill patients with a range of renal dysfunction. Anti-Xa Levels Allocation Cr Cl

Published
2004

43. Vascular progenitor recruitment in critically ill patients with acute kidney injury

Author

David S. Allan, Kevin D. Burns, Tim Ramsay, Karim Abou-Nassar, Irene Watpool, Tracy McArdle, Yuan Chung, Yuhua Li, Judy Cheesman, Lionel G. Filion, Lauralyn McIntyre, and Rhian M. Touyz

Subjects
Male, medicine.medical_specialty, Critical Illness, law.invention, Normal renal function, law, medicine, Humans, In patient, Progenitor cell, Intensive care medicine, Progenitor, Aged, Retrospective Studies, Critically ill, business.industry, Stem Cells, Acute kidney injury, Endothelial Cells, General Medicine, Acute Kidney Injury, Middle Aged, medicine.disease, Intensive care unit, Peripheral blood, Intensive Care Units, Emergency medicine, Female, business
Abstract

Purpose: Endothelial-like vascular progenitor cells (VPCs) are blood-derived angiogenic precursors that can facilitate vascular repair. The mobilization of peripheral blood VPCs and their role in recovery were investigated in patients with acute kidney injury (AKI) in the intensive care unit (ICU) setting. Methods: Blood samples were drawn on days 0, 3, 7 and 14 in 38 patients admitted to ICU: 30 with AKI and in eight controls with normal renal function. Circulating VPC levels were quantified by the early outgrowth cell cluster-forming assay and/or by flow cytometry. Results: AKI patients (16 males, mean age 62.4) were classified as Risk (R, n=5), Injury (I, n=11) and Failure (F, n=14) according to the RIFLE criteria. VPC clusters increased over time following the diagnosis of AKI (p < 0.01 for day 0 vs. day 14) while VPC clusters were higher at enrollment in control patients and decreased over time (p=0.02). Greater mobilization of VPCs occurred in patients with more severe AKI at enrollment (I and F categories compared with R, p=0.05). A trend towards greater mobilization of VPC clusters was observed in patients with improved renal function (p=0.07). Conclusion: Time-dependent increases in circulating VPCs occur in critically ill patients with established AKI. Greater mobilization of VPCs may be associated with recovery of renal function, suggesting a potential role for VPCs in repair after kidney injury.

44. Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19

Author

Angus, Derek, Derde, Lennie, Al-Beidh, Farah, Annane, Djillali, Arabi, Yaseen, Beane, Abigail, van Bentum-Puijk, Wilma, Berry, Lindsay, Bhimani, Zahra, Bonten, Marc, Bradbury, Charlotte, Brunkhorst, Frank, Buxton, Meredith, Buzgau, Adrian, Cheng, Allen, de Jong, Menno, Detry, Michelle, Estcourt, Lise, Fitzgerald, Mark, Goossens, Herman, Green, Cameron, Haniffa, Rashan, Higgins, Alisa, Horvat, Christopher, Hullegie, Sebastiaan, Kruger, Peter, Lamontagne, Francois, Lawler, Patrick, Linstrum, Kelsey, Litton, Edward, Lorenzi, Elizabeth, Marshall, John, Mcauley, Daniel, Mcglothin, Anna, Mcguinness, Shay, Mcverry, Bryan, Montgomery, Stephanie, Mouncey, Paul, Murthy, Srinivas, Nichol, Alistair, Parke, Rachael, Parker, Jane, Rowan, Kathryn, Sanil, Ashish, Santos, Marlene, Saunders, Christina, Seymour, Christopher, Turner, Anne, van de Veerdonk, Frank, Venkatesh, Balasubramanian, Zarychanski, Ryan, Berry, Scott, Lewis, Roger, Mcarthur, Colin, Webb, Steven, Gordon, Anthony, NIHR, Hôpital Raymond Poincaré [AP-HP], Writing Committee for the REMAP-CAP Investigators, Farah Al-Beidh, Derek Angus, Djillali Annane, Yaseen Arabi, Wilma van Bentum-Puijk, Scott Berry, Abigail Beane, Zahra Bhimani, Marc Bonten, Charlotte Bradbury, Frank Brunkhorst, Meredith Buxton, Allen Cheng, Menno De Jong, Lennie Derde, Lise Estcourt, Herman Goossens, Anthony Gordon, Cameron Green, Rashan Haniffa, Francois Lamontagne, Patrick Lawler, Edward Litton, John Marshall, Colin McArthur, Daniel McAuley, Shay McGuinness, Bryan McVerry, Stephanie Montgomery, Paul Mouncey, Srinivas Murthy, Alistair Nichol, Rachael Parke, Kathryn Rowan, Christopher Seymour, Anne Turner, Frank van de Veerdonk, Steve Webb, Ryan Zarychanski, Lewis Campbell, Andrew Forbes, David Gattas, Stephane Heritier, Lisa Higgins, Peter Kruger, Sandra Peake, Jeffrey Presneill, Ian Seppelt, Tony Trapani, Paul Young, Sean Bagshaw, Nick Daneman, Niall Ferguson, Cheryl Misak, Marlene Santos, Sebastiaan Hullegie, Mathias Pletz, Gernot Rohde, Kathy Rowan, Brian Alexander, Kim Basile, Timothy Girard, Christopher Horvat, David Huang, Kelsey Linstrum, Jennifer Vates, Richard Beasley, Robert Fowler, Steve McGloughlin, Susan Morpeth, David Paterson, Bala Venkatesh, Tim Uyeki, Kenneth Baillie, Eamon Duffy, Rob Fowler, Thomas Hills, Katrina Orr, Asad Patanwala, Steve Tong, Mihai Netea, Shilesh Bihari, Marc Carrier, Dean Fergusson, Ewan Goligher, Ghady Haidar, Beverley Hunt, Anand Kumar, Mike Laffan, Patrick Lawless, Sylvain Lother, Peter McCallum, Saskia Middeldopr, Zoe McQuilten, Matthew Neal, John Pasi, Roger Schutgens, Simon Stanworth, Alexis Turgeon, Alexandra Weissman, Neill Adhikari, Matthew Anstey, Emily Brant, Angelique de Man, Francois Lamonagne, Marie-Helene Masse, Andrew Udy, Donald Arnold, Phillipe Begin, Richard Charlewood, Michael Chasse, Mark Coyne, Jamie Cooper, James Daly, Iain Gosbell, Heli Harvala-Simmonds, Tom Hills, Sheila MacLennan, David Menon, John McDyer, Nicole Pridee, David Roberts, Manu