Antimicrobials and Progression to Septic Shock in Severe Sepsis Patients: Is Delay the Only Thing That Matters?

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We read with great interest the article in a recent issue of Critical Care Medicine by Whiles et al (1), which investigated the role of timing of antimicrobial therapy on the progression to septic shock in a large cohort of patients with severe sepsis admitted to their hospital’s emergency department (ED). They reported an 8% increase in the chance of developing septic shock for each hour of delay between ED admission and administration of antimicrobials, and an increased in-hospital mortality.
Early, broad-spectrum antimicrobial therapy is a mainstay of sepsis treatment (2). The evidence underpinning its use is mainly derived from retrospective analyses of databases collected for other reasons. However, its importance has become quasi-dogmatic, notwithstanding contradictory evidence from prospective studies showing no effect on survival rates despite delays in commencing treatment of up to 4–5 hours (3, 4). That being said, we would exert caution in considering delayed antimicrobial administration as the main culprit of progression from severe sepsis to septic shock, as suggested by Whiles et al (1).
First, it is unclear whether any difference existed in the distribution of site of infection between patients who progress to septic shock and those who do not. Leligdowicz et al (5) reported that site of infection is associated with mortality. As this can be reasonably extrapolated to risk of progression to septic shock (which carries a higher mortality), this confounder may bias the results of their analysis.
Second, they provide no data regarding the adequacy of source control. This is a fundamental part of sepsis treatment and a determinant of survival (4, 6). Failure to achieve adequate source control could also have influenced the progression to septic shock, especially when penetration of the antimicrobial agent into the infectious focus is likely to be suboptimal.
Third, the authors described shock as need for a vasopressor after 3 hours from ED triage time. They did not apply the new Sepsis-3 definition (7), which considers lactate values crucial in operationalizing septic shock. Although they state that “…in addition to antibiotics inhibiting progression to septic shock, it seems that they do so in the sickest patients of the cohort…” (1), first lactate values were higher (p < 0.001) in those patients who progressed to septic shock. Would such patients, who already have cellular and metabolic abnormalities as exemplified by a raised lactate, not be more likely to develop shock anyway?
Lastly, the proportion of patients who develop septic shock was the same (approximately 20%) over each of the first five 1-hour intervals. An increase in the rate of progression to septic shock became evident only when antibiotics were delayed greater than or equal to 5 hours. This interval is significantly longer than the one recommended by Surviving Sepsis guidelines (2) and consistent with the results of the meta-analysis by Sterling et al (3).

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