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1. TRPV2 modulates mechanically Induced ATP Release from Human bronchial epithelial cells

Author

Orla M. Dunne, S. Lorraine Martin, Gerard P. Sergeant, Daniel F. McAuley, Cecilia M. O’Kane, Brian Button, Lorcan P. McGarvey, and Fionnuala T. Lundy

Subjects
Transient receptor potential channels, Mechanotransduction, Adenosine triphosphate, Purinergic P2 × 3, Diseases of the respiratory system, RC705-779
Abstract

Abstract Repetitive bouts of coughing expose the large airways to significant cycles of shear stress. This leads to the release of alarmins and the tussive agent adenosine triphosphate (ATP) which may be modulated by the activity of ion channels present in the human airway. This study aimed to investigate the role of the transient receptor potential subfamily vanilloid member 2 (TRPV2) channel in mechanically induced ATP release from primary bronchial epithelial cells (PBECs). PBECs were obtained from individuals undergoing bronchoscopy. They were cultured in vitro and exposed to mechanical stress in the form of compressive and fluid shear stress (CFSS) or fluid shear stress (FSS) alone at various intensities. ATP release was measured using a luciferin–luciferase assay. Functional TRPV2 protein expression in human PBECs was investigated by confocal calcium imaging. The role of TRPV2 inhibition on FSS-induced ATP release was investigated using the TRPV2 inhibitor tranilast or siRNA knockdown of TRPV2. TRPV2 protein expression in human lung tissue was also determined by immunohistochemistry. ATP release was significantly increased in PBECs subjected to CFSS compared with control (unstimulated) PBECs (N = 3, ***P

Published
2024
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2. Physiologic Determinants of Near-Infrared Spectroscopy-Derived Cerebral and Tissue Oxygen Saturation Measurements in Critically Ill Patients

Author

Neil Cody, MB, ChB, Ian Bradbury, PhD, Ross R. McMullan, MB, ChB, Gerard Quinn, RN, Aisling O’Neill, RN, Kathryn Ward, RN, Justine McCann, RN, Daniel F. McAuley, MD, and Jonathan A. Silversides, PhD

Subjects
Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

OBJECTIVES:. Near-infrared spectroscopy (NIRS) is a potentially valuable modality to monitor the adequacy of oxygen delivery to the brain and other tissues in critically ill patients, but little is known about the physiologic determinants of NIRS-derived tissue oxygen saturations. The purpose of this study was to assess the contribution of routinely measured physiologic parameters to tissue oxygen saturation measured by NIRS. DESIGN:. An observational sub-study of patients enrolled in the Role of Active Deresuscitation After Resuscitation-2 (RADAR-2) randomized feasibility trial. SETTING:. Two ICUs in the United Kingdom. PATIENTS:. Patients were recruited for the RADAR-2 study, which compared a conservative approach to fluid therapy and deresuscitation with usual care. Those included in this sub-study underwent continuous NIRS monitoring of cerebral oxygen saturations (SctO2) and quadriceps muscle tissue saturations (SmtO2). INTERVENTION:. Synchronized and continuous mean arterial pressure (MAP), heart rate (HR), and pulse oximetry (oxygen saturation, Spo2) measurements were recorded alongside NIRS data. Arterial Paco2, Pao2, and hemoglobin concentration were recorded 12 hourly. Linear mixed effect models were used to investigate the association between these physiologic variables and cerebral and muscle tissue oxygen saturations. MEASUREMENTS AND MAIN RESULTS:. Sixty-six patients were included in the analysis. Linear mixed models demonstrated that Paco2, Spo2, MAP, and HR were weakly associated with SctO2 but only explained 7.1% of the total variation. Spo2 and MAP were associated with SmtO2, but together only explained 0.8% of its total variation. The remaining variability was predominantly accounted for by between-subject differences. CONCLUSIONS:. Our findings demonstrated that only a small proportion of variability in NIRS-derived cerebral and tissue oximetry measurements could be explained by routinely measured physiologic variables. We conclude that for NIRS to be a useful monitoring modality in critical care, considerable further research is required to understand physiologic determinants and prognostic significance.

Published
2024
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3. An International Survey of the Management of Atrial Fibrillation in Critically Unwell Patients

Author

Brian W. Johnston, MD, Andrew A. Udy, MD, PhD, Daniel F. McAuley, MD, Martin Mogk, Dipl.-Math, Ingeborg D. Welters, MD, PhD, and Stephanie Sibley, MD, SM

Subjects
Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

OBJECTIVES:. To evaluate the current management of new-onset atrial fibrillation and compare differences in practice regionally. DESIGN:. Cross-sectional survey. SETTING:. United States, Canada, United Kingdom, Europe, Australia, and New Zealand. SUBJECTS:. Critical care attending physicians/consultants and fellows. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. A total of 386 surveys were included in our analysis. Rate control was the preferred treatment approach for hemodynamically stable patients (69.1%), and amiodarone was the most used antiarrhythmic medication (70.9%). For hemodynamically unstable patients, a strategy of electrolyte supplementation and antiarrhythmic therapy was most common (54.7%). Physicians responding to the survey distributed by the Society of Critical Care Medicine were more likely to prescribe beta-blockers as a first-line antiarrhythmic medication (38.4%), use more transthoracic echocardiography than respondents from other regions (82.4%), and more likely to refer patients who survive their ICU stay for cardiology follow-up if they had new-onset atrial fibrillation (57.2%). The majority of survey respondents (83.0%) were interested in participating in future studies of atrial fibrillation in critically ill patients. CONCLUSIONS:. Significant variation exists in the management of new-onset atrial fibrillation in critically ill patients, as well as geographic variation. Further research is necessary to inform guidelines in this population and establish if differences in practice impact long-term outcomes.

Published
2024
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4. The Effect of Lower Tidal Volume Ventilation Facilitated by Extracorporeal Carbon Dioxide Removal Compared With Conventional Lung Protective Ventilation on Cardiac Function

Author

Peter J. McGuigan, MB, BCh, BAO, MRCA, FFICM, Emma M. Bowcock, MBBS (Hons), FCICM, Nicholas A. Barrett, FCICM, Bronagh Blackwood, PhD, Andrew J. Boyle, PhD, MRCP, Andrew J. Cadamy, MBChB, FRCA, FFICM, Luigi Camporota, MD, PhD, FRCP, FFICM, FERS, John Conlon, BSc, Matthew E. Cove, MB ChB, Michael A Gillies, MD, FRCA, FRCP, FFICM, Clíona McDowell, MSc, CSTAT, James J. McNamee, MB ChB, Cecilia M. O’Kane, PhD, Alex Puxty, MB ChB, FRCA, MRCP, DICM, FFICM, Malcolm Sim, MD, Rebecca Parsons-Simmonds, BSE, MSc, BSc, Tamas Szakmany, PhD, EDIC, DESA, FRCA, FFICM, FCCM, Neil Young, MBChB, MRCP, FRCA, FFICM, Sam Orde, MBBS, PhD, FCICM, and Daniel F. McAuley, MD, FMedSci

Subjects
Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

OBJECTIVES:. Lower tidal volume ventilation (targeting 3 mL/kg predicted body weight, PBW) facilitated by extracorporeal carbon dioxide removal (ECCO2R) has been investigated as a potential therapy for acute hypoxemic respiratory failure (AHRF) in the pRotective vEntilation with veno-venouS lung assisT in respiratory failure (REST) trial. We investigated the effect of this strategy on cardiac function, and in particular the right ventricle. DESIGN:. Substudy of the REST trial. SETTING:. Nine U.K. ICUs. PATIENTS:. Patients with AHRF (Pao2/Fio2 < 150 mm Hg [20 kPa]). INTERVENTION:. Transthoracic echocardiography and N-terminal pro-B-type natriuretic peptide (NT-proBNP) measurements were collected at baseline and postrandomization in patients randomized to ECCO2R or usual care. MEASUREMENTS:. The primary outcome measures were a difference in tricuspid annular plane systolic excursion (TAPSE) on postrandomization echocardiogram and difference in NT-proBNP postrandomization. RESULTS:. There were 21 patients included in the echocardiography cohort (ECCO2R, n = 13; usual care, n = 8). Patient characteristics were similar in both groups at baseline. Median (interquartile range) tidal volumes were lower in the ECCO2R group compared with the usual care group postrandomization; 3.6 (3.1–4.2) mL/kg PBW versus 5.2 (4.9–5.7) mL/kg PBW, respectively (p = 0.01). There was no difference in the primary outcome measure of mean (sd) TAPSE in the ECCO2R and usual care groups postrandomization; 21.3 (5.4) mm versus 20.1 (3.2) mm, respectively (p = 0.60). There were 75 patients included in the NT-proBNP cohort (ECCO2R, n = 36; usual care, n = 39). Patient characteristics were similar in both groups at baseline. Median (interquartile range [IQR]) tidal volumes were lower in the ECCO2R group than the usual care group postrandomization; 3.8 (3.3–4.2) mL/kg PBW versus 6.7 (5.8–8.1) mL/kg PBW, respectively (p < 0.0001). There was no difference in median (IQR) NT-proBNP postrandomization; 1121 (241–5370) pg/mL versus 1393 (723–4332) pg/mL in the ECCO2R and usual care groups, respectively (p = 0.30). CONCLUSIONS:. In patients with AHRF, a reduction in tidal volume facilitated by ECCO2R, did not modify cardiac function.

Published
2024
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5. Neutrophil-Derived Proteases in Lung Inflammation: Old Players and New Prospects

Author

Coby J. Cheetham, Michael C. McKelvey, Daniel F. McAuley, and Clifford C. Taggart

Subjects
lung disease, neutrophil, proteases, antiproteases, inflammation, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Neutrophil-derived proteases are critical to the pathology of many inflammatory lung diseases, both chronic and acute. These abundant enzymes play roles in key neutrophil functions, such as neutrophil extracellular trap formation and reactive oxygen species release. They may also be released, inducing tissue damage and loss of tissue function. Historically, the neutrophil serine proteases (NSPs) have been the main subject of neutrophil protease research. Despite highly promising cell-based and animal model work, clinical trials involving the inhibition of NSPs have shown mixed results in lung disease patients. As such, the cutting edge of neutrophil-derived protease research has shifted to proteases that have had little-to-no research in neutrophils to date. These include the cysteine and serine cathepsins, the metzincins and the calpains, among others. This review aims to outline the previous work carried out on NSPs, including the shortcomings of some of the inhibitor-orientated clinical trials. Our growing understanding of other proteases involved in neutrophil function and neutrophilic lung inflammation will then be discussed. Additionally, the potential of targeting these more obscure neutrophil proteases will be highlighted, as they may represent new targets for inhibitor-based treatments of neutrophil-mediated lung inflammation.

Published
2024
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6. Effect of total cholesterol and statin therapy on mortality in ARDS patients: a secondary analysis of the SAILS and HARP-2 trials

Author

Shaun M. Pienkos, Andrew R. Moore, Jiazhen Guan, Joseph E. Levitt, Michael A. Matthay, Rebecca M. Baron, John Conlon, Daniel F. McAuley, Cecilia M. O’Kane, and Angela J. Rogers

Subjects
Acute respiratory distress syndrome, Sepsis, Statins, Cholesterol, Critical care, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

Abstract Background Two acute respiratory distress syndrome (ARDS) trials showed no benefit for statin therapy, though secondary analyses suggest inflammatory subphenotypes may have a differential response to simvastatin. Statin medications decrease cholesterol levels, and low cholesterol has been associated with increased mortality in critical illness. We hypothesized that patients with ARDS and sepsis with low cholesterol could be harmed by statins. Methods Secondary analysis of patients with ARDS and sepsis from two multicenter trials. We measured total cholesterol from frozen plasma samples obtained at enrollment in Statins for Acutely Injured Lungs from Sepsis (SAILS) and Simvastatin in the Acute Respiratory Distress Syndrome (HARP-2) trials, which randomized subjects with ARDS to rosuvastatin versus placebo and simvastatin versus placebo, respectively, for up to 28 days. We compared the lowest cholesterol quartile (

Published
2023
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7. Re-analysis of ventilator-free days (VFD) in acute respiratory distress syndrome (ARDS) studies

Author

Rejina Mariam Verghis, Cliona McDowell, Bronagh Blackwood, Bohee Lee, Daniel F. McAuley, and Mike Clarke

Subjects
Clinical trials, Critical care, Ventilator-free days, Acute respiratory distress syndrome, Hurdle mode, Medicine (General), R5-920
Abstract

Abstract Background Over recent decades, improvements in healthcare have reduced mortality and morbidity rates in many conditions. This has resulted, in part, from the identification of effective interventions in randomised trials, and in conducting such trials, a composite outcome measure (COM) with multiple components will increase event rates, which allows study completion with a smaller sample size. In critical care research, the COM “ventilator-free days” (VFD) combines mortality and duration of mechanical ventilation (MV) into a single continuous measure, which can be analysed in a variety of ways. This study investigates the usefulness of Poisson and two-part Poisson models compared to t-distribution for the analysis of VFD. Methods Data from four studies (ALbuterol for the Treatment of ALI (ALTA), Early vs. Delayed Enteral Nutrition (EDEN), Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute Lung Injury (ALI) to reduce pulmonary dysfunction (HARP-2), Statins for Acutely Injured Lungs from Sepsis (SAILS)) were used for analysis, with the VFD results summarised using mean, standard deviation (SD), median, interquartile range (25th and 75th percentiles) and minimum and maximum values. The statistical analyses that are compared used the t-test, Poisson, zero-inflated Poisson (ZIP) and two-part Logit-Poisson hurdle models. The analyses were exploratory in nature, and the significance level for differences in the estimates was set to 0.05. Results In HARP-2, which compared simvastatin and placebo, the mean (SD) VFD for all patients was 12.0 (10.2), but this mean value did not represent the data distribution as it falls in a zone between two peaks, with the lowest frequency of occurrence. The mean (SD) VFD after excluding patients who died before day 28 and patients who did not achieve unassisted breathing were 15.9 (8.7) and 18.2 (6.6), respectively. The mean difference (95% CI) between the two groups was 1.1 (95% CI: 0.7 to 2.8; p = 0.20) based on an independent t-test. However, when the two-part hurdle model was used, the simvastatin arm had a significantly higher number of non-zero values compared to the placebo group, which indicated that more patients were alive and free of mechanical ventilation in the simvastatin group. Similarly, in ALTA, this model found that significantly more patients were alive and free of MV in the control group. In EDEN and SAILS, there was no significant difference between the control and intervention groups. Conclusion Our analyses show that the t-test and Poisson model are not appropriate for bi-modal data (such as VFD) where there is a large number of zero events. The two-part hurdle model was the most promising approach. There is a need for future research to investigate other analysis techniques, such as two-part quantile regression and to determine the impact on sample size requirements for comparative effectiveness trials.

Published
2023
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8. Baseline plasma IL-18 may predict simvastatin treatment response in patients with ARDS: a secondary analysis of the HARP-2 randomised clinical trial

Author

Andrew James Boyle, Peter Ferris, Ian Bradbury, John Conlon, Manu Shankar-Hari, Angela J. Rogers, Cecilia M. O’Kane, and Daniel F. McAuley

Subjects
Acute respiratory distress syndrome, Simvastatin, Inflammasome, Interleukin-18, Personalised medicine, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

Abstract Background Interleukin (IL)-18 is a marker of inflammasome activation, and high baseline plasma IL-18 is associated with increased mortality in patients with sepsis-induced ARDS. The aim of this analysis was to determine if simvastatin was associated with benefit in patients with ARDS and high plasma IL-18. Methods In this secondary analysis of the HARP-2 study, we compared 28-day mortality and response to simvastatin according to baseline plasma IL-18 using cox proportional hazards analysis. Separately, monocyte-derived macrophages from healthy volunteers were pre-incubated with simvastatin or rosuvastatin before stimulation with ATP and LPS, and the effect on secreted IL-18 and IL-1β compared. Results 511 patients from HARP-2 had available data. High baseline plasma IL-18 (≥ 800 pg/ml) was associated with increased 28-day mortality (high IL-18 30.6% vs. low IL-18 17.5%; HR 1.89 [95% CI 1.30–2.73]; p = 0.001). Allocation to simvastatin in patients with high baseline plasma IL-18 was associated with a lower probability of 28-day mortality compared with placebo (24.0% vs 36.8%; p = 0.01). Finally, simvastatin, but not rosuvastatin, reduced stimulated macrophage secretion of IL-18 and IL-1β. Conclusion In patients with high baseline plasma IL-18, simvastatin is associated with a higher probability of survival, and this effect may be due to reduced inflammasome activation. These data suggest that baseline plasma IL-18 may allow a personalised treatment approach by identifying patients with ARDS who could benefit from simvastatin therapy.

Published
2022
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9. Repair of acute respiratory distress syndrome by stromal cell administration (REALIST): a structured study protocol for an open-label dose-escalation phase 1 trial followed by a randomised, triple-blind, allocation concealed, placebo-controlled phase 2 trial

Author

Ellen Gorman, Manu Shankar-Hari, Phil Hopkins, William S. Tunnicliffe, Gavin D. Perkins, Jonathan Silversides, Peter McGuigan, Colette Jackson, Roisin Boyle, Jamie McFerran, Cliona McDowell, Christina Campbell, Margaret McFarland, Jon Smythe, Jacqui Thompson, Barry Williams, Gerard Curley, John G. Laffey, Mike Clarke, Daniel F. McAuley, and Cecilia O’Kane

Subjects
Acute respiratory distress syndrome, Mesenchymal stromal cells, MSCs, Mesenchymal stem cells, Clinical trial, Protocol, Medicine (General), R5-920
Abstract

Abstract Background Mesenchymal stromal cells (MSCs) may be of benefit in ARDS due to immunomodulatory and reparative properties. This trial investigates a novel CD362 enriched umbilical cord derived MSC product (REALIST ORBCEL-C), produced to Good Manufacturing Practice standards, in patients with moderate to severe ARDS due to COVID-19 and ARDS due to other causes. Methods Phase 1 is a multicentre open-label dose-escalation pilot trial. Patients will receive a single infusion of REALIST ORBCEL-C (100 × 106 cells, 200 × 106 cells or 400 × 106 cells) in a 3 + 3 design. Phase 2 is a multicentre randomised, triple blind, allocation concealed placebo-controlled trial. Two cohorts of patients, with ARDS due to COVID-19 or ARDS due to other causes, will be recruited and randomised 1:1 to receive either a single infusion of REALIST ORBCEL-C (400 × 106 cells or maximal tolerated dose in phase 1) or placebo. Planned recruitment to each cohort is 60 patients. The primary safety outcome is the incidence of serious adverse events. The primary efficacy outcome is oxygenation index at day 7. The trial will be reported according to the Consolidated Standards for Reporting Trials (CONSORT 2010) statement. Discussion The development and manufacture of an advanced therapy medicinal product to Good Manufacturing Practice standards within NHS infrastructure are discussed, including challenges encountered during the early stages of trial set up. The rationale to include a separate cohort of patients with ARDS due to COVID-19 in phase 2 of the trial is outlined. Trial registration ClinicalTrials.gov NCT03042143. Registered on 3 February 2017. EudraCT Number 2017-000584-33

Published
2022
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10. Towards a biological definition of ARDS: are treatable traits the solution?

