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.

Skin dysbiosis and loss of microbiome site specificity in critically ill patients.

An increasing amount of evidence has linked critical illness with dysbiotic microbiome signatures in different body sites. The disturbance of the indigenous microbiota structures has been further associated with disease severity and outcome and has been suggested to pose an additional risk for complications in intensive care units (ICUs), including hospital-acquired infections. A better understanding of the microbial dysbiosis in critical illness might thus help to develop strategies for the prevention of such complications. While most of the studies addressing microbiome changes in ICU patients have focused on the gut, the lung, or the oral cavity, little is known about the microbial communities on the skin of ICU patients. Since the skin is the outermost organ and the first immune barrier against pathogens, its microbiome might play an important role in the risk management for critically ill patients. This observational study characterizes the skin microbiome in ICU patients covering five different body sites at the time of admission. Our results show a profound dysbiosis on the skin of critically ill patients, which is characterized by a loss of site specificity and an overrepresentation of gut bacteria on all skin sites when compared to a healthy group. This study opens a new avenue for further investigations on the effect of skin dysbiosis in the ICU setting and points out the need of strategies for the management of dysbiosis in critically ill patients.IMPORTANCEUnbalanced gut microbiota in critically ill patients has been associated with poor outcome and complications during the intensive care unit (ICU) stay. Whether the disturbance of the microbial communities in these patients is extensive for other body sites, such as the skin, is largely unknown. The skin not only is the largest organ of the body but also serves as the first immune barrier against potential pathogens. This study characterized the skin microbiota on five different body sites in ICU patients at the time of admission. The observed disturbance of the bacterial communities might help to develop new strategies in the risk management of critically ill patients.

Sepsis and underlying comorbidities in intensive care unit patients : Analysis of the cause of death by different clinicians-a pilot study.

BACKGROUND: There is an ongoing debate as to whether death with sepsis is primarily caused by sepsis or, more often, by the underlying disease. There are no data on the influence of a researcher's background on such an assessment. Therefore, the aim of this analysis was to assess the cause of death in sepsis and the influence of an investigator's professional background on such an assessment. MATERIALS AND METHODS: We performed a retrospective observational cohort study of sepsis patients treated in the medical intensive care unit (ICU) of a tertiary care center. For deceased patients, comorbidities and severity of illness were documented. The cause of death (sepsis or comorbidities or both combined) was independently assessed by four assessors with different professional backgrounds (medical student, senior physician in the medical ICU, anesthesiological intensivist, and senior physician specialized in the predominant comorbidity). RESULTS: In all, 78 of 235 patients died in hospital. Agreement between assessors about cause of death was low (κ 0.37, 95% confidence interval 0.29-0.44). Depending on the assessor, sepsis was the sole cause of death in 6-12% of cases, sepsis and comorbidities in 54-76%, and comorbidities alone in 18-40%. CONCLUSIONS: In a relevant proportion of patients with sepsis treated in the medical ICU, comorbidities contribute significantly to mortality, and death from sepsis without relevant comorbidities is a rare event. Designation of the cause of death in sepsis patients is highly subjective and may be influenced by the professional background of the assessor.

The non-canonical inflammasome activators Caspase-4 and Caspase-5 are differentially regulated during immunosuppression-associated organ damage.

