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Sepsis is a life-threatening syndrome triggered by infection and accompanied by high mortality, with antimicrobial resistances (AMRs) further escalating clinical challenges. The rapid and reliable detection of causative pathogens and AMRs are key factors for fast and appropriate treatment, in order to improve outcomes in septic patients. However, current sepsis diagnostics based on blood culture is limited by low sensitivity and specificity while current molecular approaches fail to enter clinical routine. Therefore, we developed a suppression PCR-based selective enrichment sequencing approach (SUPSETS), providing a molecular method combining multiplex suppression PCR with Nanopore sequencing to identify most common sepsis-causative pathogens and AMRs using plasma cell-free DNA. Applying only 1 mL of plasma, we targeted eight pathogens across three kingdoms and ten AMRs in a proof-of-concept study. SUPSETS was successfully tested in an experimental research study on the first ten clinical samples and revealed comparable results to clinical metagenomics while clearly outperforming blood culture. Several clinically relevant AMRs could be additionally detected. Furthermore, SUPSETS provided first pathogen and AMR-specific sequencing reads within minutes of starting sequencing, thereby potentially decreasing time-to-results to 11-13 h and suggesting diagnostic potential in sepsis.

Triggering receptor expressed on myeloid cells-1 (TREM-1) is a pattern recognition receptor and plays a critical role in the immune response. TREM-1 activation leads to the production and release of proinflammatory cytokines, chemokines, as well as its own expression and circulating levels of the cleaved soluble extracellular portion of TREM-1 (sTREM-1). Because patients with sepsis and septic shock show elevated sTREM-1 levels, TREM-1 has attracted attention as an important contributor to the inadequate immune response in this often-deadly condition. Since 2001, when the first blockade of TREM-1 in sepsis was performed, many potential TREM-1 inhibitors have been established in animal models. However, only one of them, nangibotide, has entered clinical trials, which have yielded promising data for future treatment of sepsis, septic shock, and other inflammatory disease such as COVID-19. This review discusses the TREM-1 pathway and important ligands, and highlights the development of novel inhibitors as well as their clinical potential for targeted treatment of various inflammatory conditions., (© 2024. The Author(s).)

The time to administration of broad-spectrum antibiotics and (secondarily) to the initiation of hemodynamic stabilization are the most important factors influencing survival of patients with sepsis and septic shock; however, the basic prerequisite for the initiation of an adequate treatment is that a suspected diagnosis of sepsis is made first. Therefore, the treatment of sepsis, even before it has begun, is an interdisciplinary and interprofessional task. This article provides an overview of the current state of the art in sepsis treatment and points towards new evidence that has the potential to change guideline recommendations in the coming years. In summary, the following points are critical: (1) sepsis must be diagnosed as soon as possible and the implementation of a source control intervention (in case of a controllable source) has to be implemented as soon as (logistically) possible. (2) In general, intravenous broad-spectrum antibiotics should be given within the first hour after diagnosis if sepsis or septic shock is suspected. In organ dysfunction without shock, where sepsis is a possible but unlikely cause, the results of focused advanced diagnostics should be awaited before a decision to give broad-spectrum antibiotics is made. If it is not clear within 3 h whether sepsis is the cause, broad-spectrum antibiotics should be given when in doubt. Administer beta-lactam antibiotics as a prolonged (or if therapeutic drug monitoring is available, continuous) infusion after an initial loading dose. (3) Combination treatment with two agents for one pathogen group should remain the exception (e.g. multidrug-resistant gram-negative pathogens). (4) In the case of doubt, the duration of anti-infective treatment should rather be shorter than longer. Procalcitonin can support the clinical decision to stop (not to start!) antibiotic treatment! (5) For fluid treatment, if hypoperfusion is present, the first (approximately) 2L (30 ml/kg BW) of crystalloid solution is usually safe and indicated. After that, the rule is: less is more! Any further fluid administration should be carefully weighed up with the help of dynamic parameters, the patient's clinical condition and echo(cardio)graphy., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Acute kidney injury (AKI) secondary to sepsis results in poor outcomes and conventional kidney function indicators lack diagnostic value. Soluble urokinase plasminogen activator receptor (suPAR) is an innate immune-derived molecule implicated in inflammatory organ damage. We characterized the diagnostic ability of longitudinal serum suPAR levels to discriminate severity and course of sepsis-induced AKI (SI-AKI) in 200 critically ill patients meeting Sepsis-3 criteria. The pathophysiologic relevance of varying suPAR levels in SI-AKI was explored in a polymicrobial sepsis model in WT, (s)uPAR-knockout, and transgenic suPAR-overexpressing mice. At all time points studied, suPAR provided a robust classification of SI-AKI disease severity, with improved prediction of renal replacement therapy (RRT) and mortality compared with established kidney biomarkers. Patients with suPAR levels of greater than 12.7 ng/mL were at highest risk for RRT or death, with an adjusted odds ratio of 7.48 (95% CI, 3.00-18.63). suPAR deficiency protected mice against SI-AKI. suPAR-overexpressing mice exhibited greater kidney damage and poorer survival through inflamed kidneys, accompanied by local upregulation of potent chemoattractants and pronounced kidney T cell infiltration. Hence, suPAR allows for an innate immune-derived and kidney function-independent staging of SI-AKI and offers improved longitudinal risk stratification. suPAR promotes T cell-based kidney inflammation, while suPAR deficiency improves SI-AKI.

Rationale: Sepsis, a global health burden, is often complicated by viral infections leading to increased long-term morbidity and mortality. Interleukin-3 (IL-3) has been identified as an important mediator amplifying acute inflammation in sepsis; however, its function in the host response to viral infections during sepsis remains elusive., Objectives: To investigate the role of IL-3 during viral pneumonia in sepsis., Methods: We included septic patients from two different cohorts and used in vitro and in vivo assays. The obtained data were substantiated using a second model (SARS-CoV-2 infections)., Measurements and Main Results: Low plasma IL-3 levels were associated with increased herpes simplex virus (HSV) airway infections in septic patients, resulting in reduced overall survival. Likewise, Il-3 -deficient septic mice were more susceptible to pulmonary HSV-1 infection and exhibited higher pulmonary inflammation than control mice. Mechanistically, IL-3 increases innate antiviral immunity by promoting the recruitment of circulating plasmacytoid dendritic cells (pDCs) into the airways and by enhancing pDC-mediated T cell activation upon viral stimulation. Interestingly, the ability of IL-3 to improve adaptive immunity was confirmed in patients with SARS-CoV-2 infections., Conclusion: Our study identifies IL-3 as a predictive disease marker for viral reactivation in sepsis and reveals that IL-3 improves antiviral immunity by enhancing the recruitment and the function of pDCs., Competing Interests: The 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 © 2023 Bénard, Hansen, Uhle, Klösch, Czubayko, Mittelstädt, Jacobsen, David, Podolska, Anthuber, Swierzy, Schaack, Mühl-Zürbes, Steinkasserer, Weyand, Weigand, Brenner, Krautz, Grützmann and Weber.)