Author

Lieuwe D. J. Bos, John G. Laffey, Lorraine B. Ware, Nanon F. L. Heijnen, Pratik Sinha, Brijesh Patel, Matthieu Jabaudon, Julie A. Bastarache, Daniel F. McAuley, Charlotte Summers, Carolyn S. Calfee, and Manu Shankar-Hari

Subjects
ARDS, Diagnosis, Biomarker, Pathophysiology, Phenotype, Definition, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

Abstract The pathophysiology of acute respiratory distress syndrome (ARDS) includes the accumulation of protein-rich pulmonary edema in the air spaces and interstitial areas of the lung, variable degrees of epithelial injury, variable degrees of endothelial barrier disruption, transmigration of leukocytes, alongside impaired fluid and ion clearance. These pathophysiological features are different between patients contributing to substantial biological heterogeneity. In this context, it is perhaps unsurprising that a wide range of pharmacological interventions targeting these pathophysiological processes have failed to improve patient outcomes. In this manuscript, our goal is to provide a narrative summary of the potential methods to capture the underlying biological heterogeneity of ARDS and discuss how this information could inform future ARDS redefinitions. We discuss what biological tests are available to identify patients with any of the following predominant biological patterns: (1) epithelial and/or endothelial injury, (2) protein rich pulmonary edema and (3) systemic or within lung inflammatory responses.

Published
2022
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11. Promises and challenges of personalized medicine to guide ARDS therapy

Author

Katherine D. Wick, Daniel F. McAuley, Joseph E. Levitt, Jeremy R. Beitler, Djillali Annane, Elisabeth D. Riviello, Carolyn S. Calfee, and Michael A. Matthay

Subjects
Acute respiratory distress syndrome, Acute lung injury, Personalized medicine, COVID-19, Clinical trials, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

Abstract Identifying new effective treatments for the acute respiratory distress syndrome (ARDS), including COVID-19 ARDS, remains a challenge. The field of ARDS investigation is moving increasingly toward innovative approaches such as the personalization of therapy to biological and clinical sub-phenotypes. Additionally, there is growing recognition of the importance of the global context to identify effective ARDS treatments. This review highlights emerging opportunities and continued challenges for personalizing therapy for ARDS, from identifying treatable traits to innovative clinical trial design and recognition of patient-level factors as the field of critical care investigation moves forward into the twenty-first century.

Published
2021
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12. Oral health care for the critically ill: a narrative review

Author

Lewis Winning, Fionnuala T. Lundy, Bronagh Blackwood, Daniel F. McAuley, and Ikhlas El Karim

Subjects
VAP, Oral health, Chlorhexidine, Oral bacteria, Pneumonia, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

Abstract Background The link between oral bacteria and respiratory infections is well documented. Dental plaque has the potential to be colonized by respiratory pathogens and this, together with microaspiration of oral bacteria, can lead to pneumonia particularly in the elderly and critically ill. The provision of adequate oral care is therefore essential for the maintenance of good oral health and the prevention of respiratory complications. Main body Numerous oral care practices are utilised for intubated patients, with a clear lack of consensus on the best approach for oral care. This narrative review aims to explore the oral-lung connection and discuss in detail current oral care practices to identify shortcomings and offer suggestions for future research. The importance of adequate oral care has been recognised in guideline interventions for the prevention of pneumonia, but practices differ and controversy exists particularly regarding the use of chlorhexidine. The oral health assessment is also an important but often overlooked element of oral care that needs to be considered. Oral care plans should ideally be implemented on the basis of an individual oral health assessment. An oral health assessment prior to provision of oral care should identify patient needs and facilitate targeted oral care interventions. Conclusion Oral health is an important consideration in the management of the critically ill. Studies have suggested benefit in the reduction of respiratory complication such as Ventilator Associated Pneumonia associated with effective oral health care practices. However, at present there is no consensus as to the best way of providing optimal oral health care in the critically ill. Further research is needed to standardise oral health assessment and care practices to enable development of evidenced based personalised oral care for the critically ill.

Published
2021
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13. Extracorporeal carbon dioxide removal in acute hypoxaemic respiratory failure: a systematic review, Bayesian meta-analysis and trial sequential analysis

Author

Jonathan E. Millar, Andrew J. Boyle, Thomas M. Drake, Claire E. Adams, Adam W. Glass, Bronagh Blackwood, James J. McNamee, and Daniel F. McAuley

Subjects
Diseases of the respiratory system, RC705-779
Abstract

Purpose: To assess the safety and efficacy of extracorporeal carbon dioxide removal (ECCO2R) versus standard care in patients with acute hypoxaemic respiratory failure (AHRF). Methods: MEDLINE, Embase and clinical trial registries were searched from 1994 to 31 December 2021. We included randomised controlled trials (RCTs) and observational studies. Pairs of reviewers independently extracted data and assessed the risk of bias. The primary outcome was mortality. Secondary outcomes included ventilator-free days, length of stay, safety and adverse events and physiological changes. As a primary analysis, we performed a meta-analysis of mortality until day 30 using a Bayesian random effects model. We then performed a trial sequential analysis of RCTs. Results: 21 studies met inclusion criteria: three RCTs, enrolling 531 patients, and 18 observational studies. In a pooled analysis of RCTs, the posterior probability of increased mortality with the use of ECCO2R was 73% (relative risk 1.19, 95% credible interval 0.70–2.29). There was substantial heterogeneity in the reporting of safety and adverse events. However, the incidence of extra and intracranial haemorrhage was higher (relative risk 3.00, 95% credible interval 0.41–20.51) among those randomised to ECCO2R. Current trials have accumulated 80.8% of the diversity-adjusted required information size and the lack of effect reaches futility for a 10% absolute risk reduction in mortality. Conclusions: The use of ECCO2R in patients with AHRF is not associated with improvements in clinical outcomes. Furthermore, it is likely that further trials of ECCO2R aiming to achieve an absolute risk reduction in mortality of ≥10% are futile.

Published
2022
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14. Hyperoxaemia and hypoxaemia are associated with harm in patients with ARDS

Author

Andrew J. Boyle, David N. Holmes, Jonathan Hackett, Susanna Gilliland, Michael McCloskey, Cecilia M. O’Kane, Paul Young, Stefania Di Gangi, and Daniel F. McAuley

Subjects
Acute respiratory distress syndrome, Hyperoxia, Hyperoxaemia, Oxygen, Excess oxygen, Diseases of the respiratory system, RC705-779
Abstract

Abstract Background Oxygen therapy is routinely administered to mechanically ventilated patients. However, there remains uncertainty about the optimal oxygen titration target in patients with the acute respiratory distress syndrome (ARDS). Methods Prospectively identified adult patients meeting the Berlin definition of ARDS between 1st January 2014 and 13th December 2016 were analyzed. Oxygen exposure variables were collected at 6-hourly intervals. The primary exposure was the average time-weighted partial pressure of arterial oxygen (PaO2) calculated over a maximum of 7 days from meeting ARDS criteria. The primary outcome was ICU mortality. Univariable and multivariable logistic regression analyses were performed to assess the impact of exposure variables on clinical outcomes. Results are presented as odds ratio [95% confidence interval]. Results 202 patients were included in the final analysis. Overall ICU mortality was 31%. The average time-weighted PaO2 during the first 7 days of ARDS was similar between non-survivors and survivors (11.3 kPa [10.2, 12.5] (84.8 mmHg [76.5, 93.8]) vs. 11.9 kPa [10.9, 12.6] (89.3 mmHg [81.8, 94.5]); p = 0.08). In univariable and multivariable analysis, average time-weighted PaO2 demonstrated a U-shaped relationship with ICU mortality. There was a similar relationship identified with hospital mortality. Conclusions In patients with ARDS, the predicted probability of both ICU and hospital mortality was lowest when the average time-weighted PaO2 was between 12.5 and 14 kPa (93.8–105.0 mmHg), suggesting this is a reasonable oxygenation target for clinicians to aim for.

Published
2021
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15. Phenotypes and subphenotypes of delirium: a review of current categorisations and suggestions for progression

Author

Emily M. L. Bowman, Emma L. Cunningham, Valerie J. Page, and Daniel F. McAuley

Subjects
Delirium, Inattention, Disorientation, Awareness, Encephalopathy, Pathophysiology, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

Abstract Delirium is a clinical syndrome occurring in heterogeneous patient populations. It affects 45–87% of critical care patients and is often associated with adverse outcomes including acquired dementia, institutionalisation, and death. Despite an exponential increase in delirium research in recent years, the pathophysiological mechanisms resulting in the clinical presentation of delirium are still hypotheses. Efforts have been made to categorise the delirium spectrum into clinically meaningful subgroups (subphenotypes), using psychomotor subtypes such as hypoactive, hyperactive, and mixed, for example, and also inflammatory and non-inflammatory delirium. Delirium remains, however, a constellation of symptoms resulting from a variety of risk factors and precipitants with currently no successful targeted pharmacological treatment. Identifying specific clinical and biological subphenotypes will greatly improve understanding of the relationship between the clinical symptoms and the putative pathways and thus risk factors, precipitants, natural history, and biological mechanism. This will facilitate risk factor mitigation, identification of potential methods for interventional studies, and informed patient and family counselling. Here, we review evidence to date and propose a framework to identify subphenotypes. Endotype identification may be done by clustering symptoms with their biological mechanism, which will facilitate research of targeted treatments. In order to achieve identification of delirium subphenotypes, the following steps must be taken: (1) robust records of symptoms must be kept at a clinical level. (2) Global collaboration must facilitate large, heterogeneous research cohorts. (3) Patients must be clustered for identification, validation, and mapping of subphenotype stability.

Published
2021
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16. Parenteral thiamine for prevention and treatment of delirium in critically ill adults: a systematic review protocol

Author

Cathrine A. McKenzie, Valerie J. Page, W. David Strain, Bronagh Blackwood, Marlies Ostermann, David Taylor, Peter E. Spronk, and Daniel F. McAuley

Subjects
Thiamine, Vitamin B1, Vitamin B complex, Pabrinex, Delirium, Prevention, Medicine
Abstract

Abstract 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

Published
2020
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17. Acute respiratory distress syndrome subphenotypes and therapy responsive traits among preclinical models: protocol for a systematic review and meta-analysis

Author

Adrien Carla, Bruno Pereira, Hanifa Boukail, Jules Audard, Nathalie Pinol-Domenech, Manuela De Carvalho, Raiko Blondonnet, Ruoyang Zhai, Dominique Morand, Céline Lambert, Vincent Sapin, Lorraine B. Ware, Carolyn S. Calfee, Julie A. Bastarache, John G. Laffey, Nicole P. Juffermans, Lieuwe D. Bos, Antonio Artigas, Patricia R. M. Rocco, Michael A. Matthay, Daniel F. McAuley, Jean-Michel Constantin, Matthieu Jabaudon, and for the ESICM Translational Biology Group of the Acute Respiratory Failure section

Subjects
Systematic review protocol, Acute respiratory distress syndrome, Preclinical, Subphenotypes, Diseases of the respiratory system, RC705-779
Abstract

Abstract Background Subphenotypes were recently reported within clinical acute respiratory distress syndrome (ARDS), with distinct outcomes and therapeutic responses. Experimental models have long been used to mimic features of ARDS pathophysiology, but the presence of distinct subphenotypes among preclinical ARDS remains unknown. This review will investigate whether: 1) subphenotypes can be identified among preclinical ARDS models; 2) such subphenotypes can identify some responsive traits. Methods We will include comparative preclinical (in vivo and ex vivo) ARDS studies published between 2009 and 2019 in which pre-specified therapies were assessed (interleukin (IL)-10, IL-2, stem cells, beta-agonists, corticosteroids, fibroblast growth factors, modulators of the receptor for advanced glycation end-products pathway, anticoagulants, and halogenated agents) and outcomes compared to a control condition. The primary outcome will be a composite of the four key features of preclinical ARDS as per the American Thoracic Society consensus conference (histologic evidence of lung injury, altered alveolar-capillary barrier, lung inflammatory response, and physiological dysfunction). Secondary outcomes will include the single components of the primary composite outcome, net alveolar fluid clearance, and death. MEDLINE, Embase, and Cochrane databases will be searched electronically and data from eligible studies will be extracted, pooled, and analyzed using random-effects models. Individual study reporting will be assessed according to the Animal Research: Reporting of In Vivo Experiments guidelines. Meta-regressions will be performed to identify subphenotypes prior to comparing outcomes across subphenotypes and treatment effects. Discussion This study will inform on the presence and underlying pathophysiological features of subphenotypes among preclinical models of ARDS and should help to determine whether sufficient evidence exists to perform preclinical trials of subphenotype-targeted therapies, prior to potential clinical translation. Systematic review registration PROSPERO (ID: CRD42019157236 ).

Published
2020
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18. Interventions for oropharyngeal dysphagia in acute and critical care: a protocol for a systematic review and meta-analysis

Author

Sallyanne Duncan, Jennifer Mc Gaughey, Richard Fallis, Daniel F. McAuley, Margaret Walshe, and Bronagh Blackwood

Subjects
Dysphagia, Deglutition disorders, Acute care, Acute hospital, Critical care, Intensive care, Medicine
Abstract

Abstract Background Oropharyngeal dysphagia or swallowing difficulties are common in acute care and critical care, affecting 47% of hospitalised frail elderly, 50% of acute stroke patients and approximately 62% of critically ill patients who have been intubated and mechanically ventilated for prolonged periods. Complications of dysphagia include aspiration leading to chest infection and pneumonia, malnutrition, increased length of hospital stay and re-admission to hospital. To date, most dysphagia interventions in acute care have been tested with acute stroke populations. While intervention studies in critical care have been emerging since 2015, they are limited and so there is much to learn about the type, the delivery and the intensity of treatments in this setting to inform future clinical trials. The aim of this systematic review is to summarise the evidence regarding the relationship between dysphagia interventions and clinically important patient outcomes in acute and critical care settings. Methods We will search MEDLINE, EMBASE, CENTRAL, Web of Science, CINAHL and clinical trial registries from inception to the present. We will include studies conducted with adults in acute care settings such as acute hospital wards or units or intensive care units and critical care settings. Studies will be restricted to randomised controlled trials and quasi-randomised controlled trials comparing a new dysphagia intervention with usual care or another intervention. The main outcomes that will be collected include length of time taken to return to oral intake, change in incidence of aspiration and pneumonia, nutritional status, length of hospital stay and quality of life. Key intervention components such as delivery, intensity, acceptability, fidelity and adverse events associated with such interventions will be collected to inform future clinical trials. Two independent reviewers will assess articles for eligibility, data extraction and quality appraisal. A meta-analysis will be conducted as appropriate. Discussion No systematic review has attempted to summarise the evidence for oropharyngeal dysphagia interventions in acute and critical care. Results of the proposed systematic review will inform practice and the design of future clinical trials. Systematic review registration PROSPERO CRD 42018116849 (http://www.crd.york.ac.uk/PROSPERO/)

Published
2019
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19. Repair of acute respiratory distress syndrome by stromal cell administration (REALIST) trial: A phase 1 trial

Author

Ellen Gorman, Manu Shankar-Hari, Phil Hopkins, William S. Tunnicliffe, Gavin D. Perkins, Jonathan Silversides, Peter McGuigan, Anna Krasnodembskaya, Colette Jackson, Roisin Boyle, Jamie McFerran, Cliona McDowell, Christina Campbell, Margaret McFarland, Jon Smythe, Jacqui Thompson, Barry Williams, Gerard Curley, John G. Laffey, Mike Clarke, Daniel F. McAuley, and Cecilia M. O'Kane

Subjects
Medicine (General), R5-920
Abstract

Background: Mesenchymal stromal cells (MSCs) may be of benefit in acute respiratory distress syndrome (ARDS) due to immunomodulatory, reparative, and antimicrobial actions. ORBCEL-C is a population of CD362 enriched umbilical cord-derived MSCs. The REALIST phase 1 trial investigated the safety and feasibility of ORBCEL-C in patients with moderate to severe ARDS. Methods: REALIST phase 1 was an open label, dose escalation trial in which cohorts of mechanically ventilated patients with moderate to severe ARDS received increasing doses (100, 200 or 400 × 106 cells) of a single intravenous infusion of ORBCEL-C in a 3 + 3 design. The primary safety outcome was the incidence of serious adverse events. Dose limiting toxicity was defined as a serious adverse reaction within seven days. Trial registration clinicaltrials.gov NCT03042143. Findings: Nine patients were recruited between the 7th January 2019 and 14th January 2020. Study drug administration was well tolerated and no dose limiting toxicity was reported in any of the three cohorts. Eight adverse events were reported for four patients. Pyrexia within 24 h of study drug administration was reported in two patients as pre-specified adverse events. A further two adverse events (non-sustained ventricular tachycardia and deranged liver enzymes), were reported as adverse reactions. Four serious adverse events were reported (colonic perforation, gastric perforation, bradycardia and myocarditis) but none were deemed related to administration of ORBCEL-C. At day 28 no patients had died in cohort one (100 × 106), three patients had died in cohort two (200 × 106) and one patient had died in cohort three (400 × 106). Overall day 28 mortality was 44% (n = 4/9). Interpretation: A single intravenous infusion of ORBCEL-C was well tolerated in patients with moderate to severe ARDS. No dose limiting toxicity was reported up to 400 × 106 cells.

Published
2021
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20. Characterizing preclinical sub‐phenotypic models of acute respiratory distress syndrome: An experimental ovine study

Author

Jonathan E. Millar, Karin Wildi, Nicole Bartnikowski, Mahe Bouquet, Kieran Hyslop, Margaret R. Passmore, Katrina K. Ki, Louise E. See Hoe, Nchafatso G. Obonyo, Lucile Neyton, Sanne Pedersen, Sacha Rozencwajg, J. Kenneth Baillie, Gianluigi Li Bassi, Jacky Y. Suen, Daniel F. McAuley, and John F. Fraser

Subjects
acute respiratory distress syndrome, animal, models, phenotype, Physiology, QP1-981
Abstract

Abstract The acute respiratory distress syndrome (ARDS) describes a heterogenous population of patients with acute severe respiratory failure. However, contemporary advances have begun to identify distinct sub‐phenotypes that exist within its broader envelope. These sub‐phenotypes have varied outcomes and respond differently to several previously studied interventions. A more precise understanding of their pathobiology and an ability to prospectively identify them, may allow for the development of precision therapies in ARDS. Historically, animal models have played a key role in translational research, although few studies have so far assessed either the ability of animal models to replicate these sub‐phenotypes or investigated the presence of sub‐phenotypes within animal models. Here, in three ovine models of ARDS, using combinations of oleic acid and intravenous, or intratracheal lipopolysaccharide, we investigated the presence of sub‐phenotypes which qualitatively resemble those found in clinical cohorts. Principal Component Analysis and partitional clustering identified two clusters, differentiated by markers of shock, inflammation, and lung injury. This study provides a first exploration of ARDS phenotypes in preclinical models and suggests a methodology for investigating this phenomenon in future studies.

Published
2021
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21. The Influence of Orthopedic Surgery on Circulating Metabolite Levels, and their Associations with the Incidence of Postoperative Delirium

Author

Mijin Jung, Xiaobei Pan, Emma L. Cunningham, Anthony P. Passmore, Bernadette McGuinness, Daniel F. McAuley, David Beverland, Seamus O’Brien, Tim Mawhinney, Jonathan M. Schott, Henrik Zetterberg, and Brian D. Green

Subjects
orthopedic surgery, postoperative delirium, spermine, ornithine, polyamine, Microbiology, QR1-502
Abstract

The mechanisms underlying the occurrence of postoperative delirium development are unclear and measurement of plasma metabolites may improve understanding of its causes. Participants (n = 54) matched for age and gender were sampled from an observational cohort study investigating postoperative delirium. Participants were ≥65 years without a diagnosis of dementia and presented for primary elective hip or knee arthroplasty. Plasma samples collected pre- and postoperatively were grouped as either control (n = 26, aged: 75.8 ± 5.2) or delirium (n = 28, aged: 76.2 ± 5.7). Widespread changes in plasma metabolite levels occurred following surgery. The only metabolites significantly differing between corresponding control and delirium samples were ornithine and spermine. In delirium cases, ornithine was 17.6% higher preoperatively, and spermine was 12.0% higher postoperatively. Changes were not associated with various perioperative factors. In binary logistic regression modeling, these two metabolites did not confer a significantly increased risk of delirium. These findings support the hypothesis that disturbed polyamine metabolism is an underlying factor in delirium that warrants further investigation.

