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Purpose While our understanding of the pathogenesis and management of acute respiratory distress syndrome (ARDS) has improved over the past decade, estimates of its incidence have been controversial. The goal of this study was to examine ARDS incidence and outcome under current lung protective ventilatory support practices before and after the diagnosis of ARDS. Methods This was a 1-year prospective, multicenter, observational study in 13 geographical areas of Spain (serving a population of 3.55 million at least 18 years of age) between November 2008 and October 2009. Subjects comprised all consecutive patients meeting American-European Consensus Criteria for ARDS. Data on ventilatory management, gas exchange, hemodynamics, and organ dysfunction were collected. Results A total of 255 mechanically ventilated patients fulfilled the ARDS definition, representing an incidence of 7.2/100,000 population/year. Pneumonia and sepsis were the most common causes of ARDS. At the time of meeting ARDS criteria, mean PaO 2 /FiO 2 was 114 ± 40 mmHg, mean tidal volume was 7.2 ± 1.1 ml/kg predicted body weight, mean plateau pressure was 26 ± 5 cmH 2 O, and mean positive end-expiratory pressure (PEEP) was 9.3 ± 2.4 cmH 2 O. Overall ARDS intensive care unit (ICU) and hospital mortality was 42.7% (95%CI 37.7–47.8) and 47.8% (95%CI 42.8–53.0), respectively. Conclusions This is the first study to prospectively estimate the ARDS incidence during the routine application of lung protective ventilation. Our findings support previous estimates in Europe and are an order of magnitude lower than those reported in the USA and Australia. Despite use of lung protective ventilation, overall ICU and hospital mortality of ARDS patients is still higher than 40%.

Abstract Rationale Despite advances in clinical management, there are currently no reliable diagnostic and therapeutic targets for acute respiratory distress syndrome (ARDS). The inflammasome/caspase-1 pathway regulates the maturation and secretion of proinflammatory cytokines (e.g., IL-18). IL-18 is associated with injury in animal models of systemic inflammation. Objectives We sought to determine the contribution of the inflammasome pathway in experimental acute lung injury and human ARDS. Methods We performed comprehensive gene expression profiling on peripheral blood from patients with critical illness. Gene expression changes were assessed using real-time polymerase chain reaction, and IL-18 levels were measured in the plasma of the critically ill patients. Wild-type mice or mice genetically deficient in IL-18 or caspase-1 were mechanically ventilated using moderate tidal volume (12 ml/kg). Lung injury parameters were assessed in lung tissue, serum, and bronchoalveolar lavage fluid. Measurements and Main Results In mice, mechanical ventilation enhanced IL-18 levels in the lung, serum, and bronchoalveolar lavage fluid. IL-18–neutralizing antibody treatment, or genetic deletion of IL-18 or caspase-1, reduced lung injury in response to mechanical ventilation. In human patients with ARDS, inflammasome-related mRNA transcripts (CASP1, IL1B, and IL18) were increased in peripheral blood. In samples from four clinical centers, IL-18 was elevated in the plasma of patients with ARDS (sepsis or trauma-induced ARDS) and served as a novel biomarker of intensive care unit morbidity and mortality. Conclusions The inflammasome pathway and its downstream cytokines play critical roles in ARDS development.

Many patients with severe acute respiratory distress syndrome (ARDS) caused by influenza A(H1N1) infection receive extracorporeal membrane oxygenation (ECMO) as a rescue therapy. To analyze factors associated with death in ECMO-treated patients and the influence of ECMO on intensive care unit (ICU) mortality. Data from patients admitted for H1N1-associated ARDS to French ICUs were prospectively collected from 2009 to 2011 through the national REVA registry. We analyzed factors associated with in-ICU death in ECMO recipients, and the potential benefit of ECMO using a propensity score-matched (1:1) cohort analysis. A total of 123 patients received ECMO. By multivariate analysis, increasing values of age, lactate, and plateau pressure under ECMO were associated with death. Of 103 patients receiving ECMO during the first week of mechanical ventilation, 52 could be matched to non-ECMO patients of comparable severity, using a one-to-one matching and using control subjects only once. Mortality did not differ between the two matched cohorts (odds ratio, 1.48; 95% confidence interval, 0.68-3.23; P = 0.32). Interestingly, the 51 ECMO patients who could not be matched were younger, had lower Pa(o(2))/Fi(o(2)) ratio, had higher plateau pressure, but also had a lower ICU mortality rate than the 52 matched ECMO patients (22% vs. 50%; P < 0.01). Under ECMO, an ultraprotective ventilation strategy minimizing plateau pressure may be required to improve outcome. When patients with severe influenza A(H1N1)-related ARDS treated with ECMO were compared with conventionally treated patients, no difference in mortality rates existed. The unmatched, severely hypoxemic, and younger ECMO-treated patients had, however, a lower mortality.

