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1.  Understanding the Inflammatory Cytokine Response in Pneumonia and Sepsis 
Archives of internal medicine  2007;167(15):1655-1663.
Severe sepsis is common and frequently fatal, and community-acquired pneumonia (CAP) is the leading cause. Although severe sepsis is often attributed to uncontrolled and unbalanced inflammation, evidence from humans with infection syndromes across the breadth of disease is lacking. In this study we describe the systemic cytokine response to pneumonia and determine if specific patterns, including the balance of pro-inflammatory and anti-inflammatory markers, are associated with severe sepsis and death.
This is a cohort study of 1886 subjects hospitalized with CAP through the emergency departments in 28 US academic and community hospitals. We defined severe sepsis as CAP complicated by new-onset organ dysfunction, following international consensus conference criteria. We measured plasma tumor necrosis factor, IL-6 (interleukin 6), and IL-10 levels daily for the first week and weekly thereafter. Our main outcome measures were severe sepsis and 90-day mortality.
A total of 583 patients developed severe sepsis (31%), of whom 149 died (26%). Systemic cytokine level elevation occurred in 82% of all subjects with CAP. Mean cytokine concentrations were highest at presentation, declined rapidly over the first few days, but remained elevated throughout the first week, beyond resolution of clinical signs of infection. Cytokine levels were highest in fatal severe sepsis and lowest in CAP with no severe sepsis. Unbalanced (high/low) cytokine patterns were unusual (4.6%) and not associated with decreased survival. Highest risk of death was with combined high levels of the proinflammatory IL-6 and anti-inflammatory IL-10 cytokine activity (hazard ratio, 20.5; 95% confidence interval, 10.8–39.0) (P<.001).
The circulating cytokine response to pneumonia is heterogeneous and continues for more than a week after presentation, with considerable overlap between those who do and do not develop severe sepsis. Unbalanced activation is uncommon, and mortality is highest when both proinflammatory and anti-inflammatory cytokine levels are high.
PMCID: PMC4495652  PMID: 17698689
2.  Making a pragmatic choice for fluid resuscitation in the critically ill 
JAMA  2013;310(17):1803-1804.
PMCID: PMC4230320  PMID: 24108485
3.  Toward an Integrated Research Agenda for Critical Illness in Aging 
Aging brings an increased predisposition to critical illness. Patients older than 65 years of age account for approximately half of all intensive care unit (ICU) admissions in the United States, a proportion that is expected to increase considerably with the aging of the population. Emerging research suggests that elderly survivors of intensive care suffer significant long-term sequelae, including accelerated age-related functional decline. Existing evidence-based interventions are frequently underused and their efficacy untested in older subjects. Improving ICU outcomes in the elderly will require not only better methods for translating sound science into improved ICU practice but also an enhanced understanding of the underlying molecular, physiological, and pathophysiological interactions of critical illness with the aging process itself. Yet, significant barriers to research for critical illness in aging exist. We review the state of knowledge and identify gaps in knowledge, research opportunities, and barriers to research, with the goal of promoting an integrated research agenda for critical illness in aging.
PMCID: PMC2970850  PMID: 20558632
critical care; elderly; aging
4.  Impact of nurse-led remote screening and prompting for evidence-based practices in the ICU 
Critical care medicine  2014;42(4):896-904.
Evidence-based practices are not consistently applied in the intensive care unit (ICU). We sought to determine if nurse-led remote screening and prompting for evidence-based practices using an electronic health record could impact ICU care delivery and outcomes in an academic medical center.
Single-center, before-after evaluation of a quality improvement project.
Urban, academic medical center in the mid-Atlantic United States with 8 subspecialty ICUs and 156 ICU beds.
Adult patients admitted to the ICU between January 1, 2011 and August 31, 2012.
Beginning on July 25, 2011, trained ICU nurses screened all ICU patients for selected evidence-based practices on a daily basis. The screening was conducted from a remote office, facilitated by the electronic health record. Selected practices included compliance with a ventilator care bundle, assessment of appropriateness of indwelling venous and urinary catheters, and concordance between sedation orders and documented level of sedation. When gaps were observed they were communicated to the point-of-care bedside nurse via telephone, page or facsimile.
Measurements and Main Results
14,823 unique patients were admitted during the study period. We excluded 1,546 patients during a 2-month run-in period from July 1, 2011 to August 31, 2011, resulting in 4,339 patients in the 6-month pre-intervention period and 8,938 patients in the 12-month post-intervention period. Compared to patients admitted in the pre-intervention period, patients admitted in the post-intervention period were more likely to receive sedation interruption (incidence rate ratio: 1.57, 95% CI: 1.45 – 1.71) and a spontaneous breathing trial (incidence rate ratio: 1.24, 95% CI: 1.20 – 1.29). Hospital acquired infection rates were not different between the two periods. Adjusting for patient characteristics and illness severity, patients in the post-intervention period experienced shorter duration of mechanical ventilation (adjusted reduction: 0.61 days, 95% CI: 0.27 – 0.96, p <0.001), shorter ICU length of stay (adjusted reduction: 0.22 days, 95% CI: 0.04 – 0.41, p=0.02), and shorter hospital length of stay (adjusted reduction: 0.55 days, 95% CI: 0.15 – 0.93, p=0.006). In-hospital mortality was unchanged (adjusted odds ratio: 0.96, 95% CI 0.84 – 1.09, p=0.54). The results were robust to tests for concurrent temporal trends and coincident interventions.
