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Purpose To improve the outcome of the acute respiratory distress syndrome (ARDS), one needs to identify potentially modifiable factors associated with mortality. Methods The large observational study to understand the global impact of severe acute respiratory failure (LUNG SAFE) was an international, multicenter, prospective cohort study of patients with severe respiratory failure, conducted in the winter of 2014 in a convenience sample of 459 ICUs from 50 countries across five continents. A pre-specified secondary aim was to examine the factors associated with outcome. Analyses were restricted to patients (93.1 %) fulfilling ARDS criteria on day 1–2 who received invasive mechanical ventilation. Results 2377 patients were included in the analysis. Potentially modifiable factors associated with increased hospital mortality in multivariable analyses include lower PEEP, higher peak inspiratory, plateau, and driving pressures, and increased respiratory rate. The impact of tidal volume on outcome was unclear. Having fewer ICU beds was also associated with higher hospital mortality. Non-modifiable factors associated with worsened outcome from ARDS included older age, active neoplasm, hematologic neoplasm, and chronic liver failure. Severity of illness indices including lower pH, lower PaO 2 /FiO 2 ratio, and higher non-pulmonary SOFA score were associated with poorer outcome. Of the 578 (24.3 %) patients with a limitation of life-sustaining therapies or measures decision, 498 (86.0 %) died in hospital. Factors associated with increased likelihood of limitation of life-sustaining therapies or measures decision included older age, immunosuppression, neoplasia, lower pH and increased non-pulmonary SOFA scores. Conclusions Higher PEEP, lower peak, plateau, and driving pressures, and lower respiratory rate are associated with improved survival from ARDS. Trial Registration: ClinicalTrials.gov NCT02010073.

We previously identified two acute respiratory distress syndrome (ARDS) subphenotypes in two separate randomized controlled trials with differential response to positive end-expiratory pressure. To identify these subphenotypes in a third ARDS cohort, to test whether subphenotypes respond differently to fluid management strategy, and to develop a practical model for subphenotype identification. We used latent class analysis of baseline clinical and plasma biomarker data to identify subphenotypes in FACTT (Fluid and Catheter Treatment Trial; n = 1,000). Logistic regression was used to test for an interaction between subphenotype and treatment for mortality. We used stepwise modeling to generate a model for subphenotype identification in FACTT and validated its accuracy in the two cohorts in which we previously identified ARDS subphenotypes. We confirmed that a two-class (two-subphenotype) model best described the study population. Subphenotype 2 was again characterized by higher inflammatory biomarkers and hypotension. Fluid management strategy had significantly different effects on 90-day mortality in the two subphenotypes (P = 0.0039 for interaction); mortality in subphenotype 1 was 26% with fluid-conservative strategy versus 18% with fluid-liberal, whereas mortality in subphenotype 2 was 40% with fluid-conservative strategy versus 50% in fluid-liberal. A three-variable model of IL-8, bicarbonate, and tumor necrosis factor receptor-1 accurately classified the subphenotypes. This analysis confirms the presence of two ARDS subphenotypes that can be accurately identified with a limited number of variables and that responded differently to randomly assigned fluid management. These findings support the presence of ARDS subtypes that may require different treatment approaches.

Noninvasive ventilation (NIV) is increasingly used in patients with acute respiratory distress syndrome (ARDS). The evidence supporting NIV use in patients with ARDS remains relatively sparse. To determine whether, during NIV, the categorization of ARDS severity based on the Pa /Fi Berlin criteria is useful. The LUNG SAFE (Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure) study described the management of patients with ARDS. This substudy examines the current practice of NIV use in ARDS, the utility of the Pa /Fi ratio in classifying patients receiving NIV, and the impact of NIV on outcome. Of 2,813 patients with ARDS, 436 (15.5%) were managed with NIV on Days 1 and 2 following fulfillment of diagnostic criteria. Classification of ARDS severity based on Pa /Fi ratio was associated with an increase in intensity of ventilatory support, NIV failure, and intensive care unit (ICU) mortality. NIV failure occurred in 22.2% of mild, 42.3% of moderate, and 47.1% of patients with severe ARDS. Hospital mortality in patients with NIV success and failure was 16.1% and 45.4%, respectively. NIV use was independently associated with increased ICU (hazard ratio, 1.446 [95% confidence interval, 1.159-1.805]), but not hospital, mortality. In a propensity matched analysis, ICU mortality was higher in NIV than invasively ventilated patients with a Pa /Fi lower than 150 mm Hg. NIV was used in 15% of patients with ARDS, irrespective of severity category. NIV seems to be associated with higher ICU mortality in patients with a Pa /Fi lower than 150 mm Hg. Clinical trial registered with www.clinicaltrials.gov (NCT 02010073).

