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Abstract
Background Efficiency of randomised clinical trials of acute respiratory distress syndrome (ARDS) depends on the fraction of deaths attributable to ARDS (AFARDS) to which interventions are targeted. Estimates of AFARDS in subpopulations of ARDS could improve design of ARDS trials.
Methods We performed a matched case-control study using the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE cohort. Primary outcome was intensive care unit mortality. We used nearest neighbour propensity score matching without replacement to match ARDS to non-ARDS populations. We derived two separate AFARDS estimates by matching patients with ARDS to patients with non-acute hypoxaemic respiratory failure (non-AHRF) and to patients with AHRF with unilateral infiltrates only (AHRF-UL). We also estimated AFARDS in subgroups based on severity of hypoxaemia, number of lung quadrants involved and hyperinflammatory versus hypoinflammatory phenotypes. Additionally, we derived AFAHRF estimates by matching patients with AHRF to non-AHRF controls, and AFAHRF-UL estimates by matching patients with AHRF-UL to non-AHRF controls.
Results Estimated AFARDS was 20.9% (95% CI 10.5% to 31.4%) when compared with AHRF-UL controls and 38.0% (95% CI 34.4% to 41.6%) compared with non-AHRF controls. Within subgroups, estimates for AFARDS compared with AHRF-UL controls were highest in patients with severe hypoxaemia (41.1% (95% CI 25.2% to 57.1%)), in those with four quadrant involvement on chest radiography (28.9% (95% CI 13.4% to 44.3%)) and in the hyperinflammatory subphenotype (26.8% (95% CI 6.9% to 46.7%)). Estimated AFAHRF was 33.8% (95% CI 30.5% to 37.1%) compared with non-AHRF controls. Estimated AFAHRF-UL was 21.3% (95% CI 312.8% to 29.7%) compared with non-AHRF controls.
Conclusions Overall AFARDS mean values were between 20.9% and 38.0%, with higher AFARDS seen with severe hypoxaemia, four quadrant involvement on chest radiography and hyperinflammatory ARDS.
- ARDS
- clinical epidemiology
Data availability statement
Data may be obtained from a third party and are not publicly available. Requests for access to the LUNG-SAFE dataset should be submitted to research@esicm.org.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
The excess mortality—or attributable fraction (AF)—due to acute respiratory distress syndrome (ARDS) has been estimated to range between 15% and 37%.
We do not know how this varies by severity of hypoxaemia, radiographic findings and ARDS subphenotype.
WHAT THIS STUDY ADDS
We observed a dose-response increase in AFARDS with severity of hypoxaemia, quadrants of radiographic involvement and that AFARDS was higher in the hyperinflammatory compared with the hypoinflammatory subphenotype of ARDS.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
We highlight ARDS subpopulations that can inform enrichment options in randomised clinical trials.
Introduction
Acute respiratory distress syndrome (ARDS) refers to acute hypoxaemic respiratory failure (AHRF) occurring within 1 week of a known clinical insult, with bilateral opacities on chest radiography that are not fully explained by effusions, lobar/lung collapse or nodules.1 Treatments with biological plausibility2 and strong supporting preclinical evidence, when tested within randomised clinical trials (RCTs),3 often report statistically indeterminate results (ie, uncertainty highlighted by non-significant results of two-tailed tests, rather than proof of no difference between treatments (negative)4). Addressing this issue remains a major clinical and methodological challenge.2
There are several explanations for statistically indeterminate RCT results, aside from testing of ineffective treatments. First, as ARDS is a heterogeneous syndrome, RCTs may consist of participants who either benefit, have no effect or are harmed by the tested intervention. This explanation is supported by observations that distinct subphenotypes of ARDS respond differentially to treatments.5–11 Second, there are several design issues within ARDS RCTs. This explanation is supported by observations that sample size calculations overestimate control arm event rates, and the expected average treatment effect.12
In this manuscript, we explore another explanation—variation in the excess fraction of mortality attributable to ARDS (AFARDS)13 14 in RCT participants. Patients with ARDS may die from ARDS (ie, AFARDS) or with ARDS (ie, death may be due to risk factors like comorbidities and/or other organ dysfunction during critical illness). If we explicitly link the eligibility criteria of ARDS RCTs to AFARDS estimates (ie, the excess proportion of deaths from ARDS), then efficiency of ARDS RCTs would be increased from the generic predictive and prognostic enrichment alongside increase in average treatment effect. We hypothesised that AFARDS will vary by severity of hypoxaemia as per the Berlin ARDS definitions,1 15 by number of quadrants affected on chest radiography16 and by subphenotype. Our hypothesis was informed by the following observations: first, two small cohort studies (online supplemental eTable 1) indicated that AFARDS ranges between 15% and 37%17 18; second, in the Berlin ARDS definitions, ARDS outcomes worsened with increasing severity of hypoxaemia.1 Third, the hyperinflammatory ARDS subphenotype had higher mortality and greater treatment effect within RCTs.5–11 Recently, these ARDS subphenotypes were identified within the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG-SAFE) cohort using machine learning models,19 are available as predefined categories within the LUNG-SAFE dataset and currently there are no AFARDS estimates for them. Given recent proposals to include patients with AHRF (including those with unilateral infiltrates20) within an expanded ARDS case definition,21 we also compared AFAHRF and AFARDS.
Supplemental material
Methods
Data source
Our data source was the well-described LUNG-SAFE dataset. We summarise key elements of the LUNG-SAFE study design and data collection in online supplemental eMethods 1. National coordinators and site investigators of the LUNG-SAFE study are listed in the online supplemental file 1. AHRF was defined as concurrent presence of: (a) arterial oxygen tension:inspired fraction of oxygen (PaO2:FiO2) ratio ≤300 mm Hg; (b) new pulmonary parenchymal abnormalities (either unilateral or bilateral) on chest radiography and (c) ventilatory support with continuous positive airway pressure or expiratory positive airway pressure or positive end expiratory pressure ≥5 cmH2O. The diagnosis of ARDS in LUNG-SAFE studies was made by a computer algorithm in the analysis phase of the study using the ‘raw’ data that made up the various components of the Berlin ARDS definition.15
Study population
Selection criteria of AHRF/ARDS cohort reported in this manuscript were described previously by Pham et al.20 We defined four populations for our matched cohort study, after excluding patients with congestive heart failure: (1) patients with ARDS-AHRF who met the Berlin ARDS criteria, (2) patients with AHRF who met criteria for AHRF (and therefore includes all patients with ARDS), (3) patients with AHRF with unilateral infiltrates (AHRF-UL)—met criteria for AHRF but not ARDS and (4) non-AHRF controls—patients receiving non-invasive or invasive ventilation who did not meet criteria for AHRF (figure 1). The LUNG-SAFE study collected only the following variables for non-AHRF controls—age, sex, intensive care unit (ICU) length of stay and ICU mortality.
Flow chart of patients screened and included in the models used to generate overall and subpopulation estimates of AFARDS, AFAHRF and AFAHRF-UL. AF is the proportion of individuals with the outcome of interest, for example, death that can be attributed to the exposure, for example, ARDS. AFARDS=[(deaths in ARDS–deaths in non-ARDS)/deaths in ARDS]. Comparisons used to generate overall estimates for AFARDS, AFAHRF and AFAHRF-UL are shown in the black rectangles. Further details on each model, and the AF estimates generated are provided in the table. To generate subpopulation estimates, analysis was stratified by severity of hypoxaemia, maximum number of quadrants involved in the first 48 hours and ARDS subphenotype. *Non-respiratory Sequential Organ Failure Assessment score (as a marker of illness severity) was included as a covariate in the logistic regression model used to estimate AFARDS from propensity model 2. AF, attributable fraction; AHRF, acute hypoxaemic respiratory failure; AHRF-UL, acute hypoxaemic respiratory failure with unilateral infiltrates only; ARDS, acute respiratory distress syndrome; ICU, intensive care unit.
ARDS subphenotypes have recently been assigned in the LUNG-SAFE cohort using a clinical classifier model with a limited selection of predictor variables19 (online supplemental eMethods 2). Of note, this model used optimised probability cutoffs and did not use latent class analysis to assign subphenotypes. Patients without ARDS do not have subphenotype allocation.
There were no patients who had unilateral infiltrates without AHRF, to act as controls for AFAHRF range estimates, similar to the AFARDS range estimates we report.
Analyses framework
The primary exposure was either ARDS, or AHRF, or AHRF-UL. The primary outcome was ICU mortality, as one of the most reported outcomes in ARDS RCTs.3 Predefined enrichment categories within the primary exposures were severity of hypoxaemia, number of quadrants affected on chest radiography and subphenotypes. Due to the low proportion of missing data (online supplemental eTable 2a), without any discernible pattern of missingness, these data were assumed to be missing at random, and complete-case analyses were used for all models.
Estimation of AFARDS requires careful selection of controls and consideration of potential confounding variables. We estimated propensity scores for the exposures using logistic regression. We used nearest neighbour matching without replacement to match exposed patients to controls. With this approach, the mortality in the control groups within each prespecified ARDS severity category (severity of hypoxaemia, radiology and subphenotype) would also vary based on matching, enabling estimation of variation in AFARDS within these categories, along with AFARDS range.
Propensity score models and scenarios
Model 1 scenario
AFARDS could be reduced with treatment to mortality seen in ICU patients of similar age and sex without AHRF (one patient with ARDS was matched to two non-AHRF controls).
Model 2 scenario
AFARDS could be reduced with treatment to mortality seen in ICU patients with AHRF after accounting for variables commonly considered as part of eligibility criteria in ARDS RCTs at the time of randomisation such as age, sex, number of comorbidities, receipt of invasive mechanical ventilation and illness severity (one patient with ARDS was matched to one AHRF-UL control).
Model 3 scenario
AFAHRF could be reduced with treatment to mortality seen in ICU patients of similar age and sex without AHRF (one patient with AHRF was matched to two non-AHRF controls).
Model 4 scenario
AFAHRF-UL could be reduced with treatment to mortality seen in ICU patients of similar age and sex without AHRF scenario (one patient with AHRF-UL was matched to two non-AHRF controls).
