Particles in Exhaled Air (PExA): Clinical Uses and Future Implications.

Access to distal airway samples to assess respiratory diseases is not straightforward and requires invasive procedures such as bronchoscopy and bronchoalveolar lavage. The particles in exhaled air (PExA) device provides a non-invasive means of assessing small airways; it captures distal airway particles (PEx) sized around 0.5-7 µm and contains particles of respiratory tract lining fluid (RTLF) that originate during airway closure and opening. The PExA device can count particles and measure particle mass according to their size. The PEx particles can be analysed for metabolites on various analytical platforms to quantitatively measure targeted and untargeted lung specific markers of inflammation. As such, the measurement of distal airway components may help to evaluate acute and chronic inflammatory conditions such as asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome, and more recently, acute viral infections such as COVID-19. PExA may provide an alternative to traditional methods of airway sampling, such as induced sputum, tracheal aspirate, or bronchoalveolar lavage. The measurement of specific biomarkers of airway inflammation obtained directly from the RTLF by PExA enables a more accurate and comprehensive understanding of pathophysiological changes at the molecular level in patients with acute and chronic lung diseases.

Towards quantifying biomarkers for respiratory distress in preterm infants: Machine learning on mid infrared spectroscopy of lipid mixtures.

Neonatal respiratory distress syndrome (nRDS) is a challenging condition to diagnose which can lead to delays in receiving appropriate treatment. Mid infrared (IR) spectroscopy is capable of measuring the concentrations of two diagnostic nRDS biomarkers, lecithin (L) and sphingomyelin (S) with the potential for point of care (POC) diagnosis and monitoring. The effects of varying other lipid species present in lung surfactant on the mid IR spectra used to train machine learning models are explored. This study presents a lung lipid model of five lipids present in lung surfactant and varies each in a systematic approach to evaluate the ability of machine learning models to predict the lipid concentrations, the L/S ratio and to quantify the uncertainty in the predictions using the jackknife + -after-bootstrap and variant bootstrap methods. We establish the L/S ratio can be determined with an uncertainty of approximately ±0.3 mol/mol and we further identify the 5 most prominent wavenumbers associated with each machine learning model.

In Vivo Cellular Phosphatidylcholine Kinetics of CD15+ Leucocytes and CD3+ T-Lymphocytes in Adults with Acute Respiratory Distress Syndrome.

Mammalian cell membranes composed of a mixture of glycerophospholipids, the relative composition of individual phospholipids and the dynamic flux vary between cells. In addition to their structural role, membrane phospholipids are involved in cellular signalling and immunomodulatory functions. In this study, we investigate the molecular membrane composition and dynamic flux of phosphatidylcholines in CD15+ leucocytes and CD3+ lymphocytes extracted from patients with acute respiratory distress syndrome (ARDS). We identified compositional variations between these cell types, where CD15+ cells had relatively higher quantities of alkyl-acyl PC species and CD3+ cells contained more arachidonoyl-PC species. There was a significant loss of arachidonoyl-PC in CD3+ cells in ARDS patients. Moreover, there were significant changes in PC composition and the methyl-D9 enrichment of individual molecular species in CD15+ cells from ARDS patients. This is the first study to perform an in vivo assessment of membrane composition and dynamic changes in immunological cells from ARDS patients.

Organisation and delivery of a dedicated multidisciplinary prone ventilation team in the intensive care unit: Strategies and lessons from COVID-19.

BACKGROUND: COVID-19 placed immense strain on healthcare systems, necessitating innovative responses to the surge of critically ill patients, particularly those requiring mechanical ventilation. In this report, we detail the establishment of a dedicated critical care prone positioning team at University Hospital Southampton in response to escalating demand for prone positioning during the initial wave of the pandemic. METHODS: The formation of a prone positioning team involved meticulous planning and collaboration across disciplines to ensure safe and efficient manoeuvrers. A comprehensive training strategy, aligned with national guidelines, was implemented for approximately 550 staff members from a diverse background. We surveyed team members to gain insight to the lived experience. RESULTS: A total of 78 full-time team members were recruited and successfully executed over 1200 manoeuvres over an eight-week period. Our survey suggests the majority felt valued and expressed pride and willingness to participate again should the need arise. CONCLUSION: The rapid establishment and deployment of a dedicated prone positioning team may have contributed to both patient care and staff well-being. We provide insight and lessons that may be of value for future respiratory pandemics. Future work should explore objective clinical outcomes and long-term sustainability of such services.

