Objective: The purpose of this study was to examine the outcome implications of implementing a severe sepsis bundle in an emergency department as a quality indicator set with feedback to modify physician behavior related to the early management of severe sepsis and septic shock. Design: Two-year prospective observational cohort. Setting: Academic tertiary care facility. Patients: Patients were 330 patients presenting to the emergency department who met criteria for severe sepsis or septic shock. Interventions: Five quality indicators comprised the bundle for severe sepsis management in the emergency department: a) initiate central venous pressure (CVP)/central venous oxygen saturation (Scvo₂) monitoring within 2 hrs; b) give broad-spectrum antibiotics within 4 hrs; c) complete early goal-directed therapy at 6 hrs; d) give corticosteroid if the patient is on vasopressor or if adrenal insufficiency is suspected; and e) monitor for lactate clearance. Measurements and Main Results: Patients had a mean age of 63.8 ± 18.5 yrs, Acute Physiology and Chronic Health Evaluation II score 29.6 ± 10.6, emergency department length of stay 8.5 ± 4.4 hrs, hospital length of stay 11.3 ± 12.9 days, and in-hospital mortality 35.2%. Bundle compliance increased from zero to 51.2% at the end of the study period. During the emergency department stay, patients with the bundle completed received more CVP/Scvo₂ monitoring (100.0 vs. 64.8%, p < .01), more antibiotics (100.0 vs. 89.7%, p = .04), and more corticosteroid (29.9 vs. 16.2%, p = .01) compared with patients with the bundle not completed. In a multivariate regression analysis including the five quality indicators, completion of early goal-directed therapy was significantly associated with decreased mortality (odds ratio, 0.36; 95% confidence interval, 0.17–0.79; p = .01). In-hospital mortality was less in patients with the bundle completed compared with patients with the bundle not completed (20.8 vs. 39.5%, p < .01). Conclusions: Implementation of a severe sepsis bundle using a quality improvement feedback to modify physician behavior in the emergency department setting was feasible and was associated with decreased in-hospital mortality.

Prior to 2001 there was no standard for early management of severe sepsis and septic shock in the emergency department. In the presence of standard or usual care, the prevailing mortality was over 40-50 %. In response, a systems-based approach, similar to that in acute myocardial infarction, stroke and trauma, called early goal-directed therapy was compared to standard care and this clinical trial resulted in a significant mortality reduction. Since the publication of that trial, similar outcome benefits have been reported in over 70 observational and randomized controlled studies comprising over 70,000 patients. As a result, early goal-directed therapy was largely incorporated into the first 6 hours of sepsis management (resuscitation bundle) adopted by the Surviving Sepsis Campaign and disseminated internationally as the standard of care for early sepsis management. Recently a trio of trials (ProCESS, ARISE, and ProMISe), while reporting an all-time low sepsis mortality, question the continued need for all of the elements of early goal-directed therapy or the need for protocolized care for patients with severe and septic shock. A review of the early hemodynamic pathogenesis, historical development, and definition of early goal-directed therapy, comparing trial conduction methodology and the changing landscape of sepsis mortality, are essential for an appropriate interpretation of these trials and their conclusions.

