Publications by authors named "Gernot Marx"

213 Publications

Better COVID-19 Intensive Care Unit survival in females, independent of age, disease severity, comorbidities, and treatment.

Sci Rep 2022 Jan 14;12(1):734. Epub 2022 Jan 14.

Department of Intensive Care Medicine, Maastricht University Medical Center + (Maastricht UMC+), P. Debyelaan 25, 6229 HX, Maastricht, the Netherlands.

Although male Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) patients have higher Intensive Care Unit (ICU) admission rates and a worse disease course, a comprehensive analysis of female and male ICU survival and underlying factors such as comorbidities, risk factors, and/or anti-infection/inflammatory therapy administration is currently lacking. Therefore, we investigated the association between sex and ICU survival, adjusting for these and other variables. In this multicenter observational cohort study, all patients with SARS-CoV-2 pneumonia admitted to seven ICUs in one region across Belgium, The Netherlands, and Germany, and requiring vital organ support during the first pandemic wave were included. With a random intercept for a center, mixed-effects logistic regression was used to investigate the association between sex and ICU survival. Models were adjusted for age, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, comorbidities, and anti-infection/inflammatory therapy. Interaction terms were added to investigate effect modifications by sex with country and sex with obesity. A total of 551 patients (29% were females) were included. Mean age was 65.4 ± 11.2 years. Females were more often obese and smoked less frequently than males (p-value 0.001 and 0.042, respectively). APACHE II scores of females and males were comparable. Overall, ICU mortality was 12% lower in females than males (27% vs 39% respectively, p-value < 0.01) with an odds ratio (OR) of 0.62 (95%CI 0.39-0.96, p-value 0.032) after adjustment for age and APACHE II score, 0.63 (95%CI 0.40-0.99, p-value 0.044) after additional adjustment for comorbidities, and 0.63 (95%CI 0.39-0.99, p-value 0.047) after adjustment for anti-infection/inflammatory therapy. No effect modifications by sex with country and sex with obesity were found (p-values for interaction > 0.23 and 0.84, respectively). ICU survival in female SARS-CoV-2 patients was higher than in male patients, independent of age, disease severity, smoking, obesity, comorbidities, anti-infection/inflammatory therapy, and country. Sex-specific biological mechanisms may play a role, emphasizing the need to address diversity, such as more sex-specific prediction, prognostic, and therapeutic approach strategies.
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http://dx.doi.org/10.1038/s41598-021-04531-xDOI Listing
January 2022

[Standardized contrast-enhanced ultrasound (CEUS) in clinical acute and emergency medicine and critical care (CEUS Acute) : Consensus statement of DGIIN, DIVI, DGINA, DGAI, DGK, ÖGUM, SGUM and DEGUM].

Med Klin Intensivmed Notfmed 2022 Jan 10. Epub 2022 Jan 10.

Department für Allgemeine Innere Medizin Kliniken Hirslanden Beau Site, Salem und Permanence, Bern, Schweiz.

The present document describes the possible applications of contrast-enhanced ultrasound (CEUS) in emergency examinations. Guidelines on contrast medium ultrasound in acute and emergency care and intensive care medicine have not yet been published. Evidence-based CEUS guidelines were first provided by the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) and the World Federation for Ultrasound in Medicine and Biology (WFUMB). The presented recommendations describe the possible applications and protocols of CEUS in acute care.
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http://dx.doi.org/10.1007/s00063-021-00891-4DOI Listing
January 2022

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

Crit Care Explor 2021 Nov 17;3(11):e0577. Epub 2021 Nov 17.

InflaRx GmbH, Jena, Germany.

Anaphylatoxin C5a, a proinflammatory complement split product, plays a central role in mediating organ dysfunction.

Objectives: This phase II clinical trial was conducted to study safety, tolerability, pharmacokinetics, and pharmacodynamics of vilobelimab, a recombinant monoclonal antibody against C5a, in patients with severe sepsis or septic shock.

Design: Multicenter, randomized, and placebo-controlled study.

Setting And Participants: Eleven multidisciplinary ICUs across Germany. Adult patients with severe sepsis or septic shock and with early onset of infection-associated organ dysfunction.

Main Outcomes And Measures: Patients were randomly assigned in a ratio of 2:1 to three subsequent dosing cohorts for IV vilobelimab or placebo receiving either 2 × 2 mg/kg (0 and 12 hr), 2 × 4 mg/kg (0 and 24 hr), and 3 × 4 mg/kg (0, 24, and 72 hr). Co-primary endpoints were pharmacodynamics (assessed by C5a concentrations), pharmacokinetics (assessed by vilobelimab concentrations), and safety of vilobelimab. Preliminary efficacy was evaluated by secondary objectives.

Results: Seventy-two patients were randomized (16 patients for each vilobelimab dosing cohort and eight patients for each placebo dosing cohort). Vilobelimab application was associated with dosing dependent decrease in C5a compared with baseline ( < 0.001). Duration of C5a decrease increased with more frequent dosing. Membrane attack complex lysis capacity measured by 50% hemolytic complement was not affected. Vilobelimab was well tolerated with similar safety findings in all dose cohorts. No vilobelimab-specific adverse events emerged. For vilobelimab-treated patients, investigators attributed less treatment-emergent adverse events as related compared with placebo. Dosing cohorts 2 and 3 had the highest ICU-free and ventilator-free days. There was no difference in mortality, vasopressor-free days, or renal replacement therapy-free days between the groups.

Conclusions And Relevance: Administration of vilobelimab in patients with severe sepsis and septic shock selectively neutralizes C5a in a dose-dependent manner without blocking formation of the membrane attack complex and without resulting in detected safety issues. The data warrant further investigation of C5a inhibition in sepsis.
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http://dx.doi.org/10.1097/CCE.0000000000000577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601347PMC
November 2021

Extracorporeal membrane oxygenation in patients with COVID-19: 1-year experience.

J Thorac Dis 2021 Oct;13(10):5911-5924

Department of Cardiology, Angiology, and Intensive Care, RWTH University Hospital Aachen, Aachen, Germany.

Background: Extracorporeal membrane oxygenation (ECMO) in patients with coronavirus disease 2019 (COVID-19) showed reasonable outcomes. However, recent studies indicated a negative trend and analysis is needed.

Methods: Baseline characteristics, laboratory parameters, and outcomes of ECMO-supported patients with COVID-19 were analyzed in a retrospective single-center study. We included hospital admissions until February 28, 2021; patients were followed until discharge/death. Eventually, we compared data between patients hospitalized before and after September 1, 2020.

Results: Median age of patients treated with ECMO (n=39) was 56 years; most patients were males (n=28, 72%). Median mechanical ventilation time (prior to ECMO) was 6 days, while the median ECMO duration was 19 days. Overall survival rate was 41%. In the sub-analysis, survival until discharge in the first and second epidemic waves was 53% (n=19) and 30% (n=20), respectively (P=0.2). At baseline, compared with patients of the first wave, those of the second wave had higher median body mass index (28.2 31.1 kg/m, respectively, P=0.02), bicarbonate (27 31.8 mmol/L, respectively, P=0.033), plasma free hemoglobin (36 58 mg/L, respectively, P=0.013), alanine aminotransferase (33 52 U/L, respectively, P=0.018), and pH (7.29 7.42, respectively, P=0.005), lower rate of pulmonary hypertension (32% 0%, respectively, P=0.008), lower positive end-expiratory pressure (14 12 cmHO, respectively, P=0.04), longer median ECMO duration (16 24.5 days, respectively, P=0.074), and more frequent major bleeding events (42% 80%, respectively, P=0.022).

