Publications by authors named "Daniel F McAuley"

150 Publications

Transepithelial nasal potential difference in patients with, and at risk of acute respiratory distress syndrome.

Thorax 2021 Apr 22. Epub 2021 Apr 22.

Intensive Care Unit, Royal Victoria Hospital, Belfast, UK

Background: Impaired alveolar fluid clearance, determined in part by alveolar sodium transport, is associated with acute respiratory distress syndrome (ARDS). Nasal sodium transport may reflect alveolar transport. The primary objective of this prospective, observational study was to determine if reduced nasal sodium transport, as measured by nasal potential difference (NPD), was predictive of the development of and outcome from ARDS.

Methods: NPD was measured in 15 healthy controls and in 88 patients: 40 mechanically ventilated patients defined as 'at-risk' for ARDS, 61 mechanically ventilated patients with ARDS (13 who were previously included in the 'at-risk' group) and 8 ARDS survivors on the ward.

Results: In at-risk subjects, maximum NPD (mNPD) was greater in those who developed ARDS (difference -8.4 mV; 95% CI -13.8 to -3.7; p=0.005) and increased mNPD predicted the development of ARDS before its onset (area under the curve (AUC) 0.75; 95% CI 0.59 to 0.89). In the ARDS group, mNPD was not significantly different for survivors and non-survivors (p=0.076), and mNPD was a modest predictor of death (AUC 0.60; 95% CI 0.45 to 0.75). mNPD was greater in subjects with ARDS (-30.8 mV) than in at-risk subjects (-24.2 mV) and controls (-19.9 mV) (p<0.001). NPD values were not significantly different for survivors and controls (p=0.18).

Conclusions: Increased NPD predicts the development of ARDS in at-risk subjects but does not predict mortality. NPD increases before ARDS develops, is greater during ARDS, but is not significantly different for controls and survivors. These results may reflect the upregulated sodium transport necessary for alveolar fluid clearance in ARDS. NPD may be useful as a biomarker of endogenous mechanisms to stimulate sodium transport. Larger studies are now needed to confirm these associations and predictive performance.
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http://dx.doi.org/10.1136/thoraxjnl-2020-215587DOI Listing
April 2021

Non-invasive respiratory support strategies in COVID-19.

Lancet Respir Med 2021 Apr 16. Epub 2021 Apr 16.

Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast BT9 7BL, UK; Regional Intensive Care Unit, Belfast Health and Social Care Trust, Belfast, UK. Electronic address:

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http://dx.doi.org/10.1016/S2213-2600(21)00168-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051928PMC
April 2021

Secreted Extracellular Cyclophilin A is a Novel Mediator of Ventilator Induced Lung Injury.

Am J Respir Crit Care Med 2021 Apr 13. Epub 2021 Apr 13.

Imperial College London, Anaesthetics & Intensive Care, London, United Kingdom of Great Britain and Northern Ireland;

Rationale: Mechanical ventilation is a mainstay of intensive care but contributes to the mortality of patients through ventilator induced lung injury. Extracellular Cyclophilin A is an emerging inflammatory mediator and metalloproteinase inducer, and the gene responsible for its expression has recently been linked to COVID-19 infection.

Objectives: Here we explore the involvement of extracellular Cyclophilin A in the pathophysiology of ventilator-induced lung injury.

Methods: Mice were ventilated with low or high tidal volume for up to 3 hours, with or without blockade of extracellular Cyclophilin A signalling, and lung injury and inflammation were evaluated. Human primary alveolar epithelial cells were exposed to in vitro stretch to explore the cellular source of extracellular Cyclophilin A, and Cyclophilin A levels were measured in bronchoalveolar lavage fluid from acute respiratory distress syndrome patients, to evaluate clinical relevance.

Measurements And Main Results: High tidal volume ventilation in mice provoked a rapid increase in soluble Cyclophilin A levels in the alveolar space, but not plasma. In vivo ventilation and in vitro stretch experiments indicated alveolar epithelium as the likely major source. In vivo blockade of extracellular Cyclophilin A signalling substantially attenuated physiological dysfunction, macrophage activation and matrix metalloproteinases. Finally, we found that patients with acute respiratory distress syndrome showed markedly elevated levels of extracellular Cyclophilin A within bronchoalveolar lavage.

Conclusions: Cyclophilin A is upregulated within the lungs of injuriously ventilated mice (and critically ill patients), where it plays a significant role in lung injury. Extracellular Cyclophilin A represents an exciting novel target for pharmacological intervention.
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http://dx.doi.org/10.1164/rccm.202009-3545OCDOI Listing
April 2021

Swallowing therapy compared to standard care may not have had a beneficial effect on the incidence of pneumonia for patients in acute care. Author's reply.

Intensive Care Med 2021 Apr 13. Epub 2021 Apr 13.

Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, Northern Ireland.

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http://dx.doi.org/10.1007/s00134-021-06381-7DOI Listing
April 2021

Targeting Candida albicans in dual-species biofilms with antifungal treatment reduces Staphylococcus aureus and MRSA in vitro.

PLoS One 2021 8;16(4):e0249547. Epub 2021 Apr 8.

Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, United Kingdom.

Polymicrobial biofilms consisting of fungi and bacteria are frequently formed on endotracheal tubes and may contribute to development of ventilator associated pneumonia (VAP) in critically ill patients. This study aimed to determine the role of early Candida albicans biofilms in supporting dual-species (dual-kingdom) biofilm formation with respiratory pathogens in vitro, and investigated the effect of targeted antifungal treatment on bacterial cells within the biofilms. Dual-species biofilm formation between C. albicans and three respiratory pathogens commonly associated with VAP (Pseudomonas aeruginosa, Escherichia coli and Staphylococcus aureus) was studied using quantitative PCR. It was shown that early C. albicans biofilms enhanced the numbers of E. coli and S. aureus (including methicillin resistant S. aureus; MRSA) but not P. aeruginosa within dual-species biofilms. Transwell assays demonstrated that contact with C. albicans was required for the increased bacterial cell numbers observed. Total Internal Reflection Fluorescence microscopy showed that both wild type and hyphal-deficient C. albicans provided a scaffold for initial bacterial adhesion in dual species biofilms. qPCR results suggested that further maturation of the dual-species biofilm significantly increased bacterial cell numbers, except in the case of E.coli with hyphal-deficient C. albicans (Ca_gcn5Δ/Δ). A targeted preventative approach with liposomal amphotericin (AmBisome®) resulted in significantly decreased numbers of S. aureus in dual-species biofilms, as determined by propidium monoazide-modified qPCR. Similar results were observed when dual-species biofilms consisting of clinical isolates of C. albicans and MRSA were treated with liposomal amphotericin. However, reductions in E. coli numbers were not observed following liposomal amphotericin treatment. We conclude that early C. albicans biofilms have a key supporting role in dual-species biofilms by enhancing bacterial cell numbers during biofilm maturation. In the setting of increasing antibiotic resistance, an important and unexpected consequence of antifungal treatment of dual-species biofilms, is the additional benefit of decreased growth of multi-drug resistant bacteria such as MRSA, which could represent a novel future preventive strategy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249547PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8031443PMC
April 2021

Major differences in ICU admissions during the first and second COVID-19 wave in Germany.