Severe Parainfluenza Viral Infection-A Retrospective Study of Adult Intensive Care Patients.

There is little known about parainfluenza virus (PIV) infection in adult intensive care unit (ICU) patients. Here, we aim to describe the characteristics, clinical course and outcomes of PIV infection in adults requiring intensive care. In this retrospective study of consecutive patients admitted to our ICU with confirmed PIV infection over a 7-year period, we report the patient characteristics, laboratory tests and prognostic scores on ICU admission. The main outcomes reported are 30-day mortality and organ support required. We included 50 patients (52% male, mean age 67.6 years). The mean PaO2/FiO2 and neutrophil/lymphocyte ratios on ICU admission were 198 ± 82 mmHg and 15.7 ± 12.5. Overall, 98% of patients required respiratory support and 24% required cardiovascular support. The median length of ICU stay was 5.9 days (IQR 3.7-9.1) with a 30-day mortality of 40%. In conclusion, PIV infection in adult ICU patients is associated with significant mortality and morbidity. There were significant differences between patients who presented with primary hypoxemic respiratory failure and hypercapnic respiratory failure.

A randomized controlled trial of nebulized surfactant for the treatment of severe COVID-19 in adults (COVSurf trial).

SARS-CoV-2 directly targets alveolar epithelial cells and can lead to surfactant deficiency. Early reports suggested surfactant replacement may be effective in improving outcomes. The aim of the study to assess the feasibility and efficacy of nebulized surfactant in mechanically ventilated COVID-19 patients. Patients were randomly assigned to receive open-labelled bovine nebulized surfactant or control (ratio 3-surfactant: 2-control). This was an exploratory dose-response study starting with 1080 mg of surfactant delivered at 3 time points (0, 8 and 24 h). After completion of 10 patients, the dose was reduced to 540 mg, and the frequency of nebulization was increased to 5/6 time points (0, 12, 24, 36, 48, and an optional 72 h) on the advice of the Trial Steering Committee. The co-primary outcomes were improvement in oxygenation (change in PaO2/FiO2 ratio) and ventilation index at 48 h. 20 patients were recruited (12 surfactant and 8 controls). Demographic and clinical characteristics were similar between groups at presentation. Nebulized surfactant administration was feasible. There was no significant improvement in oxygenation at 48 h overall. There were also no differences in secondary outcomes or adverse events. Nebulized surfactant administration is feasible in mechanically ventilated patients with COVID-19 but did not improve measures of oxygenation or ventilation.

Alveolar Hyperoxia and Exacerbation of Lung Injury in Critically Ill SARS-CoV-2 Pneumonia.

Acute hypoxic respiratory failure (AHRF) is a prominent feature of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) critical illness. The severity of gas exchange impairment correlates with worse prognosis, and AHRF requiring mechanical ventilation is associated with substantial mortality. Persistent impaired gas exchange leading to hypoxemia often warrants the prolonged administration of a high fraction of inspired oxygen (FiO2). In SARS-CoV-2 AHRF, systemic vasculopathy with lung microthrombosis and microangiopathy further exacerbates poor gas exchange due to alveolar inflammation and oedema. Capillary congestion with microthrombosis is a common autopsy finding in the lungs of patients who die with coronavirus disease 2019 (COVID-19)-associated acute respiratory distress syndrome. The need for a high FiO2 to normalise arterial hypoxemia and tissue hypoxia can result in alveolar hyperoxia. This in turn can lead to local alveolar oxidative stress with associated inflammation, alveolar epithelial cell apoptosis, surfactant dysfunction, pulmonary vascular abnormalities, resorption atelectasis, and impairment of innate immunity predisposing to secondary bacterial infections. While oxygen is a life-saving treatment, alveolar hyperoxia may exacerbate pre-existing lung injury. In this review, we provide a summary of oxygen toxicity mechanisms, evaluating the consequences of alveolar hyperoxia in COVID-19 and propose established and potential exploratory treatment pathways to minimise alveolar hyperoxia.