Conclusions: ECMO-supported patients with COVID-19 had an overall survival rate of 41%. Similar to international registries, we observed less favorable outcomes during the second wave. Further research is needed to confirm this signal and find predictors for mortality.
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http://dx.doi.org/10.21037/jtd-21-971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8575858PMC
October 2021

Speckle tracking ultrasonography as a new tool to assess diaphragmatic function: a feasibility study.

Ultrasonography 2021 Aug 17. Epub 2021 Aug 17.

Department of Anesthesiology, University Hospital RWTH Aachen, Aachen, Germany.

A reliable method of measuring diaphragmatic function at the bedside is still lacking. Widely used two-dimensional (2D) ultrasonographic measurements, such as diaphragm excursion, diaphragm thickness, and fractional thickening (FT) have failed to show clear correlations with diaphragmatic function. A reason for this is that 2D ultrasonographic measurements, like FT, are merely able to measure the deformation of muscular diaphragmatic tissue in the transverse direction, while longitudinal measurements in the direction of contracting muscle fibres are not possible. Speckle tracking ultrasonography, which is widely used in cardiac imaging, overcomes this disadvantage and allows observations of movement in the direction of the contracting muscle fibres, approximating muscle deformation and the deformation velocity. Several studies have evaluated speckle tracking as a promising method to assess diaphragm contractility in healthy subjects. This technical note demonstrates the feasibility of speckle tracking ultrasonography of the diaphragm in a group of 20 patients after an aortocoronary bypass graft procedure. The results presented herein suggest that speckle tracking ultrasonography is able to depict alterations in diaphragmatic function after surgery better than 2D ultrasonographic measurements.
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http://dx.doi.org/10.14366/usg.21044DOI Listing
August 2021

Biometric covariates and outcome in COVID-19 patients: are we looking close enough?

BMC Infect Dis 2021 Nov 4;21(1):1136. Epub 2021 Nov 4.

Institute for Computational Biomedicine, RWTH Aachen University, Pauwelsstr. 19, 52074, Aachen, Germany.

Background: The impact of biometric covariates on risk for adverse outcomes of COVID-19 disease was assessed by numerous observational studies on unstratified cohorts, which show great heterogeneity. However, multilevel evaluations to find possible complex, e.g. non-monotonic multi-variate patterns reflecting mutual interference of parameters are missing. We used a more detailed, computational analysis to investigate the influence of biometric differences on mortality and disease evolution among severely ill COVID-19 patients.

Methods: We analyzed a group of COVID-19 patients requiring Intensive care unit (ICU) treatment. For further analysis, the study group was segmented into six subgroups according to Body mass index (BMI) and age. To link the BMI/age derived subgroups with risk factors, we performed an enrichment analysis of diagnostic parameters and comorbidities. To suppress spurious patterns, multiple segmentations were analyzed and integrated into a consensus score for each analysis step.

Results: We analyzed 81 COVID-19 patients, of whom 67 required mechanical ventilation (MV). Mean mortality was 35.8%. We found a complex, non-monotonic interaction between age, BMI and mortality. A subcohort of patients with younger age and intermediate BMI exhibited a strongly reduced mortality risk (p < 0.001), while differences in all other groups were not significant. Univariate impacts of BMI or age on mortality were missing. Comparing MV with non-MV patients, we found an enrichment of baseline CRP, PCT and D-Dimers within the MV group, but not when comparing survivors vs. non-survivors within the MV patient group.

Conclusions: The aim of this study was to get a more detailed insight into the influence of biometric covariates on the outcome of COVID-19 patients with high degree of severity. We found that survival in MV is affected by complex interactions of covariates differing to the reported covariates, which are hidden in generic, non-stratified studies on risk factors. Hence, our study suggests that a detailed, multivariate pattern analysis on larger patient cohorts reflecting the specific disease stages might reveal more specific patterns of risk factors supporting individually adapted treatment strategies.
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http://dx.doi.org/10.1186/s12879-021-06823-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8567725PMC
November 2021

Differences and Similarities Among Coronavirus Disease 2019 Patients Treated in Seven ICUs in Three Countries Within One Region: An Observational Cohort Study.

Crit Care Med 2021 Oct 12. Epub 2021 Oct 12.

Department of Intensive Care, Ziekenhuis Oost-Limburg, Genk, Belgium. UHasselt, Faculty of Medicine and Life Sciences, Diepenbeek, Belgium. Department of Intensive Care, Maastricht University Medical Center +, Maastricht, The Netherlands. Department of Intensive Care, Laurentius Ziekenhuis, Roermond, The Netherlands. Care and Public Health Research Institute, Maastricht University, Maastricht, The Netherlands. Department of Intensive Care, Jessa Hospital, Hasselt, Belgium. Department of Intensive Care, VieCuri Medisch Centrum, Venlo, The Netherlands. Department of Intensive Care, Zuyderland Medisch Centrum, Heerlen/Sittard, The Netherlands. Department of Surgery, Maastricht University Medical Center +, Maastricht, The Netherlands. School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands. Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands. Division for Acute and Emergency Medicine, Maastricht University Medical Center +, Maastricht, The Netherlands. Department of Intensive Care, University Hospital Rheinisch Westfälische Hochschule Aachen, Aachen, Germany.

Objectives: To investigate healthcare system-driven variation in general characteristics, interventions, and outcomes in coronavirus disease 2019 (COVID-19) patients admitted to the ICU within one Western European region across three countries.

Design: Multicenter observational cohort study.

Setting: Seven ICUs in the Euregio Meuse-Rhine, one region across Belgium, The Netherlands, and Germany.

Patients: Consecutive COVID-19 patients supported in the ICU during the first pandemic wave.

Interventions: None.

Measurements And Main Results: Baseline demographic and clinical characteristics, laboratory values, and outcome data were retrieved after ethical approval and data-sharing agreements. Descriptive statistics were performed to investigate country-related practice variation. From March 2, 2020, to August 12, 2020, 551 patients were admitted. Mean age was 65.4 ± 11.2 years, and 29% were female. At admission, Acute Physiology and Chronic Health Evaluation II scores were 15.0 ± 5.5, 16.8 ± 5.5, and 15.8 ± 5.3 (p = 0.002), and Sequential Organ Failure Assessment scores were 4.4 ± 2.7, 7.4 ± 2.2, and 7.7 ± 3.2 (p < 0.001) in the Belgian, Dutch, and German parts of Euregio, respectively. The ICU mortality rate was 22%, 42%, and 44%, respectively (p < 0.001). Large differences were observed in the frequency of organ support, antimicrobial/inflammatory therapy application, and ICU capacity. Mixed-multivariable logistic regression analyses showed that differences in ICU mortality were independent of age, sex, disease severity, comorbidities, support strategies, therapies, and complications.

