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Background: Surviving sepsis can lead to chronic physical, psychological and cognitive impairments, which affect millions of patients worldwide, including survivors after COVID-19 viral sepsis. We aimed to characterize the magnitude and trajectory of functional dependence and new impairments post-sepsis., Methods: We conducted a prospective cohort study including sepsis survivors who had been discharged from five German intensive care units (ICUs), until 36 months post-discharge. Primary outcome was functional dependence, defined as ≥1 impaired activity of daily living (ADL; 10-item ADL score <100), self-reported nursing care dependence or nursing care level. Secondary outcome was post-sepsis morbidity in the physical, psychological or cognitive domain. We used a multistate, competing risk model to address competing events in the course of dependence, and conducted multiple linear regression analyses to identify predictors associated with the ADL score., Findings: Of 3210 sepsis patients screened, 1968 survived the ICU treatment (61.3%). A total of 753 were included in the follow-up assessments of the Mid-German Sepsis cohort. Patients had a median age of 65 (Q1-Q3 56-74) years, 64.8% (488/753) were male and 76.1% (573/753) had a septic shock. Considering competing risk modelling, the probability of still being functional dependent was about 25%, while about 30% regained functional independence and 45% died within the three years post-sepsis. Patients reported a high burden of new and often overlapping impairments until three years post-sepsis. In the subgroup of three-year survivors (n = 330), new physical impairments affected 91.2% (n = 301) while new cognitive and psychological impairments were reported by 57.9% (n = 191) and 40.9% (n = 135), respectively. Patients with pre-existing functional limitations and higher age were at risk for low ADL scores three years after sepsis., Interpretation: Sepsis survivorship was associated with a broad range of new impairments and led to functional dependence in around one quarter of patients. Targeted measures are needed to mitigate the burden of this Post-Sepsis-Syndrome and increase the proportion of patients that achieve functional improvements., Funding: This work was supported by the Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC) at the Jena University Hospital funded by the German Ministry of Education and Research and by the Rudolf Presl GmbH & Co, Kreischa, Germany., Competing Interests: Over the past 5 years, Sven Bercker was investigator in studies sponsored by BioMeriéux, Boehringer Ingelheim, AM-Pharma B.V., Roche, Takeda, Dompé, and he is member of a DSMB for a study sponsored by hemotune AG. He has not received any personal fees for lectures or as a consultant or any reimbursement of travel expenses outside the sponsored studies. Konrad Reinhart holds shares from InflaRx NV, which is based in Jena, Germany and listed at NASDQ. This company recently received emergency use authorization by the FDA for an antibody against C5a—Gohibic (vilobelimab)—to treat critically ill COVID-19 patients, which fulfill the criteria for viral sepsis. E. Wesley Ely received NIH/VA Grant support. Over the last 36 months, the institution of Heinrich Groesdonk has received fees for his lectures, for his consultant activities, for his work in an advisory board or reimbursement for personal travel expenses by Edwards Lifescience, Amomed, and he personally holds shares from Fresenius SE. All other authors declare no conflict of interest., (© 2024 The Author(s).)

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.

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., Competing Interests: DS and HR were funded in part by grants from the German Federal Ministry of Education and Research during and outside the submitted work and by annual fees paid by hospitals to participate in the GQNS. CF-S was funded by grants from the German Federal Ministry of Education and Research and the German Innovations Fund of the Federal Joint Committee in Germany (G-BA), outside the submitted work. MGr reports grants from German Federal Ministry of Education and Research, outside the submitted work. MP reports grants by the Federal Ministry of Education and Research, outside the submitted work. DT-R reports grants from German Federal Ministry of Education and Research, outside the submitted work. KR was shareholder with less of 0.5% of InflaRx NV a Jena/Germany based Biotech Company that evaluates a immunmodulatory approach for the adjunctive treatment of COVID-19. MGl was employed by KH Labor GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Schwarzkopf, Rüddel, Brinkmann, Fleischmann-Struzek, Friedrich, Glas, Gogoll, Gründling, Meybohm, Pletz, Schreiber, Thomas-Rüddel and Reinhart.)

