Quality improvement lessons learned from National Implementation of the "Patient Safety Events in Community Care: Reporting, Investigation, and Improvement Guidebook".

OBJECTIVE: To evaluate nationwide implementation of a Guidebook designed to standardize safety practices across VA-delivered and VA-purchased care (i.e., Community Care) and identify lessons learned and strategies to improve them. DATA SOURCES AND STUDY SETTING: Qualitative data collected from key informants at 18 geographically diverse VA facilities across 17 Veterans Integrated Services Networks (VISNs). STUDY DESIGN: We conducted semi-structured interviews from 2019 to 2022 with VISN Patient Safety Officers (PSOs) and VA facility patient safety and quality managers (PSMs and QMs) and VA Facility Community Care (CC) staff to assess lessons learned by examining organizational contextual factors affecting Guidebook implementation based on the Consolidated Framework for Implementation Research (CFIR). DATA COLLECTION/EXTRACTION METHODS: Interviews were conducted virtually with 45 facility staff and 10 VISN PSOs. Using directed content analysis, we identified CFIR factors affecting implementation. These factors were mapped to the Expert Recommendations for Implementing Change (ERIC) strategy compilation to identify lessons learned that could be useful to our operational partners in improving implementation processes. We met frequently with our partners to discuss findings and plan next steps. PRINCIPAL FINDINGS: Six CFIR constructs were identified as both facilitators and barriers to Guidebook implementation: (1) planning for implementation; (2) engaging key knowledge holders; (3) available resources; (4) networks and communications; (5) culture; and (6) external policies. The two CFIR constructs that were only barriers included: (1) cosmopolitanism and (2) executing implementation. CONCLUSIONS: Our findings suggest several important lessons: (1) engage all collaborators involved in implementation; (2) ensure end-users have opportunities to provide feedback; (3) describe collaborators' purpose and roles/responsibilities clearly at the start; (4) communicate information widely and repeatedly; and (5) identify how multiple high priorities can be synergistic. This evaluation will help our partners and key VA leadership to determine next steps and future strategies for improving Guidebook implementation through collaboration with VA staff.

The salivary microbiota of patients with acute lower respiratory tract infection-A multicenter cohort study.

The human microbiome contributes to health and disease, but the oral microbiota is understudied relative to the gut microbiota. The salivary microbiota is easily accessible, underexplored, and may provide insight into response to infections. We sought to determine the composition, association with clinical features, and heterogeneity of the salivary microbiota in patients with acute lower respiratory tract infection (LRTI). We conducted a multicenter prospective cohort study of 147 adults with acute LRTI presenting to the emergency department of seven hospitals in three states (Pennsylvania, Michigan, and Ohio) between May 2017 and November 2018. Salivary samples were collected in the emergency department, at days 2-5 if hospitalized, and at day 30, as well as fecal samples if patients were willing. We compared salivary microbiota profiles from patients to those of healthy adult volunteers by sequencing and analyzing bacterial 16-rRNA. Compared to healthy volunteers, the salivary microbiota of patients with LRTI was highly distinct and strongly enriched with intestinal anaerobes such as Bacteroidaceae, Ruminococcaceae, and Lachnospiraceae (e.g., mean 10% relative abundance of Bacteroides vs < 1% in healthy volunteers). Within the LRTI population, COPD exacerbation was associated with altered salivary microbiota composition compared to other LRTI conditions. The largest determinant of microbiota variation within the LRTI population was geography (city in which the hospital was located).

PATHWAYS ASSOCIATED WITH POSITIVE SEPSIS SURVIVAL OUTCOMES IN AFRICAN AMERICAN/BLACK AND NON-HISPANIC WHITE PATIENTS WITH URINARY TRACT INFECTION.

