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Purpose: The purpose of this study was to determine associations between markers of inflammation and endogenous anticoagulant activity with delirium and coma during critical illness., Methods: In this prospective cohort study, we enrolled adults with respiratory failure and/or shock treated in medical or surgical intensive care units (ICUs) at 5 centers. Twice per day in the ICU, and daily thereafter, we assessed mental status using the Richmond Agitation Sedation Scale (RASS) and the Confusion Assessment Method-Intensive Care Unit (CAM-ICU). We collected blood samples on study days 1, 3, and 5, measuring levels of C-reactive protein (CRP), interferon gamma (IFN-γ), interleukin (IL)-1 beta (IL-1β), IL-6, IL-8, IL-10, IL-12, matrix metalloproteinase-9 (MMP-9), tumor necrosis factor-alpha (TNF-α), tumor necrosis factor receptor 1 (TNFR1), and protein C using validated protocols. We used multinomial logistic regression to analyze associations between biomarkers and the odds of delirium or coma versus normal mental status the following day, adjusting for age, sepsis, Sequential Organ Failure Assessment (SOFA), study day, corticosteroids, and sedatives., Results: Among 991 participants with a median age (interquartile range, IQR) of 62 [53-72] years and enrollment SOFA of 9 [7-11], higher concentrations of IL-6 (odds ratio [OR] [95% CI]: 1.8 [1.4-2.3]), IL-8 (1.3 [1.1-1.5]), IL-10 (1.5 [1.2-1.8]), TNF-α (1.2 [1.0-1.4]), and TNFR1 (1.3 [1.1-1.6]) and lower concentrations of protein C (0.7 [0.6-0.8])) were associated with delirium the following day. Higher concentrations of CRP (1.4 [1.1-1.7]), IFN-γ (1.3 [1.1-1.5]), IL-6 (2.3 [1.8-3.0]), IL-8 (1.8 [1.4-2.3]), and IL-10 (1.5 [1.2-2.0]) and lower concentrations of protein C (0.6 [0.5-0.8]) were associated with coma the following day. IL-1β, IL-12, and MMP-9 were not associated with mental status., Conclusion: Markers of inflammation and possibly endogenous anticoagulant activity are associated with delirium and coma during critical illness., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Exposures to ambient air pollutants may prime the lung enhancing risk of acute respiratory distress syndrome (ARDS) in sepsis. Our objective was to determine the association of short-, medium-, and long-term pollutant exposures and ARDS risk in critically ill sepsis patients., Methods: We analyzed a prospective cohort of 1858 critically ill patients with sepsis, and estimated short- (3 days), medium- (6 weeks), and long- (5 years) term exposures to ozone, nitrogen dioxide (NO 2 ), sulfur dioxide (SO 2 ), carbon monoxide (CO), particulate matter < 2.5 μm (PM 2.5 ), and PM < 10 μm (PM 10 ) using weighted averages of daily levels from monitors within 50 km of subjects' residences. Subjects were followed for 6 days for ARDS by the Berlin Criteria. The association between each pollutant and ARDS was determined using multivariable logistic regression adjusting for preselected confounders. In 764 subjects, we measured plasma concentrations of inflammatory proteins at presentation and tested for an association between pollutant exposure and protein concentration via linear regression., Results: ARDS developed in 754 (41%) subjects. Short- and long-term exposures to SO 2 , NO 2 , and PM 2.5 were associated with ARDS risk (SO 2 : odds ratio (OR) for the comparison of the 75-25th long-term exposure percentile 1.43 (95% confidence interval (CI) 1.16, 1.77); p < 0.01; NO 2 : 1.36 (1.06, 1.74); p = 0.04, PM 2.5 : 1.21 (1.04, 1.41); p = 0.03). Long-term exposures to these three pollutants were also associated with plasma interleukin-1 receptor antagonist and soluble tumor necrosis factor receptor-1 concentrations., Conclusion: Short and long-term exposures to ambient SO 2 , PM 2.5 , and NO 2 are associated with increased ARDS risk in sepsis, representing potentially modifiable environmental risk factors for sepsis-associated ARDS., (© 2023. Springer-Verlag GmbH Germany, part of Springer Nature.)

