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.

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.

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.

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.

Severe COVID-19 pneumonia in an intensive care setting and comparisons with historic severe viral pneumonia due to other viruses.

PURPOSE: Severe viral pneumonia is associated with significant morbidity and mortality. Recent COVID-19 pandemic continues to impose significant health burden worldwide, and individual pandemic waves often lead to a large surge in the intensive care unit (ICU) admissions for respiratory support. Comparisons of severe SARS-CoV-2 pneumonia with other seasonal and nonseasonal severe viral infections are rarely studied in an intensive care setting. METHODS: A retrospective cohort study comparing patients admitted to ICU with COVID-19 between March and June 2020 and those with viral pneumonias between January and December 2019. We compared patient specific demographic variables, duration of illness, ICU organ supportive measures and outcomes between both groups. RESULTS: Analysis of 93 COVID-19 (Group 1) and 52 other viral pneumonia patients (Group 2) showed an increased proportion of obesity (42% vs. 23%, p = 0.02), non-White ethnicities (41% vs. 6%, p < 0.001) and diabetes mellitus (30% vs. 13%, p = 0.03) in Group 1, with lower prevalence of chronic obstructive pulmonary disease (COPD)/asthma (16% vs. 34%, p = 0.02). In Group 1, the neutrophil to lymphocyte ratio was much lower (6.7 vs. 10, p = 0.006), and invasive mechanical ventilation (58% vs. 26%, p < 0.001) was more common. Length of ICU (8 vs. 4, p < 0.001) and hospital stay (22 vs. 11, p < 0.001) was prolonged in Group 1, with no significant difference in mortality. Influenza A and rhinovirus were the most common pathogens in Group 2 (26% each). CONCLUSIONS: Key differences were identified within demographics (obesity, ethnicity, age, ICU scores, comorbidities) and organ support. Despite these variations, there were no significant differences in mortality between both groups. Further studies with larger sample sizes would allow for further assessment of clinical parameters in these patients.

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%

Can a quantitative assessment of SARS-CoV-2 PCR predict degree of severity and outcomes in critical care patients with COVID-19?

Real-Time polymerase chain reaction (qPCR) is the gold standard diagnostic method for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Cycle threshold (Ct) is defined as the number of heating and cooling cycles required during the PCR process. Ct-values are inversely proportional to the amount of target nucleic acid in a sample. Our aim, in this retrospective study, was to determine the impact of serial SARS-CoV-2 qPCR Ct-values on: mortality, need for mechanical ventilation (MV) and development of acute kidney injury (AKI) in patients admitted to the intensive care unit (ICU) with COVID-19. Ct values were evaluated during the time points from pre-ICU admission to week 1, week 2 and week 3 during ICU stay; impact on mortality, need for MV and AKI was determined. There was a continuous increment in Ct-values over the ICU stay from 1st week through to 3rd week. Although not significant, lower ICU 1st week Ct-values were associated with Black ethnicity, increased need for MV and mortality. However, patients who had developed AKI at any stage of their illness had significantly lower Ct-values compared to those with normal renal function. When ICU 1st-week Ct-values are subcategorised as <20, 20-30 and >30 the 28-day survival probability was less for patients with Ct-values of <20. This report shows that the impact of Ct-values and outcomes, especially AKI, among patients at different time points prior to and during ICU stay, larger studies are required to confirm out findings.

Predictive Role of Haematological Determinants on Outcomes of Critically Ill COVID-19 Patients Admitted to Intensive Care Unit.

BACKGROUND:  The mortality of patients admitted to the intensive care unit (ICU) with COVID-19 remains significantly high. Severe COVID-19 pneumonia is characterised by refractory hypoxemia with significant shunting due to a combination of alveolar damage, vascular vasoconstriction, and occlusion due to microthrombi. Similar pathological features are seen in extra-pulmonary organs. However, the influence of thrombotic markers on the risk of mechanical ventilation (MV) and the development of acute kidney injury (AKI) is not fully defined. METHODS:  This was a cross-sectional evaluation of haemostatic and thrombotic markers of COVID-19 patients admitted to the ICU to determine their predictability for the development of thromboembolism and the need for non-invasive or invasive MV, development of AKI, and mortality. RESULTS:  An extended coagulation profile was obtained in 71 SARS-CoV-2 positive patients admitted to the ICU. All patients had acute severe hypoxic respiratory failure and required non-invasive or invasive MV. There were increases in peak D-dimer (3.0 mg/L), factor VIII levels (255 IU/dL) vWF antigen (471 IU/dL) with low ADAMTS13 activity (54.7 IU/dL) compared to the reference ranges. Peak D-dimer was consistently raised in patients who developed AKI and required invasive MV. ADAMTS13/vWF/platelet axis was associated with disease severity, multi-organ dysfunction, and mortality. CONCLUSIONS:  Haematological abnormalities are a common feature of severe COVID-19 pneumonia. We found peak D-dimer and vWF-ADAMTS13-platelet axis are associated with increased ICU severity and outcome in severe COVID-19 patients admitted to ICU. Larger studies are needed to evaluate this more comprehensively.