Additional rationale for matching methods, covariate selection and assessment of each of four different propensity score models are available in figure 1, online supplemental eMethods 3 and online supplemental eFigure 1.
We used four separate logistic regression models to estimate AF (AFARDS, AFAHRF, AFAHRF-UL).
Estimation of AFARDS range
We used model 1 and model 2 to estimate the variation in AFARDS by severity of hypoxaemia categories (mild (PaO2:FiO2 >200 mm Hg); moderate (PaO2:FiO2 100–200 mm Hg) or severe (PaO2:FIO2 <100 mm Hg)); the number of quadrants involved radiographically in the first 48 hours after ICU admission (two, three or four), and the hyperinflammatory versus hypoinflammatory ARDS subphenotypes within LUNG-SAFE dataset.19
Estimation of AFAHRF
We used model 3 to estimate the variation in AFAHRF by severity of hypoxaemia categories (mild, moderate, severe), and the number of quadrants involved radiographically in the first 48 hours after ICU admission (two, three or four).
Estimation of AFAHRF-UL
We used model 4 to estimate the variation in AFAHRF-UL by severity of hypoxaemia categories (mild, moderate, severe), and the number of quadrants involved radiographically in the first 48 hours after ICU admission (one, two).
Simulating AFARDS-based sample size estimates for different enrichment subgroups
To illustrate how AFARDS can influence sample size estimation, we compared predicted sample size estimates from 28 published ARDS RCTs22–49 that used mortality as primary outcome (identified in our previous systematic review3) to simulated sample size estimates. We simulated sample size calculations for the scenario where AFARDS=100%, and for estimates of AFARDS from model 1 stratified by severity of hypoxaemia (mild, moderate or severe), maximum number of quadrants involved on chest radiography at 48 hours (two, three or four) and (c) subphenotype of ARDS (hyperinflammatory or hypoinflammatory). For all simulations, RCT control event rate was fixed at 40%, alpha at 0.05 and power at 0.80.
Sensitivity analysis
We report the following sensitivity analyses: (i) unmatched analyses in all four models to assess how matching—and therefore, exclusion of controls—affected overall and subpopulation estimates and (ii) used hospital mortality as outcome measure in model 2—instead of ICU mortality—to assess how choice of mortality timepoint affected overall and subpopulation estimates for AFARDS.
The χ2 test was used to assess linear trends in ICU mortality across subpopulations, and to assess relationship between enrichment categories. Reported p values are two-sided and p values <0.05 were considered statistically significant. All analyses were performed using R V.3.4.2 (AF,50 Matchit51 and tidyverse52 packages).
Results
Among 12 906 admissions who received ventilatory support in the ICU, we identified 3504 eligible patients with AHRF; 2653 met the Berlin ARDS criteria and 851 patients had AHRF-UL (figure 1). Missing data are summarised in online supplemental eTable 2a. Baseline characteristics and outcomes for patients with non-AHRF are summarised in online supplemental eTable 2b. Patients with mild hypoxaemia most often had two quadrant infiltrates, while patients with severe hypoxaemia had four quadrant infiltrates (online supplemental eTable 3a). There was no association between severity of hypoxaemia and ARDS subphenotype (online supplemental eTable 3b).
Model 1 scenario
Model 1 scenario compared 2653 patients with ARDS matched to 5306 non-AHRF controls. Patients with ARDS had higher ICU mortality compared with controls (34.8% vs 13.8%) (table 1). Significant linear trends in mortality were seen with severity of hypoxaemia category (mild 28.6% vs 13.2%; moderate 33.2% vs 14.6%; severe 43.0% vs 13.1%; χ2=32.7; p<0.001); and with increase in number of quadrants involved (two quadrants 27.7% vs 14.4%; three quadrants 34.7% vs 14.7%; four quadrants 40.6% vs 12.7%; χ2=90.9; p<0.001). The ICU mortality was higher for hyperinflammatory (51.7% vs 12.4%) and hypoinflammatory (28.0% vs 14.4%) ARDS, compared with non-AHRF controls (χ2=413.07; p<0.001).
Baseline characteristics of ARDS, AHRF, AHRF-UL and corresponding propensity matched control populations to derive attributable fraction
Model 2 scenario
Model 2 scenario compared 851 patients with ARDS with 851 AHRF-UL controls. Patients with ARDS had higher ICU mortality (34.4% vs 24.2%; p<0.001), with the higher control arm mortality compared with model 1 reflecting the differences in matching variables between the models (table 1). Similar to model 1, significant linear trends in mortality were seen with severity of hypoxaemia (mild 28.9% vs 19.3%; moderate 32.8% vs 28.5%; severe 44.5% vs 22.0%; χ2=58.3; p<0.001), and with increase in the number of quadrants in patients with ARDS compared with AHRF-UL controls, the absolute differences were lower compared with model 1 (mild 28.9% vs 19.3%; moderate 32.8% vs 28.5%; severe 44.5% vs 22.0%; χ2=51.5; p<0.001). The ICU mortality was higher for hyperinflammatory (50.6% vs 26.8%) and hypoinflammatory (28.2% vs 23.2%) ARDS subphenotypes, compared with matched non-AHRF controls (χ2=147.27; p<0.001).
Range of AFARDS and categories using model 1 and model 2
The AFARDS ranges between 38.0% (95% CI 34.4% to 41.6%) from model 1 (figure 2A) and 20.9% (95% CI 10.5 to 31.4%) from model 2 (figure 2B).
Overall and subpopulation estimates of AFARDS. (A) The fraction of deaths attributable to the ARDS exposure was ascertained using proportions. Propensity for ARDS logistic regression models were used to derive estimates for AFARDS in model 1. Bar graph shows the mortality difference between ARDS population compared with propensity matched non-AHRF controls (model 1). Analysis was then stratified by severity of hypoxaemia, maximum number of quadrants involved in the first 48 hours and ARDS hypoinflammatory/hyperinflammatory subphenotype. Subpopulation AFARDS estimates from model 1 are shown in the forest plot. (B) Propensity for ARDS logistic regression models were then used to derive estimates for AFARDS in model 2. Bar graph shows the mortality difference between ARDS population compared with propensity matched controls who had AHRF with unilateral infiltrates (model 2). Analysis was also stratified by severity of hypoxaemia, maximum number of quadrants involved in the first 48 hours and ARDS hypoinflammatory/hyperinflammatory subphenotype. Subpopulation AFARDS estimates from model 2 are shown in the forest plot. AF, attributable fraction; AHRF, acute hypoxaemic respiratory failure; ARDS, acute respiratory distress syndrome; ICU, intensive care unit; RD, risk difference.
AFARDS varies by severity of hypoxaemia
In model 1, AFARDS increased with worsening severity of hypoxaemia (mild=32.1% (95% CI 24.4% to 39.8%), moderate=36.7% (95% CI 29.4% to 44.1%), severe=49.7% (95% CI 43.4 to 55.9%)) (figure 2A).
Model 2 also highlighted increase in AFARDS with worsening severity of hypoxaemia (mild=25.7% (95% CI 6.1% to 45.3%), moderate=6.1% (95% CI −11.6% to 23.8%) and severe=41.1% (95% CI 25.2% to 57.1%) (figure 2B)).
AFARDS varies by number of quadrants involved on chest radiography
In model 1, AFARDS increased with number of quadrants involved on chest radiography (two=29.4% (95% CI 22.7% to 36.2%), three=38.1% (95% CI 30.8% to 45.4%), four=45.9% (95% CI 40.7% to 51.2%)) (figure 2A).
Model 2 also highlighted increase in AFARDS with number of quadrants involved on chest radiography (two=14.4% (95% CI −3.9% to 32.6%), three=17.9% (95% CI −4.2% to 40.0%), four=28.9% (95% CI 13.4% to 44.3%) (figure 2B)).
AFARDS was higher in hyperinflammatory subphenotype
In model 1, AFARDS was higher in hyperinflammatory subphenotype (hyperinflammatory=58.7% (95% CI 53.3% to 64.1%) vs hypoinflammatory=28.0% (95% CI 23.1% to 33.0%)) (figure 2A).
Model 2 also highlighted higher AFARDS hyperinflammatory subphenotype ((hyperinflammatory=28.6% (95% CI 6.9% to 46.7%) vs hypoinflammatory 17.4% (95% CI 4.5% to 30.2%)) (figure 2B).
Model 3 scenario estimating AFAHRF
Model 3 scenario compared 3504 patients with AHRF matched to 7008 non-AHRF controls. Patients with AHRF had higher ICU mortality compared with non-AHRF controls (31.7% vs 14.1%).
The estimated AFAHRF from model 3 was 33.8% (95% CI 30.5% to 37.1%), which is lower than the AFARDS from model 1 and higher than the AFARDS from model 2. These differences were reflected in the severity of hypoxaemia and radiography categories (figure 3A).
Overall and subpopulation estimates of AFAHRF and AFAHRF-UL. (A) Bar graphs show the mortality difference between AHRF population compared with propensity matched non-AHRF controls. AFAHRF estimates stratified by severity of hypoxaemia and maximum number of quadrants involved in the first 48 hours are shown in the forest plot. (B) Bar graphs show the mortality difference between AHRF-UL population compared with propensity matched non-AHRF controls. AFAHRF-UL estimates stratified by severity of hypoxaemia and maximum number of quadrants involved in the first 48 hours are shown in the forest plot. AF, attributable fraction; AHRF, acute hypoxaemic respiratory failure; AHRF-UL, acute hypoxaemic respiratory failure with unilateral infiltrates only; ICU, intensive care unit; RD, risk difference.
Model 4 scenario estimating AFAHRF-UL
Model 4 scenario compared 851 patients with AHRF-UL matched to 1702 non-AHRF controls. Patients with AHRF-UL had higher ICU mortality (24.2% vs 14.5%). The estimate of AFAHRF-UL was 21.3% (95% CI 12.8% to 29.7%), which was which lower than the AFARDS from model 1 and comparable to model 2 (figure 3B). In patients with unilateral, two-quadrant involvement, who would be excluded from ARDS RCTs, the estimate of AFAHRF-UL was 22.8% (95% CI 7.0% to 38.7%), which was comparable to AFARDS from model 2.
