Publications by authors named "Sascha Treskatsch"

63 Publications

European Association of Cardiothoracic Anesthesiology and Intensive Care Pediatric Cardiac Anesthesia Fellowship Curriculum: First Edition.

J Cardiothorac Vasc Anesth 2021 Aug 8. Epub 2021 Aug 8.

Department of Intensive Care, Royal Papworth Hospital, Cambridge Biomedical Campus, Cambridge, United Kingdom.

Pediatric cardiac anesthesia is a subspecialty of cardiac and pediatric anesthesiology dedicated to the perioperative care of patients with congenital heart disease. Members of the Congenital and Education Subcommittees of the European Association of Cardiothoracic Anaesthesiology and Intensive Care (EACTAIC) agreed on the necessity to develop an EACTAIC pediatric cardiac anesthesia fellowship curriculum. This manuscript represents a consensus on the composition and the design of the EACTAIC Pediatric Cardiac Anesthesia Fellowship program. This curriculum provides a basis for the training of future pediatric cardiac anesthesiologists by clearly defining the theoretical and practical requirements for fellows and host centers.
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http://dx.doi.org/10.1053/j.jvca.2021.08.009DOI Listing
August 2021

High Central Venous Pressure after Cardiac Surgery Might Depict Hemodynamic Deterioration Associated with Increased Morbidity and Mortality.

J Clin Med 2021 Aug 31;10(17). Epub 2021 Aug 31.

Department of Anesthesiology and Intensive Care Medicine, Campus Charité Mitte and Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13353 Berlin, Germany.

Background: Cardiac surgery patients represent a high-risk cohort in intensive care units (ICUs). Central venous pressure (CVP) measurement seems to remain an integral part in hemodynamic monitoring, especially in cardio-surgical ICUs. However, its value as a prognostic marker for organ failure is still unclear. Therefore, we analyzed postoperative CVP values after adult cardiac surgery in a large cohort with regard to its prognostic value for morbidity and mortality.

Methods: All adult patients admitted to our ICUs between 2006 and 2019 after cardiac surgery were eligible for inclusion in the study ( = 11,198). We calculated the median initial CVP (miCVP) after admission to the ICU, which returned valid values for 9802 patients. An ROC curve analysis for optimal cut-off miCVP to predict ICU mortality was conducted with consecutive patient allocation into a (a) low miCVP (LCVP) group (≤11 mmHg) and (b) high miCVP (HCVP) group (>11 mmHg). We analyzed the impact of high miCVP on morbidity and mortality by propensity score matching (PSM) and logistic regression.

Results: ICU mortality was increased in HCVP patients. In addition, patients in the HCVP group required longer mechanical ventilation, had a higher incidence of acute kidney injury, were more frequently treated with renal replacement therapy, and showed a higher risk for postoperative liver dysfunction, parametrized by a postoperative rise of ≥ 10 in MELD Score. Multiple regression analysis confirmed HCVP has an effect on postoperative ICU-mortality and intrahospital mortality, which seems to be independent.

Conclusions: A high initial CVP in the early postoperative ICU course after cardiac surgery is associated with worse patient outcome. Whether or not CVP, as a readily and constantly available hemodynamic parameter, should promote clinical efforts regarding diagnostics and/or treatment, warrants further investigations.
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http://dx.doi.org/10.3390/jcm10173945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432196PMC
August 2021

Preoperative and ICU Scoring Models for Predicting the In-Hospital Mortality of Patients With Ruptured Abdominal Aortic Aneurysms.

J Cardiothorac Vasc Anesth 2021 Aug 14. Epub 2021 Aug 14.

Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität and Humboldt Universität zu Berlin, Department of Anesthesiology and Intensive Care Medicine, Charité Campus Benjamin Franklin, Berlin, Germany.

Objectives: This study's objective was to compare several preoperative and intensive care unit (ICU) prognostic scoring systems for predicting the in-hospital mortality of ruptured abdominal aortic aneurysms (RAAAs).

Design: Retrospective cohort study.

Setting: Single tertiary university center.

Participants: The study comprised 157 patients.

Interventions: None.

Measurements And Main Results: A total of 157 patients (82% male) presented with RAAA at Charité University Hospital from January 2011 to December 2020. The mean age was 74 years (standard deviation ten years). In-hospital mortality was 29% (n = 45), of whom nine patients (6%) died en route to the operating room, 13 (8%) on the operating table, and 23 (15%) in the ICU. A total of 135 patients (86%) were admitted to the ICU. All six models demonstrated good discriminating performance between survivors and nonsurvivors. Overall, the area under the curve (AUC) for RAAA preoperative scores was greater than those for ICU scores. The largest AUC was achieved with the Vascular Study Group of New England (VSGNE) RAAA risk score (AUC = 0.87 for all patients, AUC = 0.84 for patients admitted to the ICU), followed by Hardman Index (AUC = 0.83 for all patients, AUC = 0.81 for patients admitted to the ICU), and Glasgow Aneurysm Score (AUC = 0.74 for all patients, AUC = 0.83 for patients admitted to the ICU). The largest AUC for ICU scores (only patients admitted to the ICU) was achieved with Simplified Acute Physiology Score II (0.75), followed by Sepsis-related Organ Failure Assessment (0.73), and Acute Physiology and Chronic Health Evaluation II (0.71).

Conclusions: Preoperative and ICU scores can predict the mortality of patients presenting with RAAA. In addition, the discriminatory ability of preoperative scores between survivors and nonsurvivors was larger than that for ICU scores.
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http://dx.doi.org/10.1053/j.jvca.2021.08.015DOI Listing
August 2021

Institutional infrastructural preconditions and current perioperative anaesthesia practice in patients undergoing transfemoral transcatheter aortic valve implantation: a cross-sectional study in German heart centres.

BMJ Open 2021 08 4;11(8):e045330. Epub 2021 Aug 4.

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

Objectives: Transfemoral transcatheter aortic valve implantation (TF-TAVI) is an established therapy for patients with symptomatic aortic stenosis, which requires periprocedural anaesthesia care. In 2015, the German Federal Joint Committee released a directive on minimally invasive heart valve interventions which defines institutional infrastructural requirements in German heart centres. But still generally accepted expert consensus recommendations or national or international guidelines regarding periprocedural anaesthesia management for TF-TAVI are lacking. This nationwide cross-sectional study had two major objectives: first to assess the concordance with existing national regulations regarding infrastructural requirements and second to evaluate the status quo of periprocedural anaesthesia management for patients undergoing TF-TAVI in German heart centres.

Design: Multicentre cross-sectional online study to evaluate the periprocedural anaesthesia management.

Setting: In this nationwide cross-sectional study, electronic questionnaires were sent out to anaesthesia departments at TF-TAVI-performing centres in Germany in March 2019.

Participants: 78 anaesthesia departments of German heart centres.

Results: 54 (69.2%) centres returned the questionnaire of which 94.4% stated to hold regular Heart Team meetings, 75.9% to have ready-to-use heart-lung machines available on-site, 77.8% to have cardiac surgeons and 66.7% to have perfusionists routinely attending throughout TF-TAVI procedures. Regarding periprocedural anaesthesia management, 41 (75.9%) of the participating centres reported to predominantly use 'monitored anaesthesia care' and 13 (24.1%) to favour general anaesthesia. 49 (90.7%) centres stated to use institutional standard operating procedures for anaesthesia. Five-lead ECG, central venous lines, capnometry and intraprocedural echocardiography were reported to be routine measures in 85.2%, 83.3%, 77.8% and 51.9% of the surveyed heart centres.

Conclusions: The concordance with national regulations, anaesthesia management and in-house standards for TF-TAVI vary broadly among German heart centres. According to the opinion of the authors, international expert consensus recommendations and/or guidelines would be helpful to standardise peri interventional anaesthesia care.
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http://dx.doi.org/10.1136/bmjopen-2020-045330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8340292PMC
August 2021

Functional and Anatomical Characterization of Corticotropin-Releasing Factor Receptor Subtypes of the Rat Spinal Cord Involved in Somatic Pain Relief.

Mol Neurobiol 2021 Jul 31. Epub 2021 Jul 31.

Department of Anesthesiology and Operative Intensive Care Medicine, Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charité - Universitätsmedizin Berlin, Charité Campus Benjamin Franklin, Hindenburgdamm 30, 12203, Berlin, Germany.

Corticotropin-releasing factor (CRF) orchestrates our body's response to stressful stimuli. Pain is often stressful and counterbalanced by activation of CRF receptors along the nociceptive pathway, although the involvement of the CRF receptor subtypes 1 and/or 2 (CRF-R1 and CRF-R2, respectively) in CRF-induced analgesia remains controversial. Thus, the aim of the present study was to examine CRF-R1 and CRF-R2 expression within the spinal cord of rats with Freund's complete adjuvant-induced unilateral inflammation of the hind paw using reverse transcriptase polymerase chain reaction, Western blot, radioligand binding, and immunofluorescence confocal analysis. Moreover, the antinociceptive effects of intrathecal (i.t.) CRF were measured by paw pressure algesiometer and their possible antagonism by selective antagonists for CRF-R1 and/or CRF-R2 as well as for opioid receptors. Our results demonstrated a preference for the expression of CRF-R2 over CRF-R1 mRNA, protein, binding sites and immunoreactivity in the dorsal horn of the rat spinal cord. Consistently, CRF as well as CRF-R2 agonists elicited potent dose-dependent antinociceptive effects which were antagonized by the i.t. CRF-R2 selective antagonist K41498, but not by the CRF-R1 selective antagonist NBI35965. In addition, i.t. applied opioid antagonist naloxone dose-dependently abolished the i.t. CRF- as well as CRF-R2 agonist-elicited inhibition of somatic pain. Importantly, double immunofluorescence confocal microscopy of the spinal dorsal horn showed CRF-R2 on enkephalin (ENK)-containing inhibitory interneurons in close opposition of incoming mu-opioid receptor-immunoreactive nociceptive neurons. CRF-R2 was, however, not seen on pre- or on postsynaptic sensory neurons of the spinal cord. Taken together, these findings suggest that i.t. CRF or CRF-R2 agonists inhibit somatic inflammatory pain predominantly through CRF-R2 receptors located on spinal enkephalinergic inhibitory interneurons which finally results in endogenous opioid-mediated pain inhibition.
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http://dx.doi.org/10.1007/s12035-021-02481-zDOI Listing
July 2021

Infectious Complications after Etomidate vs. Propofol for Induction of General Anesthesia in Cardiac Surgery-Results of a Retrospective, before-after Study.

J Clin Med 2021 Jun 29;10(13). Epub 2021 Jun 29.

Department of Anesthesiology and Intensive Care Medicine (Campus Charité Mitte, Campus Virchow-Klinikum), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany.

Background: Etomidate is typically used as an induction agent in cardiac surgery because it has little impact on hemodynamics. It is a known suppressor of adrenocortical function and may increase the risk for post-operative infections, sepsis, and mortality. The aim of this study was to evaluate whether etomidate increases the risk of postoperative sepsis (primary outcome) and infections (secondary outcome) compared to propofol.

Methods: This was a retrospective before-after trial (IRB EA1/143/20) performed at a tertiary medical center in Berlin, Germany, between 10/2012 and 01/2015. Patients undergoing cardiac surgery were investigated within two observation intervals, during which etomidate and propofol were the sole induction agents.

Results: One-thousand, four-hundred, and sixty-two patients, and 622 matched pairs, after caliper propensity-score matching, were included in the final analysis. Sepsis rates did not differ in the matched cohort (etomidate: 11.5% vs. propofol: 8.2%, = 0.052). Patients in the etomidate interval were more likely to develop hospital-acquired pneumonia (etomidate: 18.6% vs. propofol: 14.0%, = 0.031).

Conclusion: Our study showed that a single-dose of etomidate is not statistically associated with higher postoperative sepsis rates after cardiac surgery, but is associated with a higher incidence of hospital-acquired pneumonia. However, there is a notable trend towards a higher sepsis rate.
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http://dx.doi.org/10.3390/jcm10132908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269440PMC
June 2021

Echocardiographic Evaluation of Right Ventricular (RV) Performance over Time in COVID-19-Associated ARDS-A Prospective Observational Study.

J Clin Med 2021 May 1;10(9). Epub 2021 May 1.

Department of Anesthesiology and Intensive Care Medicine, Charité Campus Benjamin Franklin, Corporate Member of Freie Universität and Humboldt Universität zu Berlin, Charité-Universitätsmedizin Berlin, 12203 Berlin, Germany.

(1) Background: To evaluate time-dependent right ventricular (RV) performance in patients with COVID-19-associated acute respiratory distress syndrome (ARDS) undergoing intensive care (ICU) treatment. (2) Methods: This prospective observational study included 21 ICU patients with COVID-19-associated ARDS in a university hospital in 2020 (first wave). Patients were evaluated by transthoracic echocardiography at an early (EE) and late (LE) stage of disease. Echocardiographic parameters describing RV size and function as well as RV size in correlation to PO/FO ratio were assessed in survivors and nonsurvivors. (3) Results: Echocardiographic RV parameters were within normal range and not significantly different between EE and LE. Comparing survivors and nonsurvivors revealed no differences in RV performance at EE. Linear regression analysis did not show a correlation between RV size and PO/FO ratio over all measurements. Analysing EE and LE separately showed a significant increase in RV size correlated to a lower PO/FO ratio at a later stage of COVID-19 ARDS. (4) Conclusion: The present study reveals neither a severe RV dilatation nor an impairment of systolic RV function during the initial course of COVID-19-associated ARDS. A trend towards an increase in RV size in correlation with ARDS severity in the second week after ICU admission was observed.
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http://dx.doi.org/10.3390/jcm10091944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125118PMC
May 2021

Impact of Anesthesia Strategy and Valve Type on Clinical Outcomes After Transcatheter Aortic Valve Replacement.

J Am Coll Cardiol 2021 May;77(17):2204-2215

University Clinic Schleswig-Holstein and University Heart Center Lübeck, Lübeck, Germany.

Background: The randomized SOLVE-TAVI (compariSon of secOnd-generation seLf-expandable vs. balloon-expandable Valves and gEneral vs. local anesthesia in Transcatheter Aortic Valve Implantation) trial compared newer-generation self-expanding valves (SEV) and balloon-expandable valves (BEV) as well as local anesthesia with conscious sedation (CS) and general anesthesia (GA) in patients undergoing transfemoral transcatheter aortic valve replacement (TAVR). Both strategies showed similar outcomes at 30 days.

Objectives: The purpose of this study was to compare clinical outcomes during 1-year follow-up in the randomized SOLVE-TAVI trial.

Methods: Using a 2 × 2 factorial design 447 intermediate- to high-risk patients with severe, symptomatic aortic stenosis were randomly assigned to transfemoral TAVR using either the SEV (Evolut R, Medtronic Inc., Minneapolis, Minnesota) or the BEV (Sapien 3, Edwards Lifesciences, Irvine, California) as well as CS or GA at 7 sites.

Results: In the valve-comparison strategy, rates of the combined endpoint of all-cause mortality, stroke, moderate or severe paravalvular leakage, and permanent pacemaker implantation were similar between the BEV and SEV group (n = 84, 38.3% vs. n = 87, 40.4%; hazard ratio: 0.94; 95% confidence interval: 0.70 to 1.26; p = 0.66) at 1 year. Regarding the anesthesia comparison, the combined endpoint of all-cause mortality, stroke, myocardial infarction, and acute kidney injury occurred with similar rates in the GA and CS groups (n = 61, 25.7% vs. n = 54, 23.8%; hazard ratio: 1.09; 95% confidence interval: 0.76 to 1.57; p = 0.63).