A program by which nurses screened ICU patients for best-practices from a remote location was associated with improvements in the quality of care and reductions in duration of mechanical ventilation and length of stay, but had no impact on mortality.
PMCID: PMC4553206  PMID: 24201176
mechanical ventilation; intensive care units; quality improvement; organization and administration; nursing; telemedicine
5.  The next generation of sepsis trials: What’s next after the demise of recombinant human activated Protein C? 
Critical care medicine  2014;42(7):1714-1721.
Progress in the development of novel therapeutics to treat sepsis has come to virtual standstill. While enormous strides have been made in the understanding of basic molecular mechanisms that underlie the pathophysiology of sepsis, a distressingly long list of novel therapeutic agents have been tested in large clinical trials over the past 25 years without a single, specific, immunomodulating agent showing consistent benefit in sepsis trials. The only novel anti-sepsis agent to successfully complete a phase 3 sepsis trial, human recombinant activated protein C, was recently taken off the market after a follow up placebo-controlled trial (PROWESS SHOCK) failed to replicate the results of the initial registration trial (PROWESS) performed 10 yr earlier. We must critically re-examine our basic approach in the preclinical and clinical evaluation of new sepsis therapies. We propose 12 specific recommendations that if implemented could improve the outlook for developing new drugs for sepsis.
PMCID: PMC4135726  PMID: 24717456
Sepsis; severe sepsis; septic shock; clinical trial design; activated Protein C
6.  Risk prediction with procalcitonin and clinical rules in community-acquired pneumonia 
Annals of emergency medicine  2008;52(1):48-58.e2.
The Pneumonia Severity Index (PSI) and CURB-65 predict outcomes in community acquired pneumonia (CAP), but have limitations. Procalcitonin, a biomarker of bacterial infection, may provide prognostic information in CAP. Our objective was to describe the pattern of procalcitonin in CAP, and determine if procalcitonin provides prognostic information beyond PSI and CURB-65.
We conducted a multi-center prospective cohort study in 28 community and teaching emergency departments. Patients presenting with a clinical and radiographic diagnosis of CAP were enrolled. We stratified procalcitonin levels a priori into four tiers – I: < 0.1; II: ≥ 0.1 to <0.25; III: ≥ 0.25 to < 0.5; and IV: ≥ 0.5 ng/ml. Primary outcome was 30d mortality.
1651 patients formed the study cohort. Procalcitonin levels were broadly spread across tiers: 32.8% (I), 21.6% (II), 10.2% (III), 35.4% (IV). Used alone, procalcitonin had modest test characteristics: specificity (35%), sensitivity (92%), positive likelihood ratio (LR) (1.41), and negative LR (0.22). Adding procalcitonin to PSI in all subjects minimally improved performance. Adding procalcitonin to low risk PSI subjects (Class I–III) provided no additional information. However, subjects in procalcitonin tier I had low 30d mortality regardless of clinical risk, including those in higher risk classes (1.5% vs. 1.6% for those in PSI Class I–III vs. Class IV/V). Among high risk PSI subjects (Class IV/V), one quarter (126/546) were in procalcitonin tier I, and the negative LR of procalcitonin tier I was 0.09. Procalcitonin tier I was also associated with lower burden of other adverse outcomes. Similar results were seen with CURB-65 stratification.
Selective use of procalcitonin as an adjunct to existing rules may offer additional prognostic information in high risk patients.
PMCID: PMC2775454  PMID: 18342993
Biological markers; procalcitonin; pneumonia; prediction rules
7.  Serum Biomarkers of Brain Injury after Pediatric Cardiac Arrest 
Critical care medicine  2014;42(3):664-674.
Morbidity and mortality in children with cardiac arrest (CA) largely result from neurologic injury. Serum biomarkers of brain injury can potentially measure injury to neurons (neuron specific enolase [NSE]), astrocytes (S100b), and axons (myelin basic protein [MBP]). We hypothesized that serum biomarkers can be used to predict outcome from pediatric CA.
Prospective observational study.
Single tertiary pediatric hospital.
Forty-three children with cardiac arrest.
Measurements and Main Results
We measured serum NSE, S100b, and MBP on days 1–4 and 7 after CA. We recorded demographics, details of the CA and resuscitation, and Pediatric Cerebral Performance Category (PCPC) at hospital discharge and 6 months. We analyzed the association of biomarker levels at 24, 48, and 72 hours with good (PCPC 1–3) or poor (PCPC 4–6) outcome and mortality. Forty-three children (49% female; mean age of 5.9 ± 6.3 were enrolled and 17 (40%) died. Serum concentration at 24 hours for all 3 biomarkers predicted mortality (all p<0.05). Additionally, serum NSE and S100b concentrations were increased in the poor outcome vs. good outcome group and in subjects who died at all time points (all p<0.05). Receiver operator curves for serum S100b and NSE to predict good vs. poor outcome at 6 months was superior to clinical predictors. There was no association between serum biomarker concentrations and subject temperature.
