Sepsis is one of the main problems of public health and constitutes one of the most frequent causes of hospital admission, multiple system organ dysfunction, and mortality worldwide (1, 2). Its incidence is rising and it implies important costs for national health systems and also develops serious sequelae and impairment in the quality of life in survivors (1–5). In the United States, its incidence is 750,000 cases/year with 215,000 attributable deaths annually (1, 2). In Europe, severe sepsis (SS) and septic shock (SSh) constitute 25% of all intensive care unit (ICU) admissions (6). In Spain, the population-based incidence is also high, with 25 cases/100,000 population/year of SS attended in ICU (7, 8). It seems that worldwide mortality has been decreasing over the past decade, ranging from 18% to 54%, with differences between regions in several reports (9).
The awareness of SS had been very low for years (10). This prompted the jointly development by several international scientific societies of the global initiative “Surviving Sepsis Campaign” (SSC). SSC was aimed at reducing mortality from SS and SSh by setting recommendations grouped into “bundles” based on early recognition, early use of antibiotics, early-goal-directed therapy resuscitation protocol (EGDT), and early supportive care in the ICU (11–13). The last update edition was published in 2013 and reviewed in 2015 (14–17). As part of this awareness, a nationwide educational campaign called EDUSEPSIS was conducted in Spain in 2005 and 2006 aimed at improving the compliance with the SSC recommendations and to determine how it might affect overall in-hospital mortality (18). As a result, compliance with the bundles improved and mortality decreased. The improvement of relevant outcomes has been confirmed and validated in several other studies, but the long-term adherence to its recommendations remains low (19–22).
The purpose of this study was to determine the long-term adherence to the recommendations of the SSC after a period of 5 years of the educational campaign EDUSEPSIS. We also examined whether this educational campaign resulted in significant changes in several clinically relevant associated outcomes.
This study was approved by the Ethics Committee of the coordinating center (Hospital Universitario Río Hortega, Valladolid, Spain) and by the Institutional Review Boards of all participating hospitals. Signed informed consent of the patient or his next of kin was required for participation.
Study design, data collection, and outcomes
This was a prospective, observational, multicenter cohort study conducted in a network of 11 medical-surgical ICUs in 10 hospitals of Spain for a period of 5 consecutive months (February to June, 2011) [The characteristics of the ICUs and hospitals are shown in Table S1, Supplemental Digital Content 1, at https://links.lww.com/SHK/A357]. Sepsis was defined according to the 2001 International Consensus Conference criteria (23). SS was defined as sepsis plus the presence of at least one organ dysfunction, hypoperfusion, or hypotension. SSh was defined as sepsis plus hypotension refractory to volume infusion and need of vasoactive drugs. All patients admitted to the ICU for or who developed SS or SSh after admission were considered for enrollment into the study. Screening of SS/SSh was performed in all patients upon admission and daily afterward. Patients under age 18 and those admitted for ischemic heart disease or cardiac rhythm disorders were excluded.
Demographics and clinical variables were recorded. Severity and organ failure scores were recorded using the Acute Physiology and Chronic Health Evaluation II score (APACHE II) and Sequential Organ Failure Assessment score (SOFA). Organ dysfunction was defined as scores 1 or 2, and organ failure as 3 or 4 in the SOFA score. The evolution of organ failure was determined by sequential measurement of SOFA score on days 0 to 7 (D0-D7), 14 (D14), and 28 (D28). We also calculated Delta SOFA D0-D3 and D1-D3. Day zero (D0) was defined as the date at the time of diagnosis until 12:00 AM of the next day. Fulfillment of each element of the bundles was considered “all or nothing,” according to accomplishment or not within the time required. The treatment of each patient was left to the discretion of the attending physician. Patients were classified into different categories according to patient location at the time of diagnosis, and the origin and source of the infection. The source control options varied among the different hospitals and were not specifically recorded.
We examined the degree of compliance with the SSC recommendations or bundles of resuscitation in the first 6 h (B6H) and management in the following 24 h (B24H). This study was conducted before the withdrawal of activated protein C (APC) from the market (Table S2, https://links.lww.com/SHK/A357).
