BIOMARKERS IN THE ACUTE RESPIRATORY DISTRESS SYNDROME: PAST, PRESENT, AND FUTURE.

Acute respiratory distress syndrome (ARDS), originally described in 1967, affects more than 3 million individuals each year throughout the world and accounts for approximately 10% of all admissions to the intensive care unit. Despite substantial progress in defining the epidemiology and pathogenesis of the syndrome, there is no specific treatment and mortality rates remain high. Barriers to finding specific therapeutic interventions include the inability to predict who will get ARDS, inadequate definitions and specific diagnostic markers, the heterogeneity of the patient population, complexities of the pathogenesis, and the impact of clinical care. Measurements of biomarkers have identified these barriers as well as contributed to the current understanding of the disease. The COVID-19 pandemic resulted in a dramatic increase in patients with ARDS, driving an urgent need to understand the pathogenesis and develop and implement therapeutic interventions. Past studies of biomarkers in ARDS can provide insight that could help to meet those needs more rapidly.

Bronchoalveolar fluid and plasma inflammatory biomarkers in contemporary ARDS patients.

Purpose: Bronchoalveolar fluid (BALF) and plasma biomarkers are often endpoints in early phase randomized trials (RCTs) in acute respiratory distress syndrome (ARDS). With ARDS mortality decreasing, we analyzed baseline biomarkers in samples from contemporary ARDS patients participating in a prior RCT and compared these to historical controls. Materials and methods: Ninety ARDS adult patients enrolled in the parent trial. BALF and blood were collected at baseline, day 4 ± 1, and day 8 ± 1. Interleukins-8/-6/-1ß/-1 receptor antagonist/-10; granulocyte colony stimulating factor; monocyte chemotactic protein-1; tumour necrosis factor-α; surfactant protein-D; von Willebrand factor; leukotriene B4; receptor for advanced glycosylation end products; soluble Fas ligand; and neutrophil counts were measured. Results: Compared to historical measurements, our values were generally substantially lower, despite our participants being similar to historical controls. For example, our BALF IL-8 and plasma IL-6 were notably lower than in a 1999 RCT of low tidal volume ventilation and a 2007 biomarker study, respectively. Conclusions: Baseline biomarker levels in current ARDS patients are substantially lower than 6-20 years before collection of these samples. These findings, whether from ICU care changes resulting in less inflammation or from variation in assay techniques over time, have important implications for design of future RCTs with biomarkers as endpoints.

Stability of ARDS subphenotypes over time in two randomised controlled trials.

RATIONALE: Two 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. OBJECTIVE: To determine the stability of ARDS subphenotypes over time. METHODS: Secondary 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 RESULTS: In 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. CONCLUSIONS: ARDS 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.

Effect of Ganciclovir on IL-6 Levels Among Cytomegalovirus-Seropositive Adults With Critical Illness: A Randomized Clinical Trial.

