Severe sepsis is one of the most common diseases in hospitals, especially in intensive care units (ICU).1 Recent epidemiological studies demonstrate that its incidence is increasing,2 surpassing other diseases such as stroke, cancer, or myocardial infarction. In addition to resulting in a significant consumption of resources, this disease has a high mortality rate, which in the case of septic shock can reach figures around 50%.3,4 Although until just a few years ago antibiotics were the cornerstone of sepsis treatment, and bearing in mind their great importance, it has been seen that the chances of surviving this condition depend in large part on getting an early diagnosis and starting an appropriate treatment approach early, since it is a time-dependent disease.5,6 Since Rivers et al.7 published their paper in 2001, which demonstrated how an early and “aggressive” intervention in the first 6h consisting of following an action protocol guided by specific clinical targets decreased mortality by 16%, successive guidelines and recommendations for the clinical management and treatment of patients with severe sepsis or septic shock have been published worldwide; the last main example was the project known as the Surviving Sepsis Campaign,8 with the aim of decreasing sepsis mortality by 25%.

There is sufficient scientific evidence to assert that the early and targeted application of these diagnostic/therapeutic measures (bundles) significantly increase survival and decrease both the hospital stay and healthcare costs.9 However, despite publicity and educational campaigns, the degree of compliance with these measures continues to be low in most hospital settings. A recent paper by Ferrer et al.10 demonstrated how the management and treatment measures in the first 6 and 24h recommended by the guidelines were only taken in 10% and 15.7% of cases, respectively. This fact translated to a slight decrease in the mortality and resource consumption figures, far from the expectations put forth by the Surviving Sepsis Campaign. Since delays in diagnosis, initial resuscitation, administering the right antibiotic therapy, and controlling the focus of infection raise the incidence of organ failure, mortality, hospital stay, and resource consumption,11,12 and also knowing that the degree of compliance with the recommended measures for the initial management of sepsis is low, in recent years different hospitals have started organising multidisciplinary work groups for comprehensive severe sepsis management. In our centre, the Sepsis Code Working Group (SC-WG) was created in 2011. It is a multidisciplinary group with the aim of recognising and treating severe sepsis and septic shock early by implementing a series of interventions: training and information sessions, drafting action protocols and software help tools, as well as creating records in a database (Fig. 1).

Figure 1.

Diagram of the basic objectives of the Sepsis Code programme.

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This paper analysed the effects of implementing a Sepsis Code Hospital Protocol (SCHP) for the critical patients admitted to the ICU with a diagnosis of severe sepsis or septic shock. The primary objective is to analyse the changes in the profile and appropriateness of the antibiotic therapy used and, secondly, to analyse the differences in the clinical outcomes between the two study groups.

The Hospital Clínico Universitario de Valladolid SC-WG was established in May 2011 with the aim of creating, spreading, and implementing a hospital improvement plan for providing comprehensive care for patients with severe sepsis and/or septic shock (Fig. 1). The SC-WG is formed by a select group of physicians from different specialties and nursing staff. The actions that were carried out included implementing an educational and information programme with several training sessions in medical and nursing departments, creating clinical action guidelines on septic patients in both a paper and electronic format (diagnosis algorithms, severity staging, decision and treatment trees on leaflets and posters, etc.), initial antibiotic therapy guidelines in severe sepsis and septic shock, infection focus control guidelines, collection, handling, and transport guidelines for biological samples for culture, drug preparation and administration guidelines, as well as a rapid dispensation system for antibiotics. Moreover, a software application integrated into the hospital intranet and a digital registry for including and following patients included in the SCHP were designed (Fig. 2).

Figure 2.

Specific actions of the Sepsis Code programme.

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This work demonstrates how a relatively economic intervention, albeit with significant human effort, such as implementing actions and tools aimed at improving the diagnosis and treatment of severe sepsis and septic shock by creating the SC-WG not only promoted a direct decrease in the mortality figures, but also better optimised antibiotic prescriptions, and interestingly a trend towards a shorter stay in the ICU.

The multidisciplinary nature of a project with this characteristics poses significant challenges concerning efficient teamwork, the dynamic, and group relations, cooperation, communication, and information exchange, and entails a significant endeavour for in-hospital training and information sessions. The primary objective for creating multidisciplinary SCHP teams is not only to apply the best evidence-based treatments (fluid therapy, sample collection for culture, antibiotic therapy, and early focus control, etc.), but to also optimise resources, avoid interprocedure variability, promote the spread of best practices, improve care and patient safety, as well as establish suitable care staging (placing the patients in the most appropriate place based on their severity at any given time) to, in the end, create a registry of the outcomes and analyse the programme's efficiency (Fig. 1). Therefore, the primary purpose is to decrease the high mortality rate associated with this disease, while other objectives, such as better optimisation of resource consumption resulting from this disease, are also achievable, as demonstrated in this study.