Pulmonary Surfactant in Adult ARDS: Current Perspectives and Future Directions.

Acute respiratory distress syndrome (ARDS) is a major cause of hypoxemic respiratory failure in adults, leading to the requirement for mechanical ventilation and poorer outcomes. Dysregulated surfactant metabolism and function are characteristic of ARDS. A combination of alveolar epithelial damage leading to altered surfactant synthesis, secretion, and breakdown with increased functional inhibition from overt alveolar inflammation contributes to the clinical features of poor alveolar compliance and alveolar collapse. Quantitative and qualitative alterations in the bronchoalveolar lavage and tracheal aspirate surfactant composition contribute to ARDS pathogenesis. Compared to neonatal respiratory distress syndrome (nRDS), replacement studies of exogenous surfactants in adult ARDS suggest no survival benefit. However, these studies are limited by disease heterogeneity, variations in surfactant preparations, doses, and delivery methods. More importantly, the lack of mechanistic understanding of the exact reasons for dysregulated surfactant remains a significant issue. Moreover, studies suggest an extremely short half-life of replaced surfactant, implying increased catabolism. Refining surfactant preparations and delivery methods with additional co-interventions to counteract surfactant inhibition and degradation has the potential to enhance the biophysical characteristics of surfactant in vivo.

Prone Positioning in Mechanically Ventilated COVID-19 Patients: Timing of Initiation and Outcomes.

The COVID-19 pandemic led to a broad implementation of proning to enhance oxygenation in both self-ventilating and mechanically ventilated critically ill patients with acute severe hypoxic respiratory failure. However, there is little data on the impact of the timing of the initiation of prone positioning in COVID-19 patients receiving mechanical ventilation. In this study, we analyzed our proning practices in mechanically ventilated COVID-19 patients. There were 931 total proning episodes in 144 patients, with a median duration of 16 h (IQR 15-17 h) per proning cycle. 563 proning cycles were initiated within 7 days of intubation (early), 235 within 7-14 days (intermediate), and 133 after 14 days (late). The mean change in oxygenation defined as the delta PaO2/FiO2 ratio (ΔPF) after the prone episode was 16.6 ± 34.4 mmHg (p < 0.001). For early, intermediate, and late cycles, mean ΔPF ratios were 18.5 ± 36.7 mmHg, 13.2 ± 30.4 mmHg, and 14.8 ± 30.5 mmHg, with no significant difference in response between early, intermediate, and late proning (p = 0.2), respectively. Our findings indicate a favorable oxygenation response to proning episodes at all time points, even after >14 days of intubation. However, the findings cannot be translated directly into a survival advantage, and more research is needed in this area.

Provision of Microbiology, Infection Services and Antimicrobial Stewardship in Intensive Care: A Survey across the Critical Care Networks in England and Wales.

Infection rounds in Intensive Care Units (ICU) can impact antimicrobial stewardship (AMS). The aim of this survey was to assess the availability of microbiology, infection, AMS services, and antimicrobial prescribing practices in the UK ICUs. An online questionnaire was sent to clinical leads for ICUs in each region listed in the Critical Care Network for the UK. Out of 217 ICUs, 87 deduplicated responses from England and Wales were analyzed. Three-quarters of those who responded had a dedicated microbiologist, and 50% had a dedicated infection control prevention nurse. Infection rounds varied in their frequency, with 10% providing phone advice only. Antibiotic guidance was available in 99% of the units; only 8% of those were ICU-specific. There were variations in the availability of biomarkers & the duration of antibiotics prescribed for pneumonia (community, hospital, or ventilator), urinary, intra-abdominal, and line infections/sepsis. Antibiotic consumption data were not routinely discussed in a multi-disciplinary meeting. The electronic prescription was available in ~60% and local antibiotic surveillance data in only 47% of ICUs. The survey highlights variations in practice and AMS services and may offer the opportunity to further collaborations and share learnings to support the safe use of antimicrobials in the ICU.

