Andrew J. Goodwin

Frequency, cost, and risk factors of readmissions among severe sepsis survivors.

Objective:To determine the frequency, mortality, cost, and risk factors associated with readmission after index hospitalization with severe sepsis. Design:Observational cohort study of Healthcare Cost and Utilization Project data. Setting:All nonfederal hospitals in three U.S. states. Patients:Severe sepsis survivors (n = 43,452) in the first two quarters of 2011. InterventionsNone. Measurements and Main Results:We measured readmission rates and the associated cost and mortality of readmissions in severe sepsis survivors. We used multivariable logistic regression to identify patient and hospitalization characteristics associated with readmission. Of 43,452 sepsis survivors, 26% required readmission within 30 days and 48% within 180 days. The cumulative mortality rate of sepsis survivors attributed to readmissions was 8%, and the estimated cost was over

Endothelial Progenitor Cells and a Stromal Cell–derived Factor-1α Analogue Synergistically Improve Survival in Sepsis

1.1 billion. Among survivors, 25% required multiple readmissions within 180 days and accounted for 77% of all readmissions. Age younger than 80 years (odds ratio, 1.14; 95% CI, 1.08–1.21), black race (odds ratio, 1.18; 95% CI, 1.10–1.26), and Medicare or Medicaid payor status (odds ratio, 1.21; 95% CI, 1.13–1.30; odds ratio, 1.34; 95% CI, 1.23–1.46, respectively) were associated with greater odds of 30-day readmission while female gender was associated with reduced odds (odds ratio, 0.92; 95% CI, 0.87–0.96). Comorbidities including malignancy (odds ratio, 1.34; 95% CI, 1.24–1.45), collagen vascular disease (odds ratio, 1.30; 95% CI, 1.15–1.46), chronic kidney disease (odds ratio, 1.24; 95% CI, 1.18–1.31), liver disease (odds ratio, 1.22; 95% CI, 1.11–1.34), congestive heart failure (odds ratio, 1.14; 95% CI, 1.08–1.19), lung disease (odds ratio, 1.12; 95% CI, 1.06–1.18), and diabetes (odds ratio, 1.12; 95% CI, 1.07–1.17) were associated with greater odds of 30-day readmission. Index hospitalization characteristics including longer length of stay, discharge to a care facility, higher hospital annual severe sepsis case volume, and higher hospital sepsis mortality rate were also positively associated with readmission rates. Conclusion:The 30-day and 180-day readmissions are common in sepsis survivors with significant resultant cost and mortality. Patient sociodemographics and comorbidities as well as index hospitalization characteristics are associated with 30-day readmission rates.

A Severe Sepsis Mortality Prediction Model and Score for Use With Administrative Data.

RATIONALE Endothelial progenitor cells (EPCs) have been associated with human sepsis but their role is incompletely understood. Stromal cell-derived factor (SDF)-1α facilitates EPC recruitment and is elevated in murine sepsis models. Previous studies have demonstrated that the SDF-1α analog CTCE-0214 (CTCE) is beneficial in polymicrobial sepsis induced by cecal ligation and puncture (CLP) in mice. OBJECTIVES We hypothesized that exogenously administered EPCs are also beneficial in CLP sepsis and that CTCE provides synergistic benefit. METHODS Mice were subjected to CLP and administered EPCs at varying doses, CTCE, or a combination of the two. Mouse survival, plasma miRNA expression, IL-10 production, and lung vascular leakage were determined. The in vitro effect of CTCE on miRNA expression and EPC function were determined. MEASUREMENTS AND MAIN RESULTS Survival was improved with EPC therapy at a threshold of 10(6) cells. In coculture studies, EPCs augmented LPS-induced macrophage IL-10 production. In vivo EPC administration in sepsis increased plasma IL-10, suppressed lung vascular leakage, attenuated liver and kidney injury, and augmented miR-126 and -125b expression, which regulate endothelial cell function and/or inflammation. When subthreshold numbers of EPCs were coadministered with CTCE in CLP mice they synergistically improved survival. We demonstrated that CTCE recruits endogenous EPCs in septic mice. In in vitro analysis, CTCE enhanced EPC proliferation, angiogenesis, and prosurvival signaling while inhibiting EPC senescence. These cellular effects were, in part, explained by the effect of CTCE on miR-126, -125b, -34a, and -155 expression in EPCs. CONCLUSIONS EPCs and CTCE represent important potential therapeutic strategies in sepsis.

The role of miRNAs in cardiovascular disease risk factors.