Sample size requirements for ARDS RCTs change with estimated AFARDS
As the AFARDS increases in a RCT population, the sample size required will decrease for prespecified alpha, beta and risk reduction combinations. For example, from our current work, sample size estimates were lower for severe hypoxaemia compared with mild or moderate hypoxaemia, and lower for four quadrant radiographic involvement, compared with two or three quadrant radiographic involvement, and lower for hyperinflammatory subphenotype, compared with hypoinflammatory subphenotype (figure 4).
Illustrative examples of sample size calculations for different AFARDS scenarios. These curves illustrate the AFARDS principle. Each curve represents the sample sizes required for different AF estimates (when control event rate is fixed at 40%). We show the estimates of AFARDS from model 1, stratified by (A) severity of hypoxaemia, (B) maximum number of quadrants involved on chest radiography at 48 hours and (C) subphenotype of ARDS. We contrast these against the common assumption that AFARDS is expected to be 100%. Dot plots represent ARDS RCTs with mortality as primary outcome identified previously in our systematic review12; they correspond to the actual RRR used for sample size estimation and sample size per group in these RCTs. Median (IQR) control group mortality used for sample size calculations in these RCTs was 45.0% (33.3%–52.5%) and RRR was 29.0% (24.5%–33.3%). Most trials aimed for 80% power and 5% alpha. The sample size per group varied between 53 and 704 patients. RCTs above a curve will have an adequate sample size to detect the predicted RRR. AF, attributable fraction; ARDS, acute respiratory distress syndrome; RCT, randomised controlled trial; RRR, relative risk reduction.
Sensitivity analyses
Overall unmatched estimates of AFARDS, AFAHRF and AFAHRF-UL were consistent with overall estimates from matched analyses. In the unmatched analyses of model 1, model 3 and model 4—which led to an increase in number of controls—trends within enrichment categories were no longer significant. In the unmatched analysis of model 2—which led to an increase in number of exposed patients with ARDS—trends within enrichment categories were consistent with the matched analysis (table 2).
Sensitivity analysis—overall and subpopulation estimates of AFARDS, AFAHRF and AFAHRF-UL
Overall estimate of AFARDS in model 2 was lower when hospital mortality was used as the outcome measure instead of ICU mortality; subpopulation estimates were also consistently lower, but overall trends within enrichment categories remained consistent (table 2).
Discussion
Using the LUNG-SAFE database, we report mean estimates of AFARDS between 20.9% and 38.0%. We observed a dose-response increase in AFARDS with severity of hypoxaemia and with quadrants of radiographic involvement. AFARDS was higher in the hyperinflammatory compared with the hypoinflammatory subphenotype of ARDS. Our results are consistent with previous work on AFARDS 17 18 and we have extended these previous works by modelling distinct clinical scenarios, including the value of incorporating patients with AHRF in the extended ARDS case definitions.21 Of note, our AFARDS estimates are consistent with a very different approach using marginal structural models, reported by Torres et al.17
We focused on several a priori defined ARDS subpopulations that have the potential for enrichment in clinical trials.53 From our previous work, higher all-cause control-arm mortality does not necessarily generate larger average treatment effects in ARDS RCTs,12 making us hypothesise that ARDS-specific enrichment subgroups may outperform generic illness severity-based prognostic enrichment.
Enrichment strategy, whether prognostic or predictive, is a trade-off between population prevalence, feasibility and expected treatment effect.54 In the LUNG-SAFE cohort, 23.6% of patients had severe ARDS, 36.7% had four-quadrant involvement and 36.4% were hyperinflammatory ARDS subphenotype. Severe hypoxaemia is a potentially implementable enrichment criteria for ARDS RCTs, by using the approach highlighted within the Kigali modification of the ARDS definitions.55 56 Furthermore, in previous RCTs of prone positioning and extracorporeal support,25 30 57 enriching on severe hypoxaemia has shown promise. Another element of the AHRF-ARDS debate is the interobserver and intraobserver reliability of chest radiology, and its feasibility in resource-limited settings. While acknowledging this debate,58 four-quadrant involvement appears to be an enrichment marker for high AFARDS.
Another enrichment strategy linked to precision medicine is the subphenotyping of ARDS, which would require either measuring discriminant biomarkers with near patient testing, or implementation of machine learning-derived classifier models incorporating clinically available data. Similar subphenoptypes have been reported in non-ARDS populations including COVID-19,6 AHRF and sepsis, which potentially broadens the implications of our findings.59 For illustration, we compared the sample size estimations from 28 ARDS RCTs22–49 that used mortality as a primary outcome, for different AFARDS scenarios (figure 4), which suggests that previous ARDS RCTs may lack sensitivity under the key assumption that only AFARDS deaths are affected by the tested treatment.
Our findings also lead us to consider how our work informs the debate on the need for distinction between ARDS and AHRF. Specifically, the estimate of AFAHRF-UL for patients with unilateral, two-quadrant involvement, who would be excluded currently from ARDS RCTs, was comparable to AFARDS from model 2. Currently, ARDS is conceptualised as a subset of AHRF; exclusion of patients with AHRF with similar AF and overlapping biology60 from the overall definition has implications for future RCTs and generalisability to clinical practice. Future research should explore the impact of including these populations in ARDS/AHRF RCTs.
Our analysis has strengths and limitations. We used the LUNG-SAFE dataset—a large multinational cohort recruited from 459 ICUs that was prospectively designed to enrol and follow-up patients with AHRF and which underwent systematic validation after data collection. Our assessment of enrichment categories used inclusion criteria that would be immediately applicable to inform design of ARDS RCTs. Despite the use of propensity score methods, residual confounding remains a concern, given the available characteristics of controls and because we have not accounted for differences in mortality between study site and countries. Although we have not accounted for risk factors for ARDS, type of comorbidity, potential worsening (or improvement) over time in hypoxaemia and geographic variations in usual care/outcomes in these analyses, eligibility criteria in ARDS RCTs seldom stipulate these covariates.3 The risk factor of ARDS limitation is explicit, as the LUNG-SAFE cohort did not collect ARDS risk factors for non-AHRF controls. Our primary and sensitivity analyses focus on mortality; the impact on other outcomes used in ARDS RCTs (such as ventilator-free days) needs to be assessed. An implicit assumption in these models is that the putative treatment for ARDS/AHRF has no effect on mortality of patients with non-ARDS/non-AHRF. This assumption would not bias AF-ARDS estimates, as the control groups in ARDS RCTs would either not receive the intervention or those who do, will be analysed as crossovers/intention-to-treat framework.
Conclusions
ARDS is associated with excess mortality in critically ill patients. Our results highlight generic enrichment populations based on commonly used ARDS RCT eligibility criteria such as severity of hypoxaemia, and number of quadrants involved in chest radiography. We show that hyperinflammatory ARDS subphenotype has higher attributable fraction.
Data availability statement
Data may be obtained from a third party and are not publicly available. Requests for access to the LUNG-SAFE dataset should be submitted to research@esicm.org.
