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Background Hypercoagulability in Coronavirus Disease 2019 (COVID-19) causes deep vein thrombosis and pulmonary embolism necessitating systemic anticoagulation. Case reports of intracerebral hemorrhages in ventilated COVID-19 patients warrant precaution. It is unclear, however, if COVID-19 patients with acute respiratory distress syndrome (ARDS) with or without veno-venous extracorporeal membrane oxygenation therapy (VV-ECMO) have more intracerebral hemorrhages (ICH) compared to other ARDS patients. Methods We conducted a retrospective observational single-center study enrolling all patients with ARDS from 01/2018 to 05/2020. PCR-positive SARS-CoV-2 patients with ARDS were allocated to the COVID-19 group. Propensity score matching was performed for age, VV-ECMO, and bleeding risk. Results A total of 163 patients with moderate or severe ARDS were identified, 47 (28.8%) in the COVID-19 group, and 116 (71.2%) in the non-COVID-19 group. In 63/163 cases (38.7%), VV-ECMO therapy was required. The ICU survival was 52.8%. COVID-19 patients were older, more often male, and exhibited a lower SOFA score, but the groups showed similar rates of VV-ECMO therapy. Treatments with antiplatelet agents (p = 0.043) and therapeutic anticoagulation (p = 0.028) were significantly more frequent in the COVID-19 patients. ICH was detected in 22 patients (13.5%) with no statistical difference between the groups (11.2 vs. 19.1% without and with SARS-CoV-2, respectively, p = 0.21). Propensity score matching confirmed similar rates of ICH in both groups (12.8 vs. 19.1% without and with SARS-CoV-2, respectively, p = 0.57), thus leveling out possible confounders. Conclusions Intracerebral hemorrhage was detected in every tenth patient with ARDS. Despite statistically higher rates of antiplatelet therapy and therapeutic anticoagulation in COVID-19 patients, we found a similar rate of ICH in patients with ARDS due to COVID-19 compared to other causes of ARDS.

Background There is limited information about the long-term outcome of patients suffering from acute respiratory distress syndrome (ARDS) supported with veno-venous extracorporeal membrane oxygenation (VV ECMO). Most studies focused on short- to mid-term follow-up. We aimed to investigate long-term survival and health-related quality of life (HRQL) in these patients. Methods We report retrospective data from a single-centre registry of patients with severe ARDS treated with VV ECMO at the Interdisciplinary Medical Intensive Care Unit at the Medical Centre, University of Freiburg, Germany, between 10/2010 and 06/2019. Follow-up data of all patients that survived the index hospitalisation were collected by telephone interviews from 02/2020 till 09/2020. Long-term survival, HRQL (Short-Form Health Survey-36 (SF-36), St. Georges Respiratory Questionnaire (SGRQ), Hospital Anxiety and Depression Scale (HADS)) and the return to work rate were documented. Results In total, 289 patients were treated with VV ECMO during the study period (median age 55 years, 67% males, hospital survival 45%). After a median duration of 3.9 years, follow-up assessment was complete in 94 of 129 hospital survivors (73%). Fifty-three patients completed the HRQL assessment. Hospital survivors showed a high 6- and 12-month survival rate (89% and 85%, respectively). Estimated survival rate of those discharged alive from ICU was 68.5% (95%-CI 56.9–80.1%) after 9.7 years. These patients reported high levels of HRQL (median SF-36 total score 73) and only few pulmonary (median SGRQ total score 19) and mental limitations (median HAD-D score 2 and HAD-A score 3). In total, 80% of the patients were able to resume employment. Conclusion This analysis of VV ECMO patients showed favourable long-term survival and high levels of HRQL suggesting promising prospects for VV ECMO survivors. Graphical Abstract