Up to now, sepsis is one of the most threatening diseases and its therapy remains challenging. Sepsis is currently defined as a severely dysregulated immune response to an infection resulting in organ dysfunction. The pathophysiology is mainly driven by exogenous PAMPs ("pathogen-associated molecular patterns") and endogenous DAMPs ("damage-associated molecular patterns"), which can activate PRRs ("pattern recognition receptors") on different cell types (mainly immune cells), leading to the initiation of manifold downstream pathways and a perpetuation of patients' immune response. Sepsis is neither an exclusive pro- nor an anti-inflammatory disease: both processes take place in parallel, resulting in an individual immunologic disease state depending on the severity of each component at different time points. Septic shock is a complex disorder of the macro- and microcirculation, provoking a severe lack of oxygenation further aggravating sepsis defining organ dysfunctions. An in-depth knowledge of the heterogeneity and the time-dependency of the septic immunopathology will be essential for the design of future sepsis trials and therapy planning in patients with sepsis. The big aim is to achieve a more individualized treatment strategy in patients suffering from sepsis or septic shock., Competing Interests: Erklärung zu finanziellen Interessen Forschungsförderung erhalten: ja, von einer anderen Institution (Pharma- oder Medizintechnikfirma usw.); Honorar/geldwerten Vorteil für Referententätigkeit erhalten: ja, von einer anderen Institution (Pharma- oder Medizintechnikfirma usw.); Bezahlter Berater/interner Schulungsreferent/Gehaltsempfänger: ja, von einer anderen Institution (Pharma- oder Medizintechnikfirma usw.); Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an im Bereich der Medizin aktiven Firma: ja; Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an zu Sponsoren dieser Fortbildung bzw. durch die Fortbildung in ihren Geschäftsinteressen berührten Firma: ja Erklärung zu nichtfinanziellen Interessen Thorsten Brenner ist Mitglied des DIVI-Präsidiums, des Vorstandes des Forschungszentrums der DGAI und des SepNet-Vorstandes sowie Stellv. Sprecher der SIS-Sektion der DIVI und der AG Immunologie des TIFOnet der DGAI. Jonas Gregorius gibt an, dasss kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Clinical success of Toll-Like receptor-4 (TLR-4) antagonists in sepsis therapy has thus far been lacking. As inhibition of a receptor can only be useful if the receptor is active, stratification of patients with active TLR-4 would be desirable. Our aim was to establish an assay to quantify phosphorylated TLR-4 using the proximity ligation assay (PLA). HEK293 TLR4/MD2/CD14 as well as THP-1 cells were stimulated with LPS and the activation of TLR-4 was measured using the PLA. Furthermore, peripheral blood mononuclear cells (PBMCs) from 25 sepsis patients were used to show the feasibility of this assay in clinical material. Activation of TLR-4 in these samples was compared to the PBMCs of 11 healthy individuals. We could show a transient activation of TLR-4 in both cell lines. Five min after the LPS stimulation, the signal increased 6.7-fold in the HEK293 cells and 4.3-fold in the THP-1 cells. The assay also worked well in the PBMCs of septic patients. Phosphorylation of TLR-4 at study inclusion was 2.9 times higher in septic patients compared to healthy volunteers. To conclude, we established a diagnostic assay that is able to quantify the phosphorylation of TLR-4 in cell culture and in clinical samples of sepsis patients. This makes large-scale stratification of sepsis patients for their TLR-4 activation status possible.

Purpose: Insufficient antimicrobial exposure is associated with worse outcomes in sepsis. We evaluated whether therapeutic drug monitoring (TDM)-guided antibiotic therapy improves outcomes., Methods: Randomized, multicenter, controlled trial from January 2017 to December 2019. Adult patients (n = 254) with sepsis or septic shock were randomly assigned 1:1 to receive continuous infusion of piperacillin/tazobactam with dosing guided by daily TDM of piperacillin or continuous infusion with a fixed dose (13.5 g/24 h if eGFR ≥ 20 mL/min). Target plasma concentration was four times the minimal inhibitory concentration (range ± 20%) of the underlying pathogen, respectively, of Pseudomonas aeruginosa in empiric situation. Primary outcome was the mean of daily total Sequential Organ Failure Assessment (SOFA) score up to day 10., Results: Among 249 evaluable patients (66.3 ± 13.7 years; female, 30.9%), there was no significant difference in mean SOFA score between patients with TDM (7.9 points; 95% CI 7.1-8.7) and without TDM (8.2 points; 95% CI 7.5-9.0) (p = 0.39). Patients with TDM-guided therapy showed a lower 28-day mortality (21.6% vs. 25.8%, RR 0.8, 95% CI 0.5-1.3, p = 0.44) and a higher rate of clinical (OR 1.9; 95% CI 0.5-6.2, p = 0.30) and microbiological cure (OR 2.4; 95% CI 0.7-7.4, p = 0.12), but these differences did not reach statistical significance. Attainment of target concentration was more common in patients with TDM (37.3% vs. 14.6%, OR 4.5, CI 95%, 2.9-6.9, p < 0.001)., Conclusion: TDM-guided therapy showed no beneficial effect in patients with sepsis and continuous infusion of piperacillin/tazobactam with regard to the mean SOFA score. Larger studies with strategies to ensure optimization of antimicrobial exposure are needed to definitively answer the question., (© 2022. The Author(s).)

Background: A pre-existing anticoagulation treatment and predisposing diseases for thromboembolic events represent common problems in patients with sepsis or septic shock; however, these conditions are not addressed in current national guidelines for sepsis and septic shock. One of the aims of this nationwide survey in Germany was therefore to determine how intensive care physicians deal with these problems., Methods: From October 2019 to May 2020, we conducted a nationwide survey among German medical directors of intensive care units (ICU) addressing anticoagulation and drug-based prophylaxis of venous thromboembolism (VTE) in patients with sepsis and sepsis-induced coagulopathy. One focus was the procedure for patients with a pre-existing anticoagulation treatment or a previously known heparin-induced thrombocytopenia (HIT) type 2 (acute symptomatic vs. dating back years)., Results: In most of the participating ICUs pre-existing anticoagulation is largely continued with low molecular weight heparin preparations or unfractionated heparin. In patients with pre-existing HIT type 2 both acute symptomatic and dating back years, argatroban represents the drug of choice. There is a high degree of variability in the definition of the target values, usually being well above the range for pure VTE prophylaxis., Conclusion: Data on the continuation of anticoagulation beyond VTE prophylaxis with a subsequently increased risk of bleeding in patients with sepsis and septic shock is limited and treatment decisions are in many cases subject to individual consideration by the practitioner. The results of our survey imply the need for a systematic work-up of this topic in order to support daily practice in many ICUs with the required evidence., (© 2021. The Author(s).)

Background: The 11th revision of the International Classification of Diseases (ICD-11) will come into effect in January 2022. Among other things, The Third International Consensus Definitions for Sepsis and Septic Shock (SEPSIS‑3 definition) will be implemented in it. This defines sepsis as a "life-threatening organ dysfunction caused by a dysregulated host response to infection". The aim of the present secondary analysis of a survey on the topic of "sepsis-induced coagulopathy" was to evaluate whether the SEPSIS‑3 definition, 4 years after its international introduction, has arrived in everyday clinical practice of intensive care units (ICU) run by anesthesiologists in Germany and thus the requirements for its use of the ICD-11 are given., Methods: Between October 2019 and May 2020, we carried out a nationwide survey among German medical directors of ICUs. In a separate block of questions we asked about the definition of sepsis used in daily practice. In addition, we asked whether the quick-sequential (sepsis-related) organ failure assessment (qSOFA) score is used in screening for sepsis in the hospital to which to the participating ICU belongs., Results: A total of 50 medical directors from anesthesiological ICUs took part in the survey. In total, the ICUs evaluated stated that they had around 14% of the high-care beds registered in Germany. The SEPSIS‑3 definition is integrated into everyday clinical practice at 78.9% of the university hospitals and 84.0% of the participating teaching hospitals. In contrast, the qSOFA screening test is only used by 26.3% of the participating university hospitals, but at least 52% of the teaching hospitals and 80% of the other hospitals., Conclusion: The data show that both SEPSIS‑3 and qSOFA have become part of everyday clinical practice in German hospitals. The cautious use of qSOFA at university hospitals with simultaneous broad acceptance of the SEPSIS‑3 definition can be interpreted as an indication that the search for a suitable screening test for sepsis has not yet been completed., (© 2021. The Author(s).)