ABSTRACT: Urinary tract infections (UTIs) are a common cause of sepsis worldwide. Annually, more than 60,000 US deaths can be attributed to sepsis secondary to UTIs, and African American/Black adults have higher incidence and case-fatality rates than non-Hispanic White adults. Molecular-level factors that may help partially explain differences in sepsis survival outcomes between African American/Black and Non-Hispanic White adults are not clear. In this study, patient samples (N = 166) from the Protocolized Care for Early Septic Shock cohort were analyzed using discovery-based plasma proteomics. Patients had sepsis secondary to UTIs and were stratified according to self-identified racial background and sepsis survival outcomes. Proteomics results suggest patient heterogeneity across mechanisms driving survival from sepsis secondary to UTIs. Differentially expressed proteins (n = 122, false discovery rate-adjusted P < 0.05) in Non-Hispanic White sepsis survivors were primarily in immune system pathways, while differentially expressed proteins (n = 47, false discovery rate-adjusted P < 0.05) in African American/Black patients were mostly in metabolic pathways. However, in all patients, regardless of racial background, there were 16 differentially expressed proteins in sepsis survivors involved in translation initiation and shutdown pathways. These pathways are potential targets for prognostic intervention. Overall, this study provides information about molecular factors that may help explain disparities in sepsis survival outcomes among African American/Black and Non-Hispanic White patients with primary UTIs.

Variation in Clinical Treatment and Outcomes by Race Among US Veterans Hospitalized With COVID-19.

Importance: Patients from racially and ethnically minoritized populations, such as Black and Hispanic patients, may be less likely to receive evidence-based COVID-19 treatments than White patients, contributing to adverse clinical outcomes. Objective: To determine whether clinical treatments and outcomes among patients hospitalized with COVID-19 were associated with race. Design, Setting, and Participants: This retrospective cohort study was conducted in 130 Department of Veterans Affairs Medical Centers (VAMCs) between March 1, 2020, and February 28, 2022, with a 60-day follow-up period until May 1, 2022. Participants included veterans hospitalized with COVID-19. Data were analyzed from May 6 to June 2, 2022. Exposures: Self-reported race. Main Outcomes and Measures: Clinical care processes (eg, intensive care unit [ICU] admission; organ support measures, including invasive and noninvasive mechanical ventilation; prone position therapy, and COVID-19-specific medical treatments) were quantified. Clinical outcomes of interest included in-hospital mortality, 60-day mortality, and 30-day readmissions. Outcomes were assessed with multivariable random effects logistic regression models to estimate the association of race with outcomes not attributable to known mediators, such as socioeconomic status and age, while adjusting for potential confounding between outcomes and mediators. Results: A total of 43 222 veterans (12 135 Black veterans [28.1%]; 31 087 White veterans [71.9%]; 40 717 [94.2%] men) with a median (IQR) age of 71 (62-77) years who were hospitalized with SARS-CoV-2 infection were included. Controlling for site of treatment, Black patients were equally likely to be admitted to the ICU (4806 Black patients [39.6%] vs 13 427 White patients [43.2%]; within-center adjusted odds ratio [aOR], 0.95; 95% CI, 0.88-1.02; P = .17). Two-thirds of patients treated with supplemental oxygen or noninvasive or invasive mechanical ventilation also received systemic steroids, but Black veterans were less likely to receive steroids (within-center aOR, 0.88; 95% CI, 0.80-0.96; P = .004; between-center aOR, 0.67; 95% CI, 0.48-0.96; P = .03). Similarly, Black patients were less likely to receive remdesivir (within-center aOR, 0.89; 95% CI, 0.83-0.95; P < .001; between-center aOR, 0.68; 95% CI, 0.47-0.99; P = .02) or treatment with immunomodulatory drugs (within-center aOR, 0.77; 95% CI, 0.67-0.87; P < .001). After adjusting for patient demographic characteristics, chronic health conditions, severity of acute illness, and receipt of COVID-19-specific treatments, there was no association of Black race with hospital mortality (within-center aOR, 0.98; 95% CI, 0.86-1.10; P = .71) or 30-day readmission (within-center aOR, 0.95; 95% CI, 0.88-1.04; P = .28). Conclusions and Relevance: These findings suggest that Black veterans hospitalized with COVID-19 were less likely to be treated with evidence-based COVID-19 treatments, including systemic steroids, remdesivir, and immunomodulatory drugs.

Proteomic changes associated with racial background and sepsis survival outcomes.

