Severe sepsis and septic shock are major healthcare problems worldwide, with high mortality and increasing incidence. Before the start of the Surviving Sepsis Campaign (SSC) in 2002, in the USA, there were 300 cases of severe sepsis per 100,000 population and 2.26 cases per 100 hospital discharges; half of those received intensive care. The overall rate of sepsis mortality was 28.6%; mortality increased with age, from 10% in children to 38.4% in those >85 years old. At an average cost of $22,100 per case, the total annual cost was $16.7 billion. The incidence was projected to increase by 1.5% per year.1 An epidemiological study in Spain, that analyzed the 2006–2011 National Hospital Discharge Registry, reported that overall incidence per year of severe sepsis was 86.97 cases per 100,000 population (increasing from 63.91 cases/100,000 population in 2006 to 105.51 cases/100,000 population in 2011) representing 1.1% of all hospitalisations and 54% of hospitalisations with sepsis. The overall mortality rate during the study period was 37.1 cases per 100,000 population with a significant decrease in mortality rates with an overall annual percent change of −3.24%,2 the incidence of severe sepsis attended in the Spanish ICU was 12.4% with high ICU and hospital mortality rates (48.2 and 54.3% respectively),3 with treatment costing around 500 million euros annually.4

In the past decade many studies have demonstrated improved survival in septic patients with early administration of appropriate antibiotics,5–8 lactate levels measurements,9 early goal-directed hemodynamic resuscitation,10 management with replacement doses of corticosteroids,11 glycemic control,12 drotrecogin alfa (activated) administration,13 and protective mechanical ventilation.14 These therapeutic advances were collected in the first Surviving Sepsis Campaign (SSC) guidelines15,16 with the intention to reduce sepsis mortality by 25% in five years. The progressive implementation of these recommendations achieved a progressive fall in mortality.17,18 An Spanish study showed that compliance with the resuscitation bundle is associated with improvement in survival in patients with severe sepsis/septic shock,19 also, in 2010, a meta-analysis of all studies comparing outcomes in patients who received bundled care vs. non protocolized care demonstrated a clear association between the use of bundles and lower mortality,20 even though most of the original recommendations in bundled care were changed after randomized controlled trials failed to confirm the efficacy of specific sepsis treatments (most of which conform the management bundle),21–26 as is reflected in the recently updated SSC guidelines.27,28

Two recent studies concluded that there has been a secular decrease in severe sepsis mortality. One study analyzed patients pooled from the control groups of 36 randomized controlled trials investigating severe sepsis and compared the 28-day mortality with patients in the administrative Nationwide Inpatient Sample database.29 The other study analyzed hospital mortality due to severe sepsis from a large database of patients in Australian and New Zealand intensive care units (ICU).30 Both studies found 1–3% annual improvement in crude severe sepsis mortality. The mechanism underlying this decline is unclear, but is probably related to improved processes of care.

The Edusepsis study evaluated the impact of a nationwide quality improvement intervention in Spain based on the SSC guidelines, showing an improvement in compliance with treatment recommendations accompanied by a reduction in mortality.31 However, not all the effects of the intervention were sustained; for example, early use of antibiotics decreased in the long-term follow-up. This is especially relevant considering an analysis of the impact of individual components of the resuscitation bundle on mortality in the Edusepsis study found that early empirical antibiotic administration was the most important factor.4 As in other time-dependent pathologies, in sepsis the timeliness and appropriateness of treatments administered in the first hour after the onset of disease can influence outcomes. For all these reasons, a new study was designed to focus specifically on educational interventions about early administration of empirical antibiotics in severe sepsis and septic shock (ABISS-Edusepsis study). Both the original Edusepsis study and the ABISS-Edusepsis study employed a “control group” documented before the educational interventions.

