Adverse effects of delayed antimicrobial treatment and surgical source control in adults with sepsis: results of a planned secondary analysis of a cluster-randomized controlled trial.

BACKGROUND: Timely antimicrobial treatment and source control are strongly recommended by sepsis guidelines, however, their impact on clinical outcomes is uncertain. METHODS: We performed a planned secondary analysis of a cluster-randomized trial conducted from July 2011 to May 2015 including forty German hospitals. All adult patients with sepsis treated in the participating ICUs were included. Primary exposures were timing of antimicrobial therapy and delay of surgical source control during the first 48 h after sepsis onset. Primary endpoint was 28-day mortality. Mixed models were used to investigate the effects of timing while adjusting for confounders. The linearity of the effect was investigated by fractional polynomials and by categorizing of timing. RESULTS: Analyses were based on 4792 patients receiving antimicrobial treatment and 1595 patients undergoing surgical source control. Fractional polynomial analysis identified a linear effect of timing of antimicrobials on 28-day mortality, which increased by 0.42% per hour delay (OR with 95% CI 1.019 [1.01, 1.028], p ≤ 0.001). This effect was significant in patients with and without shock (OR = 1.018 [1.008, 1.029] and 1.026 [1.01, 1.043], respectively). Using a categorized timing variable, there were no significant differences comparing treatment within 1 h versus 1-3 h, or 1 h versus 3-6 h. Delays of more than 6 h significantly increased mortality (OR = 1.41 [1.17, 1.69]). Delay in antimicrobials also increased risk of progression from severe sepsis to septic shock (OR per hour: 1.051 [1.022, 1.081], p ≤ 0.001). Time to surgical source control was significantly associated with decreased odds of successful source control (OR = 0.982 [0.971, 0.994], p = 0.003) and increased odds of death (OR = 1.011 [1.001, 1.021]; p = 0.03) in unadjusted analysis, but not when adjusted for confounders (OR = 0.991 [0.978, 1.005] and OR = 1.008 [0.997, 1.02], respectively). Only, among patients with septic shock delay of source control was significantly related to risk-of death (adjusted OR = 1.013 [1.001, 1.026], p = 0.04). CONCLUSIONS: Our findings suggest that management of sepsis is time critical both for antimicrobial therapy and source control. Also patients, who are not yet in septic shock, profit from early anti-infective treatment since it can prevent further deterioration. Trial registration ClinicalTrials.gov ( NCT01187134 ). Registered 23 August 2010, NCT01187134.

Fever and hypothermia represent two populations of sepsis patients and are associated with outside temperature.

BACKGROUND: Fever and hypothermia have been observed in septic patients. Their influence on prognosis is subject to ongoing debates. METHODS: We did a secondary analysis of a large clinical dataset from a quality improvement trial. A binary logistic regression model was calculated to assess the association of the thermal response with outcome and a multinomial regression model to assess factors associated with fever or hypothermia. RESULTS: With 6542 analyzable cases we observed a bimodal temperature response characterized by fever or hypothermia, normothermia was rare. Hypothermia and high fever were both associated with higher lactate values. Hypothermia was associated with higher mortality, but this association was reduced after adjustment for other risk factors. Age, community-acquired sepsis, lower BMI and lower outside temperatures were associated with hypothermia while bacteremia and higher procalcitonin values were associated with high fever. CONCLUSIONS: Septic patients show either a hypothermic or a fever response. Whether hypothermia is a maladaptive response, as indicated by the higher mortality in hypothermic patients, or an adaptive response in patients with limited metabolic reserves under colder environmental conditions, remains an open question. Trial registration The original trial whose dataset was analyzed was registered at ClinicalTrials.gov (NCT01187134) on August 23, 2010, the first patient was included on July 1, 2011.

Perceived Nonbeneficial Treatment of Patients, Burnout, and Intention to Leave the Job Among ICU Nurses and Junior and Senior Physicians.