Intra-abdominal infection is a common cause of sepsis, and intra-abdominal sepsis leads to ∼156 000 U.S. deaths annually. African American/Black adults have higher incidence and mortality rates from sepsis compared to Non-Hispanic White adults. A limited number of studies have traced survival outcomes to molecular changes; however, these studies primarily only included Non-Hispanic White adults. Our goal is to better understand molecular changes that may contribute to differences in sepsis survival in African American/Black and Non-Hispanic White adults with primary intra-abdominal infection. We employed discovery-based plasma proteomics of patient samples from the Protocolized Care for Early Septic Shock (ProCESS) cohort (N = 107). We identified 49 proteins involved in the acute phase response and complement system whose expression levels are associated with both survival outcome and racial background. Additionally, 82 proteins differentially-expressed in survivors were specific to African American/Black or Non-Hispanic White patients, suggesting molecular-level heterogeneity in sepsis patients in key inflammatory pathways. A smaller, robust set of 19 proteins were in common in African American/Black and Non-Hispanic White survivors and may represent potential universal molecular changes in sepsis. Overall, this study identifies molecular factors that may contribute to differences in survival outcomes in African American/Black patients that are not fully explained by socioeconomic or other non-biological factors.

Comparative COVID-19 Vaccine Effectiveness Over Time in Veterans.

Background: Comparative effectiveness of coronavirus disease 2019 (COVID-19) vaccines across patient subgroups is poorly understood and essential to precisely targeting vaccination strategies. Methods: We used the US Department of Veterans Affairs COVID-19 Shared Data Resource to identify veterans who utilize VA health care and had no documented severe acute respiratory syndrome coronavirus 2 infection before December 11, 2020. Using a test-negative case-control design (TND), we used conditional logistic regression with adjustment for covariates to estimate vaccine effectiveness (VE) over time for veterans who received 2 doses of mRNA vaccines or 1 dose of Ad26.Cov2.S. Results: We identified 4.8 million veterans with a mean age of 64 years, of whom 58% had ≥1 chronic disease. Vaccine effectiveness for symptomatic infections, hospitalizations, and ICU admission or death declined over time and varied by the type of vaccine (P < 0.01). VE estimates against symptomatic infection during months 1 and 7 for mRNA-1273 compared with BNT162b2 were 89.7% (95% CI, 84.4%-93.0%) and 57.3% (95% CI, 48.4%-64.7%) vs 81.6% (95% CI, 75.9%-85.9%) and 22.5% (95% CI, 7.2%-35.2%) for individuals age <65 years and 78.4% (95% CI, 71.1%-83.9%) and 36.2% (95% CI, 27.7%-43.6%) vs 66.3% (95% CI, 55.7%-74.4%) and -23.3% (95% CI, -40.5% to -8.2%) in subjects age ≥65 years; against hospitalization 92.0% (95% CI, 76.1%-97.3%) and 83.1% (95% CI, 66.8%-91.4%) vs 85.6% (95% CI, 72.6%-92.4%) and 57.0% (95% CI, 31.2%-73.2%) in subjects age <65 years and 66.1% (95% CI, 45.3%-79.0%) and 64.7% (95% CI, 55.2%-72.3%) vs 61.0% (95% CI, 41.3%-74.2%) and 1.7% (95% CI, -22.0% to 20.8%) in those age ≥65 years; against ICU admission or death 89.2% (95% CI, 49.5%-97.7%) and 84.4% (95% CI, 59.0%-94.1%) vs 87.6% (95% CI, 61.0%-96.1%) and 66.4% (95% CI, 7.7%-87.8%) in subjects age <65 years and 75.4% (95% CI, 51.7%-87.5%) and 73.8 (95% CI, 62.9%-81.5%) vs 67.4% (95% CI, 32.6%-84.3%) and 29.3% (95% CI, 2.3%-48.9%) in subjects age ≥65 years, respectively (P interaction < .01 for all comparisons). Similarly, mRNA-1273 was more effective than BNT162b2 in veterans with >1 chronic disease. Conclusions: mRNA-1273 was more effective than BNT162b2 in older veterans and those with chronic diseases.

Lung function impairment and risk of incident heart failure: the NHLBI Pooled Cohorts Study.

