A New Global Definition of Acute Respiratory Distress Syndrome.

Background: Since publication of the 2012 Berlin definition of acute respiratory distress syndrome (ARDS), several developments have supported the need for an expansion of the definition, including the use of high-flow nasal oxygen, the expansion of the use of pulse oximetry in place of arterial blood gases, the use of ultrasound for chest imaging, and the need for applicability in resource-limited settings. Methods: A consensus conference of 32 critical care ARDS experts was convened, had six virtual meetings (June 2021 to March 2022), and subsequently obtained input from members of several critical care societies. The goal was to develop a definition that would 1) identify patients with the currently accepted conceptual framework for ARDS, 2) facilitate rapid ARDS diagnosis for clinical care and research, 3) be applicable in resource-limited settings, 4) be useful for testing specific therapies, and 5) be practical for communication to patients and caregivers. Results: The committee made four main recommendations: 1) include high-flow nasal oxygen with a minimum flow rate of ⩾30 L/min; 2) use PaO2:FiO2 ⩽ 300 mm Hg or oxygen saturation as measured by pulse oximetry SpO2:FiO2 ⩽ 315 (if oxygen saturation as measured by pulse oximetry is ⩽97%) to identify hypoxemia; 3) retain bilateral opacities for imaging criteria but add ultrasound as an imaging modality, especially in resource-limited areas; and 4) in resource-limited settings, do not require positive end-expiratory pressure, oxygen flow rate, or specific respiratory support devices. Conclusions: We propose a new global definition of ARDS that builds on the Berlin definition. The recommendations also identify areas for future research, including the need for prospective assessments of the feasibility, reliability, and prognostic validity of the proposed global definition.

Monocyte chemotactic protein (MCP)-1 (CCL2) and its receptor (CCR2) are elevated in chronic heart failure facilitating lung monocyte infiltration and differentiation which may contribute to lung fibrosis.

BACKGROUND: Dyspnea, the cardinal manifestation of chronic heart failure (CHF), may reflect both pulmonary oedema and pulmonary remodeling resulting in tissue stiffening. Emerging evidence suggests that predominance of distinct phenotypes of alveolar and recruited macrophages, designated M1 and M2, may regulate the course of inflammatory tissue repair and remodeling in the lung. METHODS: In a CHF rat model, we found fibrotic reinforcement of the extracellular matrix with an increase in monocyte chemotactic protein (MCP)-1/CCL2 in bronchoalveolar lavage (BAL), corresponding to a 3-fold increase in recruited macrophages. In this clinical cross sectional study, we aimed to examine potential mediators of leukocyte activation and lung infiltration in parallel BAL and blood from CHF patients compared to non-CHF controls. RESULTS: Mini-BAL and peripheral blood samples were obtained from hospitalized CHF, acute decompensated CHF and non-CHF patients. CHF patients and decompensated CHF patients demonstrated increases from non-CHF patients in BAL MCP-1, as well as the M2 macrophage cytokines interleukin-10 and transforming growth factor-ß. BAL and plasma MCP-1 were significantly correlated; however, MCP-1 was 20-fold higher in epithelial lining fluid in BAL, indicative of an alveolar chemotactic gradient. An increase in transglutaminase 2 positive M2 macrophages in parallel with a decrease in the MCP-1 receptor, CC chemokine receptor 2 (CCR2), was apparent in BAL cells of CHF patients compared to non-CHF. CONCLUSION: These data suggest a pathway of MCP-1 mediated M2 macrophage prevalence in the lungs of CHF patients which may contribute to pulmonary fibrotic remodeling and consequent increased severity of dyspnea.

Improving health care efficiency one click at a time.

Computers are an integral component of modern hospitals. Mouse clicks are currently inherent to this use of computers. However, mouse clicks are not instantaneous. These clicks may be associated with significant costs. Estimated costs associated with 10 additional clicks per day for 20 000 staff exceed AU$500 000 annually. Workflow modifications that increase clicks should weigh the potential benefits of such changes against these costs. Future investigation of strategies to reduce low-value clicks may provide an avenue for health care savings.

ADMA and homoarginine independently predict mortality in critically ill patients.