Shankar-Hari, Helen Thomas, Alan Tinmouth, Darrell Triulzi, Tim Walsh, Erica Wood, Carolyn Calfee, Cecilia O’Kane, Murali Shyamsundar, Pratik Sinha, Taylor Thompson, Ian Young, Shailesh Bihari, Carol Hodgson, John Laffey, Danny McAuley, Neil Orford, Ary Neto, Michelle Detry, Mark Fitzgerald, Roger Lewis, Anna McGlothlin, Ashish Sanil, Christina Saunders, Lindsay Berry, Elizabeth Lorenzi, Eliza Miller, Vanessa Singh, Claire Zammit, Wilma van Bentum Puijk, Wietske Bouwman, Yara Mangindaan, Lorraine Parker, Svenja Peters, Ilse Rietveld, Kik Raymakers, Radhika Ganpat, Nicole Brillinger, Rene Markgraf, Kate Ainscough, Kathy Brickell, Aisha Anjum, Janis-Best Lane, Alvin Richards-Belle, Michelle Saull, Daisy Wiley, Julian Bion, Jason Connor, Simon Gates, Victoria Manax, Tom van der Poll, John Reynolds, Marloes van Beurden, Evelien Effelaar, Joost Schotsman, Craig Boyd, Cain Harland, Audrey Shearer, Jess Wren, Giles Clermont, William Garrard, Kyle Kalchthaler, Andrew King, Daniel Ricketts, Salim Malakoutis, Oscar Marroquin, Edvin Music, Kevin Quinn, Heidi Cate, Karen Pearson, Joanne Collins, Jane Hanson, Penny Williams, Shane Jackson, Adeeba Asghar, Sarah Dyas, Mihaela Sutu, Sheenagh Murphy, Dawn Williamson, Nhlanhla Mguni, Alison Potter, David Porter, Jayne Goodwin, Clare Rook, Susie Harrison, Hannah Williams, Hilary Campbell, Kaatje Lomme, James Williamson, Jonathan Sheffield, Willian van’t Hoff, Phobe McCracken, Meredith Young, Jasmin Board, Emma Mart, Cameron Knott, Julie Smith, Catherine Boschert, Julia Affleck, Mahesh Ramanan, Ramsy D’Souza, Kelsey Pateman, Arif Shakih, Winston Cheung, Mark Kol, Helen Wong, Asim Shah, Atul Wagh, Joanne Simpson, Graeme Duke, Peter Chan, Brittney Cartner, Stephanie Hunter, Russell Laver, Tapaswi Shrestha, Adrian Regli, Annamaria Pellicano, James McCullough, Mandy Tallott, Nikhil Kumar, Rakshit Panwar, Gail Brinkerhoff, Cassandra Koppen, Federica Cazzola, Matthew Brain, Sarah Mineall, Roy Fischer, Vishwanath Biradar, Natalie Soar, Hayden White, Kristen Estensen, Lynette Morrison, Joanne Smith, Melanie Cooper, Monash Health, Yahya Shehabi, Wisam Al-Bassam, Amanda Hulley, Christina Whitehead, Julie Lowrey, Rebecca Gresha, James Walsham, Jason Meyer, Meg Harward, Ellen Venz, Patricia Williams, Catherine Kurenda, Kirsy Smith, Margaret Smith, Rebecca Garcia, Deborah Barge, Deborah Byrne, Kathleen Byrne, Alana Driscoll, Louise Fortune, Pierre Janin, Elizabeth Yarad, Naomi Hammond, Frances Bass, Angela Ashelford, Sharon Waterson, Steve Wedd, Robert McNamara, Heidi Buhr, Jennifer Coles, Sacha Schweikert, Bradley Wibrow, Rashmi Rauniyar, Erina Myers, Ed Fysh, Ashlish Dawda, Bhaumik Mevavala, Ed Litton, Janet Ferrier, Priya Nair, Hergen Buscher, Claire Reynolds, John Santamaria, Leanne Barbazza, Jennifer Homes, Roger Smith, Lauren Murray, Jane Brailsford, Loretta Forbes, Teena Maguire, Vasanth Mariappa, Judith Smith, Scott Simpson, Matthew Maiden, Allsion Bone, Michelle Horton, Tania Salerno, Martin Sterba, Wenli Geng, Pieter Depuydt, Jan De Waele, Liesbet