Published
2022
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22. 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

Author

Gavin D. Perkins, Keith Couper, Bronwen Connolly, J. Kenneth Baillie, Judy M. Bradley, Paul Dark, Anthony De Soyza, Ellen Gorman, Alasdair Gray, Louisa Hamilton, Nicholas Hart, Chen Ji, Ranjit Lall, Nicola McGowan, Scott Regan, Anita K. Simonds, Emma Skilton, Nigel Stallard, Emily Stimpson, Joyce Yeung, and Daniel F. McAuley

Subjects
COVID-19, Randomised controlled trial, protocol, continuous positive airway pressure, oxygen inhalation therapy, high-flow nasal oxygen, Medicine (General), R5-920
Abstract

Abstract 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 (FiO2) ≥0.4 and peripheral oxygen saturation (SpO2) ≤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 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, 29th 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 13th April 2020. Trial registration ISRCTN, ISRCTN16912075. Registered 6th April 2020, http://www.isrctn.com/ISRCTN16912075 Full protocol The full protocol (version 4.0, 29th 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).

Published
2020
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23. 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

Author

Ellen Gorman, Manu Shankar-Hari, Phil Hopkins, William S. Tunnicliffe, Gavin D. Perkins, Jonathan Silversides, Peter McGuigan, Colette Jackson, Roisin Boyle, Jamie McFerran, Cliona McDowell, Christina Campbell, Margaret McFarland, Jon Smythe, Jacqui Thompson, Barry Williams, Gerard Curley, John G. Laffey, Mike Clarke, Cecilia O’Kane, and Daniel F. McAuley

Subjects
COVID-19, Randomised controlled trial, protocol, Mesenchymal Stromal Cells, Mesenchymal Stem Cells, MSCs, Medicine (General), R5-920
Abstract

Abstract 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 x106 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 PaO2/FiO2 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 27th March 2020 and MHRA on 30th 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 NCT 03042143 (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).

Published
2020
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24. Heterogeneity of treatment effect by baseline risk of mortality in critically ill patients: re-analysis of three recent sepsis and ARDS randomised controlled trials

Author

Shalini Santhakumaran, Anthony Gordon, A. Toby Prevost, Cecilia O’Kane, Daniel F. McAuley, and Manu Shankar-Hari

Subjects
Sepsis, acute respiratory distress syndrome, Models, statistical, Randomisation, Risk, Study design, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

Abstract Background Randomised controlled trials (RCTs) enrolling patients with sepsis or acute respiratory distress syndrome (ARDS) generate heterogeneous trial populations. Non-random variation in the treatment effect of an intervention due to differences in the baseline risk of death between patients in a population represents one form of heterogeneity of treatment effect (HTE). We assessed whether HTE in two sepsis and one ARDS RCTs could explain indeterminate trial results and inform future trial design. Methods We assessed HTE for vasopressin, hydrocortisone and levosimendan in sepsis and simvastatin in ARDS patients, on 28-day mortality, using the total Acute Physiology And Chronic Health Evaluation II (APACHE II) score as the baseline risk measurement, comparing above (high) and below (low) the median score. Secondary risk measures were the acute physiology component of APACHE II and predicted risk of mortality using the APACHE II score. HTE was quantified both in additive (difference in risk difference (RD)) and multiplicative (ratio of relative risks (RR)) scales using estimated treatment differences from a logistic regression model with treatment risk as the interaction term. Results The ratio of the odds of death in the highest APACHE II quartile was 4.9 to 7.4 times compared to the lowest quartile, across the three trials. We did not observe HTE for vasopressin, hydrocortisone and levosimendan in the two sepsis trials. In the HARP-2 trial, simvastatin reduced mortality in the low APACHE II group and increased mortality in the high APACHE II group (difference in RD = 0.34 (0.12, 0.55) (p = 0.02); ratio of RR 3.57 (1.77, 7.17) (p

Published
2019
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25. Extracorporeal membrane oxygenation (ECMO) and the acute respiratory distress syndrome (ARDS): a systematic review of pre-clinical models

Author

Jonathan E. Millar, Nicole Bartnikowski, Viktor von Bahr, Maximilian V. Malfertheiner, Nchafatso G. Obonyo, Mirko Belliato, Jacky Y. Suen, Alain Combes, Daniel F. McAuley, Roberto Lorusso, John F. Fraser, on behalf of the European Extracorporeal Life Support Organisation (EuroELSO) Innovations Workgroup, and the National Health Medical Research Council Australia Centre of Research Excellence for Advanced Cardio-respiratory Therapies Improving Organ Support (NHMRC CREACTIONS)

Subjects
Extracorporeal membrane oxygenation, Acute respiratory distress syndrome, Animal models, Pre-clinical models, Systematic review, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

Abstract Objectives Extracorporeal membrane oxygenation (ECMO) is an increasingly accepted means of supporting those with severe acute respiratory distress syndrome (ARDS). Given the high mortality associated with ARDS, numerous animal models have been developed to support translational research. Where ARDS is combined with ECMO, models are less well characterized. Therefore, we conducted a systematic literature review of animal models combining features of experimental ARDS with ECMO to better understand this situation. Data sources MEDLINE and Embase were searched between January 1996 and December 2018. Study selection Inclusion criteria: animal models combining features of experimental ARDS with ECMO. Exclusion criteria: clinical studies, abstracts, studies in which the model of ARDS and ECMO has been reported previously, and studies not employing veno-venous, veno-arterial, or central ECMO. Data extraction Data were extracted to fully characterize models. Variables related to four key features: (1) study design, (2) animals and their peri-experimental care, (3) models of ARDS and mechanical ventilation, and (4) ECMO and its intra-experimental management. Data synthesis Seventeen models of ARDS and ECMO were identified. Twelve were published after 2009. All were performed in large animals, the majority (n = 10) in pigs. The median number of animals included in each study was 17 (12–24), with a median study duration of 8 h (5–24). Oleic acid infusion was the commonest means of inducing ARDS. Most models employed peripheral veno-venous ECMO (n = 12). The reporting of supportive measures and the practice of mechanical ventilation were highly variable. Descriptions of ECMO equipment and its management were more complete. Conclusion A limited number of models combine the features of experimental ARDS with ECMO. Among those that do, there is significant heterogeneity in both design and reporting. There is a need to standardize the reporting of pre-clinical studies in this area and to develop best practice in their design.

Published
2019
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26. Identifying associations between diabetes and acute respiratory distress syndrome in patients with acute hypoxemic respiratory failure: an analysis of the LUNG SAFE database

Author

Andrew J. Boyle, Fabiana Madotto, John G. Laffey, Giacomo Bellani, Tài Pham, Antonio Pesenti, B. Taylor Thompson, Cecilia M. O’Kane, Adam M. Deane, Daniel F. McAuley, on behalf of the LUNG SAFE Investigators, and the ESICM Trials Group

Subjects
Acute hypoxemic respiratory failure, Acute respiratory distress syndrome, Diabetes mellitus, LUNG SAFE, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

Abstract Background Diabetes mellitus is a common co-existing disease in the critically ill. Diabetes mellitus may reduce the risk of acute respiratory distress syndrome (ARDS), but data from previous studies are conflicting. The objective of this study was to evaluate associations between pre-existing diabetes mellitus and ARDS in critically ill patients with acute hypoxemic respiratory failure (AHRF). Methods An ancillary analysis of a global, multi-centre prospective observational study (LUNG SAFE) was undertaken. LUNG SAFE evaluated all patients admitted to an intensive care unit (ICU) over a 4-week period, that required mechanical ventilation and met AHRF criteria. Patients who had their AHRF fully explained by cardiac failure were excluded. Important clinical characteristics were included in a stepwise selection approach (forward and backward selection combined with a significance level of 0.05) to identify a set of independent variables associated with having ARDS at any time, developing ARDS (defined as ARDS occurring after day 2 from meeting AHRF criteria) and with hospital mortality. Furthermore, propensity score analysis was undertaken to account for the differences in baseline characteristics between patients with and without diabetes mellitus, and the association between diabetes mellitus and outcomes of interest was assessed on matched samples. Results Of the 4107 patients with AHRF included in this study, 3022 (73.6%) patients fulfilled ARDS criteria at admission or developed ARDS during their ICU stay. Diabetes mellitus was a pre-existing co-morbidity in 913 patients (22.2% of patients with AHRF). In multivariable analysis, there was no association between diabetes mellitus and having ARDS (OR 0.93 (0.78–1.11); p = 0.39), developing ARDS late (OR 0.79 (0.54–1.15); p = 0.22), or hospital mortality in patients with ARDS (1.15 (0.93–1.42); p = 0.19). In a matched sample of patients, there was no association between diabetes mellitus and outcomes of interest. Conclusions In a large, global observational study of patients with AHRF, no association was found between diabetes mellitus and having ARDS, developing ARDS, or outcomes from ARDS. Trial registration NCT02010073. Registered on 12 December 2013.

Published
2018
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27. The Impact of Aging in Acute Respiratory Distress Syndrome: A Clinical and Mechanistic Overview

Author

Ryan Brown, Michael C. McKelvey, Sinéad Ryan, Shannice Creane, Dermot Linden, Joseph C. Kidney, Daniel F. McAuley, Clifford C. Taggart, and Sinéad Weldon

Subjects
acute respiratory distress syndrome, acute lung injury, aging, immunosenescence, biomarkers, Medicine (General), R5-920
Abstract

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.

Published
2020
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28. Airway Inflammation and Host Responses in the Era of CFTR Modulators

Author

Karen Keown, Ryan Brown, Declan F. Doherty, Claire Houston, Michael C. McKelvey, Shannice Creane, Dermot Linden, Daniel F. McAuley, Joseph C. Kidney, Sinéad Weldon, Damian G. Downey, and Clifford C. Taggart

Subjects
cystic fibrosis, inflammation, infection, CFTR modulator, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

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.

Published
2020
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30. The Effect of an Accelerated Renal Replacement Therapy Initiation Is Not Modified by Baseline Risk

Author

Federico Angriman, Bruno L. Ferreyro, Natalia Angeloni, Bruno R. da Costa, Ron Wald, Sean M. Bagshaw, Neill K.J. Adhikari, Rinaldo Bellomo, Didier Dreyfuss, Bin Du, Martin P. Gallagher, Stéphane Gaudry, François Lamontagne, Michael Joannidis, Kathleen D. Liu, Daniel F. McAuley, Shay P. McGuinness, Alistair D. Nichol, Marlies Ostermann, Paul M. Palevsky, Haibo Qiu, Ville Pettilä, Antoine G. Schneider, Orla M. Smith, Suvi T. Vaara, Matthew Weir, Glenn M. Eastwood, Leah Peck, Helen Young, Peter Kruger, Gordon Laurie, Emma Saylor, Jason Meyer, Ellen Venz, Krista Wetzig, Craig French, Forbes McGain, John Mulder, Gerard Fennessy, Sathyajith Koottayi, Samantha Bates, Miriam Towns, Rebecca Morgan, Anna Tippett, Andrew Udy, Chris Mason, Elisa Licari, Dashiell Gantner, Jason McClure, Alistair Nichol, Phoebe McCracken, Jasmin Board, Emma Martin, Shirley Vallance, Meredith Young, Chelsey Vladic, Steve McGloughlin, David Gattas, Heidi Buhr, Jennifer Coles, Debra Hutch, James Wun, Louise Cole, Christina Whitehead, Julie Lowrey, Kristy Masters, Rebecca Gresham, Victoria Campbell, David Gutierrez, Jane Brailsford, Loretta Forbes, Lauren Murray, Teena Maguire, Martina NiChonghaile, Neil Orford, Allison Bone, Tania Elderkin, Tania Salerno, Tim Chimunda, Jason Fletcher, Emma Broadfield, Sanjay Porwal, Cameron Knott, Catherine Boschert, Julie Smith, Angus Richardson, Dianne Hill, Graeme Duke, Peter Oziemski, Santiago Cegarra, Peter Chan, Deborah Welsh, Stephanie Hunter, Owen Roodenburg, John Dyett, Nicos Kokotsis, Max Moser, Yang Yang, Laven Padayachee, Joseph Vetro, Himangsu Gangopadhyay, Melissa Kaufman, Angaj Ghosh, Simone Said, Alpesh Patel, Shailesh Bihari, Elisha Matheson, Xia Jin, Tapaswi Shrestha, Kate Schwartz, Rosalba Cross, Winston Cheung, Helen Wong, Mark Kol, Asim Shah, Amanda Y. Wang, Zoltan Endre, Celia Bradford, Pierre Janin, Simon Finfer, Naomi Diel, Jonathan Gatward, Naomi Hammond, Anthony Delaney, Frances Bass, Elizabeth Yarad, Hergen Buscher, Claire Reynolds, Nerilee Baker, Romuald Bellmann, Andreas Peer, Julia Hasslacher, Paul Koglberger, Sebastian Klein, Klemens Zotter, Anna Brandtner, Armin Finkenstedt, Adelheid Ditlbacher, Frank Hartig, Dietmar Fries, Mirjam Bachler, Bettina Schenk, Martin Wagner, Philipp Eller, Thomas Staudinger, Esther Tiller, Peter Schellongowski, Andja Bojic, Eric A. Hoste, Stephanie Bracke, Luc De Crop, Daisy Vermeiren, Fernando Thome, Bianca Chiella, Lucia Fendt, Veronica Antunes, Frédérick D'Aragon, Charles St-Arnaud, Michael Mayette, Élaine Carbonnaeu, Joannie Marchand, Marie-Hélène Masse, Marilène Ladouceur, Alexis F. Turgeon, François Lauzier, David Bellemare, Charles Langis Francoeur, Guillaume LeBlanc, Gabrielle Guilbault, Stéphanie Grenier, Eve Cloutier, Annick Boivin, Charles Delisle-Thibault, Panagiota Giannakouros, Olivier Costerousse, Jean-François Cailhier, François-Martin Carrier, Ali Ghamraoui, Martine Lebrasseur, Fatna Benettaib, Maya Salamé, Dounia Boumahni, Ying Tung Sia, Jean-François Naud, Isabelle Roy, Henry T. Stelfox, Stacey Ruddell, Braden J. Manns, Shelley Duggan, Dominic Carney, Jennifer Barchard, Richard P. Whitlock, Emilie Belley-Cote, Nevena Savija, Alexandra Sabev, Troy Campbell, Thais Creary, Kelson Devereaux, Shira Brodutch, Claudio Rigatto, Bojan Paunovic, Owen Mooney, Anna Glybina, Oksana Harasemiw, Michelle Di Nella, John Harmon, Navdeep Mehta, Louis Lakatos, Nicole Haslam, Francois Lellouche, Mathieu Simon, Ying Tung, Patricia Lizotte, Pierre-Alexandre Bourchard, Bram Rochwerg, Tim Karachi, Tina Millen, John Muscedere, David Maslove, J. Gordon Boyd, Stephanie Sibley, John Drover, Miranda Hunt, Ilinca Georgescu, Randy Wax, Ilan Lenga, Kavita Sridhar, Andrew Steele, Kelly Fusco, Taneera Ghate, Michael Tolibas, Holly Robinson, Matthew A. Weir, Ravi Taneja, Ian M. Ball, Amit Garg, Eileen Campbell, Athena Ovsenek, Sean van Diepen, Nadia Baig, Sheldon Magder, Han Yao, Ahsan Alam, Josie Campisi, Erika MacIntyre, Ella Rokosh, Kimberly Scherr, Stephen Lapinsky, Sangeeta Mehta, Sumesh Shah, Daniel J. Niven, Michael Russell, Kym Jim, Gillian Brown, Kerry Oxtoby, Adam Hall, Luc Benoit, Colleen Sokolowski, Bhanu Prasad, Jag Rao, Shelley Giebel, Demetrios J. Kutsogiannis, Patricia Thompson, Tayne Thompson, Robert Cirone, Kanthi Kavikondala, Mark Soth, France Clarke, Alyson Takaoka, David Mazer, Karen Burns, Jan Friedrich, David Klein, Gyan Sandhu, Marlene Santos, Imrana Khalid, Jennifer Hodder, Peter Dodek, Najib Ayas, Victoria Alcuaz, Gabriel Suen, Oleksa Rewa, Gurmeet Singh, Sean Norris, Neil Gibson, Castro Arias, Aysha Shami, Celine Pelletier, Alireza Zahirieh, Andre Amaral, Nicole Marinoff, Navjot Kaur, Adic Perez, Jane Wang, Gregory Haljan, Christopher Condin, Lauralyn McIntyre, Brigette Gomes, Rebecca Porteous, Irene Watpool, Swapnil Hiremath, Edward Clark, Margaret S. Herridge, Felicity Backhouse, M. Elizabeth Wilcox, Karolina Walczak, Vincent Ki, Asheer Sharman, Martin Romano, R.T. Noel Gibney, Adam S. Romanovsky, Lorena McCoshen, Gordon Wood, Daniel Ovakim, Fiona Auld, Gayle Carney, Meili Duan, Xiaojun Ji, Dongchen Guo, Zhili Qi, Jin Lin, Meng Zhang, Lei Dong, Jingfeng Liu, Pei Liu, Deyuan Zhi, Guoqiang Bai, Yu Qiu, Ziqi Yang, Jing Bai, Zhuang Liu, Haizhou Zhuang, Haiman Wang, Jian Li, Mengya Zhao, Xiao Zhou, Xianqing Shi, Baning Ye, Manli Liu, Jing Wu, Yongjian Fu, Dali Long, Yu Pan, Jinlong Wang, Huaxian Mei, Songsong Zhang, Mingxiang Wen, Enyu Yang, Sijie Mu, Jianquan Li, Tingting Hu, Bingyu Qin, Min Li, Cunzhen Wang, Xin Dong, Kaiwu Wang, Haibo Wang, Jianxu Yang, Chuanyao Wang, Dongxin Wang, Nan Li, Zhui Yu, Song Xu, Lan Yao, Guo Hou, Zhou Liu, Liping Lu, Yingtao Lian, Chunting Wang, Jichen Zhang, Ruiqi Ding, Guoqing Qi, Qizhi Wang, Peng Wang, Zhaoli Meng, Man Chen, Xiaobo Hu, Xiandi He, Shibing Zhao, Lele Hang, Rui Li, Suhui Qin, Kun Lu, Shijuan Dun, Cheng Liu, Qi Zhou, Zhenzhen Chen, Jing Mei, Minwei Zhang, Hao Xu, Jincan Lin, Qindong Shi, Lijuan Fu, Qinjing Zeng, Hongye Ma, Jinqi Yan, Lan Gao, Hongjuan Liu, Lei Zhang, Hao Li, Xiaona He, Jingqun Fan, Litao Guo, Yu Liu, Xue Wang, Jingjing Sun, Zhongmin Liu, Juan Yang, Lili Ding, Lulu Sheng, Xingang Liu, Jie Yan, Quihui Wang, Yifeng Wang, Dan Zhao, Shuangping Zhao, Chenghuan Hu, Jing Li, Fuxing Deng, Haibo Qui, Yi Yang, Min Mo, Chun Pan, Changde Wu, Yingzi Huang, Lili Huang, Airan Liu, Anna-Maija Korhonen, Sanna Törnblom, Sari Sutinen, Leena Pettilä, Jonna Heinonen, Eliria Lappi, Taria Suhonen, Sari Karlsson, Sanna Hoppu, Ville Jalkanen, Anne Kuitunen, Markus Levoranta, Jaakko Långsjö, Sanna Ristimäki, Kaisa Malila, Anna Wootten, Simo Varila, Mikko J Järvisalo, Outi Inkinen, Satu Kentala, Keijo Leivo, Paivi Haltia, Jean-Damien Ricard, Jonathan Messika, Abirami Tiagarajah, Malo Emery, Aline Dechanet, Coralie Gernez, Damien Roux, Laurent Martin-Lefevre, Maud Fiancette, Isabelle Vinatier, Jean Claude Lacherade, Gwenhaël Colin, Christine Lebert, Marie-Ange Azais, Aihem Yehia, Caroline Pouplet, Matthieu Henry- Lagarrigue, Amélie Seguin, Laura Crosby, Julien Maizel, Dimitri Titeca-Beauport, Alain Combes, Ania Nieszkowska, Paul Masi, Alexandre Demoule, Julien Mayaux, Martin Dres, Elise Morawiec, Maxens Decalvele, Suela Demiri, Morgane Faure, Clémence Marios, Maxime Mallet, Marie Amélie Ordon, Laura Morizot, Marie Cantien, François Pousset, Florent Poirson, Yves Cohen, Laurent Argaud, Martin Cour, Laurent Bitker, Marie Simon, Romain Hernu, Thomas Baudry, Sylvie De La Salle, Adrien Robine, Nicholas Sedillot, Xavier Tchenio, Camille Bouisse, Sylvie Roux, Fabienne Tamion, Steven Grangé, Dorothée Carpentier, Guillaume Chevrel, Luis Ensenyat-Martin, Sophie Marque, Jean-Pierre Quenot, Pascal Andreu, Auguste Dargent, Audrey Large, Nicolas Chudeau, Mickael Landais, Benoit Derrien, Jean Christophe Callahan, Christophe Guitton, Charlène Le Moal, Alain Robert, Karim Asehnoune, Raphaël Cinotti, Nicolas Grillot, Dominique Demeure, Christophe Vinsonneau, Imen Rahmani, Mehdi Marzouk, Thibault Dekeyser, Caroline Sejourne, Mélanie Verlay, Fabienne Thevenin, Lucie Delecolle, Didier Thevenin, Bertrand Souweine, Elisabeth Coupez, Mireille Adda, Jean-Pierre Eraldi, Antoine Marchalot, Nicolas De Prost, Armand Mekontso Dessap, Keyvan Razazi, Ferhat Meziani, Julie Boisrame-Helms, Raphael Clere-Jehl, Xavier Delabranche, Christine Kummerlen, Hamid Merdji, Alexandra Monnier, Yannick Rabouel, Hassene Rahmani, Hayat Allam, Samir Chenaf, Vincenta Franja, Bertrand Pons, Michel Carles, Frédéric Martino, Régine Richard, Benjamin Zuber, Guillaume Lacave, Karim Lakhal, Bertrand Rozec, Hoa Dang Van, Éric Boulet, Fouad Fadel, Cedric Cleophax, Nicolas Dufour, Caroline Grant, Marie Thuong, Jean Reignier, Emmanuel Canet, Laurent Nicolet, Thierry Boulain, Mai-Anh Nay, Dalila Benzekri, François Barbier, Anne Bretagnol, Toufik Kamel, Armelle Mathonnet, Grégoire Muller, Marie Skarzynski, Julie Rossi, Amandine Pradet, Sandra Dos Santos, Aurore Guery, Lucie Muller, Luis Felix, Julien Bohé, Guillaume Thiéry, Nadia Aissaoui, Damien Vimpere, Morgane Commeureuc, Jean-Luc Diehl, Emmanuel Guerot, Orfeas Liangos, Monika Wittig, Alexander Zarbock, Mira Küllmar, Thomas van Waegeningh, Nadine Rosenow, Kathy Brickell, Peter Doran, Patrick T. Murray, Giovanni Landoni, Rosalba Lembo, Alberto Zangrillo, Giacomo Monti, Margherita Tozzi, Matteo Marzaroli, Gaetano Lombardi, Gianluca Paternoster, Michelangelo Vitiello, Shay McGuinness, Rachael Parke, Magdalena Butler, Eileen Gilder, Keri-Anne Cowdrey, Samantha Wallace, Jane Hallion, Melissa Woolett, Philippa Neal, Karina Duffy, Stephanie Long, Colin McArthur, Catherine Simmonds, Yan Chen, Rachael McConnochie, Lynette Newby, David Knight, Seton Henderson, Jan Mehrtens, Stacey Morgan, Anna Morris, Kymbalee Vander Hayden, Tara Burke, Matthew Bailey, Ross Freebairn, Lesley Chadwick, Penelope Park, Christine Rolls, Liz Thomas, Ulrike Buehner, Erin Williams, Jonathan Albrett, Simon Kirkham, Carolyn Jackson, Troy Browne, Jennifer Goodson, David Jackson, James Houghton, Owen Callender, Vicki Higson, Owen Keet, Clive Dominy, Paul Young, Anna Hunt, Harriet Judd, Cassie Lawrence, Shaanti Olatunji, Yvonne Robertson, Charlotte Latimer-Bell, Deborah Hendry, Agnes Mckay-Vucago, Nina Beehre, Eden Lesona, Leanlove Navarra, Chelsea Robinson, Ryan Jang, Andrea Junge, Bridget Lambert, Michel Thibault, Philippe Eckert, Sébastien Kissling, Erietta Polychronopoulos, Elettra Poli, Marco Altarelli, Madeleine Schnorf, Samia Abed Mallaird, Claudia Heidegger, Aurelie Perret, Philippe Montillier, Frederic Sangla, Seigenthaller Neils, Aude De Watteville, Mandeep-Kaur Phull, Aparna George, Nauman Hussain, Tatiana Pogreban, Steve Lobaz, Alison Daniels, Mishell Cunningham, Deborah Kerr, Alice Nicholson, Pradeep Shanmugasundaram, Judith Abrams, Katarina Manso, Geraldine Hambrook, Elizabeth McKerrow, Juvy Salva, Stephen Foulkes, Matthew Wise, Matt Morgan, Jenny Brooks, Jade Cole, Tracy Michelle Davies, Helen Hill, Emma Thomas, Marcela Vizcaychipi, Behrad Baharlo, Jaime Carungcong, Patricia Costa, Laura Martins, Ritoo Kapoor, Tracy Hazelton, Angela Moon, Janine Musselwhite, Ben Shelley, Philip McCall, Gill Arbane, Aneta Bociek, Martina Marotti, Rosario Lim, Sara Campos, Neus Grau Novellas, Armando Cennamo, Andrew Slack, Duncan Wyncoll, Luigi Camporota, Simon Sparkes, Rosalinde Tilley, Austin Rattray, Gayle Moreland, Jane Duffy, Elizabeth McGonigal, Philip Hopkins, Clare Finney, John Smith, Harriet Noble, Hayley Watson, Claire-Louise Harris, Emma Clarey, Eleanor Corcoran, James Beck, Clare Howcroft, Nora Youngs, Elizabeth Wilby, Bethan Ogg, Adam Wolverson, Sandra Lee, Susie Butler, Maryanne Okubanjo, Julia Hindle, Ingeborg Welters, Karen Williams, Emily Johnson, Julie Patrick-Heselton, David Shaw, Victoria Waugh, Richard Stewart, Esther Mwaura, Lynn Wren, Louise Mew, Sara-Beth Sutherland, Jane Adderley, Jim Ruddy, Margaret Harkins, Callum Kaye, Teresa Scott, Wendy Mitchell, Felicity Anderson, Fiona Willox, Vijay Jagannathan, Michele Clark, Sarah Purv, Andrew Sharman, Megan Meredith, Lucy Ryan, Louise Conner, Cecilia Peters, Dan Harvey, Ashraf Roshdy, Amy Collins, Malcolm Sim, Steven Henderson, Nigel Chee, Sally Pitts, Katie Bowman, Maria Dilawershah, Luke Vamplew, Elizabeth Howe, Paula Rogers, Clara Hernandez, Clara Prendergast, Jane Benton, Alex Rosenberg, Lui G. Forni, Alice Grant, Paula Carvelli, Ajay Raithatha, Sarah Bird, Max Richardson, Matthew Needham, Claire Hirst, Jonathan Ball, Susannah Leaver, Luisa Howlett, Carlos Castro Delgado, Sarah Farnell-Ward, Helen Farrah, Geraldine Gray, Gipsy Joseph, Francesca Robinson, Ascanio Tridente, Clare Harrop, Karen Shuker, Derek McLaughlan, Judith Ramsey, Sharon Meehan, Bernd Oliver Rose, Rosie Reece-Anthony, Babita Gurung, Tony Whitehouse, Catherine Snelson, Tonny Veenith, Andy Johnston, Lauren Cooper, Ron Carrera, Karen Ellis, Emma Fellows, Samanth Harkett, Colin Bergin, Elaine Spruce, Liesl Despy, Stephanie Goundry, Natalie Dooley, Tracy Mason, Amy Clark, Gemma Dignam, Geraldine Ward, Ben Attwood, Penny Parsons, Sophie Mason, Michael Margarson, Jenny Lord, Philip McGlone, Luke E. Hodgson, Indra Chadbourn, Raquel Gomez, Jordi Margalef, Rinus Pretorius, Alexandra Hamshere, Joseph Carter, Hazel Cahill, Lia Grainger, Kate Howard, Greg Forshaw, Zoe Guy, Kianoush B. Kashani, Robert C. Albright, Amy Amsbaugh, Anita Stoltenberg, Alexander S. Niven, Matthew Lynch, AnnMarie O'Mara, Syed Naeem, Sairah Sharif, Joyce McKenney Goulart, Ashita Tolwani, Claretha Lyas, Laura Latta, Azra Bihorac, Haleh Hashemighouchani, Philip Efron, Matthew Ruppert, Julie Cupka, Sean Kiley, Joshua Carson, Peggy White, George Omalay, Sherry Brown, Laura Velez, Alina Marceron, Javier A. Neyra, Juan Carlos Aycinena, Madona Elias, Victor M. Ortiz-Soriano, Caroline Hauschild, and Robert Dorfman