The non-canonical inflammasome, which includes caspase-11 in mice and caspase-4 and caspase-5 in humans, is upregulated during inflammatory processes and activated in response to bacterial infections to carry out pyroptosis. Inadequate activity of the inflammasome has been associated with states of immunosuppression and immunopathological organ damage. However, the regulation of the receptors caspase-4 and caspase-5 during severe states of immunosuppression is largely not understood. We report that CASP4 and CASP5 are differentially regulated during acute-on-chronic liver failure and sepsis-associated immunosuppression, suggesting non-redundant functions in the inflammasome response to infection. While CASP5 remained upregulated and cleaved p20-GSDMD could be detected in sera from critically ill patients, CASP4 was downregulated in critically ill patients who exhibited features of immunosuppression and organ failure. Mechanistically, downregulation of CASP4 correlated with decreased gasdermin D levels and impaired interferon signaling, as reflected by decreased activity of the CASP4 transcriptional activators IRF1 and IRF2. Caspase-4 gene and protein expression inversely correlated with markers of organ dysfunction, including MELD and SOFA scores, and with GSDMD activity, illustrating the association of CASP4 levels with disease severity. Our results document the selective downregulation of the non-canonical inflammasome activator caspase-4 in the context of sepsis-associated immunosuppression and organ damage and provide new insights for the development of biomarkers or novel immunomodulatory therapies for the treatment of severe infections.

Quality indicators in intensive care medicine for Germany - fourth edition 2022.

The measurement of quality indicators supports quality improvement initiatives. The German Interdisciplinary Society of Intensive Care Medicine (DIVI) has published quality indicators for intensive care medicine for the fourth time now. After a scheduled evaluation after three years, changes in several indicators were made. Other indicators were not changed or only minimally. The focus remained strongly on relevant treatment processes like management of analgesia and sedation, mechanical ventilation and weaning, and infections in the ICU. Another focus was communication inside the ICU. The number of 10 indicators remained the same. The development method was more structured and transparency was increased by adding new features like evidence levels or author contribution and potential conflicts of interest. These quality indicators should be used in the peer review in intensive care, a method endorsed by the DIVI. Other forms of measurement and evaluation are also reasonable, for example in quality management. This fourth edition of the quality indicators will be updated in the future to reflect the recently published recommendations on the structure of intensive care units by the DIVI.

The prevalence of sepsis-induced coagulopathy in patients with sepsis - a secondary analysis of two German multicenter randomized controlled trials.

BACKGROUND: Sepsis and septic shock are frequently accompanied by coagulopathy. Since the sepsis-induced coagulopathy (SIC) score was first described, subsequent studies from Asia revealed a SIC prevalence of 40-60%. In Europe, however, SIC prevalence in patients fulfilling sepsis criteria according to the third international consensus definition (SEPSIS-3) has not yet been evaluated. METHODS: The Critical Care Trials Group of the German Sepsis Competence Network (SepNet) conducted a secondary analysis of two randomized controlled trials. Only patients fulfilling sepsis criteria according SEPSIS-3 were included in this secondary analysis. In a two step approach, SIC prevalence was determined in 267 patients with sepsis but not septic shock (at the time of inclusion) from the "Effect of Hydrocortisone on Development of Shock Among Patients With Severe Sepsis" (HYPRESS) trial. Then, we estimated SIC prevalence in 1,018 patients from the "Effect of Sodium Selenite Administration and Procalcitonin-Guided Therapy on Mortality in Patients With Severe Sepsis or Septic Shock" (SISPCT) trial using a simplified SIC score based on the platelet-SIC-subscore (PSSC). Study aims were to assess (i) the prevalence of SIC in patients with SEPSIS-3, (ii) the association of SIC with 90-day mortality and morbidity, (iii) the time when patients become SIC positive during the course of sepsis, and (iv) the value of the PSSC for predicting SIC. RESULTS: In the HYPRESS trial, SIC prevalence was 22.1% (95% confidence interval [CI] 17.5-27.5%). The estimated SIC prevalence in the SISPCT trial was 24.2% (95% CI 21.6-26.9%). In the HYPRESS trial, SIC was associated with significantly higher 90-day mortality (13.9% vs. 26.8%, p = 0.027) and morbidity. Logistic regression analysis adjusted for age, sex, treatment arm, and (SIC-adapted) SOFA score confirmed the negative association of SIC with survival (p = 0.011). In the SISPCT trial, increased PSSCs were associated with higher 90-day mortality (PSSC 0: 34.4%, PSSC 1: 40.5%, PSSC 2: 53.3%; p < 0.001). In both trials, SIC was already present at sepsis diagnosis or occurred during the following 4 days. CONCLUSIONS: SIC is a clinically relevant complication of sepsis. Although it might be less frequent than previously reported, its occurrence is associated with higher morbidity and mortality and should be interpreted as an early warning sign.

