In this study, we showed that RRSs have improved compliance with sepsis bundles for 10 years, and compliance of sepsis bundles was associated with reduced 28-day mortality in patients with septic shock in hospital wards. The compliance rate of the 3/6-hour bundle increased from 26.5–70.0% and the 28-day mortality decreased from 50.0–32.1% over 10 years. It was also confirmed that bundle completion, re-measured serum lactate levels, C-reactive protein levels, source control, and SOFA score were associated with 28-day mortality. In addition, obtention of blood cultures and lactate remeasurement among the detailed elements of the sepsis bundle were classified as factors associated with 28-day mortality.
One observational study conducted over 7.5 years in SSC reported a 3–5% decrease in in-hospital mortality for every 10% increase in bundle compliance (6). In addition, a large-scale retrospective study reported that a more rapid completion of the 3-hour bundle and the administration of broad-spectrum antibiotics were associated with higher in-hospital mortality among patients with severe sepsis and septic shock in the emergency department (3). Recently, the sepsis bundle core performance measure was rolled out in the centers for medicare and medicaid services inpatient quality reporting program beginning in 2015, with the aim of facilitating timely, high-quality sepsis care, and many studies on hospital-onset sepsis have been reported (8, 12, 13). According to a recently reported large cohort study, the compliance rate for bundles in community-onset sepsis was 40.1%, whereas it was only 12.2% in hospital-onset sepsis. The complete bundle was not associated with outcome in hospital-onset sepsis, and only early broad-spectrum intravenous antibiotic treatment among the bundle elements was associated with outcome (8). In addition, a retrospective cohort study demonstrated that although sepsis bundle failure was not associated with mortality, the overall compliance rate for bundles was only 33.0%, and this study included only 9% of hospital-onset sepsis cases (14). There is still controversy over whether or not the compliance of bundle reduces mortality due to in-hospital sepsis. Our study demonstrates that bundle compliance is associated with mortality in hospitalized patients with septic shock. A possible explanation for this might be that the overall bundle compliance rate in our study was found to be 58.3%, which is higher than that of previously reported studies on hospital-onset sepsis. Considering the high rate of bundle compliance in the emergency department, the difference in bundle compliance rate might have influenced.
In this study, we analyzed the factors associated with mortality among the detailed elements of sepsis bundles, which, contrary to expectations, the obtention of blood cultures was classified as one of the factors associated with 28-day mortality. There was no significant association between the administration of broad-spectrum antibiotics and outcome. A retrospective review study demonstrated that the time required for the completion of a 3-hour bundle and the administration of broad-spectrum antibiotics were associated with higher in-hospital mortality among patients with severe sepsis and septic shock in the emergency department (3). In contrast to patients staying in the emergency room, patients who are hospitalized often get worse with sepsis while they are already infected, and they are often already administering antibiotics. In this study, antibiotic administration in septic shock was performed in 96.3% of cases. However, no analysis on the appropriateness, addition, or change of antibiotics was conducted. In general, at the onset of sepsis, blood cultures should be obtained prior to antibiotic administration, as the obtention of blood cultures during antibiotic therapy is associated with the loss of clinically relevant pathogen identification (15). It might be important to determine whether the deterioration of patients already receiving antibiotic therapy for septic shock is a deterioration of the existing infection status, a mutation of the pathogens into antibiotic-resistant bacteria, or a new infection. Therefore, further research on whether identifying the causative bacteria needs to be carried out by conducting culture tests to identify new sources of infection rather than using antibiotics will lead to the optimization of antibiotics and improved survival rates.