Background: Sepsis is triggered by an infection and represents one of the greatest challenges of modern intensive care medicine. With regard to a targeted antimicrobial treatment strategy, the earliest possible pathogen detection is of crucial importance. Until now, culture-based detection methods represent the diagnostic gold standard, although they are characterized by numerous limitations. Culture-independent molecular diagnostic procedures represent a promising alternative. In particular, the plasmatic detection of circulating, cell-free DNA by next-generation sequencing (NGS) has shown to be suitable for identifying disease-causing pathogens in patients with bloodstream infections., Methods: The DigiSep-Trial is a randomized, controlled, interventional, open-label, multicenter trial characterizing the effect of the combination of NGS-based digital precision diagnostics with standard-of-care microbiological analyses compared to solely standard-of-care microbiological analyses in the clinical picture of sepsis/septic shock. Additional anti-infective expert consultations are provided for both study groups. In 410 patients (n = 205 per arm) with sepsis/septic shock, the study examines whether the so-called DOOR-RADAR (Desirability of Outcome Ranking/Response Adjusted for Duration of Antibiotic Risk) score (representing a combined endpoint including the criteria (1) intensive/intermediate care unit length of stay, (2) consumption of antibiotics, (3) mortality, and (4) acute kidney injury (AKI)) can be improved by an additional NGS-based diagnostic concept. We also aim to investigate the cost-effectiveness of this new diagnostic procedure. It is postulated that intensive/intermediate care unit length of stay, mortality rate, incidence of AKI, the duration of antimicrobial therapy as well as the costs caused by complications and outpatient aftercare can be reduced. Moreover, a significant improvement in patient's quality of life is expected., Discussion: The authors´ previous work suggests that NGS-based diagnostics have a higher specificity and sensitivity compared to standard-of-care microbiological analyses for detecting bloodstream infections. In combination with the here presented DigiSep-Trial, this work provides the optimal basis to establish a new NGS-driven concept as part of the national standard based on the best possible evidence., Trial Registrations: DRKS-ID DRKS00022782 . Registered on August 25, 2020 ClinicalTrials.gov NCT04571801 . Registered October 1, 2020., (© 2021. The Author(s).)

Background: In the context of sepsis and septic shock, coagulopathy often occurs due to the close relationship between coagulation and inflammation. Sepsis-induced coagulopathy (SIC) is the most severe and potentially fatal form. Anticoagulants used in prophylactic or therapeutic doses are discussed to potentially exert beneficial effects in patients with sepsis and/or SIC; however, due to the lack of evidence recent guidelines are limited to recommendations for drug prophylaxis of venous thromboembolism (VTE), while treatment of SIC has not been addressed., Methods: In order to determine the status quo of VTE prophylaxis as well as treatment of SIC in German intensive care units (ICU), we conducted a Germany-wide online survey among heads of ICUs from October 2019 to May 2020. In April 2020, the survey was supplemented by an additional block of questions on VTE prophylaxis and SIC treatment in coronavirus disease 2019 (COVID-19) patients., Results: A total of 67 senior doctors took part in the survey. The majority (n = 50; 74.6%) of the responses were from ICU under the direction of an anesthesiologist and/or a department of anesthesiology. Most of the participants worked either at a university hospital (n = 31; 47.8%) or an academic teaching hospital (n = 27; 40.3%). The survey results show a pronounced heterogeneity in clinical practice with respect to the prophylaxis of VTE as well as SIC treatment. In an exemplary case of pneumogenic sepsis, low molecular weight heparins (LMWH) were by far the most frequently mentioned group of medications (n = 51; 76.1% of the responding ITS). In the majority of cases (n = 43; 64.2%), anti-FXa activity is not monitored with the use of LMWH in prophylaxis doses. Unfractionated heparin (UFH) was listed as a strategy for VTE prophylaxis in 37.3% of the responses (n = 25). In an exemplary case of abdominal sepsis 54.5% of the participants (n = 36; multiple answers possible) stated the use of UFH or LMWH and UFH with dosage controlled by PTT is used on two participating ICUs. The anti-FXa activity under prophylactic anticoagulation with LMWH is monitored in 7 participating clinics (10.6%) in abdominal sepsis. Systematic screening for sepsis-associated coagulation disorders does not take place in most hospitals and patterns in the use of anticoagulants show significant variability between ICUs. In the case of COVID-19 patients, it is particularly noticeable that in three quarters of the participating ICUs the practice of drug-based VTE prophylaxis and SIC treatment does not differ from that of non-COVID-19 patients., Conclusion: The heterogeneity of answers collected in the survey suggests that a systematic approach to this topic via clinical trials is urgently needed to underline individualized patient care with the necessary evidence., (© 2021. The Author(s).)

Introduction: Microcirculatory alterations are key mechanisms in sepsis pathophysiology leading to tissue hypoxia, edema formation, and organ dysfunction. Hyperspectral imaging (HSI) is an emerging imaging technology that uses tissue-light interactions to evaluate biochemical tissue characteristics including tissue oxygenation, hemoglobin content and water content. Currently, clinical data for HSI technologies in critical ill patients are still limited., Methods and Analysis: TIVITA® Tissue System was used to measure Tissue oxygenation (StO2), Tissue Hemoglobin Index (THI), Near Infrared Perfusion Index (NPI) and Tissue Water Index (TWI) in 25 healthy volunteers and 25 septic patients. HSI measurement sites were the palm, the fingertip, and a suprapatellar knee area. Septic patients were evaluated on admission to the ICU (E), 6 h afterwards (E+6) and three times a day (t3-t9) within a total observation period of 72 h. Primary outcome was the correlation of HSI results with daily SOFA-scores., Results: Serial HSI at the three measurement sites in healthy volunteers showed a low mean variance expressing high retest reliability. HSI at E demonstrated significantly lower StO2 and NPI as well as higher TWI at the palm and fingertip in septic patients compared to healthy volunteers. StO2 and TWI showed corresponding results at the suprapatellar knee area. In septic patients, palm and fingertip THI identified survivors (E-t4) and revealed predictivity for 28-day mortality (E). Fingertip StO2 and THI correlated to SOFA-score on day 2. TWI was consistently increased in relation to the TWI range of healthy controls during the observation time. Palm TWI correlated positively with SOFA scores on day 3., Discussion: HSI results in septic patients point to a distinctive microcirculatory pattern indicative of reduced skin oxygenation and perfusion quality combined with increased blood pooling and tissue water content. THI might possess risk-stratification properties and TWI could allow tissue edema evaluation in critically ill patients., Conclusion: HSI technologies could open new perspectives in microcirculatory monitoring by visualizing oxygenation and perfusion quality combined with tissue water content in critically ill patients - a prerequisite for future tissue perfusion guided therapy concepts in intensive care medicine., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Sepsis is a severe life-threatening syndrome caused by dysregulated host responses to infection. Biomarkers that allow for monitoring the patient's immune status are needed. Recently, a flow cytometry-based detection of in vivo inflammasome activation by formation of cytoplasmic aggregates of ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) has been proposed. Here we report on the frequency of ASC-speck + leukocytes correlating with the survival of sepsis. 25 patients with sepsis were sampled consecutively for 7 days. Blood, serum samples and patient data were collected according to the guidelines of the PredARRT-Sep-Trial. Flow cytometric analysis was performed on fresh whole blood samples to investigate the formation of ASC-specks in leukocyte subsets. Serum samples were analyzed for production of IL-1ß, IL-18 and additional inflammatory markers. ASC-speck formation was found to be increased in leukocytes from sepsis patients compared to healthy donor controls. The absolute number of ASC-speck + neutrophils peaked on day 1. For monocytes, the highest percentage and maximum absolute number of ASC-speck + cells were detected on day 6 and day 7. Inflammatory cytokines were elevated on day 1 and declined thereafter, with exception of IL-18. Survival analysis showed that patients with lower absolute numbers of ASC-speck + monocytes (<1,650 cells/ml) on day 6 had a lower probability to survive, with a hazard ratio (HR) of 10.178. Thus, the frequency of ASC-speck + monocytes on day 6 after onset of sepsis may serve to identify patients at risk of death from sepsis., Competing Interests: The 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 © 2021 Cui, Oehrl, Ahmad, Brenner, Uhle, Nusshag, Rupp, Funck, Meisel, Weigand, Morath and Schäkel.)