OBJECTIVES: Perceiving nonbeneficial treatment is stressful for ICU staff and may be associated with burnout. We aimed to investigate predictors and consequences of perceived nonbeneficial treatment and to compare nurses and junior and senior physicians. DESIGN: Cross-sectional, multicenter paper-pencil survey on personal and work-related characteristics, perceived nonbeneficial treatment, burnout, and intention to leave the job. SETTING: Convenience sample of 23 German ICUs. SUBJECTS: ICU nurses and physicians. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 847 questionnaires were returned (51% response); 778 had complete data for final multivariate analyses. Nonbeneficial treatment was in median perceived "sometimes." Adjusted for covariates, it was perceived more often by nurses and junior physicians (both p ≤ 0.001 in comparison to senior physicians), while emotional exhaustion was highest in junior physicians (p ≤ 0.015 in comparison to senior physicians and nurses), who also had a higher intention to leave than nurses (p = 0.024). Nonbeneficial treatment was predicted by high workload and low quality collaboration with other departments (both p ≤ 0.001). Poor nurse-physician collaboration predicted perception of nonbeneficial treatment among junior physicians and nurses (both p ≤ 0.001) but not among senior physicians (p = 0.753). Nonbeneficial treatment was independently associated with the core burnout dimension emotional exhaustion (p ≤ 0.001), which significantly mediated the effect between nonbeneficial treatment and intention to leave (indirect effect: 0.11 [95% CI, 0.06-0.18]). CONCLUSIONS: Perceiving nonbeneficial treatment is related to burnout and may increase intention to leave. Efforts to reduce perception of nonbeneficial treatment should improve the work environment and should be tailored to the different experiences of nurses and junior and senior physicians.

Impact of compliance with infection management guidelines on outcome in patients with severe sepsis: a prospective observational multi-center study.

INTRODUCTION: Current sepsis guidelines recommend antimicrobial treatment (AT) within one hour after onset of sepsis-related organ dysfunction (OD) and surgical source control within 12 hours. The objective of this study was to explore the association between initial infection management according to sepsis treatment recommendations and patient outcome. METHODS: In a prospective observational multi-center cohort study in 44 German ICUs, we studied 1,011 patients with severe sepsis or septic shock regarding times to AT, source control, and adequacy of AT. Primary outcome was 28-day mortality. RESULTS: Median time to AT was 2.1 (IQR 0.8 - 6.0) hours and 3 hours (-0.1 - 13.7) to surgical source control. Only 370 (36.6%) patients received AT within one hour after OD in compliance with recommendation. Among 422 patients receiving surgical or interventional source control, those who received source control later than 6 hours after onset of OD had a significantly higher 28-day mortality than patients with earlier source control (42.9% versus 26.7%, P <0.001). Time to AT was significantly longer in ICU and hospital non-survivors; no linear relationship was found between time to AT and 28-day mortality. Regardless of timing, 28-day mortality rate was lower in patients with adequate than non-adequate AT (30.3% versus 40.9%, P < 0.001). CONCLUSIONS: A delay in source control beyond 6 hours may have a major impact on patient mortality. Adequate AT is associated with improved patient outcome but compliance with guideline recommendation requires improvement. There was only indirect evidence about the impact of timing of AT on sepsis mortality.

Perceptions of Quality of Interprofessional Collaboration, Staff Well-Being and Nonbeneficial Treatment: A Comparison between Nurses and Physicians in Intensive and Palliative Care.

This study assessed differences in interprofessional collaboration, perception of nonbeneficial care, and staff well-being between critical care and palliative care teams. In six German hospitals, a staff survey was conducted between December 2013 and March 2015 among nurses and physicians in intensive and palliative care units. To allow comparability between unit types, a matching was performed for demographic characteristics of staff. N = 313 critical care and 79 palliative care staff participated, of which 72 each were successfully matched. Critical care nurses perceived the poorest overall quality of collaboration compared with critical care physicians and palliative care physicians and nurses. They also reported less inclusive leadership from attendings and head nurses, and the least collaboration on care decisions with physicians. They were most likely to perceive nonbeneficial care, and they reported the lowest levels of job satisfaction and the highest intention to leave the job. In partial correlations, aspects of high-quality collaboration were associated with less perceived nonbeneficial care and higher staff well-being for both critical care and palliative care staff. Our findings indicate that critical care teams could improve collaboration and enhance well-being, particularly among nurses, by adopting principles of collaborative work culture as established in palliative care.