[Therapy of sepsis]. / Therapie der Sepsis.

Sepsis as a development of an acute infection-related organ dysfunction significantly increases the risk of death for the patient. Therefore, fast and consistent management is required. The sepsis bundle is a convenient algorithm for initial sepsis therapy within the first hour of sepsis diagnosis consisting of blood cultures, lactate measurement, antibiotics, fluid resuscitation, and vasopressor therapy. Cristalloid solutions are first choice for fluid therapy but albumin and gelatine may be considered if colloid solutions are required. Norepinephrine is the vasopressor of first choice. After initial therapy, further fluid resuscitation should be guided by dynamic criteria. Vasopressin may be added as an additional vasopressor. Goal of resuscitation is to achieve lactate clearance. In shock refractory to therapy, addition of hydrocortisone (200 mg/day) should be considered. Further additional therapies such as immunoglobulins, blood purification, and metabolic resuscitation (combination of hydrocortisone, thiamine, vitamine C) are currently not supported by studies and should not be considered as standard therapy.

Infliximab in the treatment of patients with severe COVID-19 (INFLIXCOVID): protocol for a randomised, controlled, multicentre, open-label phase II clinical study.

BACKGROUND: Despite the intense global research endeavour to improve the treatment of patients with COVID-19, the current therapy remains insufficient, resulting in persisting high mortality. Severe cases are characterised by a systemic inflammatory reaction driven by the release of pro-inflammatory cytokines such as IL-6 and tumour-necrosis-factor alpha (TNF-α). TNF-α-blocking therapies have proved beneficial in patients with chronic inflammatory diseases and could therefore pose a new treatment option in COVID-19. Hitherto, no results from randomised controlled trials assessing the effectiveness and safety of infliximab-a monoclonal antibody targeting TNF-α-in the treatment of COVID-19 have been published. METHODS: In this phase-2 clinical trial, patients with COVID-19 and clinical and laboratory signs of hyperinflammation will be randomised to receive either one dose of infliximab (5 mg/kg body weight) in addition to the standard of care or the standard of care alone. The primary endpoint is the difference in 28-day mortality. Further assessments concern the safety of infliximab therapy in COVID-19 and the influence of infliximab on morbidity and the course of the disease. For the supplementary scientific programme, blood and urine samples are collected to assess concomitant molecular changes. The Ethics Committee of the Friedrich Schiller University Jena (2021-2236-AMG-ff) and the Paul-Ehrlich-Institute (4513/01) approved the study. DISCUSSION: The results of this study could influence the therapy of patients with COVID-19 and affect the course of the disease worldwide, as infliximab is globally available and approved by several international drug agencies. TRIAL REGISTRATION: The trial was registered at clinicaltrials.gov ( NCT04922827 , 11 June 2021) and at EudraCT ( 2021-002098-25 , 19 May 2021).

(1 → 3)-ß-D-Glucan-guided antifungal therapy in adults with sepsis: the CandiSep randomized clinical trial.