Introduction: Normalisation of macrocirculatory parameters during resuscitation therapy does not guarantee the restoration of microcirculatory perfusion in critical illness due to haemodynamic incoherence. Persistent microcirculatory abnormalities are associated with severity of organ dysfunction and mandate the development of bedside microcirculatory monitoring. A novel hyperspectral imaging (HSI) system can visualise changes in skin perfusion, oxygenation and water content at the bedside. We aim to evaluate the effectiveness of HSI for bedside monitoring of skin microcirculation and the association of HSI parameters with organ dysfunction in patients with sepsis and major abdominal surgery., Methods and Analysis: Three independent groups will be assessed and separately analysed within a clinical prospective observational study: (1) 25 patients with sepsis or septic shock (according to sepsis-3 criteria), (2) 25 patients undergoing pancreatic surgery and (3) 25 healthy controls. Patients with sepsis and patients undergoing pancreatic surgery will receive standard therapy according to local protocols derived from international guidelines. In addition, cardiac output of perioperative patients and patients with sepsis will be measured. Healthy controls undergo one standardised evaluation. The TIVITA Tissue System is a novel HSI system that uses the visible and near-infrared spectral light region to determine tissue microcirculatory parameters. HSI analysis (hand/knee) will be done in parallel to haemodynamic monitoring within defined intervals during a 72-hour observation period. HSI data will be correlated with the Sequential Organ Failure Assessment score, global haemodynamics, inflammation and glycocalyx markers, surgical complications and 30-day outcome., Ethics and Dissemination: The protocol has been approved by the local ethics committee of the University of Heidelberg (S-148/2019). Study results will be submitted to peer-reviewed journals and medical conferences., Trial Registration Number: DRKS00017313; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The increasing incidence of bloodstream infections including sepsis is a major challenge in intensive care units worldwide. However, current diagnostics for pathogen identification mainly depend on culture- and molecular-based approaches, which are not satisfactory regarding specificity, sensitivity, and time to diagnosis. Herein, we established a complete diagnostic workflow for real-time high-throughput sequencing of cell-free DNA from plasma based on nanopore sequencing for the detection of the causative agents, which was applied to the analyses of eight samples from four septic patients and three healthy controls, and subsequently validated against standard next-generation sequencing results. By optimization of library preparation protocols for short fragments with low input amounts, a 3.5-fold increase in sequencing throughput could be achieved. With tailored bioinformatics workflows, all eight septic patient samples were found to be positive for relevant pathogens. When considering time to diagnosis, pathogens were identified within minutes after start of sequencing. Moreover, an extrapolation of real-time sequencing performance on a cohort of 239 septic patient samples revealed that more than 90% of pathogen hits would have also been detected using the optimized MinION workflow. Reliable identification of pathogens based on circulating cell-free DNA sequencing using optimized workflows and real-time nanopore-based sequencing can be accomplished within 5 to 6 hours following blood draw. Therefore, this approach might provide therapy-relevant results in a clinically critical timeframe., (Copyright © 2020 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

Sepsis is a complex host response triggered by an infection, with the patient's immune system between hyper- and hypo-responsiveness being the main reason for the syndromes' development and propagation. Studies conducted in peripheral blood mononuclear cells uncovered an association between an impaired immunometabolism and the severity and outcome of the disease. With this prospective observational study, we aimed to evaluate the immunometabolic phenotype of monocytes and B cells and its association with the cell function.Monocytes and B cells were isolated from patients with sepsis (n = 10; onset, days 4 and 8) and healthy volunteers (n = 10) and subsequently analyzed for metabolic changes and human leukocyte antigen-DR (HLA-DR) expression. Contemporaneously, immune checkpoints on monocytes and the ex vivo cytokine responses (interleukins 6 and 8) upon lipopolysaccharide or zymosan stimulation were analyzed. The distribution of B cell subsets was assessed, and plasma levels of immunoglobulins and tricarboxylic acid cycle intermediates were quantified.Both monocytes and B cells exhibited decreased HLA-DR expression in patients with sepsis. Monocytes displayed a stable upregulated glycolysis while B cells augmented glycolysis and respiration over time. The monocytes' ability to respond to stimulation was stimuli-dependently reduced but recovered over time. The B cell compartment shifted toward antibody-producing subsets and elevated immunoglobulins within the first days.Our results provide evidence for the induction of a state of trained immunity in monocytes and an early but transient immunosuppressive phenotype accounting for peripheral sepsis-induced vulnerability to infections. B cells exhibit an unsustainable activation contributing to adaptive immunosuppression.

Objectives: Sepsis-induced acute kidney injury is the dominant acute kidney injury etiology in critically ill patients and is often associated with a need for renal replacement therapy. The indication and timing of renal replacement therapy are controversially discussed. We hypothesized that the product of the G1-cell cycle arrest biomarkers tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 ([TIMP-2] × [IGFBP7]), and the soluble urokinase-type plasminogen activator receptor are of diagnostic value for the prediction of septic acute kidney injury courses requiring renal replacement therapy., Design: In this prospective study, critically ill patients were enrolled immediately after the fulfillment of Sepsis-3 criteria. Urinary [TIMP-2] × [IGFBP7] levels over time and serum soluble urokinase-type plasminogen activator receptor levels once at inclusion were measured. The primary endpoint was the development of septic acute kidney injury with the need for renal replacement therapy. Area under the receiver operating characteristic curves, de Long's tests, and logistic regression models were calculated., Setting: Two ICUs at Heidelberg University Hospital between May 2017 and July 2018., Patients: One-hundred critically ill patients with positive Sepsis-3 criteria., Interventions: None., Measurement and Main Results: Nineteen patients required renal replacement therapy. Diagnostic performance of urinary [TIMP-2] × [IGFBP7] improved over time with the highest area under the receiver operating characteristic curve of 0.89 (95% CI, 0.80-0.98) 24 hours after study inclusion. Soluble urokinase-type plasminogen activator receptor levels at inclusion showed an area under the receiver operating characteristic curve of 0.83 (0.75-0.92). The best discrimination ability for the primary outcome measure was achieved for [TIMP-2] × [IGFBP7] at 24 hours after inclusion by applying a cutoff value of greater than or equal to 0.6 (ng/mL)/1,000 (sensitivity 90.9, specificity 67.1). Soluble urokinase-type plasminogen activator receptor performed best by using a cutoff value of greater than or equal to 8.53 ng/mL (sensitivity 84.2, specificity 82.7). A combination of newly tested biomarkers with cystatin C resulted in a significantly improved diagnostic accuracy. Cystatin C in combination with [TIMP-2] × [IGFBP7] 24 hours outperformed all standard renal parameters (area under the receiver operating characteristic curve 0.93 [0.86-1.00])., Conclusions: [TIMP-2] × [IGFBP7] and soluble urokinase-type plasminogen activator receptor are promising biomarker candidates for the risk stratification of septic acute kidney injury patients with the need for renal replacement therapy.