AIMS: The aim is to evaluate associations of lung function impairment with risk of incident heart failure (HF). METHODS AND RESULTS: Data were pooled across eight US population-based cohorts that enrolled participants from 1987 to 2004. Participants with self-reported baseline cardiovascular disease were excluded. Spirometry was used to define obstructive [forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) <0.70] or restrictive (FEV1/FVC ≥0.70, FVC <80%) lung physiology. The incident HF was defined as hospitalization or death caused by HF. In a sub-set, HF events were sub-classified as HF with reduced ejection fraction (HFrEF; EF <50%) or preserved EF (HFpEF; EF ≥50%). The Fine-Gray proportional sub-distribution hazards models were adjusted for sociodemographic factors, smoking, and cardiovascular risk factors. In models of incident HF sub-types, HFrEF, HFpEF, and non-HF mortality were treated as competing risks. Among 31 677 adults, there were 3344 incident HF events over a median follow-up of 21.0 years. Of 2066 classifiable HF events, 1030 were classified as HFrEF and 1036 as HFpEF. Obstructive [adjusted hazard ratio (HR) 1.17, 95% confidence interval (CI) 1.07-1.27] and restrictive physiology (adjusted HR 1.43, 95% CI 1.27-1.62) were associated with incident HF. Obstructive and restrictive ventilatory defects were associated with HFpEF but not HFrEF. The magnitude of the association between restrictive physiology and HFpEF was similar to associations with hypertension, diabetes, and smoking. CONCLUSION: Lung function impairment was associated with increased risk of incident HF, and particularly incident HFpEF, independent of and to a similar extent as major known cardiovascular risk factors.

Pooled Cohort Probability Score for Subclinical Airflow Obstruction.

Rationale: Early detection of chronic obstructive pulmonary disease (COPD) is a public health priority. Airflow obstruction is the single most important risk factor for adverse COPD outcomes, but spirometry is not routinely recommended for screening. Objectives: To describe the burden of subclinical airflow obstruction (SAO) and to develop a probability score for SAO to inform potential detection and prevention programs. Methods: Lung function and clinical data were harmonized and pooled across nine U.S. general population cohorts. Adults with respiratory symptoms, inhaler use, or prior diagnosis of COPD or asthma were excluded. A probability score for prevalent SAO (forced expiratory volume in 1 second/forced vital capacity < 0.70) was developed via hierarchical group-lasso regularization from clinical variables in strata of sex and smoking status, and its discriminative accuracy for SAO was assessed in the pooled cohort as well as in an external validation cohort (NHANES [National Health and Nutrition Examination Survey] 2011-2012). Incident hospitalizations and deaths due to COPD (respiratory events) were defined by adjudication or administrative criteria in four of nine cohorts. Results: Of 33,546 participants (mean age 52 yr, 54% female, 44% non-Hispanic White), 4,424 (13.2%) had prevalent SAO. The incidence of respiratory events (Nat-risk = 14,024) was threefold higher in participants with SAO versus those without (152 vs. 39 events/10,000 person-years). The probability score, which was based on six commonly available variables (age, sex, race and/or ethnicity, body mass index, smoking status, and smoking pack-years) was well calibrated and showed excellent discrimination in both the testing sample (C-statistic, 0.81; 95% confidence interval [CI], 0.80-0.82) and in NHANES (C-statistic, 0.83; 95% CI, 0.80-0.86). Among participants with predicted probabilities ⩾ 15%, 3.2 would need to undergo spirometry to detect one case of SAO. Conclusions: Adults with SAO demonstrate excess respiratory hospitalization and mortality. A probability score for SAO using commonly available clinical risk factors may be suitable for targeting screening and primary prevention strategies.

The Epidemiology of Extremity Threat and Amputation after Vasopressor-Dependent Sepsis.