The German Quality Network Sepsis: Evaluation of a Quality Collaborative on Decreasing Sepsis-Related Mortality in a Controlled Interrupted Time Series Analysis.

Background: Sepsis is one of the leading causes of preventable deaths in hospitals. This study presents the evaluation of a quality collaborative, which aimed to decrease sepsis-related hospital mortality. Methods: The German Quality Network Sepsis (GQNS) offers quality reporting based on claims data, peer reviews, and support for establishing continuous quality management and staff education. This study evaluates the effects of participating in the GQNS during the intervention period (April 2016-June 2018) in comparison to a retrospective baseline (January 2014-March 2016). The primary outcome was all-cause risk-adjusted hospital mortality among cases with sepsis. Sepsis was identified by International Classification of Diseases (ICD) codes in claims data. A controlled time series analysis was conducted to analyze changes from the baseline to the intervention period comparing GQNS hospitals with the population of all German hospitals assessed via the national diagnosis-related groups (DRGs)-statistics. Tests were conducted using piecewise hierarchical models. Implementation processes and barriers were assessed by surveys of local leaders of quality improvement teams. Results: Seventy-four hospitals participated, of which 17 were university hospitals and 18 were tertiary care facilities. Observed mortality was 43.5% during baseline period and 42.7% during intervention period. Interrupted time-series analyses did not show effects on course or level of risk-adjusted mortality of cases with sepsis compared to the national DRG-statistics after the beginning of the intervention period (p = 0.632 and p = 0.512, respectively). There was no significant mortality decrease in the subgroups of patients with septic shock or ventilation >24 h or predefined subgroups of hospitals. A standardized survey among 49 local quality improvement leaders in autumn of 2018 revealed that most hospitals did not succeed in implementing a continuous quality management program or relevant measures to improve early recognition and treatment of sepsis. Barriers perceived most commonly were lack of time (77.6%), staff shortage (59.2%), and lack of participation of relevant departments (38.8%). Conclusion: As long as hospital-wide sepsis quality improvement efforts will not become a high priority for the hospital leadership by assuring adequate resources and involvement of all pertinent stakeholders, voluntary initiatives to improve the quality of sepsis care will remain prone to failure.

A multifaceted educational intervention improved anti-infectious measures but had no effect on mortality in patients with severe sepsis.

Sepsis is a major reason for preventable hospital deaths. A cluster-randomized controlled trial on an educational intervention did not show improvements of sepsis management or outcome. We now aimed to test an improved implementation strategy in a second intervention phase in which new intervention hospitals (former controls) received a multifaceted educational intervention, while controls (former intervention hospitals) only received feedback of quality indicators. Changes in outcomes from the first to the second intervention phase were compared between groups using hierarchical generalized linear models controlling for possible confounders. During the two phases, 19 control hospitals included 4050 patients with sepsis and 21 intervention hospitals included 2526 patients. 28-day mortality did not show significant changes between study phases in both groups. The proportion of patients receiving antimicrobial therapy within one hour increased in intervention hospitals, but not in control hospitals. Taking at least two sets of blood cultures increased significantly in both groups. During phase 2, intervention hospitals showed higher proportion of adequate initial antimicrobial therapy and de-escalation within 5 days. A survey among involved clinicians indicated lacking resources for quality improvement. Therefore, quality improvement programs should include all elements of sepsis guidelines and provide hospitals with sufficient resources for quality improvement.Trial registration: ClinicalTrials.gov, NCT01187134. Registered 23 August 2010, https://www.clinicaltrials.gov/ct2/show/study/NCT01187134 .

Effect of positive end-expiratory pressure and positioning on jugular vein expansion in emergency department patients.