Competing Interests: The authors declare that they have no conflicts of interest.

Background: In nonneutropenic intensive care unit (ICU) patients, current risk stratification scores lack specificity to reliably predict the risk of a prospective invasive candidiasis (IC). We aimed to explore possible associations of distinct immunological markers with different degrees of Candida affection in patients with abdominal sepsis., Methods: The presented explorative, noninterventional diagnosis study recruited patients admitted to the surgical ICU at Heidelberg University Hospital with abdominal sepsis. Over 5 days, we determined white blood cell count, 1,3-β-D-glucan, and HLA-DR expression; the amount of Th1, Th17, regulatory T, T helper, and cytotoxic T cells; Dectin-1 and TLR2-expression; the amount of T, B, and NK cells; the ex vivo secretion of IL-8 upon stimulation with LPS, flagellin, and zymosan; and the distribution of distinct T-cell cytokines in a daily manner. On day 21, patients' Candida infection status was stratified in no colonization or IC, colonization or IC., Results: A total of 26 patients were included. On day 21, five patients showed no colonization or IC, in 13 patients a colonization was detected, and eight patients were diagnosed with IC. On study inclusion, the stratification groups showed comparable values in standard laboratory parameters and morbidity scores. Decreased B and NK cell counts, as well as reduced IL-8 secretion after ex vivo stimulation with LPS or flagellin seemed to be associated with a higher risk of subsequent Candida colonization. Even lower values could distinguish the therapy-relevant difference between prospective IC from colonization alone., Conclusions: We were able to show distinct immune system impairments in early abdominal sepsis by specific immune-based measurements. A possible association of these impairments with a subsequent Candida affection is shown.

Abdominal sepsis is the most severe form of abdominal infection. It is characterized by a dysregulated host response to infection leading to life-threatening organ failure or septic shock. The latter has a mortality of >40%. This article reviews the evidence on the strategic approach to treatment of patients with abdominal sepsis and septic shock. The focus is on the time-critical elements of diagnosis, anti-infective treatment and hemodynamic stabilization.

Sepsis and septic shock represent medical emergencies with persistently high mortality rates. According to the lately revised Surviving Sepsis Campaign (SSC) guidelines, focus identification/pathogen detection and the initial administration of broad-spectrum antibiotics are to be secluded within one hour after recognition of the symptoms of sepsis. However, there is dispute concerning the so called hour-1 bundle. Being a core aspect of focus identification, imaging modalities mainly depend on the suspected site of infection and the individual patient. Contrast agent-enhanced computed tomography (CT) is the modality usually used in critically ill patients. The microbiological pathogen detection still largely remains culture-based. This emphasizes the significance of microbiological specimen obtained from easily accessible body compartments and at least 2 blood culture sets. If possible, blood cultures should be drawn prior to antibiotic administration. Intraoperatively obtained swabs of otherwise sterile body compartments are of utmost importance with regard to microbiological pathogen detection. Catheters and implanted medical devices (i.e. cardiac pacemakers or defibrillators) suspicious of infection should be explanted and sent in for microbiological workup as soon as possible. All necessary source control measures should be realized as soon as medically possible but at least within 6 - (12) hours after the onset of symptoms. There is no specific biomarker for sepsis so far. Procalcitonin (PCT) and C-reactive protein (CRP) are crucial biomarkers in terms of infectious disease management and guidance of antimicrobial therapy in the ICU. Positive clinical trials showed that biomarkers like the midregional pro-adrenomedullin (MR-proADM) or presepsin might be promising candidates in the diagnosis of sepsis in the future. As an important marker of microcirculatory failure and disrupted cell metabolism, lactate serum concentrations (and lactate-clearance, respectively) are of prognostic value in septic patients., Competing Interests: Th. Brenner erhielt Honorare für Vorträge bzw. für die Teilnahme an Advisory Boards von Schöchl medical education GmbH, Boehringer Ingelheim Pharma GmbH, CSL Behring GmbH, Astellas Pharma GmbH, B. Braun Melsungen AG, MSD Sharp & Dohme GmbH, Baxter Deutschland GmbH sowie Biotest AG. Zudem ist er Miterfinder im Rahmen der folgenden Patente: EP18175538.0, EP17185036.5. Markus A. Weigand erhielt Honorare für Vorträge bzw. für die Teilnahme an Advisory Boards von MSD Sharp & Dohme GmbH, Pfizer Deutschland GmbH sowie Gilead Sciences GmbH. Zudem ist er Miterfinder im Rahmen der folgenden Patente: EP18175538.0, EP17185036.5., EP17198330.7., (Georg Thieme Verlag KG Stuttgart · New York.)

Despite the dissemination of innovative, molecular biology-based and commercially available devices for pathogen detection, culture-based methods with susceptibility testing remain the key principles for guiding antimicrobial treatment of patients suffering from sepsis or septic shock on the ICU. Culture-based methods are able to facilitate pathogen detection from a diversity of specimen (respiratory secretion, intraoperatively obtained smears, aspirates, and so forth). However, the latency from obtainment of the specimen up to pathogen detection with susceptibility testing is a major disadvantage of culture-based methods in critical illness. Molecular biology-based methods like Polymerase Chain Reaction (PCR) and especially Next-Generation Sequencing (NGS) based methods promise faster pathogen and resistance detection, but are not used in clinical routine yet. With more clinical trials to come, these innovative diagnostic tools may have the potential to lead to a paradigm shift within the context of pathogen identification in sepsis., Competing Interests: Th. Brenner erhielt Honorare für Vorträge bzw. für die Teilnahme an Advisory Boards von Schöchl medical education GmbH, Boehringer Ingelheim Pharma GmbH, CSL Behring GmbH, Astellas Pharma GmbH, B. Braun Melsungen AG, MSD Sharp & Dohme GmbH, Baxter Deutschland GmbH sowie Biotest AG. Zudem ist er Miterfinder im Rahmen der folgenden Patente: EP18175538.0, EP17185036.5. Markus A. Weigand erhielt Honorare für Vorträge bzw. für die Teilnahme an Advisory Boards von MSD Sharp & Dohme GmbH, Pfizer Deutschland GmbH sowie Gilead Sciences GmbH. Zudem ist er Miterfinder im Rahmen der folgenden Patente: EP18175538.0, EP17185036.5., EP17198330.7., (Georg Thieme Verlag KG Stuttgart · New York.)

Early sepsis identification is of paramount importance for an effective therapy and the patient outcome; however, a suitable prognostic biomarker is lacking. Anti-inflammatory nonneuronal cholinergic signaling modulates the magnitude of an immune response. Serum cholinesterase (BChE), an enzyme that hydrolyzes acetylcholine, plays an important role during inflammatory response and serves as an accurate index of cholinergic activity. BChE activity was measured in septic patients using a point-of-care system, and levels of conventional inflammatory markers and the disease severity scores were obtained. We observed a strong, sustained reduction in BChE activity in patients who died within a 90-day observation period, as compared to survivors. Reduced BChE activity when measured at the ICU admission effectively differentiated between the 90-day survivor and the nonsurvivor patient groups. We estimated a critical BChE level of 1.661 kU/L (CI 0.5-0.8, 94% sensitivity, 48% specificity, AUC 0.7) to best predict patient outcome providing a benchmark criterion for early detection of potentially fatal sepsis measured at the admission. This finding suggests that the BChE activity, used in combination with the laboratory tests, clinical examination, and the disease severity scoring, could serve to identify high-risk patients at the ICU admission, the most critical time point in the sepsis treatment.

