1. Septic shock is a complication of infection with very high mortality rates.
2. This study was one of the first to demonstrate that delaying the provision of effective antimicrobial therapy in septic shock leads to significantly higher mortality rates.
3. It supported recommendations by international guidelines to initiate broad-spectrum, empiric antimicrobial therapy in the first hour after patients present with septic shock.
Original Date of Publication: June 2006
Study Rundown: Sepsis has been defined as a systemic inflammatory response that occurs due to an infectious process. Severe sepsis refers sepsis that is complicated by acute organ dysfunction, while septic shock is a term describing sepsis that is associated with persistent hypotension despite appropriate fluid resuscitation or elevated serum lactate levels. The worldwide incidence of severe sepsis and septic shock has been estimated at 19 million cases yearly. While mortality from severe sepsis and septic shock has decreased considerably over the past few decades, the risk of death remains high and has been estimated at approximately 20-30%, while those who survive often suffer from cognitive deficits and poorer quality of life.
At the time this study was published, numerous international guidelines recommended the initiation of antibiotics within an hour of presentation for patients in severe sepsis and septic shock, though no clinical evidence was available to support these calls. The purpose of this retrospective, multicenter study was to determine the link between the delay of starting antimicrobial therapy from onset of recurrent or persistent hypotension and mortality in patients with septic shock. In summary, this study was the first to provide strong evidence to suggest that delaying antimicrobial therapy in septic shock was associated with higher mortality. It supported numerous international guidelines in their calls to start broad-spectrum, empiric antimicrobial therapy within an hour of presentation of septic shock, as any delays were linked with lower survival.
In-Depth [retrospective cohort]: This study involved three cohorts of patients ≥18 years of age presenting with septic shock. The first cohort included all cases of septic shock admitted to any intensive care unit (ICU) in Manitoba, Canada from 1999-2004. The second cohort included all cases of septic shock between 1989 and 1999 at a single tertiary care institution in Winnipeg, Manitoba. The third cohort was composed of consecutive patients with septic shock between 1999-2004 from three academic institutions in the United States. Each case was screened to determine if it met criteria for septic shock as outlined in the 1991 Society of Critical Care Medicine/American College of Chest Physicians Consensus Statement on Sepsis Definitions, with no other evident cause of shock. For each patient, data regarding antimicrobial choice, actual time of initial parenteral administration, and survival were collected.
A total of 2731 cases of septic shock were identified. The overall mortality rate was 56.2%. A total of 2154 patients received effective antimicrobial therapy after the onset of hypotension, and these patients experienced a mortality rate of 58.0%. On the other hand, 558 received antimicrobials prior to developing hypotension and they experienced a mortality rate of 52.2%. Starting effective antimicrobials in the first hour after the onset of hypotension due to septic shock was linked with 79.9% survival to discharge. In the first 6 hours after developing hypotension, each hour of delay resulted in an average survival reduction of 7.6%. On univariate analysis, the delay between recurrent or persistent hypotension and effective antimicrobial therapy was a critical determinant of survival to both ICU and hospital discharge (p < 0.0001 for both). Assessing delay of starting antimicrobials as a continuous variable, the adjusted odds ratio of death was 1.119 (95%CI 1.103-1.136, p < 0.0001) for each hour of delay, suggesting that each hour of delay in starting antimicrobial therapy was associated with a 12% increase in mortality over the previous hour.
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