We also recorded mortality in the ICU, at 28 days and in-hospital, and ICU and hospital length of stay (LOS). Data were collected on standardized forms that were sent to the coordinating center after completion for checking. A specifically designed database was built for the analysis.
Continuous variables are expressed as mean ± standard deviation (SD) or median (interquartile range), and compared using t test and Mann–Whitney U test, as appropriate. Categorical variables are expressed as frequencies and percentages with 95% confidence interval (CI), and for comparison chi-squared test was used. The results of the current cohort (GRECIA 2011) were compared with the ones obtained from a historical cohort of patients, the EDUSEPSIS cohort (18), collected in 2006 (EDUSEPSIS CyL2006) by the same group of ICUs participating in the current study.
We assessed the impact of bundles on ICU and in-hospital mortalities by using logistic regression. Crude and adjusted odds ratios (OR) of each variable were estimated. A saturated model using all control variables was built, and variables that did not change the coefficient of the bundles’ elements >10% were discarded to achieve the most parsimonious model retaining all important confounders. To assess the weight of the interventions in the bundle, we performed the process described by Castellanos-Ortega et al. (20) removing a single intervention in the whole bundle and assessing the mean effect on mortality of the rest of the bundle. All analyses were conducted using Stata 11.1 (Stata Corporation, College Station, TX). All tests were two-tailed with a significance level of P <0.05.
A total of 1,874 patients with no-exclusion criteria were admitted to the participating ICUs during the study period. Finally, 231 episodes in 229 patients were included for analysis. One hundred seventy-six episodes were septic shock (76.2%). We obtained an ICU incidence of SS/SSh of 14% (CI 95% 12.5–15.2) (see Fig. 1). The characteristics of septic episodes are reported in Table S3, https://links.lww.com/SHK/A357.
A total of 217 episodes of SS/SSh were included in the historical cohort EDUSEPSIS 2006, with no differences in demographic characteristics and categories compared with the current cohort. APACHE II scores showed no statistically significant differences between the two cohorts. Patients come more frequently from the Emergency Department prior to the ICU admission with no differences regarding origin (intra-ICU vs. extra-ICU) of the SS/SSh episode. There were no differences in origin and main location of infection, being the lung and abdominal cavity the most frequent. The proportion of urinary tract infections was similar (Table 1).
We observed a better compliance for the whole B6H bundle in the GRECIA 2011 cohort (27.3% vs. 9.7%; P < 0.01), although the overall degree of compliance remained low. The tasks with more than 90% compliance included administration of broad spectrum antibiotics, intravenous fluids, and vasopressors. The recommendation with less accomplishment was measuring SvcO2 and reaching values >70%, but a significant absolute increase of 25.7% was observed compared with the historical cohort (37.8% vs. 12.2%, P < 0.01).
Regarding the B24H, compliance with all tasks in the GRECIA 2011 cohort was significantly lower than in the EDUSEPSIS CyL2006 cohort (4.3% vs. 12.9%, P < 0.01). A plateau pressure <30 cmH2O was the individual measure with better compliance (81.5%), no significantly different to EDUSEPSIS CyL2006. Compliance with corticosteroid administration increased, close to statistical significance (52.8% vs. 43.6%, P = 0.06). Regarding APC administration, compliance was very low (13%) and no differences were found between the two cohorts (Table 2).
Mortality and LOS
Patients in the GRECIA 2011 cohort had an absolute 10.2% lower ICU mortality (27.1% vs. 37.3%; P = 0.02), and an absolute 8.6 % lower in-hospital mortality (36.7% vs. 45.3%, P = 0.06). There were no differences in early and 28-day mortalities. No differences were observed regarding ICU LOS. Longer hospital stay was observed in the GRECIA 2011 cohort due to a longer stay in non-survivors [14.7 days absolute difference (P < 0.01)] (Table 3).
