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Background: The study aimed to assess the mental well-being of healthcare professionals at a German department of anesthesiology and critical care with a specialized ICU for treatment of COVID-19 patients during the first two peaks of the 2020 pandemic, and identifying risk and protective factors.Methods: A single-center longitudinal, online-based survey was conducted in healthcare workers from a department of anesthesiology and critical care in Bavaria, the most affected federal state in Germany at the time of assessment. Validated scores for depression, anxiety, somatic disorders, burnout, resilience, and self-management were used and complemented by questions about perceived COVID-19-related stressors. In parallel, patient characteristics in the ICU were collected.Results: 24 and 23 critically ill COVID-19 patients were treated during both observation periods in April/May and November/December 2020, respectively. 87.5% and 78.2% of patients had moderate to severe acute respiratory distress syndrome. From March 6, 2020 onwards, the hospital had switched to a command and control-based hospital incident command system (HICS) and increased work forces. Point prevalence of depression-like symptoms (13.6% and 12.8%) and burnout (21.6% and 17.4%) in the department’s healthcare professionals was high. Exposure to SARS-CoV-2 did not increase psychological burden. Consequences of the lockdown were rated as highly distressing by a majority of all ICU personnel. High self-reported trait resilience was protective against signs of depression, generalized anxiety, and burnout.Conclusions: During the pandemic, healthcare professionals have been suffering from increased psychological distress compared to reference data for both the general population and ICU personnel. General effects of the lockdown appear more relevant than actual COVID-19 patient contact. High trait resilience has a protective effect, yet vulnerable individuals may require specific support. Prevention against potential after effects of the lockdown, and in particular measures allowing to avoid another lockdown, appear warranted.

BackgroundViscoelastic test–guided coagulation management has become increasingly important in assessing hemostasis. We developed Visual Clot, an animated, 3D blood clot that illustrates raw rotational thromboelastometry (ROTEM) parameters in a user-centered and situation awareness–oriented method. ObjectiveThis study aimed to evaluate the applicability of Visual Clot by examining its effects on users that are novices in viscoelastic-guided resuscitation. MethodsWe conducted an investigator-initiated, international, multicenter study between September 16, 2020, and October 6, 2020, in 5 tertiary care hospitals in central Europe. We randomly recruited medical students and inexperienced resident physicians without significant prior exposure to viscoelastic testing. The 7 participants per center managed 9 different ROTEM outputs twice, once as standard ROTEM tracings and once as the corresponding Visual Clot. We randomly presented the 18 viscoelastic cases and asked the participants for their therapeutic decisions. We assessed the performance, diagnostic confidence, and perceived workload in managing the tasks using mixed statistical models and adjusted for possible confounding factors. ResultsAnalyzing a total of 630 results, we found that the participants solved more cases correctly (odds ratio [OR] 33.66, 95% CI 21.13-53.64; P

BackgroundViscoelastic tests enable a time-efficient analysis of coagulation properties. An important limitation of viscoelastic tests is the complicated presentation of their results in the form of abstract graphs with a multitude of numbers. We developed Visual Clot to simplify the interpretation of presented clotting information. This visualization technology applies user-centered design principles to create an animated model of a blood clot during the hemostatic cascade. In a previous simulation study, we found Visual Clot to double diagnostic accuracy, reduce time to decision making and perceived workload, and improve care providers’ confidence. ObjectiveThis study aimed to investigate the opinions of physicians on Visual Clot technology. It further aimed to assess its strengths, limitations, and clinical applicability as a support tool for coagulation management. MethodsThis was a researcher-initiated, international, double-center, mixed qualitative-quantitative study that included the anesthesiologists and intensive care physicians who participated in the previous Visual Clot study. After the participants solved six coagulation scenarios using Visual Clot, we questioned them about the perceived pros and cons of this new tool. Employing qualitative research methods, we identified recurring answer patterns, and derived major topics and subthemes through inductive coding. Based on them, we defined six statements. The study participants later rated their agreement to these statements on five-point Likert scales in an online survey, which represented the quantitative part of this study. ResultsA total of 60 physicians participated in the primary Visual Clot study. Among these, 36 gave an interview and 42 completed the online survey. In total, eight different major topics were derived from the interview field note responses. The three most common topics were “positive design features” (29/36, 81%), “facilitates decision making” (17/36, 47%), and “quantification not made” (17/36, 47%). In the online survey, 93% (39/42) agreed to the statement that Visual Clot is intuitive and easy to learn. Moreover, 90% (38/42) of the participants agreed that they would like the standard result and Visual Clot displayed on the screen side by side. Furthermore, 86% (36/42) indicated that Visual Clot allows them to deal with complex coagulation situations more quickly. ConclusionsA group of anesthesia and intensive care physicians from two university hospitals in central Europe considered Visual Clot technology to be intuitive, easy to learn, and useful for decision making in situations of active bleeding. From the responses of these possible future users, Visual Clot appears to constitute an efficient and well-accepted way to streamline the decision-making process in viscoelastic test–based coagulation management.

Background: Initial treatment (ventilator settings, rescue therapy, supportive measures), and prevention of critical events improve survival in ARDS patients, but little data exists on its effect on health-related quality of life (HRQOL) and return to work (RtW) in survivors. We analyzed the association of the intensity of treatment at ARDS onset and the incidence of critical events on HRQOL and RtW a year after ICU discharge.Methods: In a prospective multi-centre cohort study, the intensity of treatment and the incidence of critical events were determined at 6CUs in Germany. At 3, 6, and 12 months, 396 survivors reported their HRQOL (Short-Form 12) and RtW. The parameters of the intensity of acute management (lung protective ventilation, prone position, hemodynamic stabilization, neuromuscular blocking agents), and critical events (hypoxemia, hypoglycemia, hypotension) were associated with HRQOL and RtW.Results: Patients ventilated at ARDS onset with a low tidal volume (VT≤l/kg) had higher arterial carbon dioxide levels (PaCO=57.5±1mHg) compared to patients ventilated with VT>7ml/kg (45.7±12, p=0.001). In a multivariate adjusted dichotomized analysis, a better mental 3-month SF-12 was observed in the higher VT-group (mean 43.1±12) compared to the lower VT-group (39.5±9, p=0.042), while a dichotomized analysis for driving pressures (≤14 mbar vs >1bar) did not show any difference neither in PaCO levels nor in HRQOL parameters. A decrease in the mental (6-month: 40.0±11 vs 44.8±13, p=0.038) and physical SF-12 (12-month: 38.3±11 vs 43.0±13, p=0.015) was reported from patients with hypoglycemia (blood glucose

Background: Refugees have a significant risk of carrying multidrug-resistant organisms (MDRO), including multidrug-resistant gram-negative organisms (MDRGN) and methicillin-resistant (MRSA). Since the duration of MDRGN colonization has been shown to last for several months, we hypothesize that the prevalence of MDRO in refugees gradually declines during their stay in Germany to the level of MDRO prevalence in non-refugee patients. Knowledge about the dynamics of refugees’ MDRO prevalence might provide the basis for appropriate infection control measures for refugees in hospitals as well as refugees’ MDRO epidemiology in general.Material and methods: MDRO prevalence in 109 refugees admitted to the University Hospital Frankfurt, Germany, were compared to 819 adult controls and 224 pediatric patients admitted to the intensive care unit between June 2016 and May 2017.Results: 41.3% (95% confidence interval=31.9–51.1) of the refugees, 5.7% (4.2–7.6) of the adult controls and 8.9% (5.5–13.5) of the pediatric controls were positive for at least one MDRGN. The highest MDRGN prevalence was found in refugees who recently arrived (≤3 months) in Germany (72.4%; 52.8–87.3). Refugees’ MDRGN prevalence declined continuously over time, reaching the adult and pediatric controls’ MDRGN prevalence 18 months at the earliest after their arrival in Germany, i.e., 14.9% (1.8–42.8). Conclusion: This study demonstrates that refugees’ MDRGN prevalence is declining over time since their arrival in Germany. 18 months after their arrival, refugees’ and locals’ MDRGN prevalence no longer differs significantly, although the refugees’ MDRGN prevalence is still higher. A decline of MRSA prevalence was found 18 months after refugees’ arrival. However, MRSA prevalence was still 14%, and thus 8 times higher than that of controls, indicating that precautionary measures continue to be necessary to prevent MRSA transmission.

Abstract In Wuerzburg, Germany, a terrorist attack and a killing rampage occurred five years apart (2016 and 2021). Following a structured evaluation of the rescue mission in 2016, a bundle of quality indicators and ten “lessons learned” were defined. Aim of the presented study was to compare the two rescue missions and to critically review the lessons learned from 2016 for their implementation and feasibility. An interdisciplinary and inter-professional group of experts analyzed the data using predefined quality indicators. All lessons defined in 2016 were critically reviewed and qualified as either lessons learned or lessons identified. While seven out of ten lessons were successfully implemented after 2016 (lessons learned), three lessons didn´t work and were recategorized as lessons identified (communication, zoning and the mutual exchange of different tactical approaches). Our results demonstrate that the conclusions drawn in 2016 have helped to improve the performance of the rescue forces in 2021. In addition, the identified lessons are now the basis for further improving emergency and disaster preparedness. It is important to understand, that the process of preparedness improvement is not completed with the definition of lessons identified. These must first be integrated into response plans and then trained intensively. A lesson identified only becomes a lesson learned once it has been successfully applied.

OBJECTIVES Mental practice, a cognitive technique for practicing skills without physical movement, holds promise for enhancing clinical outcomes in emergency medicine. This study investigates its recognition and the impact of a basic workshop on emergency physicians’ attitudes toward mental practice. METHODS This pre–post survey study involved 20 medical professionals who participated in a 2-day workshop. Assessments were conducted before and after the intervention using a structured questionnaire. RESULTS Initial findings revealed that 65% of participants were aware of mental practice, and only 10% utilized it in clinical settings. Postworkshop, familiarity, and perceived helpfulness significantly increased from 2.2 to 4.1 and 3.9 to 4.7, respectively, with marked improvements in confidence and the intention to apply these techniques clinically by 100% of the participants. CONCLUSION The results suggest that brief educational interventions can substantially influence medical professionals’ engagement with mental practice, advocating its inclusion in medical training curricula to enhance procedural skills and patient care.

Metastases are the leading cause of cancer-related deaths, and their origin is not fully elucidated. Recently, studies have shown that extracellular vesicles (EVs), particularly small extracellular vesicles (sEV), can disrupt the homeostasis of organs, promoting the development of a secondary tumor. However, the role of sEV in brain endothelium and their association with metastasis related to breast cancer is unknown. Thus, this study aimed to investigate sEV-triggered changes in the phosphorylation state of proteins on the surface of brain endothelial cells, as they form the first barrier in contact with circulating tumor cells and EVs, and once identified, to modulate its interactors and effects from this through different functional assays. We used the most aggressive breast cancer cell line, MDA-MB-231, and its brain-seeking variant, MDA-MB-231-br. From these cells, small and large extracellular vesicles were harvested to treat hCMEC/D3 cells, an immortalized cell line from the human brain microvasculature. Higher levels of phosphorylation of VEGFR1 and VEGFR2 were found in hCMEC/D3 cells treated with MDA-MB-231-br sEV. By computational analysis, the Valosin-Containing Protein (VCP) was predicted to be an important sEV cargo affecting the VEGFR2 intracellular trafficking, validated by western blotting analysis. Then, VCP was modulated by cell transfection or chemical inhibition in hCMEC/D3 cells and assessed in different functional in vitro assays evidencing a significant effect on the functionality of these cells. Thus, this study demonstrates that the VCP-containing sEVs induce modifications at different phosphor sites of VEGFR2 and effectively modulate the state of brain microvascular endothelial cells.

Introduction Currently, there is a lack of evidence on how societies and healthcare systems cope with disrupting situations like disasters, crisis and wars. The aim of the scoping review was to map evidence to the following questions: Is the fact of possible overwhelming of healthcare systems accepted or denied? Are medical standards adjusted? Are dedicated contingency concepts applied? Are there triage concepts for allocating scarce resources?Methods We conducted and reported the scoping review in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for scoping reviews. A review protocol was published a priori in the Open Science Framework. Medline via PubMed was used as data source. We considered reviews, systematic reviews, guidelines and case-control studies in English or German as eligible for this scoping review, regardless of publication year or publication status. We searched Medline via PubMed up to 8 March 2023, and updated on 20 July 2023. Title/Abstract screening, full-text screening and data extraction were performed in a dual-reviewer mode.Results A total of 2213 publications were identified and 71 publications were finally included. Of these, 87% generally accepted the possibility that the capacity of the healthcare system would be overwhelmed. A structured change of medical standards was reported in 89%. 51% deployed the crisis standard of care concept. International accepted guidelines for maintaining medical care do not exist. There is no common understanding of the medical care status with regard to the standards. There is a lack of political, legal and ethical agreement on the subject of triage.Conclusion Future research must clarify which concepts and measures are suitable for building a robust healthcare system in order to maintain medical care according to accepted standards for as long as possible. Algorithms for the allocation of scarce resources must be defined in advance to enable medical staff to act with legal certainty in a crisis.

Summary: Purpose: Until now, the Hospitalization Rate (HR) served as an indicator (among others) for the COVID-19 associated healthcare burden. To ensure that the HR accomplishes its full potential, hospitalizations caused by COVID-19 (primary cases) and hospitalizations of patients with incidental positive SARS-CoV-2 test results (incidental cases) must be differentiated. The aim of this study was to synthesize the existing evidence on differentiation criteria between hospitalizations of primary cases and incidental cases. Methods: An online survey of the members of the German Network University Medicine (NUM) was conducted. Additionally, senior clinicians with expertise in COVID-19 care were invited for qualitative, semi-structured interviews. Furthermore, a rapid literature review was undertaken on publications between 03/2020 and 12/2022. Results: In the online survey (n=30, response rate 56%), pneumonia and acute upper respiratory tract infections were the most indicative diagnoses for a primary case. In contrast, malignant neoplasms and acute myocardial infarctions were most likely to be associated with incidental cases. According to the experts (n=6), the diagnosis, ward, and type of admission (emergency or elective), low oxygen saturation, need for supplemental oxygen, and initiation of COVID-19 therapy point to a primary case. The literature review found that respiratory syndromes and symptoms, oxygen support, and elevated levels of inflammatory markers were associated with primary cases. Conclusion: There are parameters for the differentiation of primary from incidental cases to improve the objective of the HR. Ultimately, an updated HR has the potential to serve as a more accurate indicator of the COVID-19 associated healthcare burden.

Abstract Background Iron deficiency (ID) is the leading cause of anemia worldwide. The prevalence of preoperative ID ranges from 23 to 33%. Preoperative anemia is associated with worse outcomes, making it important to diagnose and treat ID before elective surgery. Several studies indicated the effectiveness of intravenous iron supplementation in iron deficiency with or without anemia (ID(A)). However, it remains challenging to establish reliable evidence due to heterogeneity in utilized study outcomes. The development of a core outcome set (COS) can help to reduce this heterogeneity by proposing a minimal set of meaningful and standardized outcomes. The aim of our systematic review was to identify and assess outcomes reported in randomized controlled trials (RCTs) and observational studies investigating iron supplementation in iron-deficient patients with or without anemia. Methods We searched MEDLINE, CENTRAL, and ClinicalTrials.gov systematically from 2000 to April 1, 2022. RCTs and observational studies investigating iron supplementation in patients with a preoperative diagnosis of ID(A), were included. Study characteristics and reported outcomes were extracted. Outcomes were categorized according to an established outcome taxonomy. Quality of outcome reporting was assessed with a pre-specified tool. Reported clinically relevant differences for sample size calculation were extracted. Results Out of 2898 records, 346 underwent full-text screening and 13 studies (five RCTs, eight observational studies) with sufficient diagnostic inclusion criteria for iron deficiency with or without anemia (ID(A)) were eligible. It is noteworthy to mention that 49 studies were excluded due to no confirmed diagnosis of ID(A). Overall, 111 outcomes were structured into five core areas including nine domains. Most studies (92%) reported outcomes within the ‘blood and lymphatic system’ domain, followed by “adverse event” (77%) and “need for further resources” (77%). All of the latter reported on the need for blood transfusion. Reported outcomes were heterogeneous in measures and timing. Merely, two (33%) of six prospective studies were registered prospectively of which one (17%) showed no signs of selective outcome reporting. Conclusion This systematic review comprehensively depicts the heterogeneity of reported outcomes in studies investigating iron supplementation in ID(A) patients regarding exact definitions and timing. Our analysis provides a systematic base for consenting to a minimal COS. Systematic review registration PROSPERO CRD42020214247

Objective:. Postoperative pulmonary embolism (PE) is a rare but potentially life-threatening complication, which can be treated with extracorporeal membrane oxygenation (ECMO) therapy, a novel therapy option for acute cardiorespiratory failure. We postulate that hospitals with ECMO availability have more experienced staff, technical capabilities, and expertise in treating cardiorespiratory failure. Design:. A retrospective analysis of surgical procedures in Germany between 2012 and 2019 was performed using hospital billing data. High-risk surgical procedures for postoperative PE were analyzed according to the availability of and expertise in ECMO therapy and its effect on outcome, regardless of whether ECMO was used in patients with PE. Methods:. Descriptive, univariate, and multivariate analyses were applied to identify possible associations and correct for confounding factors (complications, complication management, and mortality). Results:. A total of 13,976,606 surgical procedures were analyzed, of which 2,407,805 were defined as high-risk surgeries. The overall failure to rescue (FtR) rate was 24.4% and increased significantly with patient age, as well as type of surgery. The availability of and experience in ECMO therapy (defined as at least 20 ECMO applications per year; ECMO centers) are associated with a significantly reduced FtR in patients with PE after high-risk surgical procedures. In a multivariate analysis, the odds ratio (OR) for FtR after postoperative PE was significantly lower in ECMO centers (OR, 0.75 [0.70–0.81], P < 0.001). Conclusions:. The availability of and expertise in ECMO therapy lead to a significantly reduced FtR rate of postoperative PE. This improved outcome is independent of the use of ECMO in these patients.

Therapy of cerebral diseases such as brain metastatic breast cancer is still challenging. Due to the blood-brain barrier (BBB), a tight barrier that protects the brain and prevents the passage of many drugs, therapeutically sufficient drug concentrations in the brain are often not achieved. Therefore, methods and drugs to manipulate the BBB permeability are required. Here we used high-throughput screening (HTS) to identify chemicals that may increase BBB permeability. Human BBB in vitro model derived from hematopoietic CD34+ stem cells (differentiated to brain-like endothelial cells, BLECs) was used. BLECs were seeded on 96-well plates coated with biotinylated gelatin, treated with respective chemicals for 24 h followed by addition of FITC-avidin for permeability estimation. Selected substances were further tested in vitro on BLECs. Cell viability, gene and protein expression were measured using CellTiter-Glo®, qPCR and Western blot, respectively. From 1,278 compounds, we identified 175 substances that cause at least a 50 percent increase in BBB permeability. Two substances from the substance classes used in breast cancer therapy, GW2974 (tyrosine kinase inhibitor) and 4-amino-1,8-naphthalimide (ANI) (PARP inhibitor), were analyzed in more detail. ANI was nontoxic to BLECs, while GW2974 decreased or increased viability depending on the concentration used. Both compounds significantly increased BBB permeability and altered protein and mRNA expression in BLECs. Influencing the BBB permeability in patients with brain metastases could increase the response rate to systemic therapy. Using HTS, we were able to accurately and quickly identify compounds that increase BBB permeability and show that using this type of screening method can be applied to endothelial paracellular permeability testing.

Summary: In the early days of anaesthesia, the fasting period for liquids was kept short. By the mid-20th century ‘nil by mouth after midnight’ had become routine as the principles of the management of ‘full stomach’ emergencies were extended to include elective healthy patients. Back then, no distinction was made between the withholding of liquids and solids. Towards the end of the last century, recommendations of professional anaesthesiology bodies began to reduce the fasting time of clear liquids to 2 h. This reduction in fasting time was based on the understanding that gastric emptying of clear liquids is rapid, exponential, and proportional to the current filling state of the stomach. Furthermore, there was no evidence of a link between drinking clear liquids and the risk of aspiration. Indeed, most instances of aspiration are caused by failure to identify aspiration risk factors and adjust the anaesthetic technique accordingly. In contrast, long periods of liquid withdrawal cause discomfort and may also lead to serious postoperative complications. Despite this, more than two decades after the introduction of the 2 h limit, patients still fast for a median of up to 12 h before anaesthesia, mainly because of organisational issues. Therefore, some hospitals have decided to allow patients to drink clear liquids within 2 h of induction of anaesthesia. Well-designed clinical trials should investigate whether these concepts are safe in patients scheduled for anaesthesia or procedural sedation, focusing on both aspiration risk and complications of prolonged fasting.

Background: Handovers during medical emergencies are challenging due to time-critical, dynamic and oftentimes unorderly and distracting situations. We evaluated the effect of distraction-reduced clinical surroundings during handover on (1) the recall of handover information, (2) the recall of information from the surroundings and (3) self-reported workload in a simulated in-hospital cardiac arrest scenario. Methods: In a parallel group design, emergency team leaders were randomly assigned to receive a structured handover of a cardio-pulmonary resuscitation (CPR) either inside the room (“inside group”) right next to the ongoing CPR or in front of the room (“outside group”) with no audio-visual distractions from the ongoing CPR. Based on the concept of situation awareness, the primary outcome was a handover score for the content of the handover (0–19 points) derived from the pieces of information given during handover. Furthermore, we assessed team leaders’ perception of their surroundings during the scenario (0–5 points) and they rated their subjective workload using the NASA Task Load Index. Results: The outside group (n = 30) showed significant better recall of handover information than the inside group (n = 30; mean difference = 1.86, 95% CI = 0.67 to 3.06, p = 0.003). The perception of the surroundings (n = 60; mean difference = −0.27, 95% CI = −0.85 to 0.32, p = 0.365) and the NASA Task Load Index (n = 58; mean difference = 1.1; p = 0.112) did not differ between the groups. Conclusions: Concerning in-hospital emergencies, a structured handover in a distraction reduced environment can improve information uptake of the team leader.

Introduction Fitness trackers can provide continuous monitoring of vital signs and thus have the potential to become a complementary, mobile and effective tool for early detection of patient deterioration and post-operative complications. Methods To evaluate potential implementations in acute care setting, we included 36 patients after moderate to major surgery in a recent randomised pilot trial to compare the performance of vital sign monitoring by three different fitness trackers (Apple Watch 7, Garmin Fenix 6pro and Withings ScanWatch) with established standard clinical monitors in post-anaesthesia care units and monitoring wards. Results During a cumulative period of 56 days, a total of 53,197 heart rate (HR) measurements, as well as 12,219 measurements of the peripheral blood oxygen saturation (SpO 2 ) and 28,954 respiratory rate (RR) measurements were collected by fitness trackers. Under real-world conditions, HR monitoring was accurate and reliable across all benchmarked devices (r = [0.95;0.98], p

Introduction Herpes simplex virus (HSV) is frequently detected in the respiratory tract of mechanically ventilated patients and is associated with a worse outcome. The aim of this study is to determine whether antiviral therapy in HSV-positive patients improves outcome.Methods and analysis Prospective, multicentre, open-label, randomised, controlled trial in parallel-group design. Adult, mechanically ventilated patients with pneumonia and HSV type 1 detected in bronchoalveolar lavage (≥105 copies/mL) are eligible for participation and will be randomly allocated (1:1) to receive acyclovir (10 mg/kg body weight every 8 hours) for 10 days (or until discharge from the intensive care unit if earlier) or no intervention (control group). The primary outcome is mortality measured at day 30 after randomisation (primary endpoint) and will be analysed with Cox mixed-effects model. Secondary endpoints include ventilator-free and vasopressor-free days up to day 30. A total of 710 patients will be included in the trial.Ethics and dissemination The trial was approved by the responsible ethics committee and by Germany’s Federal Institute for Drugs and Medical Devices. The clinical trial application was submitted under the new Clinical Trials Regulation through CTIS (The Clinical Trials Information System). In this process, only one ethics committee, whose name is unknown to the applicant, and Germany’s Federal Institute for Drugs and Medical Devices are involved throughout the entire approval process. Results will be published in a journal indexed in MEDLINE and CTIS. With publication, de-identified, individual participant data will be made available to researchers.Trial registration number NCT06134492.

Introduction Sepsis remains the major cause of death among hospitalised patients in intensive care. While targeting sepsis-causing pathogens with source control or antimicrobials has had a dramatic impact on morbidity and mortality of sepsis patients, this strategy remains insufficient for about one-third of the affected individuals who succumb. Pharmacological targeting of mechanisms that reduce sepsis-defining organ dysfunction may be beneficial. When given at low doses, the anthracycline epirubicin promotes tissue damage control and lessens the severity of sepsis independently of the host–pathogen load by conferring disease tolerance to infection. Since epirubicin at higher doses can be myelotoxic, a first dose–response trial is necessary to assess the potential harm of this drug in this new indication.Methods and analysis Epirubicin for the Treatment of Sepsis and Septic Shock-1 is a randomised, double-blind, placebo-controlled phase 2 dose-escalation phase IIa clinical trial to assess the safety of epirubicin as an adjunctive in patients with sepsis. The primary endpoint is the 14-day myelotoxicity. Secondary and explorative outcomes include 30-day and 90-day mortality, organ dysfunction, pharmacokinetic/pharmacodynamic (PK/PD) and cytokine release. Patients will be randomised in three consecutive phases. For each study phase, patients are randomised to one of the two study arms (epirubicin or placebo) in a 4:1 ratio. Approximately 45 patients will be recruited. Patients in the epirubicin group will receive a single dose of epirubicin (3.75, 7.5 or 15 mg/m2 depending on the study phase. After each study phase, a data and safety monitoring board will recommend continuation or premature stopping of the trial. The primary analyses for each dose level will report the proportion of myelotoxicity together with a 95% CI. A potential dose-toxicity association will be analysed using a logistic regression model with dose as a covariate. All further analyses will be descriptive.Ethics and dissemination The protocol is approved by the German Federal Institute for Drugs and Medical Devices. The results will be submitted for publication in peer-reviewed journals.Trial registration number NCT05033808.

Abstract Background Recent data from the randomized SUSTAIN CSX trial could not confirm clinical benefits from perioperative selenium treatment in high-risk cardiac surgery patients. Underlying reasons may involve inadequate biosynthesis of glutathione peroxidase (GPx3), which is a key mediator of selenium's antioxidant effects. This secondary analysis aimed to identify patients with an increase in GPx3 activity following selenium treatment. We hypothesize that these responders might benefit from perioperative selenium treatment. Methods Patients were selected based on the availability of selenium biomarker information. Four subgroups were defined according to the patient's baseline status, including those with normal kidney function, reduced kidney function, selenium deficiency, and submaximal GPx3 activity. Results Two hundred and forty-four patients were included in this analysis. Overall, higher serum concentrations of selenium, selenoprotein P (SELENOP) and GPx3 were correlated with less organ injury. GPx3 activity at baseline was predictive of 6-month survival (AUC 0.73; p = 0.03). While selenium treatment elevated serum selenium and SELENOP concentrations but not GPx3 activity in the full patient cohort, subgroup analyses revealed that GPx3 activity increased in patients with reduced kidney function, selenium deficiency and low to moderate GPx3 activity. Clinical outcomes did not vary between selenium treatment and placebo in any of these subgroups, though the study was not powered to conclusively detect differences in outcomes. Conclusions The identification of GPx3 responders encourages further refined investigations into the treatment effects of selenium in high-risk cardiac surgery patients. Graphical Abstract

Abstract Background Current COVID-19 guidelines recommend the early use of systemic corticoids for COVID-19 acute respiratory distress syndrome (ARDS). It remains unknown if high-dose methylprednisolone pulse therapy (MPT) ameliorates refractory COVID-19 ARDS after many days of mechanical ventilation or rapid deterioration with or without extracorporeal membrane oxygenation (ECMO). Methods This is a retrospective observational study. Consecutive patients with COVID-19 ARDS treated with a parenteral high-dose methylprednisolone pulse therapy at the intensive care units (ICU) of two University Hospitals between January 1st 2021 and November 30st 2022 were included. Clinical data collection was at ICU admission, start of MPT, 3-, 10- and 14-days post MPT. Results Thirty-seven patients (mean age 55 ± 12 years) were included in the study. MPT started at a mean of 17 ± 12 days after mechanical ventilation. Nineteen patients (54%) received ECMO support when commencing MPT. Mean paO2/FiO2 significantly improved 3- (p = 0.034) and 10 days (p = 0.0313) post MPT. The same applied to the necessary FiO2 10 days after MPT (p = 0.0240). There were no serious infectious complications. Twenty-four patients (65%) survived to ICU discharge, including 13 out of 20 (65%) needing ECMO support. Conclusions Late administration of high-dose MPT in a critical subset of refractory COVID-19 ARDS patients improved respiratory function and was associated with a higher-than-expected survival of 65%. These data suggest that high-dose MPT may be a viable salvage therapy in refractory COVID-19 ARDS.

Anemia affects humans throughout life, and is linked to higher morbidity and mortality. Unclear is whether hemoglobin values are equivalent between women and men. This study evaluates the association of preoperative hemoglobin levels with in-hospital mortality and estimates thresholds for survival equity between men and women. All adult patients undergoing surgery between 2010 and 2019 from 14 German hospitals were included in the study. Thresholds for survival equity were determined with generalized additive models. In total, 842,130 patients with a median in-hospital follow-up time of 7 days were analyzed. During follow-up 20,370 deaths occurred. Preoperative hemoglobin stratified in-hospital mortality (log-rank test p