OBJECTIVE: Guidelines recommend Trendelenburg position for central venous cannulation. Critically ill patients in the emergency department often do not tolerate this positioning or have contraindications. Thirty-degree dorsal elevated position with positive end-expiratory pressure by noninvasive ventilation could pose an alternative. This is the first trial to investigate the feasibility of alternative for central venous cannulation in critically ill emergency department patients. METHODS: Ninety-one critically ill patients in the emergency department of Jena University Hospital were examined between August 2014 and May 2015. The cross-sectional area of the right internal jugular vein was measured in 3 different positions: 30° elevation, supine, and Trendelenburg position. Measurements were repeated with a continuous application of noninvasive ventilation. RESULTS: Cross-sectional area of the right internal jugular vein in Trendelenburg position was largest (0.99 ± 0.66 cm) compared to supine (0.57 ± 0.58 cm) and 30° elevated position (0.25 ± 0.41 cm). In 30° elevated positioning, application of positive end-expiratory pressure significantly enlarged cross-sectional area (0.62 ± 0.70 cm). Noninvasive ventilation was a well-tolerated procedure (98%). In 30° elevated positioning with positive end-expiratory pressure a safe puncture (cross-sectional area ≥ 0.4 cm) could be expected in 68.1% of cases. CONCLUSION: Thirty-degree elevated positioning with positive end-expiratory pressure via noninvasive ventilation could be a safe and well-tolerated alternative for central venous cannulation, especially for critically ill patients in emergency department unable to remain in Trendelenburg position. This proof-of-concept trial enables further studies with actual central venous cannulation.

A risk-model for hospital mortality among patients with severe sepsis or septic shock based on German national administrative claims data.

BACKGROUND: Sepsis is a major cause of preventable deaths in hospitals. Feasible and valid methods for comparing quality of sepsis care between hospitals are needed. The aim of this study was to develop a risk-adjustment model suitable for comparing sepsis-related mortality between German hospitals. METHODS: We developed a risk-model using national German claims data. Since these data are available with a time-lag of 1.5 years only, the stability of the model across time was investigated. The model was derived from inpatient cases with severe sepsis or septic shock treated in 2013 using logistic regression with backward selection and generalized estimating equations to correct for clustering. It was validated among cases treated in 2015. Finally, the model development was repeated in 2015. To investigate secular changes, the risk-adjusted trajectory of mortality across the years 2010-2015 was analyzed. RESULTS: The 2013 deviation sample consisted of 113,750 cases; the 2015 validation sample consisted of 134,851 cases. The model developed in 2013 showed good validity regarding discrimination (AUC = 0.74), calibration (observed mortality in 1st and 10th risk-decile: 11%-78%), and fit (R2 = 0.16). Validity remained stable when the model was applied to 2015 (AUC = 0.74, 1st and 10th risk-decile: 10%-77%, R2 = 0.17). There was no indication of overfitting of the model. The final model developed in year 2015 contained 40 risk-factors. Between 2010 and 2015 hospital mortality in sepsis decreased from 48% to 42%. Adjusted for risk-factors the trajectory of decrease was still significant. CONCLUSIONS: The risk-model shows good predictive validity and stability across time. The model is suitable to be used as an external algorithm for comparing risk-adjusted sepsis mortality among German hospitals or regions based on administrative claims data, but secular changes need to be taken into account when interpreting risk-adjusted mortality.

The German Quality Network Sepsis: study protocol for the evaluation of a quality collaborative on decreasing sepsis-related mortality in a quasi-experimental difference-in-differences design.

BACKGROUND: While sepsis-related mortality decreased substantially in other developed countries, mortality of severe sepsis remained as high as 44% in Germany. A recent German cluster randomized trial was not able to improve guideline adherence and decrease sepsis-related mortality within the participating hospitals, partly based on lacking support by hospital management and lacking resources for documentation of prospective data. Thus, more pragmatic approaches are needed to improve quality of sepsis care in Germany. The primary objective of the study is to decrease sepsis-related hospital mortality within a quality collaborative relying on claims data. METHOD: The German Quality Network Sepsis (GQNS) is a quality collaborative involving 75 hospitals. This study protocol describes the conduction and evaluation of the start-up period of the GQNS running from March 2016 to August 2018. Democratic structures assure participatory action, a study coordination bureau provides central support and resources, and local interdisciplinary quality improvement teams implement changes within the participating hospitals. Quarterly quality reports focusing on risk-adjusted hospital mortality in cases with sepsis based on claims data are provided. Hospitals committed to publish their individual risk-adjusted mortality compared to the German average. A complex risk-model is used to control for differences in patient-related risk factors. Hospitals are encouraged to implement a bundle of interventions, e.g., interdisciplinary case analyses, external peer-reviews, hospital-wide staff education, and implementation of rapid response teams. The effectiveness of the GQNS is evaluated in a quasi-experimental difference-in-differences design by comparing the change of hospital mortality of cases with sepsis with organ dysfunction from a retrospective baseline period (January 2014 to December 2015) and the intervention period (April 2016 to March 2018) between the participating hospitals and all other German hospitals. Structural and process quality indicators of sepsis care as well as efforts for quality improvement are monitored regularly. DISCUSSION: The GQNS is a large-scale quality collaborative using a pragmatic approach based on claims data. A complex risk-adjustment model allows valid quality comparisons between hospitals and with the German average. If this study finds the approach to be useful for improving quality of sepsis care, it may also be applied to other diseases. TRIAL REGISTRATION: ClinicalTrials.gov NCT02820675.