The aim of these guidelines is to update the 2017 clinical practice guideline (CPG) of the European Society of Intensive Care Medicine (ESICM). The scope of this CPG is limited to adult patients and to non-pharmacological respiratory support strategies across different aspects of acute respiratory distress syndrome (ARDS), including ARDS due to coronavirus disease 2019 (COVID-19). These guidelines were formulated by an international panel of clinical experts, one methodologist and patients' representatives on behalf of the ESICM. The review was conducted in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement recommendations. We followed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess the certainty of evidence and grade recommendations and the quality of reporting of each study based on the EQUATOR (Enhancing the QUAlity and Transparency Of health Research) network guidelines. The CPG addressed 21 questions and formulates 21 recommendations on the following domains: (1) definition; (2) phenotyping, and respiratory support strategies including (3) high-flow nasal cannula oxygen (HFNO); (4) non-invasive ventilation (NIV); (5) tidal volume setting; (6) positive end-expiratory pressure (PEEP) and recruitment maneuvers (RM); (7) prone positioning; (8) neuromuscular blockade, and (9) extracorporeal life support (ECLS). In addition, the CPG includes expert opinion on clinical practice and identifies the areas of future research., (© 2023. The Author(s).)

Although the acute respiratory distress syndrome (ARDS) is well defined by the development of acute hypoxemia, bilateral infiltrates and non-cardiogenic pulmonary edema, ARDS is heterogeneous in terms of clinical risk factors, physiology of lung injury, microbiology, and biology, potentially explaining why pharmacologic therapies have been mostly unsuccessful in treating ARDS. Identifying phenotypes of ARDS and integrating this information into patient selection for clinical trials may increase the chance for efficacy with new treatments. In this review, we focus on classifying ARDS by the associated clinical disorders, physiological data, and radiographic imaging. We consider biologic phenotypes, including plasma protein biomarkers, gene expression, and common causative microbiologic pathogens. We will also discuss the issue of focusing clinical trials on the patient's phase of lung injury, including prevention, administration of therapy during early acute lung injury, and treatment of established ARDS. A more in depth understanding of the interplay of these variables in ARDS should provide more success in designing and conducting clinical trials and achieving the goal of personalized medicine.

With the exception of a few successes in trials of supportive care, the majority of interventional clinical trials for acute respiratory distress syndrome (ARDS) have not led to new therapies. To improve the likelihood of benefit from clinical trial interventions in ARDS, clinical trial design must be improved. To optimize trial design, many factors need to be considered including the type of therapy to be tested, the type of trial (phase 2 or 3), how patients will be selected, primary and secondary end-points, and strategy for conduct of the trial, including potential newer trial designs such as platform or adaptive trials. Of these, optimization of patient selection is central to the likelihood of success and is particularly relevant in ARDS, which is a heterogeneous clinical syndrome, not a homogeneous disease. Recent advances including improved understanding of pathophysiologic mechanisms and better tools for outcome prediction in ARDS should facilitate both predictive and prognostic enrichment. This commentary focuses on new information and novel methods for prognostic and predictive enrichment that may be useful to optimize patient selection and increase the likelihood of positive clinical trials in ARDS.