Preliminary data show that serum S100b, NSE, and MBP may aid in outcome prediction of children surviving CA.
PMCID: PMC4478619  PMID: 24164954
Biomarker; heart arrest; hypoxia-ischemia, brain; child; outcome assessment (health care); resuscitation
8.  Inflammatory Markers at Hospital Discharge Predict Subsequent Mortality after Pneumonia and Sepsis 
Rationale: Survivors of hospitalization for community-acquired pneumonia (CAP) are at increased risk of cardiovascular events, repeat infections, and death in the following months but the cause is unknown.
Objectives: To investigate whether persistent inflammation, defined as elevating circulating inflammatory markers at hospital discharge, is associated with subsequent outcomes.
Methods: Prospective cohort study at 28 sites.
Measurements and Main Results: We used standard criteria to define CAP and the National Death Index to determine all-cause and cause-specific 1-year mortality. At hospital discharge, 1,799 subjects (77.5%) were alive and vital signs had returned to normal in 1,512 (87%) subjects. The geometric means (±SD) for circulating IL-6 and IL-10 concentrations were 6.9 (±1) pg/ml and 1.2 (±1.1) pg/ml. At 1 year, 307 (17.1%) subjects had died. Higher IL-6 and IL-10 concentrations at hospital discharge were associated with an increased risk of death, which gradually fell over time. Using Gray's survival model, the associations were independent of demographics, comorbidities, and severity of illness (for each log-unit increase, the range of adjusted hazard ratios [HRs] for IL-6 were 1.02–1.46, P < 0.0001, and for IL-10 were 1.17–1.44, P = 0.01). The ranges of HRs for each log-unit increase in IL-6 and IL-10 concentrations among subjects who did and did not develop severe sepsis were 0.95–1.27 and 1.07–1.55, respectively. High IL-6 concentrations were associated with death due to cardiovascular disease, cancer, infections, and renal failure (P = 0.008).
Conclusions: Despite clinical recovery, many patients with CAP leave hospital with ongoing subclinical inflammation, which is associated with an increased risk of death.
PMCID: PMC2720087  PMID: 18369199
cytokines; mortality; pneumonia; IL-6; IL-10
9.  Racial Variation in End-of-Life Intensive Care Use: A Race or Hospital Effect? 
Health Services Research  2006;41(6):2219-2237.
To determine if racial and ethnic variations exist in intensive care (ICU) use during terminal hospitalizations, and, if variations do exist, to determine whether they can be explained by systematic differences in hospital utilization by race/ethnicity.
Data Source
1999 hospital discharge data from all nonfederal hospitals in Florida, Massachusetts, New Jersey, New York, and Virginia.
We identified all terminal admissions (N =192,705) among adults. We calculated crude rates of ICU use among non-Hispanic whites, blacks, Hispanics, and those with “other” race/ethnicity. We performed multivariable logistic regression on ICU use, with and without adjustment for clustering of patients within hospitals, to calculate adjusted differences in ICU use and by race/ethnicity. We explored both a random-effects (RE) and fixed-effect (FE) specification to adjust for hospital-level clustering.
Data Collection
The data were collected by each state.
Principal Findings
ICU use during the terminal hospitalization was highest among nonwhites, varying from 64.4 percent among Hispanics to 57.5 percent among whites. Compared to white women, the risk-adjusted odds of ICU use was higher for white men and for nonwhites of both sexes (odds ratios [ORs] and 95 percent confidence intervals: white men =1.16 (1.14–1.19), black men =1.35 (1.17–1.56), Hispanic men =1.52 (1.27–1.82), black women =1.31 (1.25–1.37), Hispanic women =1.53 (1.43–1.63)). Additional adjustment for within-hospital clustering of patients using the RE model did not change the estimate for white men, but markedly attenuated observed differences for blacks (OR for men =1.12 (0.96–1.31), women =1.10 (1.03–1.17)) and Hispanics (OR for men =1.19 (1.00–1.42), women =1.18 (1.09–1.27)). Results from the FE model were similar to the RE model (OR for black men =1.10 (0.95–1.28), black women =1.07 (1.02–1.13) Hispanic men =1.17 (0.96–1.42), and Hispanic women =1.14 (1.06–1.24))
The majority of observed differences in terminal ICU use among blacks and Hispanics were attributable to their use of hospitals with higher ICU use rather than to racial differences in ICU use within the same hospital.
PMCID: PMC1955321  PMID: 17116117
Intensive care units; terminal care; life support care; ethnic groups; hospitals
10.  Default Options In Advance Directives Influence How Patients Set Goals For End-Of-Life Care 
Health affairs (Project Hope)  2013;32(2):408-417.