Increasing use of extracorporeal membrane oxygenation (ECMO) for acute respiratory failure may increase resource requirements and hospital costs. Better prediction of survival in these patients may improve resource use, allow risk-adjusted comparison of center-specific outcomes, and help clinicians to target patients most likely to benefit from ECMO. To create a model for predicting hospital survival at initiation of ECMO for respiratory failure. Adult patients with severe acute respiratory failure treated by ECMO from 2000 to 2012 were extracted from the Extracorporeal Life Support Organization (ELSO) international registry. Multivariable logistic regression was used to create the Respiratory ECMO Survival Prediction (RESP) score using bootstrapping methodology with internal and external validation. Of the 2,355 patients included in the study, 1,338 patients (57%) were discharged alive from hospital. The RESP score was developed using pre-ECMO variables independently associated with hospital survival on logistic regression, which included age, immunocompromised status, duration of mechanical ventilation before ECMO, diagnosis, central nervous system dysfunction, acute associated nonpulmonary infection, neuromuscular blockade agents or nitric oxide use, bicarbonate infusion, cardiac arrest, PaCO2, and peak inspiratory pressure. The receiver operating characteristics curve analysis of the RESP score was c = 0.74 (95% confidence interval, 0.72-0.76). External validation, performed on 140 patients, exhibited excellent discrimination (c = 0.92; 95% confidence interval, 0.89-0.97). The RESP score is a relevant and validated tool to predict survival for patients receiving ECMO for respiratory failure.

Estimates of the incidence of the acute respiratory distress syndrome (ARDS) in high- and middle-income countries vary from 10.1 to 86.2 per 100,000 person-years in the general population. The epidemiology of ARDS has not been reported for a low-income country at the level of the population, hospital, or intensive care unit (ICU). The Berlin definition may not allow identification of ARDS in resource-constrained settings. To estimate the incidence and outcomes of ARDS at a Rwandan referral hospital using the Kigali modification of the Berlin definition: without requirement for positive end-expiratory pressure, hypoxia cutoff of SpO2/FiO2 less than or equal to 315, and bilateral opacities on lung ultrasound or chest radiograph. We screened every adult patient for hypoxia at a public referral hospital in Rwanda for 6 weeks. For every patient with hypoxia, we collected data on demographics and ARDS risk factors, performed lung ultrasonography, and evaluated chest radiography when available. Forty-two (4.0%) of 1,046 hospital admissions met criteria for ARDS. Using various prespecified cutoffs for the SpO2/FiO2 ratio resulted in almost identical hospital incidence values. Median age for patients with ARDS was 37 years, and infection was the most common risk factor (44.1%). Only 30.9% of patients with ARDS were admitted to an ICU, and hospital mortality was 50.0%. Using traditional Berlin criteria, no patients would have met criteria for ARDS. ARDS seems to be a common and fatal syndrome in a hospital in Rwanda, with few patients admitted to an ICU. The Berlin definition is likely to underestimate the impact of ARDS in low-income countries, where resources to meet the definition requirements are lacking. Although the Kigali modification requires validation before widespread use, we hope this study stimulates further work in refining an ARDS definition that can be consistently used in all settings.

In this trial, high-frequency oscillatory ventilation was compared with conventional ventilation with a lung-protective protocol. When the study was stopped early, hospital mortality was 47% with HFOV versus 35% with the control ventilation strategy. The acute respiratory distress syndrome (ARDS) is a common complication of critical illness. 1 , 2 Mortality is high, and survivors often have long-term complications. 3 , 4 Although mechanical ventilation is life-sustaining for patients with ARDS, it can perpetuate lung injury. Basic research suggests that repetitive overstretching or collapse of lung units with each respiratory cycle can generate local and systemic inflammation, contributing to multiorgan failure and death. 5 Consistent with these findings are data from clinical trials that support the use of smaller tidal volumes (6 vs. 12 ml per kilogram of predicted body weight) 6 and higher levels of positive end-expiratory pressure (PEEP). . . .