Conclusions: In intermediate- to high-risk patients undergoing transfemoral TAVR, newer-generation SEV and BEV as well as CS and GA showed similar clinical outcomes at 1 year using a combined clinical endpoint. (SecOnd-generation seLf-expandable Versus Balloon-expandable Valves and gEneral Versus Local Anesthesia in TAVI [SOLVE-TAVI]; NCT02737150).
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http://dx.doi.org/10.1016/j.jacc.2021.03.007DOI Listing
May 2021

Cardiac arrhythmias in patients with COVID-19: Lessons from 2300 telemetric monitoring days on the intensive care unit.

J Electrocardiol 2021 May-Jun;66:102-107. Epub 2021 Apr 16.

DZHK (German Center of Cardiovascular Research), partner site Berlin, Germany; Department of Internal Medicine and Cardiology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.

Background: Patients with COVID-19 seem to be prone to the development of arrhythmias. The objective of this trial was to determine the characteristics, clinical significance and therapeutic consequences of these arrhythmias in COVID-19 patients requiring intensive care unit (ICU) treatment.

Methods And Results: A total of 113 consecutive patients (mean age 64.1 ± 14.3 years, 30 (26.5%) female) with positive PCR testing for SARS-CoV2 as well as radiographically confirmed pulmonary involvement admitted to the ICU from March to May 2020 were included and observed for a cumulative time of 2321 days. Fifty episodes of sustained atrial tachycardias, five episodes of sustained ventricular arrhythmias and thirty bradycardic events were documented. Sustained new onset atrial arrhythmias were associated with hemodynamic deterioration in 13 cases (35.1%). Patients with new onset atrial arrhythmias were older, showed higher levels of Hs-Troponin and NT-proBNP, and a more severe course of disease. The 5 ventricular arrhythmias (two ventricular tachycardias, two episodes of ventricular fibrillation, and one torsade de pointes tachycardia) were observed in 4 patients. All episodes could be terminated by immediate defibrillation/cardioversion. Five bradycardic events were associated with hemodynamic deterioration. Precipitating factors could be identified in 19 of 30 episodes (63.3%), no patient required cardiac pacing. Baseline characteristics were not significantly different between patients with or without bradycardic events.

Conclusion: Relevant arrhythmias are common in severely ill ICU patients with COVID-19. They are associated with worse courses of disease and require specific treatment. This makes daily close monitoring of telemetric data mandatory in this patient group.
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http://dx.doi.org/10.1016/j.jelectrocard.2021.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050403PMC
June 2021

CD169/SIGLEC1 is expressed on circulating monocytes in COVID-19 and expression levels are associated with disease severity.

Infection 2021 Aug 6;49(4):757-762. Epub 2021 Apr 6.

Department of Infectious Diseases and Respiratory Medicine, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117, Berlin, Germany.

Coronavirus disease 2019 (COVID-19) is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Type I interferons are important in the defense of viral infections. Recently, neutralizing IgG auto-antibodies against type I interferons were found in patients with severe COVID-19 infection. Here, we analyzed expression of CD169/SIGLEC1, a well described downstream molecule in interferon signaling, and found increased monocytic CD169/SIGLEC1 expression levels in patients with mild, acute COVID-19, compared to patients with severe disease. We recommend further clinical studies to evaluate the value of CD169/SIGLEC1 expression in patients with COVID-19 with or without auto-antibodies against type I interferons.
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http://dx.doi.org/10.1007/s15010-021-01606-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023546PMC
August 2021

Critical Illness and Systemic Inflammation Are Key Risk Factors of Severe Acute Kidney Injury in Patients With COVID-19.

Kidney Int Rep 2021 Apr 2;6(4):905-915. Epub 2021 Feb 2.

Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Introduction: Acute kidney injury (AKI) is an important complication in COVID-19, but its precise etiology has not fully been elucidated. Insights into AKI mechanisms may be provided by analyzing the temporal associations of clinical parameters reflecting disease processes and AKI development.

Methods: We performed an observational cohort study of 223 consecutive COVID-19 patients treated at 3 sites of a tertiary care referral center to describe the evolvement of severe AKI (Kidney Disease: Improving Global Outcomes stage 3) and identify conditions promoting its development. Descriptive statistics and explanatory multivariable Cox regression modeling with clinical parameters as time-varying covariates were used to identify risk factors of severe AKI.

Results: Severe AKI developed in 70 of 223 patients (31%) with COVID-19, of which 95.7% required kidney replacement therapy. Patients with severe AKI were older, predominantly male, had more comorbidities, and displayed excess mortality. Severe AKI occurred exclusively in intensive care unit patients, and 97.3% of the patients developing severe AKI had respiratory failure. Mechanical ventilation, vasopressor therapy, and inflammatory markers (serum procalcitonin levels and leucocyte count) were independent time-varying risk factors of severe AKI. Increasing inflammatory markers displayed a close temporal association with the development of severe AKI. Sensitivity analysis on risk factors of AKI stage 2 and 3 combined confirmed these findings.

Conclusion: Severe AKI in COVID-19 was tightly coupled with critical illness and systemic inflammation and was not observed in milder disease courses. These findings suggest that traditional systemic AKI mechanisms rather than kidney-specific processes contribute to severe AKI in COVID-19.
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http://dx.doi.org/10.1016/j.ekir.2021.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007085PMC
April 2021

SARS-CoV-2 in severe COVID-19 induces a TGF-β-dominated chronic immune response that does not target itself.

Nat Commun 2021 03 30;12(1):1961. Epub 2021 Mar 30.

Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany.

The pathogenesis of severe COVID-19 reflects an inefficient immune reaction to SARS-CoV-2. Here we analyze, at the single cell level, plasmablasts egressed into the blood to study the dynamics of adaptive immune response in COVID-19 patients requiring intensive care. Before seroconversion in response to SARS-CoV-2 spike protein, peripheral plasmablasts display a type 1 interferon-induced gene expression signature; however, following seroconversion, plasmablasts lose this signature, express instead gene signatures induced by IL-21 and TGF-β, and produce mostly IgG1 and IgA1. In the sustained immune reaction from COVID-19 patients, plasmablasts shift to the expression of IgA2, thereby reflecting an instruction by TGF-β. Despite their continued presence in the blood, plasmablasts are not found in the lungs of deceased COVID-19 patients, nor does patient IgA2 binds to the dominant antigens of SARS-CoV-2. Our results thus suggest that, in severe COVID-19, SARS-CoV-2 triggers a chronic immune reaction that is instructed by TGF-β, and is distracted from itself.
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http://dx.doi.org/10.1038/s41467-021-22210-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010106PMC
March 2021

Chronic Naltrexone Therapy Is Associated with Improved Cardiac Function in Volume Overloaded Rats.

Cardiovasc Drugs Ther 2021 Aug 23;35(4):733-743. Epub 2021 Jan 23.

Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Anesthesiology and Operative Intensive Care Medicine, Charité Campus Benjamin Franklin, Hindenburgdamm 30, 12203, Berlin, Germany.

Purpose: Myocardial opioid receptors were demonstrated in animals and humans and seem to colocalize with membranous and sarcolemmal calcium channels of the excitation-contraction coupling in the left ventricle (LV). Therefore, this study investigated whether blockade of the cardiac opioid system by naltrexone would affect cardiac function and neurohumoral parameters in Wistar rats with volume overload-induced heart failure.