BACKGROUND: Arginine metabolites are associated with cardiovascular and all-cause mortality in several patient groups. We investigated whether arginine metabolites are associated with mortality in patients with critical illness and whether associations are independent of other factors affecting prognosis in an Intensive Care Unit (ICU). METHODS: 1155 acutely unwell adult patients admitted to a mixed medical-surgical ICU were studied. Arginine, asymmetric dimethyl-l-arginine (ADMA), monomethyl-l-arginine (MMA), symmetric dimethyl-l-arginine (SDMA) and l-homoarginine were measured in a plasma sample collected at admission to ICU by liquid chromatography tandem mass spectrometry. Risk of death score was calculated using data submitted to the Australia and New Zealand Intensive Care Society. RESULTS: In this cohort, 163 patients (14.1%) died. ADMA (odds ratio = 1.159 (1.033-1.300) per 0.1 µmol/L increment, p = 0.012), homoarginine (odds ratio = 0.963 (0.934-0.992), p = 0.013) and risk of death score (odds ratio = 1.045 (1.037-1.053) per 1% increment, p < 0.001) were independently associated with mortality in ICU patients. The area under the receiver operator characteristic curve for risk of death score, ADMA and homoarginine combined for mortality was greater than for risk of death score alone (0.815 (95% CI 0.790-0.837) vs 0.796 (95% CI 0.781-0.820), p = 0.019). Other arginine metabolites were not independently associated with mortality. CONCLUSIONS: ADMA is positively and homoarginine negatively associated with mortality in ICU patients, independent of other clinical factors. Measuring ADMA and homoarginine may refine models to predict ICU mortality. Reducing ADMA and increasing homoarginine are potential therapeutic targets to reduce mortality in critically ill patients.

Hospital-acquired complications: the relative importance of hospital- and patient-related factors.

OBJECTIVE: To quantify the prevalence of hospital-acquired complications; to determine the relative influence of patient- and hospital-related factors on complication rates. DESIGN, PARTICIPANTS: Retrospective analysis of administrative data (Integrated South Australian Activity Collection; Victorian Admitted Episodes Dataset) for multiple-day acute care episodes for adults in public hospitals. SETTING: Thirty-eight major public hospitals in South Australia and Victoria, 2015-2018. MAIN OUTCOME MEASURES: Hospital-acquired complication rates, overall and by complication class, by hospital and hospital type (tertiary referral, major metropolitan service, major regional service); variance in rates (intra-class correlation coefficient, ICC) at the patient, hospital, and hospital type levels as surrogate measures of their influence on rates. RESULTS: Of 1 558 978 public hospital episodes (10 029 918 bed-days), 151 486 included a total of 214 286 hospital-acquired complications (9.72 [95% CI, 9.67-9.77] events per 100 episodes; 2.14 [95% CI, 2.13-2.15] events per 100 bed-days). Complication rates were highest in tertiary referral hospitals (12.7 [95% CI, 12.6-12.8] events per 100 episodes) and for episodes including intensive care components (37.1 [95% CI, 36.7-37.4] events per 100 episodes). For all complication classes, inter-hospital variation was determined more by patient factors (overall ICC, 0.55; 95% CI, 0.53-0.57) than by hospital factors (ICC, 0.04; 95% CI, 0.02-0.07) or hospital type (ICC, 0.01; 95% CI, 0.001-0.03). CONCLUSIONS: Hospital-acquired complications were recorded for 9.7% of hospital episodes, but patient-related factors played a greater role in determining their prevalence than the treating hospital.

Weaning Outcomes in Patients with Brain Injury.