Objective:Administrative data are used for research, quality improvement, and health policy in severe sepsis. However, there is not a sepsis-specific tool applicable to administrative data with which to adjust for illness severity. Our objective was to develop, internally validate, and externally validate a severe sepsis mortality prediction model and associated mortality prediction score. Design:Retrospective cohort study using 2012 administrative data from five U.S. states. Three cohorts of patients with severe sepsis were created: 1) International Classification of Diseases, 9th Revision, Clinical Modification codes for severe sepsis/septic shock, 2) Martin approach, and 3) Angus approach. The model was developed and internally validated in International Classification of Diseases, 9th Revision, Clinical Modification, cohort and externally validated in other cohorts. Integer point values for each predictor variable were generated to create a sepsis severity score. Setting:Acute care, nonfederal hospitals in New York, Maryland, Florida, Michigan, and Washington. Subjects:Patients in one of three severe sepsis cohorts: 1) explicitly coded (n = 108,448), 2) Martin cohort (n = 139,094), and 3) Angus cohort (n = 523,637) Interventions:None. Measurements and Main Results:Maximum likelihood estimation logistic regression to develop a predictive model for in-hospital mortality. Model calibration and discrimination assessed via Hosmer-Lemeshow goodness-of-fit and C-statistics, respectively. Primary cohort subset into risk deciles and observed versus predicted mortality plotted. Goodness-of-fit demonstrated p value of more than 0.05 for each cohort demonstrating sound calibration. C-statistic ranged from low of 0.709 (sepsis severity score) to high of 0.838 (Angus cohort), suggesting good to excellent model discrimination. Comparison of observed versus expected mortality was robust although accuracy decreased in highest risk decile. Conclusions:Our sepsis severity model and score is a tool that provides reliable risk adjustment for administrative data.

A Stromal Cell-derived Factor 1 alpha Analogue Improves Endothelial Cell Function in Lipopolysaccharide-induced Acute Respiratory Distress Syndrome.

Coronary artery disease and atherosclerosis are complex pathologies that develop over time due to genetic and environmental factors. Differential expression of miRNAs has been identified in patients with coronary artery disease and atherosclerosis, however, their association with cardiovascular disease risk factors, including hyperlipidemia, hypertension, obesity, diabetes, lack of physical activity and smoking, remains unclear. This review examines the role of miRNAs as either biomarkers or potential contributors to the pathophysiology of these aforementioned risk factors. It is intended to provide an overview of the published literature which describes alterations in miRNA levels in both human and animal studies of cardiovascular risk factors and when known, the possible mechanism by which these miRNAs may exert either beneficial or deleterious effects. The intent of this review is engage clinical, translational, and basic scientists to design future collaborative studies to further elucidate the potential role of miRNAs in cardiovascular diseases.

Volume-Mortality Relationships during Hospitalization with Severe Sepsis Exist Only at Low Case Volumes.

Endothelial cell (EC) dysfunction is a critical mediator of the acute respiratory distress syndrome (ARDS). Recent studies have demonstrated that stromal cell-derived factor 1α (SDF-1α) promotes EC barrier integrity. Our previous studies used a SDF-1α analogue CTCE-0214 (CTCE) in experimental sepsis and demonstrated that it attenuated vascular leak and modulated microRNA (miR) levels. We examined the hypothesis that CTCE improves EC function in lipopolysaccharide (LPS)-induced ARDS through increasing miR-126 expression. Human microvascular endothelial cells (HMVECs) were treated with thrombin to disrupt the EC integrity followed by incubation with CTCE or SDF-1α. Barrier function was determined by trans-endothelial electrical resistance assay. CTCE-induced alterations in miRNA expression and signaling pathways involved in barrier function were determined. Thrombin-induced vascular leak was abrogated by both CTCE and SDF-1α. CTCE also prevented thrombin-induced decreases of vascular endothelial (VE)-cadherin cell surface expression and expansion of the intercellular space. CTCE increased miR-126 levels and induced activation of AKT/Rac 1 signaling. Cotreatment with a miR-126 inhibitor blocked the protective effects of CTCE on AKT activation and endothelial permeability. In subsequent in vivo studies, ARDS was induced by intratracheal instillation of LPS. Intravenous injection of CTCE diminished the injury severity as evidenced by significant reductions in protein, immune cells, inflammatory cytokines and chemokines in the bronchoalveolar lavage fluid, increased miR-126 expression and decreased pulmonary vascular leak and alveolar edema. Taken together, our data show that CTCE improves endothelial barrier integrity through increased expression of miR-126 and activation of Rac 1 signaling and represents an important potential therapeutic strategy in ARDS.