Rationale: Extremity threat and amputation after sepsis is a well-publicized and devastating event. However, there is a paucity of data about the epidemiology of extremity threat after sepsis onset. Objectives: To estimate the incidence of extremity threat with or without surgical amputation in community sepsis. Methods: Retrospective cohort study of adults with Sepsis-3 hospitalized at 14 academic and community sites from 2013 to 2017. Vasopressor-dependent sepsis was identified by administration of epinephrine, norepinephrine, phenylephrine, vasopressin, or dopamine for more than 1 hour during the 48 hours before to 24 hours after sepsis onset. Outcomes included the incidence of extremity threat, defined as acute onset ischemia, with or without amputation, in the 90 days after sepsis onset. The association between extremity threat, demographics, comorbid conditions, and time-varying sepsis treatments was evaluated using a Cox proportional hazards model. Results: Among 24,365 adults with sepsis, 12,060 (54%) were vasopressor dependent (mean ± standard deviation age, 64 ± 16 years; male, 6,548 [54%]; sequential organ failure assessment [SOFA], 10 ± 4). Of these, 231 (2%) patients had a threatened extremity with 26 undergoing 37 amputations, a risk of 2.2 (95% confidence interval [CI], 1.4-3.2) per 1,000, and 205 not undergoing amputation, a risk of 17.0 (95% CI, 14.8-19.5) per 1,000. Most amputations occurred in lower extremities (95%), a median (interquartile range) of 16 (6-40) days after sepsis onset. Compared with patients with no extremity threat, patients with threat had a higher SOFA score (11 ± 4 vs. 10 ± 4; P < 0.001), serum lactate (4.6 mmol/L [2.4-8.7] vs. 3.1 [1.7-6.0]; P < 0.001), and more bacteremia (n = 37 [37%] vs. n = 2,087 [26%]; P < 0.001) at sepsis onset. Peripheral vascular disease, congestive heart failure, SOFA score, and norepinephrine equivalents were significantly associated with extremity threat. Conclusions: The evaluation of a threatened extremity resulting in surgical amputation occurred in 2 per 1,000 patients with vasopressor-dependent sepsis.

Association Between Preserved Ratio Impaired Spirometry and Clinical Outcomes in US Adults.

Importance: Chronic lung diseases are a leading cause of morbidity and mortality. Unlike chronic obstructive pulmonary disease, clinical outcomes associated with proportional reductions in expiratory lung volumes without obstruction, otherwise known as preserved ratio impaired spirometry (PRISm), are poorly understood. Objective: To examine the prevalence, correlates, and clinical outcomes associated with PRISm in US adults. Design, Setting, and Participants: The National Heart, Lung, and Blood Institute (NHLBI) Pooled Cohorts Study was a retrospective study with harmonized pooled data from 9 US general population-based cohorts (enrollment, 65 251 participants aged 18 to 102 years of whom 53 701 participants had valid baseline lung function) conducted from 1971-2011 (final follow-up, December 2018). Exposures: Participants were categorized into mutually exclusive groups by baseline lung function. PRISm was defined as the ratio of forced expiratory volume in the first second to forced vital capacity (FEV1:FVC) greater than or equal to 0.70 and FEV1 less than 80% predicted; obstructive spirometry FEV1:FVC ratio of less than 0.70; and normal spirometry FEV1:FVC ratio greater than or equal to 0.7 and FEV1 greater than or equal to 80% predicted. Main Outcomes and Measures: Main outcomes were all-cause mortality, respiratory-related mortality, coronary heart disease (CHD)-related mortality, respiratory-related events (hospitalizations and mortality), and CHD-related events (hospitalizations and mortality) classified by adjudication or validated administrative criteria. Absolute risks were adjusted for age and smoking status. Poisson and Cox proportional hazards models comparing PRISm vs normal spirometry were adjusted for age, sex, race and ethnicity, education, body mass index, smoking status, cohort, and comorbidities. Results: Among all participants (mean [SD] age, 53.2 [15.8] years, 56.4% women, 48.5% never-smokers), 4582 (8.5%) had PRISm. The presence of PRISm relative to normal spirometry was significantly associated with obesity (prevalence, 48.3% vs 31.4%; prevalence ratio [PR], 1.68 [95% CI, 1.55-1.82]), underweight (prevalence, 1.4% vs 1.0%; PR, 2.20 [95% CI, 1.72-2.82]), female sex (prevalence, 60.3% vs 59.0%; PR, 1.07 [95% CI, 1.01-1.13]), and current smoking (prevalence, 25.2% vs 17.5%; PR, 1.33 [95% CI, 1.22-1.45]). PRISm, compared with normal spirometry, was significantly associated with greater all-cause mortality (29.6/1000 person-years vs 18.0/1000 person-years; difference, 11.6/1000 person-years [95% CI, 10.0-13.1]; adjusted hazard ratio [HR], 1.50 [95% CI, 1.42-1.59]), respiratory-related mortality (2.1/1000 person-years vs 1.0/1000 person-years; difference, 1.1/1000 person-years [95% CI, 0.7-1.6]; adjusted HR, 1.95 [95% CI, 1.54-2.48]), CHD-related mortality (5.4/1000 person-years vs 2.6/1000 person-years; difference, 2.7/1000 person-years [95% CI, 2.1-3.4]; adjusted HR, 1.55 [95% CI, 1.36-1.77]), respiratory-related events (12.2/1000 person-years vs 6.0/1000 person-years; difference, 6.2/1000 person-years [95% CI, 4.9-7.5]; adjusted HR, 1.90 [95% CI, 1.69-2.14]), and CHD-related events (11.7/1000 person-years vs 7.0/1000 person-years; difference, 4.7/1000 person-years [95% CI, 3.7-5.8]; adjusted HR, 1.30 [95% CI, 1.18-1.42]). Conclusions and Relevance: In a large, population-based sample of US adults, baseline PRISm, compared with normal spirometry, was associated with a small but statistically significant increased risk for mortality and adverse cardiovascular and respiratory outcomes. Further research is needed to explore whether this association is causal.