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.

Recombinant ADAMTS13 reduces abnormally up-regulated von Willebrand factor in plasma from patients with severe COVID-19.

Thrombosis affecting the pulmonary and systemic vasculature is common during severe COVID-19 and causes adverse outcomes. Although thrombosis likely results from inflammatory activation of vascular cells, the mediators of thrombosis remain unconfirmed. In a cross-sectional cohort of 36 severe COVID-19 patients, we show that markedly increased plasma von Willebrand factor (VWF) levels were accompanied by a partial reduction in the VWF regulatory protease ADAMTS13. In all patients we find this VWF/ADAMTS13 imbalance to be associated with persistence of ultra-high-molecular-weight (UHMW) VWF multimers that are highly thrombogenic in some disease settings. Incubation of plasma samples from patients with severe COVID-19 with recombinant ADAMTS13 (rADAMTS13) substantially reduced the abnormally high VWF activity, reduced overall multimer size and depleted UHMW VWF multimers in a time and concentration dependent manner. Our data implicate disruption of normal VWF/ADAMTS13 homeostasis in the pathogenesis of severe COVID-19 and indicate that this can be reversed ex vivo by correction of low plasma ADAMTS13 levels. These findings suggest a potential therapeutic role for rADAMTS13 in helping restore haemostatic balance in COVID-19 patients.

Research Evaluation Alongside Clinical Treatment in COVID-19 (REACT COVID-19): an observational and biobanking study.

INTRODUCTION: The COVID-19 pandemic caused by SARS-CoV-2 places immense worldwide demand on healthcare services. Earlier identification of patients at risk of severe disease may allow intervention with experimental targeted treatments, mitigating the course of their disease and reducing critical care service demand. METHODS AND ANALYSIS: This prospective observational study of patients tested or treated for SARS-CoV-2, who are under the care of the tertiary University Hospital Southampton NHS Foundation Trust (UHSFT), captured data from admission to discharge; data collection commenced on 7 March 2020. Core demographic and clinical information, as well as results of disease-defining characteristics, was captured and recorded electronically from hospital clinical record systems at the point of testing. Manual data were collected and recorded by the clinical research team for assessments which are not part of the structured electronic healthcare record, for example, symptom onset date. Thereafter, participant records were continuously updated during hospital stay and their follow-up period. Participants aged >16 years were given the opportunity to provide consent for excess clinical sample storage with optional further biological sampling. These anonymised samples were linked to the clinical data in the Real-time Analytics for Clinical Trials platform and were stored within a biorepository at UHSFT. ETHICS AND DISSEMINATION: Ethical approval was obtained from the HRA Specific Review Board (REC 20/HRA/2986) for waiver of informed consent for the database-only cohort; the procedures conform with the Declaration of Helsinki. The study design, protocol and patient-facing documentation for the biobanking arm of the study have been approved by North West Research Ethics Committee (REC 17/NW/0632) as an amendment to the National Institute for Health Research Southampton Clinical Research Facility-managed Southampton Research Biorepository. This study will be published as peer-reviewed articles and presented at conferences, presentations and workshops.

Nebulised surfactant for the treatment of severe COVID-19 in adults (COV-Surf): A structured summary of a study protocol for a randomized controlled trial.