Background: Sepsis remains a major challenge, even in modern intensive care medicine. The identification of the causative pathogen is crucial for an early optimization of the antimicrobial treatment regime. In this context, culture-based diagnostic procedures (e.g., blood cultures) represent the standard of care, although they are associated with relevant limitations. Accordingly, culture-independent molecular diagnostic procedures might be of help for the identification of the causative pathogen in infected patients. The concept of an unbiased sequence analysis of circulating cell-free DNA (cfDNA) from plasma samples of septic patients by next-generation sequencing (NGS) has recently been identified to be a promising diagnostic platform for critically ill patients suffering from bloodstream infections. Although this new approach might be more sensitive and specific than culture-based state-of-the-art technologies, additional clinical trials are needed to exactly define the performance as well as clinical value of a NGS-based approach., Methods: Next GeneSiS is a prospective, observational, noninterventional, multicenter study to assess the diagnostic performance of a NGS-based approach for the detection of relevant infecting organisms in patients with suspected or proven sepsis [according to recent sepsis definitions (sepsis-3)] by the use of the quantitative sepsis indicating quantifier (SIQ) score in comparison to standard (culture-based) microbiological diagnostics. The clinical value of this NGS-based approach will be estimated by a panel of independent clinical specialists, retrospectively identifying potential changes in patients' management based on NGS results. Further subgroup analyses will focus on the clinical value especially for patients suffering from a failure of empiric treatment within the first 3 days after onset [as assessed by death of the patient or lack of improvement of the patient's clinical condition (in terms of an inadequate decrease of SOFA-score) or persistent high procalcitonin levels]., Discussion: This prospective, observational, noninterventional, multicenter study for the first time investigates the performance as well as the clinical value of a NGS-based approach for the detection of bacteremia in patients with sepsis and may therefore be a pivotal step toward the clinical use of NGS in this indication., Trial Registration: DRKS-ID: DRKS00011911 (registered October 9, 2017) https://www.drks.de/drks&#95;web/navigate.do?navigationId=trial.HTML&TRIAL&#95;ID=DRKS00011911; ClinicalTrials.gov Identifier: NCT03356249 (registered November 29, 2017) https://clinicaltrials.gov/ct2/show/NCT03356249.

Background: Severe sepsis and septic shock remain a major challenge, even in modern intensive care. In Germany, about 68,000 patients die annually because of septic diseases, characterized by a complex systemic inflammatory response. Causal treatment of the underlying infection is essential for successful management of sepsis, but the course can be positively influenced by supportive and adjuvant measures. The cholinergic anti-inflammatory pathway (CAP) represents a new approach to adjunctive therapy of septic diseases and can be pharmacologically activated by the acetylcholinesterase inhibitor physostigmine (Anticholium®). Promising effects can be found in several in vitro and in vivo models of sepsis, such as a reduction in pro-inflammatory cytokines and improved survival., Methods: Anticholium® per Se is a randomized, double-blind, placebo-controlled, monocentric trial to assess whether the CAP can be transferred from bench to bedside. In this pilot study, 20 patients with perioperative sepsis and septic shock as a result of intra-abdominal infection are enrolled. According to randomization, participants are treated with physostigmine salicylate (verum group) or 0.9% sodium chloride (placebo group) for up to 5 days. The mean Sequential Organ Failure Assessment (SOFA) score during treatment and subsequent intensive care of up to 14 days is used as surrogate outcome (primary endpoint). Secondary outcome measures include 30- and 90-day mortality. An embedded pharmacokinetics and pharmacodynamics study investigates plasma concentrations of physostigmine and its metabolite eseroline. Further analyses will contribute to our understanding of the role of various cytokines in the pathophysiology of human sepsis. A computer-generated list is used for block randomization., Discussion: This randomized, controlled, monocentric trial investigates for the first time the adjunctive use of physostigmine (Anticholium®) in patients with perioperative sepsis and septic shock and may be a pivotal step toward the clinical use in this indication., Trial Registration: EudraCT Number: 2012-001650-26 (entered 14 August 2012), ClinicalTrials.gov identifier: NCT03013322 (registered on 1 Jan 2017).

The mortality of patients with sepsis and septic shock is still unacceptably high. An effective antibiotic treatment within 1 h of recognition of sepsis is an important target of sepsis treatment. Delays lead to an increase in mortality; therefore, structured treatment concepts form a rational foundation, taking relevant diagnostic and treatment steps into consideration. In addition to the assumed focus and individual risks of each patient, local resistance patterns and specific problem pathogens must be taken into account for selection of anti-infection treatment. Many pathophysiological alterations influence the pharmacokinetics of antibiotics during sepsis. The principle of standard dosing should be abandoned and replaced by an individual treatment approach with stronger weighting of the pharmacokinetics/pharmacodynamics (PK/PD) index of the substance groups. Although this is not yet the clinical standard, prolonged (or continuous) infusion of beta-lactam antibiotics and therapeutic drug monitoring (TDM) can help to achieve defined PK targets. Prolonged infusion is sufficient without TDM but for continuous infusion TDM is basically necessary. A further argument for individual PK/PD-oriented antibiotic approaches is the increasing number of infections due to multidrug resistant pathogens (MDR) in the intensive care unit. For effective treatment antibiotic stewardship teams (ABS team) are becoming more established. Interdisciplinary cooperation of the ABS team with infectiologists, microbiologists and clinical pharmacists leads not only to a rational administration of antibiotics but also has a positive influence on the outcome. The gold standards for pathogen detection are still culture-based detection and microbiological resistance testing for the various antibiotic groups. Despite the rapid investigation time, novel polymerase chain reaction (PCR)-based procedures for pathogen identification and resistance determination, are currently only an adjunct to routine sepsis diagnostics due to the limited number of studies, high costs and limited availability. In complicated septic courses with multiple anti-infective treatment or recurrent sepsis, PCR-based procedures can be used in addition to therapy monitoring and diagnostics. Novel antibiotics represent potent alternatives in the treatment of MDR infections. Due to the often defined spectrum of pathogens and the practically absent resistance, they are suitable for targeted treatment of severe MDR infections (therapy escalation).

The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) have been available since the beginning of 2016. SEPSIS-3 completely replaces the old SIRS criteria in the definition of sepsis and defines sepsis from now on as "life-threatening organ dysfunction caused by a dysregulated host response to infection". However, it seems questionable whether in clinical practice the new definition is really superior to the old one. The most important question is the following: Is it helpful to have a definition that first recognizes a patient once organ dysfunction has occurred and the patient already needs intensive care?

Acute kidney injury (AKI) has a high incidence on intensive care units around the world and is a major complication in critically ill patients suffering from sepsis or septic shock. The short- and long-term complications are thereby devastating and impair the quality of life. Especially in terms of AKI staging, the determination of kidney function and the timing of dialytic AKI management outside of life-threatening indications are ongoing matters of debate. Despite several studies, a major problem remains in distinguishing between beneficial and unnecessary "early" or even harmful renal replacement therapy (RRT). The latter might prolong disease course and renal recovery. AKI scores, however, provide an insufficient outcome-predicting ability and the related estimation of kidney function via serum creatinine or blood urea nitrogen (BUN)/urea is not reliable in AKI and critical illness. Kidney independent alterations of creatinine- and BUN/urea-levels further complicate the situation. This review critically assesses the current AKI staging, issues and pitfalls of the determination of kidney function and RRT timing, as well as the potential harm reflected by unnecessary RRT. A better understanding is mandatory to improve future study designs and avoid unnecessary RRT for higher patient safety and lower health care costs., Competing Interests: The authors declare no conflict of interest.