Ethics statements
Patient consent for publication
Ethics approval
All participating ICUs individually obtained local ethics committee approval and obtained either patient consent or ethics committee waiver of consent in the original LUNG-SAFE study. Research ethics board approval for St. Michael’s Hospital (one of two lead sites) (REB# 13-384). Participants gave informed consent to participate in the study before taking part.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Twitter @saha_rohit, @charlot_summers, @msh_manu
Collaborators LUNG-SAFE Steering Committee: 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, LUNG-SAFE Executive Committee: John G. Laffey, Giacomo, Bellani, Tài Pham, Eddy Fan. LUNG-SAFE national coordinators: Argentina: Fernando Rios; Australia/New Zealand: Frank Van Haren; Belgium: Thierry Sottiaux, Pieter Depuydt; Bolivia: Fredy S. Lora; Brazil: Luciano Cesar Azevedo; Canada: Eddy Fan; Chile: Guillermo Bugedo; China: Haibo Qiu; Colombia: Marcos Gonzalez; Costa Rica: Juan Silesky; Czech Republic: Vladimir Cerny; Denmark: Jonas Nielsen; Ecuador: Manuel Jibaja; France: Tài Pham; Germany: Hermann Wrigge; Greece: Dimitrios Matamis; Guatemala: Jorge Luis Ranero; India: Pravin Amin; Iran: S.M. Hashemian; Ireland: Kevin Clarkson; Italy: Giacomo Bellani; Japan: Kiyoyasu Kurahashi; Mexico: Asisclo Villagomez; Morocco: Amine Ali Zeggwagh; The Netherlands: Leo M. Heunks; Norway: Jon Henrik Laake; The Philippines: Jose Emmanuel Palo; Portugal: Antero do Vale Fernandes; Romania: Dorel Sandesc; Saudi Arabia: Yaasen Arabi; Serbia: Vesna Bumbasierevic; Spain: Nicolas Nin, Jose A. Lorente; Sweden: Anders Larsson; Switzerland: Lise Piquilloud; Tunisia: Fekri Abroug; the UK: Daniel F. McAuley, Lia McNamee; Uruguay: Javier Hurtado; the USA: Ed Bajwa; Venezuela: Gabriel Démpaire. LUNG-SAFE site investigators (by country): Albania: Uhc Mother Theresa, Tirana: Hektor Sula, Lordian Nunci; University Hospital Shefqet Ndroqi, Tirana: Alma Cani; Argentina: Clinica de Especialidades, Villa Maria: Alan Zazu; Hospital Julio C. Perrando, Resistencia: Christian Dellera, Carolina S. Insaurralde; Sanatorio Las Lomas, San Isidro, Buenos Aires: Risso V. Alejandro; Sanatorio de La Trinidad San Isidro, San Isidro: Julio Daldin, Mauricio Vinzio; Hospital Español de Mendoza, Godoy Cruz-Mendoza: Ruben O. Fernandez; Hospital del Centenario, Rosario: Luis P. Cardonnet, Lisandro R. Bettini; San Antonio, Gualeguay, Entre Rios: Mariano Carboni Bisso, Emilio M. Osman; Cemic, Buenos Aires: Mariano G. Setten, Pablo Lovazzano; Hospital Universitrario Austral, Pilar: Javier Alvarez, Veronica Villar; Hospital Por + Salud, Pami Cesar Milstein, Buenos Aires: Norberto C. Pozo, Nicolas Grubissich; Sanatorio Anchorena, Buenos Aires: Gustavo A. Plotnikow, Daniela N. Vasquez; Sanatorio de La Trinidad Mitre, Buenos Aires: Santiago Ilutovich, Norberto Tiribelli; Hospital Luis agomaggiore, Mendoza: Ariel Chena, Carlos A. Pellegrini; Hospital Interzonal General de Agudos, San Martín, La Plata: María G. Saenz, Elisa Estenssoro; Hospital Misericordia, Cordoba: Matias Brizuela, Hernan Gianinetto; Sanatorio Juncal, Temperley: Pablo E. Gomez, Valeria I. Cerrato; Hospital D.F. Santojanni, Buenos Aires: Marco G. Bezzi, Silvina A. Borello; Hospital Alejandro Posadas, Buenos Aires: Flavia A. Loiacono, Adriana M. Fernandez; Australia: St. Vincent’s Hospital, Sydney: Serena Knowles, Claire Reynolds; St. George Public Hospital, Kogarah: Deborah M. Inskip, Jennene J. Miller; Westmead Hospital, Westmead: Jing Kong, Christina Whitehead; Flinders Medical Center, Bedford Park: Shailesh Bihari; John Hunter Hospital, Newcastle: Aylin Seven, Amanda Krstevski; Canberra Hospital, Garran: Helen J. Rodgers, Rebecca T. Millar; Calvary Mater Newcastle, Waratah: Toni E. Mckenna, Irene M. Bailey; Cabrini Hospital, Melbourne: Gabrielle C. Hanlon; Liverpool Hospital, Liverpool: Anders Aneman, Joan M. Lynch; Coffs Harbour Health Campus, Coffs Harbour: Raman Azad, John Neal; Sir Charles Gairdner Hospital, Nedlands: Paul W. Woods, Brigit L. Roberts; Concord Hospital, Concord: Mark R. Kol, Helen S. Wong; Austria: General Hospital of Vienna/Medical University of Vienna, Vienna: Katharina C. Riss, Thomas Staudinger; Belgium: Cliniques Universitaires St. Luc, Université Catholique de Louvain, Brussels: Xavier Wittebole, Caroline Berghe; Center Hospitalier Universitaire DinantGodinne, Yvoir: Pierre A. Bulpa, Alain M. Dive; Acuut Ziekenhuis Sint Augustinus Veurne, Veurne: Rik Verstraete, Herve Lebbinck; Ghent University Hospital, Ghent: Pieter Depuydt, Joris Vermassen; University Hospitals Leuven, Leuven: Philippe Meersseman, Helga Ceunen; Brazil: Hospital Renascentista, Pouso Alegre: Jonas I. Rosa, Daniel O. Beraldo; Vitoria Apart Hospital, Serra: Claudio Piras, Adenilton M. Rampinelli; Hospital Das Clinicas, São Paulo: Antonio P. Nassar, Jr.; Hospital Geral Do Grajaù, São Paulo: Sergio Mataloun, Marcelo Moock; Evangelical Hospital, Cachoeiro de Itapemirim/Espírito Santo: Marlus M. Thompson, Claudio H. Gonçalves; Hospital Moinhos de Vento, Porto Alegre: Ana Carolina P. Antônio, Aline Ascoli; Hospital Alvorada Taguatinga, Taguatinga: Rodrigo S. Biondi, Danielle C. Fontenele; Complexo Hospitalar Mngabeira Tarcisio Burity, Joao Pessoa: Danielle Nobrega, Vanessa M. Sales; Brunei: Raja Isteri Pengiran Anak Saleha Hospital, Bandar Seri Begawan: Ahmad Yazid Bin HJ Abul Wahab, Maizatul Ismail, Suresh Shindhe; Canada: Medical-Surgical Intensive Care Unit of St. Michael’s Hospital, Toronto: John Laffey, Francois Beloncle; St. Joseph’s Health Center, Toronto: Kyle G. Davies, Rob Cirone; Sunnybrook Health Sciences Center, Toronto: Venika Manoharan, Mehvish Ismail; Toronto Western Hospital, Toronto: Ewan C. Goligher, Mandeep Jassal; Medical Surgical Intensive Care Unit of the Toronto General Hospital, Toronto: Erin Nishikawa, Areej Javeed; Cardiovascular Intensive Care Unit of St. Michael’s Hospital, Toronto: Gerard Curley, Nuttapol Rittayamai; Cardiovascular Intensive Care Unit of the Toronto General Hospital, Toronto: Matteo Parotto, Niall D. Ferguson; Mount Sinai Hospital, Toronto: Sangeeta Mehta, Jenny Knoll; Trauma-Neuro Intensive Care Unit of St. Michael’s Hospital, Toronto: Antoine Pronovost, Sergio Canestrini; Chile: Hospital Clínico Pontificia Universidad Católica de Chile, Santiago: Alejandro R. Bruhn, Patricio H. Garcia; Hospital Militar de Santiago, Santiago: Felipe A. Aliaga, Pamela A. Farías; Clinica Davila, Santiago: Jacob S. Yumha; Hospital Guillermo Grant Benavente, Concepcion: Claudia A. Ortiz, Javier E. Salas; Clinica Las Lilas, Santiago: Alejandro A. Saez, Luis D. Vega; Hospital Naval Almirante Nef, Viña del Mar: Eduardo F. Labarca, Felipe T. Martinez; Hospital Luis Tisné Brousse, Penanolen: Nicolás G. Carreño, Pilar Lora; China: Second Affiliated Hospital of Harbin Medical University, Harbin: Haitao Liu; Nanjing Zhong-da Hospital, Southeast University, Nanjing: Haibo Qiu, Ling Liu; First Affiliated Hospital of Anhui Medical University, Hefei: Rui/Tang, Xiaoming Luo; Peking University People’s Hospital, Beijing: Youzhong An, Huiying Zhao; Fourth Affiliated Hospital of Harbin Medical University, Harbin: Yan Gao, Zhe Zhai; Nanjing Jiangbei People’s Hospital Affiliated to Medical School of Southeast University, Nanjing: Zheng L. Ye, Wei Wang; First Affiliated Hospital of Dalian Medical University, Dalian: Wenwen Li, Qingdong Li; Subei People’s Hospital of Jiangsu Province, Yanghzou: Ruiqiang Zheng; Jinling Hospital, Nanjing: Wenkui Yu, Juanhong Shen; Urumqi General Hospital, Urumqi: Xinyu Li; Intensive Care Unit, First Affiliated Hospital of Wanna Medical College, Yijishan Hospital, Wuhu: Tao Yu, Weihua Lu; Sichuan Provincial People’s Hospital, Chengdu: Ya Q. Wu, Xiao B. Huang; Hainan Province People’s Hospital, Haikou: Zhenyang He; People’s Hospital of Jiangxi Province, Nanchang: Yuanhua Lu; Qilu Hospital of Shandong University, Jinan: Hui Han, Fan Zhang; Zhejiang Provincial People’s Hospital, Hangzhou: Renhua Sun; First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui: Hua X. Wang, Shu H. Qin; Nanjing Municipal Government Hospital, Nanjing: Bao H. Zhu, Jun Zhao; First Hospital of Lanzhou University, Lanzhou: Jian Liu, Bin Li; First Affiliated Hospital of Chongqing University of Medical Science, Chongqing: Jing L. Liu, Fa C. Zhou; Xuzhou Central Hospital, Xuzhou: Qiong J. Li, Xing Y. Zhang; First People’s Hospital of Foshan, Foshan: Zhou Li-Xin, Qiang Xin-Hua; First Affiliated Hospital of