Non-Invasive Ventilation for Community-Acquired Pneumonia: Outcomes and Predictors of Failure from an ICU Cohort.

Background and Objectives: The use of non-invasive ventilation (NIV) for community-acquired pneumonia (CAP) remains controversial. NIV failure in the setting of acute hypoxemic respiratory failure is associated with increased mortality, highlighting the need for careful patient selection. Methods and Methods: This is a retrospective observational cohort study. We included 140 patients with severe CAP, treated with either NIV or invasive mechanical ventilation (IMV) as their primary oxygenation strategy. Results: The median PaO2/FiO2 ratio and SOFA score upon ICU admission were 151 mmHg and 6, respectively. We managed 76% of patients with NIV initially and report an NIV success rate of 59%. Overall, the 28-day mortality was 25%, whilst for patients with NIV success, the mortality was significantly lower at 13%. In the univariate analysis, NIV failure was associated with the SOFA score (OR 1.33), the HACOR score (OR 1.14) and the presence of septic shock (OR 3.99). The SOFA score has an AUC of 0.75 for NIV failure upon ICU admission, whilst HACOR has an AUC of 0.76 after 2 h of NIV. Conclusions: Our results suggest that a SOFA ≤ 4 and an HACOR ≤ 5 are reasonable thresholds to identify patients with severe CAP likely to benefit from NIV.

Detailed Analysis of Primary Non-invasive Respiratory Support and Outcomes of Subjects With COVID-19 Acute Hypoxaemic Respiratory Failure.

Background The role of non-invasive (continuous positive airway pressure (CPAP) or Non-invasive ventilation (NIV)) respiratory support (NIRS) as a primary oxygenation strategy for COVID-19 patients with acute severe hypoxic respiratory failure (AHRF), as opposed to invasive mechanical ventilation (invasive-MV), is uncertain. While NIRS may prevent complications related to invasive MV, prolonged NIRS and delays in intubation may lead to adverse outcomes. This study was conducted to assess the role of NIRS in COVID-19 hypoxemic respiratory failure and to explore the variables associated with NRIS failure. Methods This is a single-center, observational study of two distinct waves of severe COVID-19 patients admitted to the ICU. Patients initially managed with non-invasive respiratory support with laboratory-confirmed SARS-CoV-2 in acute hypoxaemic respiratory failure were included. Demographics, comorbidities, admission laboratory variables, and ICU admission scores were extracted from electronic health records. Univariate and multiple logistic regression was used to identify predictive factors for invasive mechanical ventilation. Kaplan-Meier survival curves were used to summarise survival between the ventilatory and time-to-intubation groups. Results There were 291 patients, of which 232 were managed with NIRS as an initial ventilation strategy. There was a high incidence of failure (48.7%). Admission APACHE II score, SOFA score, HACOR score, ROX index, and PaO2/FiO2 were all predictive of NIRS failure. Daily (days 1-4) HACOR scores and ROX index measurements highly predicted NIRS failure. Late NIRS failure (>24 hours) was independently associated with increased mortality (44%). Conclusion NIRS is effective as first-line therapy for COVID-19 patients with AHRF. However, failure, particularly delayed failure, is associated with significant mortality. Early prediction of NIRS failure may prevent adverse outcomes.

Aspergillus in COVID-19 intensive care unit; what is lurking above your head?