BACKGROUND: Despite the need for specific weaning strategies in neurological patients, evidence is generally insufficient or lacking. We aimed to describe the evolution over time of weaning and extubation practices in patients with acute brain injury compared with patients who are mechanically ventilated (MV) due to other reasons. METHODS: We performed a secondary analysis of three prospective, observational, multicenter international studies conducted in 2004, 2010, and 2016 in adults who had need of invasive MV for more than 12 h. We collected data on baseline characteristics, variables related to management ventilator settings, and complications while patients were ventilated or until day 28. RESULTS: Among the 20,929 patients enrolled, we included 12,618 (60%) who started the weaning from MV, of whom 1722 (14%) were patients with acute brain injury. In the acutely brain-injured cohort, 538 patients (31%) did not undergo planned extubation, defined as the need for a tracheostomy without an attempt of extubation, accidental extubation, and death. Among the 1184 planned extubated patients with acute brain injury, 202 required reintubation (17%). Patients with acute brain injury had a higher odds for unplanned extubation (odds ratio [OR] 1.35, confidence interval for 95% [CI 95%] 1.19-1.54; p < 0.001), a higher odds of failure after the first attempt of weaning (spontaneous breathing trial or gradual reduction of ventilatory support; OR 1.14 [CI 95% 1.01-1.30; p = 0.03]), and a higher odds for reintubation (OR 1.41 [CI 95% 1.20-1.66; p < 0.001]) than patients without brain injury. Patients with hemorrhagic stroke had the highest odds for unplanned extubation (OR 1.47 [CI 95% 1.22-1.77; p < 0.001]), of failed extubation after the first attempt of weaning (OR 1.28 [CI 95% 1.06-1.55; p = 0.009]), and for reintubation (OR 1.49 [CI 95% 1.17-1.88; p < 0.001]). In relation to weaning evolution over time in patients with acute brain injury, the risk for unplanned extubation showed a downward trend; the risk for reintubation was not associated to time; and there was a significant increase in the percentage of patients who underwent extubation after the first attempt of weaning from MV. CONCLUSIONS: Patients with acute brain injury, compared with patients without brain injury, present higher odds of undergoing unplanned extubated after weaning was started, lower odds of being extubated after the first attempt, and a higher risk of reintubation.

Perspectives of patients, family members, health professionals and the public on the impact of COVID-19 on mental health.

BACKGROUND: The coronavirus (COVID-19) pandemic has seen a global surge in anxiety, depression, post-traumatic stress disorder (PTSD), and stress. AIMS: This study aimed to describe the perspectives of patients with COVID-19, their family, health professionals, and the general public on the impact of COVID-19 on mental health. METHODS: A secondary thematic analysis was conducted using data from the COVID-19 COS project. We extracted data on the perceived causes and impact of COVID-19 on mental health from an international survey and seven online consensus workshops. RESULTS: We identified four themes (with subthemes in parenthesis): anxiety amidst uncertainty (always on high alert, ebb and flow of recovery); anguish of a threatened future (intense frustration of a changed normality, facing loss of livelihood, trauma of ventilation, a troubling prognosis, confronting death); bearing responsibility for transmission (fear of spreading COVID-19 in public; overwhelming guilt of infecting a loved one); and suffering in isolation (severe solitude of quarantine, sick and alone, separation exacerbating grief). CONCLUSION: We found that the unpredictability of COVID-19, the fear of long-term health consequences, burden of guilt, and suffering in isolation profoundly impacted mental health. Clinical and public health interventions are needed to manage the psychological consequences arising from this pandemic.

Evolution Over Time of Ventilatory Management and Outcome of Patients With Neurologic Disease.

OBJECTIVES: To describe the changes in ventilator management over time in patients with neurologic disease at ICU admission and to estimate factors associated with 28-day hospital mortality. DESIGN: Secondary analysis of three prospective, observational, multicenter studies. SETTING: Cohort studies conducted in 2004, 2010, and 2016. PATIENTS: Adult patients who received mechanical ventilation for more than 12 hours. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among the 20,929 patients enrolled, we included 4,152 (20%) mechanically ventilated patients due to different neurologic diseases. Hemorrhagic stroke and brain trauma were the most common pathologies associated with the need for mechanical ventilation. Although volume-cycled ventilation remained the preferred ventilation mode, there was a significant (p < 0.001) increment in the use of pressure support ventilation. The proportion of patients receiving a protective lung ventilation strategy was increased over time: 47% in 2004, 63% in 2010, and 65% in 2016 (p < 0.001), as well as the duration of protective ventilation strategies: 406 days per 1,000 mechanical ventilation days in 2004, 523 days per 1,000 mechanical ventilation days in 2010, and 585 days per 1,000 mechanical ventilation days in 2016 (p < 0.001). There were no differences in the length of stay in the ICU, mortality in the ICU, and mortality in hospital from 2004 to 2016. Independent risk factors for 28-day mortality were age greater than 75 years, Simplified Acute Physiology Score II greater than 50, the occurrence of organ dysfunction within first 48 hours after brain injury, and specific neurologic diseases such as hemorrhagic stroke, ischemic stroke, and brain trauma. CONCLUSIONS: More lung-protective ventilatory strategies have been implemented over years in neurologic patients with no effect on pulmonary complications or on survival. We found several prognostic factors on mortality such as advanced age, the severity of the disease, organ dysfunctions, and the etiology of neurologic disease.