Guangxi Medical University, Nanning: Liangyan Jiang; Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai: Yuan N. Gao, Xian Y. Zhao; First Hospital of Shanxi Medical University, Taiyuan: Yuan Y. Li, Xiao L. Li; Shandong Provincial Hospital, Jinan: Chunting Wang, Qingchun Yao; Fujian Provincial Hospital, Fuzhou: Rongguo Yu, Kai Chen; Henan Provincial People’s Hospital, Zhengzhou: Huanzhang Shao, Bingyu Qin; Second Affiliated Hospital of Kunming Medical University, Kunming City: Qing Q. Huang, Wei H. Zhu; Xiangya Hospital, Central South University, Changsha: Ai Y. Hang, Ma X. Hua; First Affiliated Hospital of Guangzhou Medical University, Guangzhou: Yimin Li, Yonghao Xu; People’s Hospital of Hebei Province, Shijiazhuang: Yu D. Di, Long L. Ling; Guangdong General Hospital, Guangzhou: Tie H. Qin, Shou H. Wang; Beijing Tongren Hospital, Beijing: Junping Qin; Jiangsu Province Hospital, Nanjing: Yi Han, Suming Zhou Colombia: Fundación Valle del Lili, Cali: Monica P. Vargas; Costa Rica: Hospital San Juan De Dios, San Jose: Juan I. Silesky Jimenez, Manuel A. González Rojas, Jaime E. SolisQuesada, Christian M. Ramirez-Alfaro; Czech Republic: University Hospital of Ostrava, Ostrava: Jan Máca, Peter Sklienka; Denmark: Aarhus Universitetshospital, Aarhus: Jakob Gjedsted, Aage Christiansen; Rigshopitalet: Jonas Nielsen; Ecuador: Hospital Militar, Quito: Boris G. Villamagua, iguel Llano; France: Clinique du Millenaire, Montpellier: Philippe Burtin, Gautier Buzancais; Center Hospitalier, Roanne: Pascal Beuret, Nicolas Pelletier; Center Hospitalier Universitaire d’Angers, Angers: Satar Mortaza, Alain Mercat; Hôpital Marc Jacquet, Melun: Jonathan Chelly, Sébastien Jochmans; Center Hospitalier Universitaire Caen, Caen: Nicolas Terzi, Cédric Daubin; Henri Mondor Hospital, Créteil: Guillaume Carteaux, Nicolas de Prost; Cochin Hospital, Paris: Jean-Daniel Chiche, Fabrice Daviaud; Hôpital Tenon, Paris: Tài Pham, Muriel Fartoukh; CH Mulhouse-Emile Muller, Mulhouse: Guillaume Barberet, Jerome Biehler; Archet 1 University Hospital, Nice: Jean Dellamonica, Denis Doyen; Hopital Sainte Musse, Toulon: Jean-Michel Arnal, Anais Briquet; Hopital Nord–Réanimation des Détresses Respiratoires et Infections Sévères, Marseille: Sami Hraiech, Laurent Papazian; Hôpital Européen Georges Pompidou, Paris: Arnaud Follin; Louis Mourier Hospital, Colombes: Damien Roux, Jonathan Messika; Center Hospitalier deDax, Dax: Evangelos Kalaitzis; Réanimation Médicale, Groupe Hospitalier Pitié-Salpêtrière, Paris: Laurence Dangers, Alain Combes; Assistance Publique-Hôpitaux de Paris Ambroise Paré, Boulogne-Billancourt: Siu-Ming Au; University Hospital Rouen, Rouen: Gaetan Béduneau, Dorothée Carpentier; Center Hospitalier Universitaire Amiens, Amiens–Salouel: Elie H. Zogheib, Herve Dupont; Center Hospitalier Intercommunal Robert Ballanger, Aulnay-sous-Bois: Sylvie Ricome, Francesco L. Santoli; Center Hospitalier René Dubos, Pontoise: Sebastien L. Besset; Center Hospitalier Intercommunal Portes de l’Oise, Beaumont-sur-Oise: Philippe Michel, Bruno Gelée; Archet 2 University Hospital, Nice: Pierre-Eric Danin, Bernard Goubaux; Center Hospitalier Pierre Oudot, Bourgoin Jallieu: Philippe J. Crova, Nga T. Phan; Center Hospitalier Dunkerque, Dunkerque: Frantz Berkelmans; Center Hospitalier de Belfort Montbéliard, Belfort: Julio C. Badie, Romain Tapponnier; Center Hospitalier Emile Muller, Mulhouse: Josette Gally, Samy Khebbeb; Hôpital de Hautepierre-Hôpitaux Universitaires de Strasbourg, Strasbourg: Jean-Etienne Herbrecht, Francis Schneider; Center Hospitalier de Dieppe, Dieppe: PierreLouis M. Declercq, Jean-Philippe Rigaud; Bicetre, Le Kremin–Bicetre: Jacques Duranteau, Anatole Harrois; Center Hospitalier Universitaire Gabriel Montpied, Clermont-Ferrand: Russell Chabanne, Julien Marin; Center Hospitalier Universitaire Estaing, Clermont-Ferrand: Charlene Bigot, Sandrine Thibault; Center Hospitalier Intercommunal Eure-Seine Evreux, Evreux: Mohammed Ghazi, Messabi Boukhazna; Center Hospitalier de Châlons en Champagne, Châlons en Champagne: Salem Ould Zein; CH Beauvais, Beauvais: Jack R. Richecoeur, Daniele M. Combaux; Center Hospitalier Le Mans, Le Mans: Fabien Grelon, Charlene Le Moal; Hôpital Fleyriat, Bourg-en-Bresse: Elise P. Sauvadet, Adrien Robine; Hôpital Saint Louis, Paris: Virginie Lemiale, Danielle Reuter; Service de Pneumologie Pitié-Salpétrière, Paris: Martin Dres, Alexandre Demoule; Center Hospitalier Gonesse, Gonesse: Dany Goldgran-Toledano; Hôpital Croix Rousse, Lyon: Loredana Baboi, Claude Guérin; Germany: St. Nikolaus-Stiftshospital, Andernach: Ralph Lohner; Fachkrankenhaus Coswig Gmbh, Coswig: Jens Kraßler, Susanne Schäfer; University Hospital Frankfurt, Frankfurt am Main: Kai D. Zacharowski, Patrick Meybohm; Department of Anesthesia and Intensive Care Medicine, University Hospital of Leipzig, Leipzig: Andreas W. Reske, Philipp Simon; Asklepios Klinik Langen, Langen: HansBernd F. Hopf, Michael Schuetz; Städtisches Krankenhaus Heinsberg, Heinsberg: Thomas Baltus; Greece: Hippokrateion General Hospital of Athens, Athens: Metaxia N. Papanikolaou, Theonymfi G. Papavasilopoulou; Gh Ahepa, Thessaloniki: Giannis A. Zacharas, Vasilis Ourailogloy; Hippokration General Hospital of Thessaloniki, Thessaloniki: Eleni K. Mouloudi, Eleni V. Massa; Hospital General of Kavala, Kavala: Eva O. Nagy, Electra E. Stamou; Papageorgiou General Hospital, Thessaloniki: Ellada V. Kiourtzieva, Marina A. Oikonomou; Guatemala: Hospital General de Enfermedades, Instituto Guatemalteco de Seguridad Social, Ciudad de Guatemala: Luis E. Avila; Centro Médico Militar, Guatemala: Cesar A. Cortez, Johanna E. Citalán; India: Deenanath Mangeshkar Hospital and Research Center, Pune: Sameer A. Jog, Safal D. Sable; Care Institute of Medical Sciences Hospital, Ahmedabad: Bhagyesh Shah; Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow: Mohan Gurjar, Arvind K. Baronia; Rajasthan Hospital, Ahmedabad: Mohammedfaruk Memon; National Institute of Mental Health and Neuro Sciences, Bangalore: Radhakrishnan Muthuchellappan, Venkatapura J. Ramesh; Anesthesiology Unit of the Kasturba Medical College and Department of Respiratory Therapy, School of Allied Health Sciences, Manipal University, Manipal: Anitha Shenoy, Ramesh Unnikrishnan; Sanjeevan Hospital, Pune: Subhal B. Dixit, Rachana V. Rhayakar; Apollo Hospitals, Chennai: Nagarajan Ramakrishnan,Vallish K. Bhardwaj; Medicine Unit of the Kasturba Medical College and Department of Respiratory Therapy, School of Allied Health Sciences, Manipal University, Manipal: Heera L. Mahto, Sudha V. Sagar; G. Kuppuswamy Naidu Memorial Hospital, Coimbatore: Vijayanand Palaniswamy, Deeban Ganesan; Iran: National Research Institute of Tuberculosis and Lung Disease/Masih Daneshvari, Tehran: Seyed Mohammadreza Hashemian, Hamidreza Jamaati; Milad Hospital, Tehran: Farshad Heidari; Ireland: St. Vincent’s University Hospital, Dublin: Edel A. Meaney, Alistair Nichol; Mercy University Hospital, Cork: Karl M. Knapman, Donall O’Croinin; Cork University Hospital, Cork: Eimhin S. Dunne, Dorothy M. Breen; Galway University Hospital, Galway: Kevin P. Clarkson, Rola F. Jaafar; Beaumont Hospital, Dublin: Rory Dwyer, Fahd Amir; Mater Misericordiae University Hospital, Dublin: Olaitan O. Ajetunmobi, Aogan C. O’Muircheartaigh; Tallaght Hospital, Dublin: Colin S. Black, Nuala Treanor; Saint James’s Hospital, Dublin: Daniel V. Collins, Wahid Altaf; Italy: Santa Maria delle Croci Hospital, Ravenna: Gianluca Zani, Maurizio Fusari; Arcispedale Sant’AnnaFerrara, Ferrara: Savino Spadaro, Carlo A. Volta; Ospedale Profili, Fabriano, Ancona: Romano Graziani, Barbara Brunettini; Umberto I. Nocera Inferiore, Nocera Inferiore Salerno: Salvatore Palmese; Azienda Ospedaliera San Paolo–Polo Universitario–Università degli Studi di Milano, Milan: Paolo Formenti, Michele Umbrello; Sant’Anna, San Fermo Della Battaglia, Como: Andrea Lombardo; Spedali Civili Brescia, Brescia: Elisabetta Pecci, Marco Botteri; Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca Granda, Ospedale Maggiore Policlinico, Milan: Monica Savioli, Alessandro Protti; University Campus Bio-Medico of Rome, Rome: Alessia Mattei, Lorenzo Schiavoni; Azienda Ospedaliera 'Mellino Mellini', Chiari, Brescia: Andrea Tinnirello, Manuel Todeschini; Policlinico P. Giaccone, University of Palermo, Palermo: Antonino Giarratano, Andrea Cortegiani; Niguarda Cà Granda Hospital, Milan: Sara Sher, Anna Rossi; A. Gemelli University Hospital, Rome: Massimo M. Antonelli, Luca