PURPOSE: To investigate whether (1 → 3)-ß-d-Glucan (BDG)-guidance shortens time to antifungal therapy and thereby reduces mortality of sepsis patients with high risk of invasive Candida infection (ICI). METHODS: Multicenter, randomized, controlled trial carried out between September 2016 and September 2019 in 18 intensive care units enrolling adult sepsis patients at high risk for ICI. Patients in the control group received targeted antifungal therapy driven by culture results. In addition to targeted therapy, patients in the BDG group received antifungals if at least one of two consecutive BDG samples taken during the first two study days was ≥ 80 pg/mL. Empirical antifungal therapy was discouraged in both groups. The primary endpoint was 28-day-mortality. RESULTS: 339 patients were enrolled. ICI was diagnosed in 48 patients (14.2%) within the first 96 h after enrollment. In the BDG-group, 48.8% (84/172) patients received antifungals during the first 96 h after enrollment and 6% (10/167) patients in the control group. Death until day 28 occurred in 58 of 172 patients (33.7%) in the BDG group and 51 of 167 patients (30.5%) in the control group (relative risk 1.10; 95% confidence interval, 0.80-1.51; p = 0.53). Median time to antifungal therapy was 1.1 [interquartile range (IQR) 1.0-2.2] days in the BDG group and 4.4 (IQR 2.0-9.1, p < 0.01) days in the control group. CONCLUSIONS: Serum BDG guided antifungal treatment did not improve 28-day mortality among sepsis patients with risk factors for but unexpected low rate of IC. This study cannot comment on the potential benefit of BDG-guidance in a more selected at-risk population.

New, Useful Criteria for Assessing the Evidence of Infection in Sepsis Research.

OBJECTIVES: The Sepsis-3 definition states the clinical criteria for sepsis but lacks clear definitions of the underlying infection. To address the lack of applicable definitions of infection for sepsis research, we propose new criteria, termed the Linder-Mellhammar criteria of infection (LMCI). The aim of this study was to validate these new infection criteria. DESIGN: A multicenter cohort study of patients with suspected infection who were admitted to emergency departments or ICUs. Data were collected from medical records and from study investigators. SETTING: Four academic hospitals in Sweden, Switzerland, the Netherlands, and Germany. PATIENTS: A total of 934 adult patients with suspected infection or suspected sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Agreement of infection site classification was measured using the LMCI with Cohen κ coefficient, compared with the Calandra and Cohen definitions of infection and diagnosis on hospital discharge as references. In one of the cohorts, comparisons were also made to adjudications by an expert panel. A subset of patients was assessed for interobserver agreement. MEASUREMENTS AND MAIN RESULTS: The precision of the LMCI varied according to the applied reference. LMCI performed better than the Calandra and Cohen definitions (κ = 0.62 [95% CI, 0.59-0.65] vs κ = 0.43 [95% CI, 0.39-0.47], respectively) and the diagnosis on hospital discharge (κ = 0.57 [95% CI, 0.53-0.61] vs κ = 0.43 [95% CI, 0.39-0.47], respectively). The interobserver agreement for the LMCI was evaluated in 91 patients, with agreement in 77%, κ = 0.72 (95% CI, 0.60-0.85). When tested with adjudication as the gold standard, the LMCI still outperformed the Calandra and Cohen definitions (κ = 0.65 [95% CI, 0.60-0.70] vs κ = 0.29 [95% CI, 0.24-0.33], respectively). CONCLUSIONS: The LMCI is useful criterion of infection that is intended for sepsis research, in and outside of the ICU. Useful criteria for infection have the potential to facilitate more comparable sepsis research and exclude sepsis mimics from clinical studies, thus improving and simplifying sepsis research.

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 .

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.

ImmunoSep (Personalised Immunotherapy in Sepsis) international double-blind, double-dummy, placebo-controlled randomised clinical trial: study protocol.