Subjects
Renal Replacement Therapy, Pulmonary and Respiratory Medicine, Critical Illness, Medicine and Health Sciences, Humans, Acute Kidney Injury
Published
2022

31. Proceedings of the ISCT scientific signature series symposium, 'Advances in cell and gene therapies for lung diseases and critical illnesses'

Author

Anthony E. Ting, Elizabeth K. Baker, Josee Champagne, Tushar J. Desai, Claudia C. dos Santos, Irene H. Heijink, Silviu Itescu, Katarina Le Blanc, Michael A. Matthay, Daniel F. McAuley, Lauralynn McIntyre, Shirley H.J. Mei, Biju Parekkadan, Patricia R.M. Rocco, John Sheridan, Bernard Thébaud, and Daniel J. Weiss

Subjects
Cancer Research, Transplantation, Oncology, Immunology, Immunology and Allergy, Cell Biology, Genetics (clinical)
Published
2022

32. Oral health care in adult intensive care units: a national point prevalence study

Author

Niamh Kelly, Bronagh Blackwood, Nicki Credland, Louise Stayt, Christine Causey, Lewis Winning, Daniel F. McAuley, Fionnuala T. Lundy, and Ikhlas El karim

Subjects
oral bacteria, nosocomial pneumonia, chlorhexidine, oral health, critical care nursing, ventilator associated pneumonia, Critical Care Nursing
Abstract

BackgroundThe importance of good oral hygiene for patients in Intensive Care Units (ICUs) is well recognized, however, the most effective way to achieve good oral care in the ICU is unclear.AimThis study aimed to provide a national picture of oral care practices in adult ICUs in the United Kingdom (UK) to identify areas for improvement.Study DesignA national one-day point prevalence study was undertaken in adult ICUs in the UK in the period from 30th September to 14th October 2021. Data were collected on all patients in the ICU on the date of data collection. Using a validated electronic data collection form, anonymised data were collected on methods and frequency of oral care provided, and the use of oral care protocols within the ICU. Data were analysed using descriptive analysis.ResultsData from 195 patients in 15 ICUs in England, Wales and Northern Ireland were collected. Written oral care protocols were available for use in the care of 65% (n = 127) of patients. 73% (n = 142) of patients received oral care within the 24-h period. Oral care methods included toothbrushing 41% (n = 79), foam sticks 3% (n = 5), moisturizing the oral cavity 10% (n = 19) and mouth rinse with chlorhexidine 3% (n = 5) and other oral care methods not specified 12% (n = 23). 44% (n = 85) of patients had an oral assessment within the 24-h period and variable assessment methods were used.ConclusionThere is large variability in oral care provision and methods for intubated ICU patients and a lack of consensus was revealed in the study. Oral assessment is conducted less frequently using multiple tools. Optimal oral care standards and further research into oral care provision is pivotal to address this important patient-relevant practice.Relevance to Clinical PracticeOral care is a fundamental part of care for ICU patients, however, there is a large degree of variability, and oral care is often not based upon oral assessment. The use of an oral care protocol and oral assessments would help to improve patient care, ease of use for staff and provide a tailored oral care plan for patients, improving efficiency and preventing wasted resources.

Published
2023

34. Valaciclovir for Epstein-Barr Virus Suppression in Moderate-to-Severe COPD

Author

Dermot A. Linden, Hong Guo-Parke, Michael C. McKelvey, Gisli G. Einarsson, Andrew J. Lee, Derek J. Fairley, Vanessa Brown, Gavin Lundy, Christina Campbell, Danielle Logan, Margaret McFarland, Dave Singh, Daniel F. McAuley, Clifford C. Taggart, and Joseph C. Kidney

Subjects
Pulmonary and Respiratory Medicine, Cardiology and Cardiovascular Medicine, Critical Care and Intensive Care Medicine
Published
2023

35. Aspirin as a Treatment for ARDS

Author

Margaret McFarland, Philip Toner, Christopher Nutt, James J. McNamee, Rejina Verghis, Cecilia O'Kane, Kathryn Callaghan, Andrew J. Boyle, Daniel F. McAuley, John Trinder, and Paul Johnston

Subjects
Pulmonary and Respiratory Medicine, Aspirin, medicine.medical_specialty, ARDS, Intention-to-treat analysis, business.industry, Odds ratio, Critical Care and Intensive Care Medicine, Placebo, medicine.disease, Clinical trial, Internal medicine, Intensive care, medicine, Clinical endpoint, Cardiology and Cardiovascular Medicine, business, medicine.drug
Abstract

Background There is no pharmacological treatment for the acute respiratory distress syndrome (ARDS). Platelets play an important role in the pathophysiology of ARDS. Pre-clinical, observational and clinically relevant models of ARDS indicate aspirin as a potential therapeutic option. Research question Is enteral aspirin 75mg once daily safe and effective in improving surrogate outcomes in adult patients with ARDS? Study Design and Methods This randomised, double blind (patient and investigator), allocation concealed, placebo-controlled phase 2 trial was conducted in five UK intensive care units. Patients fulfilling the Berlin definition of ARDS were randomly assigned in a 1:1 ratio to receive enteral aspirin 75mg or placebo, for a maximum of 14 days, using a computer-generated randomisation schedule, with variable block size, stratified by vasopressor requirement. The primary endpoint was oxygenation index (OI) at day 7. Secondary outcomes included safety parameters and other respiratory physiological markers. Analyses were by intention to treat. Results The trial was stopped early, due to slow recruitment, after 49 of a planned 60 patients were recruited. 24 patients were allocated to aspirin and 25 to placebo. There was no significant difference in day 7 OI (unadjusted mean 54.4 [SD 26.8] in aspirin group, 42.4 [SD 25] in placebo group; mean difference 12.0, 95% CI -6.1 to 30.1, p= 0.19). Aspirin did not significantly impact the secondary outcomes. There was no difference in the number of adverse events between the groups (13 in each, odds ratio 1.04, 95% CI 0.56 to 1.94, p=0.56). Interpretation Aspirin was well tolerated but did not improve OI or other physiological outcomes, a larger trial is not feasible in its current design.

Published
2022

36. Opioid, sedative, pre-admission medication and iatrogenic withdrawal risk in UK adult critically ill patients: a point prevalence study

Author

Rebekah Eadie, Cathrine Anne McKenzie, Daniel Hadfield, Nicola J Kalk, Scott Bolesta, Martin Dempster, Daniel F McAuley, and Bronagh Blackwood

Abstract

Background: Iatrogenic withdrawal syndrome, after exposure medication known to cause withdrawal is recognised, yet under described in adult intensive care. Aim: Investigate, opioid, sedation and preadmission medication practice in critically ill adults with focus on aspects associated with iatrogenic withdrawal syndrome Methods: One-day point prevalence study in UK ICUs. We collected ICU admission medication and/or substances with withdrawal potential, sedation policy, opioid and sedative use, dose, and duration. Results: 37 from 39 participating ICUs contributed data from 386 patients. The prevalence rate for parenteral opioid and sedative medication was 56.1%, (212 patients). 23 ICUs (59%) had no sedation/analgesia policy, and no ICUs screened for iatrogenic withdrawal. Patient admission medications with withdrawal-potential included antidepressants or antipsychotics (43, 20.3%) and nicotine (41, 19.3%). Of 212 patients, 202 (95.3%) received opioids, 163 (76.9%) sedatives and 153 (72.2%) both. 202 (95.3%) patients received opioids: 167 (82.7%) by continuous infusions and 90 (44.6%) patients for longer than 96-hours. 163 (76.9%) patients received sedatives: 157 (77.7%) by continuous infusions and 74 (45.4%) patients for longer than 96-hours. Conclusion: Opioid and sedative prevalence rates were high, and a high proportion of ICUs had no sedative/analgesic policies. Nearly half of patients received continuous opioids and sedatives for longer than 96-hours placing them at high risk of iatrogenic withdrawal. No participating unit reported using a validated tool for iatrogenic withdrawal assessment.