A Research Agenda for Precision Medicine in Sepsis and Acute Respiratory Distress Syndrome: An Official American Thoracic Society Research Statement.

Background: Precision medicine focuses on the identification of therapeutic strategies that are effective for a group of patients based on similar unifying characteristics. The recent success of precision medicine in non-critical care settings has resulted from the confluence of large clinical and biospecimen repositories, innovative bioinformatics, and novel trial designs. Similar advances for precision medicine in sepsis and in the acute respiratory distress syndrome (ARDS) are possible but will require further investigation and significant investment in infrastructure. Methods: This project was funded by the American Thoracic Society Board of Directors. A multidisciplinary and diverse working group reviewed the available literature, established a conceptual framework, and iteratively developed recommendations for the Precision Medicine Research Agenda for Sepsis and ARDS. Results: The following six priority recommendations were developed by the working group: 1) the creation of large richly phenotyped and harmonized knowledge networks of clinical, imaging, and multianalyte molecular data for sepsis and ARDS; 2) the implementation of novel trial designs, including adaptive designs, and embedding trial procedures in the electronic health record; 3) continued innovation in the data science and engineering methods required to identify heterogeneity of treatment effect; 4) further development of the tools necessary for the real-time application of precision medicine approaches; 5) work to ensure that precision medicine strategies are applicable and available to a broad range of patients varying across differing racial, ethnic, socioeconomic, and demographic groups; and 6) the securement and maintenance of adequate and sustainable funding for precision medicine efforts. Conclusions: Precision medicine approaches that incorporate variability in genomic, biologic, and environmental factors may provide a path forward for better individualizing the delivery of therapies and improving care for patients with sepsis and ARDS.

A Pilot Double-Blind Placebo-Controlled Randomized Clinical Trial to Investigate the Effects of Early Enteral Nutrients in Sepsis.

Preclinical studies from our laboratory demonstrated therapeutic effects of enteral dextrose administration in the acute phase of sepsis, mediated by the intestine-derived incretin hormone glucose-dependent insulinotropic peptide. The current study investigated the effects of an early enteral dextrose infusion on systemic inflammation and glucose metabolism in critically ill septic patients. DESIGN: Single-center, double-blind, placebo-controlled randomized pilot clinical trial (NCT03454087). SETTING: Tertiary-care medical center in Pittsburgh, PA. PATIENTS: Critically ill adult patients within 48 hours of sepsis diagnosis and with established enteral access. INTERVENTIONS: Participants were randomized 1:1 to receive a continuous water (placebo) or enteral dextrose infusion (50% dextrose; 0.5 g/mL) at 10 mL per hour for 24 hours. MEASUREMENTS AND MAIN RESULTS: We randomized 58 participants between June 2018 and January 2020 (placebo: n = 29, dextrose: n = 29). Protocol adherence was high with similar duration of study infusion in the placebo (median duration, 24 hr [interquartile range, 20.9-24 hr]) and dextrose (23.9 hr [23-24 hr]) groups (p = 0.59). The primary outcome of circulating interleukin-6 at end-infusion did not differ between the dextrose (median, 32 pg/mL [19-79 pg/mL]) and placebo groups (24 pg/mL [9-59 pg/mL]; p = 0.13) with similar results in other measures of the systemic host immune response. Enteral dextrose increased circulating glucose-dependent insulinotropic peptide (76% increase; 95% CI [35-119]; p < 0.01) and insulin (53% [17-88]; p < 0.01) compared with placebo consistent with preclinical studies, but also increased blood glucose during the 24-hour infusion period (153 mg/dL [119-223] vs 116 mg/dL [91-140]; p < 0.01). Occurrence of emesis, ICU and hospital length of stay, and 30-day mortality did not differ between the placebo and enteral dextrose groups. CONCLUSIONS: Early infusion of low-level enteral dextrose in critically ill septic patients increased circulating levels of insulin and the incretin hormone glucose-dependent insulinotropic peptide without decreasing systemic inflammation.