Lancet Respir Med 2021 05 5;9(5):e47-e48. Epub 2021 Mar 5.

Department of Health Care Management, Technische Universität Berlin, Berlin, Germany.

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http://dx.doi.org/10.1016/S2213-2600(21)00101-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078895PMC
May 2021

Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19.

N Engl J Med 2021 04 25;384(16):1491-1502. Epub 2021 Feb 25.

From Imperial College London (A.C.G., F.A.-B.), Imperial College Healthcare NHS Trust, St. Mary's Hospital (A.C.G.), Intensive Care National Audit and Research Centre (P.R.M., K.M.R.), University College London Hospital (R.H.), King's College London (M.S.-H.), and Guy's and St. Thomas' NHS Foundation Trust (M.S.-H.), London, University of Oxford (A. Beane) and NHS Blood and Transplant (L.J.E.), Oxford, and University of Bristol, Bristol (C.A.B.) - all in the United Kingdom; Monash University (A.D.N., A. Buzgau, A.C.C., A.M.H., S.P.M., J.C.P., C.G., S.A.W.) and Alfred Health (A.D.N., A.C.C.), Melbourne, VIC, Fiona Stanley Hospital (E. Litton, K.O.) and University of Western Australia (E. Litton), Perth, WA, University of Sydney and Royal Prince Alfred Hospital, Sydney (A.E.P.), and St. John of God Hospital, Subiaco, WA (S.A.W.) - all in Australia; University College Dublin, Dublin (A.D.N.); King Saud bin Abdulaziz University for Health Sciences and King Abdullah International Medical Research Center, Riyadh, Saudi Arabia (Y.M.A.); Hospital Raymond Poincaré (Assistance Publique-Hôpitaux de Paris) and Université Paris Saclay-Université de Versailles Saint-Quentin-en-Yvelines-INSERM, Garches, and Université de Versailles Saint-Quentin-en-Yvelines-Université Paris Saclay, Montigny-le-Bretonneux - all in France (D.A.); University Medical Center Utrecht, Utrecht (W.B.-P., M.J.M.B., H.L.L., E.R., L.P.G.D.), and Radboudumc, Nijmegen (F.L.V.) - both in the Netherlands; Berry Consultants, Austin, TX (L.R.B., M.A.D., M.F., E. Lorenzi, A.M., C.T.S., R.J.L., S.B.); St. Michael's Hospital Unity Health (Z.B., J.C.M., M.S.S.) and University Health Network and University of Toronto (P.R.L.), Toronto, Université de Sherbrooke, Sherbrooke, QC (F.L.), University of British Columbia, Vancouver (S.M.), University of Alberta, Edmonton (W.I.S.), Université Laval, Québec City (A.F.T.), and University of Manitoba, Winnipeg, MB (R.Z.) - all in Canada; Jena University Hospital, Jena, Germany (F.M.B.); Auckland City Hospital (E.J.D., T.E.H., S.P.M., R.L.P., C.J.M.), Middlemore Hospital (S.C.M.), and University of Auckland (R.L.P.), Auckland, and Medical Research Institute of New Zealand, Wellington (T.E.H., S.P.M., A.M.T.) - all in New Zealand; University of Antwerp, Wilrijk, Belgium (H.G.); University of Oxford, Bangkok, Thailand (R.H.); National Intensive Care Surveillance, Colombo, Sri Lanka (R.H.); UPMC Children's Hospital of Pittsburgh (C.M.H.) and University of Pittsburgh (K.M.L., F.B.M., B.J.M., S.K.M., C.W.S., D.C.A.), Pittsburgh; Queen's University Belfast and Royal Victoria Hospital, Belfast, Northern Ireland (D.F.M.); University of Helsinki and Helsinki University Hospital, Helsinki (V.P.); and Harbor-UCLA Medical Center, Torrance, CA (R.J.L.).

Background: The efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear.

Methods: We evaluated tocilizumab and sarilumab in an ongoing international, multifactorial, adaptive platform trial. Adult patients with Covid-19, within 24 hours after starting organ support in the intensive care unit (ICU), were randomly assigned to receive tocilizumab (8 mg per kilogram of body weight), sarilumab (400 mg), or standard care (control). The primary outcome was respiratory and cardiovascular organ support-free days, on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with predefined criteria for superiority, efficacy, equivalence, or futility. An odds ratio greater than 1 represented improved survival, more organ support-free days, or both.

Results: Both tocilizumab and sarilumab met the predefined criteria for efficacy. At that time, 353 patients had been assigned to tocilizumab, 48 to sarilumab, and 402 to control. The median number of organ support-free days was 10 (interquartile range, -1 to 16) in the tocilizumab group, 11 (interquartile range, 0 to 16) in the sarilumab group, and 0 (interquartile range, -1 to 15) in the control group. The median adjusted cumulative odds ratios were 1.64 (95% credible interval, 1.25 to 2.14) for tocilizumab and 1.76 (95% credible interval, 1.17 to 2.91) for sarilumab as compared with control, yielding posterior probabilities of superiority to control of more than 99.9% and of 99.5%, respectively. An analysis of 90-day survival showed improved survival in the pooled interleukin-6 receptor antagonist groups, yielding a hazard ratio for the comparison with the control group of 1.61 (95% credible interval, 1.25 to 2.08) and a posterior probability of superiority of more than 99.9%. All secondary analyses supported efficacy of these interleukin-6 receptor antagonists.

Conclusions: In critically ill patients with Covid-19 receiving organ support in ICUs, treatment with the interleukin-6 receptor antagonists tocilizumab and sarilumab improved outcomes, including survival. (REMAP-CAP ClinicalTrials.gov number, NCT02735707.).
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http://dx.doi.org/10.1056/NEJMoa2100433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953461PMC
April 2021

ARDS Subphenotypes Beyond the Syndrome: A Step Towards Treatable Traits?

Am J Respir Crit Care Med 2021 Feb 10. Epub 2021 Feb 10.

University of Belfast, Belfast, United Kingdom of Great Britain and Northern Ireland.

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http://dx.doi.org/10.1164/rccm.202101-0218EDDOI Listing
February 2021

Moral distress in end-of-life decisions: A qualitative study of intensive care physicians.

J Crit Care 2021 04 24;62:185-189. Epub 2020 Dec 24.

Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University of Belfast, Belfast, UK. Electronic address:

Purpose: The purpose is to explore triggers for moral distress, constraints preventing physicians from doing the right thing and ensuing consequences in making decisions for patients approaching end of life in intensive care.

Materials And Methods: The qualitative study was undertaken in a tertiary referral intensive care unit in Northern Ireland in the United Kingdom. Drawing upon patient case studies of decisions about non escalation and/or withdrawal of life support, we undertook indepth interviews with senior and junior physicians. Interviews were transcribed verbatim and narratively analysed.