Conclusions: COVID-19 patients admitted to ICUs within one region, the Euregio Meuse-Rhine, differed significantly in general characteristics, applied interventions, and outcomes despite presumed genetic and socioeconomic background, admission diagnosis, access to international literature, and data collection are similar. Variances in healthcare systems' organization, particularly ICU capacity and admission criteria, combined with a rapidly spreading pandemic might be important drivers for the observed differences. Heterogeneity between patient groups but also healthcare systems should be presumed to interfere with outcomes in coronavirus disease 2019.
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http://dx.doi.org/10.1097/CCM.0000000000005314DOI Listing
October 2021

Safety and tolerability of non-neutralizing adrenomedullin antibody adrecizumab (HAM8101) in septic shock patients: the AdrenOSS-2 phase 2a biomarker-guided trial.

Intensive Care Med 2021 Nov 4;47(11):1284-1294. Epub 2021 Oct 4.

Université de Paris, U942 Inserm, MASCOT, APHP, Fédération Hospitalo-Universitaire PROMICE, Hôpitaux Universitaires Saint-Louis-Lariboisière, Fernand-Widal, 2, Rue Ambroise-Paré, 75475, Paris Cedex 10, France.

Purpose: Investigate safety and tolerability of adrecizumab, a humanized monoclonal adrenomedullin antibody, in septic shock patients with high adrenomedullin.

Methods: Phase-2a, double-blind, randomized, placebo-controlled biomarker-guided trial with a single infusion of adrecizumab (2 or 4 mg/kg b.w.) compared to placebo. Patients with adrenomedullin above 70 pg/mL, < 12 h of vasopressor start for septic shock were eligible. Randomization was 1:1:2. Primary safety (90-day mortality, treatment emergent adverse events (TEAE)) and tolerability (drug interruption, hemodynamics) endpoints were recorded. Efficacy endpoints included the Sepsis Support Index (SSI, reflecting ventilator- and shock-free days alive), change in Sequential-related Organ Failure Assessment (SOFA) and 28-day mortality.

Results: 301 patients were enrolled (median time of 8.5 h after vasopressor start). Adrecizumab was well tolerated (one interruption, no hemodynamic alteration) with no differences in frequency and severity in TEAEs between treatment arms (TEAE of grade 3 or higher: 70.5% in the adrecizumab group and 71.1% in the placebo group) nor in 90-day mortality. Difference in change in SSI between adrecizumab and placebo was 0.72 (CI -1.93-0.49, p = 0.24). Among various secondary endpoints, delta SOFA score (defined as maximum versus minimum SOFA) was more pronounced in the adrecizumab combined group compared to placebo [difference at 0.76 (95% CI 0.18-1.35); p = 0.007]. 28-day mortality in the adrecizumab group was 23.9% and 27.7% in placebo with a hazard ratio of 0.84 (95% confidence interval 0.53-1.31, log-rank p = 0.44).

Conclusions: Overall, we successfully completed a randomized trial evaluating selecting patients for enrolment who had a disease-related biomarker. There were no overt signals of harm with using two doses of the adrenomedullin antibody adrecizumab; however, further randomized controlled trials are required to confirm efficacy and safety of this agent in septic shock patients.
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http://dx.doi.org/10.1007/s00134-021-06537-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487806PMC
November 2021

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

BMJ Open 2021 04 8;11(4):e045589. Epub 2021 Apr 8.

SMITH consortium of the German Medical Informatics Initiative, Leipzig, Germany.

Introduction: The acute respiratory distress syndrome (ARDS) is a highly relevant entity in critical care with mortality rates of 40%. Despite extensive scientific efforts, outcome-relevant therapeutic measures are still insufficiently practised at the bedside. Thus, there is a clear need to adhere to early diagnosis and sufficient therapy in ARDS, assuring lower mortality and multiple organ failure.

Methods And Analysis: In this quality improvement strategy (QIS), a decision support system as a mobile application (ASIC app), which uses available clinical real-time data, is implemented to support physicians in timely diagnosis and improvement of adherence to established guidelines in the treatment of ARDS. ASIC is conducted on 31 intensive care units (ICUs) at 8 German university hospitals. It is designed as a multicentre stepped-wedge cluster randomised QIS. ICUs are combined into 12 clusters which are randomised in 12 steps. After preparation (18 months) and a control phase of 8 months for all clusters, the first cluster enters a roll-in phase (3 months) that is followed by the actual QIS phase. The remaining clusters follow in month wise steps. The coprimary key performance indicators (KPIs) consist of the ARDS diagnostic rate and guideline adherence regarding lung-protective ventilation. Secondary KPIs include the prevalence of organ dysfunction within 28 days after diagnosis or ICU discharge, the treatment duration on ICU and the hospital mortality. Furthermore, the user acceptance and usability of new technologies in medicine are examined. To show improvements in healthcare of patients with ARDS, differences in primary and secondary KPIs between control phase and QIS will be tested.

Ethics And Dissemination: Ethical approval was obtained from the independent Ethics Committee (EC) at the RWTH Aachen Faculty of Medicine (local EC reference number: EK 102/19) and the respective data protection officer in March 2019. The results of the ASIC QIS will be presented at conferences and published in peer-reviewed journals.

Trial Registration Number: DRKS00014330.
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http://dx.doi.org/10.1136/bmjopen-2020-045589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039261PMC
April 2021

Machine learning identifies ICU outcome predictors in a multicenter COVID-19 cohort.

Crit Care 2021 Aug 17;25(1):295. Epub 2021 Aug 17.

Department of Anesthesiology, Heidelberg University Hospital, Heidelberg, Germany.

Background: Intensive Care Resources are heavily utilized during the COVID-19 pandemic. However, risk stratification and prediction of SARS-CoV-2 patient clinical outcomes upon ICU admission remain inadequate. This study aimed to develop a machine learning model, based on retrospective & prospective clinical data, to stratify patient risk and predict ICU survival and outcomes.

Methods: A Germany-wide electronic registry was established to pseudonymously collect admission, therapeutic and discharge information of SARS-CoV-2 ICU patients retrospectively and prospectively. Machine learning approaches were evaluated for the accuracy and interpretability of predictions. The Explainable Boosting Machine approach was selected as the most suitable method. Individual, non-linear shape functions for predictive parameters and parameter interactions are reported.

Results: 1039 patients were included in the Explainable Boosting Machine model, 596 patients retrospectively collected, and 443 patients prospectively collected. The model for prediction of general ICU outcome was shown to be more reliable to predict "survival". Age, inflammatory and thrombotic activity, and severity of ARDS at ICU admission were shown to be predictive of ICU survival. Patients' age, pulmonary dysfunction and transfer from an external institution were predictors for ECMO therapy. The interaction of patient age with D-dimer levels on admission and creatinine levels with SOFA score without GCS were predictors for renal replacement therapy.

Conclusions: Using Explainable Boosting Machine analysis, we confirmed and weighed previously reported and identified novel predictors for outcome in critically ill COVID-19 patients. Using this strategy, predictive modeling of COVID-19 ICU patient outcomes can be performed overcoming the limitations of linear regression models. Trial registration "ClinicalTrials" (clinicaltrials.gov) under NCT04455451.
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http://dx.doi.org/10.1186/s13054-021-03720-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370055PMC
August 2021

[Medical students as helpers in the pandemic : Innovative concept for recruitment, training and assignment planning of medical students as medical personnel during the COVID-19 pandemic].

