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1.  Disease Progression in Hemodynamically Stable Patients Presenting to the Emergency Department With Sepsis 
Background
Aggressive diagnosis and treatment of patients presenting to the emergency department (ED) with septic shock has been shown to reduce mortality. To enhance the ability to intervene in patients with lesser illness severity, a better understanding of the natural history of the early progression from simple infection to more severe illness is needed.
Objectives
The objectives were to 1) describe the clinical presentation of ED sepsis, including types of infection and causative microorganisms, and 2) determine the incidence, patient characteristics, and mortality associated with early progression to septic shock among ED patients with infection.
Methods
This was a multicenter study of adult ED patients with sepsis but no evidence of shock. Multivariable logistic regression was used to identify patient factors for early progression to shock and its association with 30-day mortality.
Results
Of 472 patients not in shock at ED presentation (systolic blood pressure > 90 mm Hg and lactate < 4 mmol / L), 84 (17.8%) progressed to shock within 72 hours. Independent factors associated with early progression to shock included older age, female sex, hyperthermia, anemia, comorbid lung disease, and vascular access device infection. Early progression to shock (vs. no progression) was associated with higher 30-day mortality (13.1% vs. 3.1%, odds ratio [OR] = 4.72, 95% confidence interval [CI] = 2.01 to 11.1; p ≤ 0.001). Among 379 patients with uncomplicated sepsis (i.e., no evidence of shock or any end-organ dysfunction), 86 (22.7%) progressed to severe sepsis or shock within 72 hours of hospital admission.
Conclusions
A significant portion of ED patients with less severe sepsis progress to severe sepsis or shock within 72 hours. Additional diagnostic approaches are needed to risk stratify and more effectively treat ED patients with sepsis.
doi:10.1111/j.1553-2712.2010.00664.x
PMCID: PMC4283798  PMID: 20370777
sepsis; outcomes; septic shock; progression; biomarkers
2.  An integrated transcriptome and expressed variant analysis of sepsis survival and death 
Genome Medicine  2014;6(11):111.
Background
Sepsis, a leading cause of morbidity and mortality, is not a homogeneous disease but rather a syndrome encompassing many heterogeneous pathophysiologies. Patient factors including genetics predispose to poor outcomes, though current clinical characterizations fail to identify those at greatest risk of progression and mortality.
Methods
The Community Acquired Pneumonia and Sepsis Outcome Diagnostic study enrolled 1,152 subjects with suspected sepsis. We sequenced peripheral blood RNA of 129 representative subjects with systemic inflammatory response syndrome (SIRS) or sepsis (SIRS due to infection), including 78 sepsis survivors and 28 sepsis non-survivors who had previously undergone plasma proteomic and metabolomic profiling. Gene expression differences were identified between sepsis survivors, sepsis non-survivors, and SIRS followed by gene enrichment pathway analysis. Expressed sequence variants were identified followed by testing for association with sepsis outcomes.
Results
The expression of 338 genes differed between subjects with SIRS and those with sepsis, primarily reflecting immune activation in sepsis. Expression of 1,238 genes differed with sepsis outcome: non-survivors had lower expression of many immune function-related genes. Functional genetic variants associated with sepsis mortality were sought based on a common disease-rare variant hypothesis. VPS9D1, whose expression was increased in sepsis survivors, had a higher burden of missense variants in sepsis survivors. The presence of variants was associated with altered expression of 3,799 genes, primarily reflecting Golgi and endosome biology.
Conclusions
The activation of immune response-related genes seen in sepsis survivors was muted in sepsis non-survivors. The association of sepsis survival with a robust immune response and the presence of missense variants in VPS9D1 warrants replication and further functional studies.
Trial registration
ClinicalTrials.gov NCT00258869. Registered on 23 November 2005.
Electronic supplementary material
The online version of this article (doi:10.1186/s13073-014-0111-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s13073-014-0111-5
PMCID: PMC4274761  PMID: 25538794
3.  Pain Treatment for Older Adults During Prehospital Emergency Care: Variations by Patient Gender and Pain Severity 
Older adults are less likely than younger adults to receive analgesic treatment during emergency department visits. Whether older adults are less likely to receive analgesics during protocolized prehospital care is unknown. We analyzed all ambulance transports in 2011 in the state of North Carolina and compared the administration of any analgesic or an opioid among older adults (aged 65 and older) versus adults aged 18 to 64. Complete data were available for 407,763 transports. Older men were less likely than younger men to receive an analgesic or an opioid regardless of pain severity. Among women with mild or moderate pain, older women were less likely than younger women to receive either form of pain treatment, but among women with more severe pain (pain score 8 or more), older women were more likely than younger women to receive pain treatment. Further, among women with mild or moderate pain, the oldest patients (aged 85 and older) were the least likely to receive any analgesic or an opioid, but among women with severe pain the oldest patients were the most likely to receive treatment. Further research is needed to assess the generalizability of this interaction between age, gender, and pain severity on pain treatment.