Methods: Volume overload in Wistar rats was induced by an aortocaval fistula (ACF). Left ventricular cardiac opioid receptors were identified by immunohistochemistry and their messenger ribonucleic acid (mRNA) as well as their endogenous ligand mRNA quantified by real-time polymerase chain reaction (RT-PCR). Following continuous delivery of either the opioid receptor antagonist naltrexone or vehicle via minipumps (n = 5 rats each), hemodynamic and humoral parameters were assessed 28 days after ACF induction. Sham-operated animals served as controls.

Results: In ACF rats mu-, delta-, and kappa-opioid receptors colocalized with voltage-gated L-type Ca2+ channels in left ventricular cardiomyocytes. Chronic naltrexone treatment of ACF rats reduced central venous pressure (CVP) and left ventricular end-diastolic pressure (LVEDP), and improved systolic and diastolic left ventricular functions. Concomitantly, rat brain natriuretic peptide (rBNP-45) and angiotensin-2 plasma concentrations which were elevated during ACF were significantly diminished following naltrexone treatment. In parallel, chronic naltrexone significantly reduced mu-, delta-, and kappa-opioid receptor mRNA, while it increased the endogenous opioid peptide mRNA compared to controls.

Conclusion: Opioid receptor blockade by naltrexone leads to improved LV function and decreases in rBNP-45 and angiotensin-2 plasma levels. In parallel, naltrexone resulted in opioid receptor mRNA downregulation and an elevated intrinsic tone of endogenous opioid peptides possibly reflecting a potentially cardiodepressant effect of the cardiac opioid system during volume overload.
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http://dx.doi.org/10.1007/s10557-020-07132-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266787PMC
August 2021

High frequency of cerebrospinal fluid autoantibodies in COVID-19 patients with neurological symptoms.

Brain Behav Immun 2021 03 24;93:415-419. Epub 2020 Dec 24.

Department of Neurology and Experimental Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany; German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany.

Background: COVID-19 intensive care patients can present with neurological syndromes, usually in the absence of SARS-CoV-2 in cerebrospinal fluid (CSF). The recent finding of some virus-neutralizing antibodies cross-reacting with brain tissue suggests the possible involvement of specific autoimmunity.

Design: Blood and CSF samples from eleven critically ill COVID-19 patients presenting with unexplained neurological symptoms including myoclonus, oculomotor disturbance, delirium, dystonia and epileptic seizures, were analyzed for anti-neuronal and anti-glial autoantibodies.

Results: Using cell-based assays and indirect immunofluorescence on unfixed murine brain sections, all patients showed anti-neuronal autoantibodies in serum or CSF. Antigens included intracellular and neuronal surface proteins, such as Yo or NMDA receptor, but also various specific undetermined epitopes, reminiscent of the brain tissue binding observed with certain human monoclonal SARS-CoV-2 antibodies. These included vessel endothelium, astrocytic proteins and neuropil of basal ganglia, hippocampus or olfactory bulb.

Conclusion: The high frequency of autoantibodies targeting the brain in the absence of other explanations suggests a causal relationship to clinical symptoms, in particular to hyperexcitability (myoclonus, seizures). Several underlying autoantigens and their potential molecular mimicry with SARS-CoV-2 still await identification. However, autoantibodies may already now explain some aspects of multi-organ disease in COVID-19 and can guide immunotherapy in selected cases.
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http://dx.doi.org/10.1016/j.bbi.2020.12.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834471PMC
March 2021

Vasopressor Therapy in Cardiac Surgery-An Experts' Consensus Statement.

J Cardiothorac Vasc Anesth 2021 Apr 19;35(4):1018-1029. Epub 2020 Nov 19.

Department of Anesthesiology and Intensive Care, Heart- and Diabetes Center Mecklenburg - Western Pomerania, Karlsburg, Germany. Electronic address:

Hemodynamic conditions with reduced systemic vascular resistance commonly are observed in patients undergoing cardiac surgery and may range from moderate reductions in vascular tone, as a side effect of general anesthetics, to a profound vasodilatory syndrome, often referred to as vasoplegic shock. Therapy with vasopressors is an important pillar in the treatment of these conditions. There is limited guidance on the appropriate choice of vasopressors to restore and optimize systemic vascular tone in patients undergoing cardiac surgery. A panel of experts in the field convened to develop statements and evidence-based recommendations on clinically relevant questions on the use of vasopressors in cardiac surgical patients, using a critical appraisal of the literature following the GRADE system and a modified Delphi process. The authors unanimously and strongly recommend the use of norepinephrine and/or vasopressin for restoration and maintenance of systemic perfusion pressure in cardiac surgical patients; despite that, the authors cannot recommend either of these drugs with respect to the risk of ischemic complications. The authors unanimously and strongly recommend against using dopamine for treating post-cardiac surgery vasoplegic shock and against using methylene blue for purposes other than a rescue therapy. The authors unanimously and weakly recommend that clinicians consider early addition of a second vasopressor (norepinephrine or vasopressin) if adequate vascular tone cannot be restored by a monotherapy with either norepinephrine or vasopressin and to consider using vasopressin as a first-line vasopressor or to add vasopressin to norepinephrine in cardiac surgical patients with pulmonary hypertension or right-sided heart dysfunction.
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http://dx.doi.org/10.1053/j.jvca.2020.11.032DOI Listing
April 2021

Prostanoid Receptor Subtypes and Its Endogenous Ligands with Processing Enzymes within Various Types of Inflammatory Joint Diseases.

Mediators Inflamm 2020 12;2020:4301072. Epub 2020 Nov 12.

Department of Anaesthesiology and Intensive Care Medicine, Charité-University Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Benjamin Franklin, Berlin, Germany.

A complex inflammatory process mediated by proinflammatory cytokines and prostaglandins commonly occurs in the synovial tissue of patients with joint trauma (JT), osteoarthritis (OA), and rheumatoid arthritis (RA). This study systematically investigated the distinct expression profile of prostaglandin E2 (PGE2), its processing enzymes (COX-2), and microsomal PGES-1 (mPGES-1) as well as the corresponding prostanoid receptor subtypes (EP1-4) in representative samples of synovial tissue from these patients (JT, OA, and RA). Quantitative TaqMan®-PCR and double immunofluorescence confocal microscopy of synovial tissue determined the abundance and exact immune cell types expressing these target molecules. Our results demonstrated that PGE2 and its processing enzymes COX-2 and mPGES-1 were highest in the synovial tissue of RA, followed by the synovial tissue of OA and JT patients. Corresponding prostanoid receptor, subtypes EP3 were highly expressed in the synovium of RA, followed by the synovial tissue of OA and JT patients. These proinflammatory target molecules were distinctly identified in JT patients mostly in synovial granulocytes, in OA patients predominantly in synovial macrophages and fibroblasts, whereas in RA patients mainly in synovial fibroblasts and plasma cells. Our findings show a distinct expression profile of EP receptor subtypes and PGE2 as well as the corresponding processing enzymes in human synovium that modulate the inflammatory process in JT, OA, and RA patients.
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http://dx.doi.org/10.1155/2020/4301072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676943PMC
November 2020

Current Anesthetic Care of Patients Undergoing Transcatheter Aortic Valve Replacement in Europe: Results of an Online Survey.

J Cardiothorac Vasc Anesth 2021 Jun 7;35(6):1737-1746. Epub 2020 Sep 7.

Department of Anesthesiology and Intensive Care Medicine, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. Electronic address:

Objectives: Transcatheter aortic valve replacement (TAVR) has become an alternative treatment for patients with symptomatic aortic stenosis not eligible for surgical valve replacement due to a high periprocedural risk or comorbidities. However, there are several areas of debate concerning the pre-, intra- and post-procedural management. The standards and management for these topics may vary widely among different institutions and countries in Europe.

Design: Structured web-based, anonymized, voluntary survey.

Setting: Distribution of the survey via email among members of the European Association of Cardiothoracic Anaesthesiology working in European centers performing TAVR between September and December 2018.

Participants: Physicians.