M. Montini; Ospedale 'Sandro Pertini', Rome: Paolo Casalena, Sergio Scafetti; Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione; Istituto Di Ricovero e Cura a Carattere Scientifico; University of Pittsburgh Medical Center, Palermo: Giovanna Panarello, Giovanna Occhipinti; Ospedale San Gerardo, Monza: Nicolò Patroniti, Matteo Pozzi; Santa Maria Della Scaletta, Imola: Roberto R. Biscione, Michela M. Poli; Humanitas Research Hospital, Rozzano: Ferdinando Raimondi, Daniela Albiero; Ospedale Desio–Ao Desio-Vimercate, Desio: Giulia Crapelli, Eduardo Beck; Pinetagrande Private Hospital, Castelvolturno: Vincenzo Pota, Vincenzo Schiavone; Istituto di Ricovero e Cura a Carattere Scientifico San Martino Ist, Genova: Alexandre Molin, Fabio Tarantino; Ospedale San Raffaele, Milano: Giacomo Monti, Elena Frati; Ospedali Riuniti DiFoggia, Foggia: Lucia Mirabella, Gilda Cinnella; Azienda Ospedaliera Luigi Sacco–Polo Universitario, Milano: Tommaso Fossali, Riccardo Colombo; Azienda OspedalieroUniversitaria Città della Salute e della Scienza di Torino, Turin: Pierpaolo Terragni Ilaria Pattarino; Università degli Studi di Pavia-Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia: Francesco Mojoli, Antonio Braschi; Ao Ospedale Civile Legnano, Legnano: Erika E. Borotto; Arnas Ospedale Civico Di Cristina Benfratelli, Palermo: Andrea N. Cracchiolo, Daniela M. Palma; Azienda Ospedaliera Della Provincia DiLecco–Ospedale 'A. Manzoni', Lecco: Francesco Raponi, Giuseppe Foti; A.O. Provincia Di Lecco–Ospedale Alessandro Manzoni, Lecco: Ettore R. Vascotto, Andrea Coppadoro; Cliniche Universitarie Sassari, Sassari: Luca Brazzi, Leda Floris; Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia: Giorgio A. Iotti, Aaron Venti; Japan: Yokohama City University Hospital, Yokohama: Osamu Yamaguchi, Shunsuke Takagi; Toyooka Hospital, Toyooka City: Hiroki N. Maeyama; Chiba University Hospital, Chiba City: Eizo Watanabe, Yoshihiro Yamaji; Okayma University Hospital, Okayama: Kazuyoshi Shimizu, Kyoko Shiozaki; Japanese Foundation for Cancer Research, Cancer Institute Hospital, Department of Emergency Medicine and Critical Care, Tokyo: Satoru Futami; Ibaraki Prefectural Central Hospital, Kasama: Sekine Ryosuke; Tohoku University Hospital, Sendai-Shi: Koji Saito, Yoshinobu Kameyama; Tokyo Medical University Hachioji Medical Center, Hachioji, Tokyo: Keiko Ueno; Tokushima University Hospital, Tokushima: Masayo. Izawa, Nao Okuda; Maebashi Red Cross Hospital, Gunma Maebashi: Hiroyuki Suzuki, Tomofumi Harasawa; Urasoe General Hospital, Urasoe: Michitaka Nasu, Tadaaki Takada; Ohta General Hospital Foundation Ohta Nishinouchi Hospital, Fukushima: Fumihito Ito; Jichi Medical University Hospital, Shimotsuke: Shin Nunomiya, Kansuke Koyama; Mito Kyodo General Hospital, Tsukuba University Hospital Mito Medical Center, Mito: Toshikazu Abe; Sendai City Hospital, Sendai: Kohkichi Andoh, Kohei Kusumoto; Ja Hiroshima General Hospital, Hatsukaichi City, Hiroshima: Akira Hirata, Akihiro Takaba; Yokohama Rosai Hospital, Yokohama: Hiroyasu Kimura; Nagasaki University Hospital, Nagasaki: Shuhei Matsumoto, Ushio Higashijima; Niigata University Medical and Dental Hospital, Niigata: Hiroyuki Honda, Nobumasa Aoki; Mie University Hospital, Tsu, Mie: Hiroshi Imai; Yamaguchi University Hospital, Ube, Yamaguchi: Yasuaki Ogino, Ichiko Mizuguchi; Saiseikai Kumamoto Hospital, Kumamoto City: Kazuya Ichikado; Shinshu University School of Medicine, Matsumoto City: Kenichi Nitta, Katsunori Mochizuki; Kuki General Hospital, Kuki: Tomoaki Hashida; Kyoto Medical Center, Kyoto: Hiroyuki Tanaka; Fujita Health University, Toyoake: Tomoyuki Nakamura, Daisuke Niimi; Rakwakai Marutamachi Hospital, Kyoto: Takeshi Ueda; Osaka University Hospital, Suita City, Osaka Prefecture: Yozo Kashiwa, Akinori Uchiyama; Latvia: Paul Stradins Clinical University Hospital, Riga: Olegs Sabelnikovs, Peteris Oss; Lebanon: Kortbawi Hospital, Jounieh: Youssef Haddad; Malaysia: Hospital Kapit, Kapit: Kong Y. Liew; Mexico: Instituto Nacional de Cancerología, Mexico City: Silvio A. Ñamendys-Silva, Yves D. Jarquin-Badiola; Hospital de Especialidades 'Antonio Fraga Mouret' Centro Medico Nacional La Raza Instituto Mexicano del Seguro Social, Mexico City: Luis A. Sanchez-Hurtado, Saira S. Gomez-Flores; Hospital Regional 1° de Octubre, Mexico City: Maria C. Marin, Asisclo J. Villagomez; Hospital General Dr. Manuel Gea Gonzalez, Mexico City: Jordana S. Lemus, Jonathan M. Fierro; Hospital General de Zona No. 1 Instituto Mexicano del Seguro Social Tepic Nayarit, Tepic: Mavy Ramirez Cervantes, Francisco Javier Flores Mejia; Centro Medico Dalinde, Mexico City: Dulce Dector, Alejandro Rojas; Opd Hospital Civil de Guadalajara Hospital Juan I. Menchaca, Guadalajara: Daniel R. Gonzalez, Claudia R. Estrella; Hospital Regional de Ciudad Madero Pemex, Ciudad Madero: Jorge R. Sanchez-Medina, Alvaro Ramirez-Gutierrez; Centro Médico American British Cowdray, Mexico City: Fernando G. George, Janet S. Aguirre; Hospital Juarez de Mexico, Mexico City: Juan A. Buensuseso, Manuel Poblano; Morocco: Mohammed V University, University Teaching Ibn Sina Hospital, Rabat: Tarek Dendane, Amine Ali Zeggwagh; Hopital Militaire D’Instruction Mohammed V, Rabat: Hicham Balkhi; Errazi, Marrakech: Mina Elkhayari, Nacer Samkaoui; University Teaching Hospital Ibn Rushd, Casablanca: Hanane Ezzouine, Abdellatif Benslama; Hôpital des Spécialités de Rabat, Rabat: Mourad Amor, Wajdi Maazouzi; The Netherlands: Tjongerschans, Heerenveen: Nedim Cimic, Oliver Beck; Cwz, Nijmegen: Monique M. Bruns, Jeroen A. Schouten; Rijnstate Hospital, Arnhem: Myra Rinia, Monique Raaijmakers; Radboud Umc, Nijmegen: Leo M. Heunks, Hellen M. Van Wezel; Maastricht University Medical Center, Maastricht: Serge J. Heines, Ulrich Strauch; Catharinaziekenhuis, Eindhoven: Marc P. Buise; Academic Medical Center, Amsterdam: Fabienne D. Simonis, Marcus J. Schultz; New Zealand: Tauranga Hospital, Tauranga: Jennifer C. Goodson, Troy S. Browne; Wellington Hospital, Wellington: Leanlove Navarra, Anna Hunt; Dunedin Hospital, Dunedin: Robyn A. Hutchison, Mathew B. Bailey; Auckland City Hospital, Auckland: Lynette Newby, Colin McArthur; Whangarei Base Hospital, Whangarei: Michael Kalkoff, Alex Mcleod; North Shore Hospital, Auckland: Jonathan Casement, Danielle J. Hacking; Norway: Ålesund Hospital, Ålesund: Finn H. Andersen, Merete S. Dolva; Oslo University Hospital, Rikshospitalet Medical Center, Oslo: Jon H. Laake, Andreas Barratt-Due; Stavanger University Hospital, Stavanger: Kim Andre L. Noremark, Eldar Søreide; Haukeland University Hospital, Bergen: Brit Å. Sjøbø, Anne B. Guttormsen; Peru: Hospital Nacional Edgardo Rebagliati Martins, Lima: Hector H. Leon Yoshido; Clínica Ricardo Palma, Lima: Ronald Zumaran Aguilar, Fredy A. Montes Oscanoa; The Philippines: The Medical City, Pasig: Alain U. Alisasis, Joanne B. Robles; Chong Hua Hospital, Cebu: Rossini Abbie B. Pasanting-Lim, Beatriz C. Tan; Poland: Warsaw University Hospital, Warsaw: Pawel Andruszkiewicz, Karina Jakubowska; Portugal: Centro Hospitalar Da Cova Da Beira, Covilhã: Cristina M. Coxo; Hospital Santa Maria, Chln, Lisboa: António M. Alvarez, Bruno S. Oliveira; Centro Hospitalar Trás-Os-Montes E. Alto Douro, Hospital de S. Pedro-Vila Real, Vila Real: Gustavo M. Montanha, Nelson C. Barros; Hospital Beatriz Ângelo, Loures: Carlos S. Pereira, António M. Messias; Hospital de Santa Maria, Lisboa: Jorge M. Monteiro; Centro Hospitalar Médio Tejo–Hospital de Abrantes, Abrantes: Ana M. Araujo, Nuno T. Catorze; Instituto Português de Oncologia de Lisboa, Lisboa: Susan M. Marum, Maria J. Bouw; Hospital Garcia de Orta, Almada: Rui M. Gomes, Vania A. Brito; Centro Hospitalar Do Algarve, Faro: Silvia Castro, Joana M. Estilita; Hospital de Cascais, Alcabideche: Filipa M. Barros; Hospital Professor Doutor Fernando Fonseca Epe, Amadora: Isabel M. Serra, Aurelia M. Martinho; Romania: Fundeni Clinical Institute, Bucharest: Dana R. Tomescu, Alexandra Marcu; Emergency Clinical County Hospital Timisoara, Timisoara: Ovidiu H. Bedreag, Marius Papurica; Elias University Emergency Hospital, Bucharest: Dan E. Corneci, Silvius Ioan Negoita; Russian Federation: University Hospital, Kemerovo: Evgeny Grigoriev; Krasnoyarsk Regional Hospital, Krasnoyarsk State Medical University, Krasnoyarsk: Alexey I. Gritsan, Andrey A. Gazenkampf; Saudi Arabia: General Intensive Care Unit of Prince Sultan Military Medical City, Riyadh: Ghaleb Almekhlafi, Mohamad M. Albarrak; Surgical Intensive Care