Venoarterial extracorporeal membrane oxygenation (VA-ECMO) support under extracorporeal cardiopulmonary resuscitation (eCPR) is the last option and may be offered to selected patients. Several factors predict outcome in these patients, including initial heart rhythm, comorbidities, and bystander cardiopulmonary resuscitation (CPR). We evaluated outcomes of all VA-ECMO patients treated within the last 5 years at our center in respect to low-flow duration during CPR. We report retrospective registry data on all patients with eCPR treated at a university hospital between October 2010 and May 2016. A total of 133 patients (mean age 58.7 ± 2.6 years, Simplified Acute Physiology Score II score at admission 48.1 ± 3.4) were included in the analysis. The indication for eCPR was either in-hospital or out-of-hospital cardiac arrest without return of spontaneous circulation (n = 74 and 59, respectively). There was a significant difference in survival rates between groups (eCPR in-hospital cardiac arrest [IHCA] 18.9%, eCPR out-of-hospital cardiac arrest [OHCA] 8.5%; p < 0.042). Mean low-flow duration (i.e., duration of mechanical CPR until VA-ECMO support) was 59.6 ± 5.0 minutes in all patients and significantly shorter in IHCA patients than in OHCA patients (49.6 ± 5.9 vs. 72.2 ± 7.4 minutes, p = 0.001). Low-flow time strongly correlated with survival (p < 0.001) and was an independent predictor of mortality. Time to full support is an important and alterable predictor of patient survival in eCPR, suggesting that VA-ECMO therapy should be established as fast as possible in the selected patients destined for eCPR.

During the first trimester of pregnancy, well-differentiated primary cells of the placenta known as trophoblast cells grow in an invasive and destructive fashion similar to malignancies, but limited in space and time. The comparison of trophoblast cells with their malignant counterpart, human choriocarcinoma cells, offers an attractive model to understand the origin or development of malignant growth. Several cytokines and growth factors are known to influence trophoblast migration (e.g. EGF, IGF-2, HGF), proliferation (e.g. leptin, HGF, GM-CSF) and/or invasion (e.g. leukemia inhibitory factor, LIF), each factor utilizing at least one pathway for intracellular signaling in the trophoblast. Two pathways that are crossed especially often mediate the signals of these factors and are simultaneously well established in terms of tumor invasion: the Janus kinase-signal transducers and activators of transcription (Jak-Stat) and receptor-associated tyrosine kinase-mitogen-activated protein kinase (RTK-MAPK) pathways. These two pathways are detrimental for reproduction in general, and in part for placenta development, as a series of knockout experiments demonstrate. Aspects of each pathway are also implicated to be involved in trophoblast invasion, e.g. STAT3 is constitutively activated in invasive first trimester trophoblast cells, and activated ERK is detectable in intermediate trophoblast cells, an invasive phenotype. Interaction at several intersection points between the pathways has been described in several cell systems so that the same would seem to be possible in trophoblast cells. In this review, some of the possible areas of interaction are alluded to.

Background: Prone positioning (PP) reduces mortality of patients with acute respiratory distress syndrome (ARDS). The potential benefit of prone positioning maneuvers during venovenous extracorporeal membrane oxygenation (ECMO) is unknown. The aim of this study was to evaluate the association between the use of prone positioning during extracorporeal support and ICU mortality in a pooled population of patients from previous European cohort studies. Methods: We performed a pooled individual patient data analysis of European cohort studies which compared patients treated with prone positioning during ECMO (Prone group) to “conventional” ECMO management (Supine group) in patients with severe ARDS. Results: 889 patients from five studies were included. Unadjusted ICU mortality was 52.8% in the Supine Group and 40.8% in the Prone group. At a Cox multiple regression analysis PP during ECMO was not significantly associated with a reduction of ICU mortality (HR 0.67 95% CI: 0.42–1.06). Propensity score matching identified 227 patients in each group. ICU mortality of the matched samples was 48.0% and 39.6% for patients in the Supine and Prone group, respectively (p = 0.072). Conclusions: In a large population of ARDS patients receiving venovenous extracorporeal support, the use of prone positioning during ECMO was not significantly associated with reduced ICU mortality. The impact of this procedure will have to be definitively assessed by prospective randomized controlled trials.