Importance: The role of cytomegalovirus (CMV) reactivation in mediating adverse clinical outcomes in nonimmunosuppressed adults with critical illness is unknown. Objective: To determine whether ganciclovir prophylaxis reduces plasma interleukin 6 (IL-6) levels in CMV-seropositive adults who are critically ill. Design, Setting, and Participants: Double-blind, placebo-controlled, randomized clinical trial (conducted March 10, 2011-April 29, 2016) with a follow-up of 180 days (November 10, 2016) that included 160 CMV-seropositive adults with either sepsis or trauma and respiratory failure at 14 university intensive care units (ICUs) across the United States. Interventions: Patients were randomized (1:1) to receive either intravenous ganciclovir (5 mg/kg twice daily for 5 days), followed by either intravenous ganciclovir or oral valganciclovir once daily until hospital discharge (n = 84) or to receive matching placebo (n = 76). Main Outcomes and Measures: The primary outcome was change in IL-6 level from day 1 to 14. Secondary outcomes were incidence of CMV reactivation in plasma, mechanical ventilation days, incidence of secondary bacteremia or fungemia, ICU length of stay, mortality, and ventilator-free days (VFDs) at 28 days. Results: Among 160 randomized patients (mean age, 57 years; women, 43%), 156 patients received 1or more dose(s) of study medication, and 132 patients (85%) completed the study. The mean change in plasma IL-6 levels between groups was -0.79 log10 units (-2.06 to 0.48) in the ganciclovir group and -0.79 log10 units (-2.14 to 0.56) in the placebo group (point estimate of difference, 0 [95% CI, -0.3 to 0.3]; P > .99). Among secondary outcomes, CMV reactivation in plasma was significantly lower in the ganciclovir group (12% [10 of 84 patients] vs 39% [28 of 72 patients]); absolute risk difference, -27 (95% CI, -40 to -14), P < .001. The ganciclovir group had more median VFDs in both the intention-to-treat (ITT) group and in the prespecified sepsis subgroup (ITT group: 23 days in ganciclovir group vs 20 days in the placebo group, P = .05; sepsis subgroup, 23 days in the ganciclovir group vs 20 days in the placebo group, P = .03). There were no significant differences between the ganciclovir and placebo groups in duration of mechanical ventilation (5 days for the ganciclovir group vs 6 days for the placebo group, P = .16), incidence of secondary bacteremia or fungemia (15% for the ganciclovir group vs 15% for the placebo group, P = .67), ICU length of stay (8 days for the ganciclovir group vs 8 days for the placebo group, P = .76), or mortality (12% for the ganciclovir group vs 15% for the placebo group, P = .54). Conclusions and Relevance: Among CMV-seropositive adults with critical illness due to sepsis or trauma, ganciclovir did not reduce IL-6 levels and the current study does not support routine clinical use of ganciclovir as a prophylactic agent in patients with sepsis. Additional research is necessary to determine the clinical efficacy and safety of CMV suppression in this setting. Trial Registration: clinicaltrials.gov Identifier: NCT01335932.

Multisociety task force for critical care research: key issues and recommendations.

BACKGROUND: Research in critical care extends from the bench to the bedside, involving multiple departments, specialties, and funding organizations. Because of this diversity, it has been difficult for all stakeholders to collectively identify challenges and establish priorities. OBJECTIVE: To define a comprehensive agenda for critical care research using input from a broad range of stakeholders to serve as a blueprint for future initiatives. METHODS: The Critical Care Societies Collaborative (CCSC), consisting of the leadership of the American Association of Critical-Care Nurses (AACN), the American College of Chest Physicians (ACCP), the American Thoracic Society (ATS), and the Society of Critical Care Medicine (SCCM), joined the U.S. Critical Illness and Injury Trials Group (USCIITG) in forming a task force to define a comprehensive critical care research agenda. This group of 25 identified experts was divided into subgroups to address basic, translational, clinical, implementation, and educational research. The subgroups met via conference calls, and the entire task force met in person for a 2-day session. The result was a detailed discussion of the research priorities that served as the basis for this report. RESULTS: The task force identified challenges, specific priority areas, and recommendations for process improvements to support critical care research. Additionally, four overarching themes emerged: (1) the traditional "silo-ed" approach to critical care research is counterproductive and should be modified; (2) an approach that more effectively links areas of research (i.e., basic and translational research, or clinical research and implementation) should be embraced; (3) future approaches to human research should account for disease complexity and patient heterogeneity; and (4) an enhanced infrastructure for critical care research is essential for future success. CONCLUSIONS: This document contains the themes/recommendations developed by a large, multiprofessional cross-section of critical care scientists, clinicians, and educators. It provides a unique framework for future research in critical care medicine.

How the Hospital Works: An Interdisciplinary, Systems-Based Practice Medical Student Elective.

