Timing of antibiotic administration for patients with sepsis has been identified as a key factor associated with survival. Several studies have demonstrated the association between delay in antibiotic administration and increased risk of mortality in patients with both sepsis (formerly “severe sepsis”) and septic shock (1–8). Despite some conflicting evidence, the weight of published studies has led the Centers for Medicare and Medicaid Services to incorporate administration of antibiotics within 1 hour of the identification of sepsis into the national, mandated public reporting initiative (9, 10).
In this issue of Critical Care Medicine, Seymour et al (11) ask and study a very important question: When does the risk of delay in antibiotics really start: In the emergency department (ED) or when sepsis patients (or their caregivers) first seek medical attention by calling for assistance in transport to the hospital? The “time zero” often used as the baseline in studies evaluating the relationship between antibiotic delay and outcomes is that of recognition—in the ED—of sepsis and septic shock (12). This “time zero” is, without doubt, an arbitrary reference point when, in actuality, the episode of sepsis certainly started before that time. Seymour et al (11) performed a sophisticated analysis based on their previously published methodology that evaluated the relationship between several prehospital time periods and mortality from sepsis. Of importance, a multivariable analysis, which was adjusted for potential confounders, demonstrated a statistically significant relationship between “total medical contact” and each hour delay in antibiotic administration. In addition, the authors establish a more granular view of the delay between a call to 911 and arrival in the ED by dividing that period into response delay and prehospital delay. “Total system delay” was divided into response delay, prehospital delay, and ED delay. The importance of these new terms rests in the fact that they may provide targets for future quality improvement studies.
What from this study can we apply to our practice related to antibiotic administration? Most importantly, this study confirms that any delay in antibiotic administration to a septic patient is associated with a higher risk of death. This study extends that delay to the furthest point yet identified: the time that the ambulance arrives at the door of a patient home or skilled nursing facility to pick up a patient with sepsis. Clearly, the true “time zero” begins even before that moment, but this study lays the ground for establishing a new, earlier time zero than had previously been used when a call for help is made. If a delay in antibiotic administration is associated with increased mortality when the timing starts at the ED door, then it stands to reason that the association between antibiotics delay and unfavorable outcome starts well before that moment. This may provide new targets for both clinical trials and quality improvement efforts. No longer can we focus only on improving process within the walls of the hospital. If the results of this study are confirmed by further prospective trials, attention must be focused on prehospital delays.
The authors conducted several important sensitivity analyses, all of which confirmed the initial results. Even when different criteria were used to define infection and organ dysfunction (qualified Sepsis-Related Organ Failure Assessment vs Sepsis-Related Organ Failure Assessment vs Surviving Sepsis Campaign criteria, including lactate), the results did not change. Therefore, whether or not an individual or institution applies the recently published definitions of sepsis, the results of this study remain valid.
Although the association between individual portions of “total medical contact” and mortality was not significant (most importantly, prehospital delay), the reduced power of analysis of individual elements because of the relatively narrow distribution of prehospital time likely precluded the demonstration of significance in the analysis. Therefore, despite the lack of statistical significance, we cannot infer that prehospital delay is less important than the delay of antibiotic administration in the ED.
One of the primary weaknesses of the study, as identified by the authors, is that the included patients were only those who were transported to hospitals by emergency medical services (EMS); not those patients arriving at the ED on their own or brought by their loved ones. Therefore, it is likely that the study population represents a group of patients more severely ill; thus, this study cannot be generalized to a broader population of septic patients.
As stated by the authors, many obstacles to the prehospital diagnosis of sepsis remain (13). The challenge, of course, includes precise methods and markers for early diagnosis of infection and organ dysfunction. Until robust, established markers for identifying these patients exist, operationalizing the results of this important study is premature. For now, this study provides the basis for monitoring the total time delay in antibiotic administration from a 911 call to arrival in the ED as a means to benchmark delays across institutions with an eye toward future quality improvement efforts. Such efforts should be based on robust, randomized clinical trials that demonstrate a clear survival advantage for earlier, prehospital treatment of patients suspected of sepsis.
An additional interesting question for future trials may be to evaluate routine screening in institutions from which many sepsis patients come to the hospital, such as long-term care facilities and skilled nursing facilities. Perhaps, the time zero can be redefined to include even earlier time points closer to the onset of infection and sepsis rather than the time when patients’ conditions have deteriorated to the point they require transfer to hospital.
The next question to be answered is whether clinical trials can be designed to prospectively test the hypothesis generated in this current study: will earlier administration of antibiotics—perhaps beginning on arrival of the EMS crew—be feasible and associated with improved survival or will the earlier administration of antibiotics be associated with unanticipated untoward effects. This study provides the basis for addressing this important question.
1. Ferrer R, Artigas A, Suarez D, et al; Edusepsis Study Group: Effectiveness of treatments for severe sepsis: A prospective, multicenter, observational study. Am J Respir Crit Care Med 2009; 180:861–866
2. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006; 34:1589–1596
3. Ferrer R, Martin-Loeches I, Phillips G, et al. Empiric antibiotic treatment reduces mortality in severe sepsis and septic shock from the first hour: Results from a guideline-based performance improvement program. Crit Care Med 2014; 42:1749–1755
4. Zhang D, Micek ST, Kollef MH. Time to appropriate antibiotic therapy is an independent determinant of postinfection ICU and hospital lengths of stay in patients with sepsis. Crit Care Med 2015; 43:2133–2140
5. de Groot B, Ansems A, Gerling DH, et al. The association between time to antibiotics and relevant clinical outcomes in emergency department patients with various stages of sepsis: A prospective multi-center study. Crit Care 2015; 19:194
6. Barie PS, Hydo LJ, Shou J, et al. Influence of antibiotic therapy on mortality of critical surgical illness caused or complicated by infection. Surg Infect (Larchmt) 2005; 6:41–54
7. Gaieski DF, Mikkelsen ME, Band RA, et al. Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department. Crit Care Med 2010; 38:1045–1053
8. Kumar A. Systematic bias in meta-analyses of time to antimicrobial in sepsis studies. Crit Care Med 2016; 44:e234–e235
9. Sterling SA, Miller WR, Pryor J, et al. The impact of timing of antibiotics on outcomes in severe sepsis and septic shock: A systematic review and meta-analysis. Crit Care Med 2015; 43:1907–1915
11. Seymour CW, kahn JM, Martin-Gill C, et al. Delays From First Medical Contact to Antibiotic Administration for Sepsis. Crit Care Med 2017; 45:759–765
12. Levy MM, Dellinger RP, Townsend SR, et al. The Surviving Sepsis Campaign: Results of an international guideline-based performance improvement program targeting severe sepsis. Intensive Care Med 2010; 36:222–231
13. Amaral AC, Fowler RA, Pinto R, et al; Cooperative Antimicrobial Therapy of Septic Shock Database Research Group: Patient and organizational factors associated with delays in antimicrobial therapy for septic shock. Crit Care Med 2016; 44:2145–2153
antibiotics; quality improvement; sepsis; timely