Purpose The use of non-invasive ventilation (NIV) in severe acute respiratory failure (ARF) due to community-acquired pneumonia (CAP) is controversial, and the risk factors for NIV failure in these patients are not well known. We assessed the characteristics and predictors of outcome of patients with CAP and severe ARF treated with NIV. Methods We prospectively assessed 184 consecutive patients; 102 had “de novo” ARF, and 82 previous cardiac or respiratory disease. We defined successful NIV as avoidance of intubation and intensive care unit (ICU) survival at least 24 h in the ward. We assessed predictors of NIV failure and hospital mortality in multivariate analyses. Results Patients with “de novo” ARF failed NIV more frequently than patients with previous cardiac or respiratory disease (47, 46% versus 21, 26%, p  = 0.007). Worsening radiologic infiltrate 24 h after admission, maximum Sepsis-Related Organ Failure Assessment (SOFA) score and, after 1 h of NIV, higher heart rate and lower PaO 2 /FiO 2 and bicarbonate independently predicted NIV failure. Likewise, maximum SOFA, NIV failure and older age independently predicted hospital mortality. Among intubated patients with “de novo” ARF, NIV duration was shorter in hospital survivors than non-survivors (32 ± 24 versus 78 ± 65 h, p  = 0.014). In this group, longer duration of NIV before intubation was associated with decreased hospital survival (adjusted odds ratio 0.978, 95% confidence interval 0.962–0.995, p  = 0.012). This association was not observed in patients with previous cardiac or respiratory disease. Conclusions Successful NIV was strongly associated with better survival. If predictors for NIV failure are present, avoiding delayed intubation of patients with “de novo” ARF would potentially minimise mortality.

Abstract Rationale In the critically ill patients, lung ultrasound (LUS) is increasingly being used at the bedside for assessing alveolar-interstitial syndrome, lung consolidation, pneumonia, pneumothorax, and pleural effusion. It could be an easily repeatable noninvasive tool for assessing lung recruitment. Objectives Our goal was to compare the pressure–volume (PV) curve method with LUS for assessing positive end-expiratory pressure (PEEP)-induced lung recruitment in patients with acute respiratory distress syndrome/acute lung injury (ARDS/ALI). Methods Thirty patients with ARDS and 10 patients with ALI were prospectively studied. PV curves and LUS were performed in PEEP 0 and PEEP 15 cm H2O. PEEP-induced lung recruitment was measured using the PV curve method. Measurements and Main Results Four LUS entities were defined: consolidation; multiple, irregularly spaced B lines; multiple coalescent B lines; and normal aeration. For each of the 12 lung regions examined, PEEP-induced ultrasound changes were measured, and an ultrasound reaeration score was calculated. A highly significant correlation was found between PEEP-induced lung recruitment measured by PV curves and ultrasound reaeration score (Rho = 0.88; P < 0.0001). An ultrasound reaeration score of +8 or higher was associated with a PEEP-induced lung recruitment greater than 600 ml. An ultrasound lung reaeration score of +4 or less was associated with a PEEP-induced lung recruitment ranging from 75 to 450 ml. A statistically significant correlation was found between LUS reaeration score and PEEP-induced increase in PaO2 (Rho = 0.63; P < 0.05). Conclusions PEEP-induced lung recruitment can be adequately estimated with bedside LUS. Because LUS cannot assess PEEP-induced lung hyperinflation, it should not be the sole method for PEEP titration.