Published
2023

37. Galectin-3 inhibition in COVID-19

Author

Kiran Reddy, Alistair Nichol, and Daniel F. McAuley

Subjects
Pulmonary and Respiratory Medicine, Galectin 3, COVID-19, Critical Care and Intensive Care Medicine
Published
2023

38. Update on the Features and Measurements of Experimental Acute Lung Injury in Animals: An Official American Thoracic Society Workshop Report

Author

Hrishikesh S. Kulkarni, Janet S. Lee, Julie A. Bastarache, Wolfgang M. Kuebler, Gregory P. Downey, Guillermo M. Albaiceta, William A. Altemeier, Antonio Artigas, Jason H. T. Bates, Carolyn S. Calfee, Charles S. Dela Cruz, Robert P. Dickson, Joshua A. Englert, Jeffrey I. Everitt, Michael B. Fessler, Andrew E. Gelman, Kymberly M. Gowdy, Steve D. Groshong, Susanne Herold, Robert J. Homer, Jeffrey C. Horowitz, Connie C. W. Hsia, Kiyoyasu Kurahashi, Victor E. Laubach, Mark R. Looney, Rudolf Lucas, Nilam S. Mangalmurti, Anne M. Manicone, Thomas R. Martin, Sadis Matalon, Michael A. Matthay, Daniel F. McAuley, Sharon A. McGrath-Morrow, Joseph P. Mizgerd, Stephanie A. Montgomery, Bethany B. Moore, Alexandra Noël, Carrie E. Perlman, John P. Reilly, Eric P. Schmidt, Shawn J. Skerrett, Tomeka L. Suber, Charlotte Summers, Benjamin T. Suratt, Masao Takata, Rubin Tuder, Stefan Uhlig, Martin Witzenrath, Rachel L. Zemans, and Gutavo Matute-Bello

Subjects
Pulmonary and Respiratory Medicine, Clinical Biochemistry, Cell Biology, Molecular Biology
Published
2022

39. Safety, immunogenicity, and efficacy of a COVID-19 vaccine (NVX-CoV2373) co-administered with seasonal influenza vaccines: an exploratory substudy of a randomised, observer-blinded, placebo-controlled, phase 3 trial

Author

Seth Toback, Eva Galiza, Catherine Cosgrove, James Galloway, Anna L Goodman, Pauline A Swift, Sankarasubramanian Rajaram, Alison Graves-Jones, Jonathan Edelman, Fiona Burns, Angela M Minassian, Iksung Cho, Lakshmi Kumar, Joyce S Plested, E Joy Rivers, Andreana Robertson, Filip Dubovsky, Greg Glenn, Paul T Heath, Roy L. Soiza, Robin Brittain-Long, Chiara Scicluna, Carole Edwards, Lynn Mackay, Mariella D'Allesandro, Amy Nicol, Karen Norris, Sandra Mann, Heather Lawrence, Ruth Valentine, Marianne Elizabeth Viljoen, Carol H. Pretswell, Helen Nicholls, Imrozia Munsoor, Agnieszka Meyrick, Christina Kyriakidou, Shalini Iyengar, Arham Jamal, Nick Richards, Helen Price, Bridie Rowbotham, Danielle Bird, Karen Smith, Olga Littler, Kirsty Fielding, Anna Townsend-Rose, Karen Miller, Jessica Davis, Alison Elliot-Garwood, Lauren Trottier, Paul Edwards, Margaret McFarland, Orod Osanlou, Laura Longshaw, Jane Stockport, Lynne Grundy, Katharine Lucy Broad, Karen Regan, Kim Storton, Declan Ryan-Wakeling, Brad Wilson, Malathy Munisamy, John Wright, Anil Shenoy, Beverley English, Lucy Brear, Paola Cicconi, Marta Boffito, Ana Milinkovic, Ruth Byrne, Roya Movahedi, Rosalie Housman, Naveed Kara, Ellen Brown, Andrea Cipriani, Mary-Jane Attenburrow, Katharine A. Smith, Jonathan Packham, Geoff Sparrow, Richard Smith, Josephine M. Rosier, Khalid Saja, Nyasha Nago, Brian Camilleri, Anita Immanuel, Mike Hamblin, Rawlings Osagie, Mahalakshmi Mohan, Hilary Floyd, Suzanne Goddard, Sanjay Mutgi, John Evans, Sean McKeon, Neringa Vilimiene, Rosavic Chicano, Rachel Hayre, Alice Pandaan, Catherine Henshall, Sonia Serrano, Andrea Mazzella, Thurkka Rajeswaran, Moncy Mathew, Karen Bisnauthsing, Laura Bremner, Henry Fok, Franca Morselli, Paola Cinardo, Blair Merrick, Lucy Sowole, Samantha Broadhead, Natalie Palmer, Jessica Cordle, Jaimie Wilson Goldsmith, Enya Cooney, Beth Jackson, Thilina Jayatilleke, Zelda Cheng, Toby Helliwell, Adrian Chudyk, Rafaela Giemza, John Lord Villajin, Noah Yogo, Esther Makanju, Pearl Dulawan, Deepak Nagra, April Buazon, Alice Russell, Georgie Bird, Amardeep Heer, Rex Sarmiento, Balraj Sanghera, Melanie Mullin, Adam Champion, Aisling Bevan, Kinzah Iqbal, Alshia Johnson, Rebecca Clark, Sarah Shaw, Steven Shaw, Amanda Chalk, Martin Lovatt, Caroline Lillicrap, Angela Parker, Jan Hansel, Zhi Wong, Galvin Gan, Eyad Tuma, Jane Minton, Jennifer Murira, Razan Saman, Alistair Hall, Kyra Holliday, Zara Khan, James Calderwood, George Twigg, Helena Baker, Julie Corrigan, Katy Houseman, Subhra Raguvanshi, Dominic Heining, Jake Weddell, Liz Glaves, Kim Thompson, Francis Davies, Ruth Lambley Burke, Emma C. Thomson, Dinesh Saralaya, Lisa Berry, Nancy Hopewell, Leigh Gerdes, Mihaela Pacurar, Saul N. Faust, Jeremy Turner, Christopher Jeanes, Adele Cooper, Jocelyn Keshet-Price, Lou Coke, Melissa Cambell-Kelly, Ketan Dhatariya, Claire Williams, Georgina Marks, James Sudbury, Lisa Rodolico, Judy Bradley, Sharon Carr, Roisin Martin, Angelina Madden, Paul Biagioni, Sonia McKenna, Alison Clinton, Maurice O'Kane, Justin Carter, Matthew Dewhurst, Bill Wetherill, Thandiwe Hoggarth, Katrina Lennon Collins, Marie Chowdhury, Adil Nathoo, Anna Heinen, Orla MacDonald, Claudia Hurducas, Liliana Cifuentes, Harjeevan Gill, Andy Gibson, Raha West, Jane Ewing, Rachel Blacow, John Haughney, Jonathan MacDonald, John Paul Seenan, Stewart Webb, Colin O'Leary, Scott Muir, Beth White, Neil Ritchie, Daniel F. McAuley, Jonathan Stewart, Mariella D'Alessandro, Nicki Lakeman, Laura Purandare, Duncan Browne, David Tucker, Peter Luck, Angharad Everden, Lisa Trembath, Michael Visick, Nick Morley, Laura Reid, Helen Chenoweth, Kirsty Maclean, Ray P. Sheridan, Tom Burden, Craig Francis Lunt, Shirley Todd, Stephanie Estcourt, Jasmine Marie Pearce, Suzanne Wilkins, Cathryn Love-Rouse, Eva Torok-Pollok, Mike Youle, Sara Madge, Danielle Solomon, Aarti Nandani, Janet M. North, Nargis Hemat, Rachel Newport, Philip A. Kalra, Chukwuma Chukwu, Olivia Wickens, Vikki O'Loughlin, Hema Mistry, Louise Harrison, Robert Oliver, Anne-Marie Peers, Jess Zadik, Katie Doyle, David R. Chadwick, Kerry Colling, Caroline Wroe, Marie Branch, Alison Chilvers, Sarah Essex, Mark Stone, Alberto San Francisco Ramos, Emily Beales, Olivia Bird, Zsofia Danos, Hazel Fofie, Cecilia Hultin, Sabina Ikram, Fran Mabesa, Aoife Mescall, Josyanne Pereira, Jennifer Pearce, Natalina Sutton, Emma Snashall, David Neil Baxter, Sara Bennett, Debbie Suggitt, Kerry Hughes, Wiesia Woodyatt, Lynsey Beacon, Alissa Kent, Chris Cooper, Milan Rudic, Simon Tunstall, Matthew Jackson, Claire Hombersley, Patrick Moore, Rebecca Cutts, Andrew Higham, Marwan Bukhari, Mohamed Elnaggar, Michelle Glover, Fiona Richardson, Alexandra Dent, Shahzeb Mirza, Rajiv Ark, Jennie Han, Suzy V. Hope, Philip J. Mitchelmore, Rostam Osanlou, Andrew Freedman, Alison Cooper, Katherine Burton, Kashyap Katechia, Michael Barrett, Jo Salkeld, Natalie Hill, Nathaniel Lee, Jon Perkins, and Polly Fox

Subjects
Adult, Pulmonary and Respiratory Medicine, Trivalent influenza vaccine, medicine.medical_specialty, COVID-19 Vaccines, Adolescent, Influenza vaccine, Population, Placebo, Young Adult, Immunogenicity, Vaccine, Double-Blind Method, Internal medicine, Humans, Medicine, education, Adverse effect, Aged, education.field_of_study, Reactogenicity, SARS-CoV-2, business.industry, COVID-19, Articles, Middle Aged, Vaccine efficacy, Vaccination, Influenza Vaccines, Seasons, business
Abstract

Background The safety and immunogenicity profile of COVID-19 vaccines when administered concomitantly with seasonal influenza vaccines have not yet been reported. We therefore aimed to report the results of a substudy within a phase 3 UK trial, by evaluating the safety, immunogenicity, and efficacy of NVX-CoV2373 when co-administered with licensed seasonal influenza vaccines. Methods We did a planned exploratory substudy as part of the randomised, observer-blinded, placebo-controlled, phase 3 trial of the safety and efficacy of the COVID-19 vaccine (NVX-CoV2373) by co-administrating the influenza vaccine at four study hospitals in the UK. Approximately, the first 400 participants meeting the main study entry criteria—with no contraindications to influenza vaccination—were invited to join the substudy. Participants of the main study were randomly assigned (1:1) to receive two intramuscular injections of either NVX-CoV2373 (5 μg) or placebo (normal saline) 21 days apart; participants enrolled into the substudy were co-vaccinated with a single (0·5 mL) intramuscular, age-appropriate (quadrivalent influenza cell-based vaccine [Flucelvax Quadrivalent; Seqirus UK, Maidenhead] for those aged 18–64 years and adjuvanted trivalent influenza vaccine [Fluad; Seqirus UK, Maidenhead] for those ≥65 years), licensed, influenza vaccine on the opposite deltoid to that of the first study vaccine dose or placebo. The influenza vaccine was administered in an open-label manner and at the same time as the first study injection. Reactogenicity was evaluated via an electronic diary for 7 days after vaccination in addition to monitoring for unsolicited adverse events, medically attended adverse events, and serious adverse events. Immunogenicity was assessed with influenza haemagglutination inhibition and SARS-CoV-2 anti-spike protein IgG assays. Vaccine efficacy against PCR-confirmed, symptomatic COVID-19 was assessed in participants who were seronegative at baseline, received both doses of study vaccine or placebo, had no major protocol deviations affecting the primary endpoint, and had no confirmed cases of symptomatic COVID-19 from the first dose until 6 days after the second dose (per-protocol efficacy population). Immunogenicity was assessed in participants who received scheduled two doses of study vaccine, had a baseline sample and at least one post-vaccination sample, and had no major protocol violations before unmasking (per-protocol immunogenicity population). Reactogenicity was analysed in all participants who received at least one dose of NVX-CoV2373 or placebo and had data collected for reactogenicity events. Safety was analysed in all participants who received at least one dose of NVX-CoV2373 or placebo. Comparisons were made between participants of the substudy and the main study (who were not co-vaccinated for influenza). This study is registered with ClinicalTrials.gov, number NCT04583995. Findings Between Sept 28, 2020, and Nov 28, 2020, a total of 15 187 participants were randomised into the main phase 3 trial, of whom 15 139 received treatment (7569 received dose one of NVX-CoV2373 and 7570 received dose one of placebo). 431 participants were co-vaccinated with a seasonal influenza vaccine in the substudy (217 received NVX-CoV2373 plus the influenza vaccine and 214 received placebo plus the influenza vaccine). In general, the substudy participants were younger, more racially diverse, and had fewer comorbid conditions than those in the main study. Reactogenicity events were more common in the co-administration group than in the NVX-CoV2373 alone group: tenderness (113 [64·9%] of 174 vs 592 [53·3%] of 1111) or pain (69 [39·7%] vs 325 [29·3%]) at injection site, fatigue (48 [27·7%] vs 215 [19·4%]), and muscle pain (49 [28·3%] vs 237 [21·4%]). Incidences of unsolicited adverse events, treatment-related medically attended adverse events, and serious adverse events were low and balanced between the co-administration group and the NVX-CoV2373 alone group. No episodes of anaphylaxis or deaths were reported within the substudy. Co-administration resulted in no change to influenza vaccine immune response although a reduction in antibody responses to the NVX-CoV2373 vaccine was noted. NVX-CoV2373 vaccine efficacy in the substudy (ie, participants aged 18 to

Published
2022

40. Advancing precision medicine for acute respiratory distress syndrome

Author

Theodore J. Standiford, Roger J. Lewis, Jeremy R. Beitler, Eric P. Schmidt, Loren C. Denlinger, Rebecca M. Baron, Hector R. Wong, Carolyn S. Calfee, Julie A. Bastarache, Laura J. Esserman, Neil R. Aggarwal, Thomas R. Martin, John C. Marshall, Eileen Rubin, Marc Moss, Lorraine B. Ware, Nuala J. Meyer, Lisa M. LaVange, Daniel F. McAuley, Lora A. Reineck, B. Taylor Thompson, and Michelle N. Gong

Subjects
Pulmonary and Respiratory Medicine, ARDS, medicine.medical_specialty, Clinical Sciences, MEDLINE, Lung injury, Rare Diseases, SDG 3 - Good Health and Well-being, Pandemic, medicine, Humans, Precision Medicine, Intensive care medicine, Acute Respiratory Distress Syndrome, Lung, Respiratory Distress Syndrome, Other Medical and Health Sciences, business.industry, COVID-19, medicine.disease, Precision medicine, Clinical trial, Orphan Drug, Good Health and Well Being, Respiratory, Public Health and Health Services, Position paper, Position Paper, business, Cohort study
Abstract

Acute respiratory distress syndrome (ARDS) is a heterogeneous clinical syndrome. Understanding of the complex pathways involved in lung injury pathogenesis, resolution, and repair has grown considerably in recent decades. Nevertheless, to date, only therapies targeting ventilation-induced lung injury have consistently proven beneficial, and despite these gains, ARDS morbidity and mortality remain high. Many candidate therapies with promise in preclinical studies have been ineffective in human trials, probably at least in part due to clinical and biological heterogeneity that modifies treatment responsiveness in human ARDS. A precision medicine approach to ARDS seeks to better account for this heterogeneity by matching therapies to subgroups of patients that are anticipated to be most likely to benefit, which initially might be identified in part by assessing for heterogeneity of treatment effect in clinical trials. In October 2019, the US National Heart, Lung, and Blood Institute convened a workshop of multidisciplinary experts to explore research opportunities and challenges for accelerating precision medicine in ARDS. Topics of discussion included the rationale and challenges for a precision medicine approach in ARDS, the roles of preclinical ARDS models in precision medicine, essential features of cohort studies to advance precision medicine, and novel approaches to clinical trials to support development and validation of a precision medicine strategy. In this Position Paper, we summarise workshop discussions, recommendations, and unresolved questions for advancing precision medicine in ARDS. Although the workshop took place before the COVID-19 pandemic began, the pandemic has highlighted the urgent need for precision therapies for ARDS as the global scientific community grapples with many of the key concepts, innovations, and challenges discussed at this workshop.

Published
2022

41. Feasibility of conservative fluid administration and deresuscitation compared with usual care in critical illness: the Role of Active Deresuscitation After Resuscitation-2 (RADAR-2) randomised clinical trial

Author

Jonathan A. Silversides, Ross McMullan, Lydia M. Emerson, Ian Bradbury, Jonathan Bannard-Smith, Tamas Szakmany, John Trinder, Anthony J. Rostron, Paul Johnston, Andrew J. Ferguson, Andrew J. Boyle, Bronagh Blackwood, John C. Marshall, and Daniel F. McAuley

Subjects
Oedema, Infusions, Fluid therapy, Critical illness, Diuretics, Intravenous, Critical Care and Intensive Care Medicine, Water–electrolyte balance, Deresuscitation, RT, RC
Abstract

PURPOSE: Fluid overload is common in critical illness and is associated with mortality. This study investigated the feasibility of a randomised trial comparing conservative fluid administration and deresuscitation (active removal of accumulated fluid using diuretics or ultrafiltration) with usual care in critical illness.METHODS: Open-label, parallel-group, allocation-concealed randomised clinical feasibility trial. Mechanically ventilated adult patients expected to require critical care beyond the next calendar day were enrolled between 24 and 48 h following admission to the intensive care unit (ICU). Patients were randomised to either a 2-stage fluid strategy comprising conservative fluid administration and, if fluid overload was present, active deresuscitation, or usual care. The primary endpoint was fluid balance in the 24 h up to the start of study day 3. Secondary endpoints included cumulative fluid balance, mortality, and duration of mechanical ventilation.RESULTS: One hundred and eighty patients were randomised. After withdrawal of 1 patient, 89 patients assigned to the intervention were compared with 90 patients assigned to the usual care group. The mean plus standard deviation (SD) 24-h fluid balance up to study day 3 was lower in the intervention group (- 840 ± 1746 mL) than the usual care group (+ 130 ± 1401 mL; P CONCLUSIONS: A strategy of conservative fluid administration and active deresuscitation is feasible, reduces fluid balance compared with usual care, and may cause benefit or harm. In view of wide variations in contemporary clinical practice, large, adequately powered trials investigating the clinical effectiveness of conservative fluid strategies in critically ill patients are warranted.

Published
2021

42. Extracorporeal carbon dioxide removal in acute hypoxaemic respiratory failure:a systematic review, Bayesian meta-analysis and trial sequential analysis

Author

Jonathan E. Millar, Andrew J. Boyle, Thomas M. Drake, Claire E. Adams, Adam W. Glass, Bronagh Blackwood, James J. McNamee, and Daniel F. McAuley

Subjects
Pulmonary and Respiratory Medicine, Ventilators, Mechanical, Respiratory Insufficiency/diagnosis, Carbon Dioxide/adverse effects, Humans, Carbon Dioxide, Respiratory Insufficiency
Abstract

Purpose:To assess the safety and efficacy of extracorporeal carbon dioxide removal (ECCO2R)versusstandard care in patients with acute hypoxaemic respiratory failure (AHRF).Methods:MEDLINE, Embase and clinical trial registries were searched from 1994 to 31 December 2021. We included randomised controlled trials (RCTs) and observational studies. Pairs of reviewers independently extracted data and assessed the risk of bias. The primary outcome was mortality. Secondary outcomes included ventilator-free days, length of stay, safety and adverse events and physiological changes. As a primary analysis, we performed a meta-analysis of mortality until day 30 using a Bayesian random effects model. We then performed a trial sequential analysis of RCTs.Results:21 studies met inclusion criteria: three RCTs, enrolling 531 patients, and 18 observational studies. In a pooled analysis of RCTs, the posterior probability of increased mortality with the use of ECCO2R was 73% (relative risk 1.19, 95% credible interval 0.70–2.29). There was substantial heterogeneity in the reporting of safety and adverse events. However, the incidence of extra and intracranial haemorrhage was higher (relative risk 3.00, 95% credible interval 0.41–20.51) among those randomised to ECCO2R. Current trials have accumulated 80.8% of the diversity-adjusted required information size and the lack of effect reaches futility for a 10% absolute risk reduction in mortality.Conclusions:The use of ECCO2R in patients with AHRF is not associated with improvements in clinical outcomes. Furthermore, it is likely that further trials of ECCO2R aiming to achieve an absolute risk reduction in mortality of ≥10% are futile.

Published
2022

43. Role of immunosuppression in an antibiotic stewardship intervention and its association with clinical outcomes and antibiotic use: protocol for an observational study (RISC-sepsis)

Author

Jonathan Scott, Loredana Trevi, Hannah McNeil, Tom Ewen, Phil Mawson, David McDonald, Andrew Filby, Ranjit Lall, Katie Booth, Gert Boschman, Vesna Melkebeek, Gavin Perkins, Ronan McMullan, Daniel F McAuley, Iain J McCullagh, Timothy Walsh, Anthony Rostron, Manu Shankar-Hari, Paul Dark, A John Simpson, Andrew Conway Morris, Thomas P Hellyer, McAuley, Daniel F [0000-0002-3283-1947], Shankar-Hari, Manu [0000-0002-5338-2538], Hellyer, Thomas P [0000-0001-5346-7411], and Apollo - University of Cambridge Repository

Subjects
Immunosuppression Therapy, Cross Infection, MICROBIOLOGY, INTENSIVE & CRITICAL CARE, General Medicine, INFECTIOUS DISEASES, Sepsis/drug therapy, Cross Infection/drug therapy, Anti-Bacterial Agents, Anti-Bacterial Agents/therapeutic use, Antimicrobial Stewardship, Observational Studies as Topic, Antimicrobial Stewardship/methods, Sepsis, Intensive care, Humans, Prospective Studies
Abstract

Peer reviewed: True, INTRODUCTION: Sepsis is characterised by a dysregulated immune response to infection, with exaggerated pro-inflammatory and anti-inflammatory responses. A predominant immunosuppressive profile affecting both innate and adaptive immune responses is associated with increased hospital-acquired infection and reduced infection-free survival. While hospital-acquired infection leads to additional antibiotic use, the role of the immunosuppressive phenotype in guiding complex decisions, such as those affecting antibiotic stewardship, is uncertain. This study is a mechanistic substudy embedded within a multicentre clinical and cost-effectiveness trial of biomarker-guided antibiotic stewardship. This mechanistic study aims to determine the effect of sepsis-associated immunosuppression on the trial outcome measures. METHODS AND ANALYSIS: RISC-sepsis is a prospective, multicentre, exploratory, observational study embedded within the ADAPT-sepsis trial. A subgroup of 180 participants with antibiotics commenced for suspected sepsis, enrolled in the ADAPT-sepsis trial, will be recruited. Blood samples will be collected on alternate days until day 7. At each time point, blood will be collected for flow cytometric analysis into cell preservation tubes. Immunophenotyping will be performed at a central testing hub by flow cytometry. The primary outcome measures are monocyte human leucocyte antigen-DR; neutrophil CD88; programmed cell death-1 on monocytes, neutrophils and T lymphocytes and the percentage of regulatory T cells. Secondary outcome measures will link to trial outcomes from the ADAPT-sepsis trial including antibiotic days; occurrence of hospital-acquired infection and length of ICU-stay and hospital-stay. ETHICS AND DISSEMINATION: Ethical approval has been granted (IRAS 209815) and RISC-sepsis is registered with the ISRCTN (86837685). Study results will be disseminated by peer-reviewed publications, presentations at scientific meetings and via patient and public participation groups and social media.

