National Estimates of Emergency Department Visits for Pediatric Severe Sepsis in the United States

Objective. We sought to determine the characteristics of children presenting to United States (US) Emergency Departments (ED) with severe sepsis. Study design. Cross-sectional analysis using data from the National Hospital Ambulatory Medical Care Survey (NHAMCS). Using triage vital signs and ED diagnoses (defined by the International Classification of Diseases, Ninth Revision codes), we identified children(triage fever or ICD-9 infection) and organ dysfunction (triage hypotension or ICD-9 organ dysfunction). Results. Of 28.2 million pediatric patients presenting to US EDs each year, severe sepsis was present in 95,055 (0.34%; 95% CI: 0.29-0.39%). Fever and respiratory infection were the most common indicators of an infection. Hypotension and respiratory failure were the most common indicators of organ dysfunction. Most severe sepsis occurred in children ages 31 days-1 year old (32.1%). Most visits for pediatric severe sepsis occurred during winter months (37.4%), and only 11.1% of patients arrived at the ED by ambulance. Over half of severe sepsis cases were self-pay or insured by Medicaid. A large portion (44.1%) of pediatric severe sepsis ED visits occurred in the South census region. ED length of stay was over 3 h, and 16.5% were admitted to the hospital. Conclusion. Nearly 100,000 children annually present to US EDs with severe sepsis. The findings of this study highlight the unique characteristics of children treated in the ED for severe sepsis

Evaluation Of A 5-Group Classification System For Severe Sepsis By Ed Vasopressor Use And Initial Serum Lactate

HYPOTHESIS AND SPECIFIC AIMS: The aim of this study is to characterize the incidence and outcomes of various groups within a novel classification system of severe sepsis and septic shock, for the purpose of informing more accurate risk prediction in the proximal phases of care. Our primary hypothesis is that an early classification system of septic patients categorized by organ dysfunction, initial emergency department (ED) serum lactate, and ED vasopressor utilization will offer accurate mortality prognostication in patients with severe sepsis and septic shock. METHODS: We performed a retrospective analysis of a prospectively- gathered registry of severe sepsis and septic shock patients presenting to a dual-site academic emergency department (ED). In the primary analysis, registry subjects were categorized into five groups by initial ED serum lactate level and vasopressor requirement in the ED: dysoxic shock (vasopressor use + lactate \u3e4 mmol/L), vasoplegic shock (vasopressor use + lactate \u3c4 mmol/L), cryptic shock major (no vasopressor use + lactate \u3e4 mmol/L), cryptic shock minor (no vasopressor use + lactate \u3e2 and \u3c4 mmol/L), and severe sepsis without lactate elevation (no vasopressor use + lactate \u3c2 mmol/L + evidence of organ dysfunction). For each group, the 28-day mortality rate was evaluated by logistic regression controlling for specific factors associated with sepsis severity. RESULTS: Of 521 registry subjects, 85.6% (n=446) met inclusion criteria. 4.9% (n=22) subjects presented in dysoxic shock, 11.7% (n=52) in vasoplegic shock, 12.1% (n=54) in cryptic shock major, 30.9% (n=138) in cryptic shock minor, and 40.4% (n=180) in severe sepsis without lactate elevation. The 28-day mortality rates for these groups were 50.0%, 21.1%, 18.5%, 12.3%, and 7.2%, respectively; this stepwise trend was paralleled by metrics of critical care utilization such as ICU admission, mechanical ventilation, and vasopressor use within 72 hours of admission. After controlling for known risk factors for sepsis severity, the odds ratios for death before 28 days were 15.06 for dysoxic shock, 3.61 for vasoplegic shock, 3.77 for cryptic shock major, and 1.93 for cryptic shock minor, as compared to severe sepsis without lactate elevation. CONCLUSION: This study suggests that high-risk subgroups of severe sepsis and septic shock patients can be identified at presentation and during the emergency department stay. We show that in severe sepsis and septic shock, a proximal-phase classification system based on vasopressor requirement in the ED and initial ED lactate level predicts 28-day in-hospital mortality and may inform prognostication, triage decisions and future sepsis clinical trial design