Sepsis remains one of the leading causes of death in intensive care units. Although sepsis is caused by a viral, fungal or bacterial infection, it is the dysregulated generalized host response that ultimately leads to severe dysfunction of multiple organs and death. The concomitant profound metabolic changes are characterized by hyperglycemia, insulin resistance, and profound transformations of the intracellular energy supply in both peripheral and immune cells. A further hallmark of the early phases of sepsis is a massive formation of reactive oxygen (ROS; e.g., superoxide) as well as nitrogen (RNS; e.g., nitric oxide) species. Reactive carbonyl species (RCS) form a third crucial group of highly reactive metabolites, which until today have been not the focus of interest in sepsis. However, we previously showed in a prospective observational clinical trial that patients suffering from septic shock are characterized by significant methylglyoxal (MG)-derived carbonyl stress, with the glyoxalase system being downregulated in peripheral blood mononuclear cells. In this review, we give a detailed insight into the current state of research regarding the metabolic changes that entail an increased MG-production in septicemia. Thus, we point out the special role of the glyoxalase system in the context of sepsis.

Introduction: Sepsis is a major cause of death worldwide but its orchestrating components remain incompletely understood. On the one hand, development of sepsis results from an infectious focus that cannot be controlled by the immune system, but on the other, responding immune cells that can eliminate the infection inflict damage to the host by contributing to complications such as endothelial leakage, septic shock, and multiorgan failure., Areas Covered: In this review we give a comprehensive overview of how sepsis occurs, which exogenous and endogenous factors might affect the immune-pathophysiological course of sepsis and finally how this knowledge translates into up-to-date definitions and therapeutic approaches. Expert commentary: Although new immunological mechanisms altering the course of sepsis have been identified recently, future research needs to address the limitations of experimental approaches, redirect the research focus into translational approaches, and finally evaluate personalized treatment strategies.

Here, we present a case of a tracheal fistula due to an anastomotic insufficiency following abdominothoracic esophageal resection. Despite immediate discontinuity resection, the tracheal fistula could not be surgically closed, resulting in incomplete control of the source of infection and an alternative treatment concept in the form of interventional fistula closure using a Y-tracheal stent. However, owing to existing severe acute respiratory distress syndrome (ARDS), which is associated with a considerable risk of peri-interventional hypoxia, a temporary bridging concept using venovenous extracorporeal membrane oxygenation (ECMO) was implemented successfully.

Background: Bloodstream infections remain one of the major challenges in intensive care units, leading to sepsis or even septic shock in many cases. Due to the lack of timely diagnostic approaches with sufficient sensitivity, mortality rates of sepsis are still unacceptably high. However a prompt diagnosis of the causative microorganism is critical to significantly improve outcome of bloodstream infections. Although various targeted molecular tests for blood samples are available, time-consuming blood culture-based approaches still represent the standard of care for the identification of bacteria., Methods: Here we describe the establishment of a complete diagnostic workflow for the identification of infectious microorganisms from seven septic patients based on unbiased sequence analyses of free circulating DNA from plasma by next-generation sequencing., Results: We found significant levels of DNA fragments derived from pathogenic bacteria in samples from septic patients. Quantitative evaluation of normalized read counts and introduction of a sepsis indicating quantifier (SIQ) score allowed for an unambiguous identification of Gram-positive as well as Gram-negative bacteria that exactly matched with blood cultures from corresponding patient samples. In addition, we also identified species from samples where blood cultures were negative. Reads of non-human origin also comprised fragments derived from antimicrobial resistance genes, showing that, in principle, prediction of specific types of resistance might be possible., Conclusions: The complete workflow from sample preparation to species identification report could be accomplished in roughly 30 h, thus making this approach a promising diagnostic platform for critically ill patients suffering from bloodstream infections.

Disseminated intravascular coagulation (DIC) is an acquired thrombo-haemorrhagic disorder which arises in clinical scenarios like sepsis, trauma and malignancies. The clinic-laboratory diagnosis of DIC is made in a patient who develops the combination of laboratory abnormalities in the appropriate clinical scenario. The most common laboratory parameters in this setting have been the clotting profile, platelet count, serum fibrinogen and fibrin degradation markers. These tests had the advantage that they could be performed easily and in most laboratories. However, with the better understanding of the pathophysiology of DIC, in recent years, more specific tests have been suggested to be useful in this setting. The newer tests can also prove to be useful in prognostication in DIC. In addition, they may provide assistance in the selection and monitoring of patients diagnosed with DIC., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

This single-centre retrospective cohort study evaluated the incidence and outcome of mycoses in critical ill patients (n = 283) with sepsis due to peritonitis. Overall mortality was 41.3%, and the 28-day mortality was 29.3%. Fungal pathogens were found in 51.9%. The common first location was the respiratory tract (66.6%), followed by the abdominal site (19.7%). Candida colonisation was found in 64.6%, and invasive Candida infection in 34.0%. Identified fungi were Candida spp. in 98.6% and Aspergillus spp. in 6.1%. Patients with fungal pathogens showed a higher rate of postoperative peritonitis, APACHE II and tracheotomy. In comparison to patients without fungal pathogens, these patients showed a longer duration on mechanical ventilation, and a higher overall mortality. Patients with Candida-positive swabs from abdominal sites had more fascia dehiscence and anastomosis leakage. Seventy-two patients (48.9%) received antifungal therapy, 26 patients were treated empirically. Antifungal therapy was not associated with a decrease in mortality. Age and renal replacement therapy were associated with mortality. In conclusion, fungi are common pathogens in critically ill patients with peritonitis, and detection of fungi is associated with an increase in overall mortality. Particularly, Candida-positive abdominal swabs are associated with an increase in morbidity. However, we were not able to demonstrate a survival benefit for antifungal therapy in peritonitis patients., (© 2015 Blackwell Verlag GmbH.)

Sepsis is a frequently fatal condition characterized by an uncontrolled and harmful host reaction to microbial infection. Despite the prevalence and severity of sepsis, we lack a fundamental grasp of its pathophysiology. Here we report that the cytokine interleukin-3 (IL-3) potentiates inflammation in sepsis. Using a mouse model of abdominal sepsis, we showed that innate response activator B cells produce IL-3, which induces myelopoiesis of Ly-6C(high) monocytes and neutrophils and fuels a cytokine storm. IL-3 deficiency protects mice against sepsis. In humans with sepsis, high plasma IL-3 levels are associated with high mortality even after adjusting for prognostic indicators. This study deepens our understanding of immune activation, identifies IL-3 as an orchestrator of emergency myelopoiesis, and reveals a new therapeutic target for treating sepsis., (Copyright © 2015, American Association for the Advancement of Science.)

Our understanding of the causes and pathophysiological basis of sepsis has been subject to constant change over the last decades. In today's understanding, sepsis is primarily a pathology of the immune system, triggered by an underlying infection but perpetuated by the host's response itself. Thereby, sepsis should not be categorized to be either a sole pro- or anti-inflammatory syndrome, but rather as a variable continuum of overlaying immune mechanisms. While a overshooting immune reaction predominates in early sepsis, this reaction is rapidly compensated, often leading to a immune dysfunction, rendering the host susceptible for secondary infections. This review aims to provide the reader with an overview of the broad molecular mechanisms contributing to the clinical picture of sepsis., (© Georg Thieme Verlag Stuttgart · New York.)