Published
2022
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44. Plasma Markers of Neurodegeneration Associated with Postoperative Delirium in an Older Elective Arthroplasty Population

Author

Aoife Sweeney, Anthony Peter Passmore, David Beverland, Bernadette McGuinness, Daniel F McAuley, Tim Mawhinney, Seamus O'Brien, Jonathan M Schott, Amanda Heslegrave, Henrik Zetterberg, and Emma L Cunningham

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published
2022

45. Cerebrospinal Fluid Markers of Neurodegeneration Associated with Postoperative Delirium in an Older Elective Arthroplasty Population

Author

Aoife Sweeney, Anthony Peter Passmore, David Beverland, Bernadette McGuinness, Daniel F McAuley, Tim Mawhinney, Jonathan M Schott, Amanda Heslegrave, Henrik Zetterberg, and Emma L Cunningham

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published
2022

46. High plasma IL-18 identifies high-risk ARDS patients not identified by latent class analysis sub-phenotyping: a secondary analysis of the SAILS and HARP-2 studies

Author

Andrew R Moore, Shaun M Pienkos, Pratik Sinha, Jiazhen Guan, Cecilia M O’Kane, Joseph E Levitt, Jennifer G Wilson, Manu Shankar-Hari, Michael A Matthay, Carolyn S Calfee, Rebecca M Baron, Daniel F McAuley, and Angela J Rogers

Abstract

Background: Both latent class analysis (LCA) assignment based upon a panel of plasma biomarkers and interleukin-18 (IL-18) plasma level have been shown to predict prognosis and treatment response in Acute Respiratory Distress Syndrome (ARDS). Interleukin-18 is a measure of inflammasome activation and plays a distinct role in inflammation that is not captured by the biomarkers used in LCA assignments. We hypothesized that elevated IL-18 would provide additive prognostic and therapeutic information to previously published LCA assignments in ARDS, identifying additional “high-risk” patients not captured by LCA who could be eligible for inclusion in future precision medicine-focused trials. Methods: IL-18 and a panel of protein markers used for LCA had been previously measured in plasma from 683/745 patients in the Statins for Acutely Injured Lungs from Sepsis (SAILS) and 511/540 patients in the Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP-2) trials. We tested the association between high IL-18 (>800 pg/mL) and LCA class assignment using McNemar’s test and evaluated the association of each subgrouping as well as treatment with 60-day mortality using Fisher’s exact test. We assessed 60-day mortality in each combination (high/low IL-18, hypo-/hyper-inflammatory LCA class, and treatment/placebo) using Kaplan-Meier survival analysis. We evaluated the correlation between the log2 transformed IL-18 level and LCA biomarkers using Pearson’s correlation coefficient. Results: 33% of patients in SAILS and HARP-2 were discordant by IL-18 level and LCA class. Elevated IL-18 identified a high-risk group of individuals previously classified as hypo-inflammatory by LCA in both SAILS (OR 3.3, 95% CI 1.8-6.1, p of 0.17-0.47. Conclusions: High Plasma IL-18 level provides additional prognostic information to LCA sub-phenotypes in two large ARDS cohorts.

Published
2022

47. Integration of Equipoise into Eligibility Criteria in the STARRT-AKI Trial

Author

Ron Wald, Sean M. Bagshaw, Neill K. J. Adhikari, Rinaldo Bellomo, Didier Dreyfuss, Bin Du, Martin P. Gallagher, Stéphane Gaudry, Eric A. Hoste, François Lamontagne, Michael Joannidis, Kathleen D. Liu, Daniel F. McAuley, Shay P. McGuinness, Alistair D. Nichol, Marlies Ostermann, Paul M. Palevsky, Haibo Qiu, Ville Pettilä, Antoine G. Schneider, Orla M. Smith, Suvi Vaara, and Matthew Weir

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, Randomized controlled trial, law, business.industry, medicine.medical_treatment, medicine, Generalizability theory, Renal replacement therapy, Critical Care and Intensive Care Medicine, Intensive care medicine, business, law.invention
Published
2021

48. Inflammatory sub-phenotypes in sepsis: relationship to outcomes, treatment effect and transcriptomic sub-phenotypes

Author

David B Antcliffe, Yuxin Mi, Shalini Santhakumaran, Katie L Burnham, A Toby Prevost, Josie K Ward, Timothy Marshall, Claire Bradley, Farah Al-Beidh, Paula Hutton, Stuart McKechnie, Emma E Davenport, Charles J Hinds, Cecilia M O’Kane, Daniel F McAuley, Manu Shankar-Hari, Anthony C Gordon, and Julian C Knight

Abstract

RationaleHeterogeneity of sepsis limits discovery and targeting of treatments. Clustering approaches in critical illness have identified patient groups who may respond differently to therapies. These include in acute respiratory distress syndrome (ARDS) two inflammatory sub-phenotypes, using latent class analysis (LCA), and in sepsis two Sepsis Response Signatures (SRS), based on transcriptome profiling. It is unknown if inflammatory sub-phenotypes such as those identified in ARDS are present in sepsis and how sub-phenotypes defined with different techniques compare.ObjectivesTo identify inflammatory sub-phenotypes in sepsis using LCA and assess if these show differential treatment responses. These sub-phenotypes were compared to hierarchical clusters based on inflammatory mediators and to SRS sub-phenotypes.MethodsLCA was applied to clinical and biomarker data from two septic shock randomized trials. VANISH compared norepinephrine to vasopressin and hydrocortisone to placebo and LeoPARDS compared levosimendan to placebo. Hierarchical cluster analysis (HCA) was applied to 65, 21 and 11 inflammatory mediators measured in patients from the GAinS (n=124), VANISH (n=155) and LeoPARDS (n=484) studies.Measurements and Main ResultsLCA and HCA identified a sub-phenotype of patients with high cytokine levels and worse organ dysfunction and survival, with no interaction between LCA classes and trial treatment responses. Comparison of inflammatory and transcriptomic sub-phenotypes revealed some similarities but without sufficient overlap that they are interchangeable.ConclusionsA sub-phenotype with high levels of inflammation and increased disease severity is consistently identifiable in sepsis, with similarities to that described in ARDS. There was limited overlap with the transcriptomic sub-phenotypes.

Published
2022

49. Delirium in COVID-19: can we make the unknowns knowns?

Author

Manu Shankar-Hari, M. Elizabeth Wilcox, and Daniel F. McAuley

Subjects
medicine.medical_specialty, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), SARS-CoV-2, business.industry, Pain medicine, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), MEDLINE, COVID-19, Delirium, Critical Care and Intensive Care Medicine, Anesthesiology, Humans, Medicine, medicine.symptom, COVID-19 in Intensive Care, business, Intensive care medicine
Published
2021

