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Introduction: Acute respiratory failure requiring mechanical ventilation is a leading cause of mortality in the intensive care unit. Although single peripheral blood oxygen saturation/fraction of inspired oxygen (SpO2/FiO2) ratios of hypoxemia have been evaluated to risk-stratify patients with acute respiratory distress syndrome, the utility of longitudinal SpO2/FiO2 ratios is unknown. Objective: To assess time-based SpO2/FiO2 ratios ≤ 150--Sp02/ FiO2 time at risk (SF-TAR)--for predicting mortality in mechanically ventilated patients. Methods: Retrospective, observational cohort study of mechanically ventilated patients at 21 community and 2 academic hospitals. Association between the SF-TAR in the first 24 hours of ventilation and mortality was examined using multivariable logistic regression and compared with the worst recorded isolated partial pressure of arterial oxygen/fraction of inspired oxygen (P/F) ratio. Results: In 28,758 derivation cohort admissions, every 10% increase in SF-TAR was associated with a 24% increase in adjusted odds of hospital mortality (adjusted odds ratio = 1.24; 95% confidence interval [CI] = 1.23-1.26); a similar association was observed in validation cohorts. Discrimination for mortality modestly improved with SF-TAR (area under the receiver operating characteristic curve [AUROC] = 0.81; 95% CI = 0.81-0.82) vs the worst P/F ratio (AUROC = 0.78; 95% CI = 0.78-0.79) and worst SpO2/FiO2 ratio (AUROC = 0.79; 95% CI = 0.79-0.80). The SF-TAR in the first 6 hours offered comparable discrimination for hospital mortality (AUROC = 0.80; 95% CI = 0.79-0.80) to the 24-hour SF-TAR. Conclusion: The SF-TAR can identify ventilated patients at increased risk of death, offering modest improvements compared with single SpO2/FiO2 and P/F ratios. This longitudinal, noninvasive, and broadly generalizable tool may have particular utility for early phenotyping and risk stratification using electronic health record data in ventilated patients. [ABSTRACT FROM AUTHOR]

Objective: A high plasma level of inflammasome mediator interleukin-18 was associated with mortality in observational acute respiratory distress syndrome cohorts. Statin exposure increases both inflammasome activation and lung injury in mouse models. We tested whether randomization to statin therapy correlated with increased interleukin-18 in the ARDS Network Statins for Acutely Injured Lungs from Sepsis trial.Design: Retrospective analysis of randomized controlled clinical trial.Setting: Multicenter North American clinical trial, the ARDS Network Statins for Acutely Injured Lungs from Sepsis.Patients: Six hundred eighty-three subjects with infection-related acute respiratory distress syndrome, representing 92% of the original trial population.Interventions: Random assignment of rosuvastatin or placebo for up to 28 days or 3 days after ICU discharge.Measurements and Main Results: We measured plasma interleukin-18 levels in all Statins for Acutely Injured Lungs from Sepsis patients with sample available at day 0 (baseline, n = 683) and day 3 (after randomization, n = 588). We tested the association among interleukin-18 level at baseline, rising interleukin-18, and the impact of statin therapy on 60-day mortality, adjusting for severity of illness. Baseline plasma interleukin-18 level greater than or equal to 800 pg/mL was highly associated with 60-day mortality, with a hazard of death of 2.3 (95% CI, 1.7-3.1). Rising plasma interleukin-18 was also associated with increased mortality. For each unit increase in log2 (interleukin-18) at day 3 compared with baseline, the hazard of death increased by 2.3 (95% CI, 1.5-3.5). Subjects randomized to statin were significantly more likely to experience a rise in plasma interleukin-18 levels. Subjects with acute kidney injury, shock, low baseline interleukin-18, and those not receiving systemic corticosteroids were more likely to experience rising interleukin-18. Randomization to statin therapy was associated with rising in interleukin-18 in all of those subsets, however.Conclusions: Elevated baseline plasma interleukin-18 was associated with higher mortality in sepsis-induced acute respiratory distress syndrome. A rise in plasma interleukin-18 was also associated with increased mortality and was more common in subjects randomized to statin therapy in this clinical trial. [ABSTRACT FROM AUTHOR]