Although decisions regarding end-of-life care are personal and important, they may be influenced by the ways in which options are presented. To test this hypothesis, we randomly assigned 132 seriously ill patients to complete one of three types of advance directives. Two types had end-of-life care options already checked—a default choice—but one of these favored comfort-oriented care, and the other, life-extending care. The third type was a standard advance directive with no options checked. We found that most patients preferred comfort-oriented care, but the defaults influenced those choices. For example, 77 percent of patients in the comfort-oriented group retained that choice, while 43 percent of those in the life-extending group rejected the default choice and selected comfort-oriented care instead. Among the standard advance directive group, 61 percent of patients selected comfort-oriented care. Our findings suggest that patients may not hold deep-seated preferences regarding end-of-life care. The findings provide motivation for future research examining whether using default options in advance directives may improve important outcomes, including patients’ receipt of wanted and unwanted services, resource use, survival, and quality of life.
PMCID: PMC4445426  PMID: 23381535
11.  Advance Care Planning Norms May Contribute to Hospital Variation in End-of-life ICU Use: A Simulation Study 
There is wide variation in end-of-life (EOL) intensive care unit (ICU) use among academic medical centers (AMCs).
To develop hypotheses regarding medical decision-making factors underlying this variation.
High-fidelity simulation experiment involving a critically and terminally ill elder, followed by a survey and debriefing cognitive interview and evaluated using triangulated quantitative-qualitative comparative analysis.
2 AMCs in the same state and health care system with disparate EOL ICU use.
Hospital-based physicians responsible for ICU admission decisions.
Treatment plan, prognosis, diagnosis, qualitative case perceptions and clinical reasoning.
Main Results
Sixty-seven of 111 (60%) eligible physicians agreed to participate; 48 (72%) could be scheduled. There were no significant between-AMC differences in 3-month prognosis or treatment plan, but there were systematic differences in perceptions of the case. Case perceptions at the low-intensity AMC seemed to be influenced by the absence of a DNR order in the context of norms of universal code status discussion and documentation upon admission, whereas case perceptions at the high-intensity AMC seemed to be influenced by the patient’s known metastatic gastric cancer in the context of norms of oncologists’ avoiding code status discussions.
In this simulation study of 2 AMCs, hospital-based physicians had different perceptions of an identical case. We hypothesize that different advance care planning norms may have influenced their decision-making heuristics.
PMCID: PMC4026761  PMID: 24615275
terminal care; palliative care; intensive care; physician decision making; heuristics; cancer; simulation; variation; Medicare; national health policy; qualitative research
12.  Creating an Infrastructure for Comparative Effectiveness Research in Emergency Medical Services 
Emergency medical services (EMS) providers deliver the initial care for millions of people in the United States each year. The Institute of Medicine noted a deficit in research necessary to improve prehospital care, created by the existence of data silos, absence of long-term outcomes, and limited stakeholder engagement in research. This article describes a regional effort to create a high-performing infrastructure in southwestern Pennsylvania addressing these fundamental barriers.
Regional EMS records from 33 agencies in January 2011 were linked to hospital-based electronic health records (EHRs) in a single nine-hospital system, with manual review of matches for accuracy. The use of community stakeholder engagement was included to guide scientific inquiry, as well as 2-year follow up for patient-centered outcomes.
Local EMS medicine stakeholders emphasized the limits of single-agency EMS research, and suggested that studies focus on improving cross-cutting, long-term outcomes. Guided by this input, more than 95% of EMS records (2,675 out of 2,800) were linked to hospital-based EHRs. More than 80% of records were linked to 2-year mortality, with more deaths among EMS patients with prehospital hypotension (30.5%) or respiratory distress (19.5%) than chest pain (5.4%) or non-specific complaints (9.4%).
A prehospital comparative effectiveness research infrastructure composed of patient-level EMS data, EHRs at multiple hospitals, long-term outcomes, and community stakeholder perspectives is feasible and may be scalable to larger regions and networks. The lessons learned and barriers identified offer a roadmap to answering community and policy-relevant research questions in prehospital care.
PMCID: PMC4030684  PMID: 24842512
Critical care medicine  2014;42(5):1037-1046.
Severe infections, often requiring intensive care unit (ICU) admission, have been associated with persistent cognitive dysfunction. Less severe infections are more common and whether they are associated with an increased risk of dementia is unclear. We determined the association of pneumonia hospitalization with risk of dementia in well-functioning older adults.
Secondary analysis of a randomized multicenter trial to determine the effect of Gingko biloba on incident dementia.
Setting and Subjects
Community volunteers (n=3069) with a median follow-up of 6.1 years.
Measurement and Main Results
We identified pneumonia hospitalizations using ICD-9CM codes and validated them in a subset. Less than 3% of pneumonia cases necessitated ICU admission, mechanical ventilation or vasopressor support. Dementia was adjudicated based on neuropsychological evaluation, neurological exam, and magnetic resonance imaging. Two hundred twenty one participants (7.2%) incurred at least one hospitalization with pneumonia (mean time to pneumonia=3.5 years). Of these, 38 (17%) developed dementia after pneumonia with half of these cases occurring 2 years after the pneumonia hospitalization. Hospitalization with pneumonia was associated with increased risk of time to dementia diagnosis (unadjusted hazard ratio [HR] = 2.3, CI: 1.6–3.2, p<0.0001). The association remained significant when adjusted for age, sex, race, study site, education, and baseline Mini-Mental Status Exam (HR=1.9, CI 1.4–2.8, p<.0001). Results were unchanged when additionally adjusted for smoking, hypertension, diabetes, heart disease, and pre-infection functional status. Results were similar using propensity analysis where participants with pneumonia were matched to those without pneumonia based on age, probability of developing pneumonia, and similar trajectories of cognitive and physical function prior to pneumonia (adjusted incidence rates: 91.7 vs. 65 cases per 1,000 person-years, adjusted incidence rate ratio=1.6, CI:1.06–2.7, p=0.03). Sensitivity analyses showed that the higher risk also occurred among those hospitalized with other infections.