Perspective
During prehospital care in North Carolina in 2011, older adults were generally less likely to receive pain treatment. However, older women with severe pain were more likely to receive treatment than younger women with severe pain. These results suggest an interaction between age, gender, and pain severity on pain treatment.
doi:10.1016/j.jpain.2013.03.014
PMCID: PMC3934508  PMID: 23726936
Pain; geriatrics; emergency treatment; prehospital
4.  Surge Capacity and Capability. A Review of the History and Where the Science is Today Regarding Surge Capacity during a Mass Casualty Disaster 
Disasters which include countless killed and many more injured, have occurred throughout recorded history. Many of the same reports of disaster also include numerous accounts of individuals attempting to rescue those in great peril and render aid to the injured and infirmed. The purpose of this paper is to briefly discuss the transition through several periods of time with managing a surge of many patients. This review will focus on the triggering event, injury and illness, location where the care is provided and specifically discuss where the science is today.
doi:10.3389/fpubh.2014.00029
PMCID: PMC4001022  PMID: 24795873
surge capacity; mass casualty incidents; disaster planning; disaster medicine; emergency medicine; emergency service; hospital; emergency medical services
5.  An integrated clinico-metabolomic model improves prediction of death in sepsis 
Science translational medicine  2013;5(195):195ra95.
Sepsis is a common cause of death, but outcomes in individual patients are difficult to predict. Elucidating the molecular processes that differ between sepsis patients who survive and those who die may permit more appropriate treatments to be deployed. We examined the clinical features, and the plasma metabolome and proteome of patients with and without community-acquired sepsis, upon their arrival at hospital emergency departments and 24 hours later. The metabolomes and proteomes of patients at hospital admittance who would die differed markedly from those who would survive. The different profiles of proteins and metabolites clustered into fatty acid transport and β-oxidation, gluconeogenesis and the citric acid cycle. They differed consistently among several sets of patients, and diverged more as death approached. In contrast, the metabolomes and proteomes of surviving patients with mild sepsis did not differ from survivors with severe sepsis or septic shock. An algorithm derived from clinical features together with measurements of seven metabolites predicted patient survival. This algorithm may help to guide the treatment of individual patients with sepsis.
doi:10.1126/scitranslmed.3005893
PMCID: PMC3924586  PMID: 23884467
6.  Predictive Value of Initial Triage Vital Signs for Critically Ill Older Adults 
Introduction:
Triage of patients is critical to patient safety, yet no clear information exists as to the utility of initial vital signs in identifying critically ill older emergency department (ED) patients. The objective of this study is to evaluate a set of initial vital sign thresholds as predictors of severe illness and injury among older adults presenting to the ED.
Methods:
We reviewed all visits by patients aged 75 and older seen during 2007 at an academic ED serving a large community of older adults. Patients’ charts were abstracted for demographic and clinical information including vital signs, via automated electronic methods. We used bivariate analysis to investigate the relationship between vital sign abnormalities and severe illness or injury, defined as intensive care unit (ICU) admission or ED death. In addition, we calculated likelihood ratios for normal and abnormal vital signs in predicting severe illness or injury.
Results:
4,873 visits by patients aged 75 and above were made to the ED during 2007, and of these 3,848 had a complete set of triage vital signs. For these elderly patients, the sensitivity and specificity of an abnormal vital sign taken at triage for predicting death or admission to an ICU were 73% (66,81) and 50% (48,52) respectively (positive likelihood ratio 1.47 (1.30,1.60); negative likelihood ratio 0.54 (0.30,0.60).
Conclusion:
Emergency provider assessment and triage scores that rely primarily on initial vital signs are likely to miss a substantial portion of critically ill older adults.
doi:10.5811/westjem.2013.5.13411
PMCID: PMC3789908  PMID: 24106542
7.  Discriminative Value of Inflammatory Biomarkers for Suspected Sepsis 
Background
Circulating biomarkers can facilitate sepsis diagnosis enabling early management and improved outcomes. Procalcitonin (PCT) has been suggested to have superior diagnostic utility compared to other biomarkers.
Methods
Adults with suspected sepsis in the Emergency Department were enrolled. PCT, CRP, and IL-6 were correlated with infection likelihood, sepsis severity, and septicemia. Multivariable models were constructed for length-of-stay and discharge to a higher level of care.