Measurements And Main Results: The survey consisted of 25 questions, including inquiries regarding number of TAVR procedures, technical aspects of TAVR, medical specialities present, preoperative evaluation of TAVR candidates, anesthesia regimen, as well as postoperative management. Seventy members participated in the survey. Reporting members mostly performed 151-to-300 TAVR procedures per year. In 90% of the responses, a cardiologist, cardiac surgeon, cardiothoracic anesthesiologist, and perfusionist always were available. Sixty-six percent of the members had a national curriculum for cardiothoracic anesthesia. Among 60% of responders, the decision for TAVR was made preoperatively by an interdisciplinary heart team with a cardiothoracic anesthesiologist, yet in 5 countries an anesthesiologist was not part of the decision-making. General anesthesia was employed in 40% of the responses, monitored anesthesia care in 44%, local anesthesia in 23%, and in 49% all techniques were offered to the patients. In cases of general anesthesia, endotracheal intubation almost always was performed (91%). It was stated that norepinephrine was the vasopressor of choice (63% of centers). Transesophageal echocardiography guiding, whether performed by an anesthesiologist or cardiologist, was used only ≤30%. Postprocedurally, patients were transferred to an intensive care unit by 51.43% of the respondents with a reported nurse-to-patient ratio of 1:2 or 1:3, to a post-anesthesia care unit by 27.14%, to a postoperative recovery room by 11.43%, and to a peripheral ward by 10%.

Conclusion: The results indicated that requirements and quality indicators (eg, periprocedural anesthetic management, involvement of the anesthesiologist in the heart team, etc) for TAVR procedures as published within the European guideline are largely, yet still not fully implemented in daily routine. In addition, anesthetic TAVR management also is performed heterogeneously throughout Europe.
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http://dx.doi.org/10.1053/j.jvca.2020.09.088DOI Listing
June 2021

SARS-CoV-2-specific T cell responses and correlations with COVID-19 patient predisposition.

J Clin Invest 2020 12;130(12):6477-6489

Department for General, Visceral and Vascular Surgery.

Coronavirus disease 2019 (COVID-19) has emerged as a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). So far, viral targets of cellular immunity and factors determining successful mounting of T cell responses are poorly defined. We therefore analyzed cellular responses to membrane, nucleocapsid, and spike proteins in individuals suffering from moderate or severe infection and in individuals who recovered from mild disease. We demonstrate that the CoV-2-specific CD4+ T helper cell response is directed against all 3 proteins with comparable magnitude, ex vivo proliferation, and portions of responding patients. However, individuals who died were more likely to have not mounted a cellular response to the proteins. Higher patient age and comorbidity index correlated with increased frequencies of CoV-2-specific CD4+ T cells, harboring higher portions of IL-2-secreting, but lower portions of IFN-γ-secreting, cells. Diminished frequencies of membrane protein-reactive IFN-γ+ T cells were particularly associated with higher acute physiology and chronic health evaluation II scores in patients admitted to intensive care. CoV-2-specific T cells exhibited elevated PD-1 expression in patients with active disease as compared with those individuals who recovered from previous mild disease. In summary, our data suggest a link between individual patient predisposition with respect to age and comorbidity and impairment of CoV-2-specific Th1-type cellular immunity, thereby supporting a concept of altered T cell function in at-risk patients.
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http://dx.doi.org/10.1172/JCI140965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685725PMC
December 2020

General Versus Local Anesthesia With Conscious Sedation in Transcatheter Aortic Valve Implantation: The Randomized SOLVE-TAVI Trial.

Circulation 2020 10 21;142(15):1437-1447. Epub 2020 Aug 21.

Leipzig Heart Institute, Germany (H.T., H.-J.F., G.S., P.H., P.L., M.A.-W., M.S., D.H., M.B., J.E., Y.R., A.-K.F., S.D.).

Background: In clinical practice, local anesthesia with conscious sedation (CS) is performed in roughly 50% of patients undergoing transcatheter aortic valve replacement. However, no randomized data assessing the safety and efficacy of CS versus general anesthesia (GA) are available.

Methods: The SOLVE-TAVI (Comparison of Second-Generation Self-Expandable Versus Balloon-Expandable Valves and General Versus Local Anesthesia in Transcatheter Aortic Valve Implantation) trial is a multicenter, open-label, 2×2 factorial, randomized trial of 447 patients with aortic stenosis undergoing transfemoral transcatheter aortic valve replacement comparing CS versus GA. The primary efficacy end point was powered for equivalence (equivalence margin 10% with significance level 0.05) and consisted of the composite of all-cause mortality, stroke, myocardial infarction, infection requiring antibiotic treatment, and acute kidney injury at 30 days.

Results: The primary composite end point occurred in 27.2% of CS and 26.4% of GA patients (rate difference, 0.8 [90% CI, -6.2 to 7.8]; =0.015). Event rates for the individual components were as follows: all-cause mortality, 3.2% versus 2.3% (rate difference, 1.0 [90% CI, -2.9 to 4.8]; <0.001); stroke, 2.4% versus 2.8% (rate difference, -0.4 [90% CI, -3.8 to 3.8]; <0.001); myocardial infarction, 0.5% versus 0.0% (rate difference, 0.5 [90% CI, -3.0 to 3.9]; <0.001), infection requiring antibiotics 21.1% versus 22.0% (rate difference, -0.9 [90% CI, -7.5 to 5.7]; =0.011); acute kidney injury, 9.0% versus 9.2% (rate difference, -0.2 [90% CI, -5.2 to 4.8]; =0.0005). There was a lower need for inotropes or vasopressors with CS (62.8%) versus GA (97.3%; rate difference, -34.4 [90% CI, -41.0 to -27.8]).

Conclusions: Among patients with aortic stenosis undergoing transfemoral transcatheter aortic valve replacement, use of CS compared with GA resulted in similar outcomes for the primary efficacy end point. These findings suggest that CS can be safely applied for transcatheter aortic valve replacement. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02737150.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.046451DOI Listing
October 2020

CytoResc - "CytoSorb" Rescue for critically ill patients undergoing the COVID-19 Cytokine Storm: A structured summary of a study protocol for a randomized controlled trial.

Trials 2020 Jun 26;21(1):577. Epub 2020 Jun 26.

Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Objectives: Approximately 8 - 10 % of COVID-19 patients present with a serious clinical course and need for hospitalization, 8% of hospitalized patients need ICU-treatment. Currently, no causal therapy is available and treatment is purely supportive. The main reason for death in critically ill patients is acute respiratory failure. However, in a number of patients a severe hyperinflammatory response with excessively elevated proinflammatory cytokines causes vasoplegic shock resistant to vasopressor therapy. A new polystyrene-based hemoadsorber (CytoSorb®, Cytosorbents Inc., New Jersey, USA) has been shown to adsorb effectively cytokines and other middle molecular weight toxins this way reducing their blood concentrations. This has been routinely used in clinical practice in the EU for other conditions where a cytokine storm occurs and an observational study has just been completed on COVID-19 patients. We hypothesized that the extracorporeal elimination of cytokines in critically ill COVID-19 patients with suspected hyperinflammation and shock may stabilize hemodynamics and improve outcome. The primary endpoint is time until resolution of vasoplegic shock, which is a well implemented, clinically relevant endpoint in critical care studies.

Trial Design: Phase IIb, multicenter, prospective, open-label, randomized, 1:1 parallel group pilot study comparing the additional use of "CytoSorb" to standard of care without "CytoSorb".

Participants: Patients are recruited from the Intensive Care Units (ICUs) of 7 participating centers in Germany (approximately 10 ICUs). All patients aged 18- 80 with positive polymerase chain reaction (PCR) test for SARS-CoV-2, a C-reactive protein (CRP) ≥ 100 mg/l, a Procalcitonin (PCT) < 2 ng/l, and suspected cytokine storm defined via a vasoplegic shock (Norepinephrine > 0.2 μg/min/kg to achieve a Mean Arterial Pressure ≥ 65mmHg). Patients are included irrespective of indication for renal replacement therapy. Suspected or proven bacterial cause for vasoplegic shock is a contraindication.