De Bus, Jan Fierens, Stephanie Bracke, Brenda Reeve, William Dechert, Michaël Chassé, François Martin Carrier, Dounia Boumahni, Fatna Benettaib, Ali Ghamraoui, David Bellemare, Ève Cloutier, Charles Francoeur, François Lamontagne, Frédérick D’Aragon, Elaine Carbonneau, Julie Leblond, Gloria Vazquez-Grande, Nicole Marten, Maggie Wilson, Martin Albert, Karim Serri, Alexandros Cavayas, Mathilde Duplaix, Virginie Williams, Bram Rochwerg, Tim Karachi, Simon Oczkowski, John Centofanti, Tina Millen, Erick Duan, Jennifer Tsang, Lisa Patterson, Shane English, Irene Watpool, Rebecca Porteous, Sydney Miezitis, Lauralyn McIntyre, Laurent Brochard, Karen Burns, Gyan Sandhu, Imrana Khalid, Alexandra Binnie, Elizabeth Powell, Alexandra McMillan, Tracy Luk, Noah Aref, Zdravko Andric, Sabina Cviljevic, Renata Đimoti, Marija Zapalac, Gordan Mirković, Bruno Baršić, Marko Kutleša, Viktor Kotarski, Ana Vujaklija Brajković, Jakša Babel, Helena Sever, Lidija Dragija, Ira Kušan, Suvi Vaara, Leena Pettilä, Jonna Heinonen, Anne Kuitunen, Sari Karlsson, Annukka Vahtera, Heikki Kiiski, Sanna Ristimäki, Amine Azaiz, Cyril Charron, Mathieu Godement, Guillaume Geri, Antoine Vieillard-Baron, Franck Pourcine, Mehran Monchi, David Luis, Romain Mercier, Anne Sagnier, Nathalie Verrier, Cecile Caplin, Shidasp Siami, Christelle Aparicio, Sarah Vautier, Asma Jeblaoui, Muriel Fartoukh, Laura Courtin, Vincent Labbe, Cécile Leparco, Grégoire Muller, Mai-Anh Nay, Toufik Kamel, Dalila Benzekri, Sophie Jacquier, Emmanuelle Mercier, Delphine Chartier, Charlotte Salmon, PierreFrançois Dequin, Francis Schneider, Guillaume Morel, Sylvie L’Hotellier, Julio Badie, Fernando Daniel Berdaguer, Sylvain Malfroy, Chaouki Mezher, Charlotte Bourgoin, Bruno Megarbane, Sebastian Voicu, Nicolas Deye, Isabelle Malissin, Laetitia Sutterlin, Christophe Guitton, Cédric Darreau, Mickaël Landais, Nicolas Chudeau, Alain Robert, Pierre Moine, Nicholas Heming, Virginie Maxime, Isabelle Bossard, Tiphaine Barbarin Nicholier, Gwenhael Colin, Vanessa Zinzoni, Natacham Maquigneau, André Finn, Gabriele Kreß, Uwe Hoff, Carl Friedrich Hinrichs, Jens Nee, Mathias Pletz, Stefan Hagel, Juliane Ankert, Steffi Kolanos, Frank Bloos, Sirak Petros, Bastian Pasieka, Kevin Kunz, Peter Appelt, Bianka Schütze, Stefan Kluge, Axel Nierhaus, Dominik Jarczak, Kevin Roedl, Dirk Weismann, Anna Frey, Vivantes Klinikum Neukölln, Lorenz Reill, Michael Distler, Astrid Maselli, János Bélteczki, István Magyar, Ágnes Fazekas, Sándor Kovács, Viktória Szőke, Gábor Szigligeti, János Leszkoven, Daniel Collins, Patrick Breen, Stephen Frohlich, Ruth Whelan, Bairbre McNicholas, Michael Scully, Siobhan Casey, Maeve Kernan, Peter Doran, Michael O’Dywer, Michelle Smyth, Leanne Hayes, Oscar Hoiting, Marco Peters, Els Rengers, Mirjam Evers, Anton Prinssen, Jeroen Bosch Ziekenhuis, Koen Simons, Wim Rozendaal, F Polderman, P de Jager, M Moviat, A Paling, A Salet, Emma Rademaker, Anna Linda Peters, E de Jonge, J Wigbers, E Guilder, M Butler, Keri-Anne Cowdrey, Lynette Newby, Yan Chen, Catherine