Anaesthesist 2022 Jan 20;71(1):21-29. Epub 2021 Jul 20.

Klinik für Anästhesiologie, Uniklinik RWTH Aachen, Medizinische Fakultät, RWTH Aachen, Aachen, Deutschland.

Background: The COVID-19 pandemic posed enormous challenges to the German healthcare system and highlighted the need for strategies to recruit, train, and deploy medical personnel. Until now, no holistic concept existed to use medical students as support for professionals in intensive care units (ICU) to avoid staff shortages in medical care.

Method: In a large-scale pilot project 265 medical students were trained for an ICU assignment. The innovative training module was accompanied by a pre-post questionnaire for self-assessment of the skills learned. 22 weeks after the training module and still during the pandemic deployment, another questionnaire was used to evaluate experiences in deployment and the efficiency of the training module with respect to preparation for ICU deployment.

Results: The analysis revealed significant mean differences for all COVID-19-specific variables (safety dimension) in favor of the training module (n = 168). The deployment evaluation showed that the training concept was inconsistently assessed as preparation for the work deployment for 69 of the 89 deployed students in total (53% agreement/47% disagreement).

Conclusion: The results show a good feasibility of an innovative training concept for medical students with respect to a pandemic deployment as assistants in intensive care units. The concept is suitable for providing additional helpers in intensive care units during a pandemic; however, the inconsistent evaluation indicates that the concept can be expanded and needs to be adapted.
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http://dx.doi.org/10.1007/s00101-021-01009-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290386PMC
January 2022

Key summary of German national treatment guidance for hospitalized COVID-19 patients : Key pharmacologic recommendations from a national German living guideline using an Evidence to Decision Framework (last updated 17.05.2021).

Infection 2021 Jul 6. Epub 2021 Jul 6.

Department of Intensive Care, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Purpose: This executive summary of a national living guideline aims to provide rapid evidence based recommendations on the role of drug interventions in the treatment of hospitalized patients with COVID-19.

Methods: The guideline makes use of a systematic assessment and decision process using an evidence to decision framework (GRADE) as recommended standard WHO (2021). Recommendations are consented by an interdisciplinary panel. Evidence analysis and interpretation is supported by the CEOsys project providing extensive literature searches and living (meta-) analyses. For this executive summary, selected key recommendations on drug therapy are presented including the quality of the evidence and rationale for the level of recommendation.

Results: The guideline contains 11 key recommendations for COVID-19 drug therapy, eight of which are based on systematic review and/or meta-analysis, while three recommendations represent consensus expert opinion. Based on current evidence, the panel makes strong recommendations for corticosteroids (WHO scale 5-9) and prophylactic anticoagulation (all hospitalized patients with COVID-19) as standard of care. Intensified anticoagulation may be considered for patients with additional risk factors for venous thromboembolisms (VTE) and a low bleeding risk. The IL-6 antagonist tocilizumab may be added in case of high supplemental oxygen requirement and progressive disease (WHO scale 5-6). Treatment with nMABs may be considered for selected inpatients with an early SARS-CoV-2 infection that are not hospitalized for COVID-19. Convalescent plasma, azithromycin, ivermectin or vitamin D should not be used in COVID-19 routine care.

Conclusion: For COVID-19 drug therapy, there are several options that are sufficiently supported by evidence. The living guidance will be updated as new evidence emerges.
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http://dx.doi.org/10.1007/s15010-021-01645-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259552PMC
July 2021

Prognostic Value of GDF-15 in Predicting Prolonged Intensive Care Stay following Cardiac Surgery: A Pilot Study.

Dis Markers 2021 15;2021:5564334. Epub 2021 Jun 15.

Department of Surgical Intensive Medicine and Intermediate Care, University Hospital RWTH Aachen, Aachen, Pauwelstrasse 30, 52074 Aachen, Germany.

Introduction: Predicting intensive care unit length of stay and outcome following cardiac surgery is currently based on clinical parameters. Novel biomarkers could be employed to improve the prediction models.

Materials And Methods: We performed a qualitative cytokine screening array to identify highly expressed biomarkers in preoperative blood samples of cardiac surgery patients. After identification of one highly expressed biomarker, growth differentiation factor 15 (GDF-15), a quantitative ELISA was undertaken. Preoperative levels of GDF-15 were compared in regard to duration of intensive care stay, cardiopulmonary bypass time, and indicators of organ dysfunction.

Results: Preoperatively, GDF-15 was highly expressed in addition to several less highly expressed other biomarkers. After qualitative analysis, we could show that preoperatively raised levels of GDF-15 were positively associated with prolonged ICU stay exceeding 48 h (median 713 versus 1041 pg/ml, = 0.003). It was also associated with prolonged mechanical ventilation and rates of severe sepsis but not with dialysis rates or cardiopulmonary bypass time. In univariate regression, raised GDF-15 levels were predictive of a prolonged ICU stay (OR 1.01, 95% confidence interval 1-1.02, and = 0.029). On ROC curves, GDF-15 was found to predict prolonged ICU stay (AUC = 0.86, 95% confidence interval 0.71-0.99, and = 0.003).

Conclusion: GDF-15 showed potential as predictor of prolonged intensive care stay following cardiac surgery, which might be valuable for risk stratification models.
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http://dx.doi.org/10.1155/2021/5564334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221876PMC
December 2021

Outcomes of Extracorporeal Membrane Oxygenation for Acute Respiratory Distress Syndrome in COVID-19 Patients: A Propensity-Matched Analysis.

J Clin Med 2021 Jun 9;10(12). Epub 2021 Jun 9.

Department of Cardiology, Angiology and Intensive Care, RWTH University Hospital Aachen, Medical Faculty, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany.

It remains unclear to what extent the outcomes and complications of extracorporeal membrane oxygenation (ECMO) therapy in COVID-19 patients with acute respiratory distress syndrome (ARDS) differ from non-COVID-19 ARDS patients. In an observational, propensity-matched study, outcomes after ECMO support were compared between 19 COVID-19 patients suffering from ARDS (COVID group) and 34 matched non-COVID-19 ARDS patients (NCOVID group) from our historical cohort. A 1:2 propensity matching was performed based on respiratory ECMO survival prediction (RESP) score, age, gender, bilirubin, and creatinine levels. Patients' characteristics, laboratory parameters, adverse events, and 90-day survival were analyzed. Patients' characteristics in COVID and NCOVID groups were similar. Before ECMO initiation, fibrinogen levels were significantly higher in the COVID group (median: 493 vs. 364 mg/dL, 0.001). Median ECMO support duration was similar (16 vs. 13 days, 0.714, respectively). During ECMO therapy, patients in the COVID group developed significantly more thromboembolic events (TEE) than did those in the NCOVID group (42% vs. 12%, 0.031), which were mainly pulmonary artery embolism (PAE) (26% vs. 0%, 0.008). The rate of major bleeding events (42% vs. 62%, 0.263) was similar. Fibrinogen decreased significantly more in the COVID group than in the NCOVID group ( 0.001), whereas D-dimer increased in the COVID group ( 0.011). Additionally, 90-day mortality did not differ (47% vs. 74%; 0.064) between COVID and NCOVID groups. Compared with that in non-COVID-19 ARDS patients, ECMO support in COVID-19 patients was associated with comparable in-hospital mortality and similar bleeding rates but a higher incidence of TEE, especially PAE. In contrast, coagulation parameters differed between COVID and NCOVID patients.
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http://dx.doi.org/10.3390/jcm10122547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227073PMC
June 2021

P23 Acts as Functional RBP in the Macrophage Inflammation Response.