Intervention And Comparator: Within 24 hours after meeting the inclusion criteria patients will be randomized to receive either standard of care or standard of care and additional "CytoSorb" therapy via a shaldon catheter for 3-7 days. Filter exchange is done every 24 hours. If patients receive antibiotics, an additional dose of antibiotics is administered after each change of "CytoSorb" filter in order to prevent underdosing due to "CytoSorb" treatment.

Main Outcomes: Primary outcome is time to resolution of vasoplegic shock (defined as no need for vasopressors for at least 8 hours in order to sustain a MAP ≥ 65mmHg) in days. Secondary outcomes are 7 day mortality after fulfilling the inclusion criteria, mortality until hospital discharge, Interleukin-6 (IL-6) measurement on day 1 and 3, need for mechanical ventilation, duration of mechanical ventilation, duration of ICU-stay, catecholamine dose on day 1/2/3 after start of "CytoSorb" and acute kidney injury.

Randomization: An electronic randomization will be performed using the study software secuTrial® administered by the Clinical Study Center (CSC) of the Charité - Universitätsmedizin Berlin, Germany. Randomization is done in blocks by 4 stratified by including center.

Blinding (masking): The trial will be non-blinded for the clinicians and patients. The statistician will receive a blinded data set, so that all analyses will be conducted blinded.

Numbers To Be Randomized (sample Size): As this is a pilot study with the goal to examine the feasibility of the study design as well as the intervention effect, no formal sample size calculation was conducted. A total number of approximately 80-100 patients is planned (40-50 patients per group). Safety assessment is done after the inclusion of each 10 patients per randomization group.

Trial Status: Please see the study protocol version from April 24 2020. Recruitment of patients is still pending.

Trial Registration: The study was registered on April 27 2020 in the German Registry of Clinical Trials (DRKS) under the number DRKS00021447.

Full Protocol: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
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http://dx.doi.org/10.1186/s13063-020-04501-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316574PMC
June 2020

Improving quality of care in less than 1 min: a prospective intervention study on postoperative handovers to the ICU/PACU.

BMJ Open Qual 2020 06;9(2)

Department of Anesthesiology and Operative Intensive Care Medicine, Campus Virchow Klinikum and Charité Centrum Mitte (CVK/CCM), Charité Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin, Institute of Health, Berlin, Germany.

Purpose: Standardisation of the postoperative handover process via checklists, trainings or procedural changes has shown to be effective in reducing information loss. The clinical friction of implementing these measures has received little attention. We developed and evaluated a visual aid (VA) and >1 min in situ training intervention to improve the quality of postoperative handovers to the intensive care unit (ICU) and postoperative care unit.

Materials And Methods: The VA was constructed and implemented via a brief (<1 min) training of anaesthesiologic staff during the operation. Ease of implementation was measured by amount of information transferred, handover duration and handover structure. 50 handovers were audio recorded before intervention and 50 after intervention. External validity was evaluated by blinded assessment of the recordings by experienced anaesthesiologists (n=10) on 10-point scales.

Results: The brief intervention resulted in increased information transfer (9.0-14.8 items, (98)=7.44, p<0.0001, Cohen's d=1.59) and increased handover duration (81.3-192.8 s, (98)=6.642, p=0.013, Cohen's d=1.33) with no loss in structure (1.60-1.56, (98)=0.173, p=0.43). Blinded assessment on 10-point scales by experienced anaesthesiologists showed improved overall handover quality from 7.1 to 7.8 ((98)=1.89, p=0.031, Cohen's d=0.21) and improved completeness of information ((98)=2.42, p=0.009, Cohen's d=0.28) from 7.3 to 8.3.

Conclusions: An intervention consisting of a simple VA and <1 min instructions significantly increased overall quality and amount of information transferred during ICU/postanaesthetic care unit handovers.
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http://dx.doi.org/10.1136/bmjoq-2019-000668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311016PMC
June 2020

Studying the pathophysiology of coronavirus disease 2019: a protocol for the Berlin prospective COVID-19 patient cohort (Pa-COVID-19).

Infection 2020 Aug 13;48(4):619-626. Epub 2020 Jun 13.

Division of Gastroenterology, Infectious Diseases, Rheumatology, Medical Department, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Purpose: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide causing a global health emergency. Pa-COVID-19 aims to provide comprehensive data on clinical course, pathophysiology, immunology and outcome of COVID-19, to identify prognostic biomarkers, clinical scores, and therapeutic targets for improved clinical management and preventive interventions.

Methods: Pa-COVID-19 is a prospective observational cohort study of patients with confirmed SARS-CoV-2 infection treated at Charité - Universitätsmedizin Berlin. We collect data on epidemiology, demography, medical history, symptoms, clinical course, and pathogen testing and treatment. Systematic, serial blood sampling will allow deep molecular and immunological phenotyping, transcriptomic profiling, and comprehensive biobanking. Longitudinal data and sample collection during hospitalization will be supplemented by long-term follow-up.

Results: Outcome measures include the WHO clinical ordinal scale on day 15 and clinical, functional, and health-related quality-of-life assessments at discharge and during follow-up. We developed a scalable dataset to (i) suit national standards of care, (ii) facilitate comprehensive data collection in medical care facilities with varying resources, and (iii) allow for rapid implementation of interventional trials based on the standardized study design and data collection. We propose this scalable protocol as blueprint for harmonized data collection and deep phenotyping in COVID-19 in Germany.

Conclusion: We established a basic platform for harmonized, scalable data collection, pathophysiological analysis, and deep phenotyping of COVID-19, which enables rapid generation of evidence for improved medical care and identification of candidate therapeutic and preventive strategies. The electronic database accredited for interventional trials allows fast trial implementation for candidate therapeutic agents.

Trial Registration: Registered at the German registry for clinical studies (DRKS00021688).
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http://dx.doi.org/10.1007/s15010-020-01464-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293426PMC
August 2020

Neuronal aldosterone elicits a distinct genomic response in pain signaling molecules contributing to inflammatory pain.

J Neuroinflammation 2020 Jun 12;17(1):183. Epub 2020 Jun 12.

Department of Anaesthesiology and Intensive Care Medicine, Charité - University Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Benjamin Franklin, Berlin, Germany.

Background: Recently, mineralocorticoid receptors (MR) were identified in peripheral nociceptive neurons, and their acute antagonism was responsible for immediate and short-lasting (non-genomic) antinociceptive effects. The same neurons were shown to produce the endogenous ligand aldosterone by the enzyme aldosterone synthase.

Methods: Here, we investigate whether endogenous aldosterone contributes to inflammation-induced hyperalgesia via the distinct genomic regulation of specific pain signaling molecules in an animal model of Freund's complete adjuvant (FCA)-induced hindpaw inflammation.

Results: Chronic intrathecal application of MR antagonist canrenoate-K (over 4 days) attenuated nociceptive behavior in rats with FCA hindpaw inflammation suggesting a tonic activation of neuronal MR by endogenous aldosterone. Consistently, double immunofluorescence confocal microscopy showed abundant co-localization of MR with several pain signaling molecules such as TRPV1, CGRP, Nav1.8, and trkA whose enhanced expression of mRNA and proteins during inflammation was downregulated following i.t. canrenoate-K. More importantly, inhibition of endogenous aldosterone production in peripheral sensory neurons by continuous intrathecal delivery of a specific aldosterone synthase inhibitor prevented the inflammation-induced enhanced transcriptional expression of TRPV1, CGRP, Nav1.8, and trkA and subsequently attenuated nociceptive behavior. Evidence for such a genomic effect of endogenous aldosterone was supported by the demonstration of an enhanced nuclear translocation of MR in peripheral sensory dorsal root ganglia (DRG) neurons.