Background Prone position ventilation for acute hypoxemic respiratory failure (AHRF) improves oxygenation but not survival, except possibly when AHRF is severe. Objective To determine effects of prone versus supine ventilation in AHRF and severe hypoxemia [partial pressure of arterial oxygen (PaO 2 )/inspired fraction of oxygen (FiO 2 ) <100 mmHg] compared with moderate hypoxemia (100 mmHg ≤ PaO 2 /FiO 2  ≤ 300 mmHg). Design Systematic review and meta-analysis. Data Sources Electronic databases (to November 2009) and conference proceedings. Methods Two authors independently selected and extracted data from parallel-group randomized controlled trials comparing prone with supine ventilation in mechanically ventilated adults or children with AHRF. Trialists provided subgroup data. The primary outcome was hospital mortality in patients with AHRF and PaO 2 /FiO 2  <100 mmHg. Meta-analyses used study-level random-effects models. Results Ten trials ( N  = 1,867 patients) met inclusion criteria; most patients had acute lung injury. Methodological quality was relatively high. Prone ventilation reduced mortality in patients with PaO 2 /FiO 2  <100 mmHg [risk ratio (RR) 0.84, 95% confidence interval (CI) 0.74–0.96; p  = 0.01; seven trials, N  = 555] but not in patients with PaO 2 /FiO 2  ≥100 mmHg (RR 1.07, 95% CI 0.93–1.22; p  = 0.36; seven trials, N  = 1,169). Risk ratios differed significantly between subgroups (interaction p  = 0.012). Post hoc analysis demonstrated statistically significant improved mortality in the more hypoxemic subgroup and significant differences between subgroups using a range of PaO 2 /FiO 2 thresholds up to approximately 140 mmHg. Prone ventilation improved oxygenation by 27–39% over the first 3 days of therapy but increased the risks of pressure ulcers (RR 1.29, 95% CI 1.16–1.44), endotracheal tube obstruction (RR 1.58, 95% CI 1.24–2.01), and chest tube dislodgement (RR 3.14, 95% CI 1.02–9.69). There was no statistical between-trial heterogeneity for most clinical outcomes. Conclusions Prone ventilation reduces mortality in patients with severe hypoxemia. Given associated risks, this approach should not be routine in all patients with AHRF, but may be considered for severely hypoxemic patients.

Abstract Rationale Cognitive and psychiatric morbidity is common and potentially modifiable after acute lung injury (ALI). However, practical measures of neuropsychological function for use in multicenter trials are lacking. Objectives To determine whether a validated telephone-based neuropsychological test battery is feasible in a multicenter trial. To determine the frequency and risk factors for long-term neuropsychological impairment. Methods As an adjunct study to the Acute Respiratory Distress Syndrome Clinical Trials Network Fluid and Catheter Treatment Trial, we assessed neuropsychological function at 2 and 12 months post–hospital discharge. Measurements and Main Results Of 406 eligible survivors, we approached 261 to participate and 213 consented. We tested 122 subjects at least once, including 102 subjects at 12 months. Memory, verbal fluency, and executive function were impaired in 13% (12 of 92), 16% (15 of 96), and 49% (37 of 76) of long-term survivors. Long-term cognitive impairment was present in 41 of the 75 (55%) survivors who completed cognitive testing. Depression, post-traumatic stress disorder, or anxiety was present in 36% (37 of 102), 39% (40 of 102), and 62% (63 of 102) of long-term survivors. Enrollment in a conservative fluid-management strategy (P = 0.005) was associated with cognitive impairment and lower partial pressure of arterial oxygen during the trial was associated with cognitive (P = 0.02) and psychiatric impairment (P = 0.02). Conclusions Neuropsychological function can be assessed by telephone in a multicenter trial. Long-term neuropsychological impairment is common in survivors of ALI. Hypoxemia is a risk factor for long-term neuropsychological impairment. Fluid management strategy is a potential risk factor for long-term cognitive impairment; however, given the select population studied and an unclear mechanism, this finding requires confirmation.