Front Mol Biosci 2021 11;8:625608. Epub 2021 Jun 11.

Department of Intensive Care Medicine, University Hospital RWTH Aachen, Aachen, Germany.

Macrophages exert the primary cellular immune response. Pathogen components like bacterial lipopolysaccharides (LPS) stimulate macrophage migration, phagocytotic activity and cytokine expression. Previously, we identified the poly(A) RNA interactome of RAW 264.7 macrophages. Of the 402 RNA-binding proteins (RBPs), 32 were classified as unique in macrophages, including nineteen not reported to interact with nucleic acids before. Remarkably, P23 a HSP90 co-chaperone, also known as cytosolic prostaglandin E2 synthase (PTGES3), exhibited differential poly(A) RNA binding in untreated and LPS-induced macrophages. To identify mRNAs bound by P23 and to elucidate potential regulatory RBP functions in macrophages, we immunoprecipitated P23 from cytoplasmic extracts of cross-linked untreated and LPS-induced cells. RNAseq revealed that enrichment of 44 mRNAs was reduced in response to LPS. mRNA, which encodes kinesin family member 15 (KIF15), a motor protein implicated in cytoskeletal reorganization and cell mobility was selected for further analysis. Noteworthy, phagocytic activity of LPS-induced macrophages was enhanced by P23 depletion. Specifically, in untreated RAW 264.7 macrophages, decreased P23 results in mRNA destabilization, diminished KIF15 expression and accelerated macrophage migration. We show that the unexpected RBP function of P23 contributes to the regulation of macrophage phagocytotic activity and migration.
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http://dx.doi.org/10.3389/fmolb.2021.625608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226254PMC
June 2021

Broncho-alveolar lavage in patients with acute respiratory distress syndrome due to COVID-19.

Intern Med J 2021 Jun;51(6):965-967

Department of Pneumology and Intensive Care Medicine, University Hospital RWTH Aachen, Aachen, Germany.

As data about microbiological testing and the cellular composition of the broncho-alveolar lavage (BAL) fluid in patients ventilated due to coronavirus disease 2019 (COVID-19) are lacking, this was investigated in a retrospective analysis (n = 58). Co-infection with pathogens was detected in 31 patients, whereas the analysis of BAL cellularity showed an increased total cell count and an alveolitis dominated by neutrophils. None of the physicians performing bronchoscopies in COVID-19 patients had serological evidence of severe acute respiratory syndrome coronavirus 2 infection.
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http://dx.doi.org/10.1111/imj.15363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8447080PMC
June 2021

Levels of bioactive adrenomedullin in plasma and cerebrospinal fluid in relation to delayed cerebral ischemia in patients after aneurysmal subarachnoid hemorrhage: A prospective observational study.

J Neurol Sci 2021 08 5;427:117533. Epub 2021 Jun 5.

Department of Neurosurgery, RWTH Aachen University Hospital, Aachen, Germany. Electronic address:

Objectives: Adrenomedullin (ADM) has been identified as a promising biomarker of mortality and outcome in sepsis, heart failure and after major surgery. A recently developed assay specific for bioactive adrenomedullin (bio-ADM) has not yet been assessed in aneurysmal subarachnoid hemorrhage (aSAH). The objective of this prospective trial was to assess the time course of bio-ADM after aSAH in relation to the development of delayed cerebral ischemia (DCI) and its association with clinical outcome.

Methods: Bio-ADM levels in plasma and cerebrospinal fluid (CSF) were measured during five predefined epochs, for up to 21 days in 30 aSAH patients: early, (day 0 to day 3); acute, (day 4 to day 8); early critical, (day 9 to day 12); late critical, (day 13 to day 15), and late (day 16 to day 21). DCI was diagnosed clinically or based on multimodal monitoring and imaging, and the occurrence of DCI-related cerebral infarction, and outcome after 12 months (extended Glasgow outcome scale), was noted.

Results: Higher median bio-ADM levels in plasma during the acute phase were predictive of long-term unfavorable outcome (AUC = 0.97; 95% CI 0.91 to 1.00; p < 0.001). Early critical bio-ADM levels during DCI were lower in CSF and confirmed DCI occurrence (AUC = 0.80; 95% CI 0.59 to 1.00; p = 0.044).

Conclusion: The dynamics of bio-ADM levels in CSF present a fairly different course compared to plasma with observed higher bio-ADM concentrations in patients spared from DCI and/or developing favorable outcome.
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http://dx.doi.org/10.1016/j.jns.2021.117533DOI Listing
August 2021

Efficacy and safety of early target-controlled plasma volume replacement with a balanced gelatine solution versus a balanced electrolyte solution in patients with severe sepsis/septic shock: study protocol, design, and rationale of a prospective, randomized, controlled, double-blind, multicentric, international clinical trial : GENIUS-Gelatine use in ICU and sepsis.

Trials 2021 Jun 2;22(1):376. Epub 2021 Jun 2.

Klinik für Operative Intensivmedizin und Intermediate Care, Universitätsklinikum RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany.

Background: Sepsis is associated with capillary leakage and vasodilatation and leads to hypotension and tissue hypoperfusion. Early plasma volume replacement is required to achieve haemodynamic stability (HDS) and maintain adequate tissue oxygenation. The right choice of fluids to be used for plasma volume replacement (colloid or crystalloid solutions) is still a matter of debate, and large trials investigating the use of colloid solutions containing gelatine are missing. This study aims to investigate the efficacy and safety of plasma volume replacement using either a combined gelatine-crystalloid regime (1:1 ratio) or a pure crystalloid regime.

Methods: This is a prospective, controlled, randomized, double-blind, international, multicentric phase IV study with two parallel groups that is planned to be conducted at European intensive care units (ICUs) in a population of patients with hypovolaemia in severe sepsis/septic shock. A total of 608 eligible patients will be randomly assigned to receive either a gelatine-crystalloid regime (Gelaspan® 4% and Sterofundin® ISO, B. Braun Melsungen AG, in a 1:1 ratio) or a pure crystalloid regime (Sterofundin® ISO) for plasma volume replacement. The primary outcome is defined as the time needed to achieve HDS. Plasma volume replacement will be target-controlled, i.e. fluids will only be administered to volume-responsive patients. Volume responsiveness will be assessed through passive leg raising or fluid challenges. The safety and efficacy of both regimens will be assessed daily for 28 days or until ICU discharge (whichever occurs first) as the secondary outcomes of this study. Follow-up visits/calls will be scheduled on day 28 and day 90.

Discussion: This study aims to generate evidence regarding which regimen-a gelatine-crystalloid regimen or a pure crystalloid regimen-is more effective in achieving HDS in critically ill patients with hypovolaemia. Study participants in both groups will benefit from the increased safety of target-controlled plasma volume replacement, which prevents fluid administration to already haemodynamically stable patients and reduces the risk of harmful fluid overload.