Conclusion: Taken together, chronic inhibition of local production of aldosterone by its processing enzyme aldosterone synthase within peripheral sensory neurons may contribute to long-lasting downregulation of specific pain signaling molecules and may, thus, persistently reduce inflammation-induced hyperalgesia.
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http://dx.doi.org/10.1186/s12974-020-01864-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291517PMC
June 2020

Aldosterone Synthase in Peripheral Sensory Neurons Contributes to Mechanical Hypersensitivity during Local Inflammation in Rats.

Anesthesiology 2020 04;132(4):867-880

From the Department of Anaesthesiology and Intensive Care Medicine, Charite Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Berlin, Germany (D.M.M., M. Shaqura, X.L., S.T., M. Schäfer, S.A.M.) Department of Zoology, Faculty of Science, Aswan University, Aswan, Egypt (D.M.M.) the Departments of Anatomy (M. Shakibaei) Anaesthesiology (A.B.), Ludwig Maximilian University of Munich, Munich, Germany.

Background: Recent emerging evidence suggests that extra-adrenal synthesis of aldosterone occurs (e.g., within the failing heart and in certain brain areas). In this study, the authors investigated evidence for a local endogenous aldosterone production through its key processing enzyme aldosterone synthase within peripheral nociceptive neurons.

Methods: In male Wistar rats (n = 5 to 8 per group) with Freund's complete adjuvant hind paw inflammation, the authors examined aldosterone, aldosterone synthase, and mineralocorticoid receptor expression in peripheral sensory neurons using quantitative reverse transcriptase-polymerase chain reaction, Western blot, immunohistochemistry, and immunoprecipitation. Moreover, the authors explored the nociceptive behavioral changes after selective mineralocorticoid receptor antagonist, canrenoate-K, or specific aldosterone synthase inhibitor application.

Results: In rats with Freund's complete adjuvant-induced hind paw inflammation subcutaneous and intrathecal application of mineralocorticoid receptor antagonist, canrenoate-K, rapidly and dose-dependently attenuated nociceptive behavior (94 and 48% reduction in mean paw pressure thresholds, respectively), suggesting a tonic activation of neuronal mineralocorticoid receptors by an endogenous ligand. Indeed, aldosterone immunoreactivity was abundant in peptidergic nociceptive neurons of dorsal root ganglia and colocalized predominantly with its processing enzyme aldosterone synthase and mineralocorticoid receptors. Moreover, aldosterone and its synthesizing enzyme were significantly upregulated in peripheral sensory neurons under inflammatory conditions. The membrane mineralocorticoid receptor consistently coimmunoprecipitated with endogenous aldosterone, confirming a functional link between mineralocorticoid receptors and its endogenous ligand. Importantly, inhibition of endogenous aldosterone production in peripheral sensory neurons by a specific aldosterone synthase inhibitor attenuated nociceptive behavior after hind paw inflammation (a 32% reduction in paw pressure thresholds; inflammation, 47 ± 2 [mean ± SD] vs. inflammation + aldosterone synthase inhibitor, 62 ± 2).

Conclusions: Local production of aldosterone by its processing enzyme aldosterone synthase within peripheral sensory neurons contributes to ongoing mechanical hypersensitivity during local inflammation via intrinsic activation of neuronal mineralocorticoid receptors.
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http://dx.doi.org/10.1097/ALN.0000000000003127DOI Listing
April 2020

Routine frailty assessment predicts postoperative complications in elderly patients across surgical disciplines - a retrospective observational study.

BMC Anesthesiol 2019 11 7;19(1):204. Epub 2019 Nov 7.

Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, D-10117, Berlin, Germany.

Background: Frailty is a frequent and underdiagnosed functional syndrome involving reduced physiological reserves and an increased vulnerability against stressors, with severe individual and socioeconomic consequences. A routine frailty assessment was implemented at our preoperative anaesthesia clinic to identify patients at risk.

Objective: This study examines the relationship between frailty status and the incidence of in-hospital postoperative complications in elderly surgical patients across several surgical disciplines.

Design: Retrospective observational analysis.

Setting: Single center, major tertiary care university hospital. Data collection took place between June 2016 and March 2017.

Patients: Patients 65 years old or older were evaluated for frailty using Fried's 5-point frailty assessment prior to elective non-cardiac surgery. Patients were classified into non-frail (0 criteria, reference group), pre-frail (1-2 positive criteria) and frail (3-5 positive criteria) groups.

Main Outcome Measures: The incidence of postoperative complications was assessed until discharge from the hospital, using the roster from the National VA Surgical Quality Improvement Program. Propensity score matching and logistic regression analysis were performed.

Results: From 1186 elderly patients, 46.9% were classified as pre-frail (n = 556), and 11.4% as frail (n = 135). The rate of complications were significantly higher in the pre-frail (34.7%) and frail groups (47.4%), as compared to the non-frail group (27.5%). Similarly, length of stay (non-frail: 5.0 [3.0;7.0], pre-frail: 7.0 [3.0;9.0], frail 8.0 [4.5;12.0]; p < 0.001) and discharges to care facilities (non-frail:1.6%, pre-frail: 7.4%, frail: 17.8%); p < 0.001) were significantly associated with frailty status. After propensity score matching and logistic regression analysis, the risk for developing postoperative complications was approximately two-fold for pre-frail (OR 1.78; 95% CI 1.04-3.05) and frail (OR 2.08; 95% CI 1.21-3.60) patients.

Conclusions: The preoperative frailty assessment of elderly patients identified pre-frail and frail subgroups to have the highest rate of postoperative complications, regardless of age, surgical discipline, and surgical risk. Significantly increased length of hospitalisation and discharges to care facilities were also observed. Implementation of routine frailty assessments appear to be an effective tool in identifying patients with increased risk. Now future studies are needed to investigate whether patients benefit from optimization of patient counselling, process planning, and risk reduction protocols based on the application of risk stratification.
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http://dx.doi.org/10.1186/s12871-019-0880-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839249PMC
November 2019

[Estimation of Preload Dependence in Intensive Care - Step by Step].

Dtsch Med Wochenschr 2019 03 5;144(5):340-345. Epub 2019 Mar 5.

The determination of the cardiac preload is still a challenge for intensive care physicians. In addition to clinical assessment, both non-invasive and invasive methods exist for evaluating fluid responsiveness. The following article demonstrates one possible approach for systematic assessment of fluid responsiveness using a practical algorithm for critical care patients.
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http://dx.doi.org/10.1055/a-0665-6581DOI Listing
March 2019

Identification of mineralocorticoid and glucocorticoid receptors on peripheral nociceptors: Translation of experimental findings from animal to human biology.

Brain Res 2019 06 13;1712:180-187. Epub 2019 Feb 13.

Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum, Berlin, Germany.