Purpose: Previous studies assessing impact of acute respiratory distress syndrome (ARDS) on mortality have shown conflicting results. We sought to assess the independent association of ARDS with in-hospital mortality among intensive care unit (ICU) patients with sepsis., Methods: We studied two prospective sepsis cohorts drawn from the Early Assessment of Renal and Lung Injury (EARLI; n = 474) and Validating Acute Lung Injury markers for Diagnosis (VALID; n = 337) cohorts. ARDS was defined by Berlin criteria. We used logistic regression to compare in-hospital mortality in patients with and without ARDS, controlling for baseline severity of illness. We also estimated attributable mortality, adjusted for illness severity by stratification., Results: ARDS occurred in 195 EARLI patients (41%) and 99 VALID patients (29%). ARDS was independently associated with risk of hospital death in multivariate analysis, even after controlling for severity of illness, as measured by APACHE II (odds ratio [OR] 1.65 (95% confidence interval [CI] 1.02, 2.67), p = 0.04 in EARLI; OR 2.12 (CI 1.16, 3.92), p = 0.02 in VALID). Patients with severe ARDS (P/F < 100) primarily drove this relationship. The attributable mortality of ARDS was 27% (CI 14%, 37%) in EARLI and 37% (CI 10%, 51%) in VALID. ARDS was independently associated with ICU mortality, hospital length of stay (LOS), ICU LOS, and ventilator-free days., Conclusions: Development of ARDS among ICU patients with sepsis confers increased risk of ICU and in-hospital mortality in addition to other important outcomes. Clinical trials targeting patients with severe ARDS will be best poised to detect measurable differences in these outcomes.

Purpose: Neurologic and endothelial injury biomarkers are associated with prolonged delirium during critical illness and may reflect injury pathways that lead to poor long-term outcomes. We hypothesized that blood-brain barrier (BBB), neuronal, and endothelial injury biomarkers measured during critical illness are associated with cognitive impairment and disability after discharge., Methods: We enrolled adults with respiratory failure and/or shock and measured plasma concentrations of BBB (S100B), neuronal (UCHL1, BDNF), and endothelial (E-selectin, PAI-1) injury markers within 72 h of ICU admission. At 3 and 12 months post-discharge, we assessed participants' global cognition, executive function, and activities of daily living (ADL). We used multivariable regression to determine whether biomarkers were associated with outcomes after adjusting for relevant demographic and acute illness covariates., Results: Our study included 419 survivors of critical illness with median age 59 years and APACHE II score 25. Higher S100B was associated with worse global cognition at 3 and 12 months (P = 0.008; P = 0.01). UCHL1 was nonlinearly associated with global cognition at 3 months (P = 0.02). Higher E-selectin was associated with worse global cognition (P = 0.006 at 3 months; P = 0.06 at 12 months). BDNF and PAI-1 were not associated with global cognition. No biomarkers were associated with executive function. Higher S100B (P = 0.05) and E-selectin (P = 0.02) were associated with increased disability in ADLs at 3 months., Conclusions: S100B, a marker of BBB and/or astrocyte injury, and E-selectin, an adhesion molecule and marker of endothelial injury, are associated with long-term cognitive impairment after critical illness, findings that may reflect mechanisms of critical illness brain injury.

Purpose: Mortality prediction in ARDS is important for prognostication and risk stratification. However, no prediction models have been independently validated. A combination of two biomarkers with age and APACHE III was superior in predicting mortality in the NHLBI ARDSNet ALVEOLI trial. We validated this prediction tool in two clinical trials and an observational cohort., Methods: The validation cohorts included 849 patients from the NHLBI ARDSNet Fluid and Catheter Treatment Trial (FACTT), 144 patients from a clinical trial of sivelestat for ARDS (STRIVE), and 545 ARDS patients from the VALID observational cohort study. To evaluate the performance of the prediction model, the area under the receiver operating characteristic curve (AUC), model discrimination, and calibration were assessed, and recalibration methods were applied., Results: The biomarker/clinical prediction model performed well in all cohorts. Performance was better in the clinical trials with an AUC of 0.74 (95% CI 0.70-0.79) in FACTT, compared to 0.72 (95% CI 0.67-0.77) in VALID, a more heterogeneous observational cohort. The AUC was 0.73 (95% CI 0.70-0.76) when FACTT and VALID were combined., Conclusion: We validated a mortality prediction model for ARDS that includes age, APACHE III, surfactant protein D, and interleukin-8 in a variety of clinical settings. Although the model performance as measured by AUC was lower than in the original model derivation cohort, the biomarker/clinical model still performed well and may be useful for risk assessment for clinical trial enrollment, an issue of increasing importance as ARDS mortality declines, and better methods are needed for selection of the most severely ill patients for inclusion.

