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Reassessing the value of short-term mortality in sepsis: Comparing conventional approaches to modeling

Clermont, Gilles MD, CM, MSc; Angus, Derek C. MB, ChB, MPH; Kalassian, Kenneth G. MD; Linde-Zwirble, Walter T.; Ramakrishnan, Nagarajan MBBS; Linden, Peter K. MD; Pinsky, Michael R. MD

doi: 10.1097/01.CCM.0000094233.35059.81
Clinical Investigations

Objective Clinical trials of therapies for sepsis have been mostly unsuccessful in impacting mortality. This may be partly due to the use of insensitive mortality end points. We explored whether modeling survival was more sensitive than traditional end points in detecting mortality differences in cohorts of patients with sepsis.

Design Patients were stratified into seven a priori defined paired subgroups that reflected high and low mortality risk according to known clinical risk factors. We fitted an exponential survival model to the high- and low-risk cohort of each subgroup, providing estimates of the rate of dying, long-term survival, and excess day 1 mortality. Mortality in the high- and low-risk cohorts in each subgroup was compared using model parameters, fixed-point mortality, and Kaplan-Meier survival analysis.

Setting Eight intensive care units within a university teaching institution.

Patients One hundred thirty patients with severe sepsis or suspected Gram-negative bacteremia.

Interventions None.

Measurements and Main Results Overall mortality of the cohort was 58.5% at 28 days. The survival of the entire cohort was well described by an exponential model (r2 = .99). Modeling identified differences in high- and low-risk cohorts in five of the seven paired subgroups, while conventional end-points only detected differences in 2.

Conclusions Modeling survival was more sensitive than conventional end-points in identifying survival differences between high- and low-risk subgroups. We encourage further evaluation of modeling in the search for more sensitive mortality end points.

From the CRISMA (Clinical Research, Investigation, and Systems Modeling of Acute Illness) Laboratory (GC, DCA, KGK, WTL-Z), Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA; Georgia Lung Associates (KGK), Austell, GA; Health Process Management (WTL-Z), LLC, Doylestown, PA; Acute Care Consultants of Dublin (NR), Dublin, GA; and the Department of Critical Care Medicine (PKL, MRP), University of Pittsburgh, Pittsburgh, PA.

We, therefore, recommend that intermediate outcomes suggestive of disease modification, such as time constant to death, be considered for inclusion as additional end points in sepsis trials.

© 2003 Lippincott Williams & Wilkins, Inc.