Unit of Prince Sultan Military Medical City, Riyadh: Ghanem M. Mustafa; King Faisal Hospital and Research Center, Riyadh: Khalid A. Maghrabi, Nawal Salahuddin; King Fahad Hospital, Baha: Tharwat M. Aisa; Neuro Critical Care Unit, King Abdulaziz Medical City, Riyadh: Ahmed S. Al Jabbary, Edgardo Tabhan; Intensive Care Unit, King Abdulaziz Medical City, Riyadh: Yaseen M. Arabi; Surgical Intensive Care Unit, King Abdulaziz Medical City, Riyadh: Yaseen M. Arabi, Olivia A. Trinidad; Trauma Intensive Care Unit, King Abdulaziz Medical City, Riyadh: Hasan M. Al Dorzi, Edgardo E. Tabhan; Serbia: Clinical Center of Serbia, Belgrade: Vesna Bumbasirevic, Bojan Jovanovic; Military Medical Academy, Belgrade; South Africa: Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg: Stefan Bolon, Oliver Smith; Spain: Hospital Sant Pau, Barcelona: Jordi Mancebo, Hernan Aguirre-Bermeo; Hospital Universitari Bellvitge, L’Hospitalet de Llobregat, Barcelona: Juan C. Lopez-Delgado, Francisco Esteve; Hospital Son Llatzer, Palma de Mallorca: Gemma Rialp, Catalina Forteza; Sabadell Hospital, Centro de Investigación Biomédica en Red Enfermedades Respiratorias, Sabadell: Candelaria De Haro, Antonio Artigas; Hospital Universitario Central de Asturias, Oviedo: Guillermo M. Albaiceta, Sara De Cima-Iglesias; Complejo Hospitalario Universitario A Coruña, A Coruña: Leticia Seoane-Quiroga, Alexandra Ceniceros-Barros; Hospital Universitario Miguel Servet, Zaragoza: Antonio L. RuizAguilar, Luis M. Claraco-Vega; Morales Meseguer University Hospital, Murcia: Juan Alfonso Soler, Maria del Carmen Lorente; Hospital Universitario del Henares, Coslada: Cecilia Hermosa, Federico Gordo; Complejo Asistencial de Palencia, Hospital Rio Carrión, Palencia: Miryam PrietoGonzález, Juan B. López-Messa; Fundación Jiménez Díaz, Madrid: Manuel P. Perez, Cesar P. Perez; Hospital Clínico Universitario Lozano Blesa, Zaragoza: Raquel Montoiro Allue; Hospital Verge de la Cinta, Tortosa: Ferran RocheCampo, Marcos Ibañez-Santacruz; Hospital Universitario 12 de Octubre, Madrid: Susana Temprano; Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid: Maria C. Pintado, Raul De Pablo; Hospital Universitari Germans Trias I Pujol, Badalona: Pilar Ricart Aroa Gómez; Hospital Universitario Arnau de Vilanova de Lleida, Lleida: Silvia Rodriguez Ruiz, Silvia Iglesias Moles; Cst Terrassa, Barcelona: Mª Teresa Jurado, Alfons Arizmendi; Hospital Universitari Mútua Terrassa, Terrassa: Enrique A. Piacentini; Hospital Universitario de Móstoles, Mostoles: Nieves Franco, Teresa Honrubia; Complejo Asistencial de Salamanca, Salamanca: Meisy Perez Cheng, Elena Perez Losada; Hospital General Universitario de Ciudad Real, Ciudad Real: Javier Blanco, Luis J. Yuste; Torrecardenas, Almeria: Cecilia Carbayo-Gorriz, Francisca G. Cazorla-Barranquero; Hospital Universitario Donostia, San Sebastian: Javier G. Alonso, Rosa S. Alda; Hospital Universitario de Torrejón, Madrid: Ángela Algaba, Gonzalo Navarro; Hospital Universitario de La Princesa, Madrid: Enrique Cereijo, Esther Diaz-Rodriguez; Hospital Universitario Lucus Augusti, Lugo: Diego Pastor Marcos, Laura Alvarez Montero; Hospital Universitario Santa Lucia, Cartagena: Luis Herrera Para, Roberto Jimenez Sanchez; Hospital Universitario Severo Ochoa, Leganes, Madrid: Miguel Angel Blasco Navalpotro, Ricardo Diaz Abad; University Hospital of Nuestra Señora de Candelaria, Santa Cruz de Tenerife: Raquel Montiel González, Dácil Parrilla Toribio; Hospital Universitario Marques de Valdecilla, Santander: Alejandro G. Castro, Maria Jose D. Artiga; Hospital Infanta Cristina, Parla, Madrid: Oscar Penuelas; Hospital General de Catalunya, Sant Cugat del Valles: Tomas P. Roser, Moreno F. Olga; San Pedro de Alcántara, Cáceres: Elena Gallego Curto, Rocío Manzano Sánchez; Sant Joan de Reus, Reus: Vallverdu P. Imma, Garcia M. Elisabet; Hospital Joan XXIII, Tarragona: Laura Claverias, Monica Magret; Hospital Universitario de Getafe, Madrid: Ana M. Pellicer, Lucia L. Rodriguez; Hospital Universitario Río Hortega, Valladolid: Jesús Sánchez-Ballesteros, Ángela González-Salamanca; Hospital Arquitecto Marcide, Ferrol, La Coruña: Antonio G. Jimenez, Francisco P. Huerta; Hospital General Universitario Gregorio Marañón, Madrid: Juan Carlos J. Sotillo Diaz, Esther Bermejo Lopez; Hospital General de Segovia, Segovia: David D. Llinares Moya, Alec A. Tallet Alfonso; Hospital General Universitario Reina Sofia, Murcia: Palazon Sanchez Eugenio Luis, Palazon Sanchez Cesar; Complejo Hospitalario Universitario de Albacete, Albacete: Sánchez I. Rafael, Corcoles G. Virgilio; Hospital Infanta Elena, Valdemoro: Noelia N. RecioSweden: Sahlgrenska University Hospital, Gothenburg: Richard O. Adamsson, Christian C. Rylander; Karolinska University Hospital, Stockholm: Bernhard Holzgraefe, Lars M. Broman; Akademiska Sjukhuset Uppsala, Uppsala: Joanna Wessbergh, Linnea Persson; Vrinnevisjukhuset, Norrköping: Fredrik Schiöler, Hans Kedelv; Linkoping University Hospital, Linköping: Anna Oscarsson Tibblin, Henrik Appelberg; Skellefteå Lasarett, Skellefteå: Lars Hedlund, Johan Helleberg; Karolinska University Hospital Solna, Stockholm: Karin E. Eriksson, Rita Glietsch; Umeå University Hospital, Umeå: Niklas Larsson, Ingela Nygren; Danderyd Hospital, Stockholm: Silvia L. Nunes, Anna-Karin Morin; Lund University Hospital, Lund: Thomas Kander, Anne Adolfsson; Switzerland: Centre Hospitalier Universitaire Vaudois, Lausanne: Lise Piquilloud; Hôpital Neuchâtelois–La Chaux de-Fonds, La Chaux-de-Fonds: Hervé O. Zender, Corinne Leemann-Refondini Tunisia: Hopital Taher Sfar Mahdia, Mahdia: Souheil Elatrous; University Hospital Farhat Hached Sousse, Sousse: Slaheddine Bouchoucha, Imed Chouchene; Center Hospitalier Universitaire F. Bourguiba, Monastir: Islem Ouanes; Mongi Slim University Hospital, La Marsa: Asma Ben Souissi, Salma Kamoun; Turkey: Cerrahpasa Medical Faculty Emergency Intensive Care Unit, Istanbul: Oktay Demirkiran; Cerrahpasa Medical Faculty Sadi Sun Intensive Care Unit, Istanbul: Mustafa Aker, Emre Erbabacan; Uludag University Medical Faculty, Bursa: Ilkay Ceylan, Nermin Kelebek Girgin; Ankara University Faculty of Medicine, Reanimation 3rd Level Intensive Care Unit, Ankara: Menekse Ozcelik, Necmettin Ünal; Ankara University Faculty of Medicine, 2nd Level Intensive Care Unit–Postoperative Intensive CareUnit, Ankara: Basak Ceyda Meco; Istanbul Kartal Egitim Ve Arastirma Hastanesi, Istanbul: Onat O. Akyol, Suleyman S. Derman; the UK: Papworth Hospital, Cambridge: Barry Kennedy, Ken Parhar; Royal Glamorgan Hospital, Llantrisant: Latha Srinivasa; Royal Victoria Hospital, Belfast: Lia McNamee, Danny McAuley; Jack Steinberg Intensive Care Unit of the King’s College, London: Phil Hopkins, Clare Mellis; Frank Stansil Intensive Care Unit of the King’s College Hospital, London: Vivek Kakar; Liver Intensive Care Unit of the King’s College, London: Dan Hadfield; Christine Brown Intensive Care Unit of the King’s College, London: Andre Vercueil; West Suffolk Hospital, Bury St. Edmunds: Kaushik Bhowmick, Sally K. Humphreys; Craigavon Area Hospital, Portadown: Andrew Ferguson, Raymond Mckee; Barts Health National Health Service Trust, Whipps Cross Hospital, Leytonstone: Ashok S. Raj, Danielle A. Fawkes; Kettering General Hospital, Foundation National Health Service Trust, Northamptonshire: Philip Watt, Linda Twohey; Barnet General Hospital, Barnet: Rajeev R. Jha, Matthew Thomas, Alex Morton, Varsha Kadaba; Rotherham General Hospital, Rotherham: Mark J. Smith, Anil P. Hormis; City Hospital, Birmingham: Santhana G. Kannan, Miriam Namih; Poole Hospital National Health Service Foundation Trust, Poole: Henrik Reschreiter, Julie Camsooksai; Weston General Hospital, Weston-Super-Mare: Alek Kumar, Szabolcs Rugonfalvi; Antrim Area Hospital, Antrim: Christopher Nutt, Orla Oneill; Aintree University Hospital, Liverpool: Colette Seasman, Ged Dempsey; Northern General Hospital, Sheffield: Christopher J. Scott, Helen E. Ellis; John Radcliffe Hospital, Oxford: Stuart Mckechnie, Paula J. Hutton; St. Georges Hospital, London: Nora N. Di Tomasso, Michela N. Vitale; Hillingdon Hospital, Uxbridge: Ruth O. Griffin, Michael N. Dean; Royal Bournemouth and Christchurch National Health Service Foundation Trust, Bournemouth: Julius H. Cranshaw, Emma L. Willett; Guy’s and St. Thomas’ National Health Service Foundation Trust, London: Nicholas Ioannou, Guy’s and St. Thomas’ Severe Respiratory Failure Service, Whittington Hospital, London: Sarah Gillis; Wexham Park