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This month marks the 50th anniversary of the first description of the condition now termed the acute respiratory distress syndrome, or ARDS. The authors of this review discuss our current understanding of the pathobiology and treatment of ARDS.

PurposeUsing latent class analysis (LCA), we have consistently identified two distinct subphenotypes in four randomized controlled trial cohorts of ARDS. One subphenotype has hyper-inflammatory characteristics and is associated with worse clinical outcomes. Further, within three negative clinical trials, we observed differential treatment response by subphenotype to randomly assigned interventions. The main purpose of this study was to identify ARDS subphenotypes in a contemporary NHLBI Network trial of infection-associated ARDS (SAILS) using LCA and to test for differential treatment response to rosuvastatin therapy in the subphenotypes.MethodsLCA models were constructed using a combination of biomarker and clinical data at baseline in the SAILS study (n = 745). LCA modeling was then repeated using an expanded set of clinical class-defining variables. Subphenotypes were tested for differential treatment response to rosuvastatin.ResultsThe two-class LCA model best fit the population. Forty percent of the patients were classified as the “hyper-inflammatory” subphenotype. Including additional clinical variables in the LCA models did not identify new classes. Mortality at day 60 and day 90 was higher in the hyper-inflammatory subphenotype. No differences in outcome were observed between hyper-inflammatory patients randomized to rosuvastatin therapy versus placebo.ConclusionsLCA using a two-subphenotype model best described the SAILS population. The subphenotypes have features consistent with those previously reported in four other cohorts. Addition of new class-defining variables in the LCA model did not yield additional subphenotypes. No treatment effect was observed with rosuvastatin. These findings further validate the presence of two subphenotypes and demonstrate their utility for patient stratification in ARDS.

The efficacy of drotrecogin alpha (activated) (DrotAA) for sepsis has been controversial. In this trial, there was no significant difference in all-cause mortality at 28 or 90 days between adults with sepsis who were treated with DrotAA and those treated with placebo. Recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), was approved for the treatment of severe sepsis in 2001 on the basis of the Prospective Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study, 1 a phase 3 international, randomized, controlled trial that was stopped early for efficacy after the enrollment of 1690 patients with severe sepsis. Absolute mortality in the intention-to-treat population was reduced by 6.1 percentage points, a relative risk reduction of 19.4%. Subsequent subgroup analysis suggested that the mortality benefit was limited to patients with increased illness severity (i.e., those with more than one . . .

Both quality improvement and clinical research efforts over the past few decades have focused on consensus definition of sepsis and acute respiratory distress syndrome (ARDS). Although clinical definitions based on readily available clinical data have advanced recognition and timely use of broad supportive treatments, they likely hinder the identification of more targeted therapies that manipulate select biological mechanisms underlying critical illness. Sepsis and ARDS are by definition heterogeneous, and patients vary in both their underlying biology and their severity of illness. We have long been able to identify subtypes of sepsis and ARDS that confer different prognoses. The key is that we are now on the verge of identifying subtypes that may confer different response to therapy. In this perspective, inspired by a 2015 American Thoracic Society International Conference Symposium entitled \"Lumpers and Splitters: Phenotyping in Critical Illness,\" we highlight promising approaches to uncovering patient subtypes that may predict treatment responsiveness and not just differences in prognosis. We then discuss how this information can be leveraged to improve the success and translatability of clinical trials by using predictive enrichment and other design strategies. Last, we discuss the challenges and limitations to identifying biomarkers and endotypes and incorporating them into routine clinical practice.

Purpose Our objective was to revise the definition of acute respiratory distress syndrome (ARDS) using a conceptual model incorporating reliability and validity, and a novel iterative approach with formal evaluation of the definition. Methods The European Society of Intensive Care Medicine identified three chairs with broad expertise in ARDS who selected the participants and created the agenda. After 2 days of consensus discussions a draft definition was developed, which then underwent empiric evaluation followed by consensus revision. Results The Berlin Definition of ARDS maintains a link to prior definitions with diagnostic criteria of timing, chest imaging, origin of edema, and hypoxemia. Patients may have ARDS if the onset is within 1 week of a known clinical insult or new/worsening respiratory symptoms. For the bilateral opacities on chest radiograph criterion, a reference set of chest radiographs has been developed to enhance inter-observer reliability. The pulmonary artery wedge pressure criterion for hydrostatic edema was removed, and illustrative vignettes were created to guide judgments about the primary cause of respiratory failure. If no risk factor for ARDS is apparent, however, objective evaluation (e.g., echocardiography) is required to help rule out hydrostatic edema. A minimum level of positive end-expiratory pressure and mutually exclusive PaO 2 /FiO 2 thresholds were chosen for the different levels of ARDS severity (mild, moderate, severe) to better categorize patients with different outcomes and potential responses to therapy. Conclusions This panel addressed some of the limitations of the prior ARDS definition by incorporating current data, physiologic concepts, and clinical trials results to develop the Berlin definition, which should facilitate case recognition and better match treatment options to severity in both research trials and clinical practice.