Trial Registration: The European clinical trial database EudraCT 2015-000057-20 and the ClinicalTrials.gov Protocol Registration and Results System ClinicalTrials.gov NCT02715466 . Registered on 17 March 2016.
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http://dx.doi.org/10.1186/s13063-021-05311-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170449PMC
June 2021

Six Months Follow-Up of Patients with Invasive Mechanical Ventilation due to COVID-19 Related ARDS.

Int J Environ Res Public Health 2021 May 29;18(11). Epub 2021 May 29.

Department of Pneumology and Internal Intensive Care Medicine, University Hospital RWTH, 52074 Aachen, Germany.

Although patients who recovered from acute coronavirus disease 2019 (COVID-19) may have prolonged disabilities, follow-up data of those who have survived COVID-19 related acute respiratory distress syndrome (ARDS) is still very scarce. Therefore, COVID-19-ARDS survivors requiring invasive mechanical ventilation (IMV) were followed six months after discharge. Pulmonary function tests (PFTs), 6-min walk test (6MWT) and echocardiography were performed. Quality of life (QoL), depression and anxiety were assessed using validated questionnaires. Patients were compared based on respiratory mechanics and CT-phenotype during intensive care unit (ICU) stay. Eighteen patients were included (61 ± 7 years; ICU-stay: 34 ± 16 days; IMV: 30 ± 15 days). At follow-up (197 ± 15 days after discharge), PFTs did not reveal significant limitations (VC: 92 ± 16%; FEV1: 92 ± 20%; DLco/VA: 81 ± 16%). Cardiac systolic function was normal in all patients, but 50% of them had diastolic dysfunction. 6MWT was under the lower limit of normal in only two patients. Eight patients (44%) reported tiredness, six (33%) suffered from fatigue and one patient (6%) had depression and anxiety. Surprisingly, patients with worse respiratory mechanics during IMV reported fewer symptoms and less exertional dyspnea at follow-up. In conclusion, patients with COVID-19-ARDS have the possibility to fully recover regarding pulmonary function and exercise capacity, which seems to be independent of disease severity during ICU stay.
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http://dx.doi.org/10.3390/ijerph18115861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199360PMC
May 2021

Do Digital Handover Checklists Influence the Clinical Outcome Parameters of Intensive Care Unit Patients? A Randomized Controlled Pilot Study.

Front Med (Lausanne) 2021 20;8:661343. Epub 2021 Apr 20.

Department of Anaesthesiology, Medical Faculty, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany.

Clinical handovers have been identified as high-risk situations for medical treatment errors. It has been shown that handover checklists lead to a reduced rate of medical errors and mortality. However, the influence of handover checklists on essential patient outcomes such as prevalence of sepsis, mortality, and length of hospitalization has not yet been investigated in a randomized controlled trial (RCT). The aim of the present pilot study was to estimate the effect of two different handover checklists on the 48 h sepsis-related organ failure assessment (SOFA) score and the feasibility of a respective clinical RCT. Outcome parameters and feasibility were investigated implementing and comparing an intervention with a control checklist. Single center two-armed cluster randomized prospective crossover pilot study. The study took place over three 1-month periods in an intensive care unit (ICU) setting at the University Hospital Aachen. Data from 1,882 patients on seven ICU wards were assessed, of which 1,038 were included in the analysis. A digital standardized handover checklist (ISBAR) was compared to a control checklist (VICUR). Primary outcome was the 2nd 24 h time window sepsis-related organ failure assessment (SOFA) score. Secondary outcomes were SOFA scores on the 3rd and 5th 24 h time window, mortality, reuptake, and length of stay; handover duration, degree of satisfaction, and compliance as feasibility-related outcomes. Different sepsis scores were observed only for the 1st 24 h time window after admission to the ICU, with higher values for ISBAR. With respect to the patient-centered outcomes, both checklists achieved similar results. Average handover duration was shorter for VICUR, whereas satisfaction and compliance were higher for ISBAR. However, overall compliance was low (25.4% for ISBAR and 15.8% for VICUR). Based on the results, a stratified randomization procedure is recommended for following RCTs, in which medical treatment errors should also be investigated as an additional variable. The use of control checklists is discouraged due to lower acceptance and compliance among healthcare practitioners. Measures should be undertaken to increase compliance with the use of checklists. Clinical outcome parameters should be carefully selected. ClinicalTrials.gov, Identifier [NCT03117088]. Registered April 14, 2017.
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http://dx.doi.org/10.3389/fmed.2021.661343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093756PMC
April 2021

Prognostic Value of Bioactive Adrenomedullin in Critically Ill Patients with COVID-19 in Germany: An Observational Cohort Study.

J Clin Med 2021 Apr 13;10(8). Epub 2021 Apr 13.

Department of Intensive and Intermediate Care, University Hospital RWTH Aachen, 52074 Aachen, Germany.

The coronavirus disease 2019 (COVID-19) pandemic has placed a significant burden on hospitals worldwide. Objective biomarkers for early risk stratification and clinical management are still lacking. The aim of this work was to determine whether bioactive adrenomedullin can assist in the risk stratification and clinical management of critically ill COVID-19 patients. Fifty-three patients with confirmed COVID-19 were included in this prospective observational cohort study between March and April 2020. Bioactive adrenomedullin (bio-ADM) plasma concentration was measured daily for seven days after admission. The prognostic value and clinical significance of bio-ADM plasma levels were evaluated for the severity of respiratory failure, the need for extracorporeal organ support and outcome (28-day mortality). Bio-ADM levels increased with the severity of acute respiratory distress syndrome (ARDS; < 0.001) and were significantly elevated in invasively ventilated patients ( = 0.006) and patients in need of extracorporeal membrane oxygenation ( = 0.040) or renal replacement therapy (RRT; < 0.001) compared to patients without these conditions. Non-survivors showed significantly higher bio-ADM levels than survivors ( = 0.010). Bio-ADM levels predicted 28-day mortality (C-index 0.72, 95% confidence interval 0.56-0.87, < 0.001). Bio-ADM plasma levels correlate with disease severity, the need for extracorporeal organ assistance, and outcome, and highlight the promising value of bio-ADM in the early risk stratification and management of patients with COVID-19.
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http://dx.doi.org/10.3390/jcm10081667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069401PMC
April 2021

[Attitude towards vaccination against SARS-CoV-2 : Survey among employees in hospitals before and after the start of vaccinations in German hospitals].

Med Klin Intensivmed Notfmed 2021 Jun 20;116(5):421-430. Epub 2021 Apr 20.

ARDS und ECMO Zentrum Köln-Merheim, Kliniken der Stadt Köln und Universität Witten/Herdecke, Köln, Deutschland.

Background: The vaccinations against the "severe acute respiratory syndrome coronavirus type 2" (SARS-CoV‑2) play a decisive role in the global fight against the coronavirus pandemic. In the population, but also among health care workers (HCWs), there were concerns and skepticism about vaccinations even before the corona pandemic.

Methods: An online survey on the attitude of HCWs to vaccination against SARS-CoV‑2 was carried out in December (December 3rd-December 12th, 2020) before and in February (February 1st-February 10th, 2021) after the start of the vaccinations. Members of the German Society for Internal Intensive Care Medicine and Emergency Medicine (DGIIN) and the German Interdisciplinary Association for Intensive Care Medicine and Emergency Medicine (DIVI) were invited by email and on Facebook.