Objective: Thombomodulin (TM) is an activator of protein C and a biomarker for endothelial injury. We hypothesized that (1) elevated plasma levels would be associated with clinical outcomes and (2) polymorphisms in the TM gene would be associated with plasma levels., Patients: We studied 449 patients enrolled in the Fluid and Catheter Treatment Trial (FACTT) for whom both plasma and DNA were available. We used logistic regression and receiver operator curves (ROC) to test for associations between soluble TM (sTM) and mortality at 60 days., Measurements and Results: Plasma sTM levels were higher in non-survivors than survivors at baseline [median 147 (IQR, 95-218) vs. 89 (56-129) ng/mL, p < 0.0001] and on day 3 after study enrollment [205 (146-302) vs. 127 (85-189), p < 0.0001]. The odds of death increased by 2.4 (95 % CI 1.5-3.8, p < 0.001), and by 2.8 (1.7-4.7, P < 0.001) for every log increase in baseline and day 3 sTM levels, respectively, after adjustment for age, race, gender, severity of illness, fluid management strategy, baseline creatinine, and non-pulmonary sepsis as the primary cause of ARDS. By ROC analysis, plasma sTM levels discriminated between non-survivors and survivors [AUC = 72 % (66-78 %) vs. AUC = 54 % for severity based on Berlin criteria). Addition of sTM improved discrimination based on APACHE III from 77 to 80 % (P < 0.03). sTM levels at baseline were not statistically different among subjects stratified by genotypes of tag SNPs in the TM gene., Conclusions: Higher plasma sTM levels are associated with increased mortality in ARDS. The lack of association between the sTM levels and genetic variants suggests that the increased levels of sTM may reflect severity of endothelial damage rather than genetic heterogeneity. These findings underscore the importance of endothelial injury in ARDS pathogenesis and suggest that, in combination with clinical markers, sTM could contribute to risk stratification.

Purpose: Advances in supportive care and ventilator management for acute respiratory distress syndrome (ARDS) have resulted in declines in short-term mortality, but risks of death after survival to hospital discharge have not been well described. Our objective was to quantify the difference between short-term and long-term mortality in ARDS and to identify risk factors for death and causes of death at 1 year among hospital survivors., Methods: This multi-intensive care unit, prospective cohort included patients with ARDS enrolled between January 2006 and February 2010. We determined the clinical characteristics associated with in-hospital and 1-year mortality among hospital survivors and utilized death certificate data to identify causes of death., Results: Of 646 patients hospitalized with ARDS, mortality at 1 year was substantially higher (41 %, 95% CI 37-45%) than in-hospital mortality (24%, 95% CI 21-27%), P < 0.0001. Among 493 patients who survived to hospital discharge, the 110 (22%) who died in the subsequent year were older (P < 0.001) and more likely to have been discharged to a nursing home, other hospital, or hospice compared to patients alive at 1 year (P < 0.001). Important predictors of death among hospital survivors were comorbidities present at the time of ARDS, and not living at home prior to admission. ARDS-related measures of severity of illness did not emerge as independent predictors of mortality in hospital survivors., Conclusions: Despite improvements in short-term ARDS outcomes, 1-year mortality is high, mostly because of the large burden of comorbidities, which are prevalent in patients with ARDS.