Innate immune modulation by GM-CSF and IL-3 in health and disease

Granulocyte-macrophage colony-stimulating factor (GM-CSF) and inteleukin-3 (IL-3) have long been known as mediators of emergency myelopoiesis, but recent evidence has highlighted their critical role in modulating innate immune effector functions in mice and humans. This new wealth of knowledge has uncovered novel aspects of the pathogenesis of a range of disorders, including infectious, neoplastic, autoimmune, allergic and cardiovascular diseases. Consequently, GM-CSF and IL-3 are now being investigated as therapeutic targets for some of these disorders, and some phase I/II clinical trials are already showing promising results. There is also pre-clinical and clinical evidence that GM-CSF can be an effective immunostimulatory agent when being combined with anti-cytotoxic T lymphocyte-associated protein 4 (anti-CTLA-4) in patients with metastatic melanoma as well as in novel cancer immunotherapy approaches. Finally, GM-CSF and to a lesser extent IL-3 play a critical role in experimental models of trained immunity by acting not only on bone marrow precursors but also directly on mature myeloid cells. Altogether, characterizing GM-CSF and IL-3 as central mediators of innate immune activation is poised to open new therapeutic avenues for several immune-mediated disorders and define their potential in the context of immunotherapies

Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury

Introduction Acute kidney injury (AKI) can evolve quickly and clinical measures of function often fail to detect AKI at a time when interventions are likely to provide benefit. Identifying early markers of kidney damage has been difficult due to the complex nature of human AKI, in which multiple etiologies exist. The objective of this study was to identify and validate novel biomarkers of AKI. Methods We performed two multicenter observational studies in critically ill patients at risk for AKI - discovery and validation. The top two markers from discovery were validated in a second study (Sapphire) and compared to a number of previously described biomarkers. In the discovery phase, we enrolled 522 adults in three distinct cohorts including patients with sepsis, shock, major surgery, and trauma and examined over 300 markers. In the Sapphire validation study, we enrolled 744 adult subjects with critical illness and without evidence of AKI at enrollment; the final analysis cohort was a heterogeneous sample of 728 critically ill patients. The primary endpoint was moderate to severe AKI (KDIGO stage 2 to 3) within 12 hours of sample collection. Results Moderate to severe AKI occurred in 14% of Sapphire subjects. The two top biomarkers from discovery were validated. Urine insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, a key mechanism implicated in AKI, together demonstrated an AUC of 0.80 (0.76 and 0.79 alone). Urine [TIMP-2]·[IGFBP7] was significantly superior to all previously described markers of AKI (P \u3c0.002), none of which achieved an AUC \u3e0.72. Furthermore, [TIMP-2]·[IGFBP7] significantly improved risk stratification when added to a nine-variable clinical model when analyzed using Cox proportional hazards model, generalized estimating equation, integrated discrimination improvement or net reclassification improvement. Finally, in sensitivity analyses [TIMP-2]·[IGFBP7] remained significant and superior to all other markers regardless of changes in reference creatinine method. Conclusions Two novel markers for AKI have been identified and validated in independent multicenter cohorts. Both markers are superior to existing markers, provide additional information over clinical variables and add mechanistic insight into AKI. Trial registration ClinicalTrials.gov number NCT01209169

Recent Trends in Sepsis Mortality, Associations between Initial Source of Sepsis and Hospital Mortality, and Predictors of Sepsis Readmission in Sepsis Survivors

Background: Sepsis, a leading cause of US deaths, is associated with high mortality, although advances in early recognition and treatment have increased survivorship. Many aspects of sepsis pathophysiology and epidemiology have not been fully elucidated; the heterogeneous nature of infections that lead to sepsis has made fully characterizing the underlying epidemiology challenging. Methods: The University HealthSystem Consortium (UHC) from 2011-2014 and the Cerner HealthFacts® database from 2008-2014 were used. We examined associations between infection source and in-hospital mortality in the UHC dataset, stratified by age and presenting sepsis stage. We examined recent temporal trends in present-on-admission (POA) sepsis diagnoses and mortality and predictors of 30-day sepsis readmissions following sepsis hospitalizations using the HealthFacts® dataset. Results: Patients with sepsis due to genitourinary or skin, soft tissue, or bone sources had lower mortality than patients with sepsis due to respiratory sources regardless of age or presenting sepsis stage. Overall diagnoses of sepsis increased from 2008-2014; however, POA diagnoses and case fatality rates decreased. Factors that predicted re-hospitalization for sepsis included discharge to hospice, admission from or discharge to a skilled nursing facility, and abdominal infection. Conclusion: Further investigation will reveal more detail to explain the impact of infection source on in-hospital sepsis mortality for all age groups and sepsis stages. Decreasing mortality rates for all POA sepsis stages and all age groups suggest current approaches to sepsis management are having broad impact. Sepsis survivors are at significant risk for re-hospitalization; further studies are needed to understand the post discharge risks and needs of survivors

Alkali Therapy in Lactic Acidosis

This report attempts to frame the debate about clinical administration of sodium bicarbonate in the setting of lactic acidosis in terms of simple questions. Specifically, we address why we develop lactic acidosis in some circumstances, how acute lactic acidosis impairs cardiovascular function and why sodium bicarbonate may have deleterious effects which limit its utility. We also attempt to explore treatment alternatives to sodium bicarbonate