INTRODUCTION: Sepsis is a major cause of death among hospitalised patients. Accumulating evidence suggests that immune response during sepsis cascade lies within a spectrum of dysregulated host responses. On the one side of the spectrum there are patients whose response is characterised by fulminant hyperinflammation or macrophage activation-like syndrome (MALS), and on the other side patients whose immune response is characterised by immunoparalysis. A sizeable group of patients are situated between the two extremes. Recognising immune endotype is very important in order to choose the appropriate immunotherapeutic approach for each patient resulting in the best chance to improve the outcome. METHODS AND ANALYSIS: ImmunoSep is a randomised placebo-controlled phase 2 clinical trial with a double-dummy design in which the effect of precision immunotherapy on sepsis phenotypes with MALS and immunoparalysis is studied. Patients are stratified using biomarkers. Specifically, 280 patients will be 1:1 randomly assigned to placebo or active immunotherapy as adjunct to standard-of-care treatment. In the active immunotherapy arm, patients with MALS will receive anakinra (recombinant interleukin-1 receptor antagonist) intravenously, and patients with immunoparalysis will receive subcutaneous recombinant human interferon-gamma. Τhe primary endpoint is the comparative decrease of the mean total Sequential Organ Failure Assessment score by at least 1.4 points by day 9 from randomisation. ETHICS AND DISSEMINATION: The protocol is approved by the German Federal Institute for Drugs and Medical Devices; the National Ethics Committee of Greece and by the National Organization for Medicines of Greece; the Central Committee on Research Involving Human Subjects and METC Oost Netherland for the Netherlands; the National Agency for Medicine and Medical Products of Romania; and the Commission Cantonale d'éthique de la recherche sur l'être human of Switzerland. The results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04990232.

Risk Factors for Invasive Candida Infection in Critically Ill Patients: A Systematic Review and Meta-analysis.

BACKGROUND: Current guidelines recommend empirical antifungal therapy in patients with sepsis with high risk of invasive Candida infection. However, many different risk factors have been derived from multiple studies. These risk factors lack specificity, and broad application would render most ICU patients eligible for empirical antifungal therapy. RESEARCH QUESTION: What risk factors for invasive Candida infection can be identified by a systematic review and meta-analysis? STUDY DESIGN AND METHODS: We searched PubMed, Web of Science, ScienceDirect, Biomed Central, and Cochrane and extracted the raw and adjusted OR for each risk factor associated with invasive Candida infection. We calculated pooled ORs for risk factors present in more than one study. RESULTS: We included 34 studies in our meta-analysis resulting in the assessment of 29 possible risk factors. Risk factors for invasive Candida infection included demographic factors, comorbid conditions, and medical interventions. Although demographic factors do not play a role for the development of invasive Candida infection, comorbid conditions (eg, HIV, Candida colonization) and medical interventions have a significant impact. The risk factors associated with the highest risk for invasive Candida infection were broad-spectrum antibiotics (OR, 5.6; 95% CI, 3.6-8.8), blood transfusion (OR, 4.9; 95% CI, 1.5-16.3), Candida colonization (OR, 4.7; 95% CI, 1.6-14.3), central venous catheter (OR, 4.7; 95% CI, 2.7-8.1), and total parenteral nutrition (OR, 4.6; 95% CI, 3.3-6.3). However, dependence between the various risk factors is probably high. INTERPRETATION: Our systematic review and meta-analysis identified patient- and treatment-related factors that were associated with the risk for the development of invasive Candida infection in the ICU. Most of the factors identified were either related to medical interventions during intensive care or to comorbid conditions.

Efficacy and Safety of Vilobelimab (IFX-1), a Novel Monoclonal Anti-C5a Antibody, in Patients With Early Severe Sepsis or Septic Shock-A Randomized, Placebo-Controlled, Double-Blind, Multicenter, Phase IIa Trial (SCIENS Study).