OBJECTIVES: SARS-Cov-2 virus preferentially binds to the Angiotensin Converting Enzyme 2 (ACE2) on alveolar epithelial type II cells, initiating an inflammatory response and tissue damage which may impair surfactant synthesis contributing to alveolar collapse, worsening hypoxia and leading to respiratory failure. The objective of this study is to evaluate the feasibility, safety and efficacy of nebulised surfactant in COVID-19 adult patients requiring mechanical ventilation for respiratory failure. TRIAL DESIGN: This study is a dose-escalating randomized open-label clinical trial of 20 COVID-19 patients. PARTICIPANTS: This study is conducted in two centres: University Hospital Southampton and University College London Hospitals. Eligible participants are aged ≥18, hospitalised with COVID-19 (confirmed by PCR), who require endotracheal intubation and are enrolled within 24 hours of mechanical ventilation. For patients unable to consent, assent is obtained from a personal legal representative (PerLR) or professional legal representative (ProfLR) prior to enrolment. The following are exclusion criteria: imminent expected death within 24 hours; specific contraindications to surfactant administration (e.g. known allergy, pneumothorax, pulmonary hemorrhage); known or suspected pregnancy; stage 4 chronic kidney disease or requiring dialysis (i.e., eGFR < 30); liver failure (Child-Pugh Class C); anticipated transfer to another hospital, which is not a study site, within 72 hours; current or recent (within 1 month) participation in another study that, in the opinion of the investigator, would prevent enrollment for safety reasons; and declined consent or assent. INTERVENTION AND COMPARATOR: Intervention: The study is based on an investigational drug/device combination product. The surfactant product is Bovactant (Alveofact®), a natural animal derived (bovine) lung surfactant formulated as a lyophilized powder in 108 mg vials and reconstituted to 45 mg/mL in buffer supplied in a prefilled syringe. It is isolated by lung lavage and, by weight, is a mixture of: phospholipid (75% phosphatidylcholine, 13% phosphatidylglycerol, 3% phosphatidylethanolamine, 1% phosphatidylinositol and 1% sphingomyelin), 5% cholesterol, 1% lipid-soluble surfactant-associated proteins (SP-B and SP-C), very low levels of free fatty acid, lyso-phosphatidylcholine, water and 0.3% calcium. The Drug Delivery Device is the AeroFact-COVID™ nebulizer, an investigational device based on the Aerogen® Solo vibrating mesh nebulizer. The timing and escalation dosing plans for the surfactant are as follows. Cohort 1: Three patients will receive 10 vials (1080 mg) each of surfactant at dosing times of 0 hours, 8 hours and 24 hours. 2 controls with no placebo intervention. Cohort 2: Three patients will receive 10 vials (1080 mg) of surfactant at dosing times of 0 hours and 8 hours, and 30 vials (3240 mg) at a dosing time of 24 hours. 2 controls with no placebo intervention. Cohort 3: Three patients will receive 10 vials (1080 mg) of surfactant at a dosing time of 0 hours, and 30 vials (3240 mg) at dosing times of 8 hours and 24 hours. 2 controls with no placebo intervention. Cohort 4: Three patients will receive 30 (3240 mg) vials each of surfactant at dosing times of 0 hours, 8 hours and 24 hours. 2 controls. 2 controls with no placebo intervention. The trial steering committee, advised by the data monitoring committee, will review trial progression and dose escalation/maintenance/reduction after each cohort is completed (48-hour primary outcome timepoint reached) based on available feasibility, adverse event, safety and efficacy data. The trial will not be discontinued on the basis of lack of efficacy. The trial may be stopped early on the basis of safety or feasibility concerns. Comparator: No placebo intervention. All participants will receive usual standard of care in accordance with the local policies for mechanically ventilated patients and all other treatments will be left to the discretion of the attending physician. MAIN OUTCOMES: The co-primary outcome is the improvement in oxygenation (PaO2/FiO2 ratio) and pulmonary ventilation (Ventilation Index (VI), where VI = [RR x (PIP - PEEP) × PaCO2]/1000) at 48 hours after study initiation. The secondary outcomes include frequency and severity of adverse events (AEs), Adverse Device Effects (ADEs), Serious Adverse Events (SAEs) and Serious Adverse Device Events (SADEs), change in pulmonary compliance, change in positive end-expiratory pressure (PEEP) requirement of ventilatory support at 24 and 48 hours after study initiation, clinical improvement defined by time to one improvement point on the ordinal scale described in the WHO master protocol (2020) recorded while hospitalised, days of mechanical ventilation, mechanical ventilator free days (VFD) at day 21, length of intensive care unit stay, number of days hospitalised and mortality at day 28. Exploratory end points will include quantification of SARS-CoV-2 viral load from tracheal aspirates using PCR, surfactant dynamics (synthesis and turnover) and function (surface tension reduction) from deep tracheal aspirate samples (DTAS), surfactant phospholipid concentrations in plasma and DTAS, inflammatory markers (cellular and cytokine) in plasma and DTAS, and blood oxidative stress markers. RANDOMISATION: After informed assent, patients fulfilling inclusion criteria will be randomised to 3:2 for the treatment and control arms using an internet-based block randomization service (ALEA tool for clinical trials, FormsVision BV) in combination with electronic data collection. Randomisation will be done by the recruiting centre with a unique subject identifier specific to that centre. BLINDING (MASKING): This is an open-labelled unblinded study. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The total sample size is 20 COVID-19 mechanically ventilated patients (12 intervention; 8 control). TRIAL STATUS: Current protocol version is V2 dated 5th of June 2020. The recruitment is currently ongoing and started on the 14th of October 2020. The anticipated study completion date is November 2021. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04362059 (Registered 24 April 2020), EUDAMED number: CIV-GB-20-06-033328, EudraCT number: 2020-001886-35 (Registered 11 May 2020) FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