Introduction: Implementation of the Surviving Sepsis Campaign (SSC) guidelines has been associated with improved outcome in patients with severe sepsis. Resolution of lactate elevations or lactate clearance has also been shown to be associated with outcome. The purpose of the present study was to examine the compliance and effectiveness of the SSC resuscitation bundle with the addition of lactate clearance. Methods: This was a prospective cohort study over 18 months in eight tertiary-care medical centers in Asia, enrolling adult patients meeting criteria for the SSC resuscitation bundle in the emergency department. Compliance and outcome results of a multi-disciplinary program to implement the Primary SSC Bundle with the addition of lactate clearance (Modified SSC Bundle) were examined. The implementation period was divided into quartiles, including baseline, education and four quality improvement phases. Results: A total of 556 patients were enrolled, with median (25th to 75th percentile) age 63 (50 to 74) years, lactate 4.1 (2.2 to 6.3) mmol/l, central venous pressure 10 (7 to 13) mmHg, mean arterial pressure (MAP) 70 (56 to 86) mmHg, and central venous oxygen saturation 77 (69 to 82)%. Completion of the Primary SSC Bundle over the six quartiles was 13.3, 26.9, 37.5, 45.9, 48.8, and 54.5%, respectively (P <0.01). The Modified SSC Bundle was completed in 10.2, 23.1, 31.7, 40.0, 42.5, and 43.6% patients, respectively (P 65 mmHg by 6 hours, and lactate clearance were independently associated with decreased mortality - having odds ratios (95% confidence intervals) 0.47 (0.23 to 0.96), 0.20 (0.07 to 0.55), and 0.32 (0.19 to 0.55), respectively. Conclusions: The addition of lactate clearance to the SSC resuscitation bundle is associated with improved mortality. In our study patient population with optimized baseline central venous pressure and central venous oxygen saturation, the bundle items of fluid bolus administration, achieving MAP >65 mmHg, and lactate clearance were independent predictors of outcome.

The use of novel sepsis biomarkers has increased in recent years. However, their prognostic value with respect to illness severity has not been explored. In this work, we examined the ability of mid-regional proadrenomedullin (MR-proADM) in predicting mortality in sepsis patients with different degrees of organ failure, compared to that of procalcitonin, C-reactive protein and lactate. This was a two-centre prospective observational cohort, enrolling severe sepsis or septic shock patients admitted to the ICU. Plasma biomarkers were measured during the first 12 h of admission. The association between biomarkers and 28-day mortality was assessed by Cox regression analysis and Kaplan–Meier curves. Patients were divided into three groups as evaluated by the Sequential Organ Failure Assessment (SOFA) score. The accuracy of the biomarkers for mortality was determined by area under the receiver operating characteristic curve (AUROC) analysis. A total of 326 patients with severe sepsis (21.7%) or septic shock (79.3%) were enrolled with a 28-day mortality rate of 31.0%. Only MR-proADM and lactate were associated with mortality in the multivariate analysis: hazard ratio 8.5 versus 3.4 (p < 0.001). MR-proADM showed the best AUROC for mortality prediction at 28 days in the analysis over the entire cohort (AUROC [95% CI] 0.79 [0.74–0.84]) (p < 0.001). When patients were stratified by the degree of organ failure, MR-proADM was the only biomarker to predict mortality in all severity groups (SOFA ≤ 6, SOFA = 7–12, and SOFA ≥ 13), AUROC [95% CI] of 0.75 [0.61–0.88], 0.74 [0.66–0.83] and 0.73 [0.59–0.86], respectively (p < 0.05). All patients with MR-proADM concentrations ≤0.88 nmol/L survived up to 28 days. In patients with SOFA ≤ 6, the addition of MR-proADM to the SOFA score increased the ability of SOFA to identify non-survivors, AUROC [95% CI] 0.70 [0.58–0.82] and 0.77 [0.66–0.88], respectively (p < 0.05 for both). The performance of prognostic biomarkers in sepsis is highly influenced by disease severity. MR-proADM accuracy to predict mortality is not affected by the degree of organ failure. Thus, it is a good candidate in the early identification of sepsis patients with moderate disease severity but at risk of mortality.