Hospital, Slough: Peter Csabi; Western General Hospital, Edinburgh: Rosaleen Macfadyen, Heidi Dawson; Royal Preston Hospital, Preston: Pieter D. Preez, Alexandra J. Williams; Brighton and Sussex University Hospitals National Health Service Trust, Brighton: Owen Boyd, Laura Ortiz-Ruiz de Gordoa; East and North Herts National Health Service Trust, Stevenage: Jon Bramall, Sophie Symmonds; Barnsley Hospital, Barnsley: Simon K. Chau, Tim Wenham; Prince Charles Hospital, Merthyr Tydfil: Tamas Szakmany, Piroska Toth-Tarsoly; University Hospital of South Manchester National Health Service Foundation Trust, Manchester: Katie H. Mccalman, Peter Alexander; Harrogate District Hospital, Harrogate: Lorraine Stephenson, Thomas Collyer; East and North Herts National Health Service Trust, Welwyn Garden City: Rhiannon Chapman, Raphael Cooper; Western Infirmary, Glasgow: Russell M. Allan, Malcolm Sim; Dumfries and Galloway Royal Infirmary, Dumfries: David W. Wrathall, Donald A. Irvine; Charing Cross Hospital, London: Kim S. Zantua, John C. Adams; Worcestershire Royal Hospital, Worcester: Andrew J. Burtenshaw, Gareth P. Sellors; Royal Liverpool University Hospital, Liverpool: Ingeborg D. Welters, Karen E. Williams; Royal Alexandra Hospital, Glasgow: Robert J. Hessell, Matthew G. Oldroyd; Morriston Hospital, Swansea: Ceri E. Battle, Suresh Pillai; Frimley Park Hospital, Frimley: Istvan Kajtor, Mageswaran Sivashanmugavel; Altnagelvin Hospital, Derry: Sinead C. Okane, Adrian Donnelly; Buckinghamshire Healthcare National Health Service Trust, High Wycombe, Buckinghamshire: Aniko D. Frigyik, Jon P. Careless; Milton Keynes Hospital, Milton Keynes: Martin M. May, Richard Stewart; Ulster Hospital, Belfast: T. John Trinder, Samantha J. Hagan; University Hospital of Wales, Cardiff: Jade M. Cole; Freeman Hospital, Newcastle upon Tyne: Caroline C. MacFie, Anna T. Dowling; Uruguay: Hospital Español, Montevideo: Javier Hurtado, Nicolás Nin; Cudam, Montevideo: Javier Hurtado; Sanatorio Mautone, Maldonado: Edgardo Nuñez; Sanatorio Americano, Montevideo: Gustavo Pittini, Ruben Rodriguez; Hospital de Clínicas, Montevideo: María C. Imperio, Cristina Santos; Circulo Católico Obreros Uruguay–Sanatorio Juan Pablo II, Montevido: Ana G. França, Alejandro Ebeid; Centro de Asistencia del Sindicato Médico del Uruguay, Montevideo: Alberto Deicas, Carolina Serra; the USA: St. Louis University Hospital, St. Louis, Missouri: Aditya Uppalapati, Ghassan Kamel; Beth Israel Deaconess Medical Center, Boston, Massachusetts: Valerie M. Banner-Goodspeed, Jeremy R. Beitler; Memorial Medical Center, Springfield, Illinois: Satyanarayana Reddy Mukkera, Shreedhar Kulkarni; Massachusetts General Hospital, Boston, Massachusetts: Jarone Lee, Tomaz Mesar; University of Cincinnati Medical Center, Cincinnati, Ohio: John O. Shinn III, Dina Gomaa; Massachusetts General Hospital, Boston, Massachusetts: Christopher Tainter, Jarone Lee; Massachusetts General Hospital, Boston, Massachusetts: Tomaz Mesar, Jarone Lee; R. Adams Cowley Shock Trauma Center, Baltimore, Maryland: Dale J. Yeatts, Jessica Warren; Intermountain Medical Center, Murray, Utah: Michael J. Lanspa, Russel R. Miller; Intermountain Medical Center, Murray, Utah: Colin K. Grissom, Samuel M. Brown; Mayo Clinic, Rochester, Minnesota: Philippe R. Bauer; North Shore Medical Center, Salem, Massachusetts: Ryan J. Gosselin, Barrett T. Kitch; Albany Medical Center, Albany, New York: Jason E. Cohen, Scott H. Beegle, Shazia Choudry; John H. Stoger Hospital of Cook County, Chicago, Illinois: Renaud M. Gueret, Aiman Tulaimat; University of Alabama at Birmingham, Birmingham, Alabama: William Stigler, Hitesh Batra; Duke University Hospital, Durham, North Carolina: Nidhi G. Huff; Iowa Methodist Medical Center, Des Moines, Iowa: Keith D. Lamb,Trevor W. Oetting; Surgical and Neurosciences Intensive Care Unit of the University of Iowa Hospitals and Clinics, Iowa City, Iowa: Nicholas M. Mohr, Claine Judy; Medical Center of Louisiana at New Orleans, New Orleans, Louisiana: Shigeki Saito, Fayez M. Kheir; Tulane University, New Orleans, Louisiana: Fayez Kheir; Critical Care Unit of the University of Iowa Hospitals and Clinics, Iowa City, Iowa: Adam B. Schlichting, Angela Delsing; University of California, San Diego Medical Center, San Diego, California: Daniel R. Crouch, Mary Elmasri; University of California San Diego Thornton Hospital, La Jolla, California: Daniel R. Crouch, Dina Ismail; University Hospital, Cincinnati, Ohio: Kyle R. Dreyer, Thomas C. Blakeman, Dina Gomaa; Tower 3B Medical Intensive Care Unit of Brigham and Women’s Hospital, Boston, Massachusetts: Rebecca M. Baron, Carolina Quintana Grijalba; Tower 8C Burn/Trauma Intensive Care Unit of Brigham and Women’s Hospital, Boston, Massachusetts: Peter C. Hou; Tower 8D Surgical Intensive Care Unit of Brigham and Women’s Hospital, Boston, Massachusetts: Raghu Seethala; Tower 9C Neurosurgical Intensive Care Unit of Brigham and Women’s Hospital, Boston, Massachusetts: Imo Aisiku; Tower 9D Neurological Intensive Care Unit of Brigham and Women’s Hospital, Boston, Massachusetts: Galen Henderson; Tower 11C Thoracic Intensive Care Unit of Brigham and Women’s Hospital, Boston, Massachusetts: Gyorgy Frendl; Shapiro 6W Cardiac Surgery Intensive Care Unit of Brigham and Women’s Hospital, Boston, Massachusetts: Sen-Kuang Hou; Shapiro 9E Coronary Care Unit of Brigham and Women’s Hospital, Boston, Massachusetts: Robert L. Owens, Ashley Schom.
Contributors RS, DFMcA and MS-H were responsible for study concept and design. RS, TP, PS, MVM, GB, JGL and MS-H had full access to all the data in the study and take responsibility for the integrity and accuracy of the data analyses. RS, TP, PS, MVM, GB, EF, CS, AD, GDR, CSC, JGL, DFMcA and MS-H contributed to data interpretation. RS and MS-H undertook the statistical analyses. RS and MS-H drafted the manuscript; RS, TP, PS, MVM, GB, EF, CS, AD, GDR, CSC, JGL, DFMcA and MS-H contributed to critical revision of the manuscript for important intellectual content. MS-H was responsible for overall supervision. JGL and MS-H accept full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish. Funding for the LUNG-SAFE study was obtained by GB and JGL.
Funding The LUNG-SAFE study was funded and supported by the European Society of Intensive Care Medicine (ESICM), Brussels, Belgium, by St Michael’s Hospital, Toronto, Canada, and by the University of Milan-Bicocca, Monza, Italy. ESICM provided support in data collection and study coordination. ESICM, St Michael’s Hospital, Toronto and University of Milan-Bicocca had no role in the design and conduct of the study; management, analysis and interpretation of the data; preparation, review or approval of the manuscript or decision to submit the current manuscript for publication.
Disclaimer The views expressed in this publication are those of the authors and not necessarily those of the National Health Service, the National Institute for Health and Care Research, or the Department of Health and Social Care.
Competing interests CS is funded by UKRI (MR/S035753/1 and MR/X005070/1) and the National Institute for Health and Care Research (NIHR133788). Work in her research group is supported by GlaxoSmithKline, the Wellcome Trust and the Cambridge NIHR Biomedical Research Centre, and she has received consultancy fees from AbbVie, Sanofi and GlaxoSmithKline. CSC is funded by National Institutes of Health R35-HL140026 and reports grant funding from Roche-Genentech and Quantum Leap Healthcare collaborative, in addition to the National Institutes of Health, and consulting fees from Vasomune, Gen1e Life Sciences, Cellenkos and Janssen. EF reports personal fees from ALung Technologies, Aerogen, Baxter, GE Healthcare, Inspira and Vasomune outside the submitted work. JGL is funded by a Future Research Leaders Award (16-FRL-3845) from Science Foundation Ireland and reports receiving consulting fees from Baxter and from GlaxoSmithKline. RS reports no conflicts. MS-H is funded by a clinician scientist fellowship from the National Institute for Health Research (CS-2016-16-011) and reports receiving grants from the NIHR, MRC, EME, HTA, Huo Foundation and highlights industry support for TRAITS research programme (a Chief Scientists Office, Scotland funded time critical precision medicine in adult critically ill patients (TRAITS Programme)).
Provenance and peer review Not commissioned; externally peer reviewed.
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