Sepsis and related complications are a challenge for intensive care medicine. Despite many advances in antibiotic therapy sepsis remains one of the most common diseases of patients in intensive care units and is designated as the main cause of death in critically ill patients. Persisting sepsis leads to impaired immunity, resulting in immunosuppression. Unspecific predictive signs complicate an early diagnosis; however, an early initiation of adequate therapy is of crucial importance for the prognosis. Scoring systems can be applied for the initial evaluation but are controversially discussed concerning the monitoring of disease progression and therapy as well as outcome prediction. Biomarkers are considered as a complementary approach.

Purpose of Review: Sepsis is relevant due to its high morbidity and mortality. For both sepsis diagnosis and outcome prediction many biomarkers have been described in the literature. Most of these markers are objects of scientific interest rather than being introduced into daily clinical practice. However, due to their unspecific character and their insufficient predictive value for the individual person, research focus is still on new aspects in sepsis-related biomarkers., Recent Findings: Beyond the widely used acute-phase proteins C-reactive protein (CRP) and procalcitonin (PCT), many new molecules have been studied deriving from different organs or cells affected, due to the systemic nature of sepsis. Cytokines, coagulation factors/characteristics, vasoactive hormones, and several others have been recently proved to be relevant in sepsis syndrome and probably useful for outcome prediction. However, single time point measurements may be less predictive than consideration of the time-dependent course of parameters. Clinical decision just based on a biomarker is still not feasible because of the huge inter-individual differences in the inflammatory response., Summary: Many biomarkers display relevant correlation with the clinical outcome of patients with severe sepsis and septic shock. Consideration of their time courses may be more reliable than absolute levels. Clinical decision should not be based only on biomarkers but organ dysfunctions, for example, should also be taken into account.

Dysfunctions of the L-arginine (L-arg)/nitric-oxide (NO) pathway are suspected to be important for the pathogenesis of multiple organ dysfunction syndrome (MODS) in septic shock. Therefore plasma concentrations of L-arg and asymmetric dimethylarginine (ADMA) were measured in 60 patients with septic shock, 30 surgical patients and 30 healthy volunteers using enzyme linked immunosorbent assay (ELISA) kits. Plasma samples from patients with septic shock were collected at sepsis onset, and 24 h, 4 d, 7 d, 14 d and 28 d later. Samples from surgical patients were collected prior to surgery, immediately after the end of the surgical procedure as well as 24 h later and from healthy volunteers once. In comparison to healthy volunteers and surgical patients, individuals with septic shock showed significantly increased levels of ADMA, as well as a decrease in the ratio of L-arg and ADMA at all timepoints. In septic patients with an acute liver failure (ALF), plasma levels of ADMA and L-arg were significantly increased in comparison to septic patients with an intact hepatic function. In summary it can be stated, that bioavailability of NO is reduced in septic shock. Moreover, measurements of ADMA and L-arg appear to be early predictors for survival in patients with sepsis-associated ALF.

Background: Recent evidence suggests that the endothelial glycocalix plays an important role in lethal outcomes following sepsis. We therefore tested if the endothelial glycocalix is shed in patients with sepsis compared with patients after major abdominal surgery and healthy volunteers., Material and Methods: A total of 150 individuals were tested for levels of inflammatory markers (intercellular adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1], interleukin-6 [IL-6]) and glycocalix markers (syndecan-1, heparan sulfate). Three groups consisted of patients with severe sepsis or septic shock, patients after major abdominal surgery without systemic inflammatory response syndrome, and healthy volunteers. Blood was drawn, at the time of diagnosis or surgery, and 6, 24, and 48h later. We correlated these markers to each other and to clinically used inflammation markers., Results: Levels of inflammatory markers were markedly higher in patients with sepsis compared with patients after major abdominal surgery and healthy volunteers. After major abdominal surgery, glycocalix markers in human plasma were at levels comparable to patients with sepsis. In patients with sepsis, levels of IL-6 correlated with syndecan-1, ICAM-1, VCAM-1, and lactate, while ICAM-1 furthermore correlated with CRP and lactate levels., Conclusion: High levels of glycocalix markers indicated that significant flaking of the endothelial glycocalix occurred in patients with sepsis, and to a lesser extent in patients after major abdominal surgery. This novel finding could explain the nonspecific capillary leaking syndrome of patients with sepsis and after major abdominal surgery, and may identify new targets for treating those patient populations., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background. Redox active substances (e.g., Thioredoxin-1, Macrophage Migration Inhibitory Factor) seem to be central hubs in the septic inflammatory process. Materials and Methods. Blood samples from patients with severe sepsis or septic shock (n = 15) were collected at the time of sepsis diagnosis (t0), and 24 (t24) and 48 (t48) hours later; samples from healthy volunteers (n = 18) were collected once; samples from postoperative patients (n = 28) were taken one time immediately after surgery. In all patients, we measured plasma levels of IL-6, TRX1 and MIF. Results. The plasma levels of MIF and TRX1 were significantly elevated in patients with severe sepsis or septic shock. Furthermore, TRX1 and MIF plasma levels showed a strong correlation (t0: r(sp) = 0.720, ρ = 0.698/t24: r(sp) = 0.771, ρ = 0.949). Conclusions. Proinflammatory/~oxidative and anti-inflammatory/~oxidative agents show a high correlation in order to maintain a redox homeostasis and to avoid the harmful effects of an excessive inflammatory/oxidative response.

Introduction: Severe sepsis, septic shock, and resulting organ failure represent the most common cause of death in intensive care medicine, with mortality ranging from 40% to 70%. It is still unclear whether necrosis or apoptosis plays the predominant role in severe sepsis. Determining the prevalent mode of cell death would be valuable, as new therapeutic agents (eg, antiapoptotic drugs such as caspase inhibitors) may improve unsatisfactory outcomes in patients with severe sepsis. Furthermore, the prognostic value of newly developed cell death serum biomarkers is of great interest., Methods: In total, 147 patients (101 patients with severe sepsis, 28 postoperative patients after major abdominal surgery, 18 healthy volunteers) were enrolled. Baseline and clinical data were evaluated. Blood samples from patients with severe sepsis were collected at the time of sepsis diagnosis, and 48 and 120 hours later; samples from healthy volunteers were collected once, and from postoperative patients, once immediately after surgery. We measured caspase-cleaved and uncleaved cytokeratin-18 (CK-18, intermediate filament protein) as a marker of cell death, isolated CK-18 fragments as a marker of apoptosis, as well as IL-6, soluble vascular cell adhesion molecule, and soluble intercellular adhesion molecule., Results: Age and sex of patients with severe sepsis and postoperative patients were comparable, whereas healthy volunteers were significantly younger. In healthy volunteers, the mode of cellular turnover was primarily apoptotic cell death. Postoperative patients showed comparable levels of apoptotic activity, but necrotic cell death was markedly increased, probably due to surgical tissue injury. In contrast, patients with severe sepsis, and especially non-survivors of the septic group showed increased levels of markers for both apoptotic and necrotic cell death. In severe septic patients with liver dysfunction, necrosis is increased relative to severe septic patients with intact hepatic function. For severe septic patients with liver dysfunction, a cut-off value for caspase-cleaved and uncleaved cytokeratin-18 could be calculated, in order to identify patients at high risk for death due to severe sepsis., Conclusions: The measurement of caspase-cleaved and uncleaved cytokeratin-18 appears to be an early predictor for survival in severe septic patients with hepatic dysfunction. Furthermore, the loss of parenchymal cells due to necrosis may be the primary mode of cell death in these patients. This may limit possible therapeutic options.