Core Outcome Measures for Trials in People With Coronavirus Disease 2019: Respiratory Failure, Multiorgan Failure, Shortness of Breath, and Recovery.

OBJECTIVES: Respiratory failure, multiple organ failure, shortness of breath, recovery, and mortality have been identified as critically important core outcomes by more than 9300 patients, health professionals, and the public from 111 countries in the global coronavirus disease 2019 core outcome set initiative. The aim of this project was to establish the core outcome measures for these domains for trials in coronavirus disease 2019. DESIGN: Three online consensus workshops were convened to establish outcome measures for the four core domains of respiratory failure, multiple organ failure, shortness of breath, and recovery. SETTING: International. PATIENTS: About 130 participants (patients, public, and health professionals) from 17 countries attended the three workshops. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Respiratory failure, assessed by the need for respiratory support based on the World Health Organization Clinical Progression Scale, was considered pragmatic, objective, and with broad applicability to various clinical scenarios. The Sequential Organ Failure Assessment was recommended for multiple organ failure, because it was routinely used in trials and clinical care, well validated, and feasible. The Modified Medical Research Council measure for shortness of breath, with minor adaptations (recall period of 24 hr to capture daily fluctuations and inclusion of activities to ensure relevance and to capture the extreme severity of shortness of breath in people with coronavirus disease 2019), was regarded as fit for purpose for this indication. The recovery measure was developed de novo and defined as the absence of symptoms, resumption of usual daily activities, and return to the previous state of health prior to the illness, using a 5-point Likert scale, and was endorsed. CONCLUSIONS: The coronavirus disease 2019 core outcome set recommended core outcome measures have content validity and are considered the most feasible and acceptable among existing measures. Implementation of the core outcome measures in trials in coronavirus disease 2019 will ensure consistency and relevance of the evidence to inform decision-making and care of patients with coronavirus disease 2019.

Bolus intravenous 0.9% saline leads to interstitial permeability pulmonary edema in healthy volunteers.

PURPOSE: Bolus intravenous administration of 0.9% saline has been associated with the development of pulmonary edema, and increased mortality. An animal model has previously demonstrated that rapid intravenous administration of 0.9% saline was associated with non-hydrostatic lung injury with increased lung lavage protein. We hypothesized that this non-hydrostatic effect would also occur in human volunteers. METHODS: In a randomized, cross-over study of 14 healthy male subjects, the lung lavage protein concentration and cardiorespiratory effects of an intervention with rapid intravenous administration of 30 mL/kg of 0.9% saline were compared with sham intervention. Bronchoalveolar lavage (BAL) was performed after fluid administration. Doppler echocardiography, lung ultrasound, pulmonary function tests, and blood sampling were performed before and after each intervention. RESULTS: The BAL total protein concentration was greater after 0.9% saline administration than with sham (196.1 µg/mL (SD 87.6) versus 129.8 µg/mL (SD 55.4), respectively (p = 0.020). Plasma angiopoietin-2 concentration was also increased to 2.26 ng/mL (SD 0.87) after 0.9% saline administration compared with sham 1.53 ng/mL (SD 0.69) (p < 0.001). There were small increases in stroke volume (from 58 mL (IQR 51-74) to 66 mL (IQR 58-74), p = 0.045) and Doppler echocardiography left ventricle E/e' ratio (from 5.0 (IQR 4.5-6.0) to 5.7 (IQR 5.3-6.3), p = 0.007), but no changes to right ventricular function. CONCLUSION: Rapid intravenous administration of 0.9% saline leads to interstitial permeability pulmonary edema in healthy human volunteers. Further research is now warranted to understand these effects in critically ill patients.

Machine learning predicts mortality based on analysis of ventilation parameters of critically ill patients: multi-centre validation.

