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Early Goal-Directed Therapy for Sepsis: A Novel Solution for Discordant Survival Outcomes in Clinical Trials

Kalil, Andre C. MD, MPH; Johnson, Daniel W. MD; Lisco, Steven J. MD; Sun, Junfeng PhD

doi: 10.1097/CCM.0000000000002235
Clinical Investigations
Editor's Choice

Objectives: Early goal-directed therapy has shown discordant survival outcomes in sepsis studies. We aim to find the reasons for this discordance.

Design: Random-effects and Bayesian hierarchical analyses.

Setting: Studies that evaluated early goal-directed therapy.

Subjects: Patients with severe sepsis and/or septic shock.

Interventions: Early goal-directed therapy.

Measurements and Main Results: A total of 19,998 patients were included in the main analysis: 31 observational (n = 15,656) and six randomized (n = 4,342) studies. The analysis from 37 studies showed that early goal-directed therapy was associated with a 23% reduction in the risk of death: relative risk = 0.77 (95% CI, 0.71–0.83); p value of less than 0.0001. Mortality reduction was seen with observational studies: relative risk = 0.73 (0.67–0.80); p value of less than 0.0001 but not with randomized studies: relative risk = 0.92 (0.78–1.07); p = 0.268. Meta-regression analysis showed lower risk of death in observational compared with randomized studies: relative risk = 0.81 (0.68–0.95); p = 0.01. Differences in age, country, hospital location, era, systolic pressure, mean arterial pressure, lactate, bundle compliance, amount of fluid administered, and hemodynamic goal achievements were not associated with survival differences between studies. Factors associated with mortality differences between early goal-directed therapy and control included Acute Physiology and Chronic Health Evaluation II (relative risk = 1.05 [1.02–1.09]; p = 0.003), Sequential Organ Failure Assessment (relative risk = 1.09 [1.00–1.18]; p = 0.04), presence of shock (relative risk = 1.007 [1.002–1.013]; p = 0.006), time-to-first antibiotic (relative risk = 1.22 [1.09–1.36]; p = 0.0006), antibiotic administration within 6 hours (relative risk = 0.20 [0.09–0.45]; p = 0.0001), 4 hours (relative risk = 0.16 [0.06–0.39]; p = 0.0001), and 3 hours (relative risk = 0.09 [0.03–0.27]; p < 0.0001). The only factors that explained mortality differences between randomized and observational studies were time-to-first antibiotic (R2 = 87%), antibiotic administration within 6 hours (R2 = 94%), 4 hours (R2 = 99%), 3 hours (R2 = 99%), and appropriate antibiotic use (R2 = 96%).

Conclusions: Survival discordance was not associated with differences in early goal-directed therapy bundle compliance or hemodynamic goal achievement. Our results suggest that it was associated with faster and more appropriate antibiotic co-intervention in the early goal-directed therapy arm compared with controls in the observational studies but not in the randomized trials. Early goal-directed therapy was associated with increased mortality in patients with high-disease severity.

1Infectious Disease Division, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE.

2Critical Care Division, Department of Anesthesiology, University of Nebraska Medical Center, Omaha, NE.

3Critical Care Department, National Institutes of Health, Bethesda, MD.

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Dr. Kalil contributed in study and concept design, literature search, data collection, statistical analysis, data analysis, data interpretation, writing, critical revision, and submission. Dr. Johnson contributed in data collection, data analysis, data interpretation, writing, and critical revision. Dr. Lisco contributed in data analysis, data interpretation, writing, and critical revision. Dr. Sun contributed in statistical analysis, data analysis, data interpretation, writing, and critical revision.

All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf. Dr. Sun has disclosed government work. The remaining authors have disclosed that they do not have any potential conflicts of interest.

For information regarding this article, E-mail: akalil@unmc.edu

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