Anaphylatoxin C5a, a proinflammatory complement split product, plays a central role in mediating organ dysfunction. OBJECTIVES: This phase II clinical trial was conducted to study safety, tolerability, pharmacokinetics, and pharmacodynamics of vilobelimab, a recombinant monoclonal antibody against C5a, in patients with severe sepsis or septic shock. DESIGN: Multicenter, randomized, and placebo-controlled study. SETTING AND PARTICIPANTS: Eleven multidisciplinary ICUs across Germany. Adult patients with severe sepsis or septic shock and with early onset of infection-associated organ dysfunction. MAIN OUTCOMES AND MEASURES: Patients were randomly assigned in a ratio of 2:1 to three subsequent dosing cohorts for IV vilobelimab or placebo receiving either 2 × 2 mg/kg (0 and 12 hr), 2 × 4 mg/kg (0 and 24 hr), and 3 × 4 mg/kg (0, 24, and 72 hr). Co-primary endpoints were pharmacodynamics (assessed by C5a concentrations), pharmacokinetics (assessed by vilobelimab concentrations), and safety of vilobelimab. Preliminary efficacy was evaluated by secondary objectives. RESULTS: Seventy-two patients were randomized (16 patients for each vilobelimab dosing cohort and eight patients for each placebo dosing cohort). Vilobelimab application was associated with dosing dependent decrease in C5a compared with baseline (p < 0.001). Duration of C5a decrease increased with more frequent dosing. Membrane attack complex lysis capacity measured by 50% hemolytic complement was not affected. Vilobelimab was well tolerated with similar safety findings in all dose cohorts. No vilobelimab-specific adverse events emerged. For vilobelimab-treated patients, investigators attributed less treatment-emergent adverse events as related compared with placebo. Dosing cohorts 2 and 3 had the highest ICU-free and ventilator-free days. There was no difference in mortality, vasopressor-free days, or renal replacement therapy-free days between the groups. CONCLUSIONS AND RELEVANCE: Administration of vilobelimab in patients with severe sepsis and septic shock selectively neutralizes C5a in a dose-dependent manner without blocking formation of the membrane attack complex and without resulting in detected safety issues. The data warrant further investigation of C5a inhibition in sepsis.

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.

Algorithmic surveillance of ICU patients with acute respiratory distress syndrome (ASIC): protocol for a multicentre stepped-wedge cluster randomised quality improvement strategy.

INTRODUCTION: The acute respiratory distress syndrome (ARDS) is a highly relevant entity in critical care with mortality rates of 40%. Despite extensive scientific efforts, outcome-relevant therapeutic measures are still insufficiently practised at the bedside. Thus, there is a clear need to adhere to early diagnosis and sufficient therapy in ARDS, assuring lower mortality and multiple organ failure. METHODS AND ANALYSIS: In this quality improvement strategy (QIS), a decision support system as a mobile application (ASIC app), which uses available clinical real-time data, is implemented to support physicians in timely diagnosis and improvement of adherence to established guidelines in the treatment of ARDS. ASIC is conducted on 31 intensive care units (ICUs) at 8 German university hospitals. It is designed as a multicentre stepped-wedge cluster randomised QIS. ICUs are combined into 12 clusters which are randomised in 12 steps. After preparation (18 months) and a control phase of 8 months for all clusters, the first cluster enters a roll-in phase (3 months) that is followed by the actual QIS phase. The remaining clusters follow in month wise steps. The coprimary key performance indicators (KPIs) consist of the ARDS diagnostic rate and guideline adherence regarding lung-protective ventilation. Secondary KPIs include the prevalence of organ dysfunction within 28 days after diagnosis or ICU discharge, the treatment duration on ICU and the hospital mortality. Furthermore, the user acceptance and usability of new technologies in medicine are examined. To show improvements in healthcare of patients with ARDS, differences in primary and secondary KPIs between control phase and QIS will be tested. ETHICS AND DISSEMINATION: Ethical approval was obtained from the independent Ethics Committee (EC) at the RWTH Aachen Faculty of Medicine (local EC reference number: EK 102/19) and the respective data protection officer in March 2019. The results of the ASIC QIS will be presented at conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: DRKS00014330.

Ex vivo immune profiling in patient blood enables quantification of innate immune effector functions.

The assessment of a patient's immune function is critical in many clinical situations. In complex clinical immune dysfunction like sepsis, which results from a loss of immune homeostasis due to microbial infection, a plethora of pro- and anti-inflammatory stimuli may occur consecutively or simultaneously. Thus, any immunomodulatory therapy would require in-depth knowledge of an individual patient's immune status at a given time. Whereas lab-based immune profiling often relies solely on quantification of cell numbers, we used an ex vivo whole-blood infection model in combination with biomathematical modeling to quantify functional parameters of innate immune cells in blood from patients undergoing cardiac surgery. These patients experience a well-characterized inflammatory insult, which results in mitigation of the pathogen-specific response patterns towards Staphylococcus aureus and Candida albicans that are characteristic of healthy people and our patients at baseline. This not only interferes with the elimination of these pathogens from blood, but also selectively augments the escape of C. albicans from phagocytosis. In summary, our model could serve as a valuable functional immune assay for recording and evaluating innate responses to infection.