BACKGROUND: Mechanical Ventilation (MV) is a complex and central treatment process in the care of critically ill patients. It influences acid-base balance and can also cause prognostically relevant biotrauma by generating forces and liberating reactive oxygen species, negatively affecting outcomes. In this work we evaluate the use of a Recurrent Neural Network (RNN) modelling to predict outcomes of mechanically ventilated patients, using standard mechanical ventilation parameters. METHODS: We performed our analysis on VENTILA dataset, an observational, prospective, international, multi-centre study, performed to investigate the effect of baseline characteristics and management changes over time on the all-cause mortality rate in mechanically ventilated patients in ICU. Our cohort includes 12,596 adult patients older than 18, associated with 12,755 distinct admissions in ICUs across 37 countries and receiving invasive and non-invasive mechanical ventilation. We carry out four different analysis. Initially we select typical mechanical ventilation parameters and evaluate the machine learning model on both, the overall cohort and a subgroup of patients admitted with respiratory disorders. Furthermore, we carry out sensitivity analysis to evaluate whether inclusion of variables related to the function of other organs, improve the predictive performance of the model for both the overall cohort as well as the subgroup of patients with respiratory disorders. RESULTS: Predictive performance of RNN-based model was higher with Area Under the Receiver Operating Characteristic (ROC) Curve (AUC) of 0.72 (± 0.01) and Average Precision (AP) of 0.57 (± 0.01) in comparison to RF and LR for the overall patient dataset. Higher predictive performance was recorded in the subgroup of patients admitted with respiratory disorders with AUC of 0.75 (± 0.02) and AP of 0.65 (± 0.03). Inclusion of function of other organs further improved the performance to AUC of 0.79 (± 0.01) and AP 0.68 (± 0.02) for the overall patient dataset and AUC of 0.79 (± 0.01) and AP 0.72 (± 0.02) for the subgroup with respiratory disorders. CONCLUSION: The RNN-based model demonstrated better performance than RF and LR in patients in mechanical ventilation and its subgroup admitted with respiratory disorders. Clinical studies are needed to evaluate whether it impacts decision-making and patient outcomes. TRIAL REGISTRATION: NCT02731898 ( https://clinicaltrials.gov/ct2/show/NCT02731898 ), prospectively registered on April 8, 2016.

Systemic Markers of Monocyte Activation in Acute Pulmonary Oedema.

BACKGROUND: Hydrostatic lung injury followed by pulmonary remodelling variably complicates cardiogenic acute pulmonary oedema (APO). Pulmonary remodelling may be regulated by the balance between distinct phenotypes of pulmonary macrophages; activated/inflammatory (M1), and reparative/anti-inflammatory (M2), derived from circulating monocyte populations. The aim of this study was to identify biomarkers in peripheral blood that are consistent with hydrostatic lung injury and pulmonary remodelling in APO and which follow the variable clinical course. METHODS: To examine peripheral markers of lung inflammation, resolution and remodelling, 18 patients, admitted to the intensive care unit (ICU) with a clinical diagnosis of APO, were enrolled. Admission, 12- and 24-hour post-admission bloods were assayed for cytokines by ELISA (R&D Systems, Minneapolis, MN, USA) and leukocyte surface markers by flow cytometry. RESULTS: Admission PaO2 to FiO2 ratio was positively correlated with Mon 2 (intermediate) monocyte prevalence, through increasing ratio of CD16+ monocytes to CD11b+ and CD40+ monocytes, and negatively correlated with Mon 1 (classical) monocyte prevalence, through decreasing ratio of CD16+ monocytes to CD62L+. Secondary cohort analysis compared 10 APO patients with established chronic heart failure (CHF) to eight without CHF. An increase in monocyte chemotactic peptide (MCP)-1, monocyte prevalence, and CD16-CD62L+ monocytes with CHF, all characteristic of monocyte activation to a Mon 1 phenotype, were found in the CHF APO patients. CONCLUSIONS: Increased systemic monocyte prevalence and expression of cell surface markers suggest a Mon 1 profile in CHF patients during episodes of APO. Future studies should define the role of systemic monocyte prevalence and activation in decompensated CHF.

Prospective Randomized Controlled Trial of Video- Versus Recall-Assisted Reflection in Simulation-Based Teaching on Acquisition and Retention of Airway Skills Among Trainees Intubating Critically Ill Patients.

