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.

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.

Cancer Care in the Wake of a Cyberattack: How to Prepare and What to Expect.

PURPOSE: Cyberattacks targeting health care organizations are becoming more frequent and affect all aspects of care delivery. Cancer care is particularly susceptible to major disruptions because of the potential of immediate and long-term consequences for patients who often rely on timely diagnostic testing and regular administration of systemic therapy in addition to other local treatment modalities to cure or control their diseases. On October 28, 2020, a cyberattack was launched on the University of Vermont Health Network with wide-ranging consequences for oncology, including loss of access to all network intranet servers, e-mail communications, and the electronic medical record (EMR). METHODS: This review details the immediate challenges faced by hematology and oncology during the cyberattack. The impact and response on inpatient, outpatient, and special patient populations are described. Steps that other academic- and community-based oncology practices can take to lessen the brunt of such an assault are suggested. RESULTS: The two areas of immediate impact after the cyberattack were communications and lack of EMR access. The oncology-specific impact included loss of the individualized EMR chemotherapy plan templates and electronic safeguards built into multistep treatment preparation and delivery. With loss of access to schedules, basic patient information, encrypted communications platforms and radiology, and laboratory and pharmacy services, clinical outpatient care delivery was reduced by 40%. The infusion visit volume dropped by 52% in the first week and new patients could not access necessary services for timely diagnostic evaluation, requiring the creation of command centers to oversee ethical and transparent triage and allocation of systemic therapies and address new patient referrals. This included appropriate transfer of patients to alternate sites to minimize delays. Inpatient care including transitions of care was particularly challenging and addressing patient populations whose survival might be affected by delays in care. CONCLUSION: Oncology health care leaders and providers should be aware of the potential impact of a cyberattack on cancer care delivery and preventively develop processes to mitigate the impact.

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.

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.

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.

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.

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.

Hyperleptinemia is associated with impaired pulmonary host defense.

We have previously reported that obesity attenuates pulmonary inflammation in both patients with acute respiratory distress syndrome (ARDS) and in mouse models of the disease. We hypothesized that obesity-associated hyperleptinemia, and not body mass per se, drives attenuation of the pulmonary inflammatory response and that this e_ect could also impair the host response to pneumonia. We examined the correlation between circulating leptin levels and risk, severity, and outcome of pneumonia in 2 patient cohorts (NHANES III and ARDSNet-ALVEOLI) and in mouse models of diet-induced obesity and lean hyperleptinemia. Plasma leptin levels in ambulatory subjects (NHANES) correlated positively with annual risk of respiratory infection independent of BMI. In patients with severe pneumonia resulting in ARDS (ARDSNet-ALVEOLI), plasma leptin levels were found to correlate positively with subsequent mortality. In obese mice with pneumonia, plasma leptin levels were associated with pneumonia severity, and in obese mice with sterile lung injury, leptin levels were inversely related to bronchoalveolar lavage neutrophilia, as well as to plasma IL-6 and G-CSF levels. These results were recapitulated in lean mice with experimentally induced hyperleptinemia. Our findings suggest that the association between obesity and elevated risk of pulmonary infection may be driven by hyperleptinemia.

Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials.

BACKGROUND: Subphenotypes have been identified within heterogeneous diseases such as asthma and breast cancer, with important therapeutic implications. We assessed whether subphenotypes exist within acute respiratory distress syndrome (ARDS), another heterogeneous disorder. METHODS: We used data from two ARDS randomised controlled trials (ARMA trial and ALVEOLI trial), sponsored by the National Heart, Lung, and Blood Institute. We applied latent class modelling to identify subphenotypes using clinical and biological data. We modelled data from both studies independently. We then tested the association of subphenotypes with clinical outcomes in both cohorts and with the response to positive end-expiratory pressure (PEEP) in the ALVEOLI cohort. FINDINGS: We analysed data for 1022 patients: 473 in the ARMA cohort and 549 in the ALVEOLI cohort. Independent latent class models indicated that a two-class (ie, two subphenotype) model was the best fit for both cohorts. In both cohorts, we identified a hyperinflammatory subphenotype (phenotype 2) that was characterised by higher plasma concentrations of inflammatory biomarkers, a higher prevalence of vasopressor use, lower serum bicarbonate concentrations, and a higher prevalence of sepsis than phenotype 1. Participants in phenotype 2 had higher mortality and fewer ventilator-free days and organ failure-free days in both cohorts than did those in phenotype 1 (p<0·007 for all). In the ALVEOLI cohort, the effects of ventilation strategy (high PEEP vs low PEEP) on mortality, ventilator-free days and organ failure-free days differed by phenotype (p=0·049 for mortality, p=0·018 for ventilator-free days, p=0·003 for organ-failure-free days). INTERPRETATION: We have identified two subphenotypes within ARDS, one of which is categorised by more severe inflammation, shock, and metabolic acidosis and by worse clinical outcomes. Response to treatment in a randomised trial of PEEP strategies differed on the basis of subphenotype. Identification of ARDS subphenotypes might be useful in selecting patients for future clinical trials. FUNDING: National Institutes of Health.

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 (ie, 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.