Introduction: Through routine respiratory samples surveillance among COVID-19 patients in the intensive care, three patients with aspergillus were identified in a newly opened general intensive care unit during the second wave of the pandemic. Methodology: As no previous cases of aspergillus had occurred since the unit had opened. An urgent multidisciplinary outbreak meeting was held. The possible sources of aspergillus infection were explored. The multidisciplinary approach enabled stakeholders from different skills to discuss possible sources and management strategies. Environmental precipitants like air handling units were considered and the overall clinical practice was reviewed. Settle plates were placed around the unit to identify the source. Reports of recent water leaks were also investigated. Results: Growth of aspergillus on a settle plate was identified the potential source above a nurse's station. This was the site of a historic water leak from the ceiling above, that resolved promptly and was not investigated further. Subsequent investigation above the ceiling tiles found pooling of water and mould due to a slow water leak from a pipe. Conclusion: Water leaks in patient areas should be promptly notified to infection prevention. Detailed investigation to ascertain the actual cause of the leak and ensure any remedial work could be carried out swiftly. Outbreak meetings that include diverse people with various expertises (clinical and non-clinical) can enable prompt identification and resolution of contaminated areas to minimise risk to patients and staff. During challenging pandemic periods hospitals must not lose focus on other clusters and outbreaks occurring simultaneously.

Body mass index and clinical outcome of severe COVID-19 patients with acute hypoxic respiratory failure: Unravelling the "obesity paradox" phenomenon.

BACKGROUND AND AIMS: Although obesity have been generally shown to be an independent risk factor for poor outcomes in COVID-19 infection, some studies demonstrate a paradoxical protective effect ("obesity paradox"). This study examines the influence of obesity categories on clinical outcomes of severe COVID-19 patients admitted to an intensive care unit with acute hypoxic respiratory failure requiring either non-invasive or invasive mechanical ventilation. METHODS: This is a single centre, retrospective study of consecutive COVID-19 patients admitted to the intensive care unit between 03/2020 to 03/2021. Patients were grouped according to the NICE Body Mass Index (BMI) category. Admission variables including age, sex, comorbidities, and ICU severity indices (APACHE-II, SOFA and PaO2/FiO2) were collected. Data were compared between BMI groups for outcomes such as need for invasive mechanical ventilation (IMV), renal replacement therapy (RRT) and 28-day and overall hospital mortality. RESULTS: 340 patients were identified and of those 333 patients had their BMI documented. Just over half of patients (53%) had obesity. Those with extreme obesity (obesity groups II and III) were younger with fewer comorbidities, but were more hypoxaemic at presentation, than the healthy BMI group. Although non-significant, obesity groups II and III paradoxically showed a lower in-hospital mortality than the healthy weight group. However, adjusted (age, sex, APACHE-II and CCI) competing risk regression analysis showed three-times higher mortality in obese category I (sub-distribution hazard ratio = 3.32 (95% CI 1.30-8.46), p = 0.01) and a trend to higher mortality across all obesity groups compared to the healthy weight group. CONCLUSIONS: In this cohort, those with obesity were at higher risk of mortality after adjustment for confounders. We did not identify an "obesity paradox" in this cohort. The obesity paradox may be explained by confounding factors such as younger age, fewer comorbidities, and less severe organ failures. The impact of obesity on indicators of morbidity including likelihood of requirement for organ support measures was not conclusively demonstrated and requires further scrutiny.

Molecular point-of-care testing for lower respiratory tract pathogens improves safe antibiotic de-escalation in patients with pneumonia in the ICU: Results of a randomised controlled trial.

