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

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)607-614
Number of pages8
JournalCritical care medicine
Volume45
Issue number4
DOIs
StatePublished - Apr 1 2017

Fingerprint

Sepsis
Clinical Trials
Survival
Anti-Bacterial Agents
Therapeutics
Observational Studies
Mortality
Compliance
Hemodynamics
APACHE
Bayes Theorem
Risk Reduction Behavior
Septic Shock
Meta-Analysis
Shock
Lactic Acid
Arterial Pressure
Regression Analysis
Blood Pressure

Keywords

  • early goal-directed therapy
  • sepsis
  • septic shock

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

@article{f359aa77a083455d828e43765227e80c,
title = "Early Goal-Directed Therapy for Sepsis: A Novel Solution for Discordant Survival Outcomes in Clinical Trials",
abstract = "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.",
keywords = "early goal-directed therapy, sepsis, septic shock",
author = "Kalil, {Andre C} and Johnson, {Daniel W} and Lisco, {Steven J} and Junfeng Sun",
year = "2017",
month = "4",
day = "1",
doi = "10.1097/CCM.0000000000002235",
language = "English (US)",
volume = "45",
pages = "607--614",
journal = "Critical Care Medicine",
issn = "0090-3493",
publisher = "Lippincott Williams and Wilkins",
number = "4",

}

TY - JOUR

T1 - Early Goal-Directed Therapy for Sepsis

T2 - A Novel Solution for Discordant Survival Outcomes in Clinical Trials

AU - Kalil, Andre C

AU - Johnson, Daniel W

AU - Lisco, Steven J

AU - Sun, Junfeng

PY - 2017/4/1

Y1 - 2017/4/1

N2 - 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.

AB - 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.

KW - early goal-directed therapy

KW - sepsis

KW - septic shock

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