Aim Cardiac arrest is the most serious complication in acute coronary syndromes. Glycoprotein IIb/IIIa inhibitors (GPI) are used in selected acute coronary syndrome patients. If the use of GPI leads to an increase in bleeding events and influences survival in patients after cardiac arrest is unknown. Methods We report retrospective data of a single center registry of patients after successful intra- and out-of-hospital cardiac arrest between 2002 and 2013. Inclusion criteria were survival for at least 6 h and successful percutaneous coronary intervention (PCI) within the first 24 h. Patients treated with other fibrinolytic agents or being supported by an extracorporeal life support system were excluded from the analysis. Results 310 patients were included in our study. 204 received GPI (GPI+), 106 did not (GPI−). Patients in the GPI+ group were significantly younger (62.8 vs. 68.0 years, p

Microbiological sampling is an indispensable targeted antibiotic therapy for critically ill patients. Invasive respiratory sampling by bronchoalveolar lavage (BAL) can be performed to obtain samples from the lower respiratory tract. It is debated as to whether blood markers of infection can predict the outcome of BAL in a medical intensive care unit (ICU). Retrospectively, all ICU patients undergoing BAL from 2009&ndash, 2018 were included. A total of 468 BAL samples from 276 patients (average age 60 years, SAPS2 47, ICU-mortality 41.7%) were analyzed. At the time of BAL, 94.4% patients were mechanically ventilated, 92.9% had suspected pneumonia, 96.2% were on antibiotic therapy and 36.3% were immunocompromised. Relevant bacteria were cultured in 114/468 (24.4%) cases of BAL. Patients with relevant bacteria in the culture had a higher ICU mortality rate (45.6 vs. 40.4%, p = 0.33) and were significantly less likely to be on a steroid (36 vs. 52%, p &lt, 0.01) or antimycotic (14.9 vs. 34.2%, p &lt, 0.01), while procalcitonin (PCT), C-reactive protein (CRP), and white blood cell (WBC) counts were similar. The area under the receiver operating curve (AUC) values for positive culture and PCT, CRP and WBC counts were low (0.53, 0.54 and 0.51, respectively). In immunocompromised patients, AUC values were higher (0.65, 0.57 and 0.61, respectively). Therefore, microbiological cultures by BAL revealed relevant bacteria in 24.4% of samples. Our data, therefore, might suggest that indication for BAL should not be based on blood markers of infection.

Veno‐venous extracorporeal membrane oxygenation (V‐V ECMO) is used to sustain blood oxygenation and decarboxylation in severe acute respiratory distress syndrome (ARDS). It is under debate if V‐V ECMO is as appropriate for coronavirus disease 2019 (Covid‐19) ARDS as it is for influenza. In this retrospective study, we analyzed all patients with confirmed SARS‐CoV‐2 or influenza A/B infection, ARDS and V‐V ECMO, treated at our medical intensive care unit (ICU) between October 2010 and June 2020. Baseline and procedural characteristics as well as survival 30 days after ECMO cannulation were analyzed. A total of 62 V‐V ECMO patients were included (15 with Covid‐19 and 47 with influenza). Both groups had similar baseline characteristics at cannulation. Thirty days after ECMO cannulation, 13.3% of all patients with Covid‐19 were discharged alive from our ICU compared to 44.7% with influenza (P = .03). Patients with Covid‐19 had fewer ECMO‐free days (0 (0‐9.7) days vs. 13.2 (0‐22.1) days; P = .05). Cumulative incidences of 30‐day‐survival showed no significant differences (48.6% in Covid‐19 patients, 63.7% in influenza patients; P = .23). ICU treatment duration was significantly longer in ARDS patients with V‐V ECMO for Covid‐19 compared to influenza. Thirty‐day mortality was higher in Covid‐19, but not significant., Patients with severe Covid‐19 supported with V‐V ECMO are less likely to be discharged from ICU within 30 days after initiation of V‐V ECMO than patients with influenza virus infection and V‐V ECMO. Hospital mortality was higher in patients with Covid‐19, but not significant.

