Bedside hyperspectral imaging indicates a microcirculatory sepsis pattern - an observational study.

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.

Implementation of the Sepsis-3 definition in German university intensive care units : A survey.

BACKGROUND: The old definition of sepsis was replaced by Sepsis-3 in February 2016. The new screening diagnostic tools sequential organ failure assessment (SOFA) score and quick SOFA (qSOFA) score were incorporated into the definition. The resulting scientific controversy led to several retrospective and prospective evaluations. In contrast no evaluation of the state of play of national implementation of Sepsis-3 has been conducted so far. OBJECTIVE: The aim of this study was to capture the current situation in German academic intensive care units 1 year after the implementation of Sepsis-3. METHODS: An internet-based questionnaire consisting of 22 items was developed. The identification of eligible departments was performed by an online search of the homepages of all university hospitals located in Germany. Departments regardless of the discipline with an explicit indication of involvement in intensive care were extracted. The link to the internet-based questionnaire was sent to all identified departments on 22 February 2017 and was accessible for 19 days. RESULTS: Out of 259 departments 76 answered the online survey. The response rate was 29.3% from 13 specializations. Anesthesiology, internal medicine and general surgery were the three main participants in this study. The majority of intensive care units (54.75%) treated more than 100 patients with sepsis or septic shock annually and more than 30% treated more than 250 patients. While 76.7% of respondents had a standard operating procedure, 55% of those were based on the Sepsis-3 definition. When asked to rate the usefulness of the Sepsis-3 definition, answers were heterogeneous with a slight tendency towards a higher usefulness and the majority (72.9%) were in favor of Sepsis-3 being included in the national S2K guidelines. CONCLUSION: The results demonstrate the heterogeneity of Sepsis-3 implementation in German intensive care units. Sepsis-3 is finding its way but there is a need for standardized implementation.

[New Sepsis-3 definition : Do we have to treat sepsis before we can diagnose it from now on?] / Neue SEPSIS-3-Definition : Müssen wir Sepsis in Zukunft behandeln, bevor wir sie diagnostizieren dürfen?

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?

Sepsis-induced long-term immune paralysis--results of a descriptive, explorative study.

BACKGROUND: Long-lasting impairment of the immune system is believed to be the underlying reason for delayed deaths after surviving sepsis. We tested the hypothesis of persisting changes to the immune system in survivors of sepsis for the first time. METHODS: In our prospective, cross-sectional pilot study, eight former patients who survived catecholamine-dependent sepsis and eight control individuals matched for age, sex, diabetes and renal insufficiency were enrolled. Each participant completed a questionnaire concerning morbidities, medications and infection history. Peripheral blood was collected for determination of i) immune cell subsets (CD4(+), CD8(+) T cells; CD25(+) CD127(-) regulatory T cells; CD14(+) monocytes), ii) cell surface receptor expression (PD-1, BTLA, TLR2, TLR4, TLR5, Dectin-1, PD-1 L), iii) HLA-DR expression, and iv) cytokine secretion (IL-6, IL10, TNF-α, IFN-γ) of whole blood stimulated with either α-CD3/28, LPS or zymosan. RESULTS: After surviving sepsis, former patients presented with increased numbers of clinical apparent infections, including those typically associated with an impaired immune system. Standard inflammatory markers indicated a low-level inflammatory situation in former sepsis patients. CD8(+) cell surface receptor as well as monocytic HLA-DR density measurements showed no major differences between the groups, while CD4(+) T cells tended towards two opposed mechanisms of negative immune cell regulation via PD-1 and BTLA. Moreover, the post-sepsis group showed alterations in monocyte surface expression of distinct pattern recognition receptors; most pronouncedly seen in a decrease of TLR5 expression. Cytokine secretion in response to important activators of both the innate (LPS, zymosan) and the adaptive immune system (α-CD3/28) seemed to be weakened in former septic patients. CONCLUSIONS: Cytokine secretion as a reaction to different activators of the immune system seemed to be comprehensively impaired in survivors of sepsis. Among others, this could be based on trends in the downregulation of distinct cell surface receptors. Based on our results, the conduct of larger validation studies seems feasible, aiming to characterize alterations and to find potential therapeutic targets to engage.

[Epigenetic regulation in sepsis : current state of knowledge]. / Epigenetische Regulation in der Sepsis : Aktueller Wissensstand.

Sepsis is known to be a severe systemic immune reaction based on an infection of various origins. The initial immune response is accompanied by excess activation of immune cells and release of proinflammatory cytokines. Simultaneously initiated compensatory mechanisms lead to high levels of anti-inflammatory mediators to counterbalance the generalized inflammatory reaction; however, the compensatory immunoreaction itself equally overreacts and results in a prolonged sepsis-induced immunosuppression. The underlying mechanisms for these exaggerated immune responses and the resulting global immunosuppression that increase the risk for secondary infection are still unknown. Recent findings indicate that epigenetic mechanisms change basic properties of important immune cells by mechanisms leading to changes in gene expression. Dynamic exchanges of histone modifications result in a variation of transcription and seem to play a key role in cell function of macrophages and other immune cells. This article provides a current overview of epigenetic sepsis research and the sepsis-induced effects on the immune system.

Diagnostics, therapy and outcome prediction in abdominal sepsis: current standards and future perspectives.