In our analysis, another detailed element of the sepsis bundle associated with mortality in our study was lactate remeasurement and not initial lactate measurement. A possible explanation for this might be that that lactate clearance is associated with the outcome rather than the initial measurement of the level of lactate, reflecting tissue perfusion. This differs from the result of a previous study that reported that early lactate measurement among bundle items was associated with mortality in community-onset sepsis; however, lactate remeasurement was not included in the statistics and analysis in that study (8). A meta-analysis of four small randomized trials reported that the use of lactate clearance as an umpire to guide early therapy is associated with a reduction in the risk of death in adult patients with sepsis (16). Early lactate clearance-guided therapy was found to be effective in terms of significantly reducing mortality, shortening the length of ICU stay and duration mechanical ventilation, and reducing the Acute Physiology and Chronic Health Evaluation-II (APACHE-II) score (17). Lactate remeasurement within 2–4 hours is easy to forget because it is not included in the one-hour bundle of sepsis; however, this study suggests that it is necessary to check the repeated lactate level and perform additional treatment according to the lactate clearance.
This study has confirmed that the overall bundle compliance rate of septic shock continues to increase as the RRS continues to operate and matures. Although sepsis bundles consist of many simple elements, it is difficult to achieve all items in a fixed time. In a previous study, 1,647 out of 4,108 patients with community-onset sepsis achieved an overall compliance rate of 40.0%, while only 281 of 2,296 patients with hospital-onset sepsis achieved a bundle, showing an overall compliance rate of 12.2% (8). Rhee et al. reported that the cases in which sepsis bundles failed were more likely to have septic shock, hospital-onset sepsis, vague rather than explicit infectious symptoms, and non-pulmonary infections compared to cases that passed (14). Although sepsis 3 definition criteria have been announced, the diagnosis of sepsis is still equivocal, and clinical judgment of whether or not there is an infection is complicated (18). In addition, since vital signs are intermittently measured every 8–12 hours and laboratory tests are not routinely performed in hospital wards, the early detection of sepsis there is more difficult than it is in emergency or ICUs. SSC international guidelines have emphasized that hospitals should have a system for sepsis screening (4); however, existing studies lack analysis of systems. The RRS is equipped with a screening system that uses early warning scores or physiological parameters that include hemodynamic indicators; as such, it is used as an important tool for the early detection of sepsis patients. Our RRS is operating a 24-hour electronic medical recording (EMR)-based screening system, and we observed that 57.5% of patients with septic shock were triggered to RRS by the EMR-based screening system. Given that the detection of sepsis should lead to immediate treatment, these findings suggest the RRS as a sepsis team plays an excellent role in the early detection of sepsis and its early management in hospital wards.
This study has some strengths, among which is the fact that we have identified treatment performances and outcomes for septic shock patients in hospital wards. However, there are several limitations that hinder the generalizability of our results. First, this study was conducted on septic shock patients activated to the RRS due to clinical deterioration. It is hard to verify whether the delayed recognition or delayed management of sepsis in the ward caused the sepsis to deteriorate before the RRS was activated. The SSC recommends the performance of the bundle of sepsis if sepsis is suspected, which should be carried out before resorting to RRS, which is difficult to confirm through a record review due to the uncertainty of time zero and is beyond the scope of this study. However, questions about the initial treatment delay still stand. Second, the overall compliance rate in this study was higher than those of other studies because the time zero was clearly based on the RRS contact time assessed with sepsis. The criterion of “time zero” should be considered as the reason why the bundle compliance rate differs in many studies (19–21). It is difficult to objectively define the timing of sepsis recognition presented in the SSC, and the definitions of time zero in existing retrospective studies vary. In addition, it is difficult to determine whether the subtle change worsens sepsis, as patients who are hospitalized are already undergoing acute treatment, unlike those in emergency rooms. Therefore, setting the time zero of sepsis treatment also often depends on the clinical decision of the physician. This suggests the need for objective criteria for a clear time zero. Third, we evaluated the administration of antibiotics but not antibiotic adequacy or escalation to guidelines. In-hospital sepsis, antibiotics are often already being administered, so clear guidelines for proper antibiotics to be administered or escalated are required. Lastly, as with all retrospective studies, our findings are at risk for inherent factors in the analysis and interpretation of data.