Sepsis Subclasses: A Framework for Development and Interpretation.

Sepsis is defined as a dysregulated host response to infection that leads to life-threatening acute organ dysfunction. It afflicts approximately 50 million people worldwide annually and is often deadly, even when evidence-based guidelines are applied promptly. Many randomized trials tested therapies for sepsis over the past 2 decades, but most have not proven beneficial. This may be because sepsis is a heterogeneous syndrome, characterized by a vast set of clinical and biologic features. Combinations of these features, however, may identify previously unrecognized groups, or "subclasses" with different risks of outcome and response to a given treatment. As efforts to identify sepsis subclasses become more common, many unanswered questions and challenges arise. These include: 1) the semantic underpinning of sepsis subclasses, 2) the conceptual goal of subclasses, 3) considerations about study design, data sources, and statistical methods, 4) the role of emerging data types, and 5) how to determine whether subclasses represent "truth." We discuss these challenges and present a framework for the broader study of sepsis subclasses. This framework is intended to aid in the understanding and interpretation of sepsis subclasses, provide a mechanism for explaining subclasses generated by different methodologic approaches, and guide clinicians in how to consider subclasses in bedside care.

Feasibility of a Home-Based Palliative Care Intervention for Elderly Multimorbid Survivors of Critical Illness.

BACKGROUND: Elderly patients frequently experience deteriorating health after critical illness, which may threaten their independence and predispose them to unplanned hospital readmissions and premature death. OBJECTIVES: To evaluate the operational feasibility of a 90-day home-based palliative care intervention in multimorbid elderly Veteran survivors of critical illness. METHODS: A multidisciplinary home-based palliative care intervention was provided for multimorbid elderly veterans who were discharged home after admission to the intensive care unit for sepsis, pneumonia, heart failure, or exacerbation of chronic obstructive lung disease. RESULTS: Fifteen patients enrolled in the study, 11 (73%) of whom completed all visits; thus the prespecified goal of >70% completion was met. Median (interquartile range [IQR]) age of the patients was 76 (69-87) years. Participants had a median (IQR) of 8 (7-8) concurrent chronic health conditions, were moderately debilitated at baseline, and were all male. The median (IQR) time to the first study visit was 8 (5-12) days. Patients had a median (IQR) of 8 (5-11) in-home visits and 6 (3-7) telephone encounters during the 90-day study period. Nurses spent a median (IQR) cumulative time of 330 (240-585) minutes on home visits and 30 (10-70) minutes on telephone visits. The median (IQR) time per home provider visit was 90 (75-90) minutes. We estimated the median (IQR) cost per patient to be $2321 ($1901-$3331). CONCLUSION: A comprehensive home-based palliative care intervention is operationally feasible in elderly multi-morbid survivors of critical illness and may result in improved physical functioning and quality of life and fewer unplanned emergency department visits.

Estimating the Impact of Necrotizing Soft Tissue Infections in the United States: Incidence and Re-Admissions.