Critical Care Clinical Trials: Getting Off the Roller Coaster

RATIONALE Volume-outcome associations have been demonstrated in conditions with high morbidity and mortality; however, the existing literature regarding such associations in sepsis is not definitive. OBJECTIVES To test the hypothesis that annual hospital severe sepsis case volume is associated with mortality during admissions with severe sepsis in teaching and nonteaching hospitals. METHODS This work was a retrospective cohort study of administrative data from the South Carolina State Inpatient Database using multivariate logistic regression and case mix adjustment. MEASUREMENTS AND MAIN RESULTS In the calendar year 2010, 9,815 patients were admitted with severe sepsis or septic shock. Hospitals were stratified into low- (0-75 cases/yr, n = 26), intermediate- (76-300 cases/yr, n = 19), and high (>300 cases/yr, n = 12) -volume tertiles. Patients admitted to hospitals with a low annual case volume for sepsis had higher adjusted odds of dying before discharge (odds ratio, 1.56; 95% confidence interval, 1.25-1.94) compared with patients admitted to high-volume hospitals. Hospitalization at intermediate-volume hospitals was not associated with a difference in mortality (odds ratio, 0.99; 95% confidence interval, 0.90-1.09) compared with high-volume hospitals. There was no difference between the mortality rates of intermediate- and high-volume hospitals at different severity of illness quartiles. Hospital length of stay differed significantly by hospital case volume (low = 8.0, intermediate = 12.7, high = 14.9 [d]; P < 0.0001). CONCLUSIONS Hospitals with low annual sepsis case volume are associated with higher mortality rates, whereas hospitals with intermediate sepsis case volumes are associated with similar mortality rates compared with hospitals with high case volumes.

Patient and Hospital Characteristics Associated with Interhospital Transfer for Adults with Ventilator-Dependent Respiratory Failure

Optimizing care in the ICU is an important goal. The heightened severity of illness in patients who are critically ill combined with the tremendous costs of critical care make the ICU an ideal target for improvement in outcomes and efficiency. Incorporation of evidence-based medicine into everyday practice is one method to optimize care; however, intensivists have struggled to define optimal practices because clinical trials in the ICU have yielded conflicting results. This article reviews examples where such conflicts have occurred and explores possible causes of these discrepant data as well as strategies to better use critical care clinical trials in the future.

Opportunities for microRNAs in the Crowded Field of Cardiovascular Biomarkers.

Rationale: Patients with ventilator‐dependent respiratory failure have improved outcomes at centers with greater expertise; yet, most patients are not treated in such facilities. Efforts to align care for respiratory failure and hospital capability would necessarily require interhospital transfer. Objectives: To characterize the prevalence and the patient and hospital factors associated with interhospital transfer of adults residing in Florida with ventilator‐dependent respiratory failure. Methods: We performed a retrospective, observational study using Florida Healthcare Cost and Utilization Project data. We selected patients 18 years of age and older with International Classification of Diseases, Ninth Revision, codes of respiratory failure and mechanical ventilation during 2012 and 2013, and we identified cohorts of patients that did and did not undergo interhospital transfer. We obtained patient sociodemographic and clinical variables and categorized hospitals into subtypes on the basis of patient volume and services provided: large, medium (nonprofit or for‐profit), and small. Results: Interhospital transfer was our primary outcome measure. Patient sociodemographics, clinical variables, and hospital types were used as covariates. We identified 2,580 patients with ventilator‐dependent respiratory failure who underwent interhospital transfer. Overall, transfer was uncommon, with only 2.9% of patients being transferred. In a hierarchical model, age less than 65 years (odds ratio [OR], 2.09; 95% confidence interval [CI], 1.77‐2.45) and tracheostomy (OR, 3.19; 95% CI, 2.80‐3.65) were associated with higher odds of transfer, whereas having Medicaid was associated with lower odds of transfer than having commercial insurance (OR, 0.65; 95% CI, 0.56‐0.75). Additionally, care in medium‐sized for‐profit hospitals was associated with lower odds of transfer (OR, 1.37 vs. 2.70) than care in medium nonprofit hospitals, despite similar hospital characteristics. Conclusions: In Florida, interhospital transfer of patients with ventilator‐dependent respiratory failure is uncommon and more likely among younger, commercially insured, medically resource‐intensive patients. For‐profit hospitals are less likely to transfer than nonprofit hospitals. In future studies, researchers should test for geographic variations and examine the clinical implications of selectivity in interhospital transfer of patients with ventilator‐dependent respiratory failure.

Fli-1 Governs Pericyte Dysfunction in a Murine Model of Sepsis

Cardiovascular diseases exist across all developed countries. Biomarkers that can predict or diagnose diseases early in their pathogeneses can reduce their morbidity and mortality in afflicted individuals. microRNAs are small regulatory RNAs that modulate translation and have been identified as potential fluid-based biomarkers across numerous maladies. We describe the current state of cardiovascular disease biomarkers across a range of diseases, including myocardial infarction, acute coronary syndrome, myocarditis, hypertension, heart failure, heart transplantation, aortic stenosis, diabetic cardiomyopathy, atrial fibrillation, and sepsis. We present the current understanding of microRNAs as possible biomarkers in these categories and where their best opportunities exist to enter clinical practice.