Purpose The trajectory of mechanically ventilated patients with coronavirus disease 2019 (COVID-19) is essential for clinical decisions, yet the focus so far has been on admission characteristics without consideration of the dynamic course of the disease in the context of applied therapeutic interventions. Methods We included adult patients undergoing invasive mechanical ventilation (IMV) within 48 h of intensive care unit (ICU) admission with complete clinical data until ICU death or discharge. We examined the importance of factors associated with disease progression over the first week, implementation and responsiveness to interventions used in acute respiratory distress syndrome (ARDS), and ICU outcome. We used machine learning (ML) and Explainable Artificial Intelligence (XAI) methods to characterise the evolution of clinical parameters and our ICU data visualisation tool is available as a web-based widget ( https://www.CovidUK.ICU ). Results Data for 633 adults with COVID-19 who underwent IMV between 01 March 2020 and 31 August 2020 were analysed. Overall mortality was 43.3% and highest with non-resolution of hypoxaemia [60.4% vs17.6%; P < 0.001; median PaO 2 /FiO 2 on the day of death was 12.3(8.9–18.4) kPa] and non-response to proning (69.5% vs.31.1%; P < 0.001). Two ML models using weeklong data demonstrated an increased predictive accuracy for mortality compared to admission data (74.5% and 76.3% vs 60%, respectively). XAI models highlighted the increasing importance, over the first week, of PaO 2 /FiO 2 in predicting mortality. Prone positioning improved oxygenation only in 45% of patients. A higher peak pressure (OR 1.42[1.06–1.91]; P < 0.05), raised respiratory component (OR 1.71[ 1.17–2.5]; P < 0.01) and cardiovascular component (OR 1.36 [1.04–1.75]; P < 0.05) of the sequential organ failure assessment (SOFA) score and raised lactate (OR 1.33 [0.99–1.79]; P = 0.057) immediately prior to application of prone positioning were associated with lack of oxygenation response. Prone positioning was not applied to 76% of patients with moderate hypoxemia and 45% of those with severe hypoxemia and patients who died without receiving proning interventions had more missed opportunities for prone intervention [7 (3–15.5) versus 2 (0–6); P < 0.001]. Despite the severity of gas exchange deficit, most patients received lung-protective ventilation with tidal volumes less than 8 mL/kg and plateau pressures less than 30cmH 2 O. This was despite systematic errors in measurement of height and derived ideal body weight. Conclusions Refractory hypoxaemia remains a major associ...

Background. To date the description of mechanically ventilated patients with Coronavirus Disease 2019 (COVID-19) has focussed on admission characteristics with no consideration of the dynamic course of the disease. Here, we present a data-driven analysis of granular, daily data from a representative proportion of patients undergoing invasive mechanical ventilation (IMV) within the United Kingdom (UK) to evaluate the complete natural history of COVID-19. Methods. We included adult patients undergoing IMV within 48 hours of ICU admission with complete clinical data until intensive care unit (ICU) death or discharge. We examined factors and trajectories that determined disease progression and responsiveness to interventions used in acute respiratory distress syndrome (ARDS). Our data visualisation tool is available as a web-based widget (https://www.CovidUK.ICU). Findings. Data for 633 adults with COVID-19 who were mechanically ventilated between 01 March 2020 and 31 August 2020 were analysed. Mortality, intensity of mechanical ventilation and severity of organ injury increased with severity of hypoxaemia. Median PaO2/FiO2 in non-survivors on the day of death was 12.3(8.9-18.4) kPa suggesting severe refractory hypoxaemia as a major contributor to mortality. Non-resolution of hypoxaemia over the first week of IMV was associated with higher ICU mortality (60.4% versus 17.6%; P<0.001). The reported ideal body weight overestimated our calculated ideal body weight derived from reported height, with three-quarters of all reported tidal volume values were above 6mL/kg of ideal body weight. Overall, 76% of patients with moderate hypoxaemia and 46% with severe did not undergo prone position at any stage of admission. Furthermore, only 45% showed a persistent oxygenation response on prone position. Non-responders to prone position show higher lactate, D-Dimers, troponin, cardiovascular component of the sequential organ failure assessment (SOFA) score, and higher ICU mortality (69.5% versus 31.1%; P<0.001). There was no difference in number of prone sessions between survivors and non-survivors, however, patients who died without receiving prone position had a greater number of missed opportunities for prone intervention (7(3-15.5) versus 2(0-6); P<0.001). Interpretation. A sizeable proportion of patients with progressive worsening of hypoxaemia had no application of and were refractory to evidence based ARDS strategies and showed a higher mortality. Strategies for early recognition and management of COVID-19 patients refractory to conventional management strategies will be critical to improving future outcomes.

Scientific Knowledge on the SubjectCyclophilin A (CypA) is a ubiquitously expressed cytosolic protein most known for its role in intracellular protein folding. The gene responsible for CypA expression has very recently been implicated in susceptibility to COVID-19 infection. A secreted form, extracellular CypA (eCypA) has been identified as having involvement in diseases such as rheumatoid arthritis and coronary artery disease, but little is known regarding any role within the lungs. What This Study Adds to the FieldWe have identified a novel role for secreted eCypA in the pathogenesis of ventilatorinduced lung injury (VILI). eCypA is secreted from epithelial cells during VILI in mice and promotes alveolar macrophage activation, such that in vivo inhibition attenuates development of injury. Furthermore eCypA levels are increased in bronchoalveolar AJRCCM Articles in Press.