Objectives: SARS-CoV2 infection leads to a concomitant pulmonary inflammation. This inflammation is supposed to be the main driver in the pathogenesis of lung failure (Acute Respiratory Distress Syndrome) in COVID-19. Objective of this study is to evaluate the efficacy and safety of a single dose treatment with Tocilizumab in patients with severe COVID-19. We hypothesize that Tocilizumab slows down the progression of SARS-CoV-2 induced pneumonia and inflammation. We expect an improvement in pulmonary function compared to placebo-treated patients. Desirable outcomes would be that tocilizumab reduces the number of days that patients are dependent on mechanical ventilation and reduces the invasiveness of breathing assistance. Furthermore, this treatment might result in fewer admissions to intensive care units. Next to these efficacy parameters, safety of a therapy with Tocilizumab in COVID-19 patients has to be monitored closely, since immunosuppression could lead to an increased rate of bacterial infections, which could negatively influence the patient’s outcome. Trial design: Multicentre, prospective, 2-arm randomised (ratio 1:1), double blind, placebo-controlled trial with parallel group design. Participants: Inclusion criteria Proof of SARS-CoV2 (Symptoms and positive polymerase chain reaction (PCR)) Severe respiratory failure: Ambient air SpO₂ ≤ 92% or Need of ≥ 6l O2/min or NIV (non-invasive ventilation) or IMV (invasive mechanical ventilation) Age ≥ 18 years Exclusion criteria Non-invasive or invasive mechanical ventilation ≥ 48 hours Pregnancy or breast feeding Liver injury or failure (AST/ALT ≥ 5x ULN) Leukocytes < 2 × 10³/μl Thrombocytes < 50 × 10³/μl Severe bacterial infection (PCT > 3ng/ml) Acute or chronic diverticulitis Immunosuppressive therapy (e.g. mycophenolate, azathioprine, methotrexate, biologicals, prednisolone >10mg/d; exceptions are: prednisolone ≤ 10mg/d, sulfasalazine or hydroxychloroquine) Known active or chronic tuberculosis Known active or chronic viral hepatitis Known allergic reactions to tocilizumab or its ingredients Life expectation of less than 1 year (independent of COVID-19) Participation in any other interventional clinical trial within the last 30 days before the start of this trial Simultaneous participation in other interventional trials (except for participation in COVID-19 trials) which could interfere with this trial; simultaneous participation in registry and diagnostic trials is allowed Failure to use one of the following safe methods of contraception: female condoms, diaphragm or coil, each used in combination with spermicides; intra-uterine device; hormonal contraception in combination with a mechanical method of contraception. The data collection of the primary follow up (28 days after randomisation) takes place during the hospital stay. Subsequently, a telephone interview on the quality of life is conducted after 6 and 12 months. Participants will be recruited from inpatients at ten medical centres in Germany. Intervention and comparator: Intervention arm: Application of 8mg/kg body weight (BW) Tocilizumab i.v. once immediately after randomisation (12 mg/kg for patients with <30kg BW; total dose should not exceed 800 mg) AND conventional treatment. Control arm: Placebo (NaCl) i.v. once immediately after randomisation AND conventional treatment. Main outcomes: Primary endpoint is the number of ventilator free days (d) (VFD) in the first 28 days after randomisation. Non-invasive ventilation (NIV), Invasive mechanical ventilation (IMV) and extracorporeal membrane oxygenation (ECMO) are defined as ventilator days. VFD’s are counted as zero if the patient dies within the first 28 days. Randomisation: The randomisation code will be generated by the CTU (Clinical Trials Unit, ZKS Freiburg) using the following procedure to ensure that treatment assignment is unbiased and concealed from patients and investigator staff. Randomisation will be stratified by centre and will be performed in blocks of variable length in a ratio of 1:1 within each centre. The block lengths will be documented separately and will not be disclosed to the investigators. The randomisation code will be produced by validated programs based on the Statistical Analysis System (SAS). Blinding (masking): Participants, caregivers, and the study team assessing the outcomes are blinded to group assignment. Numbers to be randomised (sample size): 100 participants will be randomised to each group (thus 200 participants in total). Trial Status: Protocol Version: V 1.2, 16.04.2020. Recruitment began 27th April 2020 and is anticipated to be completed by December 2020. Trial registration: The trial was registered before trial start in trial registries (EudraCT: No. 2020-001408-41, registered 21st April 2020, and DRKS: No. DRKS00021238, registered 22nd April 2020). 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.