Natural history, trajectory, and management of mechanically ventilated COVID-19 patients in the United Kingdom
Authors: Patel Brijesh V , Haar Shlomi , Handslip Rhodri , Lee Teresa Mei-Ling , Patel Sunil , Harston J. Alex , Hosking-Jervis Feargus , Kelly Donna , Sanderson Barnaby , Bogatta Barbara , Tatham Kate , Welters Ingeborg , Camporota Luigi , Gordon Anthony C , Komorowski Matthieu , Antcliffe David , Prowle John R , Puthucheary Zudin , Faisal A. Aldo 
Published: November 2020

AbstractBackgroundTo 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.MethodsWe 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).FindingsData 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).InterpretationA 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.Research in contextEvidence before this studyBeyond the regular literature expertise of our consortium, we enhanced our literature review - due to the fast-evolving Covid-19 publication situation-by searching PubMed for articles published in English or with English language abstracts on October 26, 2020 (and before), with the terms “mechanical ventilation”, “prone position”, “AND (“coronavirus” OR “COVID-19”). Studies including patients not receiving ventilation were excluded, as were those reporting on paediatric and single-centre populations. Note, that neither of those studies analysed the data with respect to the temporal evolution of patients and at our level of granularity. Only four multicentre studies reported detailed ventilator settings and outcomes in ventilated patients with COVID-19. All studies showed only ventilator settings with restricted time points either on admission or the first 4 days of admission. None enabled granular visualisation and analysis of longitudinal ICU trajectory and management.Added value of this studyThis study provides a comprehensive analysis and visualisation of routine clinical measurements tracking the whole ICU time course of patients undergoing invasive mechanical ventilation for COVID-19. Mechanically ventilated patients with COVID-19 have a different natural history and trajectory from descriptions of non-COVID ARDS patients, not predictable from admission physiology. Refractory hypoxaemia is an attributable factor associated with poor outcomes in Covid-19 and hence, understanding of use and utility of evidence-based ARDS interventions is clinically crucial. Opportunities to apply prone positioning appropriately are frequently missed, application of high levels of PEEP, and higher tidal volume delivery than planned is common. Lack of responsiveness to advanced ARDS management is associated with hypercoagulation and cardiovascular instability. These data may help homogenise future clinical management protocols and suggest change-of-practice trials.Implications of all the available evidenceThis study shows that disease progression in Covid-19 during the first surge occurred more frequently and for longer than other forms of respiratory failure from pre-Covid19 studies. Furthermore, variations in clinical practise occur across sites which may benefit from standardisation of evidence-based practise. Patients that do not resolve hypoxaemia over the first week have a significantly higher mortality, and, crucially, that a significant proportion are refractory to prone interventions and show variability in responses to PEEP changes. Opportunities to implement prone position were missed in many patients and this was compounded with its reduced effect on oxygenation with delayed application. This lack of responsiveness is related to indices of inflammation, thrombosis, and cardiac dysfunction suggesting that pulmonary thrombosis could influence prone responsiveness and should be pro-actively investigated in the setting of refractory Covid-19 ARDS. Prediction of failure to resolve or respond to ARDS interventions could further focus research on this group with worse outcome.