Simmonds, Rachael McConnochie, Jay Ritzema Carter, Seton Henderson, Kym Van Der Heyden, Jan Mehrtens, Tony Williams, Alex Kazemi, Rima Song, Vivian Lai, Dinu Girijadevi, Robert Everitt, Robert Russell, Danielle Hacking, Ulrike Buehner, Erin Williams, Troy Browne, Kate Grimwade, Jennifer Goodson, Owen Keet, Owen Callender, Robert Martynoga, Kara Trask, Amelia Butler, Livia Schischka, Chelsea Young, Eden Lesona, Shaanti Olatunji, Yvonne Robertson, Nuno José, Teodoro Amaro dos Santos Catorze, Tiago Nuno Alfaro de Lima Pereira, Lucilia Maria Neves Pessoa, Ricardo Manuel Castro Ferreira, Joana Margarida Pereira Sousa Bastos, Simin Aysel Florescu, Delia Stanciu, Miahela Florentina Zaharia, Alma Gabriela Kosa, Daniel Codreanu, Yaseen Marabi, Eman Al Qasim, Mohamned Moneer Hagazy, Lolowa Al Swaidan, Hatim Arishi, Rosana Muñoz-Bermúdez, Judith Marin-Corral, Anna Salazar Degracia, Francisco Parrilla Gómez, Maria Isabel Mateo López, Jorge Rodriguez Fernandez, Sheila Cárcel Fernández, Rosario Carmona Flores, Rafael León López, Carmen de la Fuente Martos, Angela Allan, Petra Polgarova, Neda Farahi, Stephen McWilliam, Daniel Hawcutt, Laura Rad, Laura O’Malley, Jennifer Whitbread, Olivia Kelsall, Laura Wild, Jessica Thrush, Hannah Wood, Karen Austin, Adrian Donnelly, Martin Kelly, Sinéad O’Kane, Declan McClintock, Majella Warnock, Paul Johnston, Linda Jude Gallagher, Clare Mc Goldrick, Moyra Mc Master, Anna Strzelecka, Rajeev Jha, Michael Kalogirou, Christine Ellis, Vinodh Krishnamurthy, Vashish Deelchand, Jon Silversides, Peter McGuigan, Kathryn Ward, Aisling O’Neill, Stephanie Finn, Barbara Phillips, Dee Mullan, Laura Oritz-Ruiz de Gordoa, Matthew Thomas, Katie Sweet, Lisa Grimmer, Rebekah Johnson, Jez Pinnell, Matt Robinson, Lisa Gledhill, Tracy Wood, Matt Morgan, Jade Cole, Helen Hill, Michelle Davies, David Antcliffe, Maie Templeton, Roceld Rojo, Phoebe Coghlan, Joanna Smee, Euan Mackay, Jon Cort, Amanda Whileman, Thomas Spencer, Nick Spittle, Vidya Kasipandian, Amit Patel, Suzanne Allibone, Roman Mary Genetu, Mohamed Ramali, Alison Ghosh, Peter Bamford, Emily London, Kathryn Cawley, Maria Faulkner, Helen Jeffrey, Tim Smith, Chris Brewer, Jane Gregory, James Limb, Amanda Cowton, Julie O’Brien, Nikitas Nikitas, Colin Wells, Liana Lankester, Mark Pulletz, Patricia Williams, Jenny Birch, Sophie Wiseman, Sarah Horton, Ana Alegria, Salah Turki, Tarek Elsefi, Nikki Crisp, Louise Allen, Iain McCullagh, Philip Robinson, Carole Hays, Maite Babio-Galan, Hannah Stevenson, Divya Khare, Meredith Pinder, Selvin Selvamoni, Amitha Gopinath, Richard Pugh, Daniel Menzies, Callum Mackay, Elizabeth Allan, Gwyneth Davies, Kathryn Puxty, Claire McCue, Susanne Cathcart, Naomi Hickey, Jane Ireland, Hakeem Yusuff, Graziella Isgro, Chris Brightling, Michelle Bourne, Michelle Craner, Malcolm Watters, Rachel Prout, Louisa Davies, Suzannah Pegler, Lynsey Kyeremeh, Gill Arbane, Karen Wilson, Linda Gomm, Federica Francia, Stephen Brett, Sonia Sousa Arias, Rebecca Elin Hall, Joanna Budd, Charlotte Small, Janine Birch, Emma