Conscious prone positioning during non-invasive ventilation in COVID-19 patients: experience from a single centre.

Critically ill patients admitted to hospital following SARS-CoV-2 infection often experience hypoxic respiratory failure and a proportion require invasive mechanical ventilation to maintain adequate oxygenation. The combination of prone positioning and non-invasive ventilation in conscious patients may have a role in improving oxygenation. The purpose of this study was to assess the effect of prone positioning in spontaneously ventilating patients receiving non-invasive ventilation admitted to the intensive care.  Clinical data of 81 patients admitted with COVID 19 pneumonia and acute hypoxic respiratory failure were retrieved from electronic medical records and examined. Patients who had received prone positioning in combination with non-invasive ventilation were identified. A total of 20 patients received prone positioning in conjunction with non-invasive ventilation. This resulted in improved oxygenation as measured by a change in PaO 2/FiO 2 (P/F) ratio of 28.7 mmHg while prone, without significant change in heart rate or respiratory rate. Patients on average underwent 5 cycles with a median duration of 3 hours. There were no reported deaths, 7 of the 20 patients (35%) failed non-invasive ventilation and subsequently required intubation and mechanical ventilation. In our cohort of 20 COVID-19 patients with moderate acute hypoxic respiratory failure, prone positioning with non-invasive ventilation resulted in improved oxygenation. Prone positioning with non-invasive ventilation may be considered as an early therapeutic intervention in COVID-19 patients with moderate acute hypoxic respiratory failure.

Recurrent Pneumothorax in a Critically Ill Ventilated COVID-19 Patient.

We present this case of a young woman with SARS-CoV-2 viral infection resulting in coronavirus 2019 (COVID-19) lung disease complicated by a complex hydropneumothorax, recurrent pneumothorax, and pneumatoceles. A 33-year-old woman presented to the hospital with a one-week history of cough, shortness of breath, and myalgia, with no other significant past medical history. She tested positive for COVID-19 and subsequently, her respiratory function rapidly deteriorated, necessitating endotracheal intubation and mechanical ventilation. She had severe hypoxic respiratory failure requiring a protracted period on the mechanical ventilator with different ventilation strategies and multiple cycles of prone positioning. During her proning, after two weeks on the intensive care unit, she developed tension pneumothorax that required bilateral intercostal chest drains (ICD) to stabilise her. After 24 days, she had a percutaneous tracheostomy and began her respiratory wean; however, this was limited due to the ongoing infection. Thorax CT demonstrated a left-sided pneumothorax, with bilateral pneumatoceles and a sizeable, complex hydropneumothorax. Despite the insertion of ICDs, the hydropneumothorax persisted over months and initially progressed in size on serial scans needing multiple ICDs. She was too ill for surgical interventions initially, opting for conservative management. After 60 days, she successfully underwent a video-assisted thoracoscopic surgery (VATS) for a washout and placement of further ICDs. She was successfully decannulated after 109 days on the intensive care unit and was discharged to a rehabilitation unit after 116 days of being an inpatient, with her last thorax CT showing some residual pneumatoceles but significant improvement. Late changes may mean patients recovering from the COVID-19 infection are at increased risk of pneumothoracies. Clinicians need to be alert to this, especially as bullous rupture may not present as a classical pneumothorax.