Results
Of 336 enrolled subjects, 60% had definite infection, 13% possible infection and 27% no infection. Of those with infection, 202 presented with sepsis, 28 with severe sepsis, and 17 with septic shock. Overall, 21% of subjects were septicemic. PCT, IL6, and CRP levels were significantly higher in septicemia (median PCT 2.3 vs. 0.2ng/mL; IL-6 178 vs. 72pg/mL; CRP 106 vs. 62mg/dL, p<0.001). Biomarker concentrations increased with greater likelihood of infection and sepsis severity. Using ROC analysis, PCT best predicted septicemia (0.78 vs. IL-6 0.70 and CRP 0.67) but CRP better identified clinical infection (0.75 vs. PCT 0.71 and IL-6 0.69). A PCT cut-off of 0.5ng/mL had 72.6% sensitivity and 69.5% specificity for bacteremia as well as 40.7% sensitivity and 87.2% specificity for diagnosing infection. A combined clinical-biomarker model revealed that CRP was marginally associated with length-of-stay (p=0.015), but no biomarker independently predicted discharge to a higher level of care.
Conclusions
In adult Emergency Department patients with suspected sepsis, PCT, IL-6, and CRP highly correlate with several infection parameters, but do not meaningfully predict length-of-stay or need for discharge to a higher level of care.
doi:10.1016/j.jemermed.2011.05.072
PMCID: PMC3740117  PMID: 22056545
Sepsis; Procalcitonin; Interleukin-6; C-Reactive Protein; Sensitivity and Specificity
8.  Nursing Home Revenue Source and Information Availability During the Emergency Department Evaluation of Nursing Home Residents 
OBJECTIVES
Lack of access to medical information for nursing home residents during Emergency Department (ED) evaluation is a barrier to quality care. We hypothesized that the quantity of information available in the ED differs based on the funding source of the resident’s nursing home.
DESIGN
Cross-sectional observational study.
SETTING
Single academic ED.
PARTICIPANTS
128 skilled nursing facility (SNF) residents age 65 or older from 12 SNFs.
MEASUREMENTS
Emergency physicians documented knowledge of 9 essential information items. SNFs were categorized as accepting or not accepting Medicaid.
RESULTS
Questionnaires were completed for 128 patients, of whom 95 (74%) were from one of 8 Medicaid-funded SNFs and 33 (26%) were from one of 4 SNFs not accepting Medicaid. Patients from SNFs accepting Medicaid were younger (79 vs. 87, p<.001) and less frequently white (62% vs. 97%, p<.001). The mean number of 9 possible information items available was lower for patients from SNFs that accept Medicaid (7.13 vs. 8.15, p<.001). Emergency providers also reported lower satisfaction regarding access to information for residents from SNFs that accept Medicaid (p<.05). The association between residence in a SNF that accepts Medicaid and lower ED information scores remained after linear regression with clustering by SNF controlling for age, gender, and race. The most common source of information for residents from both types of SNFs was transfer papers from the SNF.
CONCLUSION
Less information is available to ED providers for patients from SNFs that accept Medicaid than for residents from SNFs that do not accept Medicaid. Further study is needed to examine this information gap.
doi:10.1016/j.jamda.2010.12.009
PMCID: PMC3134611  PMID: 21450234
9.  Gene Expression-Based Classifiers Identify Staphylococcus aureus Infection in Mice and Humans 
PLoS ONE  2013;8(1):e48979.
Staphylococcus aureus causes a spectrum of human infection. Diagnostic delays and uncertainty lead to treatment delays and inappropriate antibiotic use. A growing literature suggests the host’s inflammatory response to the pathogen represents a potential tool to improve upon current diagnostics. The hypothesis of this study is that the host responds differently to S. aureus than to E. coli infection in a quantifiable way, providing a new diagnostic avenue. This study uses Bayesian sparse factor modeling and penalized binary regression to define peripheral blood gene-expression classifiers of murine and human S. aureus infection. The murine-derived classifier distinguished S. aureus infection from healthy controls and Escherichia coli-infected mice across a range of conditions (mouse and bacterial strain, time post infection) and was validated in outbred mice (AUC>0.97). A S. aureus classifier derived from a cohort of 94 human subjects distinguished S. aureus blood stream infection (BSI) from healthy subjects (AUC 0.99) and E. coli BSI (AUC 0.84). Murine and human responses to S. aureus infection share common biological pathways, allowing the murine model to classify S. aureus BSI in humans (AUC 0.84). Both murine and human S. aureus classifiers were validated in an independent human cohort (AUC 0.95 and 0.92, respectively). The approach described here lends insight into the conserved and disparate pathways utilized by mice and humans in response to these infections. Furthermore, this study advances our understanding of S. aureus infection; the host response to it; and identifies new diagnostic and therapeutic avenues.
doi:10.1371/journal.pone.0048979
PMCID: PMC3541361  PMID: 23326304
10.  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.
doi:10.1164/rccm.201110-1848ST
PMCID: PMC3361348  PMID: 22210788
11.  Research Priorities for Palliative and End-of-life Care in the Emergency Setting 
Academic Emergency Medicine  2011;18(6):e70-e76.