BACKGROUND: Effective treatment of pneumonia requires timely administration of appropriate antimicrobials but standard diagnostic tests take around 48 h to generate results. Highly accurate, rapid molecular tests have been developed for identifying organisms in lower respiratory tract samples, however their impact on antibiotic use is unknown. The aim of this study was to assess the impact of syndromic molecular point-of-care testing compared to conventional diagnostic testing, on antibiotic use. METHODS: In this pragmatic, randomised controlled trial, we enrolled critically ill adults with pneumonia. Patients were assigned (1:1) to molecular testing of samples at the point-of-care or routine clinical care. The primary outcome was the proportion of patients who received results-directed antimicrobial therapy. RESULTS: 200 patients were randomly assigned to point-of-care testing (n = 100) or the control group (n = 100). 85 patients had community acquired pneumonia (42 in the mPOCT group and 43 in the control group), 69 hospital acquired pneumonia (30 in mPOCT and 39 in control) and 46 ventilator associated pneumonia (28 in mPOCT and 18 in control). The median [IQR] time to results was 1.7 [1.6-1.9] hours for point-of-care testing and 66.7 [56.7-88.5] hours for standard diagnostics (difference of -65.0 h, 95%CI -68.0 to -62.0; p < 0.0001). 71 (71%) patients in the point-of-care testing arm had pathogens detected compared to 51 (51%) in the control arm (difference of 20%, 95%CI 7 to 33; p = 0.004). 80 (80%) of patients in the point-of-care group received results-directed therapy, compared with 29 (29%) of 99 in the control group (difference of 51%, 95%CI 39-63; p < 0.0001). Time to results-directed therapy was 2.3 [1.8-7.2] hours in the mPOCT group and 46.1 [23.0-51.5] hours in the control group (difference of -43.8 h, 95% CI -48.9 to -38.6; p < 0.0001). 42 (42%) patients in mPOCT group had antibiotics de-escalated compared with 8 (8%) of 98 in the control group (difference of 34%, 95%CI 23-45; p < 0.0001). Time to de-escalation was 4.8 [2.4-13.0] hours in the mPOCT group compared with 46.5 [26.3-48.6] hours in the control group (difference of -41.4 h, 95%CI -53 to -29.7; p < 0.0001). There was no major difference in antibiotic duration or in clinical or safety outcomes between the two groups. CONCLUSIONS: Use of molecular point-of-care testing in patients with pneumonia returned results more rapidly and identified more pathogens than conventional testing. This was associated with improvements in appropriate antimicrobial use and appeared safe.

Intensive care physicians' perceptions of the diagnosis & management of patients with acute hypoxic respiratory failure associated with COVID-19: A UK based survey.

Background: Whilst the management of Coronavirus disease-2019 (COVID-19) has evolved in response to the emerging data, treating such patients remains a challenge, and many treatments lack robust clinical evidence. We conducted a survey to evaluate Intensive Care Unit (ICU) management of COVID-19 patients with acute hypoxic respiratory failure and compared the results with data from a similar survey focusing on Acute Respiratory Distress Syndrome (ARDS) that was conducted in 2013. Methods: The questionnaire was refined from a previous survey of ARDS-related clinical practice using an online electronic survey engine (Survey Monkey®) and all UK intensivists were encouraged to participate. The survey was conducted between 16/05/2020 and 17/06/2020. Results: There were 137 responses from 89 UK centres. Non-invasive ventilation was commonly used in the form of CPAP. The primary ventilation strategy was the ARDSnet protocol, with 63% deviating from its PEEP recommendations. Similar to our previous ARDS survey, most allowed permissive targets for hypoxia (94%), hypercapnia (55%) and pH (94%). The routine use of antibiotics was common, and corticosteroids were frequently used, usually in the context of a clinical trial (45%). Late tracheostomy (>7 days) was preferred (92%). Routine follow-up was offered by 66% with few centres providing routine dedicated rehabilitation programmes following discharge. Compared to the ARDS survey, there is an increased use of neuromuscular agents, APRV ventilation and improved provision of rehabilitation services. Conclusions: Similar to our previous ARDS survey, this survey highlights variations in the management strategies used for patients with acute hypoxic respiratory failure due to COVID-19.

Dynamic blood oxygen indices in mechanically ventilated COVID-19 patients with acute hypoxic respiratory failure: A cohort study.

