title: The influence of corticosteroid treatment on the outcome of influenza A(H1N1pdm09)-related critical illness.
abstract: BACKGROUND
  Patients with 2009 pandemic influenza A(H1N1pdm09)-related critical illness were frequently treated with systemic corticosteroids. While observational studies have reported significant corticosteroid-associated mortality after adjusting for baseline differences in patients treated with corticosteroids or not, corticosteroids have remained a common treatment in subsequent influenza outbreaks, including avian influenza A(H7N9). Our objective was to describe the use of corticosteroids in these patients and investigate predictors of steroid prescription and clinical outcomes, adjusting for both baseline and time-dependent factors.
  
  
  METHODS
  In an observational cohort study of adults with H1N1pdm09-related critical illness from 51 Canadian ICUs, we investigated predictors of steroid administration and outcomes of patients who received and those who did not receive corticosteroids. We adjusted for potential baseline confounding using multivariate logistic regression and propensity score analysis and adjusted for potential time-dependent confounding using marginal structural models.
  
  
  RESULTS
  Among 607 patients, corticosteroids were administered to 280 patients (46.1%) at a median daily dose of 227 (interquartile range, 154-443) mg of hydrocortisone equivalents for a median of 7.0 (4.0-13.0) days. Compared with patients who did not receive corticosteroids, patients who received corticosteroids had higher hospital crude mortality (25.5% vs 16.4%, p = 0.007) and fewer ventilator-free days at 28 days (12.5 ± 10.7 vs 15.7 ± 10.1, p < 0.001). The odds ratio association between corticosteroid use and hospital mortality decreased from 1.85 (95% confidence interval 1.12-3.04, p = 0.02) with multivariate logistic regression, to 1.71 (1.05-2.78, p = 0.03) after adjustment for propensity score to receive corticosteroids, to 1.52 (0.90-2.58, p = 0.12) after case-matching on propensity score, and to 0.96 (0.28-3.28, p = 0.95) using marginal structural modeling to adjust for time-dependent between-group differences.
  
  
  CONCLUSIONS
  Corticosteroids were commonly prescribed for H1N1pdm09-related critical illness. Adjusting for only baseline between-group differences suggested a significant increased risk of death associated with corticosteroids. However, after adjusting for time-dependent differences, we found no significant association between corticosteroids and mortality. These findings highlight the challenges and importance in adjusting for baseline and time-dependent confounders when estimating clinical effects of treatments using observational studies.
authors.affiliation: Interdepartmental Division of Critical Care Medicine, Department of Medicine, University of Toronto, Toronto, ON, Canada.|Rouge Valley Health System, Scarborough, ON, Canada.
authors.forename: Jesse W
authors.initials: JW
authors.lastname: Delaney
authors.affiliation: Sunnybrook Hospital, Toronto, ON, Canada.
authors.forename: Ruxandra
authors.initials: R
authors.lastname: Pinto
authors.affiliation: Sunnybrook Hospital, Toronto, ON, Canada.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Long
authors.affiliation: Centre de recherche clinique Étienne-Le Bel, Université de Sherbrooke, Sherbrooke, PQ, Canada.
authors.forename: François
authors.initials: F
authors.lastname: Lamontagne
authors.affiliation: Interdepartmental Division of Critical Care Medicine, Department of Medicine, University of Toronto, Toronto, ON, Canada.|Department of Critical Care Medicine, Sunnybrook Hospital, 2075 Bayview Avenue, Room D478, Toronto, ON, M4N 3M5, Canada.
authors.forename: Neill K
authors.initials: NK
authors.lastname: Adhikari
authors.affiliation: Section of Critical Care Medicine, Department of Internal Medicine, Faculty of Health Sciences, College of Medicine, University of Manitoba, Winnipeg, MB, Canada.|Section of Infectious Diseases, Department of Internal Medicine, Faculty of Health Sciences, College of Medicine, University of Manitoba, Winnipeg, MB, Canada.|Department of Medical Microbiology, Faculty of Health Sciences, College of Medicine, University of Manitoba, Winnipeg, MB, Canada.|Department of, Faculty of Health Sciences, College of Medicine, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: Anand
authors.initials: A
authors.lastname: Kumar
authors.affiliation: St. Michael's Hospital, University of Toronto, Toronto, ON, Canada.
authors.forename: John C
authors.initials: JC
authors.lastname: Marshall
authors.affiliation: St. Joseph's Hospital, McMaster University, Hamilton, ON, Canada.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Cook
authors.affiliation: CHU Sainte Justine, Université de Montréal, Montréal, PQ, Canada.
authors.forename: Philippe
authors.initials: P
authors.lastname: Jouvet
authors.affiliation: Interdepartmental Division of Critical Care Medicine, Department of Medicine, University of Toronto, Toronto, ON, Canada.|Department of Medicine, University of Toronto, Toronto, ON, Canada.|Department of Physiology, University of Toronto, Toronto, ON, Canada.|Division of Respirology, Department of Medicine, University Health Network and Mount Sinai Hospital, Toronto, ON, Canada.|Critical Care Program, Department of Medicine, University Health Network and Mount Sinai Hospital, Toronto, ON, Canada.
authors.forename: Niall D
authors.initials: ND
authors.lastname: Ferguson
authors.affiliation: Vancouver General Hospital, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Donald
authors.initials: D
authors.lastname: Griesdale
authors.affiliation: Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Burry
authors.affiliation: Interdepartmental Division of Critical Care Medicine, Department of Medicine, University of Toronto, Toronto, ON, Canada.|Division of Critical Care, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada.
authors.forename: Karen E A
authors.initials: KE
authors.lastname: Burns
authors.affiliation: Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
authors.forename: Jamie
authors.initials: J
authors.lastname: Hutchison
authors.affiliation: Interdepartmental Division of Critical Care Medicine, Department of Medicine, University of Toronto, Toronto, ON, Canada.|Department of Medicine, University of Toronto, Toronto, ON, Canada.|Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
authors.forename: Sangeeta
authors.initials: S
authors.lastname: Mehta
authors.affiliation: Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Kusum
authors.initials: K
authors.lastname: Menon
authors.affiliation: Interdepartmental Division of Critical Care Medicine, Department of Medicine, University of Toronto, Toronto, ON, Canada. rob.fowler@sunnybrook.ca.|Department of Critical Care Medicine, Sunnybrook Hospital, 2075 Bayview Avenue, Room D478, Toronto, ON, M4N 3M5, Canada. rob.fowler@sunnybrook.ca.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Fowler
mesh_terms: D000305:Adrenal Cortex Hormones / Q000009:adverse effects* / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D015331:Cohort Studies; D003422:Critical Care / Q000379:methods*; D005260:Female; D017052:Hospital Mortality; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects / Q000472:pathogenicity; D007251:Influenza, Human / Q000188:drug therapy / Q000401:mortality; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
chemical_list: D000305:Adrenal Cortex Hormones; D006854:Hydrocortisone