50. Outcome of acute hypoxaemic respiratory failure: insights from the LUNG SAFE Study

Author

Pham, Tài, Pesenti, Antonio, Bellani, Giacomo, Rubenfeld, Gordon, Fan, Eddy, Bugedo, Guillermo, Lorente, José Angel, Fernandes, Antero do Vale, Van Haren, Frank, Bruhn, Alejandro, Rios, Fernando, Esteban, Andres, Gattinoni, Luciano, Larsson, Anders, McAuley, Daniel F., Ranieri, Marco, Thompson, B. Taylor, Wrigge, Hermann, Brochard, Laurent J., Laffey, John G, Antonio Pesenti, John G Laffey, Laurent Brochard, Andres Esteban, Luciano Gattinoni, Frank van Haren, Anders Larsson, Daniel F McAuley, Marco Ranieri, Gordon Rubenfeld, B Taylor Thompson, Hermann Wrigge, Arthur S Slutsky, Giacomo Bellani, Tài Pham, Eddy Fan, Fernando Rios, Thierry Sottiaux, Pieter Depuydt, Fredy S Lora, Luciano Cesar Azevedo, Guillermo Bugedo, Haibo Qiu, Marcos Gonzalez, Juan Silesky, Vladimir Cerny, Jonas Nielsen, Manuel Jibaja, Dimitrios Matamis, Jorge Luis Ranero, Pravin Amin, S M Hashemian, Kevin Clarkson, Kiyoyasu Kurahashi, Asisclo Villagomez, Amine Ali Zeggwagh, Leo M Heunks, Jon Henrik Laake, Jose Emmanuel Palo, Antero do Vale Fernandes, Dorel Sandesc, Yaasen Arabi, Vesna Bumbasierevic, Nicolas Nin, Jose A Lorente, Lise Piquilloud, Fekri Abroug, Lia McNamee, Javier Hurtado, Ed Bajwa, Gabriel Démpaire, Hektor Sula, Lordian Nunci, Alma Cani, Alan Zazu, Christian Dellera, Carolina S Insaurralde, Risso V Alejandro, Julio Daldin, Mauricio Vinzio, Ruben O Fernandez, Luis P Cardonnet, Lisandro R Bettini, Mariano Carboni Bisso, Emilio M Osman, Mariano G Setten, Pablo Lovazzano, Javier Alvarez, Veronica Villar, Norberto C Pozo, Nicolas Grubissich, Gustavo A Plotnikow, Daniela N Vasquez, Santiago Ilutovich, Norberto Tiribelli, Ariel Chena, Carlos A Pellegrini, María G Saenz, Elisa Estenssoro, Matias Brizuela, Hernan Gianinetto, Pablo E Gomez, Valeria I Cerrato, Marco G Bezzi, Silvina A Borello, Flavia A Loiacono, Adriana M Fernandez, Serena Knowles, Claire Reynolds, Deborah M Inskip, Jennene J Miller, Jing Kong, Christina Whitehead, Shailesh Bihari, Aylin Seven, Amanda Krstevski, Helen J Rodgers, Rebecca T Millar, Toni E McKenna, Irene M Bailey, Gabrielle C Hanlon, Anders Aneman, Joan M Lynch, Raman Azad, John Neal, Paul W Woods, Brigit L Roberts, Mark R Kol, Helen S Wong, Katharina C Riss, Thomas Staudinger, Xavier Wittebole, Caroline Berghe, Pierre A Bulpa, Alain M Dive, Rik Verstraete, Herve Lebbinck, Joris Vermassen, Philippe Meersseman, Helga Ceunen, Jonas I Rosa, Daniel O Beraldo, Claudio Piras, Adenilton M Rampinelli, Antonio P Nassar Jr, Sergio Mataloun, Marcelo Moock, Marlus M Thompson, Claudio H Gonçalves, Ana Carolina P Antônio, Aline Ascoli, Rodrigo S Biondi, Danielle C Fontenele, Danielle Nobrega, Vanessa M Sales, Ahmad Yazid Bin Hj Abul Wahab, Maizatul Ismail, Suresh Shindhe, John Laffey, Francois Beloncle, Kyle G Davies, Rob Cirone, Venika Manoharan, Mehvish Ismail, Ewan C Goligher, Mandeep Jassal, Erin Nishikawa, Areej Javeed, Gerard Curley, Nuttapol Rittayamai, Matteo Parotto, Niall D Ferguson, Sangeeta Mehta, Jenny Knoll, Antoine Pronovost, Sergio Canestrini, Alejandro R Bruhn, Patricio H Garcia, Felipe A Aliaga, Pamela A Farías, Jacob S Yumha, Claudia A Ortiz, Javier E Salas, Alejandro A Saez, Luis D Vega, Eduardo F Labarca, Felipe T Martinez, Nicolás G Carreño, Pilar Lora, Haitao Liu, Ling Liu, Rui Tang, Xiaoming Luo, Youzhong An, Huiying Zhao, Yan Gao, Zhe Zhai, Zheng L Ye, Wei Wang, Wenwen Li, Qingdong Li, Ruiqiang Zheng, Wenkui Yu, Juanhong Shen, Xinyu Li, Tao Yu, Weihua Lu, Ya Q Wu, Xiao B Huang, Zhenyang He, Yuanhua Lu, Hui Han, Fan Zhang, Renhua Sun, Hua X Wang, Shu H Qin, Bao H Zhu, Jun Zhao, Jian Liu, Bin Li, Jing L Liu, Fa C Zhou, Qiong J Li, Xing Y Zhang, Zhou Li-Xin, Qiang Xin-Hua, Liangyan Jiang, Yuan N Gao, Xian Y Zhao, Yuan Y Li, Xiao L Li, Chunting Wang, Qingchun Yao, Rongguo Yu, Kai Chen, Huanzhang Shao, Bingyu Qin, Qing Q Huang, Wei H Zhu, Ai Y Hang, Ma X Hua, Yimin Li, Yonghao Xu, Yu D Di, Long L Ling, Tie H Qin, Shou H Wang, Junping Qin, Yi Han, Suming Zhou, Monica P Vargas, Juan I Silesky Jimenez, Manuel A González Rojas, Jaime E SolisQuesada, Christian M Ramirez-Alfaro, Jan Máca, Peter Sklienka, Jakob Gjedsted, Aage Christiansen, Boris G Villamagua, Iguel Llano, Philippe Burtin, Gautier Buzancais, Pascal Beuret, Nicolas Pelletier, Satar Mortaza, Alain Mercat, Jonathan Chelly, Sébastien Jochmans, Nicolas Terzi, Cédric Daubin, Guillaume Carteaux, Nicolas de Prost, Jean-Daniel Chiche, Fabrice Daviaud, Muriel Fartoukh, Guillaume Barberet, Jerome Biehler, Jean Dellamonica, Denis Doyen, Jean-Michel Arnal, Anais Briquet, Sami Hraiech, Laurent Papazian, Arnaud Follin, Damien Roux, Jonathan Messika, Evangelos Kalaitzis, Laurence Dangers, Alain Combes, Siu-Ming Au, Gaetan Béduneau, Dorothée Carpentier, Elie H Zogheib, Herve Dupont, Sylvie Ricome, Francesco L Santoli, Sebastien L Besset, Philippe Michel, Bruno Gelée, Pierre-Eric Danin, Bernard Goubaux, Philippe J Crova, Nga T Phan, Frantz Berkelmans, Julio C Badie, Romain Tapponnier, Josette Gally, Samy Khebbeb, Jean-Etienne Herbrecht, Francis Schneider, PierreLouis M Declercq, Jean-Philippe Rigaud, Jacques Duranteau, Anatole Harrois, Russell Chabanne, Julien Marin, Charlene Bigot, Sandrine Thibault, Mohammed Ghazi, Messabi Boukhazna, Salem Ould Zein, Jack R Richecoeur, Daniele M Combaux, Fabien Grelon, Charlene Le Moal, Elise P Sauvadet, Adrien Robine, Virginie Lemiale, Danielle Reuter, Martin Dres, Alexandre Demoule, Dany Goldgran-Toledano, Loredana Baboi, Claude Guérin, Ralph Lohner, Jens Kraßler, Susanne Schäfer, Kai D Zacharowski, Patrick Meybohm, Andreas W Reske, Philipp Simon, HansBernd F Hopf, Michael Schuetz, Thomas Baltus, Metaxia N Papanikolaou, Theonymfi G Papavasilopoulou, Giannis A Zacharas, Vasilis Ourailogloy, Eleni K Mouloudi, Eleni V Massa, Eva O Nagy, Electra E Stamou, Ellada V Kiourtzieva, Marina A Oikonomou, Luis E Avila, Cesar A Cortez, Johanna E Citalán, Sameer A Jog, Safal D Sable, Bhagyesh Shah, Mohan Gurjar, Arvind K Baronia, Mohammedfaruk Memon, Radhakrishnan Muthuchellappan, Venkatapura J Ramesh, Anitha Shenoy, Ramesh Unnikrishnan, Subhal B Dixit, Rachana V Rhayakar, Nagarajan Ramakrishnan, Vallish K Bhardwaj, Heera L Mahto, Sudha V Sagar, Vijayanand Palaniswamy, Deeban Ganesan, Seyed Mohammadreza Hashemian, Hamidreza Jamaati, Farshad Heidari, Edel A Meaney, Alistair Nichol, Karl M Knapman, Donall O'Croinin, Eimhin S Dunne, Dorothy M Breen, Kevin P Clarkson, Rola F Jaafar, Rory Dwyer, Fahd Amir, Olaitan O Ajetunmobi, Aogan C O'Muircheartaigh, Colin S Black, Nuala Treanor, Daniel V Collins, Wahid Altaf, Gianluca Zani, Maurizio Fusari, Savino Spadaro, Carlo A Volta, Romano Graziani, Barbara Brunettini, Salvatore Palmese, Paolo Formenti, Michele Umbrello, Andrea Lombardo, Elisabetta Pecci, Marco Botteri, Monica Savioli, Alessandro Protti, Alessia Mattei, Lorenzo Schiavoni, Andrea Tinnirello, Manuel Todeschini, Antonino Giarratano, Andrea Cortegiani, Massimo M Antonelli, Luca M Montini, Paolo Casalena, Sergio Scafetti, Giovanna Panarello, Giovanna Occhipinti, Nicolò Patroniti, Matteo Pozzi, Roberto R Biscione, Michela M Poli, Ferdinando Raimondi, Daniela Albiero, Giulia Crapelli, Eduardo Beck, Vincenzo Pota, Vincenzo Schiavone, Alexandre Molin, Fabio Tarantino, Giacomo Monti, Elena Frati, Lucia Mirabella, Gilda Cinnella, Tommaso Fossali, Riccardo Colombo, Pierpaolo Terragni, Ilaria Pattarino, Francesco Mojoli, Antonio Braschi, Erika E Borotto, Andrea N Cracchiolo, Daniela M Palma, Francesco Raponi, Giuseppe Foti, Ettore R Vascotto, Andrea Coppadoro, Luca Brazzi, Leda Floris, Giorgio A Iotti, Aaron Venti, Osamu Yamaguchi, Shunsuke Takagi, Hiroki N Maeyama, Eizo Watanabe, Yoshihiro Yamaji, Kazuyoshi Shimizu, Kyoko Shiozaki, Satoru Futami, Sekine Ryosuke, Koji Saito, Yoshinobu Kameyama, Keiko Ueno, Masayo Izawa, Nao Okuda, Hiroyuki Suzuki, Tomofumi Harasawa, Michitaka Nasu, Tadaaki Takada, Fumihito Ito, Shin Nunomiya, Kansuke Koyama, Toshikazu Abe, Kohkichi Andoh, Kohei Kusumoto, Akira Hirata, Akihiro Takaba, Hiroyasu Kimura, Shuhei Matsumoto, Ushio Higashijima, Hiroyuki Honda, Nobumasa Aoki, Hiroshi Imai, Yasuaki Ogino, Ichiko Mizuguchi, Kazuya Ichikado, Kenichi Nitta, Katsunori Mochizuki, Tomoaki Hashida, Hiroyuki Tanaka, Tomoyuki Nakamura, Daisuke Niimi, Takeshi Ueda, Yozo Kashiwa, Akinori Uchiyama, Olegs Sabelnikovs, Peteris Oss, Youssef Haddad, Kong Y Liew, 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Barratt-Due, Kim Andre L Noremark, Eldar Søreide, Brit Å Sjøbø, Anne B Guttormsen, Hector H Leon Yoshido, Ronald Zumaran Aguilar, Fredy A Montes Oscanoa, Alain U Alisasis, Joanne B Robles, Rossini Abbie B Pasanting-Lim, Beatriz C Tan, Pawel Andruszkiewicz, Karina Jakubowska, Cristina M Coxo, António M Alvarez, Bruno S Oliveira, Gustavo M Montanha, Nelson C Barros, Carlos S Pereira, António M Messias, Jorge M Monteiro, Ana M Araujo, Nuno T Catorze, Susan M Marum, Maria J Bouw, Rui M Gomes, Vania A Brito, Silvia Castro, Joana M Estilita, Filipa M Barros, Isabel M Serra, Aurelia M Martinho, Dana R Tomescu, Alexandra Marcu, Ovidiu H Bedreag, Marius Papurica, Dan E Corneci, Silvius Ioan Negoita, Evgeny Grigoriev, Alexey I Gritsan, Andrey A Gazenkampf, Ghaleb Almekhlafi, Mohamad M Albarrak, Ghanem M Mustafa, Khalid A Maghrabi, Nawal Salahuddin, Tharwat M Aisa, Ahmed S Al Jabbary, Edgardo Tabhan, Yaseen M Arabi, Olivia A Trinidad, Hasan M Al Dorzi, Edgardo E Tabhan, Vesna Bumbasirevic, Bojan 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Pastor Marcos, Laura Alvarez Montero, Luis Herrera Para, Roberto Jimenez Sanchez, Miguel Angel Blasco Navalpotro, Ricardo Diaz Abad, Raquel Montiel González, Dácil Parrilla Toribio, Alejandro G Castro, Maria Jose D Artiga, Oscar Penuelas, Tomas P Roser, Moreno F Olga, Elena Gallego Curto, Rocío Manzano Sánchez, Vallverdu P Imma, Garcia M Elisabet, Laura Claverias, Monica Magret, Ana M Pellicer, Lucia L Rodriguez, Jesús Sánchez-Ballesteros, Ángela González-Salamanca, Antonio G Jimenez, Francisco P Huerta, Juan Carlos J Sotillo Diaz, Esther Bermejo Lopez, David D Llinares Moya, Alec A Tallet Alfonso, Palazon Sanchez Eugenio Luis, Palazon Sanchez Cesar, Sánchez I Rafael, Corcoles G Virgilio, Noelia N Recio, Christian C Rylander, Bernhard Holzgraefe, Lars M Broman, Joanna Wessbergh, Linnea Persson, Fredrik Schiöler, Hans Kedelv, Anna Oscarsson Tibblin, Henrik Appelberg, Lars Hedlund, Johan Helleberg, Karin E Eriksson, Rita Glietsch, Niklas Larsson, Ingela Nygren, Silvia L Nunes, Anna-Karin 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Dean, Julius H Cranshaw, Emma L Willett, Nicholas Ioannou, Sarah Gillis, Peter Csabi, Rosaleen Macfadyen, Heidi Dawson, Pieter D Preez, Alexandra J Williams, Owen Boyd, Laura Ortiz-Ruiz de Gordoa, Jon Bramall, Sophie Symmonds, Simon K Chau, Tim Wenham, Tamas Szakmany, Piroska Toth-Tarsoly, Katie H McCalman, Peter Alexander, Lorraine Stephenson, Thomas Collyer, Rhiannon Chapman, Raphael Cooper, Russell M Allan, Malcolm Sim, David W Wrathall, Donald A Irvine, Kim S Zantua, John C Adams, Andrew J Burtenshaw, Gareth P Sellors, Ingeborg D Welters, Karen E Williams, Robert J Hessell, Matthew G Oldroyd, Ceri E Battle, Suresh Pillai, Istvan Kajtor, Mageswaran Sivashanmugavel, Sinead C Okane, Adrian Donnelly, Aniko D Frigyik, Jon P Careless, Martin M May, Richard Stewart, T John Trinder, Samantha J Hagan, Jade M Cole, Caroline C MacFie, Anna T Dowling, Nicolás Nin, Edgardo Nuñez, Gustavo Pittini, Ruben Rodriguez, María C Imperio, Cristina Santos, Ana G França, Alejandro Ebeid, Alberto Deicas, 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Angel, Fernandes, Antero do Vale, Van Haren, Frank, Bruhn, Alejandro, Rios, Fernando, Esteban, Andre, Gattinoni, Luciano, Larsson, Ander, McAuley, Daniel F., Ranieri, Marco, Thompson, B. Taylor, Wrigge, Hermann, Brochard, Laurent J., Laffey, John G, Antonio Pesenti, John G Laffey, Laurent Brochard, Andres Esteban, Luciano Gattinoni, Frank van Haren, Anders Larsson, Daniel F McAuley, Marco Ranieri, Gordon Rubenfeld, B Taylor Thompson, Hermann Wrigge, Arthur S Slutsky, John G Laffey, Giacomo Bellani, Tài Pham, Eddy Fan, Fernando Rios, Frank van Haren, Thierry Sottiaux, Pieter Depuydt, Fredy S Lora, Luciano Cesar Azevedo, Eddy Fan, Guillermo Bugedo, Haibo Qiu, Marcos Gonzalez, Juan Silesky, Vladimir Cerny, Jonas Nielsen, Manuel Jibaja, Tài Pham, Hermann Wrigge, Dimitrios Matamis, Jorge Luis Ranero, Pravin Amin, S M Hashemian, Kevin Clarkson, Giacomo Bellani, Kiyoyasu Kurahashi, Asisclo Villagomez, Amine Ali Zeggwagh, Leo M Heunks, Jon Henrik Laake, Jose Emmanuel Palo, Antero do Vale Fernandes, Dorel Sandesc, Yaasen Arabi, Vesna Bumbasierevic, Nicolas Nin, Jose A Lorente, Anders Larsson, Lise Piquilloud, Fekri Abroug, Daniel F McAuley, Lia McNamee, Javier Hurtado, Ed Bajwa, Gabriel Démpaire, Hektor Sula, Lordian Nunci, Alma Cani, Alan Zazu, Christian Dellera, Carolina S Insaurralde, Risso V Alejandro, Julio Daldin, Mauricio Vinzio, Ruben O Fernandez, Luis P Cardonnet, Lisandro R Bettini, Mariano Carboni Bisso, Emilio M Osman, Mariano G Setten, Pablo Lovazzano, Javier Alvarez, Veronica Villar, Norberto C Pozo, Nicolas Grubissich, Gustavo A Plotnikow, Daniela N Vasquez, Santiago Ilutovich, Norberto Tiribelli, Ariel Chena, Carlos A Pellegrini, María G Saenz, Elisa Estenssoro, Matias Brizuela, Hernan Gianinetto, Pablo E Gomez, Valeria I Cerrato, Marco G Bezzi, Silvina A Borello, Flavia A Loiacono, Adriana M Fernandez, Serena Knowles, Claire Reynolds, Deborah M Inskip, Jennene J Miller, Jing Kong, Christina Whitehead, Shailesh Bihari, Aylin Seven, Amanda Krstevski, Helen J Rodgers, Rebecca T Millar, Toni E McKenna, Irene M Bailey, Gabrielle C Hanlon, Anders Aneman, Joan M Lynch, Raman Azad, John Neal, Paul W Woods, Brigit L Roberts, Mark R Kol, Helen S Wong, Katharina C Riss, Thomas Staudinger, Xavier Wittebole, Caroline Berghe, Pierre A Bulpa, Alain M Dive, Rik Verstraete, Herve Lebbinck, Pieter Depuydt, Joris Vermassen, Philippe Meersseman, Helga Ceunen, Jonas I Rosa, Daniel O Beraldo, Claudio Piras, Adenilton M Rampinelli, Antonio P Nassar Jr, Sergio Mataloun, Marcelo Moock, Marlus M Thompson, Claudio H Gonçalves, Ana Carolina P Antônio, Aline Ascoli, Rodrigo S Biondi, Danielle C Fontenele, Danielle Nobrega, Vanessa M Sales, Ahmad Yazid Bin Hj Abul Wahab, Maizatul Ismail, Suresh Shindhe, John Laffey, Francois Beloncle, Kyle G Davies, Rob Cirone, Venika Manoharan, Mehvish Ismail, Ewan C Goligher, Mandeep Jassal, Erin Nishikawa, Areej Javeed, Gerard Curley, Nuttapol Rittayamai, Matteo Parotto, Niall D Ferguson, Sangeeta Mehta, Jenny Knoll, Antoine Pronovost, Sergio Canestrini, Alejandro R Bruhn, Patricio H Garcia, Felipe A Aliaga, Pamela A Farías, Jacob S Yumha, Claudia A Ortiz, Javier E Salas, Alejandro A Saez, Luis D Vega, Eduardo F Labarca, Felipe T Martinez, Nicolás G Carreño, Pilar Lora, Haitao Liu, Haibo Qiu, Ling Liu, Rui Tang, Xiaoming Luo, Youzhong An, Huiying Zhao, Yan Gao, Zhe Zhai, Zheng L Ye, Wei Wang, Wenwen Li, Qingdong Li, Ruiqiang Zheng, Wenkui Yu, Juanhong Shen, Xinyu Li, Tao Yu, Weihua Lu, Ya Q Wu, Xiao B Huang, Zhenyang He, Yuanhua Lu, Hui Han, Fan Zhang, Renhua Sun, Hua X Wang, Shu H Qin, Bao H Zhu, Jun Zhao, Jian Liu, Bin Li, Jing L Liu, Fa C Zhou, Qiong J Li, Xing Y Zhang, Zhou Li-Xin, Qiang Xin-Hua, Liangyan Jiang, Yuan N Gao, Xian Y Zhao, Yuan Y Li, Xiao L Li, Chunting Wang, Qingchun Yao, Rongguo Yu, Kai Chen, Huanzhang Shao, Bingyu Qin, Qing Q Huang, Wei H Zhu, Ai Y Hang, Ma X Hua, Yimin Li, Yonghao Xu, Yu D Di, Long L Ling, Tie H Qin, Shou H Wang, Junping Qin, Yi Han, Suming Zhou, Monica P Vargas, Juan I Silesky Jimenez, Manuel A González Rojas, Jaime E SolisQuesada, Christian M Ramirez-Alfaro, Jan Máca, Peter Sklienka, Jakob Gjedsted, Aage Christiansen, Jonas Nielsen, Boris G Villamagua, Iguel Llano, Philippe Burtin, Gautier Buzancais, Pascal Beuret, Nicolas Pelletier, Satar Mortaza, Alain Mercat, Jonathan Chelly, Sébastien Jochmans, Nicolas Terzi, Cédric Daubin, Guillaume Carteaux, Nicolas de Prost, Jean-Daniel Chiche, Fabrice Daviaud, Tài Pham, Muriel Fartoukh, Guillaume Barberet, Jerome Biehler, Jean Dellamonica, Denis Doyen, Jean-Michel Arnal, Anais Briquet, Sami Hraiech, Laurent Papazian, Arnaud Follin, Damien Roux, Jonathan Messika, Evangelos Kalaitzis, Laurence Dangers, Alain Combes, Siu-Ming Au, Gaetan Béduneau, Dorothée Carpentier, Elie H Zogheib, Herve Dupont, Sylvie Ricome, Francesco L Santoli, Sebastien L Besset, Philippe Michel, Bruno Gelée, Pierre-Eric Danin, Bernard Goubaux, Philippe J Crova, Nga T Phan, Frantz Berkelmans, Julio C Badie, Romain Tapponnier, Josette Gally, Samy Khebbeb, Jean-Etienne Herbrecht, Francis Schneider, PierreLouis M Declercq, Jean-Philippe Rigaud, Jacques Duranteau, Anatole Harrois, Russell Chabanne, Julien Marin, Charlene Bigot, Sandrine Thibault, Mohammed Ghazi, Messabi Boukhazna, Salem Ould Zein, Jack R Richecoeur, Daniele M Combaux, Fabien Grelon, Charlene Le Moal, Elise P Sauvadet, Adrien Robine, Virginie Lemiale, Danielle Reuter, Martin Dres, Alexandre Demoule, Dany Goldgran-Toledano, Loredana Baboi, Claude Guérin, Ralph Lohner, Jens Kraßler, Susanne Schäfer, Kai D Zacharowski, Patrick Meybohm, Andreas W Reske, Philipp Simon, HansBernd F Hopf, Michael Schuetz, Thomas Baltus, Metaxia N Papanikolaou, Theonymfi G Papavasilopoulou, Giannis A Zacharas, Vasilis Ourailogloy, Eleni K Mouloudi, Eleni V Massa, Eva O Nagy, Electra E Stamou, Ellada V Kiourtzieva, Marina A Oikonomou, Luis E Avila, Cesar A Cortez, Johanna E Citalán, Sameer A Jog, Safal D Sable, Bhagyesh Shah, Mohan Gurjar, Arvind K Baronia, Mohammedfaruk Memon, Radhakrishnan Muthuchellappan, Venkatapura J Ramesh, Anitha Shenoy, Ramesh Unnikrishnan, Subhal B Dixit, Rachana V Rhayakar, Nagarajan Ramakrishnan, Vallish K Bhardwaj, Heera L 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Pota, Vincenzo Schiavone, Alexandre Molin, Fabio Tarantino, Giacomo Monti, Elena Frati, Lucia Mirabella, Gilda Cinnella, Tommaso Fossali, Riccardo Colombo, Pierpaolo Terragni, Ilaria Pattarino, Francesco Mojoli, Antonio Braschi, Erika E Borotto, Andrea N Cracchiolo, Daniela M Palma, Francesco Raponi, Giuseppe Foti, Ettore R Vascotto, Andrea Coppadoro, Luca Brazzi, Leda Floris, Giorgio A Iotti, Aaron Venti, Osamu Yamaguchi, Shunsuke Takagi, Hiroki N Maeyama, Eizo Watanabe, Yoshihiro Yamaji, Kazuyoshi Shimizu, Kyoko Shiozaki, Satoru Futami, Sekine Ryosuke, Koji Saito, Yoshinobu Kameyama, Keiko Ueno, Masayo Izawa, Nao Okuda, Hiroyuki Suzuki, Tomofumi Harasawa, Michitaka Nasu, Tadaaki Takada, Fumihito Ito, Shin Nunomiya, Kansuke Koyama, Toshikazu Abe, Kohkichi Andoh, Kohei Kusumoto, Akira Hirata, Akihiro Takaba, Hiroyasu Kimura, Shuhei Matsumoto, Ushio Higashijima, Hiroyuki Honda, Nobumasa Aoki, Hiroshi Imai, Yasuaki Ogino, Ichiko Mizuguchi, Kazuya Ichikado, Kenichi Nitta, Katsunori 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C Rylander, Bernhard Holzgraefe, Lars M Broman, Joanna Wessbergh, Linnea Persson, Fredrik Schiöler, Hans Kedelv, Anna Oscarsson Tibblin, Henrik Appelberg, Lars Hedlund, Johan Helleberg, Karin E Eriksson, Rita Glietsch, Niklas Larsson, Ingela Nygren, Silvia L Nunes, Anna-Karin Morin, Thomas Kander, Anne Adolfsson, Lise Piquilloud, Hervé O Zender, Corinne Leemann-Refondini, Souheil Elatrous, Slaheddine Bouchoucha, Imed Chouchene, Islem Ouanes, Asma Ben Souissi, Salma Kamoun, Oktay Demirkiran, Mustafa Aker, Emre Erbabacan, Ilkay Ceylan, Nermin Kelebek Girgin, Menekse Ozcelik, Necmettin Ünal, Basak Ceyda Meco, Onat O Akyol, Suleyman S Derman, Barry Kennedy, Ken Parhar, Latha Srinivasa, Lia McNamee, Danny McAuley, Phil Hopkins, Clare Mellis, Vivek Kakar, Dan Hadfield, Andre Vercueil, Kaushik Bhowmick, Sally K Humphreys, Andrew Ferguson, Raymond Mckee, Ashok S Raj, Danielle A Fawkes, Philip Watt, Linda Twohey, Rajeev R Jha, Matthew Thomas, Alex Morton, Varsha Kadaba, Mark J Smith, Anil P Hormis, Santhana G Kannan, Miriam Namih, Henrik Reschreiter, Julie Camsooksai, Alek Kumar, Szabolcs Rugonfalvi, Christopher Nutt, Orla Oneill, Colette Seasman, Ged Dempsey, Christopher J Scott, Helen E Ellis, Stuart Mckechnie, Paula J Hutton, Nora N Di Tomasso, Michela N Vitale, Ruth O Griffin, Michael N Dean, Julius H Cranshaw, Emma L Willett, Nicholas Ioannou, Sarah Gillis, Peter Csabi, Rosaleen Macfadyen, Heidi Dawson, Pieter D Preez, Alexandra J Williams, Owen Boyd, Laura Ortiz-Ruiz de Gordoa, Jon Bramall, Sophie Symmonds, Simon K Chau, Tim Wenham, Tamas Szakmany, Piroska Toth-Tarsoly, Katie H McCalman, Peter Alexander, Lorraine Stephenson, Thomas Collyer, Rhiannon Chapman, Raphael Cooper, Russell M Allan, Malcolm Sim, David W Wrathall, Donald A Irvine, Kim S Zantua, John C Adams, Andrew J Burtenshaw, Gareth P Sellors, Ingeborg D Welters, Karen E Williams, Robert J Hessell, Matthew G Oldroyd, Ceri E Battle, Suresh Pillai, Istvan Kajtor, Mageswaran Sivashanmugavel, Sinead C Okane, Adrian Donnelly, Aniko D Frigyik, Jon P Careless, Martin M May, Richard Stewart, T John Trinder, Samantha J Hagan, Jade M Cole, Caroline C MacFie, Anna T Dowling, Javier Hurtado, Nicolás Nin, Javier Hurtado, Edgardo Nuñez, Gustavo Pittini, Ruben Rodriguez, María C Imperio, Cristina Santos, Ana G França, Alejandro Ebeid, Alberto Deicas, Carolina Serra, Aditya Uppalapati, Ghassan Kamel, Valerie M Banner-Goodspeed, Jeremy R Beitler, Satyanarayana Reddy Mukkera, Shreedhar Kulkarni, John O Shinn Iii, Dina Gomaa, Christopher Tainter, Jarone Lee, Tomaz MesarJarone Lee, Dale J Yeatts, Jessica Warren, Michael J Lanspa, Russel R Miller, Colin K Grissom, Samuel M Brown, Philippe R Bauer, Ryan J Gosselin, Barrett T Kitch, Jason E Cohen, Scott H Beegle, Shazia Choudry, Renaud M Gueret, Aiman Tulaimat, William Stigler, Hitesh Batra, Nidhi G Huff, Keith D Lamb, Trevor W Oetting, Nicholas M Mohr, Claine Judy, Shigeki Saito, Fayez M Kheir, Fayez Kheir, Adam B Schlichting, Angela Delsing, Daniel R Crouch, Mary Elmasri, Daniel R Crouch, Dina Ismail, Kyle R Dreyer, Thomas C Blakeman, Dina Gomaa, Rebecca M Baro, Carolina Quintana Grijalba, Peter C Hou, Raghu Seethala, Imo Aisiku, Galen Henderson, Gyorgy Frendl, Sen-Kuang Hou, Robert L Owens, Ashley Schomer, Intensive Care Medicine, ACS - Diabetes & metabolism, ACS - Pulmonary hypertension & thrombosis, ACS - Microcirculation, Pham, T, Pesenti, A, Bellani, G, Rubenfeld, G, Fan, E, Bugedo, G, Lorente, J, Fernandes, A, Van Haren, F, Bruhn, A, Rios, F, Esteban, A, Gattinoni, L, Larsson, A, Mcauley, D, Ranieri, M, Thompson, B, Wrigge, H, Brochard, L, Laffey, J, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), St. Michael's Hospital, University of Toronto, Groupe de recherche clinique CARMAS, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Università degli Studi di Milano [Milano] (UNIMI), University of Milan, San Gerardo Hospital, Sunnybrook Health Sciences Center, Mount Sinai Hospital [Toronto, Canada] (MSH), Pontificia Universidad Católica de Chile (UC), University Hospital of Getafe, CIBER Enfermedades Respiratorias (CIBERES), Universidad Europea de Madrid, Hospital Garcia de Orta (EPE), Canberra Hospital, Medical School [Australian National University - ANU], Australian National University (ANU), University of Canberra, Centro de Investigación Biomédica en Red Enfermedades Respiratorias (CIBERES), University of Göttingen - Georg-August-Universität Göttingen, Uppsala University, Queen's University [Belfast] (QUB), Royal Victoria Hospital, McGill University Health Center [Montreal] (MUHC), Università degli Studi di Bologna, Massachusetts General Hospital [Boston], University Hospital Leipzig, Department of Anaesthesiology, Intensive Care and Emergency Medicine, Pain Therapy, Bergmannstrost Hospital Halle, 06112, Halle, National University of Ireland [Galway] (NUI Galway), Bayer GlaxoSmithKline, GSK Baxter International Boehringer Ingelheim Wellcome Trust, WT National Institute for Health Research, NIHR Queen's University Belfast, QUB Medical Research Council Canada, MRC European Society of Intensive Care Medicine, ESICM, Support statement: This work was supported by the European Society of Intensive Care Medicine. Funding information for this article has been deposited with the Crossref Funder Registry., Conflict of interest: T. Pham has nothing to disclose. A. Pesenti reports personal fees from Maquet, Novalung/Xenios, Baxter, Gilead and Boehringer Ingelheim, outside the submitted work. G. Bellani reports grants and personal fees from Draeger Medical, personal fees from Getinge, Hamilton, GE Healthcare, Dimar SRL, Intersurgical and Flowmeter SPA, outside the submitted work. G. Rubenfeld has nothing to disclose. E. Fan reports personal fees from ALung Technologies, Getinge and MC3 Cardiopulmonary, grants, personal fees and non-financial support from Fresenius Medical Care, outside the submitted work. G. Bugedo has nothing to disclose. J.A. Lorente has nothing to disclose. A.D. V. Fernandes has nothing to disclose. F. Van Haren has nothing to disclose. A. Bruhn has nothing to disclose. F. Rios has nothing to disclose. A. Esteban has nothing to disclose. L. Gattinoni has nothing to disclose. A. Larsson reports grants from the Swedish Heart and Lung Foundation, during the conduct of the study. D.F. McAuley reports personal fees from consultancy for GlaxoSmithKline, Boehringer Ingelheim and Bayer, outside the submitted work, in addition, his institution has received funds from grants from the UK NIHR, Wellcome Trust, Innovate UK, NI HSC R&D Division, NI Chest Heart and Stroke, and MRC, is one of four named inventors on a patent US8962032 covering the use of sialic acid-bearing nanoparticles as anti-inflammatory agents issued to his institution, The Queen’s University of Belfast (http://www.google.com/patents/US8962032), and is a Director of Research for the Intensive Care Society and NIHR EME Programme Director. M. Ranieri has nothing to disclose. B.T. Thompson reports personal fees from Bayer, Thetis and Novartis, outside the submitted work. H. Wrigge reports personal fees for consultancy from Dräger Medical, personal fees for advisory board work from Liberate Medical, grants and personal fees for lectures from InfectoPharm, personal fees for lectures from MSD and GE, outside the submitted work. L.J. Brochard reports grants from Medtronic Covidien, grants and non-financial support from Fisher Paykel, non-financial support from Air Liquide, Sentec and Philips, other (patent) from General Electric, outside the submitted work. J.G. Laffey reports grants and personal fees from Baxter, grants and non-financial support from Aerogen and Factor Biosciences, outside the submitted work., LUNG SAFE Investigators and the European Society of Intensive Care Medicine Trials Group: Antonio Pesenti, John G Laffey, Laurent Brochard, Andres Esteban, Luciano Gattinoni, Frank van Haren, Anders Larsson, Daniel F McAuley, Marco Ranieri, Gordon Rubenfeld, B Taylor Thompson, Hermann Wrigge, Arthur S Slutsky, John G Laffey, Giacomo Bellani, Tài Pham, Eddy Fan, Fernando Rios, Frank van Haren, Thierry Sottiaux, Pieter Depuydt, Fredy S Lora, Luciano Cesar Azevedo, Eddy Fan, Guillermo Bugedo, Haibo Qiu, Marcos Gonzalez, Juan Silesky, Vladimir Cerny, Jonas Nielsen, Manuel Jibaja, Tài Pham, Hermann Wrigge, Dimitrios Matamis, Jorge Luis Ranero, Pravin Amin, S M Hashemian, Kevin Clarkson, Giacomo Bellani, Kiyoyasu Kurahashi, Asisclo Villagomez, Amine Ali Zeggwagh, Leo M Heunks, Jon Henrik Laake, Jose Emmanuel Palo, Antero do Vale Fernandes, Dorel Sandesc, Yaasen Arabi, Vesna Bumbasierevic, Nicolas Nin, Jose A Lorente, Anders Larsson, Lise Piquilloud, Fekri Abroug, Daniel F McAuley, Lia McNamee, Javier Hurtado, Ed Bajwa, Gabriel Démpaire, Hektor Sula, Lordian Nunci, Alma Cani, Alan Zazu, Christian Dellera, Carolina S Insaurralde, Risso V Alejandro, Julio Daldin, Mauricio Vinzio, Ruben O Fernandez, Luis P Cardonnet, Lisandro R Bettini, Mariano Carboni Bisso, Emilio M Osman, Mariano G Setten, Pablo Lovazzano, Javier Alvarez, Veronica Villar, Norberto C Pozo, Nicolas Grubissich, Gustavo A Plotnikow, Daniela N Vasquez, Santiago Ilutovich, Norberto Tiribelli, Ariel Chena, Carlos A Pellegrini, María G Saenz, Elisa Estenssoro, Matias Brizuela, Hernan Gianinetto, Pablo E Gomez, Valeria I Cerrato, Marco G Bezzi, Silvina A Borello, Flavia A Loiacono, Adriana M Fernandez, Serena Knowles, Claire Reynolds, Deborah M Inskip, Jennene J Miller, Jing Kong, Christina Whitehead, Shailesh Bihari, Aylin Seven, Amanda Krstevski, Helen J 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Kusumoto, Akira Hirata, Akihiro Takaba, Hiroyasu Kimura, Shuhei Matsumoto, Ushio Higashijima, Hiroyuki Honda, Nobumasa Aoki, Hiroshi Imai, Yasuaki Ogino, Ichiko Mizuguchi, Kazuya Ichikado, Kenichi Nitta, Katsunori Mochizuki, Tomoaki Hashida, Hiroyuki Tanaka, Tomoyuki Nakamura, Daisuke Niimi, Takeshi Ueda, Yozo Kashiwa, Akinori Uchiyama, Olegs Sabelnikovs, Peteris Oss, Youssef Haddad, Kong Y Liew, Silvio A Ñamendys-Silva, Yves D Jarquin-Badiola, Luis A Sanchez-Hurtado, Saira S Gomez-Flores, Maria C Marin, Asisclo J Villagomez, Jordana S Lemus, Jonathan M Fierro, Mavy Ramirez Cervantes, Francisco Javier Flores Mejia, Dulce Dector, Alejandro Rojas, Daniel R Gonzalez, Claudia R Estrella, Jorge R Sanchez-Medina, Alvaro Ramirez-Gutierrez, Fernando G George, Janet S Aguirre, Juan A Buensuseso, Manuel Poblano, Juan A Buensuseso, Manuel Poblano, Tarek Dendane, Amine Ali Zeggwagh, Hicham Balkhi, Mina Elkhayari, Nacer Samkaoui, Hanane Ezzouine, Abdellatif Benslama, Mourad Amor, Wajdi Maazouzi, Nedim Cimic, Oliver Beck, Monique M Bruns, Jeroen A Schouten, Myra Rinia, Monique Raaijmakers, Leo M Heunks, Hellen M van Wezel, Serge J Heines, Ulrich Strauch, Marc P Buise, Fabienne D Simonis, Marcus J Schultz, Jennifer C Goodson, Troy S Browne, Leanlove Navarra, Anna Hunt, Robyn A Hutchison, Mathew B Bailey, Lynette Newby, Colin McArthur, Michael Kalkoff, Alex Mcleod, Jonathan Casement, Danielle J Hacking, Finn H Andersen, Merete S Dolva, Jon H Laake, Andreas Barratt-Due, Kim Andre L Noremark, Eldar Søreide, Brit Å Sjøbø, Anne B Guttormsen, Hector H Leon Yoshido, Ronald Zumaran Aguilar, Fredy A Montes Oscanoa, Alain U Alisasis, Joanne B Robles, Rossini Abbie B Pasanting-Lim, Beatriz C Tan, Pawel Andruszkiewicz, Karina Jakubowska, Cristina M Coxo, António M Alvarez, Bruno S Oliveira, Gustavo M Montanha, Nelson C Barros, Carlos S Pereira, António M Messias, Jorge M Monteiro, Ana M Araujo, Nuno T Catorze, Susan M Marum, Maria J Bouw, Rui M Gomes, Vania A Brito, Silvia Castro, Joana M Estilita, Filipa M Barros, Isabel M Serra, Aurelia M Martinho, Dana R Tomescu, Alexandra Marcu, Ovidiu H Bedreag, Marius Papurica, Dan E Corneci, Silvius Ioan Negoita, Evgeny Grigoriev, Alexey I Gritsan, Andrey A Gazenkampf, Ghaleb Almekhlafi, Mohamad M Albarrak, Ghanem M Mustafa, Khalid A Maghrabi, Nawal Salahuddin, Tharwat M Aisa, Ahmed S Al Jabbary, Edgardo Tabhan, Yaseen M Arabi, Yaseen M Arabi, Olivia A Trinidad, Hasan M Al Dorzi, Edgardo E Tabhan, Vesna Bumbasirevic, Bojan Jovanovic, Stefan Bolon, Oliver Smith, Jordi Mancebo, Hernan Aguirre-Bermeo, Juan C Lopez-Delgado, Francisco Esteve, Gemma Rialp, Catalina Forteza, Candelaria De Haro, Antonio Artigas, Guillermo M Albaiceta, Sara De Cima-Iglesias, Leticia Seoane-Quiroga, Alexandra Ceniceros-Barros, Antonio L RuizAguilar, Luis M Claraco-Vega, Juan Alfonso Soler, Maria Del Carmen Lorente, Cecilia Hermosa, Federico Gordo, Miryam PrietoGonzález, Juan B López-Messa, Manuel P Perez, Cesar P Perez, Raquel Montoiro Allue, Ferran RocheCampo, Marcos Ibañez-Santacruz, Susana TempranoSusana, Maria C Pintado, Raul De Pablo, Pilar Ricart Aroa Gómez, Silvia Rodriguez Ruiz, Silvia Iglesias Moles, Mª Teresa Jurado, Alfons Arizmendi, Enrique A Piacentini, Nieves Franco, Teresa Honrubia, Meisy Perez Cheng, Elena Perez Losada, Javier Blanco, Luis J Yuste, Cecilia Carbayo-Gorriz, Francisca G Cazorla-Barranquero, Javier G Alonso, Rosa S Alda, Ángela Algaba, Gonzalo Navarro, Enrique Cereijo, Esther Diaz-Rodriguez, Diego Pastor Marcos, Laura Alvarez Montero, Luis Herrera Para, Roberto Jimenez Sanchez, Miguel Angel Blasco Navalpotro, Ricardo Diaz Abad, Raquel Montiel González, Dácil Parrilla Toribio, Alejandro G Castro, Maria Jose D Artiga, Oscar Penuelas, Tomas P Roser, Moreno F Olga, Elena Gallego Curto, Rocío Manzano Sánchez, Vallverdu P Imma, Garcia M Elisabet, Laura Claverias, Monica Magret, Ana M Pellicer, Lucia L Rodriguez, Jesús Sánchez-Ballesteros, Ángela González-Salamanca, Antonio G Jimenez, Francisco P Huerta, Juan Carlos J Sotillo Diaz, Esther Bermejo Lopez, David D Llinares Moya, Alec A Tallet Alfonso, Palazon Sanchez Eugenio Luis, Palazon Sanchez Cesar, Sánchez I Rafael, Corcoles G Virgilio, Noelia N Recio, Christian C Rylander, Bernhard Holzgraefe, Lars M Broman, Joanna Wessbergh, Linnea Persson, Fredrik Schiöler, Hans Kedelv, Anna Oscarsson Tibblin, Henrik Appelberg, Lars Hedlund, Johan Helleberg, Karin E Eriksson, Rita Glietsch, Niklas Larsson, Ingela Nygren, Silvia L Nunes, Anna-Karin Morin, Thomas Kander, Anne Adolfsson, Lise Piquilloud, Hervé O Zender, Corinne Leemann-Refondini, Souheil Elatrous, Slaheddine Bouchoucha, Imed Chouchene, Islem Ouanes, Asma Ben Souissi, Salma Kamoun, Oktay Demirkiran, Mustafa Aker, Emre Erbabacan, Ilkay Ceylan, Nermin Kelebek Girgin, Menekse Ozcelik, Necmettin Ünal, Basak Ceyda Meco, Onat O Akyol, Suleyman S Derman, Barry Kennedy, Ken Parhar, Latha Srinivasa, Lia McNamee, Danny McAuley, Phil Hopkins, Clare Mellis, Vivek Kakar, Dan Hadfield, Andre Vercueil, Kaushik Bhowmick, Sally K Humphreys, Andrew Ferguson, Raymond Mckee, Ashok S Raj, Danielle A Fawkes, Philip Watt, Linda Twohey, Rajeev R Jha, Matthew Thomas, Alex Morton, Varsha Kadaba, Mark J Smith, Anil P Hormis, Santhana G Kannan, Miriam Namih, Henrik Reschreiter, Julie Camsooksai, Alek Kumar, Szabolcs Rugonfalvi, Christopher Nutt, Orla Oneill, Colette Seasman, Ged Dempsey, Christopher J Scott, Helen E Ellis, Stuart Mckechnie, Paula J Hutton, Nora N Di Tomasso, Michela N Vitale, Ruth O Griffin, Michael N Dean, Julius H Cranshaw, Emma L Willett, Nicholas Ioannou, Sarah Gillis, Peter Csabi, Rosaleen Macfadyen, Heidi Dawson, Pieter D Preez, Alexandra J Williams, Owen Boyd, Laura Ortiz-Ruiz de Gordoa, Jon Bramall, Sophie Symmonds, Simon K Chau, Tim Wenham, Tamas Szakmany, Piroska Toth-Tarsoly, Katie H McCalman, Peter Alexander, Lorraine Stephenson, Thomas Collyer, Rhiannon Chapman, Raphael Cooper, Russell M Allan, Malcolm Sim, David W Wrathall, Donald A Irvine, Kim S Zantua, John C Adams, Andrew J Burtenshaw, Gareth P Sellors, Ingeborg D Welters, Karen E Williams, Robert J Hessell, Matthew G Oldroyd, Ceri E Battle, Suresh Pillai, Istvan Kajtor, Mageswaran Sivashanmugavel, Sinead C Okane, Adrian Donnelly, Aniko D Frigyik, Jon P Careless, Martin M May, Richard Stewart, T John Trinder, Samantha J Hagan, Jade M Cole, Caroline C MacFie, Anna T Dowling, Javier Hurtado, Nicolás Nin, Javier Hurtado, Edgardo Nuñez, Gustavo Pittini, Ruben Rodriguez, María C Imperio, Cristina Santos, Ana G França, Alejandro Ebeid, Alberto Deicas, Carolina Serra, Aditya Uppalapati, Ghassan Kamel, Valerie M Banner-Goodspeed, Jeremy R Beitler, Satyanarayana Reddy Mukkera, Shreedhar Kulkarni, John O Shinn Iii, Dina Gomaa, Christopher Tainter, Jarone Lee, Tomaz MesarJarone Lee, Dale J Yeatts, Jessica Warren, Michael J Lanspa, Russel R Miller, Colin K Grissom, Samuel M Brown, Philippe R Bauer, Ryan J Gosselin, Barrett T Kitch, Jason E Cohen, Scott H Beegle, Shazia Choudry, Renaud M Gueret, Aiman Tulaimat, William Stigler, Hitesh Batra, Nidhi G Huff, Keith D Lamb, Trevor W Oetting, Nicholas M Mohr, Claine Judy, Shigeki Saito, Fayez M Kheir, Fayez Kheir, Adam B Schlichting, Angela Delsing, Daniel R Crouch, Mary Elmasri, Daniel R Crouch, Dina Ismail, Kyle R Dreyer, Thomas C Blakeman, Dina Gomaa, Rebecca M Baro, Carolina Quintana Grijalba, Peter C Hou, Raghu Seethala, Imo Aisiku, Galen Henderson, Gyorgy Frendl, Sen-Kuang Hou, Robert L Owens, Ashley Schomer, UCL - SSS/IREC/MEDA - Pôle de médecine aiguë, UCL - (MGD) Services des soins intensifs, and UCL - (SLuc) Service de soins intensifs