Results: Eighteen senior and junior physicians involved in 21 patient case studies were interviewed. Analysis determined two predominant themes: key moral distress triggers; and strategies and consequences. Junior residents reported most instances of moral distress, triggered by perceived futility, lack of continuity, protracted decisions and failure to ensure 'good death'. Senior physicians' triggers included constraint of clinical autonomy. Moral distress was far reaching, affecting personal life, working relationships and career choice.

Conclusion: This study is the first to explore physicians' moral distress in end-of-life decisions in intensive care via a narrative inquiry approach using case studies. Results have implications for the education, recruitment and retention of physicians, relevant in the Covid 19 pandemic.
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http://dx.doi.org/10.1016/j.jcrc.2020.12.019DOI Listing
April 2021

Outcome of Acute Hypoxaemic Respiratory Failure. Insights from the Lung Safe Study.

Eur Respir J 2020 Dec 17. Epub 2020 Dec 17.

Keenan Research Centre, Li Ka Shing Knowledge Institute, St Michael's Hospital, Unity Heath Toronto, Toronto, Ontario, Canada.

Background: The current incidence and outcome of patients with acute hypoxaemic respiratory failure requiring mechanical ventilation in intensive care unit are unknown, especially for patients not meeting criteria for acute respiratory distress syndrome (ARDS).

Methods: An international, multicentre, prospective cohort study of patients presenting with hypoxemia early in the course of mechanical ventilation, conducted during four consecutive weeks in the winter of 2014 in 459 ICUs from 50 countries (LUNG SAFE). Patients were enrolled with PaO/FiO ≤300 mmHg, new pulmonary infiltrates and need for mechanical ventilation with a positive end-expiratory pressure (PEEP) of at least 5 cm HO. ICU prevalence, causes of hypoxemia, hospital survival, factors associated with hospital mortality were measured. Patients with unilateral bilateral opacities were compared.

Findings: 12 906 critically ill patients received mechanical ventilation and 34.9% with hypoxaemia and new infiltrates were enrolled, separated into ARDS (69.0%), unilateral infiltrate (22.7%) and congestive heart failure (8.2%, CHF). The global hospital mortality was 38.6%. CHF patients had a mortality comparable to ARDS (44.1% 40.4%). Patients with unilateral-infiltrate had lower unadjusted mortality but similar adjusted mortality than ARDS. The number of quadrants on chest imaging was associated with an increased risk of death. There was no difference in mortality comparing patients with unilateral-infiltrate and ARDS with only 2 quadrants involved.

Interpretation: More than one third of the patients receiving mechanical ventilation have hypoxaemia and new infiltrates with an hospital mortality of 38.6%. Survival is dependent on the degree of pulmonary involvement whether or not ARDS criteria are reached.
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http://dx.doi.org/10.1183/13993003.03317-2020DOI Listing
December 2020

Will Not Breathing on Extracorporeal Membrane Oxygenation Help One Survive Acute Respiratory Distress Syndrome?

Crit Care Med 2020 Dec;48(12):1901-1904

Department of Medicine, Columbia University College of Physicians and Surgeons; and, Centre for Acute Respiratory Failure, New York-Presbyterian Hospital, New York, NY.

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http://dx.doi.org/10.1097/CCM.0000000000004647DOI Listing
December 2020

The Impact of Aging in Acute Respiratory Distress Syndrome: A Clinical and Mechanistic Overview.

Front Med (Lausanne) 2020 26;7:589553. Epub 2020 Oct 26.

Airway Innate Immunity Research (AiiR) Group, Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, United Kingdom.

Acute respiratory distress syndrome (ARDS) is associated with increased morbidity and mortality in the elderly population (≥65 years of age). Additionally, age is widely reported as a risk factor for the development of ARDS. However, the underlying pathophysiological mechanisms behind the increased risk of developing, and increased severity of, ARDS in the elderly population are not fully understood. This is compounded by the significant heterogeneity observed in patients with ARDS. With an aging population worldwide, a better understanding of these mechanisms could facilitate the development of therapies to improve outcomes in this population. In this review, the current clinical evidence of age as a risk factor and prognostic indicator in ARDS and the potential underlying mechanisms that may contribute to these factors are outlined. In addition, research on age-dependent treatment options and biomarkers, as well as future prospects for targeting these underlying mechanisms, are discussed.
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http://dx.doi.org/10.3389/fmed.2020.589553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649269PMC
October 2020

Airway Inflammation and Host Responses in the Era of CFTR Modulators.

Int J Mol Sci 2020 Sep 2;21(17). Epub 2020 Sep 2.

Airway Innate Immunity Research (AiiR) group, Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast BT9 7BL, Northern Ireland, UK.

The arrival of cystic fibrosis transmembrane conductance regulator (CFTR) modulators as a new class of treatment for cystic fibrosis (CF) in 2012 represented a pivotal advance in disease management, as these small molecules directly target the upstream underlying protein defect. Further advancements in the development and scope of these genotype-specific therapies have been transformative for an increasing number of people with CF (PWCF). Despite clear improvements in CFTR function and clinical endpoints such as lung function, body mass index (BMI), and frequency of pulmonary exacerbations, current evidence suggests that CFTR modulators do not prevent continued decline in lung function, halt disease progression, or ameliorate pathogenic organisms in those with established lung disease. Furthermore, it remains unknown whether their restorative effects extend to dysfunctional CFTR expressed in phagocytes and other immune cells, which could modulate airway inflammation. In this review, we explore the effects of CFTR modulators on airway inflammation, infection, and their influence on the impaired pulmonary host defences associated with CF lung disease. We also consider the role of inflammation-directed therapies in light of the widespread clinical use of CFTR modulators and identify key areas for future research.
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http://dx.doi.org/10.3390/ijms21176379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504341PMC
September 2020

Delving beneath the surface of hyperinflammation in COVID-19.

Lancet Rheumatol 2020 Oct 21;2(10):e578-e579. Epub 2020 Aug 21.

Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.

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http://dx.doi.org/10.1016/S2665-9913(20)30304-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442423PMC
October 2020

Prevalence of phenotypes of acute respiratory distress syndrome in critically ill patients with COVID-19: a prospective observational study.

Lancet Respir Med 2020 12 27;8(12):1209-1218. Epub 2020 Aug 27.

Critical Care Directorate, Royal Gwent Hospital, Newport, UK; Department of Anaesthesia, Intensive Care and Pain Medicine, Division of Population Medicine, Cardiff University, Cardiff, UK.

Background: In acute respiratory distress syndrome (ARDS) unrelated to COVID-19, two phenotypes, based on the severity of systemic inflammation (hyperinflammatory and hypoinflammatory), have been described. The hyperinflammatory phenotype is known to be associated with increased multiorgan failure and mortality. In this study, we aimed to identify these phenotypes in COVID-19-related ARDS.

Methods: In this prospective observational study done at two UK intensive care units, we recruited patients with ARDS due to COVID-19. Demographic, clinical, and laboratory data were collected at baseline. Plasma samples were analysed for interleukin-6 (IL-6) and soluble tumour necrosis factor receptor superfamily member 1A (TNFR1) using a novel point-of-care assay. A parsimonious regression classifier model was used to calculate the probability for the hyperinflammatory phenotype in COVID-19 using IL-6, soluble TNFR1, and bicarbonate levels. Data from this cohort was compared with patients with ARDS due to causes other than COVID-19 recruited to a previous UK multicentre, randomised controlled trial of simvastatin (HARP-2).