Hospitalization with pneumonia is associated with increased risk of dementia.
PMCID: PMC4071960  PMID: 24368344
pneumonia; dementia; older adults
14.  Risk of Cardiovascular Events in Survivors of Severe Sepsis 
Rationale: The risk of cardiovascular events after severe sepsis is not known, and these events may explain increased long-term mortality in survivors of severe sepsis.
Objectives: To determine whether survivors of severe sepsis hospitalization have high long-term risk of cardiovascular events. We examined whether higher risk is due to severe sepsis hospitalization or poor prehospitalization health status, and if the higher risk is also observed in patients hospitalized for infectious and noninfectious reasons, and in other critically ill patients.
Methods: Unmatched and matched-cohort analyses of Medicare beneficiaries. For unmatched analysis, we compared patients with severe sepsis admitted to the intensive care unit (ICU) and survived hospitalization (n = 4,179) to unmatched population control subjects (n = 819,283). For matched analysis, we propensity-score-matched each patient with severe sepsis to four control subjects (population, hospitalized, non–severe sepsis ICU control subjects, and infection hospitalization). Primary outcome was 1-year incidence rate of hospitalization for cardiovascular events.
Measurements and Main Results: Cardiovascular events were common among patients discharged alive after severe sepsis hospitalization (29.5%; 498.2 events/1,000 person-years). Survivors of severe sepsis had a 13-fold higher risk of cardiovascular events compared with unmatched control subjects (498.2 vs. 36 events/1,000 person-years; P < 0.0001), and a 1.9-fold higher risk compared with matched-population control subjects (P < 0.0001). Survivors of severe sepsis had 1.1-fold higher risk compared with matched hospitalized patients and infection hospitalizations (P = 0.002 and 0.001) and similar risk compared with matched-ICU control subjects.
Conclusions: Survivors of severe sepsis have high risk of cardiovascular events. The higher risk is mainly due to poor prehospitalization health status, and is also seen in a broader population of acutely ill patients.
PMCID: PMC4098105  PMID: 24456535
sepsis; severe sepsis; cardiovascular disease; mortality
15.  Interplay between sepsis and chronic health 
Trends in molecular medicine  2014;20(4):234-238.
Severe sepsis is associated with high short-term mortality. Several studies suggest that severe sepsis also worsens health status and increases disability among survivors. As the incidence of severe sepsis increases, and advances in critical care reduce the short-term mortality, the number of individuals who are at risk for poor long-term outcomes will increase. Recent studies suggest that the relationship between sepsis and chronic health may be bidirectional, however the mechanisms underlying this relationship remain poorly understood. Here we review the epidemiologic studies examining the interplay between sepsis and chronic health and propose a conceptual model, which has implications for preclinical and human study design.
PMCID: PMC4016696  PMID: 24636941
16.  The PIRO concept: P is for predisposition 
Critical Care  2003;7(3):248-251.
PMCID: PMC270687  PMID: 12793879
infection; organ dysfunction; PIRO; predisposition; response
17.  Proteomics Reveals Age-related Differences in the Host Immune Response to Sepsis 
Journal of proteome research  2013;13(2):422-432.
Sepsis is commonly caused by community-acquired pneumonia (CAP) and may develop into severe sepsis, characterized by multiple organ failure. The risk of severe sepsis among CAP patients and subsequent mortality increases sharply after the age of 65. The molecular mechanisms associated with this age-related risk are not fully understood. To better understand factors involved with increased incidence and mortality of severe sepsis in the elderly, we used a nested case-control study of patients enrolled in a multicenter observational cohort of 2,320 participants with CAP. We identified a total of 39 CAP patients 50-65 and 70-85 years old who did or did not develop severe sepsis. Plasma samples were obtained on presentation to the emergency department and prior to therapeutic interventions. A semi-quantitative plasma proteomics workflow was applied which incorporated tandem immunoaffinity depletion, iTRAQ labeling, strong cation exchange fractionation, and nanoflow-liquid chromatography coupled to high resolution mass spectrometry. In total, 772 proteins were identified, of which, 58 proteins exhibit statistically significant differences in expression levels amongst patients with severe sepsis as a function of age. Differentially-expressed proteins are involved in pathways such as acute phase response, coagulation signaling, atherosclerosis signaling, lipid metabolism, and production of nitric oxide and reactive oxygen species. This study provides insight into factors that may explain age-related differences in incidence of severe sepsis in the elderly.
