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Interaction Between Fluids and Vasoactive Agents on Mortality in Septic Shock: A Multicenter, Observational Study*

Waechter, Jason MD; Kumar, Anand MD; Lapinsky, Stephen E. MB, MSc; Marshall, John MD; Dodek, Peter MD, MHSc; Arabi, Yaseen MD; Parrillo, Joseph E. MD; Dellinger, R. Phillip MD; Garland, Allan MD, MA

doi: 10.1097/CCM.0000000000000520
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Objective: Fluids and vasoactive agents are both used to treat septic shock, but little is known about how they interact or the optimal way to administer them. We sought to determine how hospital mortality was influenced by combined use of these two treatments.

Design: Retrospective evaluation using multivariable logistic regression to evaluate the association between hospital mortality and categorical variables representing initiation of vasoactive agents and volumes of IV fluids given 0–1, 1–6, and 6–24 hours after onset, including interactions and adjusting for potential confounders.

Setting: ICUs of 24 hospitals in 3 countries.

Patients: Two thousand eight hundred forty-nine patients who survived more than 24 hours after after onset of septic shock, admitted between 1989 and 2007.

Interventions: None.

Measurements and Main Results: Fluids and vasoactive agents had strong, interacting associations with mortality (p < 0.0001). Mortality was lowest when vasoactive agents were begun 1–6 hours after onset, with more than 1 L of fluids in the initial hour after shock onset, more than 2.4 L from hours 1–6, and 1.6–3.5 L from 6 to 24 hours. The lowest mortality rates were associated with starting vasoactive agents 1–6 hours after onset.

Conclusions: The focus during the first hour of resuscitation for septic shock should be aggressive fluid administration, only thereafter starting vasoactive agents, while continuing aggressive fluid administration. Starting vasoactive agents in the initial hour may be detrimental, and not all of that association is due to less fluids being given with such early initiation of vasoactive agents.

Supplemental Digital Content is available in the text.

1Department of Critical Care, University of Calgary, Calgary, AB, Canada.

2Department of Medicine, University of Manitoba, Winnipeg, MB, Canada.

3Department of Medicine, University of Toronto, Toronto, ON, Canada.

4Center for Health Evaluation and Division of Critical Care Medicine, St. Paul’s Hospital and University of British Columbia, Vancouver, BC, Canada.

5Department of Intensive Care, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.

6Department of Medicine, Hackensack University Medical Center, Hackensack, NJ.

7Department of Medicine, Cooper Medical School of Rowan University, Camden, NJ.

* See also p. 2294.

This work was performed at University of Manitoba and University of Calgary.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (

Development of the existing database used for this study was supported in the past by unrestricted grants from Lilly, Wyeth, Pfizer, Merck, Astra-Zeneca, Astellas, Manitoba Health Research Council, Manitoba Health Sciences Foundation, and the Deacon Foundation.

Dr. Kumar’s institution received grant support from Astellas, Lilly, Pfizer, Merk, Bayer, GSK, and Roche (unrestricted grants). Dr. Marshall served as board member for Asahi Kasei Pharma America (Data Monitoring Committee Member, ART-123). Dr. Parrillo served as board member for Artisan, Sangart, and Cytosorbents. His institution received grant support from the Salem Foundation. The remaining authors have disclosed that they do not have any potential conflicts of interest.

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