Findings: Between March 17 and April 25, 2020, 39 patients were recruited to the study. Median ratio of partial pressure of arterial oxygen to fractional concentration of oxygen in inspired air (PaO/FiO) was 18 kpa (IQR 15-21) and acute physiology and chronic health evaluation II score was 12 (10-16). 17 (44%) of 39 patients had died by day 28 of the study. Compared with survivors, patients who died were older and had lower PaO/FiO. The median probability for the hyperinflammatory phenotype was 0·03 (IQR 0·01-0·2). Depending on the probability cutoff used to assign class, the prevalence of the hyperinflammatory phenotype was between four (10%) and eight (21%) of 39, which is lower than the proportion of patients with the hyperinflammatory phenotype in HARP-2 (186 [35%] of 539). Using the Youden index cutoff (0·274) to classify phenotype, five (63%) of eight patients with the hyperinflammatory phenotype and 12 (39%) of 31 with the hypoinflammatory phenotype died. Compared with matched patients recruited to HARP-2, levels of IL-6 were similar in our cohort, whereas soluble TNFR1 was significantly lower in patients with COVID-19-associated ARDS.

Interpretation: In this exploratory analysis of 39 patients, ARDS due to COVID-19 was not associated with higher systemic inflammation and was associated with a lower prevalence of the hyperinflammatory phenotype than that observed in historical ARDS data. This finding suggests that the excess mortality observed in COVID-19-related ARDS is unlikely to be due to the upregulation of inflammatory pathways described by the parsimonious model.

Funding: US National Institutes of Health, Innovate UK, and Randox.
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http://dx.doi.org/10.1016/S2213-2600(20)30366-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718296PMC
December 2020

Apples and oranges: international comparisons of COVID-19 observational studies in ICUs.

Lancet Respir Med 2020 10 21;8(10):952-953. Epub 2020 Aug 21.

Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, BT9 7BL, UK. Electronic address:

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http://dx.doi.org/10.1016/S2213-2600(20)30368-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442432PMC
October 2020

The National Institute for Health Research Critical Care Research Priority Setting Survey 2018.

J Intensive Care Soc 2020 Aug 8;21(3):198-201. Epub 2019 Jul 8.

Department of Surgery and Cancer, Imperial College London, London, UK.

Introduction: Defining research priorities in intensive care is key to determining appropriate allocation of funding. Several topics were identified from the 2014 James Lind Alliance priority setting exercise conducted with the Intensive Care Society. The James Lind Alliance process included significant (and vital) patient/public contribution, but excluded professionals without a bedside role. As a result it may have failed to identify potential early-stage translational research topics, which are more likely identified by medical and/or academic members of relevant specialist basic science groups. The objective of the present project was to complement the James Lind Alliance project by generating an updated list of research priorities by facilitating academic research input.

Method: A survey was conducted by the National Institute for Health Research (NIHR) to identify the key research priorities from intensive care clinicians, including allied health professionals and academics, along with any evolving themes arising from translational research. Feasibility of all identified topics were then discussed and allocated to themes by a joint clinical academics/NIHR focus group.

Results: The survey was completed by 94 intensive care clinicians (including subspecialists), academics and allied health professions. In total, 203 research questions were identified, with the top five themes focusing on: appropriate case selection (e.g. who and when to treat; 24%), ventilation (7%), sepsis (6%), delirium (5%) and rehabilitation (5%).

Discussion: Utilising a methodology distinct from that employed by the James Lind Alliance process, from a broad spectrum of intensive care clinicians/scientists, enabled identification of a variety of priority research areas. These topics can now inform not only the investigator-led research agenda, but will also be considered in due course by the NIHR for potential future funding calls.
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http://dx.doi.org/10.1177/1751143719862244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7401440PMC
August 2020

RECOVERY- Respiratory Support: Respiratory Strategies for patients with suspected or proven COVID-19 respiratory failure; Continuous Positive Airway Pressure, High-flow Nasal Oxygen, and standard care: A structured summary of a study protocol for a randomised controlled trial.

Trials 2020 Jul 29;21(1):687. Epub 2020 Jul 29.

Wellcome Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Science Queen's University Belfast, Belfast, UK.

Objective: The trial objective is to determine if Continuous Positive Airway Pressure (CPAP) or High-Flow Nasal Oxygen (HFNO) is clinically effective compared to standard oxygen therapy in patients with confirmed or suspected COVID-19.

Trial Design: Adaptive (group-sequential), parallel group, pragmatic, superiority randomised controlled, open-label, multi-centre, effectiveness trial.

Participants: The trial is being conducted across approximately 60 hospitals across England, Wales, Scotland, and Northern Ireland. Inpatients at participating hospitals are eligible to participate if they have respiratory failure with suspected or proven COVID-19, and meet all of the inclusion criteria and none of the exclusion criteria.

Inclusion Criteria: 1) Adults ≥ 18 years; 2) Admitted to hospital with suspected or proven COVID-19; 3) Receiving oxygen with fraction of inspired oxygen (FiO) ≥0.4 and peripheral oxygen saturation (SpO) ≤94%; and 4) Plan for escalation to tracheal intubation if needed.

Exclusion Criteria: 1) Planned tracheal intubation and mechanical ventilation imminent within 1 hour; 2) Known or clinically apparent pregnancy; 3) Any absolute contraindication to CPAP or HFNO; 4) Decision not to intubate due to ceiling of treatment or withdrawal of treatment anticipated; and 5) Equipment for both CPAP and HFNO not available.

Intervention And Comparator: Intervention one: Continuous positive airway pressure delivered by any device. Set-up and therapy titration is not protocolised and is delivered in accordance with clinical discretion. Intervention two: High-flow nasal oxygen delivered by any device. Set-up and therapy titration is not protocolised and is delivered in accordance with clinical discretion. Comparator group: Standard care- oxygen delivered by face mask or nasal cannula (excluding the use of continuous positive airway pressure or high-flow nasal oxygen). Set-up and therapy titration is not protocolised and is delivered in accordance with clinical discretion. Intervention delivery continues up to the point of death, tracheal intubation, or clinical determination that there is no ongoing need (palliation or improvement).

Main Outcomes: The primary outcome is a composite outcome comprising tracheal intubation or mortality within 30 days following randomisation. Secondary outcomes include tracheal intubation rate, time to tracheal intubation, duration of invasive ventilation, mortality rate, time to mortality, length of hospital stay, and length of critical care stay.

Randomisation: Participants are randomised in a 1:1:1 ratio to receive either continuous positive airway pressure, high-flow nasal oxygen or standard care. Due to the challenging environment of study delivery, a specific intervention may not always be available at the hospital site. The study uses two integrated randomisation systems to allow, where required, the site to randomise between all three interventions, between CPAP and standard care, and between HFNO and standard care. System integration ensures maintenance of balance between interventions. Randomisation is performed using a telephone-based interactive voice response system to maintain allocation concealment. The randomisation sequence was computer-generated using the minimisation method. Participant randomisation is stratified by site, gender (M/F), and age (<50, >=50 years).