Some studies in the medical literature have already demonstrated the possibility of achieving the objective of decreasing mortality by implementing the use of bundles.16,17 However, the repercussions of implementing the SCHP programmes on antibiotic treatment optimisation had not been analysed until now. This optimisation would consist of improving and rationalising the antibiotic consumption and prescriptions through measures such as establishing more appropriate and rational antibiotic coverage, early antibiotic de-escalation, selecting the appropriate drug, and personalised treatment adjustments.

In this sense, this paper is innovative, since it analyses this relationship and shows satisfactory results. So it demonstrates a decrease in the use of the linezolid/carbapenem combination as an empirical treatment in the post-intervention period on the one hand, while a very significant increase in the antibiotic de-escalation rate was observed during the post-SC period on the other. The first studies on antibiotic “de-escalation” were conducted in critical patients with nosocomial pneumonia. One of these studies, conducted in 24 Spanish ICUs prospectively analysed 244 pneumonia patients treated empirically with imipenem plus aminoglycoside or vancomycin, and no influence from the de-escalation was observed on mortality.18 However, in a recent study by Garnacho-Montero et al., antibiotic therapy de-escalation in a population of 628 patients with severe sepsis or septic shock was independently correlated with a lower in-hospital 28-day mortality rate.19 In our case, the BLR analysis did not demonstrate that de-escalation was a variable that was correlated with mortality. The limited sample size could have affected this finding.

In terms of antibiotic consumption, a statistically significant decrease in the number of days under antibiotic therapy in the ICU was observed after implementing the SC, likely in relation to the shorter intra-ICU stay. Nevertheless, no differences in the total number of DDD/100 stays were observed for severe sepsis/septic shock patients in the ICU between the two periods. This means that the number of patients who were exposed to antimicrobial treatment for every 100 stays was similar after the SC was implemented. This value is similar to that presented by other centres in this type of patient.20 In contrast, differences were observed in the consumption of certain antibiotic groups after implementing the SC. The use of antibiotics against resistant gram-positive bacteria decreased in 17.3% of the DDD/100 stays, as did the use of macrolides, which decreased in 22% of the DDD/100 stays. The more than two-fold increase in the consumption of piperacillin-tazobactam vs the PRE-SC group is also noteworthy. These data reflect a reduction in the antibiotic spectrum used after implementing the SC. It is worth pointing out that the DDD is a unit of measurement that does not necessarily reflect the daily recommended or prescribed dose, since these are based on individual characteristics (age, weight) and on pharmacokinetic considerations, especially in critical patients. The consumption data expressed in DDD provide an approximate estimate and not an accurate picture of their real use.

Regarding the clinical outcomes from the patients studied after implementing the SCHP, it should be noted that although the intra-ICU and in-hospital mortality figures in the post-SC period are similar to those from other recent series,2,21–23 they are significantly lower than the ones in our centre prior to implementing the programme. In fact, the multivariate BLR model demonstrates how implementing the SCHP was, along with the APACHE II score and the presence of septic shock at admission, the only variable independently associated with in-hospital and 28-day mortality, such that the risk of a septic patient dying was more than 3-fold higher in the pre-SC period than in the post-SC period. This is logical, since applying a SC promotes education about diagnosing the disease early as well as implementing measures earlier such as administering antibiotic therapy, vigorous fluid therapy, controlling the focus, extracting cultures, better risk staging, etc., in the early hours of the disease, measures which alone have been demonstrated to improve the prognosis for this condition if they are optimally carried out. It is logical that implementing all these measures also translates to a decrease in the intra-ICU and/or in-hospital stay, as the results from this study suggest. It should be mentioned that during both periods no other intervention was performed on this group of patients that could justify these findings.

This study has some limitations that should be pointed out: the main one is that it is not a prospective trial, but rather a retrospective comparison of the effect of implementing the SC with a historical cohort from before it was implemented in a limited number of patients. No other laboratory data were collected, not even regarding treatments other than the antibiotics (doses of amines, corticosteroids, need for renal support therapy, etc.). Furthermore, the increase in gram-negative infections that occurred in the second study period may have partially influenced the results by decreasing the consumption of linezolid, although it is true that this drug was mainly used empirically, when the microbiology results were not yet available to guide the treatment.

In summary, the SC-WG's implementation of actions and tools aimed at better diagnosis and treatment for severe sepsis and septic shock not only contributed to an optimisation of antibiotic prescriptions, but also to a decrease in-hospital and 28-day mortality figures, and a trend towards a shorter intra-ICU stay.

Although larger, multicentre studies with a higher number of patients are necessary to confirm these findings, undoubtedly the presented results should motivate and bring about the creation of multidisciplinary work groups to promote establishing SCHP programmes in all our healthcare centres.

This study was conducted within the grant programme to increase research activity awarded by the Castilla and Leon Regional Health Authority for the year 2016.

LGL, SGC, and DAO coordinated the study design. LGL, FBD, RCG, FDG, and DAO participated in collecting and analysing the data. LGL reviewed the patients’ medical records. LGL, SGC, AFS, and TSS performed the pharmacoeconomic analysis. MFM and DAO performed the statistical analysis on the clinical and survival endpoints. Lastly, LGL, SGC, DAO, and FGM drafted and wrote the manuscript.

The authors declare that they have no conflicts of interest.