Evidence is accumulating that activation of mineralocorticoid (MR) and glucocorticoid (GR) receptors on peripheral sensory neurons modulates pain sensation. While the expression and exact anatomical localization of MR and GR in the various subpopulations of peripheral sensory neurons has been shown in animals, it is still unknown for the human skin. Therefore, we aimed to identify MR and GR mRNA and protein as well as the exact subpopulations of sensory neurons in human versus rat skin. Tissue samples from rat and human skin were subjected to RT-PCR, Western blot and double immunofluorescence confocal analysis of MR and GR with the neuronal markers calcitonin gene-related peptide (CGRP), neurofilament 200 (NF200) and tyrosine hydroxylase (TH). Using RT-PCR we were able to isolate MR as well as GR specific transcripts from human skin. Consistently, Western blot analysis identified MR- as well as GR- specific protein bands at the expected molecular weights of 110 and 87 kD, respectively. Double immunofluorescence confocal microscopy of human skin revealed that MR predominantly colocalized with calcitonin-gene-related peptide (CGRP)-immunoreactive (IR) nociceptive neurons - similar to rat skin - underscoring a pivotal role for MR in the modulation of pain. The majority of GR-immmunoreactivity was localized in peripheral peptidergic CGRP-IR sensory nerve fibers, but in addition on TH-IR sympathetic postganglionic, and NF200-IR myelinated mechanoreceptive nerve fibers, both within human and rat skin. Moreover, GR but not MR were localized in keratinocytes of the epidermal layer of human and rat skin. Overall, our results indicate considerable overlap in sensory neuron expression of MR and GR in humans and rats endorsing a common systems approach in mammals that may modulate the transmission of sensory information by MR and GR activation.
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http://dx.doi.org/10.1016/j.brainres.2019.02.015DOI Listing
June 2019

Liberal transfusion strategy to prevent mortality and anaemia-associated, ischaemic events in elderly non-cardiac surgical patients - the study design of the LIBERAL-Trial.

Trials 2019 Feb 4;20(1):101. Epub 2019 Feb 4.

Department of Anaesthesiology and Intensive Care Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

Background: Perioperative anaemia leads to impaired oxygen supply with a risk of vital organ ischaemia. In healthy and fit individuals, anaemia can be compensated by several mechanisms. Elderly patients, however, have less compensatory mechanisms because of multiple co-morbidities and age-related decline of functional reserves. The purpose of the study is to evaluate whether elderly surgical patients may benefit from a liberal red blood cell (RBC) transfusion strategy compared to a restrictive transfusion strategy.

Methods: The LIBERAL Trial is a prospective, randomized, multicentre, controlled clinical phase IV trial randomising 2470 elderly (≥ 70 years) patients undergoing intermediate- or high-risk non-cardiac surgery. Registered patients will be randomised only if Haemoglobin (Hb) reaches ≤9 g/dl during surgery or within 3 days after surgery either to the LIBERAL group (transfusion of a single RBC unit when Hb ≤ 9 g/dl with a target range for the post-transfusion Hb level of 9-10.5 g/dl) or the RESTRICTIVE group (transfusion of a single RBC unit when Hb ≤ 7.5 g/dl with a target range for the post-transfusion Hb level of 7.5-9 g/dl). The intervention per patient will be followed until hospital discharge or up to 30 days after surgery, whichever occurs first. The primary efficacy outcome is defined as a composite of all-cause mortality, acute myocardial infarction, acute ischaemic stroke, acute kidney injury (stage III), acute mesenteric ischaemia and acute peripheral vascular ischaemia within 90 days after surgery. Infections requiring iv antibiotics with re-hospitalisation are assessed as important secondary endpoint. The primary endpoint will be analysed by logistic regression adjusting for age, cancer surgery (y/n), type of surgery (intermediate- or high-risk), and incorporating centres as random effect.

Discussion: The LIBERAL-Trial will evaluate whether a liberal transfusion strategy reduces the occurrence of major adverse events after non-cardiac surgery in the geriatric population compared to a restrictive strategy within 90 days after surgery.

Trial Registration: ClinicalTrials.gov (identifier: NCT03369210 ).
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http://dx.doi.org/10.1186/s13063-019-3200-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360712PMC
February 2019

Genome-wide association study of myocardial infarction, atrial fibrillation, acute stroke, acute kidney injury and delirium after cardiac surgery - a sub-analysis of the RIPHeart-Study.

BMC Cardiovasc Disord 2019 01 24;19(1):26. Epub 2019 Jan 24.

Department of Anaesthesiology, University Hospital Wuerzburg, Wuerzburg, Germany.

Background: The aim of our study was the identification of genetic variants associated with postoperative complications after cardiac surgery.

Methods: We conducted a prospective, double-blind, multicenter, randomized trial (RIPHeart). We performed a genome-wide association study (GWAS) in 1170 patients of both genders (871 males, 299 females) from the RIPHeart-Study cohort. Patients undergoing non-emergent cardiac surgery were included. Primary endpoint comprises a binary composite complication rate covering atrial fibrillation, delirium, non-fatal myocardial infarction, acute renal failure and/or any new stroke until hospital discharge with a maximum of fourteen days after surgery.

Results: A total of 547,644 genotyped markers were available for analysis. Following quality control and adjustment for clinical covariate, one SNP reached genome-wide significance (PHLPP2, rs78064607, p = 3.77 × 10) and 139 (adjusted for all other outcomes) SNPs showed promising association with p < 1 × 10 from the GWAS.

Conclusions: We identified several potential loci, in particular PHLPP2, BBS9, RyR2, DUSP4 and HSPA8, associated with new-onset of atrial fibrillation, delirium, myocardial infarction, acute kidney injury and stroke after cardiac surgery.

Trial Registration: The study was registered with ClinicalTrials.gov NCT01067703, prospectively registered on 11 Feb 2010.
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http://dx.doi.org/10.1186/s12872-019-1002-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345037PMC
January 2019

Local infiltration anaesthesia versus sciatic nerve and adductor canal block for fast-track knee arthroplasty: A randomised controlled clinical trial.

Eur J Anaesthesiol 2019 04;36(4):255-263

Background: Local infiltration anaesthesia (LIA) was introduced as an innovative analgesic procedure for enhanced recovery after primary total knee arthroplasty (TKA). However, LIA has never been compared with analgesia based on an adductor canal catheter and a single-shot sciatic nerve block.

Objective: To evaluate two analgesic regimens for TKA comparing mobility, postoperative pain and patient satisfaction.

Design: Two-group randomised, controlled clinical trial.

Setting: Charité-Universitätsmedizin Berlin, Campus Charité Mitte, Germany between April and August 2017.

Patients: Adults undergoing primary TKA under general anaesthesia were eligible for study participation. Exclusion criteria were heart insufficiency (New York Heart Association class >2), liver insufficiency (Child Pugh Score >B), evidence of diabetic polyneuropathy, severe obesity (BMI > 40 kg m), chronic opioid therapy for more than 3 months before scheduled surgery and allergy to local anaesthetics.

Interventions: Nerve block patients group (n=20) underwent surgery with two ultrasound-guided regional anaesthesia blocks: a single-shot sciatic nerve block with 20 ml of ropivacaine 0.75% combined with an adductor canal block with a catheter placed for less than 4 days with an infusion of ropivacaine 0.2% at a rate of 6 ml h. LIA patients (LIA group, n=20) received LIA of the knee capsule at the end of surgery with 150 ml of ropivacaine 0.2%.

Main Outcome Measures: The primary endpoint was postoperative time to patient mobilisation (ability to walk) on the ward.

Results: Baseline characteristics were similar in each study group. Patients in both groups were mobilised to walk after TKA in similar time frames (LIA 24.0 h versus nerve block 27.1 h, 95% CI of difference -9.6 to 3.3 h). Maximum postoperative pain scores on exertion were higher in LIA patients with a mean 1.3 of 10 numerical rating scale points (95% CI 0.3 to 2.3, P = 0.010) as were intra-operative opioid requirements (LIA median 107 [IQR 100 to 268] mg versus nerve block median 78 [60 to 98] mg, P < 0.001). Patient satisfaction, postoperative oral morphine-equivalents and resting pain levels were comparable between groups. Anaesthesia induction time was reduced in LIA patients (LIA 10 min versus nerve block 35 min, 95% CI of difference 13 to 38 min, P < 0.001).

Conclusion: Both analgesic regimens allow early mobilisation after TKA with high patient satisfaction. LIA shortened peri-operative time. Further research is required to optimise especially pain control during the later postoperative period with LIA.

Clinical Trial Registration: Clinicaltrials.gov identifier NCT03114306.
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http://dx.doi.org/10.1097/EJA.0000000000000929DOI Listing
April 2019
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