Leukocyte Activation Profile Assessed by Raman Spectroscopy Helps Diagnosing Infection and Sepsis.

OBJECTIVES: Leukocytes are first responders to infection. Their activation state can reveal information about specific host immune response and identify dysregulation in sepsis. This study aims to use the Raman spectroscopic fingerprints of blood-derived leukocytes to differentiate inflammation, infection, and sepsis in hospitalized patients. Diagnostic sensitivity and specificity shall demonstrate the added value of the direct characterization of leukocyte's phenotype. DESIGN: Prospective nonrandomized, single-center, observational phase-II study (DRKS00006265). SETTING: Jena University Hospital, Germany. PATIENTS: Sixty-one hospitalized patients (19 with sterile inflammation, 23 with infection without organ dysfunction, 18 with sepsis according to Sepsis-3 definition). INTERVENTIONS: None (blood withdrawal). MEASUREMENTS AND MAIN RESULTS: Individual peripheral blood leukocytes were characterized by Raman spectroscopy. Reference diagnostics included established clinical scores, blood count, and biomarkers (C-reactive protein, procalcitonin and interleukin-6). Binary classification models using Raman data were able to distinguish patients with infection from patients without infection, as well as sepsis patients from patients without sepsis, with accuracies achieved with established biomarkers. Compared with biomarker information alone, an increase of 10% (to 93%) accuracy for the detection of infection and an increase of 18% (to 92%) for detection of sepsis were reached by adding the Raman information. Leukocytes from sepsis patients showed different Raman spectral features in comparison to the patients with infection that point to the special immune phenotype of sepsis patients. CONCLUSIONS: Raman spectroscopy can extract information on leukocyte's activation state in a nondestructive, label-free manner to differentiate sterile inflammation, infection, and sepsis.

Population pharmacokinetics and probability of target attainment in patients with sepsis under renal replacement therapy receiving continuous infusion of meropenem: Sustained low-efficiency dialysis and continuous veno-venous haemodialysis.

AIMS: To describe the population pharmacokinetics (PK) and probability of target attainment (PTA) of continuous infusion (CI) of meropenem in septic patients receiving renal replacement therapy (RRT). METHODS: Fifteen patients without RRT, 13 patients receiving sustained low-efficiency dialysis and 12 patients receiving continuous veno-venous haemodialysis were included. Population PK analysis with Monte Carlo simulations for different dosing regimens was performed. For minimum inhibitory concentration 2 mg/L was chosen. The target was set as 50% time ≥4× minimum inhibitory concentration. RESULTS: The PK of meropenem was best described by a 1-compartment model with linear elimination. Serum creatinine, residual diuresis and time on RRT, with no difference between sustained low-efficiency dialysis and continuous veno-venous haemodialysis, were found to be significant covariates affecting clearance, explaining >20% of the clearance between subject variability. PTA analysis showed that in patients with RRT, 2 g/24 h, meropenem CI achieved a PTA of 95%. In patients without RRT, the target was achieved with 3 g/24 h CI or prolonged infusion of 1 g meropenem over 8 hours but not with bolus application of 1 g meropenem for 8 hours. Only 2 patients (both without RRT) had meropenem concentrations below the target level. However, approximately half of the patients with RRT receiving CI 3 g/24 h meropenem had toxic concentrations. CONCLUSION: We found relevant PK variability for meropenem CI in septic patients with or without RRT, leading to a substantial risk for overdosing in patients with RRT. This finding highlights the strong demand for personalized dosing in critically ill patients.