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 ., (© 2022. The Author(s).)

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., (© 2022. The Author(s).)

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., (© 2021. The Author(s).)

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.

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.

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.

Background: Although cognitive-behavioural therapy (CBT) and psychodynamic therapy (PDT) are both effective treatments for mental disorders, they show clear dissimilarities concerning their therapeutic models and treatment rationales., Aims: To determine the effectiveness of systematic treatment selection (STS) to CBT or PDT in a mental healthcare setting compared with a control procedure of random treatment selection (RTS)., Method: A randomised controlled trial in a consecutive sample of 291 in-patients with at least one ICD-10 mental disorder was performed. The primary outcome was symptom severity (General Severity Index of the Symptom Checklist-14) at 6-month follow-up. Health-related quality of life was the secondary outcome, determined using the Short Form-8., Results: Analyses revealed no general effect for systematic treatment selection. However, there was a differential effect: systematic selection resulted in a better longer-term outcome for PDT, but not for CBT; STS-PDT patients showed a significantly larger reduction in symptom severity than RTS-PDT patients. This difference was not observed in CBT., Conclusions: Since systematic treatment selection seems to be able to optimise treatment outcome, at least for PDT, pursuing systematic treatment assignment strategies in mental healthcare settings is a worthwhile endeavour.

Background: Providing reassurance is one of physicians' most frequently used verbal interventions. However, medical reassurance can fail or even have negative effects. This is frequently the case in patients with medically unexplained symptoms. It is hypothesized that these patients are more likely than patients from other groups to incorrectly recall the likelihoods of medical explanations provided by doctors., Methods and Findings: Thirty-three patients with medically unexplained symptoms, 22 patients with major depression, and 30 healthy controls listened to an audiotaped medical report, as well as to two control reports. After listening to the reports, participants were asked to rate what the doctor thinks the likelihood is that the complaints are caused by a specific medical condition. Although the doctor rejected most of the medical explanations for the symptoms in his verbal report, the patients with medically unexplained complaints remembered a higher likelihood for medical explanations for their symptoms. No differences were found between patients in the other groups, and for the control conditions. When asked to imagine that the reports were applicable to themselves, patients with multiple medical complaints reported more concerns about their health state than individuals in the other groups., Conclusions: Physicians should be aware that patients with medically unexplained symptoms recall the likelihood of medical causes for their complaints incorrectly. Therefore, physicians should verify correct understanding by using check-back questions and asking for summaries, to improve the effect of reassurance.

Objective: To test the hypothesis that beta blockers lower blood pressure more effectively than calcium entry blockers in obese hypertensive patients and that calcium entry blockers are more effective in lean patients., Design: Double blind, randomised controlled trial of treatment over six weeks., Setting: Tertiary referral centre., Subjects: 42 white men with uncomplicated mild to moderate essential hypertension (World Health Organisation stage I or II); 36 completed the study., Intervention: Patients were randomised to metoprolol 50-100 mg twice daily or isradipine 2.5-5.0 mg twice daily for six weeks after a two week run in phase., Main Outcome Measure: Blood pressure after six weeks of treatment., Results: When stratified according to treatment and presence of obesity (body mass index < or = 27 kg/m2), the mean (SD) fall in blood pressure in the beta blocker group was 24 (13)/18 (10) mm Hg in obese patients and 18 (19)/12 (13) mm Hg in lean patients. In the calcium entry blocker group, the fall in blood pressure was 21 (15)/17 (6) mm Hg in lean patients and 18 (11)/8 (10) mm Hg in obese patients. After taking age and blood pressure before treatment into account there was a significant interaction between obesity and drug therapy (p = 0.019) with a better diastolic blood pressure response to calcium entry blockers in lean patients and to beta blockers in obese hypertensive patients., Conclusion: Obesity affects the efficacy of metoprolol and isradipine in reducing blood pressure.