OBJECTIVES: Although proficient systems-based practice is a foundational skill for physicians, how best to teach it has not been well established. An elective course for fourth-year medical students wherein participants had an immersive experience with multiple interprofessional staff was created and analyzed. The authors hypothesized that participating students and interprofessional staff would show gains in systems-based knowledge and interprofessional communication. METHODS: The course was a 2-week elective experience for fourth-year medical students at the Larner College of Medicine at the University of Vermont, Burlington, VT, USA. Participants integrated into a variety of interprofessional, non-physician, and administrative roles within the hospital system. Pre- and post-elective systems-based knowledge and interprofessional communication were assessed. Participating interprofessional staff were also surveyed on their experiences. RESULTS: From 2019 through 2022, 14 students participated in the elective, all of whom provided data. All participating students showed a quantitative improvement in systems-based knowledge and qualitatively commented on the high value of the elective in furthering their understanding of interdisciplinary care and communication. Of the 22 participating interprofessional staff surveyed, 17 responded (response rate 77%), and data showed high satisfaction with the experience and that having students learn more about their jobs improved their own job satisfaction. CONCLUSIONS: An immersive, hands-on experience with interprofessional colleagues showed dual benefits for both students and staff alike. Such an elective experience is scalable to other institutions nationally and should become a standard part of medical student curricula.

Promoting scholarship in improvement science: A model for academic clinical departments.

Introduction: Clinical departments at academic medical centers strive to deliver clinical care, provide education and training, support faculty development, and promote scholarship. These departments have experienced increasing demands to improve the quality, safety, and value of care delivery. However, many academic departments lack a sufficient number of clinical faculty members with expertise in improvement science to lead initiatives, teach, and generate scholarship. In this article, we describe the structure, activities, and early outcomes of a program within an academic department of medicine to promote scholarly improvement work. Methods: The Department of Medicine at the University of Vermont Medical Center launched a Quality Program with three primary goals: (a) improve care delivery, (b) provide education and training, and (c) promote scholarship in improvement science. The program serves as a resource center for students, trainees and faculty, offering education and training, analytic support, consultation in design and methodology, and project management. It strives to integrate education, research, and care delivery to learn, apply evidence and improve health care. Results: Over the first 3 years of full implementation, the Quality Program supported an average of 123 projects annually, including prospective clinical quality improvement initiatives, retrospective assessment of clinical programs and practices, and curriculum development and evaluation. The projects have yielded a total of 127 scholarly products, defined as peer-reviewed publications and abstracts, posters, and oral presentations at local, regional, and national conferences. Conclusions: The Quality Program may serve as a practical model for promoting care delivery improvement, training, and scholarship in improvement science while advancing the goals of a learning health system at the level of an academic clinical department. Dedicated resources within such departments offer the potential to enhance care delivery while promoting academic success for faculty and trainees in improvement science.

Multisociety Task Force for Critical Care Research: key issues and recommendations.

BACKGROUND: Research in critical care extends from the bench to the bedside, involving multiple departments, specialties, and funding organizations. Because of this diversity, it has been difficult for all stakeholders to collectively identify challenges and establish priorities. OBJECTIVE: To define a comprehensive agenda for critical care research using input from a broad range of stakeholders to serve as a blueprint for future initiatives. METHODS: The Critical Care Societies Collaborative (CCSC), consisting of the leadership of the American Association of Critical-Care Nurses (AACN), the American College of Chest Physicians (ACCP), the American Thoracic Society (ATS), and the Society of Critical Care Medicine (SCCM), joined the US Critical Illness and Injury Trials Group (USCIITG) in forming a task force to define a comprehensive critical care research agenda. This group of 25 identified experts was divided into subgroups to address basic, translational, clinical, implementation, and educational research. The subgroups met via conference calls, and the entire task force met in person for a 2-day session. The result was a detailed discussion of the research priorities that served as the basis for this report. RESULTS: The task force identified challenges, specific priority areas, and recommendations for process improvements to support critical care research. Additionally, four overarching themes emerged: 1) the traditional "silo-ed" approach to critical care research is counterproductive and should be modified; 2) an approach that more effectively links areas of research (i.e., basic and translational research, or clinical research and implementation) should be embraced; 3) future approaches to human research should account for disease complexity and patient heterogeneity; and 4) an enhanced infrastructure for critical care research is essential for future success. CONCLUSIONS: This document contains the themes/recommendations developed by a large, multiprofessional cross section of critical care scientists, clinicians, and educators. It provides a unique framework for future research in critical care medicine.

Use of risk reclassification with multiple biomarkers improves mortality prediction in acute lung injury.