Subjects
Pulmonary and Respiratory Medicine, ARDS, Unidades de cuidados intensivos, [SDV]Life Sciences [q-bio], medicine.medical_treatment, mechanical ventilation, NO, law.invention, 03 medical and health sciences, Tratamiento médico, 0302 clinical medicine, law, Settore MED/41 - ANESTESIOLOGIA, Insuficiencia respiratoria, Medicine, Humans, 030212 general & internal medicine, Prospective Studies, Prospective cohort study, Lung, Mechanical ventilation, Respiratory Distress Syndrome, business.industry, Respiration, Incidence (epidemiology), medicine.disease, Intensive care unit, Respiration, Artificial, 3. Good health, Intensive Care Units, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], medicine.anatomical_structure, 030228 respiratory system, Respiratory failure, Heart failure, Anesthesia, Artificial, ards, business, Respiratory Insufficiency, Enfermedad
Abstract

BackgroundCurrent incidence and outcome of patients with acute hypoxaemic respiratory failure requiring mechanical ventilation in the intensive care unit (ICU) are unknown, especially for patients not meeting criteria for acute respiratory distress syndrome (ARDS).MethodsAn international, multicentre, prospective cohort study of patients presenting with hypoxaemia 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 arterial oxygen tension/inspiratory oxygen fraction ratio ≤300 mmHg, new pulmonary infiltrates and need for mechanical ventilation with a positive end-expiratory pressure of ≥5 cmH2O. ICU prevalence, causes of hypoxaemia, hospital survival and factors associated with hospital mortality were measured. Patients with unilateral versus bilateral opacities were compared.Findings12 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 (CHF; 8.2%). The global hospital mortality was 38.6%. CHF patients had a mortality comparable to ARDS (44.1% versus 40.4%). Patients with unilateral-infiltrate had lower unadjusted mortality, but similar adjusted mortality compared to those with 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 two quadrants involved.InterpretationMore than one-third of patients receiving mechanical ventilation have hypoxaemia and new infiltrates with a hospital mortality of 38.6%. Survival is dependent on the degree of pulmonary involvement whether or not ARDS criteria are reached.

Published
2021

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