Our recent study detected the expression of a tissue Renin-Angiotensin System (tRAS) in human intervertebral discs (IVDs). The present study sought to investigate the impact of angiotensin II receptor type 1 (AGTR1) antagonist losartan on human nucleus pulposus (NP) cell inflammation and degeneration induced by tumor necrosis factor-α (TNF-α). Human NP cells (4 donors, Pfirrmann grade 2-3, 30-37 years old, male) were isolated and expanded. TNF-α (10 ng/mL) was used to induce inflammation and degeneration. We examined the impact of losartan supplementation and measured gene expression of tRAS, anabolic, catabolic, and inflammatory markers in NP cells after 24 h and 72 h of exposure, respectively. T0070907, a PPAR-gamma antagonist, was applied to examine the regulatory pathway of losartan. Losartan (1 mM) significantly impaired TNF-α induced increase of pro-inflammatory (nitric oxide and TNF-α), catabolic (matrix metalloproteinases), and tRAS (AGTR1a and Angiotensin Converting Enzyme) markers. Further, losartan maintained the NP cell phenotype by upregulating aggrecan and downregulating collagen type I expression. In summary, losartan showed anti-inflammatory, anti-catabolic, and positive phenotype modulating effects on human NP cells. These results indicate that tRAS signaling plays an important role in IVD degeneration, and tRAS modulation with losartan could represent a novel therapeutic approach.

Background: SARS-CoV2 can cause pulmonary failure requiring prolonged invasive mechanical ventilation (MV). Lung protective ventilation strategies are recommended in order to minimize ventilator induced lung injury. Whether patients with COVID-19 have the same risk for complications including barotrauma is still unknown. Therefore, we investigated barotrauma in patients with COVID-19 pneumonia requiring prolonged MV. Methods: All patients meeting diagnosis criteria for ARDS according to the Berlin Definition, with PCR positive SARS-CoV2 infection and prolonged mechanical ventilation, defined as ≥2 days, treated at our ARDS referral center between March and April 2020 were included in a retrospective registry analysis. Complications were detected by manual review of all patient data including respiratory data, imaging studies, and patient files. Results: A total of 20 patients with severe COVID-19 pulmonary failure (Overall characteristics: median age: 61 years, female gender 6, median duration of MV 22 days) were analyzed. Eight patients (40%) developed severe barotrauma during MV (after median 18 days, range: 1-32) including pneumothorax (5/20), pneumomediastinum (5/20), pneumopericard (1/20), and extended subcutaneous emphysema (5/20). Median respirator settings 24 hours before barotrauma were: Peak inspiratory pressure (Ppeak) 29 cm H2O (range: 27-35), positive end-expiratory pressure (PEEP) 14 cm H2O (range: 5-24), tidal volume (VT) 5.4ml/kg predicted body weight (range 0.4-8.6), plateau pressure (Pplateau) 27 cm H2O (range: 19-30). Mechanical ventilation was significantly more invasive on several occasions in patients without barotrauma. Conclusion: Barotrauma in COVID-19 induced respiratory failure requiring mechanical ventilation was found in 40% of patients included in this registry. Our data suggest that barotrauma in COVID-19 may occur even when following recommendations for lung protective MV.

Background: Hypercoagulopathy in coronavirus disease 2019 (COVID-19) causing deep vein thrombosis and pulmonary artery embolism necessitate systemic anticoagulation. Case reports of intracerebral hemorrhages in ventilated COVID-19 patients warrant precaution. It is unclear however, if COVID-19 patients with acute respiratory distress syndrome (ARDS) with and without extracorporeal membrane oxygenation therapy (ECMO) have more intracerebral hemorrhages (ICH) compared to other ARDS patients.Methods: We conducted a retrospective observational single center study enrolling all patients with ARDS from 01/2018-05/2020. Patients with ARDS positive for SARS-CoV2 PCR were allocated to the COVID-19 group. Propensity score matching was performed for age, ECMO and risk of bleeding according to HAS-BLED score.Results: A total of 163, mostly severe ARDS patients were identified, 116 (71.2%) without COVID-19 and 47 (28.8%) positive for SARS-CoV-2. The two groups were comparable concerning the main confounders of ICH including age, HAS-BLED score, need for ECMO-therapy as well as anticoagulation levels reported. In 63/163 cases (38.7%), veno-venous ECMO therapy was required and ICU survival was 52.8%. Although HAS-BLED-score on admission was generally low (1.6±1.3), intracerebral hemorrhage was detected in 22 patients (13.5%) with no statistical difference between the groups (11.2 vs. 19.1% with and without SARS-CoV-2, respectively, p=0.21). Propensity score matching confirmed similar intracerebral bleeding rates in both groups (12.8 vs. 19.1% with and without SARS-CoV-2, respectively, p=0.57). Conclusions: Intracerebral hemorrhage was detectable in every tenth patient with ARDS. We found no statistically significant increased bleeding rate in patients with ARDS due to COVID-19 compared to other causes of ARDS.

