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Assessing the Course of Organ Dysfunction Using Joint Longitudinal and Time-to-Event Modeling in the Vasopressin and Septic Shock Trial.

Authors
  • Harhay, Michael O1, 2
  • Gasparini, Alessandro3
  • Walkey, Allan J4
  • Weissman, Gary E1, 5
  • Crowther, Michael J3
  • Ratcliffe, Sarah J6
  • Russell, James A7, 8
  • 1 Palliative and Advanced Illness Research (PAIR) Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
  • 2 Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
  • 3 Biostatistics Research Group, Department of Health Sciences, University of Leicester, Leicester, United Kingdom. , (United Kingdom)
  • 4 Evans Center for Implementation and Improvement Sciences, Department of Medicine and the Pulmonary Center, Boston University School of Medicine, Boston, MA.
  • 5 Division of Pulmonary, Allergy and Critical Care Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
  • 6 Division of Biostatistics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA.
  • 7 Centre for Heart Lung Innovation, University of British Columbia, Vancouver, BC, Canada. , (Canada)
  • 8 Division of Critical Care Medicine, St. Paul's Hospital, University of British Columbia, Vancouver, BC, Canada. , (Canada)
Type
Published Article
Journal
Critical care explorations
Publication Date
Apr 01, 2020
Volume
2
Issue
4
Identifiers
DOI: 10.1097/CCE.0000000000000104
PMID: 32426746
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Non-mortality septic shock outcomes (e.g., Sequential Organ Failure Assessment score) are important clinical endpoints in pivotal sepsis trials. However, comparisons of observed longitudinal non-mortality outcomes between study groups can be biased if death is unequal between study groups or is associated with an intervention (i.e., informative censoring). We compared the effects of vasopressin versus norepinephrine on the Sequential Organ Failure Assessment score in the Vasopressin and Septic Shock Trial to illustrate the use of joint modeling to help minimize potential bias from informative censoring. Secondary analysis of the Vasopressin and Septic Shock Trial data. Twenty-seven ICUs in Canada, Australia, and United States. Seven hundred sixty-three participants with septic shock who received blinded vasopressin (n = 389) or norepinephrine infusions (n = 374). Sequential Organ Failure Assessment scores were calculated daily until discharge, death, or day 28 after randomization. Mortality was numerically higher in the norepinephrine arm (28 d mortality of 39% vs 35%; p = 0.25), and there was a positive association between higher Sequential Organ Failure Assessment scores and patient mortality, characteristics that suggest a potential for bias from informative censoring of Sequential Organ Failure Assessment scores by death. The best-fitting joint longitudinal (i.e., linear mixed-effects model) and survival (i.e., Cox proportional hazards model for the time-to-death) model showed that norepinephrine was associated with a more rapid improvement in the total Sequential Organ Failure Assessment score through day 4, and then the daily Sequential Organ Failure Assessment scores converged and overlapped for the remainder of the study period. Short-term reversal of organ dysfunction occurred more rapidly with norepinephrine compared with vasopressin, although differences between study arms did not persist after day 4. Joint models are an accessible methodology that could be used in critical care trials to assess the effects of interventions on the longitudinal progression of key outcomes (e.g., organ dysfunction, biomarkers, or quality of life) that may be informatively truncated by death or other censoring events. Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.

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