The primary objective of the study was to analyze the evolution of sepsis-related mortality in Spanish ICUs since the introduction of the Surviving Sepsis Campaing (SSC) guidelines and the relationship with the improvement of sepsis process-of-care. The secondary objective was to analyze the evolution of sepsis process-of-care by using the sepsis resuscitation bundle.

Data from the 41 ICUs participating in both studies were included. All ICUs were medical-surgical and most (86%) were in teaching hospitals training residents. No patients were excluded.

Change in compliance with bundle items over time

Rates of compliance with resuscitation bundle items increased between the two periods. Compliance with the resuscitation bundle increased from 5.7% in the 2005 group to 9.9% in the 2011 group (p=0.005). Fig. 1 shows compliance with the items in the resuscitation bundle. In 2005, the only two items in the resuscitation bundle for which compliance was higher than 50% were blood extraction for cultures before antibiotic administration (54.8%) and early administration of broad spectrum antibiotics (68.3%); compliance with these two items was similar in 2011. Compliance with the other 4 items was lower than 50% in 2005 and improved significantly in 2011.

Figure 1.

Resuscitation bundle, accomplished within 6h.

Abbreviation: CVP: central venous pressure; ScvO2: central venous oxygen saturation; ATB: antibiotic.

(0.11MB).

We assessed whether sepsis-related mortality in Spanish ICUs has decreased since the introduction of the Surviving Sepsis Campaign (SSC) guidelines and whether decreases are attributable to bundle compliances and other improvements in sepsis care. We found that compliance with the 6-h and 24-h bundles improved and that 28-day and hospital mortality decreased in this 6 years period, suggesting a sustained effect of the SSC moreover, this reduction in hospital mortality remained significant after adjustments. We also found that compliance with the resuscitation bundle are independent protective factors for mortality. Our results are consistent with recent clinical trials, where the mortality due to septic shock was around 24–26%,32 and with epidemiological studies that show a declining trend in severe sepsis mortality over time.2,33 We found that 28-day mortality and hospital mortality decreased despite an increase in predicted mortality as evidenced by higher APACHE II scores; these results corroborate those reported in Stevensons et al.’s29 meta-analysis and Kaukonen et al.’s30 large epidemiological study. A recently published study of a collaborative change intervention aimed at facilitating adoption of SCC bundles in 218 hospitals over 7.5 years found compliance improved over time and increased compliance is associated with decreased mortality.34

The dramatic decrease in sepsis mortality between 2011 and 2005 probably is multifactorial. Increased bundled care is playing a role but the lack of change in adjusted mortality between Model II and III is suggesting that other uncontrolled factors are also important. Probably, implementing the SSC guidelines beginning in 2005 resulted in earlier diagnosis (reflected in the increased proportion of sepsis diagnosed in the emergency department), and lower treatment variability both among clinicians and within clinicians between patients.35 According to Kaukonen et al.30 perhaps there are other reasons we have not controlled in our study (better source control, more adequate empirical antibiotic therapy, earlier transfer to ICU, better overall management of the septic patient, dissemination of protocols, greater expertise of health workers, increased sensitivity for this disease, greater involvement of health institutions, etc.), that also affect the drop in mortality over time. In addition, in a recently published study36 was described a number of factors associated with in-hospital mortality among patients with severe sepsis or septic shock (age, active cancer, diabetes, DNR status on ED arrival, lack of fever, hypoglycemia, and intubation) despite receipt of early protocolized resuscitation in the ED, providing insights into aspects of early sepsis care that can be targets for future intervention.

Most process-of-care indicators improved over time, but compliance with two recommended tasks (acquiring blood cultures before antibiotic administration and broad-spectrum antibiotics administration before 3h) did not change. In the 2005 group, these were the two items in the resuscitation bundle with the highest compliance (54.8% and 68.3%, respectively), improved compliance with these tasks should have an important impact on mortality.9,13 Miller et al.35 underlined the importance of these early interventions when they reported that compliance with early resuscitation bundle items was associated with a lower probability of being eligible for later resuscitation and maintenance bundle items, probably reflecting lesser severity due to the improvements brought about by the early treatments.