BackgroundReported mortality of hospitalised COVID-19 patients varies substantially, particularly in critically ill patients. So far COVID-19 in-hospital mortality and modes of death under optimised care conditions have not been systematically studied.MethodsThis retrospective observational monocenter cohort study was performed after implementation of a non-restricted, dynamic tertiary care model at the University Medical Center Freiburg, an experienced ARDS and ECMO referral center. All hospitalised patients with PCR-confirmed SARS-CoV-2 infection were included. The primary endpoint was in-hospital mortality, secondary endpoints included major complications and modes of death. A multistate analysis and a Cox regression analysis for competing risk models were performed. Modes of death were determined by two independent reviewers.ResultsBetween February 25, and May 8, 213 patients were included in the analysis. The median age was 65 years, 129 patients (61%) were male. 70 patients (33%) were admitted to the intensive care unit (ICU), of which 57 patients (81%) received mechanical ventilation and 23 patients (33%) extracorporeal membrane-oxygenation (ECMO) support. According to the multistate model the probability to die within 90 days after COVID-19 onset was 24% in the whole cohort. If the levels of care at time of study entry were accounted for, the probabilities to die were 16% if the patient was initially on a regular ward, 47% if in the ICU and 57% if mechanical ventilation was required at study entry. Age ≥65 years and male sex were predictors for in-hospital death. Predominant complications – as judged by two independent reviewers – determining modes of death were multi-organ failure, septic shock and thromboembolic and hemorrhagic complications.ConclusionIn a dynamic care model COVID-19-related in-hospital mortality remained substantial. In the absence of potent antiviral agents, strategies to alleviate or prevent the identified complications should be investigated. In this context, multistate analyses enable comparison of models-of-care and treatment strategies and allow estimation and allocation of health care resources.RegistrationGerman Clinical Trials Register (identifier DRKS00021775), retrospectively registered June 10, 2020.

Background: Germany reported sufficient intensive care unit (ICU) resources throughout the first wave of coronavirus disease 2019 (COVID-19). The treatment of critically ill COVID-19 patients without rationing may improve the outcome. We therefore analyzed resources allocated to critically ill COVID-19 patients and their outcomes. Methods: Retrospectively, we enrolled SARS-CoV2 PCR positive patients with respiratory failure from 03/08/2020 to 04/08/2020 and followed until 05/28/2020 in the university hospital of Freiburg, Germany. Results: Thirty-four COVID-19 patients were admitted to the ICU in the defined interval with medium age of 67±13 (31-86) years. 6/34 (17.6%) were female. All patients suffered from moderate or severe acute respiratory distress syndrome (ARDS), 91.2% of the patients were intubated and 23.5% required extracorporeal membrane oxygenation (ECMO). Proning was performed in 67.6%, renal replacement therapy (RRT) was required in 35.3%. 96% required more than 20 nursing hours per day. Mean ICU stay was 21±19 (1-81) days. 60-day survival of critically ill COVID-19 patients was 50.0% (17/34). Causes of death were multi-organ failure (52.9%), refractory ARDS (17.6%) and intracerebral hemorrhage (17.6%). Conclusions: Treatment of critically ill COVID-19 patients is protracted and resource intense. In a context without resources shortage, 50% of critically ill COVID-19 survived up to 60 days.