A better understanding of the pathogenesis and the resolution of the acute respiratory distress syndrome (ARDS) is needed. Although some progress has been made with the use of protein biomarkers and candidate gene studies in understanding the pathobiology of ARDS, we propose that new studies that measure the chemical breakdown products of cellular metabolism (metabolomics) may provide new insights into ARDS, in part because metabolomics targets a later point in the genomics cascade than is possible with studies of DNA, RNA, and protein biomarkers. Technological advances have made largescale metabolomic profiling increasingly feasible. Metabolomic approaches have already achieved novel insights in nonpulmonary diseases such as diabetes mellitus and malignancy, as well as in sepsis, a major risk factor for developing ARDS. Metabolomic profiling is a promising approach to identify novel pathways in both patients at risk for developing ARDS as well as in the early phase of established ARDS. [ABSTRACT FROM AUTHOR]

Specifically, rosuvastatin (used in the SAILS trial) is one of the more hydrophilic statins, and the hydrophilic statin pravastatin was associated with inflammasome activation enhanced bleomycin-induced lung inflammation in mice ([7]). Importantly, we view our results as a provocative hypothesis-generating study to facilitate future precision medicine-targeted treatment approaches for sepsis and ARDS. 2 Rogers AJ, Guan J, Trtchounian A. Association of elevated plasma interleukin-18 level with increased mortality in a clinical trial of statin treatment for acute respiratory distress syndrome. [Extracted from the article]

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OBJECTIVES: Interleukin-18 (IL-18) plasma level and latent class analysis (LCA) have separately been shown to predict prognosis and treatment response in acute respiratory distress syndrome (ARDS). IL-18 is a measure of inflammasome activation, a pathway potentially distinct from inflammation captured by biomarkers defining previously published LCA classes. We hypothesized that elevated IL-18 would identify distinct “high-risk” patients not captured by prior LCA classifications. DESIGN: Statins for acutely injured lungs from sepsis (SAILS) and hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in acute lung injury to reduce pulmonary dysfunction trial (HARP-2) are two large randomized, controlled trials in ARDS in which both LCA assignments and IL-18 levels were shown to predict mortality. We first evaluated the overlap between high IL-18 levels (≥ 800 pg/mL) with prior LCA class assignments using McNemar’s test and then tested the correlation between IL-18 and LCA biomarkers using Pearson’s exact test on log-2 transformed values. Our primary analysis was the association of IL-18 level with 60-day mortality in the hypoinflammatory LCA class, which was assessed using the Fisher exact test and Cox proportional hazards modeling adjusting for age, Acute Physiology and Chronic Health Evaluation score, and gender. Secondary analyses included the association of IL-18 and LCA with mortality within each IL-18/LCA subgroup. SETTING: Secondary analysis of two multicenter, randomized controlled clinical trials of ARDS patients. SUBJECTS: Six hundred eighty-three patients in SAILS and 511 patients in HARP-2. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We found that 33% of patients in SAILS and HARP-2 were discordant by IL-18 level and LCA class. We further found that IL-18 level was only modestly correlated (0.17–0.47) with cytokines used in the LCA assignment. A substantial subset of individuals classified as hypoinflammatory by LCA (14% of SAILS and 43% of HARP-2) were classified as high risk by elevated IL-18. These individuals were at high risk for mortality in both SAILS (42% 60-d mortality, odds ratio [OR] 3.3; 95% CI, 1.8–6.1; p < 0.001) and HARP-2 (27% 60-d mortality, OR 2.1; 95% CI, 1.2–3.8; p = 0.009). CONCLUSIONS: Plasma IL-18 level provides important additional prognostic information to LCA subphenotypes defined largely by traditional inflammatory biomarkers in two large ARDS cohorts. [ABSTRACT FROM AUTHOR]

The article discusses a study by D. J. Kor and colleagues which examines the accuracy of early warning identification systems, pulmonary vascular permeability index (PVPI) and peak extravascular lung water (EVLWi), in identifying early acute respiratory distress syndrome (ARDS). It says that PVPI and EVLWi were examined as markers of pulmonary edema in patients undergoing high-risk cardiac surgery. It discusses how area under curve (AUC) compare to identification methods for high-risk patients.

Using latent class analysis (LCA) of clinical and protein biomarkers, researchers have identified two phenotypes of the acute respiratory distress syndrome (ARDS) with divergent clinical trajectories and treatment responses. We investigated whether plasma metabolites differed among patients with LCA-derived hyperinflammatory and hypoinflammatory ARDS, and we tested the prognostic utility of adding metabolic clusters to LCA phenotypes. We analyzed data from 93 patients with ARDS and sepsis enrolled in a multicenter prospective cohort of critically ill patients, comparing 970 metabolites between the two LCA-derived phenotypes. In all, 188 metabolites were differentially abundant between the two LCA-derived phenotypes. After adjusting for age, sex, confounding medications, and comorbid liver and kidney disease, 82 metabolites remained significantly different. Patients with hyperinflammatory ARDS had reduced circulating lipids but high levels of pyruvate, lactate, and malate. Metabolic cluster and LCA-derived phenotypes were each significantly and independently associated with survival. Patients with hyperinflammatory ARDS may be experiencing a glycolytic shift leading to dysregulated lipid metabolism. Metabolic profiling offers prognostic information beyond what is captured by LCA phenotypes alone. Deeper biological profiling may identify key differences in pathogenesis among patients with ARDS and may lead to novel targeted therapies. [ABSTRACT FROM AUTHOR]