A recent multicenter cohort study conducted in Holland37 showed that the implementation of a national program sepsis resulted in improved adherence to sepsis bundles in severe sepsis and septic shock patients and was associated with reduced adjusted in-hospital mortality only in participating ICUs, suggesting direct impact of sepsis screening and application bundle on in-hospital mortality. Our study demonstrated improvements in hemodynamic resuscitation over time. However, recent trials in patients with septic shock failed to demonstrate any benefit of protocolized resuscitation when compared with “usual care”.38–41 Although no consensus exists among clinicians regarding optimal hemodynamic monitoring and to date no method has proven superior, the “usual care” in these trials includes early identification of septic patients, early antibiotic treatment, and early volume resuscitation measures. The improvement in hemodynamic resuscitation between the two periods in our study is probably due to earlier resuscitation more than greater protocolized resuscitation. One of the most important changes between the two periods was the place where sepsis was diagnosed. The proportion of cases diagnosed in the emergency department increased from 42.5% in 2005 to 72.3% in 2011, and the proportion of cases diagnosed in the wards decreased from 44.1% in 2005 to 22% in 2011. These findings indicate earlier detection of sepsis and hence earlier initiation of treatment. Importantly, in the above-mentioned studies38–41 comparing “usual care” with protocolized resuscitation, all cases of septic shock benefited from early detection and initiation of treatment, so perhaps earlier diagnosis and treatment rather than differences in how treatment is administered is what determines prognosis. We agree with Levy42 that the priority should be to establish systems to identify and treat septic patients early.

On the other side, there are several differences between the 2 cohorts: the 2011 group had a higher rate of urinary tract infection and lower rate of respiratory dysfunction (associated to lower mortality), but also those patients were older and had higher APACHE II score (associated to higher mortality); we cannot discard that, despite the adjustments, those differences in the case-mix also influences the difference in mortality.

Our study shows several limitations, the participation in both studies was entirely voluntary, and the hospitals that participated are not necessarily representative of those that did not participate; therefore, our findings may not be generalizable. The length of study periods, its nonrandomized design and the lack of control group precludes establishing a causal connection between the improvements in process-of-care variables and outcomes. Thus, although we observed a better compliance with most of the resuscitation bundle in 2011, related with a decrease in mortality, these findings do not necessarily imply a causal relationship between the compliance with sepsis bundles and outcomes.

Moreover, our study was limited to patients admitted to the ICU, and we cannot know how possible improvement in process-of-care variables in other areas of the hospital affected outcomes.

Finally, the latest SSC guidelines reflect some changes in the standard of care at the time of our study, such as the use of hydroxyethyl starch or drotrecogin alfa (activated). Considering these changes actually strengthens conclusions drawn from our results.

In conclusion, the mortality related to severe sepsis/septic shock in Spain, between two cohorts of patients in 2005 and 2011, decreased dramatically attributable to earliness and improvements in sepsis care, including higher compliance with resuscitation bundle. Nevertheless, compliance with some important items of the resuscitation bundle have not improved enough; early administration of effective antimicrobials could further improve outcomes.

Baltasar Sánchez: data analysis, drafted, translated and corrected the manuscript.

Ricard Ferrer: national coordinator, study design, data analysis, drafted, translated and corrected the manuscript.

David Suárez: database development, data analysis, corrected the manuscript.

Eduardo Romay: data collection, corrected the manuscript.

Enrique Piacentini: site coordinator, data collection and corrected the manuscript.

Gemma Gomá: data collection and corrected the manuscript.

María Luisa Martínez: data collection and corrected the manuscript.

Antonio Artigas: project coordinator, drafted and corrected de manuscript.

This work was supported by Instituto de Salud Carlos III: PI10/01497 and CM12/00066.

The authors declare no conflict of interest.