Effect of a multifaceted educational intervention for anti-infectious measures on sepsis mortality: a cluster randomized trial.

PURPOSE: Guidelines recommend administering antibiotics within 1 h of sepsis recognition but this recommendation remains untested by randomized trials. This trial was set up to investigate whether survival is improved by reducing the time before initiation of antimicrobial therapy by means of a multifaceted intervention in compliance with guideline recommendations. METHODS: The MEDUSA study, a prospective multicenter cluster-randomized trial, was conducted from July 2011 to July 2013 in 40 German hospitals. Hospitals were randomly allocated to receive conventional continuous medical education (CME) measures (control group) or multifaceted interventions including local quality improvement teams, educational outreach, audit, feedback, and reminders. We included 4183 patients with severe sepsis or septic shock in an intention-to-treat analysis comparing the multifaceted intervention (n = 2596) with conventional CME (n = 1587). The primary outcome was 28-day mortality. RESULTS: The 28-day mortality was 35.1% (883 of 2596 patients) in the intervention group and 26.7% (403 of 1587 patients; p = 0.01) in the control group. The intervention was not a risk factor for mortality, since this difference was present from the beginning of the study and remained unaffected by the intervention. Median time to antimicrobial therapy was 1.5 h (interquartile range 0.1-4.9 h) in the intervention group and 2.0 h (0.4-5.9 h; p = 0.41) in the control group. The risk of death increased by 2% per hour delay of antimicrobial therapy and 1% per hour delay of source control, independent of group assignment. CONCLUSIONS: Delay in antimicrobial therapy and source control was associated with increased mortality but the multifaceted approach was unable to change time to antimicrobial therapy in this setting and did not affect survival.

Hyperlactatemia is an independent predictor of mortality and denotes distinct subtypes of severe sepsis and septic shock.

PURPOSE: Current guidelines and most trials do not consider elevated lactate (Lac) serum concentrations when grading sepsis severity. We therefore assessed the association of different types of circulatory dysfunction regarding presence of hyperlactatemia and need for vasopressor support with clinical presentation and outcome of sepsis. METHODS: In a secondary analysis of a prospective observational multicenter cohort study, 988 patients with severe sepsis were investigated regarding vasopressor support, Lac levels, and outcome. RESULTS: Twenty-eight-day mortality regarding shock or hyperlactatemia was as follows: hyperlactatemia more than 2.5 mmol/L and septic shock (tissue dysoxic shock): 451 patients with a mortality of 44.8%; hyperlactatemia without vasopressor need (cryptic shock): 72 patients, mortality 35.3%; no hyperlactatemia with vasopressor need (vasoplegic shock): 331 patients, mortality 27.7%; and absence of hyperlactemia or overt shock (severe sepsis): 134 patients, mortality 14.2% (P < .001). These groups showed differences in source and origin of infection. The influence of hyperlactatemia on 28-day mortality (P < .001) (odds ratio 3.0, 95% confidence interval 2.1-4.1 for Lac >4 mmol/L) was independent of vasopressor support (P < .001) (odds ratio 2.0, 95% confidence interval 1.3-3.0 for norepinephrine >0.1 µg/kg per minute) in logistic regression. CONCLUSIONS: Hyperlactatemia increases risk of death independent of vasopressor need resulting in different phenotypes within the classic categories of severe sepsis and septic shock.