PMCID: PMC3976438  PMID: 24266763
sepsis; severe sepsis; proteomics; CAP; plasma; aging; immunosenescence; pneumonia
18.  Accuracy of Prehospital Transport Time Estimation 
Estimates of prehospital transport times are an important part of emergency care system research and planning; however the accuracy of these estimates is unknown. We examined the accuracy of three estimation methods against observed transport times in a large cohort of prehospital patient transports.
We performed a validation study using prehospital records in King County, Washington and southwestern Pennsylvania from 2002 to 2006 and 2005 to 2011, respectively. We generated transport time estimates using three methods: linear arc distance, Google Maps and ArcGIS Network Analyst. We assessed estimation error, defined as the absolute difference between observed and estimated transport time, and the proportion of estimated times that were within specified error thresholds. Based on the primary results, we then tested whether a regression estimate that incorporated population density, time-of-day and season could improve accuracy. Finally, we compared hospital catchment areas using each method with a fixed drive time.
We analyzed 29,935 prehospital transports to 44 hospitals. The mean absolute error was 4.8 minutes (± 7.3) using linear arc, 3.5 minutes (± 5.4) using Google Maps and 4.4 minutes (± 5.7) using ArcGIS. All pairwise comparisons were statistically significant (p<0.01). Estimation accuracy was lower for each method among transports more than twenty minutes (mean absolute error was 12.7 minutes (± 11.7) for linear arc, 9.8 minutes (± 10.5) for Google Maps and 11.6 minutes (± 10.9) for ArcGIS). Estimates were within five minutes of observed transport time for 79% of linear arc estimates, 86.6% of Google Maps estimates and 81.3% of ArcGIS estimates. The regression-based approach did not substantially improve estimation. There were large differences in hospital catchment areas estimated by each method.
We showed that route-based transport time estimates demonstrate moderate accuracy. These methods can be valuable for informing a host of decisions related to the system organization and patient access to emergency medical care; however, they should be employed with sensitivity to their limitations.
PMCID: PMC4251659  PMID: 24552519
19.  Calcium supplementation during sepsis exacerbates organ failure and mortality via calcium/calmodulin-dependent protein kinase kinase (CaMKK) signaling 
Critical care medicine  2013;41(11):10.1097/CCM.0b013e31828cf436.
Calcium plays an essential role in nearly all cellular processes. As such, cellular and systemic calcium concentrations are tightly regulated. During sepsis derangements in such tight regulation frequently occur, and treating hypocalcemia with parenteral calcium administration remains the current practice guideline.
We investigated whether calcium administration worsens mortality and organ dysfunction using an experimental murine model of sepsis and explored the mechanistic role of the family of calcium/calmodulin-dependent protein kinases in mediating these physiologic effects. To highlight the biological relevance of these observations, we conducted a translational study of the association between calcium administration, organ dysfunction and mortality among a cohort of critically ill septic ICU patients
Prospective, randomized controlled experimental murine study. Observational clinical cohort analysis.
University research laboratory. Eight ICUs at a tertiary care center.
870 septic ICU patients.
C57BL/6 and CaMKK−/− mice.
Mice underwent cecal ligation and puncture polymicrobial sepsis and were administered calcium chloride (0.25 or 0.25 mg/kg) or normal saline.
Measurements and Main Results
Administering calcium chloride to septic C57BL/6 mice heightened systemic inflammation and vascular leak, exacerbated hepatic and renal dysfunction, and increased mortality. These events were significantly attenuated in CaMKK−/− mice. In a risk–adjusted analysis of septic patients, calcium administration was associated with an increased risk of death, OR 1.92 (95% CI 1.00–3.68, p=0.049), a significant increase in the risk of renal dysfunction, OR 4.74 (95% CI 2.48–9.08, p<0.001), and a significant reduction in ventilator free days, mean decrease 3.29 days (0.50–6.08 days, p=0.02).
Derangements in calcium homeostasis occur during sepsis that are sensitive to calcium administration. This altered calcium signaling, transduced by the CaMKK cascade, mediates heightened inflammation and vascular leak that culminates in elevated organ dysfunction and mortality. In the clinical management of septic patients calcium supplementation provides no benefit and may impose harm.
PMCID: PMC3812408  PMID: 23887235
calcium; sepsis; infection; inflammation; calcium/calmodulin-dependent protein kinase; mortality; organ failure
20.  Improving risk classification of critical illness with biomarkers: a simulation study 
Journal of critical care  2013;28(5):541-548.
Optimal triage of patients at risk of critical illness requires accurate risk prediction, yet little data exists on the performance criteria required of a potential biomarker to be clinically useful.
Materials and Methods
We studied an adult cohort of non-arrest, non-trauma emergency medical services encounters transported to a hospital from 2002–2006. We simulated hypothetical biomarkers increasingly associated with critical illness during hospitalization, and determined the biomarker strength and sample size necessary to improve risk classification beyond a best clinical model.
Of 57,647 encounters, 3,121 (5.4%) were hospitalized with critical illness and 54,526 (94.6%) without critical illness. The addition of a moderate strength biomarker (odds ratio=3.0 for critical illness) to a clinical model improved discrimination (c-statistic 0.85 vs. 0.8, p<0.01), reclassification (net reclassification improvement=0.15, 95%CI: 0.13,0.18), and increased the proportion of cases in the highest risk categoryby+8.6% (95%CI: 7.5,10.8%). Introducing correlation between the biomarker and physiological variables in the clinical risk score did not modify the results. Statistically significant changes in net reclassification required a sample size of at least 1000 subjects.