Purpose: To assess the associations between a priori-selected markers of inflammation and coagulation and delirium during critical illness., Methods: In this prospective cohort study, we collected blood from mechanically ventilated medical intensive care unit (ICU) patients and measured nine plasma markers of inflammation and coagulation. We assessed patients daily for delirium using the Confusion Assessment Method for the ICU and used multivariable regression to analyze the associations between plasma markers and subsequent delirium, after adjusting for age, severity of illness, and sepsis., Results: Among the 138 patients studied, with median age of 66 years and median Acute Physiology and Chronic Health Evaluation (APACHE) II of 27, 107 (78 %) were delirious at some point during the study. Two markers of inflammation and one of coagulation were significantly associated with delirium. After adjusting for covariates, lower plasma concentrations of matrix metalloproteinase-9 (MMP-9) and protein C were associated with increased probability of delirium (p = 0.04 and 0.01, respectively), and higher concentrations of soluble tumor necrosis factor receptor-1 (sTNFR1) were associated with increased probability of delirium (p < 0.01). Concentrations of C-reactive protein (p = 0.82), myeloperoxidase (p = 0.11), neutrophil gelatinase-associated lipocalin (p = 0.70), D-dimer (p = 0.83), plasminogen activator inhibitor type 1 (p = 0.98), and Von Willebrand factor antigen (p = 0.65) were not associated with delirium., Conclusions: In this study, MMP-9, protein C, and sTNFR1 were independently associated with subsequent ICU delirium. These results suggest that specific aspects of inflammation and coagulation may play a role in the evolution of delirium during critical illness and that these markers should be examined in larger studies of ICU patients.

Objective: Laminin-5, a cell adhesive molecule expressed solely by epithelium, is known to enhance epithelial cell migration and repair of injured epithelium, after its essential component gamma2-chain is processed proteolytically. Our previous study revealed circulating levels of amino-terminal fragment of laminin gamma2-chain (G2F) reflect epithelial tumor invasiveness in carcinoma patients, but its physiological role in alveolar epithelial injury remains unknown., Design: Sampling of epithelial lining fluids or pulmonary edema fluids from patients with acute lung injury (ALI) or related diseases was performed. Plasma samples were obtained from them at the time of disease onset or later. G2F concentrations were determined by immunoassay constructed by ourselves., Results: We found a significantly higher amount of G2F in pulmonary edema and epithelial lining fluids of patients with ALI, as compared with those with the other respiratory diseases. Their plasma levels were also elevated significantly early at the onset of ALI (mean +/- SD; 147 +/- 82 ng/ml in non-surviving and 90 +/- 56 in surviving patients) as compared with those in the patients with cardiogenic pulmonary edema (59 +/- 36) or idiopathic pulmonary fibrosis (37 +/- 17), indicating alveolar epithelium rapidly secrete laminin-5 in ALI. At 5 days after onset, non-surviving patients maintained higher plasma concentrations (152 +/- 84), but in contrast, the levels in surviving patients declined (71 +/- 35), suggesting secretion of laminin-5 was suppressed, associated with recovery from ALI., Conclusion: Circulating G2F may be a biomarker for alveolar laminin-5 secreted early at disease onset in ALI, potentially regulating alveolar re-epithelialization.

Objective: To determine if levels of soluble intercellular adhesion molecule-1 (sICAM-1), a marker of alveolar epithelial and endothelial injury, differ in patients with hydrostatic pulmonary edema and acute lung injury (ALI) and are associated with clinical outcomes in patients with ALI., Design, Setting, and Participants: Measurement of sICAM-1 levels in (1) plasma and edema fluid from 67 patients with either hydrostatic pulmonary edema or ALI enrolled in an observational, prospective single center study, and (2) in plasma from 778 patients with ALI enrolled in a large multi-center randomized controlled trial of ventilator strategy., Results: In the single-center study, levels of sICAM-1 were significantly higher in both edema fluid and plasma (median 938 and 545 ng/ml, respectively) from ALI patients compared to hydrostatic edema patients (median 384 and 177 ng/ml, P < 0.03 for both comparisons). In the multi-center study, higher plasma sICAM-1 levels were associated with poor clinical outcomes in both unadjusted and multivariable models. Subjects with ALI whose plasma sICAM-1 levels increased over the first 3 days of the study had a higher risk of death, after adjusting for other important predictors of outcome (odds ratio 1.48; 95% CI 1.03-2.12, P = 0.03)., Conclusions: Both plasma and edema fluid levels of sICAM-1 are higher in patients with ALI than in patients with hydrostatic pulmonary edema. Higher plasma sICAM-1 levels and increasing sICAM-1 levels over time are associated with poor clinical outcomes in ALI. Measurement of sICAM-1 levels may be useful for identifying patients at highest risk of poor outcomes from ALI.