Results: In December 2305 and in February 3501 people took part. The approval rate for vaccination increased from 85.2% to 92.1% (p < 0.001). There was also an increase in willingness to vaccinate (63.8% vs. 75.9%; p < 0.001). The female gender, membership of the professional group nursing staff and age < 45 years were significantly associated with a restricted willingness to vaccinate. There was also a decrease in concerns about efficacy, side effects and long-term damage. There was clear skepticism about the vaccine from AstraZeneca (Cambridge, United Kingdom). Before and after the introduction of vaccinations against SARS-CoV‑2, an increase in the willingness to vaccinate against SARS-CoV-2 can be shown in German HCWs. Technical experts must bring objectivity into the currently controversial debate through precise and transparent information and thus counteract vaccination skepticism, not only among HCWs.
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http://dx.doi.org/10.1007/s00063-021-00821-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056372PMC
June 2021

Thromboembolic and Bleeding Events in COVID-19 Patients receiving Extracorporeal Membrane Oxygenation.

Thorac Cardiovasc Surg 2021 09 16;69(6):526-536. Epub 2021 Apr 16.

Department of Thoracic and Cardiovascular Surgery, Uniklinik RWTH Aachen, Aachen, Germany.

Background: Extracorporeal membrane oxygenation (ECMO) is a potential treatment option in critically ill COVID-19 patients suffering from acute respiratory distress syndrome (ARDS) if mechanical ventilation (MV) is insufficient; however, thromboembolic and bleeding events (TEBE) during ECMO treatment still need to be investigated.

Methods: We conducted a retrospective, single-center study including COVID-19 patients treated with ECMO. Additionally, we performed a univariate analysis of 85 pre-ECMO variables to identify factors influencing incidences of thromboembolic events (TEE) and bleeding events (BE), respectively.

Results: Seventeen patients were included; the median age was 57 years (interquartile range [IQR]: 51.5-62), 11 patients were males (65%), median ECMO duration was 16 days (IQR: 10.5-22), and the overall survival was 53%. Twelve patients (71%) developed TEBE. We observed 7 patients (41%) who developed TEE and 10 patients (59%) with BE. Upper respiratory tract (URT) bleeding was the most frequent BE with eight cases (47%). Regarding TEE, pulmonary artery embolism (PAE) had the highest incidence with five cases (29%). The comparison of diverse pre-ECMO variables between patients with and without TEBE detected one statistically significant value. The platelet count was significantly lower in the BE group ( = 10) than in the non-BE group ( = 7) with 209 (IQR: 145-238) versus 452 G/L (IQR: 240-560), with  = 0.007.

Conclusion: This study describes the incidences of TEE and BE in critically ill COVID-19 patients treated with ECMO. The most common adverse event during ECMO support was bleeding, which occurred at a comparable rate to non-COVID-19 patients treated with ECMO.
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http://dx.doi.org/10.1055/s-0041-1725180DOI Listing
September 2021

Neurological symptoms in COVID-19: a cross-sectional monocentric study of hospitalized patients.

Neurol Res Pract 2021 Mar 12;3(1):17. Epub 2021 Mar 12.

Department of Neurology, RWTH University Hospital, Aachen, Germany.

Background: The SARS-Coronavirus-2 (SARS-CoV-2) invades the respiratory system, causing acute and sometimes severe pulmonary symptoms, but turned out to also act multisystematically with substantial impact on the brain. A growing number of studies suggests a diverse spectrum of neurological manifestations. To investigate the spectrum of symptoms, we here describe the neurological manifestations and complications of patients with proven SARS-CoV-2 infection who have been hospitalized at the RWTH University Hospital Aachen, Germany.

Methods: Between March and September 2020, we evaluated common symptoms, clinical characteristics, laboratory (including cerebrospinal fluid (CSF) analysis), radiological, and electroencephalography (EEG) data from 53 patients admitted with a positive SARS-CoV-2 polymerase chain reaction (PCR). We used the Montreal Cognitive Assessment Test (MoCA) to screen for cognitive impairment, when feasible. We compared critically ill and non-critically ill patients categorized according to the presence of Acute Respiratory Distress Syndrome (ARDS).

Results: Major clinical neurological features of hospitalized COVID-19 patients were coordination deficits (74%), cognitive impairment (61.5%), paresis (47%), abnormal reflex status (45%), sensory abnormalities (45%), general muscle weakness and pain (32%), hyposmia (26%), and headache (21%). Patients with ARDS were more severely affected than non-ADRS patients. 29.6% of patients with ARDS presented with subarachnoid bleedings, and 11.1% showed ischemic stroke associated with SARS-CoV-2 infection. Cognitive deficits mainly affected executive functions, attention, language, and delayed memory recall. We obtained cerebrospinal fluid (CSF) by lumbar puncture in nine of the 53 patients, none of which had a positive SARS-CoV-2 PCR.

Conclusions: In line with previous findings, our results provide evidence for a range of SARS-CoV-2-associated neurological manifestations. 26% of patients reported hyposmia, emphasizing the neuro-invasive potential of SARS-CoV-2, which can enter the olfactory bulb. It can therefore be speculated that neurological manifestations may be caused by direct invasion of the virus in the CNS; however, PCR did not reveal positive intrathecal SARS-CoV-2. Therefore, we hypothesize it is more likely that the para-infectious severe pro-inflammatory impact of COVID-19 is responsible for the neurological deficits including cognitive impairment. Future studies with comprehensive longitudinal assessment of neurological deficits are required to determine potential long-term complications of COVID-19.
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http://dx.doi.org/10.1186/s42466-021-00116-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953515PMC
March 2021

Decision-Making Authority During Tele-ICU Care Reduces Mortality and Length of Stay-A Systematic Review and Meta-Analysis.

Crit Care Med 2021 07;49(7):1169-1181

All authors: Department of Intensive Care Medicine and Intermediate Care, Medical Faculty, RWTH Aachen University, Aachen, Germany.

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.
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http://dx.doi.org/10.1097/CCM.0000000000004943DOI Listing
July 2021

Macrophage Migration Inhibitory Factor (MIF) Plasma Concentration in Critically Ill COVID-19 Patients: A Prospective Observational Study.

Diagnostics (Basel) 2021 Feb 17;11(2). Epub 2021 Feb 17.

Department of Intensive Care and Intermediate Care, Medical Faculty Rheinisch-Westfälische Technische Hochschule Aachen University Hospital, D-52074 Aachen, Germany.