Blinding (masking): The nature of the trial interventions precludes blinding of the researcher, patient and clinical team. Primary and secondary outcomes are all objective outcomes, thereby minimising the risk of detection bias.

Numbers To Be Randomised (sample Size): 4002 participants (1334 to be randomized to each of the three study arms) TRIAL STATUS: Current protocol: Version 4.0, 29 May 2020. Recruitment began on April 6, 2020 and is anticipated to be complete by April 5, 2021. The trial has been awarded Urgent Public Health status by the National Institute of Health Research on 13 April 2020.

Trial Registration: ISRCTN, ISRCTN16912075. Registered 6 April 2020, http://www.isrctn.com/ISRCTN16912075 FULL PROTOCOL: The full protocol (version 4.0, 29 May 2020) 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).
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http://dx.doi.org/10.1186/s13063-020-04617-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388424PMC
July 2020

Airway clearance techniques and use of mucoactive agents for adult critically ill patients with acute respiratory failure: a qualitative study exploring UK physiotherapy practice.

Physiotherapy 2020 09 1;108:78-87. Epub 2020 Jul 1.

Centre for Health and Rehabilitation Technologies, Institute of Nursing and Health Research, Ulster University, Newtownabbey, UK. Electronic address:

Objectives: To explore and describe current UK physiotherapy practice relating to airway clearance techniques and mucoactive agents in critically ill adult patients with acute respiratory failure in the intensive care unit.

Design: A descriptive, qualitative study using focus group interviews. Focus groups were audio-recorded, independently transcribed, and data analysed thematically. Participants Senior, experienced physiotherapists, clinically active in critical care.

Results: Fifteen physiotherapists participated in four interview sessions. Five themes emerged describing airway clearance techniques: 'Repertoire of airway clearance techniques', 'Staffing and skillset', 'Commencing respiratory physiotherapy', 'Technique selection', and 'Determining effectiveness' were themes related to airway clearance techniques. Five themes were also identified in relation to mucoactive agents: 'Use in clinical practice', 'Decision to commence', 'Selection of agent', 'Stopping mucoactive agents', and 'Determining effectiveness'. A summary of key features of standard practice was developed.

Conclusions: Standard UK physiotherapy practice of airway clearance techniques is variable, but patient-centred and targeted to individual need, with adjunctive use of mucoactive agents to enhance and optimise patient management if required. Based on this study, key features of airway clearance techniques have been summarised to help capture standard care, which could be used in future trials involving ACT as part of usual care.
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http://dx.doi.org/10.1016/j.physio.2020.06.003DOI Listing
September 2020

Timing of Initiation of Renal-Replacement Therapy in Acute Kidney Injury.

N Engl J Med 2020 07;383(3):240-251

From the Department of Critical Care Medicine, Faculty of Medicine and Dentistry, University of Alberta and Alberta Health Services, Edmonton (S.M.B.), the Division of Nephrology (R.W.), St. Michael's Hospital and the University of Toronto, Li Ka Shing Knowledge Institute (R.W., B.R.C., O.M.S., K.E.T.), Department of Medicine (R.W., O.M.S.), and Applied Health Research Centre (B.R.C., K.E.T.), St. Michael's Hospital, the Dalla Lana School of Public Health (K.E.T.), the Institute of Health Policy, Management, and Evaluation (R.W., B.R.C.), University of Toronto, and the Department of Critical Care Medicine, Sunnybrook Health Sciences Centre and the University of Toronto (N.K.J.A.), Toronto, the Department of Medicine, Université de Sherbrooke and Centre de Recherche du Centre Hospitalier Universitaire (CHU) de Sherbrooke, Sherbrooke, QC (F.L.), the Division of Critical Care, Juravinski Hospital, McMaster University, Hamilton, ON (B.R.), and the Division of Nephrology, London Health Sciences Centre, London, ON (M.W.) - all in Canada; the Department of Intensive Care, Austin Hospital and Royal Melbourne Hospital, School of Medicine, University of Melbourne, Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University (R.B., A.D.N.), Melbourne, VIC, and the George Institute for Global Health, Concord Clinical School, Faculty of Medicine, University of Sydney, Sydney (M.P.G., A.Y.W.) - both in Australia; the Institute of Primary Health Care, University of Bern, Bern (B.R.C.), and the Department of Critical Care Medicine, CHU Vaudois, Lausanne (A.G.S.) - both in Switzerland; Hôpital Louis Mourier (D.D.) and Université Léonard de Vinci (S.G.), INSERM Unité UMR S1155, Sorbonne Université and Université de Paris, Paris, Hôpital Avicenne, Bobigny (S.G.), and Hôpital Universitaire François Mitterrand, Lipness Team, INSERM Research Center Lipids, Nutrition, Cancer-Unité Mixte de Recherche 1231 and Laboratoire d'Excellence LipSTIC, Centre d'Investigation Clinique-Epidemiologie Clinique, CHU Dijon-Bourgogne, and INSERM Centre d'Investigation Clinique 1432, Université de Bourgogne, Dijon (J.-P.Q.) - all in France; the Department of Critical Care Medicine, Peking Union Medical College Hospital, Beijing (B.D.), and the Department of Critical Care Medicine, Zhongda Hospital Southeast University, Nanjing (H.Q.) - both in China; the Department of Intensive Care, University of Ghent, Ghent, Belgium (E.A.H.); the Division of Intensive Care and Emergency Medicine, Department of Internal Medicine, Medical University Innsbruck, Innsbruck, Austria (M.J.); Vita Salute San Raffaele University and IRCCS San Raffaele Scientific Institute, Milan (G.L.); the Divisions of Nephrology and Critical Care Medicine, University of California, San Francisco, San Francisco (K.D.L.); the Wellcome-Wolfson Institute for Experimental Medicine, Queen's University, and the Regional Intensive Care Unit, Royal Victoria Hospital, Belfast (D.F.M.), and King's College London, Guy's and St. Thomas' Hospital, London (M.O.) - both in the United Kingdom; the Cardiothoracic and Vascular Intensive Care Unit, Auckland City Hospital, Auckland (S.P.M.), and the Medical Research Institute of New Zealand (S.P.M.) and the Intensive Care Unit, Wellington Regional Hospital and Medical Research Institute of New Zealand (P.Y.), Wellington - both in New Zealand; the Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky, Lexington (J.A.N.); University College Dublin Clinical Research Centre at St. Vincent's University Hospital, Dublin (A.D.N.); the Division of Nephrology, University of Pittsburgh, and Veterans Affairs Pittsburgh Healthcare System, Pittsburgh (P.M.P.); the Department of Intensive Care, University of Helsinki, and Helsinki University Hospital, Helsinki (V.P., S.V.); Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil (F.T.); and the Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, Germany (A.Z.).

Background: Acute kidney injury is common in critically ill patients, many of whom receive renal-replacement therapy. However, the most effective timing for the initiation of such therapy remains uncertain.