OBJECTIVE: Multiple single biomarkers have been associated with poor outcomes in acute lung injury; however, no single biomarker has sufficient discriminating power to clearly indicate prognosis. Using both derivation and replication cohorts, we tested novel risk reclassification methods to determine whether measurement of multiple plasma biomarkers at the time of acute lung injury diagnosis would improve mortality prediction in acute lung injury. DESIGN: Analysis of plasma biomarker levels and prospectively collected clinical data from patients enrolled in two randomized controlled trials of ventilator therapy for acute lung injury. SETTING: Intensive care units of university hospitals participating in the National Institutes of Health Acute Respiratory Distress Syndrome Network. PATIENTS: Subjects enrolled in a trial of lower tidal volume ventilation (derivation cohort) and subjects enrolled in a trial of higher vs. lower positive end-expiratory pressure (replication cohort). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The plasma biomarkers were intercellular adhesion molecule-1, von Willebrand factor, interleukin-8, soluble tumor necrosis factor receptor-1, and surfactant protein-D. In the derivation cohort (n = 547), adding data on these biomarkers to clinical predictors (Acute Physiology and Chronic Health Evaluation III score) at the time of study enrollment improved the accuracy of risk prediction, as reflected by a net reclassification improvement of 22% (95% confidence interval 13% to 32%; p < .001). In the replication cohort (n = 500), the net reclassification improvement was 17% (95% confidence interval 7% to 26%; p < .001). A reduced set of three biomarkers (interleukin-8, soluble tumor necrosis factor receptor-1, and surfactant protein-D) had nearly equivalent prognostic value in both cohorts. CONCLUSIONS: When combined with clinical data, plasma biomarkers measured at the onset of acute lung injury can improve the accuracy of risk prediction. Combining three or more biomarkers may be useful for selecting a high-risk acute lung injury population for enrollment in clinical trials of novel therapies.

A phase II randomized placebo-controlled trial of omega-3 fatty acids for the treatment of acute lung injury.

OBJECTIVES: Administration of eicosapentaenoic acid and docosahexanoic acid, omega-3 fatty acids in fish oil, has been associated with improved patient outcomes in acute lung injury when studied in a commercial enteral formula. However, fish oil has not been tested independently in acute lung injury. We therefore sought to determine whether enteral fish oil alone would reduce pulmonary and systemic inflammation in patients with acute lung injury. DESIGN: Phase II randomized controlled trial. SETTING: Five North American medical centers. PATIENTS: Mechanically ventilated patients with acute lung injury ≥18 yrs of age. INTERVENTIONS: Subjects were randomized to receive enteral fish oil (9.75 g eicosapentaenoic acid and 6.75 g docosahexanoic acid daily) or saline placebo for up to 14 days. MEASUREMENTS AND MAIN RESULTS: Bronchoalveolar lavage fluid and blood were collected at baseline (day 0), day 4 ± 1, and day 8 ± 1. The primary end point was bronchoalveolar lavage fluid interleukin-8 levels. Forty-one participants received fish oil and 49 received placebo. Enteral fish oil administration was associated with increased serum eicosapentaenoic acid concentration (p < .0001). However, there was no significant difference in the change in bronchoalveolar lavage fluid interleukin-8 from baseline to day 4 (p = .37) or day 8 (p = .55) between treatment arms. There were no appreciable improvements in other bronchoalveolar lavage fluid or plasma biomarkers in the fish oil group compared with the control group. Similarly, organ failure score, ventilator-free days, intensive care unit-free days, and 60-day mortality did not differ between the groups. CONCLUSIONS: Fish oil did not reduce biomarkers of pulmonary or systemic inflammation in patients with acute lung injury, and the results do not support the conduct of a larger clinical trial in this population with this agent. This experimental approach is feasible for proof-of-concept studies evaluating new treatments for acute lung injury.

Plasma interleukin-8 is not an effective risk stratification tool for adults with vasopressor-dependent septic shock.