Palliative care focuses on the physical, spiritual, psychological, and social care from diagnosis to cure or death of a potentially life-threatening illness. When cure is not attainable and end of life approaches, the intensity of palliative care is enhanced to deliver the highest quality care experience. The emergency department (ED) frequently cares for patients and families during the end-of-life phase of the palliative care continuum. The intersection between palliative care and emergency care continues to be more clearly defined. Currently, there is a mounting body of evidence to guide the most effective strategies for improving palliative and end-of-life care in the ED. In a workgroup session at the 2009 Agency for Healthcare Research and Quality (AHRQ)/American College of Emergency Physicians (ACEP) conference “Improving the Quality and Efficiency of Emergency Care Across the Continuum: A Systems Approach,” four key research questions arose: 1) which patients are in greatest need of palliative care services in the ED, 2) what is the optimal role of emergency clinicians in caring for patients along a chronic trajectory of illness, 3) how does the integration and initiation of palliative care training and services in the ED setting affect health care utilization, and 4) what are the educational priorities for emergency clinical providers in the domain of palliative care? Workgroup leaders suggest that these four key questions may be answered by strengthening the evidence using six categories of inquiry: descriptive, attitudinal, screening, outcomes, resource allocation, and education of clinicians.
doi:10.1111/j.1553-2712.2011.01088.x
PMCID: PMC3368013  PMID: 21676052
12.  Multiplex PCR To Diagnose Bloodstream Infections in Patients Admitted from the Emergency Department with Sepsis ▿  
Sepsis is caused by a heterogeneous group of infectious etiologies. Early diagnosis and the provision of appropriate antimicrobial therapy correlate with positive clinical outcomes. Current microbiological techniques are limited in their diagnostic capacities and timeliness. Multiplex PCR has the potential to rapidly identify bloodstream infections and fill this diagnostic gap. We identified patients from two large academic hospital emergency departments with suspected sepsis. The results of a multiplex PCR that could detect 25 bacterial and fungal pathogens were compared to those of blood culture. The results were analyzed with respect to the likelihood of infection, sepsis severity, the site of infection, and the effect of prior antibiotic therapy. We enrolled 306 subjects with suspected sepsis. Of these, 43 were later determined not to have infectious etiologies. Of the remaining 263 subjects, 70% had sepsis, 16% had severe sepsis, and 14% had septic shock. The majority had a definite infection (41.5%) or a probable infection (30.7%). Blood culture and PCR performed similarly with samples from patients with clinically defined infections (areas under the receiver operating characteristic curves, 0.64 and 0.60, respectively). However, blood culture identified more cases of septicemia than PCR among patients with an identified infectious etiology (66 and 46, respectively; P = 0.0004). The two tests performed similarly when the results were stratified by sepsis severity or infection site. Blood culture tended to detect infections more frequently among patients who had previously received antibiotics (P = 0.06). Conversely, PCR identified an additional 24 organisms that blood culture failed to detect. Real-time multiplex PCR has the potential to serve as an adjunct to conventional blood culture, adding diagnostic yield and shortening the time to pathogen identification.
doi:10.1128/JCM.01447-09
PMCID: PMC2812289  PMID: 19846634
13.  Unsuspected Pulmonary Embolism in Observation Unit Patients 
Objective:
Many emergency department (ED) patients with cardiopulmonary symptoms such as chest pain or dyspnea are placed in observation units but do not undergo specific diagnostic testing for pulmonary embolism (PE). The role of observation units in the diagnosis of PE has not been studied. We hypothesized that there was a small but significant rate of unsuspected PE in our observation unit population.
Methods:
We performed a retrospective chart review at an urban academic hospital of all ED patients with an International Classification of Diseases, Ninth Revision diagnosis of PE between January 2005 and July 2006. The number of such patients assigned to observation at any point in their stay was recorded, in addition to events leading to diagnosis and subsequent in-hospital outcomes.
Results:
Thirteen of the 190 ED patients diagnosed with PE were placed in the observation unit. Six of these either had a known recent diagnosis of PE or had testing for PE initiated prior to placement in the observation unit. Two of the remaining seven patients with undiagnosed PE were placed in observation for undifferentiated chest pain, accounting for 0.09% of the 2190 patients under the chest pain protocol. Twelve of 13 PE patients (92%) were admitted with an average stay of 4.3 days. Of the 13 patients, five were ultimately determined after admission to not have PE, leaving a rate of confirmed PE in the observation unit population of 0.12% (8/6182), with five of eight being classified as unsuspected prior to assignment to observation (0.08% rate).
Conclusion:
We identified a small number of patients assigned to observation with unsuspected PE. The high rate of hospital admission and prolonged hospital stay suggests that patients with PE are inappropriate for observation status. Given the low incidence of unsuspected PE, there may be a need for a specific approach to screening for PE in observation unit patients.
PMCID: PMC2729208  PMID: 19718369

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