Collins, Jeremy Henning, Stephen Bonner, Keith Hugill, Emanuel Cirstea, Dean Wilkinson, Michal Karlikowski, Helen Sutherland, Elva Wilhelmsen, Jane Woods, Julie North, Dhinesh Sundaran, Laszlo Hollos, Susan Coburn, Joanne Walsh, Margaret Turns, Phil Hopkins, John Smith, Harriet Noble, Maria Theresa Depante, Emma Clarey, Shondipon Laha, Mark Verlander, Alexandra Williams, Abby Huckle, Andrew Hall, Jill Cooke, Caroline Gardiner-Hill, Carolyn Maloney, Hafiz Qureshi, Neil Flint, Sarah Nicholson, Sara Southin, Andrew Nicholson, Barbara Borgatta, Ian Turner-Bone, Amie Reddy, Laura Wilding, Loku Chamara Warnapura, Ronan Agno Sathianathan, David Golden, Ciaran Hart, Jo Jones, Jonathan Bannard-Smith, Joanne Henry, Katie Birchall, Fiona Pomeroy, Rachael Quayle, Arystarch Makowski, Beata Misztal, Iram Ahmed, Thyra KyereDiabour, Kevin Naiker, Richard Stewart, Esther Mwaura, Louise Mew, Lynn Wren, Felicity Willams, Richard Innes, Patricia Doble, Joanne Hutter, Charmaine Shovelton, Benjamin Plumb, Tamas Szakmany, Vincent Hamlyn, Nancy Hawkins, Sarah Lewis, Amanda Dell, Shameer Gopal, Saibal Ganguly, Andrew Smallwood, Nichola Harris, Stella Metherell, Juan Martin Lazaro, Tabitha Newman, Simon Fletcher, Jurgens Nortje, Deirdre Fottrell-Gould, Georgina Randell, Mohsin Zaman, Einas Elmahi, Andrea Jones, Kathryn Hall, Gary Mills, Kim Ryalls, Helen Bowler, Jas Sall, Richard Bourne, Zoe Borrill, Tracey Duncan, Thomas Lamb, Joanne Shaw, Claire Fox, Jeronimo Moreno Cuesta, Kugan Xavier, Dharam Purohit, Munzir Elhassan, Dhanalakshmi Bakthavatsalam, Matthew Rowland, Paula Hutton, Archana Bashyal, Neil Davidson, Clare Hird, Manish Chhablani, Gunjan Phalod, Amy Kirkby, Simon Archer, Kimberley Netherton, Henrik Reschreiter, Julie Camsooksai, Sarah Patch, Sarah Jenkins, David Pogson, Steve Rose, Zoe Daly, Lutece Brimfield, Helen Claridge, Dhruv Parekh, Colin Bergin, Michelle Bates, Joanne Dasgin, Christopher McGhee, Malcolm Sim, Sophie Kennedy Hay, Steven Henderson, Mandeep-Kaur Phull, Abbas Zaidi, Tatiana Pogreban, Lace Paulyn Rosaroso, Daniel Harvey, Benjamin Lowe, Megan Meredith, Lucy Ryan, Anil Hormis, Rachel Walker, Dawn Collier, Sarah Kimpton, Susan Oakley, Kevin Rooney, Natalie Rodden, Emma Hughes, Nicola Thomson, Deborah McGlynn, Andrew Walden, Nicola Jacques, Holly Coles, Emma Tilney, Emma Vowell, Martin Schuster-Bruce, Sally Pitts, Rebecca Miln, Laura Purandare, Luke Vamplew, Michael Spivey, Sarah Bean, Karen Burt, Lorraine Moore, Christopher Day, Charly Gibson, Elizabeth Gordon, Letizia Zitter, Samantha Keenan, Evelyn Baker, Shiney Cherian, Sean Cutler, Anna Roynon-Reed, Kate Harrington, Ajay Raithatha, Kris Bauchmuller, Norfaizan Ahmad, Irina Grecu, Dawn Trodd, Jane Martin, Caroline Wrey Brown, Ana-Marie Arias, Thomas Craven, David Hope, Jo Singleton, Sarah Clark, Nicola Rae, Ingeborg Welters, David Oliver Hamilton, Karen Williams, Victoria Waugh, David Shaw, Zudin Puthucheary, Timothy Martin, Filipa Santos, Ruzena Uddin, Alastair Somerville, Kate Colette Tatham, Shaman Jhanji, Ethel Black, Arnold Dela