BackgroundA central element in the management of cardiogenic shock (CS) comprises mechanical circulatory support (MCS) systems to maintain cardiac output (CO). This study aims to quantify incidence, outcome and influence of MCS in CS over the last decade.MethodsAll patients hospitalized with CS in a tertiary university hospital in Germany between 2007 and 2017 were identified utilizing the international coding system ICD-10 with code R57.0. Application of MCS was identified via German procedure classification codes (OPS).Results383,983 cases of cardiogenic shock were reported from 2007 to 2017. Patients had a mean age of 71 years and 38.5% were female. The incidence of CS rose by 65.6% from 26,828 cases in 2007 (33.1 per 100,000 person-years, hospital survival 39.2%) to 44,425 cases in 2017 (53.7 per 100,000 person-years, survival 41.2%). In 2007, 16.0% of patients with CS received MCS (4.6 per 100,000 person-years, survival 46.6%), dropping to 13.9% in 2017 (6.6 per 100,000 person-years, survival 38.6%). Type of MCS changed over the years, with decreasing use of the intra-aortic balloon pump (IABP), an increase in extracorporeal membrane oxygenation (VA-ECMO) and percutaneous ventricular assist device (pVAD) usage. Significant differences regarding in-hospital survival were observed between the devices (survival: overall: 40.2%; medical treatment = 39.5%; IABP = 49.5%; pVAD = 36.2%; VA-ECMO = 30.5%;p ConclusionsThe incidence of CS is increasing, but hospital survival remains low. MCS was used in a minority of patients, and the percentage of MCS usage in CS has decreased. The use rates of the competing devices change over time.Graphical Abstract

AIMS Short-QT syndrome 1 (SQT1) is an inherited channelopathy with accelerated repolarization due to gain-of-function in HERG/IKr. Patients develop atrial fibrillation, ventricular tachycardia (VT), and sudden cardiac death with pronounced inter-individual variability in phenotype. We generated and characterized transgenic SQT1 rabbits and investigated electrical remodelling. METHODS AND RESULTS Transgenic rabbits were generated by oocyte-microinjection of β-myosin-heavy-chain-promoter-KCNH2/HERG-N588K constructs. Short-QT syndrome 1 and wild type (WT) littermates were subjected to in vivo ECG, electrophysiological studies, magnetic resonance imaging, and ex vivo action potential (AP) measurements. Electrical remodelling was assessed using patch clamp, real-time PCR, and western blot. We generated three SQT1 founders. QT interval was shorter and QT/RR slope was shallower in SQT1 than in WT (QT, 147.8 ± 2 ms vs. 166.4 ± 3, P

Key Clinical Message This case is a reminder not to overlook rare causes of electrolyte shifts, which may cause reversible changes in pacemaker pacing thresholds.

Purpose Patients hospitalized for infection with SARS-CoV-2 typically present with pneumonia. The respiratory failure is frequently complicated by pulmonary embolism in segmental pulmonary arteries. The distribution of pulmonary embolism in regard to lung parenchymal opacifications has not been investigated yet. Methods All patients with COVID-19 treated at a medical intensive care unit between March 8th and April 15th, 2020 undergoing computed tomography pulmonary angiography (CTPA) were included. All CTPA were assessed by two radiologists independently in respect to parenchymal changes and pulmonary embolism on a lung segment basis. Results Out of 22 patients with severe COVID-19 treated within the observed time period, 16 (age 60.4 ± 10.2 years, 6 female SAPS2 score 49.2 ± 13.9) underwent CT. A total of 288 lung segment were analyzed. Thrombi were detectable in 9/16 (56.3%) patients, with 4.4 ± 2.9 segments occluded per patient and 40/288 (13.9%) segments affected in the whole cohort. Patients with thrombi had significantly worse segmental opacifications in CT (p, Highlights (mandatory) • In COVID-19 respiratory failure, thrombi in segmental pulmonary arteries are common. • All Thrombi detected were localized in opacitated (presumably COVID-19 affected) lung segments. • This might suggest local clot formation.