There is evidence that dysregulation of coagulation and fibrinolysis may participate in the pathogenesis of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS). Altered concentrations of several proteins of the coagulation and fibrinolytic pathways in plasma and pulmonary edema fluid from patients with acute lung injury have been related to the severity of lung injury and clinical outcomes. Polymorphisms in the genes encoding for proteins of the protein C and fibrinolysis pathways are known to regulate the production of the respective proteins. It is plausible that these polymorphisms may be associated with the susceptibility to and severity of illness in ALI and ARDS. Well-designed studies that examine the association of these polymorphisms with susceptibility and severity of ALI and ARDS are needed to test the influence of both genetic and environmental factors on the clinical outcomes in patients with ALI and ARDS. There are several important considerations in the design of these genetic association studies, including selection of candidate genes with the most biological plausibility, definition of the phenotype, selection of appropriate controls, determination of the appropriate sample size and assessment of Hardy-Weinberg equilibrium among controls as a measure of internal validity.

Objective: The primary objective was to test the hypothesis that clinical re-expansion pulmonary edema is predominantly due to increased permeability of the alveolar-capillary barrier. A secondary objective was to determine if the alveolar epithelium was functionally intact in patients with re-expansion pulmonary edema by measuring net alveolar epithelial fluid transport in a subset of patients., Design: Retrospective study of mechanically ventilated patients with re-expansion pulmonary edema., Setting: Two academic tertiary care hospitals., Patients: Seven patients with acute onset of re-expansion pulmonary edema after tube thoracostomy or thoracentesis., Interventions: Pulmonary edema fluid and plasma were collected at the time of onset of re-expansion edema., Measurements and Results: Contrary to our hypothesis, the mean initial edema fluid to plasma protein ratio was 0.58+/-0.21, supporting a hydrostatic mechanism of edema formation. Four of the patients had an initial edema fluid to plasma protein ratio of less than 0.65, consistent with pure hydrostatic pulmonary edema, while the others had a slight increase in permeability (edema fluid to plasma ratios of 0.67, 0.71 and 0.77), perhaps due to capillary stress failure from hydrostatic stress. Alveolar fluid clearance (mean 9.8+/-8.0%/h) was intact in the subset of three patients in whom it was measured., Conclusions: This study provides the first direct evidence that hydrostatic forces may contribute to the development of re-expansion pulmonary edema.

Objective: Experimental studies demonstrate that beta-adrenergic agonists markedly stimulate alveolar fluid clearance if concentrations of 10(-6) M are achieved in alveolar fluid. However, no studies have determined whether aerosolized beta-adrenergic agonists are delivered to the distal air spaces of the lung in therapeutic concentrations in patients with pulmonary edema., Design and Setting: This retrospective study measured albuterol levels in the pulmonary edema fluid and plasma from mechanically ventilated patients with pulmonary edema from a hydrostatic mechanism ( n=10) or from acute lung injury ( n=12)., Measurements and Results: After a total aerosolized albuterol dose of 4.2+/-3.2 mg in the prior 6 h the median pulmonary edema fluid albuterol level was 1,250 ng/ml (10(-6) M) in patients with hydrostatic pulmonary edema; after 3.5+/-2.6 mg the figure was 1,240 ng/ml (10(-6) M) in patients with pulmonary edema from acute lung injury. Plasma albuterol levels were much lower, with a median of 5.2 ng/ml (0.01 x 10(-6) M) in patients with hydrostatic pulmonary edema and 3.1 ng/ml (0.01 x 10(-6) M) in patients with pulmonary edema from acute lung injury., Conclusions: These results provide the first evidence that levels of beta-adrenergic agonists that are physiologically efficacious in experimental models can be achieved with conventional delivery systems in ventilated, critically ill patients with acute respiratory failure from pulmonary edema.