BACKGROUND: Acute hypoxic respiratory failure (AHRF) is a hallmark of severe COVID-19 pneumonia and often requires supplementary oxygen therapy. Critically ill COVID-19 patients may require invasive mechanical ventilation, which carries significant morbidity and mortality. Understanding of the relationship between dynamic changes in blood oxygen indices and clinical variables is lacking. We evaluated the changes in blood oxygen indices-PaO2, PaO2/FiO2 ratio, oxygen content (CaO2) and oxygen extraction ratio (O2ER) in COVID-19 patients through the first 30-days of intensive care unit admission and explored relationships with clinical outcomes. METHODS AND FINDINGS: We performed a retrospective observational cohort study of all adult COVID-19 patients in a single institution requiring invasive mechanical ventilation between March 2020 and March 2021. We collected baseline characteristics, clinical outcomes and blood oxygen indices. 36,383 blood gas data points were analysed from 184 patients over 30-days. Median participant age was 59.5 (IQR 51.0, 67.0), BMI 30.0 (IQR 25.2, 35.5) and the majority were men (62.5%) of white ethnicity (70.1%). Median duration of mechanical ventilation was 15-days (IQR 8, 25). Hospital survival at 30-days was 72.3%. Non-survivors exhibited significantly lower PaO2 throughout intensive care unit admission: day one to day 30 averaged mean difference -0.52 kPa (95% CI: -0.59 to -0.46, p<0.01). Non-survivors exhibited a significantly lower PaO2/FiO2 ratio with an increased separation over time: day one to day 30 averaged mean difference -5.64 (95% CI: -5.85 to -5.43, p<0.01). While all patients had sub-physiological CaO2, non-survivors exhibited significantly higher values. Non-survivors also exhibited significantly lower oxygen extraction ratio with an averaged mean difference of -0.08 (95% CI: -0.09 to -0.07, p<0.01) across day one to day 30. CONCLUSIONS: As a novel cause of acute hypoxic respiratory failure, COVID-19 offers a unique opportunity to study a homogenous cohort of patients with hypoxaemia. In mechanically ventilated adult COVID-19 patients, blood oxygen indices are abnormal with substantial divergence in PaO2/FiO2 ratio and oxygen extraction ratio between survivors and non-survivors. Despite having higher CaO2 values, non-survivors appear to extract less oxygen implying impaired oxygen utilisation. Further exploratory studies are warranted to evaluate and improve oxygen extraction which may help to improve outcomes in severe hypoxaemic mechanically ventilated COVID-19 patients.

Improving physical function of patients following intensive care unit admission (EMPRESS): protocol of a randomised controlled feasibility trial.

INTRODUCTION: Physical rehabilitation delivered early following admission to the intensive care unit (ICU) has the potential to improve short-term and long-term outcomes. The use of supine cycling together with other rehabilitation techniques has potential as a method of introducing rehabilitation earlier in the patient journey. The aim of the study is to determine the feasibility of delivering the designed protocol of a randomised clinical trial comparing a protocolised early rehabilitation programme including cycling with usual care. This feasibility study will inform a larger multicentre study. METHODS AND ANALYSIS: 90 acute care medical patients from two mixed medical-surgical ICUs will be recruited. We will include ventilated patients within 72 hours of initiation of mechanical ventilation and expected to be ventilated a further 48 hours or more. Patients will receive usual care or usual care plus two 30 min rehabilitation sessions 5 days/week.Feasibility outcomes are (1) recruitment of one to two patients per month per site; (2) protocol fidelity with >75% of patients commencing interventions within 72 hours of mechanical ventilation, with >70% interventions delivered; and (3) blinded outcome measures recorded at three time points in >80% of patients. Secondary outcomes are (1) strength and function, the Physical Function ICU Test-scored measured on ICU discharge; (2) hospital length of stay; and (3) mental health and physical ability at 3 months using the WHO Disability Assessment Schedule 2. An economic analysis using hospital health services data reported with an embedded health economic study will collect and assess economic and quality of life data including the Hospital Anxiety and Depression Scales core, the Euroqol-5 Dimension-5 Level and the Impact of Event Score. ETHICS AND DISSEMINATION: The study has ethical approval from the South Central Hampshire A Research Ethics Committee (19/SC/0016). All amendments will be approved by this committee. An independent trial monitoring committee is overseeing the study. Results will be made available to critical care survivors, their caregivers, the critical care societies and other researchers. TRIAL REGISTRATION NUMBER: NCT03771014.

