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1.  Making a pragmatic choice for fluid resuscitation in the critically ill 
JAMA  2013;310(17):1803-1804.
PMCID: PMC4230320  PMID: 24108485
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  The PIRO concept: P is for predisposition 
Critical Care  2003;7(3):248-251.
PMCID: PMC270687  PMID: 12793879
infection; organ dysfunction; PIRO; predisposition; response
16.  Assessing the Validity of Using Serious Game Technology to Analyze Physician Decision Making 
PLoS ONE  2014;9(8):e105445.
Physician non-compliance with clinical practice guidelines remains a critical barrier to high quality care. Serious games (using gaming technology for serious purposes) have emerged as a method of studying physician decision making. However, little is known about their validity.
We created a serious game and evaluated its construct validity. We used the decision context of trauma triage in the Emergency Department of non-trauma centers, given widely accepted guidelines that recommend the transfer of severely injured patients to trauma centers. We designed cases with the premise that the representativeness heuristic influences triage (i.e. physicians make transfer decisions based on archetypes of severely injured patients rather than guidelines). We randomized a convenience sample of emergency medicine physicians to a control or cognitive load arm, and compared performance (disposition decisions, number of orders entered, time spent per case). We hypothesized that cognitive load would increase the use of heuristics, increasing the transfer of representative cases and decreasing the transfer of non-representative cases.
We recruited 209 physicians, of whom 168 (79%) began and 142 (68%) completed the task. Physicians transferred 31% of severely injured patients during the game, consistent with rates of transfer for severely injured patients in practice. They entered the same average number of orders in both arms (control (C): 10.9 [SD 4.8] vs. cognitive load (CL):10.7 [SD 5.6], p = 0.74), despite spending less time per case in the control arm (C: 9.7 [SD 7.1] vs. CL: 11.7 [SD 6.7] minutes, p<0.01). Physicians were equally likely to transfer representative cases in the two arms (C: 45% vs. CL: 34%, p = 0.20), but were more likely to transfer non-representative cases in the control arm (C: 38% vs. CL: 26%, p = 0.03).
We found that physicians made decisions consistent with actual practice, that we could manipulate cognitive load, and that load increased the use of heuristics, as predicted by cognitive theory.
PMCID: PMC4143260  PMID: 25153149
18.  Metabolomics in pneumonia and sepsis: an analysis of the GenIMS cohort study 
Intensive care medicine  2013;39(8):1423-1434.
To determine the global metabolomic profile as measured in circulating plasma from surviving and non-surviving patients with community-acquired pneumonia (CAP) and sepsis.
Random, outcome-stratified case–control sample from a prospective study of 1,895 patients hospitalized with CAP and sepsis. Cases (n = 15) were adults who died before 90 days, and controls (n = 15) were adults who survived, matched on demographics, infection type, and procalcitonin. We determined the global metabolomic profile in the first emergency department blood sample using non-targeted mass-spectrometry. We derived metabolite-based prognostic models for 90-day mortality. We determined if metabolites stimulated cytokine production by differentiated Thp1 monocytes in vitro, and validated metabolite profiles in mouse liver and kidney homogenates at 8 h in cecal ligation and puncture (CLP) sepsis.
We identified 423 small molecules, of which the relative levels of 70 (17 %) were different between survivors and non-survivors (p ≤ 0.05). Broad differences were present in pathways of oxidative stress, bile acid metabolism, and stress response. Metabolite-based prognostic models for 90-day survival performed modestly (AUC = 0.67, 95 % CI 0.48, 0.81). Five nucleic acid metabolites were greater in non-survivors (p ≤ 0.05). Of these, pseudouridine increased monocyte expression of TNFα and IL1β versus control (p < 0.05). Pseudouridine was also increased in liver and kidney homogenates from CLP mice versus sham (p < 0.05 for both).
Although replication is required, we show the global metabolomic profile in plasma broadly differs between survivors and non-survivors of CAP and sepsis. Metabolite-based prognostic models had modest performance, though metabolites of oxidative stress may act as putative damage-associated molecular patterns.
PMCID: PMC3932707  PMID: 23673400
Sepsis; Pneumonia; Metabolomics; Biomarker
19.  Are the American College of Surgeons’ Guidelines for the Transfer of Trauma Patients Feasible? 
Regionalization is intended to optimize outcomes by matching patient needs with institutional resources. The American College of Surgeons – Committee on Trauma (ACS-COT) recommends <5% under-triage (treatment of patients with moderate-severe injuries at non-trauma centers (NTCs)) and <50% over-triage (transfer of patients with minor injuries to trauma centers (TCs)).