Clinical models for triage of critical illness could be significantly improved by incorporating biomarkers, yet, substantial sample sizes and biomarker strength may be required.
PMCID: PMC3707977  PMID: 23566734
Biomarker; simulation; sample size; reclassification
21.  Hospitalizations of children with neurological disorders in the United States 
Although neurologic disorders are among the most serious acute pediatric illnesses, epidemiologic data are scarce. We sought to determine the scope and outcomes of children with these disorders in the US.
Retrospective cohort study
All non-federal hospitals in 11 states encompassing 38% of the US pediatric population.
Children 29 days-19 years old hospitalized in 2005
Measurements and Main Results
Using ICD-9-CM codes, we identified admissions with neurological diagnoses, analyzed patient and hospitalization characteristics, and generated age- and sex-adjusted national estimates. Of 960,020 admissions in the 11 states, 10.7% (103,140) included a neurological diagnosis, which yields a national estimate of 273,900 admissions of children with neurological diagnoses. The most common were seizures (53.9%) and traumatic brain injury (17.3%). Children with neurological diagnoses had nearly 3 times greater intensive care unit (ICU) use than other hospitalized children (30.6% vs. 10.6%, p<0.001). Neurological diagnoses were associated with nearly half of deaths (46.2%, n=1,790). Among ICU patients, children with neurological diagnoses had more than 3 times the mortality of other patients (4.8% vs.1.5%, p<.001). Children with neurological diagnoses had a significantly longer median hospital LOS than other children (3 days [1, 5] vs. 2 days [2,4], p<.001) and greater median hospital costs ($4,630 [$2,380, $9,730] vs. $2,840 [$1,520, $5,550], p<.001).
Children with neurological diagnoses account for a disproportionate amount of ICU stays and deaths compared to children hospitalized for other reasons.
PMCID: PMC3795828  PMID: 23842588
epidemiology; neurological outcome; pediatric; intensive care; pediatric neurocritical care; hospitalization
22.  Mortality among Patients Admitted to Strained Intensive Care Units 
Rationale: The aging population may strain intensive care unit (ICU) capacity and adversely affect patient outcomes. Existing fluctuations in demand for ICU care offer an opportunity to explore such relationships.
Objectives: To determine whether transient increases in ICU strain influence patient mortality, and to identify characteristics of ICUs that are resilient to surges in capacity strain.
Methods: Retrospective cohort study of 264,401 patients admitted to 155 U.S. ICUs from 2001 to 2008. We used logistic regression to examine relationships of measures of ICU strain (census, average acuity, and proportion of new admissions) near the time of ICU admission with mortality.
Measurements and Main Results: A total of 36,465 (14%) patients died in the hospital. ICU census on the day of a patient’s admission was associated with increased mortality (odds ratio [OR], 1.02 per standardized unit increase; 95% confidence interval [CI]: 1.00, 1.03). This effect was greater among ICUs employing closed (OR, 1.07; 95% CI: 1.02, 1.12) versus open (OR, 1.01; 95% CI: 0.99, 1.03) physician staffing models (interaction P value = 0.02). The relationship between census and mortality was stronger when the census was composed of higher acuity patients (interaction P value < 0.01). Averaging strain over the first 3 days of patients’ ICU stays yielded similar results except that the proportion of new admissions was now also associated with mortality (OR, 1.04 for each 10% increase; 95% CI: 1.02, 1.06).
Conclusions: Several sources of ICU strain are associated with small but potentially important increases in patient mortality, particularly in ICUs employing closed staffing models. Although closed ICUs may promote favorable outcomes under static conditions, they are susceptible to being overwhelmed by patient influxes.
PMCID: PMC3826272  PMID: 23992449
critical care; resource allocation; intensive care unit; physician staffing; regionalization
23.  Prehospital intravenous access and fluid resuscitation in severe sepsis: an observational cohort study 
Critical Care  2014;18(5):533.
Prompt treatment of severe sepsis in the Emergency Department reduces deaths, but the role of prehospital fluid resuscitation is unknown. We sought to determine the risk-adjusted association between prehospital fluid administration and hospital mortality among emergency medical services (EMS) patients admitted with severe sepsis.
We performed a prospective, observational study of patients hospitalized with severe sepsis on admission among 45,394 adult EMS encounters taken to 15 hospitals from 11/2009 to 12/2010 by a two-tier EMS system in King County, Washington. The region mandated recording of prehospital intravenous catheter and fluid administration in prehospital records, along with detailed demographic, incident, physiologic, and hospital adjustment variables. We determined the effect of prehospital intravenous catheter or fluid versus no catheter or fluid on all-cause mortality using multivariable logistic regression.