Compassionate use of Pulmonary Vasodilators in Acute Severe Hypoxic Respiratory Failure due to COVID-19.

BACKGROUND: There have been over 200 million cases and 4.4 million deaths from COVID-19 worldwide. Despite the lack of robust evidence one potential treatment for COVID-19 associated severe hypoxaemia is inhaled pulmonary vasodilator (IPVD) therapy, using either nitric oxide (iNO) or prostaglandins. We describe the implementation of, and outcomes from, a protocol using IPVDs in a cohort of patients with severe COVID-19 associated respiratory failure receiving maximal conventional support. METHODS: Prospectively collected data from adult patients with SARS-CoV-2 admitted to the intensive care unit (ICU) at a large teaching hospital were analysed for the period 14th March 2020 - 11th February 2021. An IPVD was considered if the PaO2/FiO2 (PF) ratio was less than 13.3kPa despite maximal conventional therapy. Nitric oxide was commenced at 20ppm and titrated to response. If oxygenation improved Iloprost nebulisers were commenced and iNO weaned. The primary outcome was percentage changes in PF ratio and Alveolar-arterial (A-a) gradient. RESULTS: Fifty-nine patients received IPVD therapy during the study period. The median PF ratio before IPVD therapy was commenced was 11.33kPa (9.93-12.91). Patients receiving an IPVD had a lower PF ratio (14.37 vs. 16.37kPa, p = 0.002) and higher APACHE-II score (17 vs. 13, p = 0.028) at ICU admission. At 72 hours after initiating an IPVD the median improvement in PF ratio was 33.9% (-4.3-84.1). At 72 hours changes in PF ratio (70.8 vs. -4.1%, p < 0.001) and reduction in A-a gradient (44.7 vs. 14.8%, p < 0.001) differed significantly between survivors (n = 33) and non-survivors (n = 26). CONCLUSIONS: The response to IPVDs in patients with COVID-19 associated acute hypoxic respiratory failure differed significantly between survivors and non-survivors. Both iNO and prostaglandins may offer therapeutic options for patients with severe refractory hypoxaemia due to COVID-19. The use of inhaled prostaglandins, and iNO where feasible, should be studied in adequately powered prospective randomised trials.

Biomarker identification using dynamic time warping analysis: a longitudinal cohort study of patients with COVID-19 in a UK tertiary hospital.

OBJECTIVES: COVID-19 is a heterogeneous disease, and many reports have described variations in demographic, biochemical and clinical features at presentation influencing overall hospital mortality. However, there is little information regarding longitudinal changes in laboratory prognostic variables in relation to disease progression in hospitalised patients with COVID-19. DESIGN AND SETTING: This retrospective observational report describes disease progression from symptom onset, to admission to hospital, clinical response and discharge/death among patients with COVID-19 at a tertiary centre in South East England. PARTICIPANTS: Six hundred and fifty-one patients treated for SARS-CoV-2 between March and September 2020 were included in this analysis. Ethical approval was obtained from the HRA Specific Review Board (REC 20/HRA/2986) for waiver of informed consent. RESULTS: The majority of patients presented within 1 week of symptom onset. The lowest risk patients had low mortality (1/45, 2%), and most were discharged within 1 week after admission (30/45, 67%). The highest risk patients, as determined by the 4C mortality score predictor, had high mortality (27/29, 93%), with most dying within 1 week after admission (22/29, 76%). Consistent with previous reports, most patients presented with high levels of C reactive protein (CRP) (67% of patients >50 mg/L), D-dimer (98%>upper limit of normal (ULN)), ferritin (65%>ULN), lactate dehydrogenase (90%>ULN) and low lymphocyte counts (81%