Methods: We conducted a multinational, randomized, controlled trial involving critically ill patients with severe acute kidney injury. Patients were randomly assigned to receive an accelerated strategy of renal-replacement therapy (in which therapy was initiated within 12 hours after the patient had met eligibility criteria) or a standard strategy (in which renal-replacement therapy was discouraged unless conventional indications developed or acute kidney injury persisted for >72 hours). The primary outcome was death from any cause at 90 days.

Results: Of the 3019 patients who had undergone randomization, 2927 (97.0%) were included in the modified intention-to-treat analysis (1465 in the accelerated-strategy group and 1462 in the standard-strategy group). Of these patients, renal-replacement therapy was performed in 1418 (96.8%) in the accelerated-strategy group and in 903 (61.8%) in the standard-strategy group. At 90 days, death had occurred in 643 patients (43.9%) in the accelerated-strategy group and in 639 (43.7%) in the standard-strategy group (relative risk, 1.00; 95% confidence interval [CI], 0.93 to 1.09; P = 0.92). Among survivors at 90 days, continued dependence on renal-replacement therapy was confirmed in 85 of 814 patients (10.4%) in the accelerated-strategy group and in 49 of 815 patients (6.0%) in the standard-strategy group (relative risk, 1.74; 95% CI, 1.24 to 2.43). Adverse events occurred in 346 of 1503 patients (23.0%) in the accelerated-strategy group and in 245 of 1489 patients (16.5%) in the standard-strategy group (P<0.001).

Conclusions: Among critically ill patients with acute kidney injury, an accelerated renal-replacement strategy was not associated with a lower risk of death at 90 days than a standard strategy. (Funded by the Canadian Institutes of Health Research and others; STARRT-AKI ClinicalTrials.gov number, NCT02568722.).
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http://dx.doi.org/10.1056/NEJMoa2000741DOI Listing
July 2020

Subphenotypes in critical care: translation into clinical practice.

Lancet Respir Med 2020 06;8(6):631-643

Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK; Regional Intensive Care Unit, Royal Victoria Hospital, Belfast, UK.

Despite progress in the supportive care available for critically ill patients, few advances have been made in the search for effective disease-modifying therapeutic options. The fact that many trials in critical care medicine have not identified a treatment benefit is probably due, in part, to the underlying heterogeneity of critical care syndromes. Numerous approaches have been proposed to divide populations of critically ill patients into more meaningful subgroups (subphenotypes), some of which might be more useful than others. Subclassification systems driven by clinical features and biomarkers have been proposed for acute respiratory distress syndrome, sepsis, acute kidney injury, and pancreatitis. Identifying the systems that are most useful and biologically meaningful could lead to a better understanding of the pathophysiology of critical care syndromes and the discovery of new treatment targets, and allow recruitment in future therapeutic trials to focus on predicted responders. This Review discusses proposed subphenotypes of critical illness syndromes and highlights the issues that will need to be addressed to translate subphenotypes into clinical practice.
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http://dx.doi.org/10.1016/S2213-2600(20)30124-7DOI Listing
June 2020

Interventions for oropharyngeal dysphagia in acute and critical care: a systematic review and meta-analysis.

Intensive Care Med 2020 07 8;46(7):1326-1338. Epub 2020 Jun 8.

Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK.

Purpose: To determine the effectiveness of dysphagia interventions compared to standard care in improving oral intake and reducing aspiration for adults in acute and critical care.

Methods: We searched electronic literature for randomised and quasi-randomised trials and bibliography lists of included studies to March 2020. Study screening, data extraction, risk of bias and quality assessments were conducted independently by two reviewers. Meta-analysis used fixed effects modelling. The systematic review protocol is registered and published.

Results: We identified 22 studies (19 stroke, 2 intensive care stroke and 1 general intensive care) testing 9 interventions and representing 1700 patients. Swallowing treatment showed no evidence of a difference in the time to return to oral intake (n = 33, MD (days) - 4.5, 95% CI - 10.6 to 1.6, 1 study, P = 0.15) (very low certainty) or in aspiration following treatment (n = 113, RR 0.79, 95% CI 0.44 to 1.45, 4 studies, I = 0%, P = 0.45) (low certainty). Swallowing treatment showed evidence of a reduced risk of pneumonia (n = 719, RR 0.71, 95% CI 0.56 to 0.89, 8 studies, I = 15%, P = 0.004) (low certainty) but no evidence of a difference in swallowing quality of life scores (n = 239, MD - 11.38, 95% CI - 23.83 to 1.08, I  = 78%, P = 0.07) (very low certainty).

Conclusion: There is limited evidence for the effectiveness of swallowing treatments in the acute and critical care setting. Clinical trials consistently measuring patient-centred outcomes are needed.
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http://dx.doi.org/10.1007/s00134-020-06126-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334257PMC
July 2020

Mucoactive agents for acute respiratory failure in the critically ill: a systematic review and meta-analysis.

Thorax 2020 08 8;75(8):623-631. Epub 2020 Jun 8.

Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK.

Purpose: Acute respiratory failure (ARF) is a common cause of admission to intensive care units (ICUs). Mucoactive agents are medications that promote mucus clearance and are frequently administered in patients with ARF, despite a lack of evidence to underpin clinical decision making. The aim of this systematic review was to determine if the use of mucoactive agents in patients with ARF improves clinical outcomes.

Methods: We searched electronic and grey literature (January 2020). Two reviewers independently screened, selected, extracted data and quality assessed studies. We included trials of adults receiving ventilatory support for ARF and involving at least one mucoactive agent compared with placebo or standard care. Outcomes included duration of mechanical ventilation. Meta-analysis was undertaken using random-effects modelling and certainty of the evidence was assessed using Grades of Recommendation, Assessment, Development and Evaluation.

Results: Thirteen randomised controlled trials were included (1712 patients), investigating four different mucoactive agents. Mucoactive agents showed no effect on duration of mechanical ventilation (seven trials, mean difference (MD) -1.34, 95% CI -2.97 to 0.29, I=82%, very low certainty) or mortality, hospital stay and ventilator-free days. There was an effect on reducing ICU length of stay in the mucoactive agent groups (10 trials, MD -3.22, 95% CI -5.49 to -0.96, I=89%, very low certainty).

Conclusion: Our findings do not support the use of mucoactive agents in critically ill patients with ARF. The existing evidence is of low quality. High-quality randomised controlled trials are needed to determine the role of specific mucoactive agents in critically ill patients with ARF.

Prospero Registration Number: CRD42018095408.
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http://dx.doi.org/10.1136/thoraxjnl-2019-214355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402561PMC
August 2020

Parenteral thiamine for prevention and treatment of delirium in critically ill adults: a systematic review protocol.

Syst Rev 2020 06 5;9(1):131. Epub 2020 Jun 5.

Wellcome-Wolfson Institute of Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast, Northern Ireland, BT9 7BL, UK.