OBJECTIVE: Plasma interleukin-8 levels of <220 pg/mL have an excellent negative predictive value (94% to 95%) for death at 28 days in children with septic shock and thus may be useful for risk stratification in clinical trial enrollment in this population. Whether plasma interleukin-8 would have similar utility in adults with septic shock is unknown. DESIGN: Analysis of plasma interleukin-8 levels and prospectively collected clinical data from patients enrolled in two large randomized controlled trials of ventilator strategy for acute lung injury. SETTING: Intensive care units of university hospitals participating in the National Institutes of Health Acute Respiratory Distress Syndrome Network. PATIENTS: One hundred ninety-two adult patients with vasopressor-dependent septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Plasma interleukin-8 levels > or =220 pg/mL were significantly associated with death at 28 days in this cohort (odds ratio, 2.92; 95% confidence interval, 1.42 to 5.99; p = .001). However, in contrast to the findings in pediatric septic shock, a plasma interleukin-8 cutoff <220 pg/mL had a negative predictive value for death of only 74% (95% confidence interval, 66% to 81%) in adults with septic shock. Receiver operating characteristic analysis found an area under the curve of 0.59 for plasma interleukin-8, indicating that plasma interleukin-8 is a poor predictor of mortality in this group. In adults aged <40 yrs, a plasma interleukin-8 cutoff <220 pg/mL had a negative predictive value of 92%. CONCLUSIONS: In contrast to similar pediatric patients, plasma interleukin-8 levels are not an effective risk stratification tool in older adults with septic shock. Future studies of biomarkers for risk stratification in critically ill subjects will need to be replicated in multiple different populations before being applied in screening for clinical trials.

Multisociety task force recommendations of competencies in Pulmonary and Critical Care Medicine.

RATIONALE: Numerous accrediting organizations are calling for competency-based medical education that would help define specific specialties and serve as a foundation for ongoing assessment throughout a practitioner's career. Pulmonary Medicine and Critical Care Medicine are two distinct subspecialties, yet many individual physicians have expertise in both because of overlapping content. Establishing specific competencies for these subspecialties identifies educational goals for trainees and guides practitioners through their lifelong learning. OBJECTIVES: To define specific competencies for graduates of fellowships in Pulmonary Medicine and Internal Medicine-based Critical Care. METHODS: A Task Force composed of representatives from key stakeholder societies convened to identify and define specific competencies for both disciplines. Beginning with a detailed list of existing competencies from diverse sources, the Task Force categorized each item into one of six core competency headings. Each individual item was reviewed by committee members individually, in group meetings, and conference calls. Nominal group methods were used for most items to retain the views and opinions of the minority perspective. Controversial items underwent additional whole group discussions with iterative modified-Delphi techniques. Consensus was ultimately determined by a simple majority vote. MEASUREMENTS AND MAIN RESULTS: The Task Force identified and defined 327 specific competencies for Internal Medicine-based Critical Care and 276 for Pulmonary Medicine, each with a designation as either: (1) relevant, but competency is not essential or (2) competency essential to the specialty. CONCLUSIONS: Specific competencies in Pulmonary and Critical Care Medicine can be identified and defined using a multisociety collaborative approach. These recommendations serve as a starting point and set the stage for future modification to facilitate maximum quality of care as the specialties evolve.

Pharmacokinetics of omega-3 fatty acids in patients with severe sepsis compared with healthy volunteers: A prospective cohort study.