Purpose Experimental animal models of acute respiratory distress syndrome (ARDS) have shown that the updated airway pressure release ventilation (APRV) methodologies may significantly improve oxygenation, maximize lung recruitment, and attenuate lung injury, without circulatory depression. This led us to hypothesize that early application of APRV in patients with ARDS would allow pulmonary function to recover faster and would reduce the duration of mechanical ventilation as compared with low tidal volume lung protective ventilation (LTV). Methods A total of 138 patients with ARDS who received mechanical ventilation for <48 h between May 2015 to October 2016 while in the critical care medicine unit (ICU) of the West China Hospital of Sichuan University were enrolled in the study. Patients were randomly assigned to receive APRV ( n  = 71) or LTV ( n  = 67). The settings for APRV were: high airway pressure (P high ) set at the last plateau airway pressure (P plat ), not to exceed 30 cmH 2 O) and low airway pressure ( P low ) set at 5 cmH 2 O; the release phase (T low ) setting adjusted to terminate the peak expiratory flow rate to ≥ 50%; release frequency of 10–14 cycles/min. The settings for LTV were: target tidal volume of 6 mL/kg of predicted body weight; P plat not exceeding 30 cmH 2 O; positive end-expiratory pressure (PEEP) guided by the PEEP–FiO 2 table according to the ARDSnet protocol. The primary outcome was the number of days without mechanical ventilation from enrollment to day 28. The secondary endpoints included oxygenation, P plat , respiratory system compliance, and patient outcomes. Results Compared with the LTV group, patients in the APRV group had a higher median number of ventilator-free days {19 [interquartile range (IQR) 8–22] vs. 2 (IQR 0–15); P  < 0.001}. This finding was independent of the coexisting differences in chronic disease. The APRV group had a shorter stay in the ICU ( P  = 0.003). The ICU mortality rate was 19.7% in the APRV group versus 34.3% in the LTV group ( P  = 0.053) and was associated with better oxygenation and respiratory system compliance, lower P plat , and less sedation requirement during the first week following enrollment ( P  < 0.05, repeated-measures analysis of variance). Conclusions Compared with LTV, early application of APRV in patients with ARDS improved oxygenation and respiratory system compliance, decreased P plat and reduced the duration of both mechanical ventilation and ICU stay.

This analysis of previously reported trials shows that low tidal volumes, a key component of safer ventilation strategies, confer a protective effect against complications only if the lower volume results in a lower pulmonary driving pressure. Mechanical-ventilation strategies that use lower end-inspiratory (plateau) airway pressures, lower tidal volumes (V T ), and higher positive end-expiratory pressures (PEEPs) — collectively termed lung-protective strategies — have been associated with survival benefits in randomized clinical trials involving patients with the acute respiratory distress syndrome (ARDS). 1 – 4 The different components of lung protection in those strategies, such as lower V T , lower plateau pressure, and higher PEEP, can all reduce mechanical stresses on the lung, which are thought to induce ventilator-induced lung injury. 5 – 9 Clinical trials, however, have reported conflicting responses to the manipulation of separate components of lung . . .

Positive end-expiratory pressure (PEEP) is used to improve oxygenation in patients with acute lung injury or the acute respiratory distress syndrome. In this pilot trial, the investigators show that adjusting PEEP with the use of measurements of esophageal pressure to estimate transpulmonary pressure leads to improved oxygenation as compared with the conventional approach to ventilator management. Patients with acute lung injury or ARDS were randomly assigned to mechanical ventilation directed either by esophageal-pressure measurements or according to standard-of-care recommendations. The use of esophageal pressures to estimate the transpulmonary pressure significantly improved oxygenation and respiratory-system compliance. Recent changes in the practice of mechanical ventilation have improved survival in patients with the acute respiratory distress syndrome (ARDS), but mortality remains unacceptably high. Whereas low tidal volumes are clearly beneficial in patients with ARDS, how to choose a positive end-expiratory pressure (PEEP) is uncertain. 1 – 4 Ideally, mechanical ventilation should provide sufficient transpulmonary pressure (airway pressure minus pleural pressure) to maintain oxygenation while minimizing repeated alveolar collapse or overdistention leading to lung injury. 5 In critical illness, however, there is marked variability among patients in abdominal and pleural pressures 6 , 7 ; thus, for a given level of PEEP, transpulmonary pressures . . .

RationaleWe hypothesised that patients with acute respiratory distress syndrome (ARDS) can be clustered based on concentrations of plasma biomarkers and that the thereby identified biological phenotypes are associated with mortality.MethodsConsecutive patients with ARDS were included in this prospective observational cohort study. Cluster analysis of 20 biomarkers of inflammation, coagulation and endothelial activation provided the phenotypes in a training cohort, not taking any outcome data into account. Logistic regression with backward selection was used to select the most predictive biomarkers, and these predicted phenotypes were validated in a separate cohort. Multivariable logistic regression was used to quantify the independent association with mortality.ResultsTwo phenotypes were identified in 454 patients, which we named ‘uninflamed’ (N=218) and ‘reactive’ (N=236). A selection of four biomarkers (interleukin-6, interferon gamma, angiopoietin 1/2 and plasminogen activator inhibitor-1) could be used to accurately predict the phenotype in the training cohort (area under the receiver operating characteristics curve: 0.98, 95% CI 0.97 to 0.99). Mortality rates were 15.6% and 36.4% (p<0.001) in the training cohort and 13.6% and 37.5% (p<0.001) in the validation cohort (N=207). The ‘reactive phenotype’ was independent from confounders associated with intensive care unit mortality (training cohort: OR 1.13, 95% CI 1.04 to 1.23; validation cohort: OR 1.18, 95% CI 1.06 to 1.31).ConclusionsPatients with ARDS can be clustered into two biological phenotypes, with different mortality rates. Four biomarkers can be used to predict the phenotype with high accuracy. The phenotypes were very similar to those found in cohorts derived from randomised controlled trials, and these results may improve patient selection for future clinical trials targeting host response in patients with ARDS.