This trial revisited research conducted about a decade ago that showed a survival benefit with early neuromuscular blockade in patients with acute respiratory distress syndrome. The new trial did not show a benefit with neuromuscular blockade with respect to overall survival or other clinical outcomes.

RationaleTwo distinct acute respiratory distress syndrome (ARDS) subphenotypes have been identified using data obtained at time of enrolment in clinical trials; it remains unknown if these subphenotypes are durable over time.ObjectiveTo determine the stability of ARDS subphenotypes over time.MethodsSecondary analysis of data from two randomised controlled trials in ARDS, the ARMA trial of lung protective ventilation (n=473; patients randomised to low tidal volumes only) and the ALVEOLI trial of low versus high positive end-expiratory pressure (n=549). Latent class analysis (LCA) and latent transition analysis (LTA) were applied to data from day 0 and day 3, independent of clinical outcomes.Measurements and main resultsIn ALVEOLI, LCA indicated strong evidence of two ARDS latent classes at days 0 and 3; in ARMA, evidence of two classes was stronger at day 0 than at day 3. The clinical and biological features of these two classes were similar to those in our prior work and were largely stable over time, though class 2 demonstrated evidence of progressive organ failures by day 3, compared with class 1. In both LCA and LTA models, the majority of patients (>94%) stayed in the same class from day 0 to day 3. Clinical outcomes were statistically significantly worse in class 2 than class 1 and were more strongly associated with day 3 class assignment.ConclusionsARDS subphenotypes are largely stable over the first 3 days of enrolment in two ARDS Network trials, suggesting that subphenotype identification may be feasible in the context of clinical trials.

Patients with vasodilatory shock were randomly assigned to angiotensin II or placebo. At 3 hours, more patients in the angiotensin II group than in the placebo group had an increase in mean arterial pressure of at least 10 mm Hg or to at least 75 mm Hg.

Septic shock is a highly heterogeneous condition which is part of the challenge in its diagnosis and treatment. In this study we aim to identify clinically relevant subphenotypes of septic shock using a novel statistic al approach. Baseline patient data from a large global clinical trial of septic shock (n = 1696) was analysed using latent class analysis (LCA). This approach allowed investigators to identify subgroups in a heterogeneous population by estimating a categorical latent variable that detects relatively homogeneous subgroups within a complex phenomenon. LCA identified six different, clinically meaningful subphenotypes of septic shock each with a typical profile: (1) “Uncomplicated Septic Shock, (2) “Pneumonia with adult respiratory distress syndrome (ARDS)”, (3) “Postoperative Abdominal”, (4) “Severe Septic Shock”, (5): “Pneumonia with ARDS and multiple organ dysfunction syndrome (MODS)”, (6) “Late Septic Shock”. The 6-class solution showed high entropy approaching 1 (i.e., 0.92), indicating there was excellent separation between estimated classes. LCA appears to be an applicable statistical tool in analysing a heterogenous clinical cohort of septic shock. The results may lead to a better understanding of septic shock complexity and form a basis for considering targeted therapies and selecting patients for future clinical trials. •Latent class analysis (LCA) can be used to identify subphenotypes within a complex phenomenon like septic shock•LCA identified six distinctive subphenotypes of septic shock with a high degree of separation•Each subphenotype has its specific, clinically relevant, characteristics

Observational data had suggested that statin treatment may improve outcomes in patients with the acute respiratory distress syndrome from sepsis. This randomized trial showed no benefit to statin treatment in such patients. Despite progress in supportive care strategies for the acute respiratory distress syndrome (ARDS), mortality remains high, especially among patients with sepsis. 1 Inflammation leading to cellular damage and cellular death contributes to both pulmonary and nonpulmonary organ failure. Therapies that attenuate inflammation may improve outcomes in patients with ARDS. 2 Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, known collectively as statins, are commonly prescribed for hypercholesterolemia. However, statins also reduce inflammation and have been shown to prevent ARDS in murine models. 3 – 13 Several (but not all) large observational studies, a small randomized, controlled trial, and meta-analyses before study initiation have suggested that patients . . .