BACKGROUND: Pharmacokinetics (PK) of pharmaceuticals and pharmaconutrients are poorly understood in critically ill patients, and dosing is often based on healthy subject data. This might be particularly problematic with enteral medications due to metabolic abnormalities and impaired gastrointestinal tract absorption common in critically ill patients. Utilizing enteral fish oil, this study was undertaken to better understand and define PK of enteral omega-3 fatty acids (eicospentaenoic acid [EPA] and docosahexaenoic acid [DHA]) in critically ill patients with severe sepsis. MATERIALS AND METHODS: Healthy volunteers (n = 15) and mechanically ventilated (MV) adults with severe sepsis (n = 10) were recruited and received 9.75 g EPA and 6.75 g DHA daily in two divided enteral doses of fish oil for 7 days. Volunteers continued their normal diet without other sources of fish oil, and sepsis patients received standard enteral feeding. Blood was collected at frequent intervals during the 14-day study period. Peripheral blood mononuclear cells (PMBCs) and neutrophils were isolated and analyzed for membrane fatty acid (FA) content. Mixed linear models and t-tests were used to analyze changes in FA levels over time and FA levels at individual time points, respectively. PK parameters were obtained based on single compartment models of EPA and DHA kinetics. RESULTS: Healthy volunteers were 41.1 ± 10.3 years; 67% were women. In patients with severe sepsis (55.6 ± 13.4 years, 50% women), acute physiologic and chronic health evaluation (APACHE) II score was 27.2 ± 8.8 at ICU admission and median MV duration was 10.5 days. Serum EPA and DHA were significantly lower in sepsis vs. healthy subjects over time. PBMC EPA concentrations were generally not different between groups over time, while PBMC DHA was higher in sepsis patients. Neutrophil EPA and DHA concentrations were similar between groups. The half-life of EPA in serum and neutrophils was significantly shorter in sepsis patients, whereas other half-life parameters did not vary significantly between healthy volunteers and sepsis patients. CONCLUSIONS: While incorporation of n-3 FAs into PBMC and neutrophil membranes was relatively similar between healthy volunteers and sepsis patients receiving identical high doses of fish oil for one week, serum EPA and DHA were significantly lower in sepsis patients. These findings imply that serum concentrations and EPA and DHA may not be the dominant driver of leukocyte membrane incorporation of EPA and DHA. Furthermore, lower serum EPA and DHA concentrations suggest that either these n-3 FAs were being metabolized rapidly in sepsis patients or that absorption of enteral medications and pharmaconutrients, including fish oil, may be impaired in sepsis patients. If enteral absorption is impaired, doses of enteral medications administered to critically ill patients may be suboptimal.

Plasma granulocyte colony-stimulating factor levels correlate with clinical outcomes in patients with acute lung injury.

OBJECTIVES: To evaluate the association between plasma granulocyte colony-stimulating factor (G-CSF) levels and clinical outcomes including mortality in patients with acute lung injury (ALI), and to determine whether lower tidal volume ventilation was associated with a more rapid decrease in plasma G-CSF over time in patients with ALI. DESIGN: Retrospective measurement of G-CSF levels in plasma samples that were collected prospectively as part of a large multicenter clinical trial. SETTING: Intensive care units in ten university centers. PATIENTS: The study included 645 patients enrolled in the National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Clinical Network trial of lower tidal volumes compared with traditional tidal volumes for ALI. MEASUREMENTS AND MAIN RESULTS: Baseline plasma levels of G-CSF were associated with an increased risk of death and a decrease in ventilator-free days and organ failure-free days in multivariate analyses controlling for ventilation strategy, age, and sex (Odds ratio death 1.2/log10 increment G-CSF, 95% confidence interval 1.01 to 1.4). Stratification of G-CSF levels into quartiles revealed a strong association between the highest levels of G-CSF and an increased risk of death and decreased ventilator-free days and organ failure-free days in multivariate analyses controlling for ventilation strategy, Acute Physiology and Chronic Health Evaluation III score, Pao2/Fio2 ratio, creatinine, and platelet count (p < 0.05). Subgroup multivariate analysis of patients with sepsis as their risk factor for ALI revealed a U-shaped association between mortality and G-CSF levels such that risk increased linearly from the second through fourth (highest) quartiles, yet also increased in the first (lowest) quartile. G-CSF levels decreased over time in both tidal volume groups, and there was no statistical difference in the extent of decrease between ventilator strategies. CONCLUSIONS: In patients with ALI, plasma G-CSF levels are associated with morbidity and mortality, but these levels are not influenced by tidal volume strategy. In patients with sepsis-related ALI, a bimodal association between baseline plasma G-CSF levels and subsequent morbidity and mortality from this disease was found.

The United States critical illness and injury trials group: an introduction.