OBJECTIVES: Conventionally, simulation-based teaching involves reflection on recalled events (recall-assisted reflection). Instead of recall, video-assisted reflection may reduce recall bias and improve skills retention by contributing to visual memory. Here, we test the hypothesis that when compared with recall, video-assisted reflection results in higher acquisition and retention of skills involved in airway management among junior critical care doctors. DESIGN: Randomized control trial. Participants were randomized 1:1 to video-assisted reflection or recall-assisted reflection group. SETTING: University-affiliated tertiary care center. SUBJECTS: Junior critical care doctors. INTERVENTION: Video-assisted reflection. MEASUREMENTS AND MAIN RESULTS: All participants underwent simulation-based teaching of technical and nontechnical airway skills involved in managing a critically ill patient. These skills were assessed before, post-workshop, and in the following fourth week, by two independent blinded assessors using a validated scoring tool. Quality of debrief was assessed using a validated questionnaire. Repeated-measures analysis of variance was used to assess time and group interaction. Forty doctors were randomized. At baseline, the groups had similar airway experience (p = 0.34) and skill scores (p = 0.97). There was a significant interaction between study groups and changes over time for total skill scores (F[2, 37] = 4.06; p = 0.02). Although both the study groups had similar and significant improvement in total skills scores at the postworkshop assessment, the decline in total skills scores at delayed assessment (F[1, 38] = 5.64; p = 0.02) was significantly more in the recall-assisted reflection group when compared with the video-assisted reflection group. This resulted in lower mean skill scores in the recall-assisted reflection group when compared with the video-assisted reflection group in the delayed assessment (89.45 [19.32] vs 110.10 [19.54]; p < 0.01). Better retention was predominantly in the nontechnical skills. The perceived quality of debrief was similar between the two groups. CONCLUSION: When compared with recall, video-assisted reflection resulted in similar improvement in airway skills, but better retention over time.

Relative Hyperglycemia Is an Independent Determinant of In-Hospital Mortality in Patients With Critical Illness.

OBJECTIVES: To determine whether relative hyperglycemia was associated with in-hospital mortality in critically ill patients independent of other prognostic variables and whether this association is affected by background glycemia. DESIGN: Prospective observational study. SETTING: Mixed medical-surgical ICU in a metropolitan teaching hospital. PATIENTS: From 2,617 admissions to ICU between January 27, 2016, and March 30, 2017, 1,262 consecutive patients who met inclusion and exclusion criteria were studied. INTERVENTIONS: Glycosylated hemoglobin was used to estimate average glucose concentration over the prior 3 months. Glucose concentration on ICU admission was divided by estimated average glucose concentration to calculate the stress hyperglycemia ratio, an index of relative glycemia. Risk of death score was calculated using data submitted to the Australia and New Zealand Intensive Care Society. MEASUREMENTS AND MAIN RESULTS: In this study, there were 186 deaths (14.7%). Admission glucose was significantly associated with mortality in univariate analysis (odds ratio = 1.08 per mmol/L glucose increment; p < 0.001) but not after adjustment for risk of death score (odds ratio = 1.01; p = 0.338). In contrast, stress hyperglycemia ratio was significantly associated with mortality both in univariate analysis (odds ratio = 1.09 per 0.1 stress hyperglycemia ratio increment; p < 0.001) and after adjustment for risk of death score (odds ratio = 1.03; p = 0.014). Unlike admission glucose concentration, stress hyperglycemia ratio was significantly associated with mortality in patients with glycosylated hemoglobin less than 6.5% (odds ratio = 1.08 per 0.1 stress hyperglycemia ratio increment; p < 0.001) and glycosylated hemoglobin greater than or equal to 6.5% (48 mmol/mol) (odds ratio = 1.08 per 0.1 stress hyperglycemia ratio increment; p = 0.005). CONCLUSIONS: Unlike absolute hyperglycemia, relative hyperglycemia, as assessed by the stress hyperglycemia ratio, independently predicts in-hospital mortality in critically ill patients across the glycemic spectrum. Future studies should investigate whether using measures of relative hyperglycemia to determine individualized glycemic treatment targets improves outcomes in ICU.

International Survey to Establish Prioritized Outcomes for Trials in People With Coronavirus Disease 2019.