Of all encounters, 1,350 met criteria for severe sepsis on admission, of whom 205 (15%) died by hospital discharge, 312 (23%) received prehospital intravenous fluid, 90 (7%) received a prehospital catheter alone and 948 (70%) did not receive catheter or fluid. EMS administered a median prehospital fluid volume of 500 mL (interquartile range (IQR): 200, 1000 mL). In adjusted models, the administration of any prehospital fluid was associated with reduced hospital mortality (Odds ratio =0.46; 95% Confidence interval: 0.23, 0.88; P =0.02) compared to no prehospital fluid. The odds of hospital mortality were also lower among severe sepsis patients treated with prehospital intravenous catheter alone (Odds ratio =0.3; 95% Confidence interval: 0.17 to 0.57; P <0.01).
In a population-based study, the administration of prehospital fluid and placement of intravenous access were associated with decreased odds of hospital mortality compared with no prehospital catheter or fluid.
Electronic supplementary material
The online version of this article (doi:10.1186/s13054-014-0533-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4212132  PMID: 25260233
24.  Effects of intra-abdominal sepsis on atherosclerosis in mice 
Critical Care  2014;18(5):469.
Sepsis and other infections are associated with late cardiovascular events. Although persistent inflammation is implicated, a causal relationship has not been established. We tested whether sepsis causes vascular inflammation and accelerates atherosclerosis.
We performed prospective, randomized animal studies at a university research laboratory involving adult male ApoE-deficient (ApoE−/−) and young C57B/L6 wild-type (WT) mice. In the primary study conducted to determine whether sepsis accelerates atherosclerosis, we fed ApoE−/− mice (N = 46) an atherogenic diet for 4 months and then performed cecal ligation and puncture (CLP), followed by antibiotic therapy and fluid resuscitation or a sham operation. We followed mice for up to an additional 5 months and assessed atheroma in the descending aorta and root of the aorta. We also exposed 32 young WT mice to CLP or sham operation and followed them for 5 days to determine the effects of sepsis on vascular inflammation.
ApoE−/− mice that underwent CLP had reduced activity during the first 14 days (38% reduction compared to sham; P < 0.001) and sustained weight loss compared to the sham-operated mice (−6% versus +9% change in weight after CLP or sham surgery to 5 months; P < 0.001). Despite their weight loss, CLP mice had increased atheroma (46% by 3 months and 41% increase in aortic surface area by 5 months; P = 0.03 and P = 0.004, respectively) with increased macrophage infiltration into atheroma as assessed by immunofluorescence microscopy (0.52 relative fluorescence units (rfu) versus 0.97 rfu; P = 0.04). At 5 months, peritoneal cultures were negative; however, CLP mice had elevated serum levels of interleukin 6 (IL-6) and IL-10 (each at P < 0.05). WT mice that underwent CLP had increased expression of intercellular adhesion molecule 1 in the aortic lumen versus sham at 24 hours (P = 0.01) that persisted at 120 hours (P = 0.006). Inflammatory and adhesion genes (tumor necrosis factor α, chemokine (C-C motif) ligand 2 and vascular cell adhesion molecule 1) and the adhesion assay, a functional measure of endothelial activation, were elevated at 72 hours and 120 hours in mice that underwent CLP versus sham-operations (all at P <0.05).
Using a combination of existing murine models for atherosclerosis and sepsis, we found that CLP, a model of intra-abdominal sepsis, accelerates atheroma development. Accelerated atheroma burden was associated with prolonged systemic, endothelial and intimal inflammation and was not explained by ongoing infection. These findings support observations in humans and demonstrate the feasibility of a long-term follow-up murine model of sepsis.
Electronic supplementary material
The online version of this article (doi:10.1186/s13054-014-0469-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4172909  PMID: 25182529
25.  The effect of multidisciplinary care teams on intensive care unit mortality 
Archives of internal medicine  2010;170(4):369-376.
Critically ill patients are medically complex and may benefit from a multidisciplinary approach to care.
We conducted a population-based retrospective cohort study of medical patients admitted to Pennsylvania acute hospitals (N=169) from July 1, 2004 to June 30, 2006, linking a statewide hospital organizational survey to hospital discharge data. Multivariate logistic regression was used to determine the independent relationship between daily multidisciplinary rounds and 30-day mortality.
112 hospitals and 107,324 patients were included in the final analysis. Overall 30-day mortality was 18.3%. After adjusting for patient and hospital characteristics, multidisciplinary care was associated with significant reductions in the odds of death (OR=0.84, 95% CI: 0.76–0.93, p=0.001). When stratifying by intensivist physician staffing, the lowest odds of death were in ICUs with high-intensity physician staffing and multidisciplinary care teams (OR=0.78, 95% CI: 0.68–0.89, p<0.0001), followed by ICUs with low intensity physician staffing and multidisciplinary care teams (OR=0.88, 95%CI: 0.79–0.97, p=0.014), compared to hospitals with low intensity physician staffing but without multidisciplinary care teams. The effects of multidisciplinary care were consistent across key subgroups including patients with sepsis, patients requiring invasive mechanical ventilation, and patients in the highest quartile of severity of illness
Daily rounds by a multidisciplinary team are associated with lower mortality among medical ICU patients. The survival benefit of intensivist physician staffing is in part explained by the presence of multidisciplinary teams in high-intensity staffed ICUs.
PMCID: PMC4151479  PMID: 20177041

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