In sepsis, the vitamin D active metabolite 1,25-dihydroxyvitamin D (1,25(OH)₂D) may play a crucial role by its action to produce cathelicidin and improve endothelial barrier function, such that a deficiency in 1,25(OH)₂D is associated with poor outcome. To test our hypothesis, we performed analysis of stored plasma samples from a prospective observational study in 91 patients with sepsis, age of 59.1+/−2.0 years, 52.7% females, and 11.0% deaths at 30 days. Vitamin D status, including 25-hydroxyvitamin D (25(OH)D), 1,25(OH)₂D, 24,25-dihydroxyvitamin D (24,25(OH)₂D), and parathyroid hormone (PTH), were measured daily over 3 days after hospital admission. At baseline, 1,25(OH)₂D was significantly different between survivors vs. non-survivors. But there was no significant difference in 25(OH)D, 24,25(OH)₂D, and PTH. In a multivariable binomial logistic regression model, age, total calcium and 1,25(OH)₂D were significant predictors of 30-day mortality. Kaplan Meier analysis showed that patients with mean 1,25(OH)₂D measured over 3 days of < = 13.6 pg/mL had 57.1% 30-day survival compared to 91.7% in patients with 1,25 (OH)₂D level >13.6 pg/mL (p<0.01). From repeated measures regression analysis, there was significant increase in 1,25(OH)₂D for increases in 25(OH)D in both survivors and non-survivors. However, compared to survivors, the low 25(OH)D in non-survivors was insufficient to account for the larger decrease in 1,25(OH)₂D, indicating a dysfunctional 1α-hydroxylase. Additionally, there was a significant negative correlation between PTH and 1,25(OH)₂D in both survivors and non-survivors, suggesting a severe impairment in the effect of PTH to increase renal 1α-hydroxylase activity. In conclusion, low 1,25(OH)₂D levels are associated with increased 30-day mortality in sepsis patients, likely due to impaired 25(OH)D hydroxylation and PTH insensitivity. Our data also suggest that the active metabolite 1,25(OH)₂D may be an important therapeutic target in the design of sepsis clinical trials.

Objective: Recent studies have reported decreased overall severe sepsis mortality, but associations with organism trends have not yet been investigated. This study explored organism-specific severe sepsis mortality trends from 1999 to 2008 in a large hospital-based administrative database. Design: Secondary data analysis using the Nationwide Inpatient Sample. Setting: United States hospitals sampled in the Nationwide Inpatient Sample dataset. Patients: This sample approximates a stratified 20% sample of all nonfederal, short-term, general, and specialty hospitals serving adults in the United States. Severe sepsis hospitalizations and organism-specific causes were identified using predetermined International Classification of Diseases, 9th Revision, Clinical Modification codes. Interventions: None. Measurements and Main Results: Analysis was conducted using descriptive Cox proportional hazards and linear regression trend analysis. Adjustments were made for the influence of demographics, comorbidities, number of organisms, and number of organ failures on hospital mortality. The data for 5,033,257 severe sepsis hospitalizations were examined and revealed decreased in-hospital mortality from 40.0% to 27.8% during the study period. The leading cause of severe sepsis was 51.5% Gram-negative bacteria, followed by 45.6% Gram-positive, 1.7% anaerobic, and 1.2% fungal species. The most common Gram-negative organisms were 39.9% Escherichia coli and 17.6% Pseudomonas. Staphylococcus species (62.2% methicillin-sensitive Staphylococcus aureus and 22.6% Streptococcus) were the most commonly reported Gram-positive organisms. Crude mortality estimates were higher for anaerobic and fungal organisms, 34.5% and 31.4%, respectively. Among Gram-positive bacteria, mortality was highest for methicillin-sensitive S. aureus, 30.9%, whereas Pseudomonas was associated with the highest mortality for Gram-negative septicemia cases, 29.5%. After adjusting for covariates, anaerobes were associated with the highest mortality hazard of 1.31 (95% CI, 1.23–1.40). Methicillin-resistant S. aureus had the highest mortality hazard of 1.38 (1.33–1.44) for Gram-positive organisms, whereas all Gram-negative bacteria had decreased mortality hazards. Conclusions: We not only confirmed an overall decline in severe sepsis mortality from 1999 to 2008 but also identified previously unreported variations in organism-specific severe sepsis mortality. Gram-negative organisms predominate, whereas anaerobes and methicillin-resistant S. aureus are significant predictors of mortality. Future clinical trials exploring new treatments in severe sepsis should incorporate individual organism trends to elucidate potential effect on mortality.