Background: Delirium is an acute confusional state, common in critical illness and associated with cognitive decline. There is no effective pharmacotherapy to prevent or treat delirium, although it is scientifically plausible that thiamine could be effective. Thiamine studies in dementia patients are inconclusive. Aside from small numbers, all used oral administration: bioavailability of thiamine is poor; parenteral thiamine bypasses this. In the UK, parenteral thiamine is administered as a compound vitamin B and C solution (Pabrinex®). The aim of this review is to evaluate the effectiveness of parenteral thiamine (alone or in a compound solution) in preventing or treating delirium in critical illness.

Methods: We will search for studies in electronic databases (MEDLINE (Pro-Quest), EMBASE, CINAHL, LILACS, CNKI, AMED, and Cochrane CENTRAL), clinical trials registries (WHO International Clinical Trials Registry, ClinicalTrials.gov, and Controlled-trials.com), and grey literature (Google Scholar, conference proceedings, and Index to Theses). We will perform complementary searches of reference lists of included studies, relevant reviews, clinical practice guidelines, or other pertinent documents (e.g. official documents and government reports). We will consider quasi-randomised or randomised controlled trials in critically ill adults. We will include studies that evaluate parenteral thiamine versus standard of care, placebo, or any other non-pharmacological or pharmacological interventions. The primary outcomes will be the delirium core outcome set, including incidence and severity of delirium and cognition. Secondary outcomes are adapted from the ventilation core outcome set: duration of mechanical ventilation, length of stay, and adverse events incidence. Screening, data extraction, and risk of bias assessment will be undertaken independently by two reviewers. If data permits, we will conduct meta-analyses using a random effects model and, where appropriate, sensitivity and subgroup analyses to explore sources of heterogeneity.

Discussion: This review will provide evidence for the effectiveness of parental thiamine in the prevention or treatment of delirium in critical care. Findings will contribute to establishing the need for a multicentre study of parenteral thiamine in the prevention and treatment of critical care delirium.

Systematic Review Registration: PROSPERO CRD42019118808.
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http://dx.doi.org/10.1186/s13643-020-01380-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275448PMC
June 2020

Repair of Acute Respiratory Distress Syndrome by Stromal Cell Administration in COVID-19 (REALIST-COVID-19): A structured summary of a study protocol for a randomised, controlled trial.

Trials 2020 Jun 3;21(1):462. Epub 2020 Jun 3.

Wellcome Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Science Queen's University Belfast, Belfast, UK.

Objectives: The primary objective of the study is to assess the safety of a single intravenous infusion of Mesenchymal Stromal Cells (MSCs) in patients with Acute Respiratory Distress Syndrome (ARDS) due to COVID-19. Secondary objectives are to determine the effects of MSCs on important clinical outcomes, as described below.

Trial Design: REALIST COVID 19 is a randomised, placebo-controlled, triple blinded trial.

Participants: The study will be conducted in Intensive Care Units in hospitals across the United Kingdom. Patients with moderate to severe ARDS as defined by the Berlin definition, receiving invasive mechanical ventilation and with a diagnosis of COVID-19 based on clinical diagnosis or PCR test will be eligible. Patients will be excluded for the following reasons: more than 72 hours from the onset of ARDS; age < 16 years; patient known to be pregnant; major trauma in previous 5 days; presence of any active malignancy (other than non-melanoma skin cancer); WHO Class III or IV pulmonary hypertension; venous thromboembolism currently receiving anti-coagulation or within the past 3 months; patient receiving extracorporeal life support; severe chronic liver disease (Child-Pugh > 12); Do Not Attempt Resuscitation order in place; treatment withdrawal imminent within 24 hours; prisoners; declined consent; non-English speaking patients or those who do not adequately understand verbal or written information unless an interpreter is available; previously enrolled in the REALIST trial.

Intervention And Comparator: Intervention: Allogeneic donor CD362 enriched human umbilical cord derived mesenchymal stromal cells (REALIST ORBCEL-C) supplied as sterile, single-use cryopreserved cell suspension of a fixed dose of 400 x10 cells in 40ml volume, to be diluted in Plasma-Lyte 148 to a total volume of 200mls for administration. Comparator (placebo): Plasma-Lyte 148 Solution for Infusion (200mls). The cellular product (REALIST ORBCEL-C) was developed and patented by Orbsen Therapeutics.

Main Outcomes: The primary safety outcome is the incidence of serious adverse events. The primary efficacy outcome is Oxygenation Index (OI) at day 7. Secondary outcomes include: OI at days 4 and 14; respiratory compliance, driving pressure and PaO/FiO ratio (PF ratio) at days 4, 7 and 14; Sequential Organ Failure Assessment (SOFA) score at days 4, 7 and 14; extubation and reintubation; ventilation free days at day 28; duration of mechanical ventilation; length of ICU and hospital stay; 28-day and 90-day mortality.

Randomisation: After obtaining informed consent, patients will be randomised via a centralised automated 24-hour telephone or web-based randomisation system (CHaRT, Centre for Healthcare Randomised Trials, University of Aberdeen). Randomisation will be stratified by recruitment centre and by vasopressor use and patients will be allocated to REALIST ORBCEL-C or placebo control in a 1:1 ratio.

Blinding (masking): The investigator, treating physician, other members of the site research team and participants will be blinded. The cell therapy facility and clinical trials pharmacist will be unblinded to facilitate intervention and placebo preparation. The unblinded individuals will keep the treatment information confidential. The infusion bag will be masked at the time of preparation and will be administered via a masked infusion set.

Numbers To Be Randomised (sample Size): A sample size of 60 patients with 30 patients randomised to the intervention and 30 to the control group. If possible, recruitment will continue beyond 60 patients to provide more accurate and definitive trial results. The total number of patients recruited will depend on the pandemic and be guided by the data monitoring and ethics committee (DMEC).

Trial Status: REALIST Phase 1 completed in January 2020 prior to the COVID-19 pandemic. This was an open label dose escalation study of REALIST ORBCEL-C in patients with ARDS. The COVID-19 pandemic emerged as REALIST Phase 2 was planned to commence and the investigator team decided to repurpose the Phase 2 trial as a COVID-19 specific trial. This decision was discussed and approved by the Trial Steering Committee (TSC) and DMEC. Submissions were made to the Research Ethics Committee (REC) and MHRA to amend the protocol to a COVID-19 specific patient population and the protocol amendment was accepted by the REC on 27 March 2020 and MHRA on 30 March 2020 respectively. Other protocol changes in this amendment included an increase in the time of onset of ARDS from 48 to 72 hours, inclusion of clinical outcomes as secondary outcomes, the provision of an option for telephone consent, an indicative sample size and provision to continue recruitment beyond this indicative sample size. The current protocol in use is version 4.0 23.03.2020 (Additional file 1). Urgent Public Health status was awarded by the NIHR on 2 April 2020 and the trial opened to recruitment and recruited the first participant the same day. At the time of publication the trial was open to recruitment at 5 sites across the UK (Belfast Health and Social Care Trust, King's College London, Guys and St Thomas' Hospital London, Birmingham Heartlands Hospital and the Queen Elizabeth Hospital Birmingham) and 12 patients have been recruited across these sites. Additional sites are planned to open and appropriate approvals for these are being obtained. It is estimated recruitment will continue for 6 months.

