RESUMO
BackgroundTo 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 contextO_ST_ABSEvidence before this studyC_ST_ABSBeyond 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.
RESUMO
ObjectivesTo audit implementation of a local protocol for the treatment of vitamin D deficiency (VDD) among patients hospitalized for Coronavirus Disease 2019 (COVID-19), including an assessment of the prevalence of VDD in these patients, and of potential associations with disease severity and fatality. DesignThis was not a study or clinical trial, but rather a retrospective interim audit (Newcastle-upon-Tyne Hospitals Registration No. 10075) of a local clinical care pathway for hospitalized patients with COVID-19-related illness. The Information (Caldicott) Guardian permitted these data to be shared beyond the confines of our institution. SettingA large tertiary academic NHS Foundation Trust in the North East of England, UK, providing care to COVID-19 patients. ParticipantsOne hundred thirty-four hospitalized patients with documented COVID-19 infection. Main outcome measuresAdherence to local investigation and treatment protocol; prevalence of VDD, and relationship of baseline serum 25(OH)D with markers of COVID-19 severity and inpatient fatality versus recovery. Results55.8% of eligible patients received Colecalciferol replacement, albeit not always loaded as rapidly as our protocol suggested, and no cases of new hypercalcaemia occurred following treatment. Patients admitted to ITU were younger than those managed on medical wards (61.1 years {+/-} 11.8 vs. 76.4 years {+/-} 14.9, p<0.001), with greater prevalence of hypertension, and higher baseline respiratory rate, National Early Warning Score-2 and C-reactive protein level. While mean serum 25(OH)D levels were comparable [i.e. ITU: 33.5 nmol/L {+/-} 16.8 vs. Non-ITU: 48.1 nmol/L {+/-} 38.2, mean difference for Ln-transformed-25(OH)D: 0.14, 95% Confidence Interval (CI) (-0.15, 0.41), p=0.3], only 19% of ITU patients had 25(OH)D levels greater than 50 nmol/L vs. 39.1% of non-ITU patients (p=0.02). However, we found no association with fatality, potentially due to small sample size, limitations of no-trial data and, potentially, the prompt diagnosis and treatment of VDD. ConclusionsSubject to the inherent limitations of observational (non-trial) audit data, analysed retrospectively, we found that patients requiring ITU admission were more frequently vitamin D deficient than those managed on medical wards, despite being significantly younger. Larger prospective studies and/or clinical trials are needed to elucidate the role of vitamin D as a preventive and/or therapeutic strategy for mitigating the effects of COVID-19 infection in patients with VDD. What is already known on this topicO_LIVitamin D deficiency (VDD) is associated with increased risk for acute respiratory tract infections C_LIO_LIA link between VDD and severity of COVID-19 pathophysiology has been proposed C_LIO_LITwo recent (non-peer-reviewed) studies have reported crude associations between VDD in defined geographic populations and COVID-19 severity and mortality C_LI What this study addsO_LIThese data do not arise from a clinical study; rather from an audit of a local replacement protocol for VDD in COVID-19 inpatients in a large UK centre, which found a significantly higher prevalence of VDD among ITU patients compared to non-ITU patients, despite the ITU patients being significantly younger. C_LIO_LIPrompt treatment of VDD following a local protocol did not result in any adverse events, such as hypercalcaemia. C_LIO_LIWhilst by no means conclusive, these data suggest an important association between VDD and COVID-19 severity; hence our report of interim findings in advance of achieving completed outcomes (fatality vs. recovery) for all patients. C_LIO_LIThere is an urgent need for larger studies exploring vitamin D as a potential preventative measure and/or treatment of Covid-19-related illness among individuals with VDD. C_LI