OBJECTIVES: There are over 4,000 trials conducted in people with coronavirus disease 2019. However, the variability of outcomes and the omission of patient-centered outcomes may diminish the impact of these trials on decision-making. The aim of this study was to generate a consensus-based, prioritized list of outcomes for coronavirus disease 2019 trials. DESIGN: In an online survey conducted in English, Chinese, Italian, Portuguese, and Spanish languages, adults with coronavirus disease 2019, their family members, health professionals, and the general public rated the importance of outcomes using a 9-point Likert scale (7-9, critical importance) and completed a Best-Worst Scale to estimate relative importance. Participant comments were analyzed thematically. SETTING: International. SUBJECTS: Adults 18 years old and over with confirmed or suspected coronavirus disease 2019, their family members, members of the general public, and health professionals (including clinicians, policy makers, regulators, funders, and researchers). INTERVENTIONS: None. MEASUREMENTS: None. MAIN RESULTS: In total, 9,289 participants from 111 countries (776 people with coronavirus disease 2019 or family members, 4,882 health professionals, and 3,631 members of the public) completed the survey. The four outcomes of highest priority for all three groups were: mortality, respiratory failure, pneumonia, and organ failure. Lung function, lung scarring, sepsis, shortness of breath, and oxygen level in the blood were common to the top 10 outcomes across all three groups (mean > 7.5, median ≥ 8, and > 70% of respondents rated the outcome as critically important). Patients/family members rated fatigue, anxiety, chest pain, muscle pain, gastrointestinal problems, and cardiovascular disease higher than health professionals. Four themes underpinned prioritization: fear of life-threatening, debilitating, and permanent consequences; addressing knowledge gaps; enabling preparedness and planning; and tolerable or infrequent outcomes. CONCLUSIONS: Life-threatening respiratory and other organ outcomes were consistently highly prioritized by all stakeholder groups. Patients/family members gave higher priority to many patient-reported outcomes compared with health professionals.

Core Outcomes Set for Trials in People With Coronavirus Disease 2019.

OBJECTIVES: The outcomes reported in trials in coronavirus disease 2019 are extremely heterogeneous and of uncertain patient relevance, limiting their applicability for clinical decision-making. The aim of this workshop was to establish a core outcomes set for trials in people with suspected or confirmed coronavirus disease 2019. DESIGN: Four international online multistakeholder consensus workshops were convened to discuss proposed core outcomes for trials in people with suspected or confirmed coronavirus disease 2019, informed by a survey involving 9,289 respondents from 111 countries. The transcripts were analyzed thematically. The workshop recommendations were used to finalize the core outcomes set. SETTING: International. SUBJECTS: Adults 18 years old and over with confirmed or suspected coronavirus disease 2019, their family members, members of the general public and health professionals (including clinicians, policy makers, regulators, funders, researchers). INTERVENTIONS: None. MEASUREMENTS: None. MAIN RESULTS: Six themes were identified. "Responding to the critical and acute health crisis" reflected the immediate focus on saving lives and preventing life-threatening complications that underpinned the high prioritization of mortality, respiratory failure, and multiple organ failure. "Capturing different settings of care" highlighted the need to minimize the burden on hospitals and to acknowledge outcomes in community settings. "Encompassing the full trajectory and severity of disease" was addressing longer term impacts and the full spectrum of illness (e.g. shortness of breath and recovery). "Distinguishing overlap, correlation and collinearity" meant recognizing that symptoms such as shortness of breath had distinct value and minimizing overlap (e.g. lung function and pneumonia were on the continuum toward respiratory failure). "Recognizing adverse events" refers to the potential harms of new and evolving interventions. "Being cognizant of family and psychosocial wellbeing" reflected the pervasive impacts of coronavirus disease 2019. CONCLUSIONS: Mortality, respiratory failure, multiple organ failure, shortness of breath, and recovery are critically important outcomes to be consistently reported in coronavirus disease 2019 trials.

Reduced Surfactant Contributes to Increased Lung Stiffness Induced by Rapid Inspiratory Flow.

INTRODUCTION: The mechanism of fast inspiratory flow rate (VI') induced lung injury is unclear. As fast VI' increases hysteresis, a measure of surface tension at the air-liquid interface, surfactant release or function may be important. This experimental study examines the contribution of impaired surfactant release or function to dynamic-VILI. METHODS: Isolated perfused lungs from male Sprague Dawley rats were randomly allocated to four groups: a long or short inspiratory time (Ti = 0.5 s; slow VI' or Ti = 0.1 s; fast VI') at PEEP of 2 or 10 cmH2O. Tidal volume was constant (7 ml/kg), with f = 60 breath/min. Forced impedance mechanics (tissue elastance (Htis), tissue resistance (Gtis) and airway resistance (Raw) were measured at 30, 60 and 90 min following which the lung was lavaged for surfactant phospholipids (PL) and disaturated PL (DSP). RESULTS: Fast VI' resulted in a stiffer lung. Concurrently, PL and DSP were decreased in both tubular myelin rich and poor fractions. Phospholipid decreases were similar with PEEP. In a subsequent cohort, laser confocal microscopy-based assessment demonstrated increased cellular injury with increased VI' at both 30 and 90 min ventilation. CONCLUSION: Rapid VI' may contribute to ventilator induced lung injury (VILI) through reduced surfactant release and/or more rapid reuptake despite unchanged tidal stretch.