The assessment of asthma control is pivotal to the evaluation of treatment response in individuals and in clinical trials. Previously, asthma control, severity, and exacerbations were defined and assessed in many different ways. The Task Force was established to provide recommendations about standardization of outcomes relating to asthma control, severity, and exacerbations in clinical trials and clinical practice, for adults and children aged 6 years or older. A narrative literature review was conducted to evaluate the measurement properties and strengths/weaknesses of outcome measures relevant to asthma control and exacerbations. The review focused on diary variables, physiologic measurements, composite scores, biomarkers, quality of life questionnaires, and indirect measures. The Task Force developed new definitions for asthma control, severity, and exacerbations, based on current treatment principles and clinical and research relevance. In view of current knowledge about the multiple domains of asthma and asthma control, no single outcome measure can adequately assess asthma control. Its assessment in clinical trials and in clinical practice should include components relevant to both of the goals of asthma treatment, namely achievement of best possible clinical control and reduction of future risk of adverse outcomes. Recommendations are provided for the assessment of asthma control in clinical trials and clinical practice, both at baseline and in the assessment of treatment response. The Task Force recommendations provide a basis for a multicomponent assessment of asthma by clinicians, researchers, and other relevant groups in the design, conduct, and evaluation of clinical trials, and in clinical practice.

Purpose Ultrasonography allows the direct observation of the diaphragm. Its thickness variation measured in the zone of apposition has been previously used to diagnose diaphragm paralysis. We assessed the feasibility and accuracy of this method to assess diaphragmatic function and its contribution to respiratory workload in critically ill patients under non-invasive ventilation. Methods This was a preliminary physiological study in the intensive care unit of a university hospital. Twelve patients requiring planned non-invasive ventilation after extubation were studied while spontaneously breathing and during non-invasive ventilation at three levels of pressure support (5, 10 and 15 cmH 2 O). Diaphragm thickness was measured in the zone of apposition during tidal ventilation and the thickening fraction (TF) was calculated as (thickness at inspiration − thickness at expiration)/thickness at expiration. Diaphragmatic pressure–time product per breath (PTP di ) was measured from oesophageal and gastric pressure recordings. Results PTP di and TF both decreased as the level of pressure support increased. A significant correlation was found between PTP di and TF (ρ = 0.74, p  < 0.001). The overall reproducibility of TF assessment was good but the coefficient of repeatability reached 18 % for inter-observer reproducibility. Conclusions Ultrasonographic assessment of the diaphragm TF is a non-invasive method that may prove useful in evaluating diaphragmatic function and its contribution to respiratory workload in intensive care unit patients.

Abstract Rationale Accurate, early identification of patients at risk for developing acute lung injury (ALI) provides the opportunity to test and implement secondary prevention strategies. Objectives To determine the frequency and outcome of ALI development in patients at risk and validate a lung injury prediction score (LIPS). Methods In this prospective multicenter observational cohort study, predisposing conditions and risk modifiers predictive of ALI development were identified from routine clinical data available during initial evaluation. The discrimination of the model was assessed with area under receiver operating curve (AUC). The risk of death from ALI was determined after adjustment for severity of illness and predisposing conditions. Measurements and Main Results Twenty-two hospitals enrolled 5,584 patients at risk. ALI developed a median of 2 (interquartile range 1–4) days after initial evaluation in 377 (6.8%; 148 ALI-only, 229 adult respiratory distress syndrome) patients. The frequency of ALI varied according to predisposing conditions (from 3% in pancreatitis to 26% after smoke inhalation). LIPS discriminated patients who developed ALI from those who did not with an AUC of 0.80 (95% confidence interval, 0.78–0.82). When adjusted for severity of illness and predisposing conditions, development of ALI increased the risk of in-hospital death (odds ratio, 4.1; 95% confidence interval, 2.9–5.7). Conclusions ALI occurrence varies according to predisposing conditions and carries an independently poor prognosis. Using routinely available clinical data, LIPS identifies patients at high risk for ALI early in the course of their illness. This model will alert clinicians about the risk of ALI and facilitate testing and implementation of ALI prevention strategies. Clinical trial registered with www.clinicaltrials.gov (NCT00889772).