Relationship between bundles compliance and outcomes
Overall compliance with the B6H in the joint analysis of the two cohorts was achieved in only 73 (15.8%) patients. Since mortality was similar in those patients in whom compliance with ≤3 tasks was achieved, we decided to group them into different categories using zero to three tasks completed as the reference category and to compare it with four, five, and six tasks completed. We observed a reduction in ICU mortality with four or more tasks completed for both crude and adjusted OR for APACHE II in the multivariate analysis, achieving the greatest reduction with six tasks completed [OR (95%CI): 0.24 (0.12–0.51)]. This risk reduction occurred linearly with the number of tasks completed, suggesting an additive beneficial effect. Reduction of in-hospital mortality also reached statistical significance with four completed tasks (P = 0.04) in the same linear fashion. Compliance with the whole B6H showed the greater risk reduction [adjusted OR (95% CI) of 0.51 (0.27–0.97)].
Regarding compliance with B24H, the results were not so favorable. Total compliance was limited in the two cohorts (19 patients) and most patients only achieved one or two tasks completed (286 patients, 63.8%). When we grouped compliance with zero to one task in a single category and compared it with at least two tasks completed, we observed a higher mortality (both crude as adjusted for APACHE II) when more number of tasks were completed, with a significant linear trend in the multivariate analysis for ICU mortality (P < 0.01). This finding was also seen for in-hospital mortality, but without reaching statistical significance (P = 0.11) (Table 4).
Influence of each single element of the bundles on mortality
To assess the influence of each bundle element in ICU and in-hospital mortalities, we performed a multivariate analysis for each single measure (20) and evaluated for both B6 and B24 the potential loss of benefit and statistical significance of removing one element compared with full accomplishment of the remaining elements of the corresponding bundle, adjusted for age and APACHE II (Table 5). In B6H, removal of any one of the elements did not result in a loss of benefit with respect to the fulfilment of all remaining elements of the bundle, maintaining a significant effect in mortality reduction. Every single measure was also associated with decreased ICU mortality. For hospital outcome, only lactate measurement, performing blood cultures and use of broad-spectrum antibiotics were associated with improvement in survival.
Regarding B24H, only removal of glycemic control changed the effect of compliance with the rest of the bundle, with increased risk of mortality [OR (95% CI) 1.5 (1.16–1.92) (P < 0.01)], suggesting a detrimental effect if not completed. Maintaining blood glucose control <150 mg/dL reached statistical significance in the multivariate analysis after adjustment for APACHE II, and was associated with lower in-hospital mortality [OR (95% CI) 0.65 (0.43–0.98)] (P = 0.04). When we analyzed the number of hypoglycemic episodes (blood glucose <70 mg/dL) within the first 24 h and its association with mortality, a higher incidence of hypoglycemia was observed in ICU and hospital non-survivors than in survivors: 12.3% vs. 5.5% (P = 0.01) and 11.5% vs. 5.1% (P = 0.01).
The main finding of our study is that compliance with the SSC bundles increased markedly after 5 years of an EDUSEPSIS campaign. Although the proportion of patients in whom all elements were applied remained low, ICU and hospital mortalities decreased over this 5-year period, within a range lower than in some observational studies (1–3, 6–8) and higher than in others (9). The fact that we did not find differences between the two cohorts in terms of demographics, location of infection, and severity on admission suggests that the reduction in mortality may be due to a change in patient management and clinical behavior, as reflected by better compliance with the bundles.
Several studies have shown a clear relationship between the implementation of an early management bundle and a lower mortality rate (13). Gao et al. (19) showed a higher compliance (50% for B6H, 30% for B24H), and lower ICU and hospital mortalities (36% and 39%, respectively). Lack of compliance with B6H was associated with more than two-fold increase in hospital mortality. Our reference study EDUSEPSIS (18) confirmed the association of lower hospital mortality with better accomplishment of the bundles, although compliance with both B6H and B24 was low (10% and 15.7%, respectively). Similar results have also been obtained by Castellanos-Ortega et al. (20) in a study conducted in a single ICU. They reported an increase in compliance with the SSC bundles compared with a historical cohort, although much lower than in our study (11.2% with B6H and only 1.3% with B24H). Despite this poor compliance, hospital mortality decreased from 57.3% to 37.5%. They observed a mortality reduction related to the number of completed tasks. Compliance with ScvO2>70% was the individual measure with the highest impact on mortality (20). Cardoso et al. (21) also found an association between the implementation of B6H and reduced mortality, with six patients as a number of patients needed to treat for saving one life. The mortality rates for SS and SSh were 19% and 44% respectively, higher than the one observed in our study.