Background: Previous estimates of the incidence of necrotizing soft tissue infections (NSTI) in the United States have substantial limitations and underestimate its occurrence. Improvements in hospital mortality after NSTI have increased the number of survivors at risk for long-term sequelae. This study estimates the incidence of NSTI and the burden of re-admission and associated healthcare spending in patients who survived admission for NSTI. Methods: Index admissions for NSTI were identified using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes combined with either Current Procedural Technology (CPT) or diagnosis-related group codes to increase specificity. Two separate datasets were used to provide primary and secondary estimates of the annual incidence of NSTIs in the United States: the National Inpatient Sample (NIS) for the years 2012-2016 and the Watson Health dataset for 2009-2013, respectively, and extrapolated to estimate the incidence for 2018. The Nationwide Readmissions Database (NRD) from 2013-2015 was used to estimate of the risk for re-admission, cost of re-admissions, and to compare 90-day re-admission rates for NSTI to common medical conditions. Results: National Inpatient Sample and Watson Health datasets demonstrated an increasing annual incidence and estimated 33,600 and 28,500 cases in 2018, respectively. The estimated annual incidences in the United States in 2018 were 10.3 and 8.7 per 100,000 persons, respectively. Risk of 90-day re-admission ranged from 24%-29% over the 3 years, 89% of which were unplanned. Of those re-admitted, 90% had one or more comorbidities, the most common diagnoses associated with re-admission were infection in 65%, acute kidney injury in 22%, and shock in 10%. The median re-admission length of stay was seven days (interquartile range [IQR]: 4-13 days) with a median cost of re-admission of $13,590 (IQR: $7186-$27440). Conclusion: The incidence of NSTI is more common than generally reported. Re-admission within 90 days is common, occurring in more than one in four survivors resulting in high healthcare costs.

Plasma lipid profiling for the prognosis of 90-day mortality, in-hospital mortality, ICU admission, and severity in bacterial community-acquired pneumonia (CAP).

INTRODUCTION: Pneumonia is the most common cause of mortality from infectious diseases, the second leading cause of nosocomial infection, and the leading cause of mortality among hospitalized adults. To improve clinical management, metabolomics has been increasingly applied to find specific metabolic biopatterns (profiling) for the diagnosis and prognosis of various infectious diseases, including pneumonia. METHODS: One hundred fifty bacterial community-acquired pneumonia (CAP) patients whose plasma samples were drawn within the first 24 h of hospital admission were enrolled in this study and separated into two age- and sex-matched cohorts: non-survivors (died ≤ 90 days) and survivors (survived > 90 days). Three analytical tools, 1H-NMR spectroscopy, GC-MS, and targeted DI-MS/MS, were used to prognosticate non-survivors from survivors by means of metabolic profiles. RESULTS: We show that quantitative lipid profiling using DI-MS/MS can predict the 90-day mortality and in-hospital mortality among patients with bacterial CAP compared to 1H-NMR- and GC-MS-based metabolomics. This study showed that the decreased lysophosphatidylcholines and increased acylcarnitines are significantly associated with increased mortality in bacterial CAP. Additionally, we found that decreased lysophosphatidylcholines and phosphatidylcholines (> 36 carbons) and increased acylcarnitines may be used to predict the prognosis of in-hospital mortality for bacterial CAP as well as the need for ICU admission and severity of bacterial CAP. DISCUSSION: This study demonstrates that lipid-based plasma metabolites can be used for the prognosis of 90-day mortality among patients with bacterial CAP. Moreover, lipid profiling can be utilized to identify patients with bacterial CAP who are at the highest risk of dying in hospital and who need ICU admission as well as the severity assessment of CAP.

A Dyadic Growth Modeling Approach for Examining Associations Between Weight Gain and Lung Function Decline.

The relationship between body weight and lung function is complex. Using a dyadic multilevel linear modeling approach, treating body mass index (BMI; weight (kg)/height (m)2) and lung function as paired, within-person outcomes, we tested the hypothesis that persons with more rapid increase in BMI exhibit more rapid decline in lung function, as measured by forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and their ratio (FEV1:FVC). Models included random intercepts and slopes and adjusted for sociodemographic and smoking-related factors. A sample of 9,115 adults with paired measurements of BMI and lung function taken at ≥3 visits were selected from a pooled set of 5 US population-based cohort studies (1983-2018; mean age at baseline = 46 years; median follow-up, 19 years). At age 46 years, average annual rates of change in BMI, FEV1, FVC, and FEV1:FVC ratio were 0.22 kg/m2/year, -25.50 mL/year, -21.99 mL/year, and -0.24%/year, respectively. Persons with steeper BMI increases had faster declines in FEV1 (r = -0.16) and FVC (r = -0.26) and slower declines in FEV1:FVC ratio (r = 0.11) (all P values < 0.0001). Results were similar in subgroup analyses. Residual correlations were negative (P < 0.0001), suggesting additional interdependence between BMI and lung function. Results show that greater rates of weight gain are associated with greater rates of lung function loss.