Background: A better understanding of the clinical features associated with prolonged hospitalization in acute respiratory failure may allow for better-informed care planning.Research Question: What are the incidence, mortality, cost, and clinical determinants of prolonged hospitalization among patients with acute respiratory failure (ARF)?Study Design and Methods: Using the National Inpatient Sample data from 2004 to 2014, we identified adults 18 years and older with International Classification of Diseases, 9th edition (ICD-9) codes for ARF requiring mechanical ventilation for at least 2 days (ICD-9 518.81 or 518.82, 96.7 or 96.04, and 96.05). Outcomes studied included incidence, in-hospital mortality, cost of hospitalization, and associated patient-level and hospital-level characteristics. Trends were assessed by logistic regression, linear regression, and general linear modeling with Poisson distribution.Results: Of the 5,539,567 patients with ARF, 77,665 (1.4%) had a prolonged length of stay (pLOS), defined as ≥ 60 days. Among those with pLOS, 52,776 (68%) survived to discharge. Over the study period, the incidence of pLOS decreased by 48%, in-patient mortality decreased by 18%, per-patient cost of care rose, but the percentage of the total cost of ARF care consumed by patients with pLOS did not significantly decrease (P = .06). Prolonged LOS was more likely to occur in urban teaching hospitals (OR, 6.8; 95% CI, 4.6-10.2; P < .001), hospitals located in the northeastern United States (OR, 3.6; 95% CI, 3.0-4.3; P < .001), and among patients with Medicaid insurance coverage (OR, 2.1; 95% CI, 1.9-2.4; P < .001).Interpretation: From 2004 to 2014, incidence and mortality decreased among patients with ARF and pLOS, and although per-patient costs rose, the percentage of total cost of care remained stable. There is substantial variation in length of stay for patients with ARF by US region, hospital teaching status, and patient insurance coverage. [ABSTRACT FROM AUTHOR]

Objectives: To identify a novel, generalizable diagnostic for acute respiratory distress syndrome using whole-blood gene expression arrays from multiple acute respiratory distress syndrome cohorts of varying etiologies.Data Sources: We performed a systematic search for human whole-blood gene expression arrays of acute respiratory distress syndrome in National Institutes of Health Gene Expression Omnibus and ArrayExpress. We also included the Glue Grant gene expression cohorts.Study Selection: We included investigator-defined acute respiratory distress syndrome within 48 hours of diagnosis and compared these with relevant critically ill controls.Data Extraction: We used multicohort analysis of gene expression to identify genes significantly associated with acute respiratory distress syndrome, both with and without adjustment for clinical severity score. We performed gene ontology enrichment using Database for Annotation, Visualization and Integrated Discovery and cell type enrichment tests for both immune cells and pneumocyte gene expression. Finally, we selected a gene set optimized for diagnostic power across the datasets and used leave-one-dataset-out cross validation to assess robustness of the model.Data Synthesis: We identified datasets from three adult cohorts with sepsis, one pediatric cohort with acute respiratory failure, and two datasets of adult patients with trauma and burns, for a total of 148 acute respiratory distress syndrome cases and 268 critically ill controls. We identified 30 genes that were significantly associated with acute respiratory distress syndrome (false discovery rate < 20% and effect size >1.3), many of which had been previously associated with sepsis. When metaregression was used to adjust for clinical severity scores, none of these genes remained significant. Cell type enrichment was notable for bands and neutrophils, suggesting that the gene expression signature is one of acute inflammation rather than lung injury per se. Finally, an attempt to develop a generalizable diagnostic gene set for acute respiratory distress syndrome showed a mean area under the receiver-operating characteristic curve of only 0.63 on leave-one-dataset-out cross validation.Conclusions: The whole-blood gene expression signature across a wide clinical spectrum of acute respiratory distress syndrome is likely confounded by systemic inflammation, limiting the utility of whole-blood gene expression studies for uncovering a generalizable diagnostic gene signature. [ABSTRACT FROM AUTHOR]