Rosa, Ryan Howle, Redmond Tully, Andrew Drummond, Joy Dearden, Jennifer Philbin, Sheila Munt, Alain Vuylsteke, Charles Chan, Saji Victor, Ramprasad Matsa, Minerva Gellamucho, Ben Creagh-Brown, Joe Tooley, Laura Montague, Fiona De Beaux, Laetitia Bullman, Ian Kersiake, Carrie Demetriou, Sarah Mitchard, Lidia Ramos, Katie White, Phil Donnison, Maggie Johns, Ruth Casey, Lehentha Mattocks, Sarah Salisbury, Paul Dark, Andrew Claxton, Danielle McLachlan, Kathryn Slevin, Stephanie Lee, Jonathan Hulme, Sibet Joseph, Fiona Kinney, Ho Jan Senya, Aneta Oborska, Abdul Kayani, Bernard Hadebe, Rajalakshmi Orath Prabakaran, Lesley Nichols, Matt Thomas, Ruth Worner, Beverley Faulkner, Emma Gendall, Kati Hayes, Colin Hamilton-Davies, Carmen Chan, Celina Mfuko, Hakam Abbass, Vineela Mandadapu, Susannah Leaver, Daniel Forton, Kamal Patel, Elankumaran Paramasivam, Matthew Powell, Richard Gould, Elizabeth Wilby, Clare Howcroft, Dorota Banach, Ziortza Fernández de Pinedo Artaraz, Leilani Cabreros, Ian White, Maria Croft, Nicky Holland, Rita Pereira, Ahmed Zaki, David Johnson, Matthew Jackson, Hywel Garrard, Vera Juhaz, Alistair Roy, Anthony Rostron, Lindsey Woods, Sarah Cornell, Suresh Pillai, Rachel Harford, Tabitha Rees, Helen Ivatt, Ajay Sundara Raman, Miriam Davey, Kelvin Lee, Russell Barber, Manish Chablani, Farooq Brohi, Vijay Jagannathan, Michele Clark, Sarah Purvis, Bill Wetherill, Ahilanandan Dushianthan, Rebecca Cusack, Kim de Courcy-Golder, Simon Smith, Susan Jackson, Ben Attwood, Penny Parsons, Valerie Page, Xiao Bei Zhao, Deepali Oza, Jonathan Rhodes, Tom Anderson, Sheila Morris, Charlotte Xia Le Tai, Amy Thomas, Alexandra Keen, Stephen Digby, Nicholas Cowley, Laura Wild, David Southern, Harsha Reddy, Andy Campbell, Claire Watkins, Sara Smuts, Omar Touma, Nicky Barnes, Peter Alexander, Tim Felton, Susan Ferguson, Katharine Sellers, Joanne Bradley-Potts, David Yates, Isobel Birkinshaw, Kay Kell, Nicola Marshall, Lisa Carr-Knott, Charlotte Summers, and Mégarbane, Bruno

Subjects
[SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, General Medicine, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Writing Committee for the REMAP-CAP Investigators, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.TOX] Life Sciences [q-bio]/Toxicology, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.TOX]Life Sciences [q-bio]/Toxicology, General & Internal Medicine, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, 11 Medical and Health Sciences
Abstract

Importance Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures The primary end point was organ support–free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned –1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support–free days were 0 (IQR, –1 to 15), 0 (IQR, –1 to 13), and 0 (–1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support–free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support–free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions.

Published
2020

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