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Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock*

Kumar, Anand MD; Roberts, Daniel MD; Wood, Kenneth E. DO; Light, Bruce MD; Parrillo, Joseph E. MD; Sharma, Satendra MD; Suppes, Robert BSc; Feinstein, Daniel MD; Zanotti, Sergio MD; Taiberg, Leo MD; Gurka, David MD; Kumar, Aseem PhD; Cheang, Mary MSc

doi: 10.1097/01.CCM.0000217961.75225.E9
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Objective: To determine the prevalence and impact on mortality of delays in initiation of effective antimicrobial therapy from initial onset of recurrent/persistent hypotension of septic shock.

Design: A retrospective cohort study performed between July 1989 and June 2004.

Setting: Fourteen intensive care units (four medical, four surgical, six mixed medical/surgical) and ten hospitals (four academic, six community) in Canada and the United States.

Patients: Medical records of 2,731 adult patients with septic shock.

Interventions: None.

Measurements and Main Results: The main outcome measure was survival to hospital discharge. Among the 2,154 septic shock patients (78.9% total) who received effective antimicrobial therapy only after the onset of recurrent or persistent hypotension, a strong relationship between the delay in effective antimicrobial initiation and in-hospital mortality was noted (adjusted odds ratio 1.119 [per hour delay], 95% confidence interval 1.103–1.136, p < .0001). Administration of an antimicrobial effective for isolated or suspected pathogens within the first hour of documented hypotension was associated with a survival rate of 79.9%. Each hour of delay in antimicrobial administration over the ensuing 6 hrs was associated with an average decrease in survival of 7.6%. By the second hour after onset of persistent/recurrent hypotension, in-hospital mortality rate was significantly increased relative to receiving therapy within the first hour (odds ratio 1.67; 95% confidence interval, 1.12–2.48). In multivariate analysis (including Acute Physiology and Chronic Health Evaluation II score and therapeutic variables), time to initiation of effective antimicrobial therapy was the single strongest predictor of outcome. Median time to effective antimicrobial therapy was 6 hrs (25–75th percentile, 2.0–15.0 hrs).

Conclusions: Effective antimicrobial administration within the first hour of documented hypotension was associated with increased survival to hospital discharge in adult patients with septic shock. Despite a progressive increase in mortality rate with increasing delays, only 50% of septic shock patients received effective antimicrobial therapy within 6 hrs of documented hypotension.

From the Section of Critical Care Medicine, Health Sciences Centre/St. Boniface Hospital, University of Manitoba, Winnipeg, MB, Canada (AK, DR, BL, SS, RS); Section of Pulmonary and Critical Care Medicine, University of Wisconsin Hospital and Clinics, Madison, WI (KEW); Cooper Hospital/University Medical Center, Robert Wood Johnson Medical School, UMDNJ, Camden, NJ (JEP, SZ); St. Agnes Medical Center, Baltimore, MD (DF); Section of Pulmonary and Critical Care Medicine, Rush-Presbyterian-St. Luke's Medical Center, Chicago, IL (LT, DG); Laurentian University, Biomolecular Sciences Program and Department of Chemistry and Biochemistry, Sudbury, ON (AK); and Biostatistical Consulting Unit, Department of Community Health Sciences, University of Manitoba, Winnipeg, MB (MC).

Supported, in part, by unrestricted grants from Eli-Lilly, Pfizer, Merck, and Astra-Zeneca. Additional support was provided by the Health Sciences Centre Department of Research and Health Sciences Centre Foundation. Companies that provided partial grant support for this project had no role in study design; collection, analysis, or interpretation of data; writing of the report; or the decision to submit the work for publication.

Dr. Kumar has received honoraria for lectures from Eli-Lilly and Co. and Merck and Co. He has also received grant support for this project as noted. Dr. Light is a consultant for Eli-Lilly and Co. Dr. Parrillo has received research grants from GlaxoSmithKline for porcine/human research on sepsis; he also holds grants from Arginox, DeepBreeze, and Minimitter. Dr. Parrillo is also on Advisory Boards for Edwards, GlaxoSmithKline, and OrthoBioTech (Johnson & Johnson). The remaining authors do not have any conflicts of interest to disclose.

Address requests for reprints to: Anand Kumar, MD, E-mail:

© 2006 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins