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Julia Dormann,1 Sebastian Wendt,1 Michael Dreher,2 Kelly Ansems,1 Carole Rolland,3 Jan Spillner,4 Agnieszka Szafran,1 Thomas Breuer,1 Christophe Pison,5– 7,&ast; Tom Verbelen,8,&ast; Carina Benstoem1,&ast; 1Department of Intensive Care Medicine and Intermediate Care, Medical Faculty, RWTH Aachen University, Aachen, Germany; 2Department of Pneumology and Intensive Care Medicine, RWTH Aachen University, Aachen, Germany; 3Techniques de l’Ingénierie Médicale et de la Complexité (TIMC), Centre National de la Recherche Scientifique (CNRS), University Grenoble Alpes, Grenoble, France; 4Department of Thoracic Surgery, Medical Faculty, RWTH Aachen University, Aachen, Germany; 5Department of Pneumology and Physiology, CHU Grenoble Alpes; University Grenoble Alpes, Grenoble, France; 6Laboratory of Fundamental and Applied Bioenergetics, LBFA, Inserm1055, Grenoble, France; 7Département Universitaire des Patients Grenoble Alpes, University Grenoble Alpes, Grenoble, France; 8Department of Cardiovascular Sciences, KU Leuven and Department of Cardiac Surgery, University Hospitals Leuven, Leuven, Belgium&ast;These authors contributed equally to this workCorrespondence: Carina Benstoem, Department of Intensive Care Medicine and Intermediate Care, Medical Faculty, RWTH Aachen University, Pauwelsstr. 30, Aachen, D-52074, Tel +49 241 80 38038, Fax +49 241 80 33 82182, Email cbenstoem@ukaachen.deBackground: Terminal lung diseases such as chronic obstructive pulmonary disease (COPD) and pulmonary hypertension (PH) in progression cause a large reduction in quality of life and may lead to bilateral lung transplantation (bLTx). An artificial portable lung could provide a bridge to lung transplantation, allowing patients to remain at home and mobile for longer. To advance the development of such an artificial lung, patient feedback is essential. The aim of this study is to analyze patient acceptance about an extracorporeal artificial lung and to implement these findings into the development.Methods: In collaboration with a medical device developer, we presented a portable dummy oxygenator to patients with advanced lung disease, as potential end users. Data collection in Germany and France was based on two different methods: an online questionnaire and face-to-face interviews (F2F).Results: A total of 604 participants answered the online questionnaire and 17 participants were included in the F2F interviews. The majority of participants (COPD n=140, PH n=17) were able to walk more than 1 km with a mean suffering pressure of 2.87 and 3, respectively. Six of the 17 F2F participants who could walk < 1 km were interested in an assistive device. The statistical value of Fisher’s exact test for suffering pressure and desire for a portable oxygenator was 0.45.Conclusion: In patients with advanced lung disease, there is no statistically significant association between subjectively increased suffering pressure and desire for a portable oxygenator, so market introduction may be difficult. Potential end users should be implemented early in device development. Data collection via an online questionnaire combined with personal interviews has proven to be a successful approach here.Keywords: chronic obstructive pulmonary disease, pulmonary hypertension, artificial lung, patient feedback

Anneke Damberg, Carina Benstoem, Ruediger Autschbach, Andreas GoetzenichDepartment of Cardiovascular and Thoracic Surgery, University Clinic RWTH Aachen, Aachen, GermanyAbstract: The standard treatment for symptomatic severe aortic valve stenosis is surgical aortic valve replacement. Over the last decade, transcatheter aortic valve replacement has emerged as an option for patients judged inoperable. It might also constitute an alternative for high-risk patients, even though which patients might benefit from this approach is still being discussed and remains controversial. Transcatheter heart valve replacement is a rapidly spreading technology. However, a number of problems still need to be addressed, such as paravalvular regurgitation, stroke rate, and postoperative conduction disturbances. Further, the durability of transcatheter heart valves remains unclear. Randomized clinical trials and long-term follow-up will help define the role of transcatheter heart valve replacement in aortic stenosis therapy.Keywords: TAVI, aortic valve replacement, transcatheter surgery

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Objectives: We present the 'COVID-19 evidence ecosystem' (CEOsys) as a German network to inform pandemic management and to support clinical and public health decision-making. We discuss challenges faced when organizing the ecosystem and derive lessons learned for similar networks acting during pandemics or health-related crises., Study Design and Setting: Bringing together 18 university hospitals and additional institutions, CEOsys key activities included research prioritization, conducting living systematic reviews (LSRs), supporting evidence-based (living) guidelines, knowledge translation (KT), detecting research gaps, and deriving recommendations, backed by technical infrastructure and capacity building., Results: CEOsys rapidly produced 31 high-quality evidence syntheses and supported three living guidelines on COVID-19-related topics, while also developing methodological procedures. Challenges included CEOsys' late initiation in relation to the pandemic outbreak, the delayed prioritization of research questions, the continuously evolving COVID-19-related evidence, and establishing a technical infrastructure. Methodological-clinical tandems, the cooperation with national guideline groups and international collaborations were key for efficiency., Conclusion: CEOsys provided a proof-of-concept for a functioning evidence ecosystem at the national level. Lessons learned include that similar networks should, among others, involve methodological and clinical key stakeholders early on, aim for (inter)national collaborations, and systematically evaluate their value. We particularly call for a sustainable network., Competing Interests: Declaration of competing interest F.B. reports a relationship with Pfizer that includes: speaking and lecture fees; reports a relationship with Hans-Bockler-Foundation that includes: funding grants; reports a relationship with German Research Foundation that includes: funding grants; reports a relationship with German Federal Ministry of Health that includes: funding grants; reports a relationship with Federal German Ministry of Education and Research that includes: funding grants; reports a relationship with Charité Foundation that includes: funding grants; reports a relationship with Joint Federal Committee that includes: funding grants; reports a relationship with General Electric that includes: speaking and lecture fees; reports a relationship with Medtronic that includes: board membership. I.K. reports the following grants or contracts from any entity in the past 36 months (type of grant: third party fund; recipient: institutional): German Cancer Aid Foundation, German Ministry of Health (BMG), German Federal Joint Committee independent Funding Programme for Clinical Practice Guidelines developed under the auspices of AWMF member societies (2020-2023), German Ministry for Education and Research (BMBF; 2020-2022); reports consulting fees (recipient: personal) were provided by: European Federation of Periodontology (honoraria, travel costs; 2020-2023), British Society for Periodontology (honoraria, travel costs; 2020-2023), European Society of Endotontology (ESE; honoraria; 2021 – 2023), European Society for Contact Dermatitis (ESCD; honoraria; 2021-2021); reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events (recipient: personal) by EBM Frankfurt, Working Group at the Institute for Family Medicine, Goethe-University Frankfurt (honoraria, travel costs; 2020-2022), German Society for Pediatric Infectiology (honoraria; 2021-2022), European Business School (EBS) Wiesbaden (honoraria; 2021-2022), European Association of Dental Implantologists (BDIZ; honoraria, travel costs; 2022-2022); reports payment for expert testimony was provided by German Accreditation Body (DAkkS; honoraria, travel costs); reports participation on a Data Safety Monitoring Board or Advisory Board (Agency for Quality in Medicine (ÄZQ) (a nonprofit organization)—advisory board; type of grant: honoraria, 2020-2023); reports leadership or a fiduciary role in other board, society, committee, or advocacy group (unpaid, nonfinancial): AWMF-Representative in the Board of Trustees- IQTIG (German Institute for Quality and Transparency in Health Care) a nonprofit, governmental institution), Honorary Member—German Society for Breast Health, Member—German Network for Evidence based Medicine (DNEbM), German Society of Surgery (DGCH), Member—Steering Committee for the Guideline Program in Oncology of the German Cancer Society, German Cancer Aid and AWMF, Member—Advisory Board for the Program National Disease Management Guidelines under the auspices of AWMF, German Cancer Society and AWMF, Deputy Chair- Standing Commission on Guidelines of the German Medical Association, the National Association of Statutory Health Insurance Physicians, and the AWMF, Primary Contact on behalf of the AWMF in the Guidelines International Network, Trustee, Guidelines International Network, AWMF Curriculum for guideline developers and guideline advisors; Reviewer, GIN-Mcmaster INGUIDE Program. Other financial or nonfinancial interests: Research interests (Guidelines, Health Services Research, Digitalization); and explicitly declares that she has no ties to pharmaceutical or medical product industry. M.S. reports financial support and administrative support were provided by Charité Universitätsmedizin Berlin Infectious Diseases; reports a relationship with Charité University Hospital Berlin that includes: employment. F.v.D. reports a relationship with Charité University Hospital Berlin that includes: funding grants; reports a relationship with University Medicine Greifswald that includes: funding grants. There are no competing interests for any other author., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The Sequential Organ Failure Assessment, also known as SOFA score, was introduced to assess organ dysfunction of critical ill patients. However, understanding the impact of missing SOFA scores in randomized controlled trials and how this affect the validity and applicability of the SOFA score as a surrogate endpoint for predicting mortality has been a matter of interest. To address this, a secondary analysis of a systematic review was conducted to quantify the relationship between SOFA scores and the prediction of mortality in critically ill adults in randomized controlled trials (RCTs). The systematic review being referred to included 87 RCTs with a total of 12,064 critically ill patients. This analysis focused on missing SOFA score data in relation to the length of stay on the intensive care unit (ICU) and the methods used to handle missing data. SOFA score measurements from the included studies were categorized into three time frames: Early (t ≤ 4 days), Intermediate (t = 5-10 days) and Late (t > 10 days) measurement. Only one study reported a complete data set for calculating the SOFA score for an Early measurement. When considering all methods used to address missing data, 32% of studies still had missing data for Early measurements, and this percentage increased to 64% for Late measurements. These findings suggested that, over time, the number of studies with incomplete data sets has been increasing. The longer a patient is treated on the ICU, the higher the number of missing data which can impact the validity of SOFA score analyses. There was no clear trend towards a specific method for compensating missing data. An exemplary calculation demonstrated that ignoring missing data may lead to an underestimated variability of the treatment effect. This, in turn, could bias the interpretation of study results by policy- and clinical decision-makers. Overall, there are several limitations that need to be considered when using SOFA score as a surrogate endpoint for mortality. When employed as an outcome, the SOFA score is frequently missing and most studies do not adequately describe the amount or nature of missing data, or the methods used to handle missing data in the analysis., (© 2024. The Author(s).)

Background: Citizens can represent a relevant key resource in health care, for example by actively practicing preventive health care and managing their own health care needs. In Germany, the role of citizens in the health care system has not yet been defined. Therefore, the aim of this study is, as a first step, to determine what is meant by "citizen-centred healthcare", since there is, as yet, no clear definition., Methods: Between September and November 2022, semi-structured expert interviews were conducted with representatives from the fields of politics and self-administration and service providers and, with their consent, recorded and transcribed. A category system was developed inductively and deductively based on Mayring's content analysis. Using this, two members of the project team coded the interviews independently of each other using the QCAmap software. After a replication check of the deviations, the content could then be analyzed., Results: A total of n = 10 interviews were conducted (n = 3 service providers, n = 2 self-administration, n = 5 politicians). The analysis revealed two different understandings of citizen-centred healthcare. Some of the experts understand citizen-centred healthcare as care that is provided close to home and easily accessible for citizens. The others interpret the term as care where citizens take on an active role. All interviewees saw the lack of health literacy among citizens as a key challenge. The social imbalance, which creates an inequality of opportunity in the involvement of citizens, was also mentioned several times. Opportunities were generally understood as the possibility of conserving resources and maintaining health. The analysis shows that there is still a lack of solutions that specifically address these challenges as well as the implementation of citizen-centred health care., Discussion: The expert interviews demonstrate that there are two fundamentally different understandings of citizen-centred healthcare and how it should be established in Germany. Future research should therefore pursue the goal of developing a definition of "citizen-centred health care" by expert consensus. This can then form the basis for concrete, future goals for action. There was consensus among the experts regarding the problems that need to be considered in this context. Factors such as citizens' lack of health literacy and social imbalance should therefore be given more attention in the future., (Copyright © 2023. Published by Elsevier GmbH.)

Background: The role of early tracheostomy as an intervention for critically ill COVID-19 patients is unclear. Previous reports have described prolonged intensive care stays and difficulty weaning from mechanical ventilation in critically ill COVID-19 patients, particularly in those developing acute respiratory distress syndrome. Pre-pandemic evidence on the benefits of early tracheostomy is conflicting but suggests shorter hospital stays and lower mortality rates compared to late tracheostomy., Objectives: To assess the benefits and harms of early tracheostomy compared to late tracheostomy in critically ill COVID-19 patients., Search Methods: We searched the Cochrane COVID-19 Study Register, which comprises CENTRAL, PubMed, Embase, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, and medRxiv, as well as Web of Science (Science Citation Index Expanded and Emerging Sources Citation Index) and WHO COVID-19 Global literature on coronavirus disease to identify completed and ongoing studies without language restrictions. We conducted the searches on 14 June 2022., Selection Criteria: We followed standard Cochrane methodology. We included randomized controlled trials (RCTs) and non-randomized studies of interventions (NRSI) evaluating early tracheostomy compared to late tracheostomy during SARS-CoV-2 infection in critically ill adults irrespective of gender, ethnicity, or setting., Data Collection and Analysis: We followed standard Cochrane methodology. To assess risk of bias in included studies, we used the Cochrane RoB 2 tool for RCTs and the ROBINS-I tool for NRSIs. We used the GRADE approach to assess the certainty of evidence for outcomes of our prioritized categories: mortality, clinical status, and intensive care unit (ICU) length of stay. As the timing of tracheostomy was very heterogeneous among the included studies, we applied GRADE only to studies that defined early tracheostomy as 10 days or less, which was chosen according to clinical relevance., Main Results: We included one RCT with 150 participants diagnosed with SARS-CoV-2 infection and 24 NRSIs with 6372 participants diagnosed with SARS-CoV-2 infection. All participants were admitted to the ICU, orally intubated and mechanically ventilated. The RCT was a multicenter, parallel, single-blinded study conducted in Sweden. Of the 24 NRSIs, which were mostly conducted in high- and middle-income countries, eight had a prospective design and 16 a retrospective design. We did not find any ongoing studies. RCT-based evidence We judged risk of bias for the RCT to be of low or some concerns regarding randomization and measurement of the outcome. Early tracheostomy may result in little to no difference in overall mortality (RR 0.82, 95% CI 0.52 to 1.29; RD 67 fewer per 1000, 95% CI 178 fewer to 108 more; 1 study, 150 participants; low-certainty evidence). As an indicator of improvement of clinical status, early tracheostomy may result in little to no difference in duration to liberation from invasive mechanical ventilation (MD 1.50 days fewer, 95%, CI 5.74 days fewer to 2.74 days more; 1 study, 150 participants; low-certainty evidence). As an indicator of worsening clinical status, early tracheostomy may result in little to no difference in the incidence of adverse events of any grade (RR 0.94, 95% CI 0.79 to 1.13; RD 47 fewer per 1000, 95% CI 164 fewer to 102 more; 1 study, 150 participants; low-certainty evidence); little to no difference in the incidence of ventilator-associated pneumonia (RR 1.08, 95% CI 0.23 to 5.20; RD 3 more per 1000, 95% CI 30 fewer to 162 more; 1 study, 150 participants; low-certainty evidence). None of the studies reported need for renal replacement therapy. Early tracheostomy may result in little benefit to no difference in ICU length of stay (MD 0.5 days fewer, 95% CI 5.34 days fewer to 4.34 days more; 1 study, 150 participants; low-certainty evidence). NRSI-based evidence We considered risk of bias for NRSIs to be critical because of possible confounding, study participant enrollment into the studies, intervention classification and potentially systematic errors in the measurement of outcomes. We are uncertain whether early tracheostomy (≤ 10 days) increases or decreases overall mortality (RR 1.47, 95% CI 0.43 to 5.00; RD 143 more per 1000, 95% CI 174 less to 1218 more; I 2 = 79%; 2 studies, 719 participants) or duration to liberation from mechanical ventilation (MD 1.98 days fewer, 95% CI 0.16 days fewer to 4.12 more; 1 study, 50 participants), because we graded the certainty of evidence as very low. Three NRSIs reported ICU length of stay for 519 patients with early tracheostomy (≤ 10 days) as a median value, which we could not include in the meta-analyses. We are uncertain whether early tracheostomy (≤ 10 days) increases or decreases the ICU length of stay, because we graded the certainty of evidence as very low., Authors' Conclusions: We found low-certainty evidence that early tracheostomy may result in little to no difference in overall mortality in critically ill COVID-19 patients requiring prolonged mechanical ventilation compared with late tracheostomy. In terms of clinical improvement, early tracheostomy may result in little to no difference in duration to liberation from mechanical ventilation compared with late tracheostomy. We are not certain about the impact of early tracheostomy on clinical worsening in terms of the incidence of adverse events, need for renal replacement therapy, ventilator-associated pneumonia, or the length of stay in the ICU. Future RCTs should provide additional data on the benefits and harms of early tracheostomy for defined main outcomes of COVID-19 research, as well as of comparable diseases, especially for different population subgroups to reduce clinical heterogeneity, and report a longer observation period. Then it would be possible to draw conclusions regarding which patient groups might benefit from early intervention. Furthermore, validated scoring systems for more accurate predictions of the need for prolonged mechanical ventilation should be developed and used in new RCTs to ensure safer indication and patient safety. High-quality (prospectively registered) NRSIs should be conducted in the future to provide valuable answers to clinical questions. This could enable us to draw more reliable conclusions about the potential benefits and harms of early tracheostomy in critically ill COVID-19 patients., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Cardiac surgery patients not only undergo a highly invasive procedure but are at risk for a diversity of postoperative complications. Up to 53% of these patients suffer from postoperative delirium (POD). This severe and common adverse event increases mortality and prolonged mechanical ventilation and extends the intensive care unit stay. The objective of this study was to test the hypothesis that standardized pharmacological management of delirium (SPMD) may reduce the length of stay in the intensive care unit (ICU), duration of postoperative mechanical ventilation, and the incidence of postoperative complications such as pneumonia or bloodstream infections in on-pump cardiac surgery ICU patients. In this retrospective, single-center observational cohort study, 247 patients were examined between May 2018 to June 2020, who underwent on-pump cardiac surgery, suffered from POD, and received pharmacological POD treatment. 125 were treated before and 122 after SPMD implementation in the ICU. The primary endpoint was a composite outcome, including the length of ICU stay, postoperative mechanical ventilation time, and ICU survival rate. The secondary endpoints were complications including postoperative pneumonia and bloodstream infections. Although the ICU survival rate was not significantly different between both groups, the length of ICU stay (control group: 23 ± 27 days; SPMD group: 16 ± 16 days; p = 0.024) and the duration of mechanical ventilation were significantly reduced in the SPMD-cohort (control group: 230 ± 395 h; SPMD group: 128 ± 268 h; p = 0.022). Concordantly, the pneumonic risk was reduced after SPMD introduction (control group: 44.0%; SPMD group: 27.9%; p = 0.012) as well as the incidence for bloodstream infections (control group: 19.2%; SPMD group: 6.6%; p = 0.004). Standardized pharmacological management of postoperative delirium in on-pump cardiac surgery ICU patients reduced the length of ICU stay and duration of mechanical ventilation significantly, leading to a decrease in pneumonic complications and bloodstream infections., (© 2023. The Author(s).)

Background: At the end of 2021, the European Medicines Agency (EMA) expanded its approval for the recombinant human interleukin-1 (IL-1) receptor antagonist Anakinra for the treatment of COVID-19 patients with elevated soluble urokinase plasminogen activator receptor (suPAR). However, the role of Anakinra in COVID-19 remains unanswered, especially in patients receiving different forms of respiratory support. Therefore, the objective of this systematic review is to assess the safety and effects of Anakinra compared to placebo or standard care alone on clinical outcomes in adult hospitalized patients with SARS-CoV-2 infection., Methods: We searched the Cochrane COVID-19 Study Register (comprising MEDLINE, Embase, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, medRxiv, and the Cochrane Central Register of Controlled Trials (CCSR)) and the WHO COVID-19 Global literature on coronavirus disease database to identify completed and ongoing studies from inception of each database to December 13, 2021. Since then, we monitored new published studies weekly up to June 30, 2022 using the CCSR. We included RCTs comparing treatment with Anakinra to placebo or standard care alone in adult hospitalized patients with SARS-CoV-2 infection., Results: We included five RCTs with 1,627 patients (n Anakinra  = 888, n control  = 739, mean age 59.63 years, 64% male). Random-effects meta-analysis was used to pool data. We found that Anakinra makes little or no difference to all-cause mortality at up to day 28 compared to placebo or standard care alone (RR 0.96, 95% CI 0.64-1.45; RD 9 fewer per 1000, 95% CI 84 fewer to 104 more; 4 studies, 1593 participants; I 2  = 49%; low certainty of evidence)., Conclusions: Anakinra has no effect on adult hospitalized patients with SARS-CoV-2 infection regarding mortality, clinical improvement and worsening as well as on safety outcomes compared to placebo or standard care alone., Trial Registration: PROSPERO Registration Number: CRD42021257552., (© 2023. The Author(s).)

Background: Remdesivir is an antiviral medicine approved for the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19). This led to widespread implementation, although the available evidence remains inconsistent. This update aims to fill current knowledge gaps by identifying, describing, evaluating, and synthesising all evidence from randomised controlled trials (RCTs) on the effects of remdesivir on clinical outcomes in COVID-19., Objectives: To assess the effects of remdesivir and standard care compared to standard care plus/minus placebo on clinical outcomes in patients treated for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection., Search Methods: We searched the Cochrane COVID-19 Study Register (which comprises the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase, ClinicalTrials.gov, World Health Organization (WHO) International Clinical Trials Registry Platform, and medRxiv) as well as Web of Science (Science Citation Index Expanded and Emerging Sources Citation Index) and WHO COVID-19 Global literature on coronavirus disease to identify completed and ongoing studies, without language restrictions. We conducted the searches on 31 May 2022., Selection Criteria: We followed standard Cochrane methodology. We included RCTs evaluating remdesivir and standard care for the treatment of SARS-CoV-2 infection compared to standard care plus/minus placebo irrespective of disease severity, gender, ethnicity, or setting. We excluded studies that evaluated remdesivir for the treatment of other coronavirus diseases., Data Collection and Analysis: We followed standard Cochrane methodology. To assess risk of bias in included studies, we used the Cochrane RoB 2 tool for RCTs. We rated the certainty of evidence using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for outcomes that were reported according to our prioritised categories: all-cause mortality, in-hospital mortality, clinical improvement (being alive and ready for discharge up to day 28) or worsening (new need for invasive mechanical ventilation or death up to day 28), quality of life, serious adverse events, and adverse events (any grade). We differentiated between non-hospitalised individuals with asymptomatic SARS-CoV-2 infection or mild COVID-19 and hospitalised individuals with moderate to severe COVID-19., Main Results: We included nine RCTs with 11,218 participants diagnosed with SARS-CoV-2 infection and a mean age of 53.6 years, of whom 5982 participants were randomised to receive remdesivir. Most participants required low-flow oxygen at baseline. Studies were mainly conducted in high- and upper-middle-income countries. We identified two studies that are awaiting classification and five ongoing studies. Effects of remdesivir in hospitalised individuals with moderate to severe COVID-19 With moderate-certainty evidence, remdesivir probably makes little or no difference to all-cause mortality at up to day 28 (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.81 to 1.06; risk difference (RD) 8 fewer per 1000, 95% CI 21 fewer to 6 more; 4 studies, 7142 participants), day 60 (RR 0.85, 95% CI 0.69 to 1.05; RD 35 fewer per 1000, 95% CI 73 fewer to 12 more; 1 study, 1281 participants), or in-hospital mortality at up to day 150 (RR 0.93, 95% CI 0.84 to 1.03; RD 11 fewer per 1000, 95% CI 25 fewer to 5 more; 1 study, 8275 participants). Remdesivir probably increases the chance of clinical improvement at up to day 28 slightly (RR 1.11, 95% CI 1.06 to 1.17; RD 68 more per 1000, 95% CI 37 more to 105 more; 4 studies, 2514 participants; moderate-certainty evidence). It probably decreases the risk of clinical worsening within 28 days (hazard ratio (HR) 0.67, 95% CI 0.54 to 0.82; RD 135 fewer per 1000, 95% CI 198 fewer to 69 fewer; 2 studies, 1734 participants, moderate-certainty evidence). Remdesivir may make little or no difference to the rate of adverse events of any grade (RR 1.04, 95% CI 0.92 to 1.18; RD 23 more per 1000, 95% CI 46 fewer to 104 more; 4 studies, 2498 participants; low-certainty evidence), or serious adverse events (RR 0.84, 95% CI 0.65 to 1.07; RD 44 fewer per 1000, 95% CI 96 fewer to 19 more; 4 studies, 2498 participants; low-certainty evidence). We considered risk of bias to be low, with some concerns for mortality and clinical course. We had some concerns for safety outcomes because participants who had died did not contribute information. Without adjustment, this leads to an uncertain amount of missing values and the potential for bias due to missing data. Effects of remdesivir in non-hospitalised individuals with mild COVID-19 One of the nine RCTs was conducted in the outpatient setting and included symptomatic people with a risk of progression. No deaths occurred within the 28 days observation period. We are uncertain about clinical improvement due to very low-certainty evidence. Remdesivir probably decreases the risk of clinical worsening (hospitalisation) at up to day 28 (RR 0.28, 95% CI 0.11 to 0.75; RD 46 fewer per 1000, 95% CI 57 fewer to 16 fewer; 562 participants; moderate-certainty evidence). We did not find any data for quality of life. Remdesivir may decrease the rate of serious adverse events at up to 28 days (RR 0.27, 95% CI 0.10 to 0.70; RD 49 fewer per 1000, 95% CI 60 fewer to 20 fewer; 562 participants; low-certainty evidence), but it probably makes little or no difference to the risk of adverse events of any grade (RR 0.91, 95% CI 0.76 to 1.10; RD 42 fewer per 1000, 95% CI 111 fewer to 46 more; 562 participants; moderate-certainty evidence). We considered risk of bias to be low for mortality, clinical improvement, and safety outcomes. We identified a high risk of bias for clinical worsening., Authors' Conclusions: Based on the available evidence up to 31 May 2022, remdesivir probably has little or no effect on all-cause mortality or in-hospital mortality of individuals with moderate to severe COVID-19. The hospitalisation rate was reduced with remdesivir in one study including participants with mild to moderate COVID-19. It may be beneficial in the clinical course for both hospitalised and non-hospitalised patients, but certainty remains limited. The applicability of the evidence to current practice may be limited by the recruitment of participants from mostly unvaccinated populations exposed to early variants of the SARS-CoV-2 virus at the time the studies were undertaken.  Future studies should provide additional data on the efficacy and safety of remdesivir for defined core outcomes in COVID-19 research, especially for different population subgroups., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Warm ischaemia is usually induced by the Pringle manoeuver (PM) during hepatectomy. Currently, there is no widely accepted standard protocol to minimise ischaemia-related injury, so reducing ischaemia-reperfusion damage is an active area of research. This systematic review and meta-analysis focused on inducible nitric oxide synthase (iNOS) as an early inflammatory response to hepatic ischaemia reperfusion injury (HIRI) in mouse- and rat-liver models. A systematic search of studies was performed within three databases. Studies meeting the inclusion criteria were subjected to qualitative and quantitative synthesis of results. We performed a meta-analysis of studies grouped by different HIRI models and ischaemia times. Additionally, we investigated a possible correlation of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) regulation with iNOS expression. Of 124 included studies, 49 were eligible for the meta-analysis, revealing that iNOS was upregulated in almost all HIRIs. We were able to show an increase of iNOS regardless of ischemia or reperfusion time. Additionally, we found no direct associations of eNOS or NO with iNOS. A sex gap of primarily male experimental animals used was observed, leading to a higher risk of outcomes not being translatable to humans of all sexes.

Background: Systemic inflammation and oxidative stress remain the main causes of complications in patients with heart failure receiving a left ventricular assist device (LVAD). Selenoproteins are a cornerstone of antioxidant defense mechanisms for improving inflammatory conditions., Methods: In a monocentric, double-blinded pilot trial patients scheduled for LVAD implantation were randomized to receive 300 mcg of selenium orally the evening before surgery, followed by a high-dose of intravenous selenium supplementation (3000 mcg after anesthesia induction, 1000 mcg upon intensive care unit [ICU] admission, and 1000 mcg daily in the ICU for a maximum of 14 days) or placebo. The main outcomes were feasibility and effectiveness in restoring serum selenium concentrations., Results: Twenty patients were included in the analysis. The average duration of study intervention was 12.6 days (7-14), with 97.7% dose compliance. No patient received open-label selenium. The supplementation strategy was effective in compensating low serum selenium concentrations (before surgery: control, 63.5 ± 11.9 mcg/L vs intervention, 65.8 ± 16.5 mcg/L; ICU admission: control, 49.0 ± 9.8 mcg/L vs intervention, 144.2 ± 45.4 mcg/L). Serum selenium concentrations in the intervention group were significantly higher during the observation period (baseline: mean of placebo (MoP), 63.1 vs mean of selenium (MoS), 64.0; ICU admission: MoP, 49.0 vs MoS, 144.6; day 1-13: MoP, 43.6-48.5 vs MoS, 100.4-131.0)., Conclusion: Selenium supplementation in patients receiving LVAD implantation is feasible and effective to compensate a selenium deficiency., (© 2022 The Authors. Journal of Parenteral and Enteral Nutrition published by Wiley Periodicals LLC on behalf of American Society for Parenteral and Enteral Nutrition.)

Background: The effect of mild changes in CO 2 levels to organ perfusion and tissue inflammation are well known, whereas an influence of hypercapnia under general anesthesia on adverse events as nausea and vomiting, or length of hospital stay is barely examined. The goal of our meta-analysis was to identify possibly positive effects of hypercapnia versus normocapnia in general anesthesia in adult patients., Methods: We conducted a systematic review of parallel-arm randomised controlled trials comparing hypercapnia versus normocapnia in adult patients undergoing general anesthesia. In July 2018 and September 2019 we searched "CENTRAL‿, "MEDLINE‿, and "Embase‿, checked reference lists of all included studies and relevant systematic reviews for additional references to trials. Two review authors independently assessed trials for inclusion, extracted data, and completed a "Risk of bias‿ assessment for all included studies., Results: Our search identified 297 records after abstract screening 30 full-text papers remained for further examination. Ten publications met our inclusion criteria and were used for narrative description of this systematic review. Three studies were eligible for the meta-analysis normocapnia versus hypercapnia with the outcomes: time to extubation and adverse events. On average, time to extubation was significantly reduced in the hypercapnia group with a mean difference 3.78 (95% CI 0.85 to 6.71). No difference was found regarding adverse events., Conclusions: The findings of our study do not enable us to produce evidence of a positive influence of increased CO 2 partial pressure levels during general anesthesia. A well-planned, adequately powered randomized controlled trial would be desirable in the future., (Copyright © 2021 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. All rights reserved.)

Technical possibilities for patient support must be user-friendly. This includes acceptance on the part of the patients, and safe function that must not lead to the user being overtaxed. In a study of Ventricular Assist Device (VAD) patients at the Department of Thoracic and Cardiovascular Surgery at the University Hospital RWTH Aachen, a questionnaire was used to investigate the current situation in dealing with the VAD system. This was followed by a query about ideas, wishes, and fears regarding the increased use of telemedical applications. An adapted Service User Technology Acceptability Questionnaire (SUTAQ) was used and the evaluation was carried out with the help of Office-based applications. As a result, it can be stated that the patients do not want to see personal contacts and care be completely replaced by telemedical remote support. If the application is stable and functioning, the majority is very much open to such support.

Background: Evidence-based infectious disease and intensive care management is more relevant than ever. Medical expertise in the two disciplines is often geographically limited to university institutions. In addition, the interconnection between inpatient and outpatient care is often insufficient (eg, no shared electronic health record and no digital transfer of patient findings)., Objective: This study aims to establish and evaluate a telemedical inpatient-outpatient network based on expert teleconsultations to increase treatment quality in intensive care medicine and infectious diseases., Methods: We performed a multicenter, stepped-wedge cluster randomized trial (February 2017 to January 2020) to establish a telemedicine inpatient-outpatient network among university hospitals, hospitals, and outpatient physicians in North Rhine-Westphalia, Germany. Patients aged ≥18 years in the intensive care unit or consulting with a physician in the outpatient setting were eligible. We provided expert knowledge from intensivists and infectious disease specialists through advanced training courses and expert teleconsultations with 24/7/365 availability on demand respectively once per week to enhance treatment quality. The primary outcome was adherence to the 10 Choosing Wisely recommendations for infectious disease management. Guideline adherence was analyzed using binary logistic regression models., Results: Overall, 159,424 patients (10,585 inpatients and 148,839 outpatients) from 17 hospitals and 103 outpatient physicians were included. There was a significant increase in guideline adherence in the management of Staphylococcus aureus infections (odds ratio [OR] 4.00, 95% CI 1.83-9.20; P<.001) and in sepsis management in critically ill patients (OR 6.82, 95% CI 1.27-56.61; P=.04). There was a statistically nonsignificant decrease in sepsis-related mortality from 29% (19/66) in the control group to 23.8% (50/210) in the intervention group. Furthermore, the extension of treatment with prophylactic antibiotics after surgery was significantly less likely (OR 9.37, 95% CI 1.52-111.47; P=.04). Patients treated by outpatient physicians, who were regularly participating in expert teleconsultations, were also more likely to be treated according to guideline recommendations regarding antibiotic therapy for uncomplicated upper respiratory tract infections (OR 1.34, 95% CI 1.16-1.56; P<.001) and asymptomatic bacteriuria (OR 9.31, 95% CI 3.79-25.94; P<.001). For the other recommendations, we found no significant effects, or we had too few observations to generate models. The key limitations of our study include selection effects due to the applied on-site triage of patients as well as the limited possibilities to control for secular effects., Conclusions: Telemedicine facilitates a direct round-the-clock interaction over broad distances between intensivists or infectious disease experts and physicians who care for patients in hospitals without ready access to these experts. Expert teleconsultations increase guideline adherence and treatment quality in infectious disease and intensive care management, creating added value for critically ill patients., Trial Registration: ClinicalTrials.gov NCT03137589; https://clinicaltrials.gov/ct2/show/NCT03137589., (©Gernot Marx, Wolfgang Greiner, Christian Juhra, Svenja Elkenkamp, Daniel Gensorowsky, Sebastian Lemmen, Jan Englbrecht, Sandra Dohmen, Antje Gottschalk, Miriam Haverkamp, Annette Hempen, Christian Flügel-Bleienheuft, Daniela Bause, Henna Schulze-Steinen, Susanne Rademacher, Jennifer Kistermann, Stefan Hoch, Hans-Juergen Beckmann, Christian Lanckohr, Volker Lowitsch, Arne Peine, Fabian Juzek-Kuepper, Carina Benstoem, Kathrin Sperling, Robert Deisz. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 02.03.2022.)

The Corona pandemic is a clear demonstration of the need for an alternative to face-to-face medicine. This demand makes telemedicine the tool of choice. In the preliminary stage of the Virtual Hospital North Rhine-Westphalia (VKh), tele-intensive care consultation services have contributed to both a benefit in terms of care and a benefit for individual patients. The task now is to roll out and use digitally-supported intensive-care networks across the board, including throughout Europe. The goal of telemedicine is to ensure comprehensive patient care - also across sector boundaries of the healthcare system - and to improve quality. Tele-intensive care is already an evidence-based added value and addresses current and future challenges such as resource shortage and citizen-centered care. The Virtual Hospital NRW is a telemedical network structure that is unique in Germany. It provides telemedical services from expert centers in a quality-assured and comprehensive manner for general hospitals as well as for outpatient players. Telemedical services help to overcome rigid sector boundaries and to optimize treatment processes. As a result, service-differentiated care networks are goal-oriented. The medium-term perspective could be cross-border network structures. Medical expertise and also intensive care data, both from care and research, could thus be used throughout Europe. In October 2021, the Aachen Expert Center reported on its first 112 telemedically co-managed COVID-19 patients as part of the preliminary stage of the virtual hospital. With a lethality rate of 34.2% in the group of ventilated severely ill COVID-19 patients and a transfer rate of 8%, high-quality care close to the patient's home was achieved through tele-intensive medical consultation services., Competing Interests: Erklärung zu finanziellen Interessen Forschungsförderung erhalten: nein; Honorar/geldwerten Vorteil für Referententätigkeit erhalten: nein; Bezahlter Berater/interner Schulungsreferent/Gehaltsempfänger: nein; Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an im Bereich der Medizin aktiven Firma: nein; Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an zu Sponsoren dieser Fortbildung bzw. durch die Fortbildung in ihren Geschäftsinteressen berührten Firma: nein Erklärung zu nichtfinanziellen Interessen Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Background: Remdesivir is an antiviral medicine with properties to inhibit viral replication of SARS-CoV-2. Positive results from early studies attracted media attention and led to emergency use authorisation of remdesivir in COVID-19.  A thorough understanding of the current evidence regarding the effects of remdesivir as a treatment for SARS-CoV-2 infection based on randomised controlled trials (RCTs) is required., Objectives: To assess the effects of remdesivir compared to placebo or standard care alone on clinical outcomes in hospitalised patients with SARS-CoV-2 infection, and to maintain the currency of the evidence using a living systematic review approach., Search Methods: We searched the Cochrane COVID-19 Study Register (which comprises the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, and medRxiv) as well as Web of Science (Science Citation Index Expanded and Emerging Sources Citation Index) and WHO COVID-19 Global literature on coronavirus disease to identify completed and ongoing studies without language restrictions. We conducted the searches on 16 April 2021., Selection Criteria: We followed standard Cochrane methodology. We included RCTs evaluating remdesivir for the treatment of SARS-CoV-2 infection in hospitalised adults compared to placebo or standard care alone irrespective of disease severity, gender, ethnicity, or setting.  We excluded studies that evaluated remdesivir for the treatment of other coronavirus diseases., Data Collection and Analysis: We followed standard Cochrane methodology. To assess risk of bias in included studies, we used the Cochrane RoB 2 tool for RCTs. We rated the certainty of evidence using the GRADE approach for outcomes that were reported according to our prioritised categories: all-cause mortality at up to day 28, duration to liberation from invasive mechanical ventilation, duration to liberation from supplemental oxygen, new need for mechanical ventilation (high-flow oxygen or non-invasive or invasive mechanical ventilation), new need for invasive mechanical ventilation, new need for non-invasive mechanical ventilation or high-flow oxygen, new need for oxygen by mask or nasal prongs, quality of life, adverse events (any grade), and serious adverse events., Main Results: We included five RCTs with 7452 participants diagnosed with SARS-CoV-2 infection and a mean age of 59 years, of whom 3886 participants were randomised to receive remdesivir. Most participants required low-flow oxygen (n=4409) or mechanical ventilation (n=1025) at baseline. We identified two ongoing studies, one was suspended due to a lack of COVID-19 patients to recruit. Risk of bias was considered to be of some concerns or high risk for clinical status and safety outcomes because participants who had died did not contribute information to these outcomes. Without adjustment, this leads to an uncertain amount of missing values and the potential for bias due to missing data. Effects of remdesivir in hospitalised individuals  Remdesivir probably makes little or no difference to all-cause mortality at up to day 28 (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.81 to 1.06; risk difference (RD) 8 fewer per 1000, 95% CI 21 fewer to 7 more; 4 studies, 7142 participants; moderate-certainty evidence). Considering the initial severity of condition, only one study showed a beneficial effect of remdesivir in patients who received low-flow oxygen at baseline (RR 0.32, 95% CI 0.15 to 0.66, 435 participants), but conflicting results exists from another study, and we were unable to validly assess this observations due to limited availability of comparable data. Remdesivir may have little or no effect on the duration to liberation from invasive mechanical ventilation (2 studies, 1298 participants, data not pooled, low-certainty evidence). We are uncertain whether remdesivir increases or decreases the chance of clinical improvement in terms of duration to liberation from supplemental oxygen at up to day 28 (3 studies, 1691 participants, data not pooled, very low-certainty evidence).   We are very uncertain whether remdesivir decreases or increases the risk of clinical worsening in terms of new need for mechanical ventilation at up to day 28 (high-flow oxygen or non-invasive ventilation or invasive mechanical ventilation) (RR 0.78, 95% CI 0.48 to 1.24; RD 29 fewer per 1000, 95% CI 68 fewer to 32 more; 3 studies, 6696 participants; very low-certainty evidence); new need for non-invasive mechanical ventilation or high-flow oxygen (RR 0.70, 95% CI 0.51 to 0.98; RD 72 fewer per 1000, 95% CI 118 fewer to 5 fewer; 1 study, 573 participants; very low-certainty evidence); and new need for oxygen by mask or nasal prongs (RR 0.81, 95% CI 0.54 to 1.22; RD 84 fewer per 1000, 95% CI 204 fewer to 98 more; 1 study, 138 participants; very low-certainty evidence). The evidence suggests that remdesivir may decrease the risk of clinical worsening in terms of new need for invasive mechanical ventilation (67 fewer participants amongst 1000 participants; RR 0.56, 95% CI 0.41 to 0.77; 2 studies, 1159 participants; low-certainty evidence).  None of the included studies reported quality of life. Remdesivir probably decreases the serious adverse events rate at up to 28 days (RR 0.75, 95% CI 0.63 to 0.90; RD 63 fewer per 1000, 95% CI 94 fewer to 25 fewer; 3 studies, 1674 participants; moderate-certainty evidence). We are very uncertain whether remdesivir increases or decreases adverse events rate (any grade) (RR 1.05, 95% CI 0.86 to 1.27; RD 29 more per 1000, 95% CI 82 fewer to 158 more; 3 studies, 1674 participants; very low-certainty evidence)., Authors' Conclusions: Based on the currently available evidence, we are moderately certain that remdesivir probably has little or no effect on all-cause mortality at up to day 28 in hospitalised adults with SARS-CoV-2 infection. We are uncertain about the effects of remdesivir on clinical improvement and worsening. There were insufficient data available to validly examine the effect of remdesivir on mortality in subgroups depending on the extent of respiratory support at baseline.  Future studies should provide additional data on efficacy and safety of remdesivir for defined core outcomes in COVID-19 research, especially for different population subgroups. This could allow us to draw more reliable conclusions on the potential benefits and harms of remdesivir in future updates of this review. Due to the living approach of this work, we will update the review periodically., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Objectives: Although the current coronavirus disease 2019 pandemic demonstrates the urgent need for the integration of tele-ICUs, there is still a lack of uniform regulations regarding the level of authority. We conducted a systematic review and meta-analysis to evaluate the impact of the level of authority in tele-ICU care on patient outcomes., Data Sources: We searched MEDLINE, EMBASE, CENTRAL, and Web of Science from inception until August 30, 2020., Study Selection: We searched for randomized controlled trials and observational studies comparing standard care plus tele-ICU care with standard care alone in critically ill patients., Data Extraction: Two authors performed data extraction and risk of bias assessment. Mean differences and risk ratios were calculated using a random-effects model., Data Synthesis: A total of 20 studies with 477,637 patients (ntele-ICU care = 292,319, ncontrol = 185,318) were included. Although "decision-making authority" as the level of authority was associated with a significant reduction in ICU mortality (pooled risk ratio, 0.82; 95% CI, 0.71-0.94; p = 0.006), we found no advantage of tele-ICU care in studies with "expert tele-consultation" as the level of authority. With regard to length of stay, "decision-making authority" resulted in an advantage of tele-ICU care (ICU length of stay: pooled mean difference, -0.78; 95% CI, -1.46 to -0.10; p = 0.14; hospital length of stay: pooled mean difference, -1.54; 95% CI, -3.13 to 0.05; p = 0.06), whereas "expert tele-consultation" resulted in an advantage of standard care (ICU length of stay: pooled mean difference, 0.31; 95% CI, 0.10-0.53; p = 0.005; hospital length of stay: pooled mean difference, 0.58; 95% CI, -0.04 to 1.21; p = 0.07)., Conclusions: In contrast to expert tele-consultations, decision-making authority during tele-ICU care reduces mortality and length of stay in the ICU. This work confirms the urgent need for evidence-based ICU telemedicine guidelines and reveals potential benefits of uniform regulations regarding the level of authority when providing tele-ICU care., Competing Interests: Gernot Marx received funding from BBraun Melsungen, Sphingotec, and 4TEEN4 Pharmaceuticals GmbH. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: The role of vitamin D supplementation as a treatment for COVID-19 has been a subject of considerable discussion. A thorough understanding of the current evidence regarding the effectiveness and safety of vitamin D supplementation for COVID-19 based on randomised controlled trials is required., Objectives: To assess whether vitamin D supplementation is effective and safe for the treatment of COVID-19 in comparison to an active comparator, placebo, or standard of care alone, and to maintain the currency of the evidence, using a living systematic review approach., Search Methods: We searched the Cochrane COVID-19 Study Register, Web of Science and the WHO COVID-19 Global literature on coronavirus disease to identify completed and ongoing studies without language restrictions to 11 March 2021., Selection Criteria: We followed standard Cochrane methodology. We included randomised controlled trials (RCTs) evaluating vitamin D supplementation for people with COVID-19, irrespective of disease severity, age, gender or ethnicity. We excluded studies investigating preventive effects, or studies including populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS))., Data Collection and Analysis: We followed standard Cochrane methodology. To assess bias in included studies, we used the Cochrane risk of bias tool (ROB 2) for RCTs. We rated the certainty of evidence using the GRADE approach for the following prioritised outcome categories: individuals with moderate or severe COVID-19: all-cause mortality, clinical status, quality of life, adverse events, serious adverse events, and for individuals with asymptomatic or mild disease: all-cause mortality, development of severe clinical COVID-19 symptoms, quality of life, adverse events, serious adverse events., Main Results: We identified three RCTs with 356 participants, of whom 183 received vitamin D. In accordance with the World Health Organization (WHO) clinical progression scale, two studies investigated participants with moderate or severe disease, and one study individuals with mild or asymptomatic disease. The control groups consisted of placebo treatment or standard of care alone. Effectiveness of vitamin D supplementation for people with COVID-19 and moderate to severe disease We included two studies with 313 participants. Due to substantial clinical and methodological diversity of both studies, we were not able to pool data. Vitamin D status was unknown in one study, whereas the other study reported data for vitamin D deficient participants. One study administered multiple doses of oral calcifediol at days 1, 3 and 7,  whereas the other study gave a single high dose of oral cholecalciferol at baseline. We assessed one study with low risk of bias for effectiveness outcomes, and the other with some concerns about randomisation and selective reporting. All-cause mortality at hospital discharge (313 participants) We found two studies reporting data for this outcome. One study reported no deaths when treated with vitamin D out of 50 participants, compared to two deaths out of 26 participants in the control group (Risk ratio (RR) 0.11, 95% confidence interval (CI) 0.01 to 2.13). The other study reported nine deaths out of 119 individuals in the vitamin D group, whereas six participants out of 118 died in the placebo group (RR 1.49, 95% CI 0.55 to 4.04]. We are very uncertain whether vitamin D has an effect on all-cause mortality at hospital discharge (very low-certainty evidence). Clinical status assessed by the need for invasive mechanical ventilation (237 participants) We found one study reporting data for this outcome. Nine out of 119 participants needed invasive mechanical ventilation when treated with vitamin D, compared to 17 out of 118 participants in the placebo group (RR 0.52, 95% CI 0.24 to 1.13). Vitamin D supplementation may decrease need for invasive mechanical ventilation, but the evidence is uncertain (low-certainty evidence). Quality of life We did not find data for quality of life. Safety of vitamin D supplementation for people with COVID-19 and moderate to severe disease We did not include data from one study, because assessment of serious adverse events was not described and we are concerned that data might have been inconsistently measured. This study reported vomiting in one out of 119 participants immediately after vitamin D intake (RR 2.98, 95% CI 0.12 to 72.30). We are very uncertain whether vitamin D supplementation is associated with higher risk for adverse events (very low-certainty). Effectiveness and safety of vitamin D supplementation for people with COVID-19 and asymptomatic or mild disease We found one study including 40 individuals, which did not report our prioritised outcomes, but instead data for viral clearance, inflammatory markers, and vitamin D serum levels. The authors reported no events of hypercalcaemia, but recording and assessment of further adverse events remains unclear. Authors administered oral cholecalciferol in daily doses for at least 14 days, and continued with weekly doses if vitamin D blood levels were > 50 ng/mL., Authors' Conclusions: There is currently insufficient evidence to determine the benefits and harms of vitamin D supplementation as a treatment of COVID-19. The evidence for the effectiveness of vitamin D supplementation for the treatment of COVID-19 is very uncertain. Moreover, we found only limited safety information, and were concerned about consistency in measurement and recording of these outcomes. There was substantial clinical and methodological heterogeneity of included studies, mainly because of different supplementation strategies, formulations, vitamin D status of participants, and reported outcomes. There is an urgent need for well-designed and adequately powered randomised controlled trials (RCTs) with an appropriate randomisation procedure, comparability of study arms and preferably double-blinding. We identified 21 ongoing and three completed studies without published results, which indicates that these needs will be addressed and that our findings are subject to change in the future. Due to the living approach of this work, we will update the review periodically., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background & Aims: Phosphate is the main intracellular anion essential for numerous biological processes. Symptoms of hypophosphatemia are non-specific, yet potentially life-threatening. This systematic review process was initiated to gain a global insight into hypophosphatemia, associated morbidity and treatments., Methods: A systematic review was conducted (PROSPERO CRD42020163191). Nine clinically relevant questions were generated, seven for adult and two for pediatric critically ill patients, and prevalence of hypophosphatemia was assessed in both groups. We identified trials through systematic searches of Medline, EMBASE, Scopus, Cochrane Central Register of Controlled Trials, CINAHL, and Web of Science. Quality assessment was performed using the Cochrane risk of bias tool for randomized controlled trials and the Newcastle-Ottawa Scale for observational studies., Results: For all research questions, we identified 2727 titles in total, assessed 399 full texts, and retained 82 full texts for evidence synthesis, with 20 of them identified for several research questions. Only 3 randomized controlled trials were identified with two of them published only in abstract form, as well as 28 prospective and 31 retrospective studies, and 20 case reports. Relevant risk of bias regarding selection and comparability was identified for most of the studies. No meta-analysis could be performed. The prevalence of hypophosphatemia varied substantially in critically ill adults and children, but no study assessed consecutive admissions to intensive care. In both critically ill adults and children, several studies report that hypophosphatemia is associated with worse outcome (prolonged length of stay and the need for respiratory support, and higher mortality). However, there was insufficient evidence regarding the optimal threshold upon which hypophosphatemia becomes critical and requires treatment. We found no studies regarding the optimal frequency of phosphate measurements, and regarding the time window to correct hypophosphatemia. In adults, nutrient restriction on top of phosphate repletion in patients with refeeding syndrome may improve survival, although evidence is weak., Conclusions: Evidence on the definition, outcome and treatment of clinically relevant hypophosphatemia in critically ill adults and children is scarce and does not allow answering clinically relevant questions. High quality clinical research is crucial for the development of respective guidelines., Competing Interests: Conflict of Interest None of the co-authors has any competing interest to declare regarding the present systematic review., (Copyright © 2020 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

The German health care system faces the great challenge of ensuring high-quality and comprehensive health care in the future as the shortage of physicians continues to grow. Telemedicine-supported healthcare networks, which guarantee access to specialized medical expertise close to the patient's home and tailored to their needs, and thus to high-quality patient-centered treatment, could provide a solution. The TELnet@NRW best-practice project provides a blueprint for expert teleconsultations and put them into practice. TELnet@NRW demonstrated that expert teleconsultations improve interdisciplinary exchange and thus increase quality and efficiency in healthcare. With the widespread telemedical network as a new structure of the healthcare system, TELnet@NRW enabled a more efficient use of existing resources. TELnet@NRW was funded in the first phase of the Innovation Fund. The experts from the two university hospitals in Aachen and Münster provided daily expert teleconsultations to the 17 cooperating hospitals and two physician networks. A 24/7/365 availability was provided, accompanied by training for doctors and nursing staff aimed at improving evidence-based care. Communication took place via an encrypted audio-video conferencing system and the certified data exchange platform FallAkte Plus. The aim of TELnet@NRW was to establish a cross-sectoral telemedical network as a new digital form of care. A total of > 150 000 patients were included. With TELnet@NRW, a major step towards future-proof healthcare was taken, and for us this means providing patients with high-quality care close to patients' homes. This is currently being used as the conceptual basis for the Virtuelles Krankenhaus NRW as a possible solution for the continuation of former project services., Competing Interests: CLINOMIC, GWKM innovation UG, PHILIPS, (Thieme. All rights reserved.)

Background: Chronic heart failure is one of the most common medical conditions, affecting more than 23 million people worldwide. Despite established guideline-based, multidrug pharmacotherapy, chronic heart failure is still the cause of frequent hospitalisation, and about 50% die within five years of diagnosis., Objectives: To assess the effectiveness and safety of ivabradine in individuals with chronic heart failure., Search Methods: We searched CENTRAL, MEDLINE, Embase, and CPCI-S Web of Science in March 2020. We also searched ClinicalTrials.gov and the WHO ICTRP. We checked reference lists of included studies. We did not apply any time or language restrictions., Selection Criteria: We included randomised controlled trials in which adult participants diagnosed with chronic heart failure were randomly assigned to receive either ivabradine or placebo/usual care/no treatment. We distinguished between type of heart failure (heart failure with a reduced ejection fraction or heart failure with a preserved ejection fraction) as well as between duration of ivabradine treatment (short term (< 6 months) or long term (≥ 6 months))., Data Collection and Analysis: Two review authors independently assessed trials for inclusion, extracted data, and checked data for accuracy. We calculated risk ratios (RR) using a random-effects model. We completed a comprehensive 'Risk of bias' assessment for all studies. We contacted authors for missing data. Our primary endpoints were: mortality from cardiovascular causes; quality of life; time to first hospitalisation for heart failure during follow-up; and number of days spent in hospital due to heart failure during follow-up. Our secondary endpoints were: rate of serious adverse events; exercise capacity; and economic costs (narrative report). We assessed the certainty of the evidence applying the GRADE methodology., Main Results: We included 19 studies (76 reports) involving a total of 19,628 participants (mean age 60.76 years, 69% male). However, few studies contributed data to meta-analyses due to inconsistency in trial design (type of heart failure) and outcome reporting and measurement. In general, risk of bias varied from low to high across the included studies, with insufficient detail provided to inform judgement in several cases. We were able to perform two meta-analyses focusing on participants with heart failure with a reduced ejection fraction (HFrEF) and long-term ivabradine treatment. There was evidence of no difference between ivabradine and placebo/usual care/no treatment for mortality from cardiovascular causes (RR 0.99, 95% confidence interval (CI) 0.88 to 1.11; 3 studies; 17,676 participants; I 2 = 33%; moderate-certainty evidence). Furthermore, we found evidence of no difference in rate of serious adverse events amongst HFrEF participants randomised to receive long-term ivabradine compared with those randomised to placebo, usual care, or no treatment (RR 0.96, 95% CI 0.92 to 1.00; 2 studies; 17,399 participants; I 2 = 12%; moderate-certainty evidence). We were not able to perform meta-analysis for all other outcomes, and have low confidence in the findings based on the individual studies., Authors' Conclusions: We found evidence of no difference in cardiovascular mortality and serious adverse events between long-term treatment with ivabradine and placebo/usual care/no treatment in participants with heart failure with HFrEF. Nevertheless, due to indirectness (male predominance), the certainty of the available evidence is rated as moderate., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background and Objectives: Coronary artery disease (CAD) is the number one cause of death worldwide. The I f channel inhibitor ivabradine serves as second line medication for the CAD leading symptom angina pectoris. This systematic review and meta-analysis assess the existing evidence of ivabradine in angina pectoris., Methods: We systematically searched MEDLINE, Embase, CENTRAL, and Web of Science (September 2019) for randomized controlled trials (RCTs) that compared ivabradine versus placebo, standard therapy (ST) or other anti-anginal drugs. Two review authors independently assessed trials for inclusion and performed data extraction. We completed a 'risk of bias' assessment for all studies and assessed quality of the trial evidence using the Grading of Recommendations Assessment, Development and Evaluation methodology. We meta-analysed data were applicable and calculated mean differences (MDs) and risk ratios using a random-effects model., Results: A total of 11 RCTs (n=16,039) were included. Compared to placebo/ST, we found significant effects on the frequency of hospitalisation in a small cohort (n=90; hazard ratio [HR], 0.19; 95% confidence interval [CI], 0.04, -0.92; p=0.04), but no effects on cardiovascular mortality (n=19,102; HR, 1.10; 95% CI, 0.94, 1.28; p=0.25) or the frequency of angina pectoris episodes (n=167; weighted MD, -1.06; 95% CI, -2.74, -0.61; p=0.21)., Conclusions: The present work makes an important contribution to optimal patient care in angina pectoris by complementing the current European Society of Cardiology guideline-recommending class IIa with evidence level B-decisively with 8 further studies., Competing Interests: The authors have no financial conflicts of interest., (Copyright © 2020. The Korean Society of Cardiology.)

Background & Aims: Recent studies indicate that vitamin D deficiency is associated with increased morbidity and mortality in critically ill patients. Knowledge about the functional role and clinical relevance of vitamin D for patients undergoing cardiac surgery is sparse. Therefore, we investigated the clinical significance of vitamin D levels on outcome of cardiac surgery patients., Methods: 92 patients undergoing elective cardiac surgery with cardiopulmonary arrest were included in this prospective observational pilot study. 25-hydroxyvitamin D (25OHD) and 1,25-dihydroxyvitamin D (1,25(OH) 2 D) levels were measured prior to surgery, immediately postoperatively as well as 6, 12 and 24 h after surgery. We assessed postoperative organ dysfunctions, infections and death until hospital discharge., Results: The serum concentration of 1,25(OH) 2 D significantly decreased intraoperatively by 29.3% (p < 0.001) and was significantly lower at any postoperative time point compared to baseline values, whereas 25OHD levels did not show significant changes during the observation period. Coronary artery bypass graft (CABG) patients had significant higher baseline 1,25(OH) 2 D values than patients with valve surgery (39.7 ± 13.9 ng/l vs. 30.1 ± 14.1 ng/l, p = 0.010) or CABG + valve surgery (39.7 ± 13.9 ng/l vs. 32.6 ± 11.8 ng/l, p = 0.044). Our data showed a significant odds ratio to develop postoperative organ dysfunction (OR 0.95; p = 0.009) and PCT levels ≥5 μg/l (OR 0.94; p = 0.046) for every ng/l increment in 1,25(OH) 2 D, when performing multivariable analysis and after adjusting for preoperative illness and demographics. In addition, multivariable-adjusted statistical analyses revealed that patients stayed significantly shorter on ICU (-0.21 h; p = 0.001) and in hospital (-2.6 days; p = 0.009) for every ng/l increment in 1,25(OH) 2 D., Conclusion: Our data highlight important evidence about the clinical significance of 1,25(OH) 2 D levels in cardiac surgery patients. Higher levels were associated with significantly less postoperative organ dysfunctions, elevated PCT levels, death and prolonged hospital stay. 1,25(OH) 2 D levels decreased significantly intra- and postoperatively, while serum levels of 25OHD did not., Trial Registration: clinicaltrials.gov (NCT02488876), registered May 1, 2015., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Cardiac surgery is associated with oxidative stress and systemic inflammation, which both contribute to postoperative organ dysfunction. Vitamin C is a pleiotropic, antioxidant, and potentially organ-protective micronutrient. Past clinical trials and meta-analyses have focused predominantly on occurrence of postoperative atrial fibrillation. Therefore, we investigated the influence of perioperative vitamin C administration on clinically relevant parameters closer related to the patient's recovery, especially organ function, and overall outcomes after cardiac surgery., Methods: Randomized controlled trials (RCTs) comparing perioperative vitamin C administration versus placebo or standard of care in adult patients undergoing cardiac surgery were identified through systematic searches in Pubmed, EMBASE, and CENTRAL on 23 November 2018. Published and unpublished data were included. Assessed outcomes include organ function after cardiac surgery, adverse events, in-hospital mortality, intensive care unit, and hospital length-of-stay. Data was pooled only when appropriate., Results: A total of 19 RCTs with 2008 patients were included in this meta-analysis. Vitamin C significantly decreased the incidence of atrial fibrillation ( p = 0.008), ventilation time ( p < 0.00001), ICU length-of-stay ( p = 0.004), and hospital length-of-stay ( p < 0.0001). However, on average, vitamin C had no significant effects on in-hospital mortality ( p = 0.76), or on the incidence of stroke ( p = 0.82). High statistical heterogeneity was observed in most analyses., Conclusions: Vitamin C impacts clinically and economically important outcomes, such as ICU and hospital length-of-stay, duration of mechanical ventilation and lowers the incidence of atrial fibrillation. Due to missing reports on organ dysfunction, this meta-analysis cannot answer the question, if vitamin C can improve single- or multiorgan function after cardiac surgery.

Background: Cardiovascular surgery patients with a prolonged intensive care unit (ICU) stay may benefit most from early nutrition support. Using established scoring systems for nutrition assessment and operative risk stratification, we aimed to develop a model to predict a prolonged ICU stay ≥5 days in order to identify patients who will benefit from early nutrition interventions., Methods: This is a retrospective analysis of a prospective observational study of patients undergoing elective valvular, coronary artery bypass grafting, or combined cardiac surgery. The nutrition risk was assessed by well-established screening tools. Patients' preoperative EuroSCORE (European System for Cardiac Operative Risk Evaluation), primary disease, and intraoperative cardiopulmonary bypass (CPB) time were included as independent variables in a multivariate logistic regression analysis to predict a prolonged ICU stay (>4 days)., Results: The number of cardiac surgery patients included was 1193. Multivariate analysis revealed that for prediction of ICU stay >4 days, both Nutritional Risk Screening 2002 (area under the curve (AUC): 0.716, P = .020) and Mini Nutritional Assessment (MNA) score (AUC: 0.715, P = .037) were significant, whereas for prediction of ICU stay >5 days, only the MNA score showed significant results (AUC: 0.762, P = .011)., Conclusion: Present data provide first evidence about the combined use of EuroSCORE, primary disease, CPB time, and nutrition risk screening tools for prediction of prolonged ICU stay in cardiac surgery patients. If prospectively evaluated in adequately designed studies, this model may help to identify patients with prolonged ICU stay to initiate early postoperative nutrition therapy and thus, facilitate an enhanced recovery., (© 2018 The Authors. Journal of Parenteral and Enteral Nutrition published by Wiley Periodicals, Inc. on behalf of American Society for Parenteral and Enteral Nutrition.)

Ventricular assist device (VAD) implantation has developed into a well-established option when conservative treatment of terminal heart failure has been exhausted. Figures from 2015 make this clear: only 283 heart transplantations were performed nationwide but 959 VAD systems were implanted. It is noteworthy that the survival times with a VAD are approaching the survival times after heart transplantation. Patients with VADs have a life-long dependency on their proximity to specialists. So far, the requirements for outpatient care have not been systematically recorded from the perspective of VAD patients and their relatives. In September 2016, VAD patients (n = 30) and their relatives (n = 25) were anonymously questioned about their views on postoperative outpatient care. For this purpose, the VAD Patient Satisfaction Survey was adapted to the needs of this study. Patients with VADs and their relatives were found to experience their daily life with a VAD in a positive manner. Information, training, accessibility and regular contacts with the implantation clinic and the VAD coordinator are important pillars of outpatient care after VAD implantation. Almost 95% of surveyed patients regarded good home support as an important factor that makes life with a VAD easier. These aspects should be taken into account in the care of patients living with a VAD.

Background: Sepsis is a major health care problem with high morbidity and mortality rates and affects millions of patients. Telemedicine, defined as the exchange of medical information via electronic communication, improves the outcome of patients with sepsis and decreases the mortality rate and length of stay in the intensive care unit (ICU). Additional telemedicine rounds could be an effective component of performance-improvement programs for sepsis, especially in underserved rural areas and hospitals without ready access to critical care physicians., Objective: Our aim was to evaluate the impact of additional daily telemedicine rounds on adherence to sepsis bundles. We hypothesized that additional telemedicine support may increase adherence to sepsis guidelines and improve the detection rates of sepsis and septic shock., Methods: We conducted a retrospective, observational, multicenter study between January 2014 and July 2015 with one tele-ICU center and three ICUs in Germany. We implemented telemedicine as part of standard care and collected data continuously during the study. During the daily telemedicine rounds, routine screening for sepsis was conducted and adherence to the Surviving Sepsis Campaign's 3-hour and 6-hour sepsis bundles were evaluated., Results: In total, 1168 patients were included in this study, of which 196 were positive for severe sepsis and septic shock. We found that additional telemedicine rounds improved adherence to the 3-hour (Quarter 1, 35% vs Quarter 6, 76.2%; P=.01) and 6-hour (Quarter 1, 50% vs Quarter 6, 95.2%; P=.001) sepsis bundles. In addition, we noted an increase in adherence to the item "Administration of fluids when hypotension" (Quarter 1, 80% vs Quarter 6, 100%; P=.049) of the 3-hour bundle and the item "Remeasurement of lactate" (Quarter 1, 65% vs Quarter 6, 100%, P=.003) of the 6-hour bundle. The ICU length of stay after diagnosis of severe sepsis and septic shock remained unchanged over the observation period. Due to a higher number of patients with sepsis in Quarter 5 (N=60) than in other quarters, we observed stronger effects of the additional rounds on mortality in this quarter (Quarter 1, 50% vs Quarter 5, 23.33%, P=.046)., Conclusions: Additional telemedicine rounds are an effective component of and should be included in performance-improvement programs for sepsis management., (©Robert Deisz, Susanne Rademacher, Katrin Gilger, Rudolf Jegen, Barbara Sauerzapfe, Christina Fitzner, Christian Stoppe, Carina Benstoem, Gernot Marx. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 15.01.2019.)

Objectives: The first aim was the development of a human blood miniature mock-loop system consisting of 2 identical extracorporeal circuits, which enable systematic head-to-head comparisons of test substances. In a second step, we evaluated the suitability of the mock-loop system, by comparing 2 different brands of heparin (ROTEXMEDICA vs B.BRAUN), which have showed different anticoagulation capacities in the clinic., Methods: For 1 experiment (18 in total), blood of the same healthy human donor was divided into 2 portions (2 × 50 ml), heparinized with 37.5 IU⋅ml-1 of the competing test substances and diluted to a haematocrit value of 20-25%. Each mock loop was filled with 70 ml, and in vivo heparin degradation was simulated in 3 different groups by protamine application, representing 0%, 50% and 100% heparin antagonization. At baseline, 5, 60, 120, 240 and 360 min, blood samples were taken to perform thromboelastometry, flow cytometry, haemolysis and general haemostasis analysis., Results: Blood pressure, blood flow and blood temperature within the loops remained stable for 6 h in all groups. After 6 h, in the 100% antagonized ROTEXMEDICA heparin group, significantly increased haemolysis (148.7 ± 80 mg⋅dl-1 vs 57.5 ± 15.8 mg⋅dl-1), activated platelets (8 ± 3.8% vs 3.3 ± 0.7%), D-dimers (7376 ± 7144 ng ml-1 vs 576.2 ± 190 ng ml-1) and fulminant blood clots were detected., Conclusions: Our in vitro system is suitable for the detection of reduced anticoagulation capacity of a test drug, which was reported in vivo previously.

Introduction: So far, the concept of remote ischemic preconditioning (RIPC) failed its translation from experimental to clinical studies. In addition to our Cochrane Systematic Review, we systematically assessed the use of the intravenous anesthetic propofol, as a potential confounding factor., Evidence Acquisition: We searched CENTRAL, MEDLINE, Embase and Web of Science. We included randomized controlled trials comparing RIPC with no RIPC in adult patients scheduled for coronary artery bypass graft surgery (with or without valve surgery) receiving either exclusively propofol or exclusively volatile anesthetics. Two authors independently assessed methodological quality and extracted data. We report odds ratios (ORs) with 95% confidence intervals as our summary statistics are based on random-effects models., Evidence Synthesis: We included 14 studies involving 4060 participants. We found no difference in treatment effect between the propofol and volatile anesthetic groups when RIPC or no RIPC is applied on a composite endpoint (all-cause mortality, non-fatal myocardial infarction and/or any new stroke), all-cause mortality, non-fatal myocardial infarction, stroke, or length of stay on ICU. On cardiac markers, RIPC did show a treatment effect on cardiac troponin T measured as AUC 72 hours (SMD -0.80, CI -1.34, -0.25) in the propofol group. However, these findings have to be interpreted with great caution, to date only a very limited number of patients received volatile anesthetics in RIPC trials (minimum N.=15, maximum N.=232)., Conclusions: Present data do not permit a final assessment regarding the role of volatile or intravenous anesthetics as a possible confounding factor in RIPC trials.

Cardiovascular diseases are the main cause of death worldwide, demanding new treatments and interventions. Recently, extracellular vesicles (EVs) came in focus as important carriers of protective molecules such as miRNAs and proteins which might contribute to e.g. improved cardiac function after myocardial infarction. EVs can be secreted from almost every cell type in the human body and can be transferred via the bloodstream in almost every compartment. To provide an all-encompassing overview of studies investigating these beneficial properties of EVs we performed a systematic review/meta-analysis of studies investigating the cardioprotective characteristics of EVs. Forty-three studies were investigated and catalogued according to the EV source. We provide an in-depth analysis of the purification method, size of the EVs, the conducted experiments to investigate the beneficial properties of EVs as well as the major effector molecule encapsulated in EVs mediating protection. This study provides evidence that EVs from different cell types and body fluids provide cardioprotection in different in vivo and in vitro studies. A meta-analysis was performed to estimate the underlying effect size. In conclusion, we demonstrated that EVs from different sources might serve as a promising tool for treating cardiovascular diseases in the future.

Purpose: Cardiac surgery with the use of extracorporeal circulation is associated with a significant risk for gaseous microemboli (GME) despite excellent surgical techniques and highest operative standards. GME are associated with postoperative neurocognitive dysfunction and negative clinical outcome. This study determines whether oxygenator design has influence on perioperative outcome after cardiac surgery., Methods: Three different oxygenator models with integrated arterial filter (HiliteAF 7000, Fusion Affinity, and Synthesis) were retrospectively evaluated in 55 patients undergoing elective cardiac surgery with the use of extracorporeal circulation. The two-channel ultrasound bubble counter BCC200 was used to detect GME in real time., Results: All three oxygenators differ in terms of structural specifications and have different rates of number and volume GME reduction. The Fusion Affinity had the lowest arterial GME volume (1.81 µL ± 0.23 µL), which was statistically significant compared to the Synthesis (3.37 µL ± 0.71 µL, p = 0.014). However, the Synthesis had lower absolute numbers at the venous GME count (31771 µL ± 6579 µL) versus the Fusion Affinity (49304 µL ± 8196 µL). However, with regard to clinical outcome after cardiac surgery (duration of invasive and non-invasive mechanical ventilation, incidence of delirium, stroke, acute renal failure, or new myocardial infarction), we found no differences between groups., Conclusion: Despite significant differences in the design specifications, all oxygenators eliminated relevant GME volumes safely.