The adherence to SSC recommendations improves with long-term educational campaigns and the better outcomes are obtained by centers that continuously participate in those campaigns. Levy et al. (22) published the results of a 7.5-year multicenter study conducted in the United States, Europe, and South America examining the compliance with SSC bundles in the largest prospective cohort of septic patients ever reported. There was a 25% relative risk reduction in mortality with increased compliance with the SSC initiative, with an associated decrease of 7% in-hospital mortality for every additional quarter of participation time. Their campaign revealed active participation and dose-effects over time which led to better compliance and lower mortality. The mortality in the B6H highly compliant sites was 29%. They defined a higher compliance center if more than 15% of the patients had all items completed (in our study, 27% of centers reported full B6H accomplishment). These better outcomes obtained in high compliant sites have been confirmed with the last updated bundles (26).
Regarding the impact of individual recommendations of B6H in mortality, there are different results in the literature. Castellanos-Ortega et al. (20) identified the achievement of ScvO2 >70% as the unique measure associated with better survival, which reinforce Rivers results. Ferrer et al. (27) identified the early antibiotic administration and the use of APC in septic shock as the measures associated with less mortality, and observed no benefit with fluid challenge. In our study, the compliance with more number of recommendations is associated with lower mortality and all of the B6H measures are associated with lower ICU mortality.
There also are studies reporting lower mortality without adherence to the SSC recommendations. The utility of an early goal-directed therapy protocol (EGDT) based on the work by Rivers et al. (11) has been questioned in recent randomized controlled trials (RCTs) (24, 28, 29). Their results are surprising: EGDT did not improve survival compared with usual care or less invasive haemodynamic resuscitation protocols. The mortality was around 20% in these studies and the EGDT arm was associated with a higher ICU admission rate and use of resources. These RCTs have been reviewed and included in a meta-analysis by Angus et al. (30), confirming that routine use of EGDT protocol cannot be recommended in the management of septic patients. Since part of the elements of the EGDT are included in the 6 h bundle evaluated in our study, these findings pose the question of which of the measures has the greatest impact on outcome or whether there are other factors (out of the specific resuscitation protocol) that influenced the outcomes.
Continued improvements in processes of care that enhance early recognition, early antibiotic treatment, and resuscitation with appropriate doses of fluids, vasopressors and positive inotropics are necessary to further improve outcomes of severe sepsis. These issues have been reviewed and discussed by the SSC panel in a recent update of the bundles by recommending the determination of CVP and ScvO2 for the reassessment of volume status and tissue perfusion, in case of persistent signs of hypoperfusion and need of advanced hemodynamic monitoring (17, 31).
The low compliance with B24H seen in our study is consistent with previous reports (13, 18, 20). This poor implementation could be explained by an unclear benefit-to-risk ratio observed in the original studies (32). APC administration was minimal and similar to the one described in the literature until its withdrawal from the market, after the results of the PROWESS-Shock study (25). Although corticosteroids administration has increased in our study, use in septic shock is controversial (33, 34). In our analysis benefits were not found regarding B24H implementation.
It is known that the protocolized management of ICU patients leads to better results, regardless of the implementation of educational campaigns (35). However, the low compliance with the B24H reflects the difficulty for translating the recommendations into daily practice (36). Rubenfeld (37) identified three major reasons for the gap between the evidence-based guidelines and their implementation into clinical practice: knowledge barriers, attitude barriers, and behavioral barriers of the attending personal. Carlbom and Rubenfeld (38) identified the reduced staff, limited resources, and difficulties for early identification of severe sepsis as the main factors associated with limited implementation of time-sensitive resuscitation measures in the emergency department. We agree with these reasons.
Another cause of low compliance in our study could be that most of our patients were admitted from medical-surgical wards, where the initial treatment is not protocolized. The delay in ICU admission could affect the compliance with the bundles. The participating hospitals in our study also have personnel on training in their ICUs staff, who participate actively in the initial treatment of septic shock patients. The learning curve of this staff may influence the compliance with the bundles and we do not know if a longer period of the study could improve the results.