Mortality in critically ill coronavirus disease 2019 (COVID-19) patients is high and pharmacological treatment strategies remain limited. Early-stage predictive biomarkers are needed to identify patients with a high risk of severe clinical courses and to stratify treatment strategies. Macrophage migration inhibitory factor (MIF) was previously described as a potential predictor for the outcome of critically ill patients and for acute respiratory distress syndrome (ARDS), a hallmark of severe COVID-19 disease. This prospective observational study evaluates the predictive potential of MIF for the clinical outcome after severe COVID-19 infection. Plasma MIF concentrations were measured in 36 mechanically ventilated COVID-19 patients over three days after intensive care unit (ICU) admission. Increased compared to decreased MIF was significantly associated with aggravated organ function and a significantly lower 28-day survival (sequential organ failure assessment (SOFA) score; 8.2 ± 4.5 to 14.3 ± 3, = 0.009 vs. 8.9 ± 1.9 to 12 ± 2, = 0.296; survival: 56% vs. 93%; = 0.003). Arterial hypertension was the predominant comorbidity in 85% of patients with increasing MIF concentrations (vs. decreasing MIF: 39%; = 0.015). Without reaching significance, more patients with decreasing MIF were able to improve their ARDS status ( = 0.142). The identified association between an early MIF response, aggravation of organ function and 28-day survival may open future perspectives for biomarker-based diagnostic approaches for ICU management of COVID-19 patients.
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http://dx.doi.org/10.3390/diagnostics11020332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922575PMC
February 2021

Future Medical Artificial Intelligence Application Requirements and Expectations of Physicians in German University Hospitals: Web-Based Survey.

J Med Internet Res 2021 03 5;23(3):e26646. Epub 2021 Mar 5.

Department of Intensive Care Medicine, University Hospital RWTH Aachen, Aachen, Germany.

Background: The increasing development of artificial intelligence (AI) systems in medicine driven by researchers and entrepreneurs goes along with enormous expectations for medical care advancement. AI might change the clinical practice of physicians from almost all medical disciplines and in most areas of health care. While expectations for AI in medicine are high, practical implementations of AI for clinical practice are still scarce in Germany. Moreover, physicians' requirements and expectations of AI in medicine and their opinion on the usage of anonymized patient data for clinical and biomedical research have not been investigated widely in German university hospitals.

Objective: This study aimed to evaluate physicians' requirements and expectations of AI in medicine and their opinion on the secondary usage of patient data for (bio)medical research (eg, for the development of machine learning algorithms) in university hospitals in Germany.

Methods: A web-based survey was conducted addressing physicians of all medical disciplines in 8 German university hospitals. Answers were given using Likert scales and general demographic responses. Physicians were asked to participate locally via email in the respective hospitals.

Results: The online survey was completed by 303 physicians (female: 121/303, 39.9%; male: 173/303, 57.1%; no response: 9/303, 3.0%) from a wide range of medical disciplines and work experience levels. Most respondents either had a positive (130/303, 42.9%) or a very positive attitude (82/303, 27.1%) towards AI in medicine. There was a significant association between the personal rating of AI in medicine and the self-reported technical affinity level (H=48.3, P<.001). A vast majority of physicians expected the future of medicine to be a mix of human and artificial intelligence (273/303, 90.1%) but also requested a scientific evaluation before the routine implementation of AI-based systems (276/303, 91.1%). Physicians were most optimistic that AI applications would identify drug interactions (280/303, 92.4%) to improve patient care substantially but were quite reserved regarding AI-supported diagnosis of psychiatric diseases (62/303, 20.5%). Of the respondents, 82.5% (250/303) agreed that there should be open access to anonymized patient databases for medical and biomedical research.

Conclusions: Physicians in stationary patient care in German university hospitals show a generally positive attitude towards using most AI applications in medicine. Along with this optimism comes several expectations and hopes that AI will assist physicians in clinical decision making. Especially in fields of medicine where huge amounts of data are processed (eg, imaging procedures in radiology and pathology) or data are collected continuously (eg, cardiology and intensive care medicine), physicians' expectations of AI to substantially improve future patient care are high. In the study, the greatest potential was seen in the application of AI for the identification of drug interactions, assumedly due to the rising complexity of drug administration to polymorbid, polypharmacy patients. However, for the practical usage of AI in health care, regulatory and organizational challenges still have to be mastered.
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http://dx.doi.org/10.2196/26646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980122PMC
March 2021

Methylated HNRNPK acts on RPS19 to regulate ALOX15 synthesis in erythropoiesis.

Nucleic Acids Res 2021 04;49(6):3507-3523

Department of Intensive Care Medicine, University Hospital, RWTH Aachen University, Aachen Germany.

Post-transcriptional control is essential to safeguard structural and metabolic changes in enucleated reticulocytes during their terminal maturation to functional erythrocytes. The timely synthesis of arachidonate 15-lipoxygenase (ALOX15), which initiates mitochondria degradation at the final stage of reticulocyte maturation is regulated by the multifunctional protein HNRNPK. It constitutes a silencing complex at the ALOX15 mRNA 3' untranslated region that inhibits translation initiation at the AUG by impeding the joining of ribosomal 60S subunits to 40S subunits. To elucidate how HNRNPK interferes with 80S ribosome assembly, three independent screens were applied. They consistently demonstrated a differential interaction of HNRNPK with RPS19, which is localized at the head of the 40S subunit and extends into its functional center. During induced erythroid maturation of K562 cells, decreasing arginine dimethylation of HNRNPK is linked to a reduced interaction with RPS19 in vitro and in vivo. Dimethylation of residues R256, R258 and R268 in HNRNPK affects its interaction with RPS19. In noninduced K562 cells, RPS19 depletion results in the induction of ALOX15 synthesis and mitochondria degradation. Interestingly, residue W52 in RPS19, which is frequently mutated in Diamond-Blackfan Anemia (DBA), participates in specific HNRNPK binding and is an integral part of a putative aromatic cage.
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http://dx.doi.org/10.1093/nar/gkab116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034617PMC
April 2021

Development and validation of a reinforcement learning algorithm to dynamically optimize mechanical ventilation in critical care.

NPJ Digit Med 2021 Feb 19;4(1):32. Epub 2021 Feb 19.

Department of Intensive Care and Intermediate Care, University Hospital RWTH Aachen, Pauwelsstreet 30, Aachen, Germany.

The aim of this work was to develop and evaluate the reinforcement learning algorithm VentAI, which is able to suggest a dynamically optimized mechanical ventilation regime for critically-ill patients. We built, validated and tested its performance on 11,943 events of volume-controlled mechanical ventilation derived from 61,532 distinct ICU admissions and tested it on an independent, secondary dataset (200,859 ICU stays; 25,086 mechanical ventilation events). A patient "data fingerprint" of 44 features was extracted as multidimensional time series in 4-hour time steps. We used a Markov decision process, including a reward system and a Q-learning approach, to find the optimized settings for positive end-expiratory pressure (PEEP), fraction of inspired oxygen (FiO) and ideal body weight-adjusted tidal volume (Vt). The observed outcome was in-hospital or 90-day mortality. VentAI reached a significantly increased estimated performance return of 83.3 (primary dataset) and 84.1 (secondary dataset) compared to physicians' standard clinical care (51.1). The number of recommended action changes per mechanically ventilated patient constantly exceeded those of the clinicians. VentAI chose 202.9% more frequently ventilation regimes with lower Vt (5-7.5 mL/kg), but 50.8% less for regimes with higher Vt (7.5-10 mL/kg). VentAI recommended 29.3% more frequently PEEP levels of 5-7 cm HO and 53.6% more frequently PEEP levels of 7-9 cmHO. VentAI avoided high (>55%) FiO values (59.8% decrease), while preferring the range of 50-55% (140.3% increase). In conclusion, VentAI provides reproducible high performance by dynamically choosing an optimized, individualized ventilation strategy and thus might be of benefit for critically ill patients.
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http://dx.doi.org/10.1038/s41746-021-00388-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895944PMC
February 2021
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