Maximal Recruitment Open Lung Ventilation in Acute Respiratory Distress Syndrome (PHARLAP). A Phase II, Multicenter Randomized Controlled Clinical Trial.

Rationale: Open lung ventilation strategies have been recommended in patients with acute respiratory distress syndrome (ARDS).Objectives: To determine whether a maximal lung recruitment strategy reduces ventilator-free days in patients with ARDS.Methods: A phase II, multicenter randomized controlled trial in adults with moderate to severe ARDS. Patients received maximal lung recruitment, titrated positive end expiratory pressure and further Vt limitation, or control "protective" ventilation.Measurements and Main Results: The primary outcome was ventilator-free days at Day 28. Secondary outcomes included mortality, barotrauma, new use of hypoxemic adjuvant therapies, and ICU and hospital stay. Enrollment halted October 2, 2017, after publication of ART (Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial), when 115 of a planned 340 patients had been randomized (57% male; mean age, 53.6 yr). At 28 days after randomization, there was no difference between the maximal lung recruitment and control ventilation strategies in ventilator-free days (median, 16 d [interquartile range (IQR), 0-21 d], n = 57, vs. 14.5 d [IQR, 0-21.5 d], n = 56; P = 0.95), mortality (24.6% [n = 14/56] vs. 26.8% [n = 15/56]; P = 0.79), or the rate of barotrauma (5.2% [n = 3/57] vs. 10.7% [n = 6/56]; P = 0.32). However, the intervention group showed reduced use of new hypoxemic adjuvant therapies (i.e., inhaled nitric oxide, extracorporeal membrane oxygenation, prone; median change from baseline 0 [IQR, 0-1] vs. 1 [IQR, 0-1]; P = 0.004) and increased rates of new cardiac arrhythmia (n = 17 [29%] vs. n = 7 [13%]; P = 0.03).Conclusions: Compared with control ventilation, maximal lung recruitment did not reduce the duration of ventilation-free days or mortality and was associated with increased cardiovascular adverse events but lower use of hypoxemic adjuvant therapies.Clinical trial registered with www.clinicaltrials.gov (NCT01667146).

Prevention and Amelioration of Rodent Ventilation-Induced Lung Injury with Either Prophylactic or Therapeutic feG Administration.

PURPOSE: Mechanical ventilation is a well-established therapy for patients with acute respiratory failure. However, up to 35% of mortality in acute respiratory distress syndrome may be attributed to ventilation-induced lung injury (VILI). We previously demonstrated the efficacy of the synthetic tripeptide feG for preventing and ameliorating acute pancreatitis-associated lung injury. However, as the mechanisms of induction of injury during mechanical ventilation may differ, we aimed to investigate the effect of feG in a rodent model of VILI, with or without secondary challenge, as a preventative treatment when administered before injury (prophylactic), or as a therapeutic treatment administered following initiation of injury (therapeutic). METHODS: Lung injury was assessed following prophylactic or therapeutic intratracheal feG administration in a rodent model of ventilation-induced lung injury, with or without secondary intratracheal lipopolysaccharide challenge. RESULTS: Prophylactic feG administration resulted in significant improvements in arterial blood oxygenation and respiratory mechanics, and decreased lung oedema, bronchoalveolar lavage protein concentration, histological tissue injury scores, blood vessel activation, bronchoalveolar lavage cell infiltration and lung myeloperoxidase activity in VILI, both with and without lipopolysaccharide. Therapeutic feG administration similarly ameliorated the severity of tissue damage and encouraged the resolution of injury. feG associated decreases in endothelial adhesion molecules may indicate a mechanism for these effects. CONCLUSIONS: This study supports the potential for feG as a pharmacological agent in the prevention or treatment of lung injury associated with mechanical ventilation.