Trial Registration: ClinicalTrials.gov NCT03042143 (Registered 3 Feb 2017). EudraCT 2017-000585-33 (Registered 28 Nov 2017).

Full Protocol: The full protocol (version 4.0 23.03.2020) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of 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).
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http://dx.doi.org/10.1186/s13063-020-04416-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267756PMC
June 2020

Fluid management and deresuscitation practices: A survey of critical care physicians.

J Intensive Care Soc 2020 May 13;21(2):111-118. Epub 2019 May 13.

Interdepartmental Division of Critical Care, University of Toronto, Toronto, ON, Canada.

Accumulation of a positive fluid balance is common in critically ill patients, and is associated with adverse outcomes, including mortality. However, there are few randomised clinical trials to guide clinicians as to the most appropriate fluid strategy following initial resuscitation and on the use of deresuscitation (removal of accumulated fluid using diuretics and/or renal replacement therapy). To inform the design of randomised trials, we surveyed critical care physicians with regard to perceptions of fluid overload in critical care, self-reported practice, acceptability of a variety of approaches to deresuscitation, appropriate safety parameters, and overall acceptability of a randomised trial of deresuscitation. Of 524 critical care specialists completing the survey, the majority practiced in mixed medical/surgical intensive care units in the United Kingdom. Most (309 of 363 respondents, 85%) believed fluid overload to be a modifiable source of morbidity; there was strong support (395 of 457, 86%) for a randomised trial of deresuscitation in critical illness. Marked practice variability was evident among respondents. In a given clinical scenario, self-reported practice ranged from the administration of fluid (N = 59, 14%) to the administration of a diuretic (N = 285, 67%). The majority (95%) considered it appropriate to administer diuretics for fluid overload in the setting of noradrenaline infusion and to continue to administer diuretics despite mild dysnatraemias, hypotension, metabolic alkalosis, and hypokalaemia. The majority of critical care physicians view fluid overload as a common and modifiable source of morbidity; deresuscitation is widely practiced, and there is widespread support for randomised trials of deresuscitation in critical illness.
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http://dx.doi.org/10.1177/1751143719846442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238475PMC
May 2020

A nebulised antitumour necrosis factor receptor-1 domain antibody in patients at risk of postoperative lung injury: A randomised, placebo-controlled pilot study.

Eur J Anaesthesiol 2020 11;37(11):1014-1024

From The James Cook University Hospital, South Tees Hospitals NHS Foundation Trust, Middlesbrough (JR), GlaxoSmithKline Research and Development, Stevenage (AIB, TJW, EM,WP, RW, AF), Centre for Experimental Medicine, Queen's University of Belfast (DFM), Regional Intensive Care Unit, Royal Victoria Hospital, Belfast (DFM), Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick, Coventry (JY, GDP), Birmingham Acute Care Research Group, Institute of Inflammation and Aging, School of Clinical and Experimental Medicine, University of Birmingham (DRT, PAH), University Hospitals Birmingham, NHS Foundation Trust, Birmingham (JY, DRT, PAH, GDP), Department of Anaesthesia, Royal Victoria Hospital, Belfast (COD, MOS), Department of Medicine, University of Cambridge, Cambridge (AMV, CS), GlaxoSmithKline R&D, Stockley Park (KH), Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK (CS) and GlaxoSmithKline Research and Development, Collegeville, Pennsylvania, USA (ALL).

Background: Tumour necrosis factor receptor 1 (TNFR1) signalling mediates the cell death and inflammatory effects of TNF-α.

Objective: The current clinical trial investigated the effects of a nebulised TNFR1 antagonist (GSK2862277) on signs of lung injury in patients undergoing oesophagectomy.

Design: Randomised double-blind (sponsor unblind), placebo-controlled, parallel group study.

Setting: Eight secondary care centres, the United Kingdom between April 2015 and June 2017.

Patients: Thirty-three patients undergoing elective transthoracic oesophagectomy.

Interventions: Patients randomly received a single nebulised dose (26 mg) of GSK2862277 (n = 17) or placebo (n = 16), given 1 to 5 h before surgery; 14 and 16, respectively competed the study.

Main Outcome Measurements: Physiological and biochemical markers of lung injury, pharmacokinetic and safety endpoints were measured. The primary endpoint was the change from baseline in pulmonary vascular permeability index (PVPI) at completion of surgery, measured using single-indicator transpulmonary thermodilution. Adjusted point estimates and 95% credible intervals (analogous to conventional confidence intervals) were constructed for each treatment using Bayesian statistical models.

Results: The mean change (with 95% credible intervals) from baseline in PVPI on completion of surgery was 0.00 (-0.23, 0.39) in the placebo and 0.00 (-0.24, 0.37) in the GSK2862277 treatment groups. There were no significant treatment-related differences in PaO2/FiO2 or Sequential Organ Failure Assessment score. Levels of free soluble TNFR1, Macrophage Inflammatory Protein-1 alpha and total protein were significantly reduced in the bronchoalveolar lavage fluid of patients treated with GSK2862277 (posterior probability of decrease with GSK2862277 vs. placebo:≥0.977; equivalent to P < 0.05). The frequency of adverse events and serious adverse events were distributed evenly across the two treatment arms.

Conclusion: Pre-operative treatment with a single 26 mg inhaled dose of GSK2862277 did not result in significantly lower postoperative alveolar capillary leak or extra vascular lung water. Unexpectedly small increases in transpulmonary thermodilution-measured PVPI and extra vascular lung water index at completion of surgery suggest less postoperative lung injury than historically reported, which may have also compromised a clear assessment of efficacy in this trial. GSK2862277 was well tolerated, resulted in expected lung exposure and reduced biomarkers of lung permeability and inflammation.

Trial Registration: clinicaltrials.gov: NCT02221037.
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http://dx.doi.org/10.1097/EJA.0000000000001245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575021PMC
November 2020

Human lipopolysaccharide models provide mechanistic and therapeutic insights into systemic and pulmonary inflammation.

Eur Respir J 2020 07 30;56(1). Epub 2020 Jul 30.

Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK

Inflammation is a key feature in the pathogenesis of sepsis and acute respiratory distress syndrome (ARDS). Sepsis and ARDS continue to be associated with high mortality. A key contributory factor is the rudimentary understanding of the early events in pulmonary and systemic inflammation in humans, which are difficult to study in clinical practice, as they precede the patient's presentation to medical services. Lipopolysaccharide (LPS), a constituent of the outer membrane of Gram-negative bacteria, is a trigger of inflammation and the dysregulated host response in sepsis. Human LPS models deliver a small quantity of LPS to healthy volunteers, triggering an inflammatory response and providing a window to study early inflammation in humans. This allows biological/mechanistic insights to be made and new therapeutic strategies to be tested in a controlled, reproducible environment from a defined point in time. We review the use of human LPS models, focussing on the underlying mechanistic insights that have been gained by studying the response to intravenous and pulmonary LPS challenge. We discuss variables that may influence the response to LPS before considering factors that should be considered when designing future human LPS studies.
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http://dx.doi.org/10.1183/13993003.01298-2019DOI Listing
July 2020