Despite our better results, the low compliance with B6H and B24H shows that efforts to maintaining awareness about severe sepsis and performing continuous educational programs must be necessary to improve the outcomes.
Our study has several strengths. First, it was multicenter and conducted in a heterogeneous cohort of ICU patients. Second, the study was performed in the same ICUs of the historical cohort, suggesting that the change in the bundles accomplishment reflects a change in the working methodology leading to a change in the results. Third, the similar demographics and severity scores between the two cohorts reinforce this concept. Fourth, we determined the long-term compliance after an educational campaign without any interventional program between the two cohorts, in an environment with sufficient resources to fulfill the recommendations over time. We know that these results may seem old news in the current literature, but we emphasize the long-term influence of performing educational campaigns in outcomes even with no feedback programs performed after the educational initiative.
We also acknowledge some limitations of our study. First, since this is an observational study, it is difficult to clearly identify a causal link between better compliance and lower mortality. This association might be related or not to the education and attention to these patients or might to some degree be associated with the bundles accomplishment, mainly in the case of B6H. Second, although the compliance with the measures improved, a motivation bias in the participating centers during the study period could exist. Third, although we were able to reliably relate better bundle's compliance with improved results by statistical analysis with a well-defined methodology, the relatively low number of patients and the limited number of variables compared between the two cohorts may limit the interpretation and validity of the results. Fourth, we do not register if participating hospitals developed educational initiatives after the completion of the educational campaign, or whether they use protocol adherence or checklists to analyze the treatment of septic patients. However, we think that a global interventional campaign produces a longer motivation effect and the implementation of local and heterogeneous initiatives in some hospitals hardly can influence the better results observed in this study. Finally, we are unaware of what happened to those hospitalized septic patients who did not receive intensive care.
Our study has demonstrated that after 5 years of the EDUSEPSIS educational campaign (24), the long-term compliance of B6H improved and the overall mortality decreased, despite that the compliance with the B24H did not improve. The number of completed measures of B6H was linearly associated with a reduction in ICU and hospital mortality. All the measures recommended in B6H were individually associated with a reduction in ICU mortality. Lactate measurement, blood cultures, and administration of broad-spectrum antibiotics were associated with lower in-hospital mortality. No benefits with B24H accomplishment were observed. Only glycemic control was associated with a reduction in hospital mortality. Therefore, maintaining educational campaigns for improving the process of critical care in combination with initiatives aimed at early recognition of septic patients, such as EWSs and RRTs, may be useful to further improve outcomes.
The authors gratefully acknowledge the staff members and nursery of all hospitals involved in the study for their help and collaboration.
Appendix: Members of GRECIA network
Hospital Universitario Río Hortega de Valladolid (SACYL, Spain): Arturo F. Muriel-Bombin, Rubén Herrán Monge, Marta M. García García, Pedro A Merino García, Jesús Blanco Varela; Complejo Asistencial Universitario de Burgos (SACYL, Spain): Maria Jesús López-Pueyo, José Antonio Fernández Ratero, Miguel Martínez Barrios, Fernando Callejo Torre, Sergio Ossa Echeverri, Arroyo M; Complejo Hospitalario de León (SACYL, Spain): Demetrio Carriedo Ule, Ana María Domínguez Berrot, Francisco Javier Díaz Domínguez; Hospital Clínico Universitario de Valladolid (SACYL, Spain): Francisco Gandía Martínez, Rafael Cítores González, David Andaluz; Complejo Asistencial Universitario de Palencia (SACYL, Spain): Susana Moradillo Gonzalez; Hospital El Bierzo, Ponferrada (SACYL, Spain): Braulio Álvarez Martinez; Complejo Asistencial Universitario de Salamanca (SACYL, Spain): Noelia Albalá, Elena Pérez Losada, Juan Carlos Ballesteros, Marta Paz Pérez; Complejo Asistencial de Segovia (SACYL, Spain): Santiago Macías, Rafael Pajares, Noelia Recio García; Complejo Asistencial de Soria (SACYL, Spain): Mª Mar Gobernado Serrano, Daniel Moreno Torres, Mª José Fernández Calavia; Complejo Asistencial de Zamora (SACYL, Spain): Concha Tarancón, Teresa Álvarez, Priscila Carcelén.
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