Nebulized recombinant tissue plasminogen activator (rt-PA) for acute COVID-19-induced severe respiratory failure: an exploratory proof of concept trial (preprint)

Nebulized thrombolysis offers locally targeted therapy with potentially lower bleeding risk than systemic administration for coronavirus disease 2019 (COVID-19) respiratory failure. In a proof-of-concept safety study, adult patients with COVID-19-induced respiratory failure and a <300mmHg PaO2/FiO2 (P/F) ratio, requiring invasive mechanical ventilation (IMV) or non-invasive respiratory support (NIRS) received nebulized rt-PA in two cohorts (C1 and C2), alongside standard of care during the first two UK COVID-19 waves. Matched historical controls (MHC; n=18) were used in C1. Safety co-primary endpoints were treatment-related bleeds and fibrinogen reduction to <1.0–1.5 g/L. A dose escalation strategy for improved efficacy with the least safety concerns was determined in C1 for use in C2; patients were stratified by ventilation type to receive 40–60 mg rt-PA per day for ≤14 days. Nine patients in C1 (IMV, 6/9; NIRS, 3/9) and 26 in C2 (IMV, 12/26; NIRS, 14/26) received nebulized rt-PA for a mean (SD) of 6.7 (4.6) and 9.1(4.6) days, respectively. Four bleeding events (one severe and three mild) in three patients were considered treatment-related. No significant fibrinogen reductions were reported. Greater improvement in mean P/F ratio from baseline to end of study was observed in C1 compared with MHC [C1; 154 to 299 vs MHC; 154 to 212). In C2, there was no difference in the baseline P/F ratio of NIRS and IMV patients. However, a larger improvement in P/F ratio was observed in NIRS patients [NIRS; 126 to 240 vs IMV; 120 to 188) and they required fewer treatment days (NIRS; 7.86 vs IMV; 10.5). Nebulized rt-PA appears to be well-tolerated, showing a trend of improved oxygenation and faster recovery in patients with acute COVID-19-induced respiratory failure requiring respiratory support; this effect was more pronounced in the NIRS group. Further investigation is required to study the potential of this novel treatment approach.

Hospital Trainees Worries, Perceived Sufficiency of Information and Reported Psychological Health During The COVID-19 Pandemic (preprint)

Introduction: The COVID-19 pandemic has been unsurpassed in clinical severity or infectivity since the 1918 Spanish influenza pandemic and continues to impact the world. During the A/H1N1 influenza pandemic, healthcare workers presented frequent concerns regarding their ownand their families health, as well as high levels of psychological distress. Objectives: To assess hospital trainees concerns, perceived sufficiency of information, behaviour and reported psychological health during the COVID-19 pandemic in the NHS Design: Cross-sectional 39-point questionnaire study conducted in May 2020 Setting: A large NHS foundation trust in London Participants: 204 hospital trainee doctors Outcome measures: Quantitative analysis of trainees worries and concerns while working during the COVID-19 pandemic were assessed across 8 domains: trainee demographics; concerns and worries regarding COVID-19; perceived sufficiency of information about the COVID-19 pandemic; social distancing; use of personal protective equipment (PPE) and training in PPE; COVID-19 acquisition and risk; reported psychological health; and medical education. Results: 91.7% looked after COVID-19 patients. 91.6% were worried about COVID-19; the most frequent concern was that of family and friends dying from COVID-19 (74.6%). 22.2% reported being infected with COVID-19. 6.8% of trainees were so concerned about COVID-19 infection that they would avoid going to work. Perceived sufficiency of information about COVID-19 was moderately high. 25.9% reported that they were able to socially distance at work compared to 94.4% able to socially distance outside work. 98.2% reported using PPE and 24.7% were confident the provided PPE protected them against infection with COVID-19. 41.9% reported that their psychological health had been affected by their work with the commonest being anxiety (56.6%), emotional distress (50.9%) and burnout (37.7%). 95.6% felt it is important to have a service that provides psychological support during this pandemic and 62.5% reported they would consider using this at work. Conclusions: A significant proportion of hospital trainees are worried about the COVID-19 pandemic with high levels of reported psychological distress. Given that almost a third would not use psychological support services at work, hospital leaders and liaison psychiatry need to explore the reasons for not wanting to use services at work and highlight the provision of psychological services provided outside work such that provided by the London deaneries professional support unit (PSU). Seeking solutions to support trainee wellbeing in addition to this, such as larger offices, adequate rest facilities and alternative methods of teaching, with their input would enable empowerment of trainees and improve their health and morale while working in a pandemic.

Excess deaths in people with cardiovascular diseases during the COVID-19 pandemic. (preprint)

Background: Cardiovascular diseases(CVD) increase mortality risk from coronavirus infection(COVID-19), but there are concerns that the pandemic has affected supply and demand of acute cardiovascular care. We estimated excess mortality in specific CVDs, both direct, through infection, and indirect, through changes in healthcare. Methods: We used population-based electronic health records from 3,862,012 individuals in England to estimate pre- and post-COVID-19 mortality risk(direct effect) for people with incident and prevalent CVD. We incorporated: (i)pre-COVID-19 risk by age, sex and comorbidities, (ii)estimated population COVID-19 prevalence, and (iii)estimated relative impact of COVID-19 on mortality(relative risk, RR: 1.5, 2.0 and 3.0). For indirect effects, we analysed weekly mortality and emergency department data for England/Wales and monthly hospital data from England(n=2), China(n=5) and Italy(n=1) for CVD referral, diagnosis and treatment until 1 May 2020. Findings: CVD service activity decreased by 60-100% compared with pre-pandemic levels in eight hospitals across China, Italy and England during the pandemic. In China, activity remained below pre-COVID-19 levels for 2-3 months even after easing lockdown, and is still reduced in Italy and England. Mortality data suggest indirect effects on CVD will be delayed rather than contemporaneous(peak RR 1.4). For total CVD(incident and prevalent), at 10% population COVID-19 rate, we estimated direct impact of 31,205 and 62,410 excess deaths in England at RR 1.5 and 2.0 respectively, and indirect effect of 49932 to 99865 excess deaths. Interpretation: Supply and demand for CVD services have dramatically reduced across countries with potential for substantial, but avoidable, excess mortality during and after the COVID-19 pandemic.