The US Critical Illness and Injury Trials Group is funded to engage the relevant scientific communities and federal agencies to jointly advocate for clinical research. An inclusive, nationwide network of experts has been created to establish national priorities and pursue a strategic plan in conjunction with professional societies and existing research networks. Investigator-initiated clinical proposals will be presented and discussed at the inaugural National Institutes of Health meeting to promote collaboration and establish working groups to develop projects and core resources. Future US Critical Illness and Injury Trials Group meetings will convene triannually, providing a venue to gauge progress on strategic deliverables, foster development of the clinical projects, discuss education and training in clinical trial design, and address the ethical, legal, and social implications of research in the critically ill or injured patients.

Implementation Research to Address the United States Health Disadvantage: Report of a National Heart, Lung, and Blood Institute Workshop.

Four decades ago, U.S. life expectancy was within the same range as other high-income peer countries. However, during the past decades, the United States has fared worse in many key health domains resulting in shorter life expectancy and poorer health-a health disadvantage. The National Heart, Lung, and Blood Institute convened a panel of national and international health experts and stakeholders for a Think Tank meeting to explore the U.S. health disadvantage and to seek specific recommendations for implementation research opportunities for heart, lung, blood, and sleep disorders. Recommendations for National Heart, Lung, and Blood Institute consideration were made in several areas including understanding the drivers of the disadvantage, identifying potential solutions, creating strategic partnerships with common goals, and finally enhancing and fostering a research workforce for implementation research. Key recommendations included exploring why the United States is doing better for health indicators in a few areas compared with peer countries; targeting populations across the entire socioeconomic spectrum with interventions at all levels in order to prevent missing a substantial proportion of the disadvantage; assuring partnership have high-level goals that can create systemic change through collective impact; and finally, increasing opportunities for implementation research training to meet the current needs. Connecting with the research community at large and building on ongoing research efforts will be an important strategy. Broad partnerships and collaboration across the social, political, economic, and private sectors and all civil society will be critical-not only for implementation research but also for implementing the findings to have the desired population impact. Developing the relevant knowledge to tackle the U.S. health disadvantage is the necessary first step to improve U.S. health outcomes.

Strategies for Developing and Recognizing Faculty Working in Quality Improvement and Patient Safety.

Academic clinical departments have the opportunity and responsibility to improve the quality and value of care and patient safety by supporting effective quality improvement activities. The pressure to provide high-value care while further developing academic programs has increased the complexity of decision making and change management in academic health systems. Overcoming these challenges will require faculty engagement and leadership; however, most academic departments do not have a sufficient number of individuals with expertise and experience in quality improvement and patient safety (QI/PS). Accordingly, the authors of this article advocate for a targeted and proactive approach to developing faculty working in QI/PS. They propose a strategy predicated on the identification of QI/PS as a strategic priority for academic departments, the creation of enabling resources in QI/PS, and the expansion of rigorous training programs in change management and in improvement and implementation sciences. Professional organizations, health systems, medical schools, and academic departments should recognize successful QI/PS work with awards and promotions. Individual faculty members should expand their collaborative networks, consider the generalizability and scholarly impact of their efforts when designing QI/PS initiatives, and benchmark the outcomes of their performance. Appointments and promotions committees should work proactively with department and QI/PS leaders to ensure that outstanding achievement in QI/PS is defined and recognized. As with the development of physician-investigators and clinician-educators, departments and health systems need a comprehensive approach to support and recognize the contributions of faculty working in QI/PS to meet the considerable needs and opportunities in health care.

Pathogenetic significance of biological markers of ventilator-associated lung injury in experimental and clinical studies.

For patients with acute lung injury, positive pressure mechanical ventilation is life saving. However, considerable experimental and clinical data have demonstrated that how clinicians set the tidal volume, positive end-expiratory pressure, and plateau airway pressure influences lung injury severity and patient outcomes including mortality. In order to better identify ventilator-associated lung injury (VALI), clinical investigators have sought to measure blood-borne and airspace biological markers of VALI. At the same time, several laboratory-based studies have focused on biological markers of inflammation and organ injury in experimental models in order to clarify the mechanisms of ventilator-induced lung injury (VILI) and VALI. This review summarizes data on biological markers of VALI and VILI from both clinical and experimental studies with an emphasis on markers identified in patients and in the experimental setting. This analysis suggests that measurement of some of these biological markers may be of value in diagnosing VALI and in understanding its pathogenesis.