Aims: Strain rate imaging techniques have been proposed for the detection of ischemic or viable myocardium in coronary artery disease, which is still a challenge in clinical cardiology. This retrospective comparative study analyzed regional left ventricular function and scaring with two-dimensional strain (2DS) in the first 4 to 10 days after acute anterior myocardial infarction (AMI).Methods and results: The study population consisted of 32 AMI patients with an LAD occlusion and successful reperfusion. The assessment of peak systolic 2DS and peak systolic strain rate (SR) was performed segment-oriented with the angle-independent speckle tracking algorithm Velocity Vector Imaging (VVI). The infarcted, adjacent and non-infarcted segments were revealed by late enhancement MRI (LE-MRI), which was used as reference for the comparison with 2DS. The infarcted segments showed a significant decrease of tissue velocities, 2DS and SR in comparison to the non-affected segments.Conclusion: 2DS and SR as assessed by VVI seem to be a suitable approach for echocardiographic quantification of global and regional myocardial function as well as a promising tool for multimodal risk stratification after anterior AMI.

Introduction and Hypothesis: Short QT syndrome is an inherited ion channelopathy with an accelerated cardiac repolarization due to gain-of-function mutations in K+ channel genes. Patients are prone to ventricular tachycardia and sudden cardiac death (SCD). Detailed knowledge about mechanisms of arrhythmogenesis is lacking. We aimed at generating transgenic SQT1 rabbits as novel tool to investigate these mechanisms. Methods: FLAG-HA-tagged HERG-N588K cDNA and the b-MyHC promoter were integrated into a pBSII SK vector and microinjected into rabbit oocytes. SQT1 rabbits and their wildtype (WT) littermates were subjected to in vivo ECG and ex vivo monophasic action potential (AP) measurements. Electrical remodeling was investigated using real-time PCR. Results: We successfully generated 3 transgenic SQT1 founder rabbits. One of the founders died suddenly at the age of 60 days. In SQT1 rabbits (F1) not subjected to any experiments 3/11 died around day 40 vs. 0/8 WT rabbits (p FLAG-HA-HERG-N588K channels expressed in HEK cells demonstrated increased IKr steady currents and impaired inactivation indicative of a gain-of-function. Remodeling of ion channels and Ca2+ handling proteins occurred in SQT1 rabbits with a downregulation of L-type Ca2+ channel mRNA in LV septum-mid (SQT1, n=4, 0.84±0.1 vs. WT, n=6, 1.03±0.1, p Conclusion: These first transgenic SQT1 rabbits over-expressing a HERG-N588K gain-of-function mutation mimic the human phenotype with shortening of QT and APD, a high rate of VF and SCD. These models are thus a useful tool to explore arrhythmogenic mechanisms in SQTS.

Aims: Strain rate imaging techniques have been proposed for the detection of ischemic or viable myocardium in coronary artery disease, which is still a challenge in clinical cardiology. This retrospective comparative study analyzed regional left ventricular function and scaring with two-dimensional strain (2DS) in the first 4 to 10 days after acute anterior myocardial infarction (AMI). Methods and results: The study population consisted of 32 AMI patients with an LAD occlusion and successful reperfusion. The assessment of peak systolic 2DS and peak systolic strain rate (SR) was performed segment-oriented with the angle-independent speckle tracking algorithm Velocity Vector Imaging (VVI). The infarcted, adjacent and non-infarcted segments were revealed by late enhancement MRI (LE-MRI), which was used as reference for the comparison with 2DS. The infarcted segments showed a significant decrease of tissue velocities, 2DS and SR in comparison to the non-affected segments. Conclusion: 2DS and SR as assessed by VVI seem to be a suitable approach for echocardiographic quantification of global and regional myocardial function as well as a promising tool for multimodal risk stratification after anterior AMI.