PURPOSE: In the perioperative phase, sepsis and sepsis-associated death are the most important problems for both the surgeon and the intensivist. Critically ill patients profit from an early identification and implementation of an interdisciplinary therapy. The purpose of this review on septic peritonitis is to give an update on the diagnosis and its evidence-based treatment. RESULTS: Rapid diagnosis of sepsis is essential for patient´s survival. A bundle of studies was performed on early recognition and on new diagnostic tools for abdominal sepsis. Although surgical intervention is considered as an essential therapeutic step in sepsis therapy the time-point of source control is still controversially discussed in the literature. Furthermore, the Surviving Sepsis Campaign (SSC) guidelines were updated in 2012 to facilitate evidence-based medicine for septic patients. CONCLUSION: Despite many efforts, the mortality of surgical septic patients remains unacceptably high. Permanent clinical education and further surgical trials are necessary to improve the outcome of critically ill patients.

[Use of biomarkers in sepsis. Update and perspectives]. / Einsatz von Biomarkern in der Sepsis. Update und Ausblick.

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.

Effects of echinocandin preparations on adult rat ventricular cardiomyocytes. Preliminary results of an in vitro study.

BACKGROUND: Candida infections represent a relevant risk for patients in intensive care units resulting in increased mortality. Echinocandins have become the agents of choice for early and specific antifungal treatment in critically ill patients. Due to cardiac effects following echinocandin administration seen in intensive care unit (ICU) patients the in vitro effects of echinocandins and fluconazole on isolated cardiomyocytes of the rat were examined. AIM: The study was designed to investigate a possible impact of echinocandins and fluconazole in clinically relevant concentrations on the in vitro contractile responsiveness and shape of isolated rat cardiomyocytes. MATERIAL AND METHODS: Ventricular cardiomyocytes were isolated from Lewis rats. Cardiomyocytes were cultured in the presence of all licensed echinocandin preparations and fluconazole at concentrations of 0 (control), 0.1, 1, 3.3, 10, 33 and 100 µg/ml for 90 min. Cells were stimulated by biphasic electrical stimuli and contractile responsiveness was measured as shortening amplitude. Additionally, the ratio of rod-shaped to round cells was determined. RESULTS: Anidulafungin concentrations of 3.3 and 10 µg/ml caused a significant increase in contractile responsiveness, caspofungin showed a significant decrease at 10 µg/ml and micafungin concentrations of 3.3-33 µg/ml led to a significant increase in cell shortening. Measurement was not possible at 33 µg/ml for anidulafungin and caspofungin and at 100 µg/ml for all echinocandins due to a majority of round-shaped, non-contracting cardiomyocytes. Fluconazole showed no significant effect on cell shortening at all concentrations tested. For the three echinocandins the ratio of round-shaped, non-contracting versus rod-shaped normal contracting cardiomyocytes increased in a dose-dependent manner. CONCLUSIONS: Echinocandins impact the in vitro contractility of isolated cardiomyocytes of rats. This observation could be of great interest in the context of antifungal treatment.

Cardiac effects of echinocandin preparations - three case reports.

WHAT IS KNOWN AND OBJECTIVE: Echinocandins are antifungal agents, routinely used in invasive candida infections in critically ill patients. Their excellent anticandidal activity and their low frequency of reported adverse events and drug interactions make them first-line guideline treatments of candidiasis especially in intensive care units (ICU). We report on three ICU patients who developed cardiac insufficiency and hemodynamic instability during administration of loading doses of an echinocandin. CASE SUMMARY: Three ICU patients showed a substantial drop in their cardiac index or a deterioration of the mean arterial pressure following start of echinocandin administration. The patients were 75 years (female), 71 years (male) and 66 years (male) old. One patient received caspofungin, and two patients received anidulafungin as empirical antifungal treatment for severe sepsis. WHAT IS NEW AND CONCLUSION: Our cases suggest that the observed cardiac impairment could be associated with echinocandin administration. Therefore, we recommend close hemodynamic monitoring of critically ill patients receiving echinocandins.

Sphingosine­1­phosphate analogue FTY720 exhibits a potent anti­proliferative effect on glioblastoma cells.

Sphingosine­1­phosphate (S1P) plays a key role in cell survival, growth, migration, and in angiogenesis. In glioma, it triggers the activity of the S1P­receptor 1 and of the sphingosine kinase 1; thus influencing the survival rate of patients. The aim of the present study was to investigate the anti­proliferative effect of the S1P analogue FTY720 (fingolimod) in glioblastoma (GBM) cells. A172, G28, and U87 cells were incubated with micromolar concentrations of FTY720 or temozolomide (TMZ) for 24 to 72 h. Proliferation and half maximal inhibitory concentration (IC50) were determined by using the xCELLigence system. FACS analysis was performed to check the cell cycle distribution of the cells after a 72­h incubation with FTY720. This was then compared to TMZ­incubated and to untreated cells. Gene expression was detected by RT­qPCR in A172, G28, U87 and three primary GBM­derived cell lines. FTY720 was able to reduce the number of viable cells. The IC50 value was 4.6 µM in A172 cells, 17.3 µM in G28 cells, and 25.2 µM in U87 cells. FTY720 caused a significant arrest of the cell cycle in all cells and stabilized or over­expressed the level of AKT1, MAPK1, PKCE, RAC1, and ROCK1 transcripts. The TP53 transcript level remained stable or was downregulated after treatment with FTY720. FTY720 may be a promising target drug for the treatment of GBM, as it has a strong anti­proliferative effect on GBM cells.