The effects of the calcium antagonist isradipine and the beta-blocker metoprolol, which are based on different antihypertensive therapeutic principles, were evaluated in 52 men with mild-to-moderate hypertension in a 6-week, double-blind, randomized study. Mental stress-testing was performed before and after active treatment. With isradipine (n = 26), the stress-induced responses of cardiac output and total peripheral resistance were not significantly changed, but the blood pressure (BP) response, specifically the diastolic response, was decreased. With metoprolol (n = 26), there was a decreased response of cardiac output and an increased response of total peripheral resistance, and the BP response was even greater than it had been before treatment. Thus, these results indicate that beta-blockade is effective in reducing cardiac responsiveness but, because of vascular counterregulatory mechanisms, BP responsiveness is not decreased. In contrast, calcium antagonism preserves the physiological hemodynamic profile while reducing BP responsiveness to stress.

To determine whether calcium antagonists might be used alternatively to beta-blockers in antihypertensive therapy, we investigated if monotherapy with oxprenolol (160-320 mg/day) and nitrendipine (20-40 mg/day) were equally effective on clinical casual blood pressure (BP), ambulatory BP monitoring (Remler), and BP during mental challenge (video game). In a prospective randomized long-term study, 60 white male civil servants (mean +/- SD = 43 +/- 6 years) with mild essential hypertension only were treated for at least 4 months. Average BP before therapy was 149 +/- 11/97 +/- 11 mm Hg. The antihypertensive effect was not different between the two groups (19/14 versus 21/12 mm Hg). Both groups did not differ in BP at rest, in BP during mental challenge (141 +/- 7/109 +/- 5 versus 146 +/- 9/112 +/- 8 mm Hg, NS), and average ambulatory BP monitoring at work (122 +/- 12/81 +/- 17 versus 132 +/- 14/79 +/- 17 mm Hg, NS), which was identical with the clinical casual BP. Thus, nitrendipine can effectively be used in long-term baseline antihypertensive monotherapy.

To evaluate the role of the sympathetic nervous system in essential hypertension and the influence of clonidine, 28 male subjects with mild to moderate hypertension were either treated with low-dose clonidine (n = 14, mean age: 42.4 +/- 2.1 years) or were randomized to a nontreated control group (n = 14, mean age: 40.2 +/- 2.4 years). Clinical blood pressure and heart rate were assessed, and after 4 weeks of treatment plasma catecholamines and the hemodynamic response to mental arithmetic, cold stimulation, and ergometric exercise were compared between both groups. Under therapy with 0.075 mg of clonidine per day casual blood pressure dropped and diastolic BP was significantly lower than in the control group. Heart rate did not change. After 4 weeks the plasma levels of epinephrine and norepinephrine were the same in both groups. During mental arithmetic total peripheral resistance decreased in the treated group while it did not change in the control group, but both groups did not differ in their percentage changes in the hemodynamic parameters in response to the three stress tests. It has been concluded that clonidine reduces sympathoadrenergic activity, but in a low dosage this effect is obviously restricted to a reduction of arteriolar tone.

Cardiovascular reactivity to mental stress was studied in 41 male borderline hypertensives in comparison with 37 male normotensives of the same age. In addition to a higher near-basal blood pressure, the borderline hypertensive group showed stronger absolute and percentage increases of systolic and diastolic blood pressure during stress. The increases of heart rate and cardiac output and the decreases of total peripheral resistance were also greater in borderline hypertensives. Stroke volume showed a slight increase only in this group. The reaction of mean arterial pressure correlated in both groups with the increase of cardiac output. The relationship between the reactions of cardiac output and total peripheral resistance was high both in normotensives and borderline hypertensives, and the regression line in normotensives was shifted to the right in borderline hypertensives. The results indicate an increased integrated change of circulatory parameters during mental stress in borderline hypertension, with a dominantly stronger cardiac reaction. They underline the significance of an autonomic imbalance for the pathogenesis of borderline hypertension.

A method of determining baroreceptor reflex sensitivity is proposed that is based on spectral analysis of systolic pressure values and RR interval times, namely, the modulus (or gain) in the mid frequency band (0.07-0.14 Hz) between these two signals. Results using this method were highly correlated (0.94; n = 8) with results of the phenylephrine method. In addition, compared with the values for the preceding rest period, the modulus decreased during mental challenge, as might be expected from the literature.