To test the feasibility of accomplishing the ACS-COT benchmarks given current practice patterns by describing transfer patterns for patients taken initially to NTCs and estimating volume shifts and potential lives saved if full implementation occurred.
Design, Setting and Patients
Retrospective cohort study of adult trauma patients initially evaluated at NTCs in Pennsylvania (2001–2005). We used published estimates of mortality risk reduction associated with treatment at TCs.
Main Outcome Measures
Under- and over-triage rates; estimated patient volume shifts; number of lives saved.
93,880 adult trauma patients were initially evaluated at NTCs in Pennsylvania between 2001–2005. Under-triage was 69%; over-triage was 53%. Achieving <5% under-triage would require the transfer of 18,945 patients/year, a five-fold increase from current practice (3,650 transfers/year). Given an absolute mortality risk reduction of 1.9% for patients with moderate-severe injuries treated at TCs, this change in practice would save 99 potential lives/year, or require 191 transfers/year to save 1 potential life.
Given current practice patterns, ACS-COT recommendations for the regionalization of trauma patients may not be feasible. To achieve 5% under-triage, TCs must increase their capacity 5-fold, physicians at NTCs must increase their capacity to discriminate between moderate-severe and other injuries, or the guidelines must be modified.
PMCID: PMC4090942  PMID: 21422329
decision making; compliance; safety; quality assurance; triage; discrimination
20.  Protocolized Care for Early Septic Shock (ProCESS) statistical analysis plan 
The Protocolized Care for Early Septic Shock study is a randomised, multicentre, prospective, three-arm, parallel-group trial of alternative resuscitation strategies for early septic shock.
To state our analysis plan for trial data.
Our plan is to guide data collection and analysis using pre-existing definitions and testing, with local consensus-based efforts where needed. We examine protocolised care (two experimental approaches) and compare this to usual “wild type” care.
Our plan is to address three aims (clinical efficacy, biology of illness and recovery, and costs and cost-effectiveness) and four hypotheses, and we specify rules for handling data and determining outcomes.
By using measures to maintain study conduct and analysis rigour, we hope to improve understanding of early septic shock resuscitation and care of patients.
PMCID: PMC4081520  PMID: 24289512
Clinical research will increasingly play a core role in the evolution and growth of acute care surgery (ACS) program development across the country. What constitutes an efficient and effective clinical research infrastructure in the current fiscal and academic environment remains obscure. We sought to characterize the effects of implementation of a multidisciplinary acute care research organization (MACRO) at a busy tertiary referral university setting.
In 2008, to minimize redundancy, cost, and maximize existing resources promoting acute care research, MACRO was created unifying clinical research infrastructure between the Departments of Critical Care Medicine, Emergency Medicine and Surgery. Over the time periods 2008–2012 we performed a retrospective analysis and determined volume of clinical studies, patient enrollment for both observational (OBS) and interventional (INTV) trials, and staff growth since MACROs origination and characterized changes over time.
From 2008 to 2011, the volume of patients enrolled in clinical studies which MACRO facilitates has significantly increased over 300%. The % of INTV/OBS trials has remained stable over the same time period (50–60%). Staff has increased from 6 coordinators to 10 with an additional 15 research associates allowing 24/7 service. With this significant growth, MACRO has become financially self-sufficient and additional outside departments now seek MACROs services.
Appropriate organization of acute care clinical research infrastructure minimizes redundancy and can promote sustainable, efficient growth in the current academic environment. Further studies are required to determine if similar models can be successful at other ACS programs.
PMCID: PMC3702269  PMID: 23778448
clinical research; infrastructure; acute care surgery
22.  Acute Care Practices Relevant to Quality End-of-life Care: A Survey of Pennsylvania Hospitals 
Improving end-of-life care in the hospital is a national priority.
To explore the prevalence and reasons for implementation of hospital-wide and ICU practices relevant to quality care in key end-of-life care domains,and to discern major structural determinants of practice implementation.
Cross-sectional mixed-mode survey of Chief Nursing Officers of Pennsylvania structural determinants of practice implementation.
The response rate was 74% (129 of 174). The prevalence of hospital and ICU practices ranged from 95% for a hospital-wide formal code policy to 6% for regularly scheduled family meetings with an attending physician in the ICU. Most practices had less than 50% implementation; most were implemented primarily for quality improvement or to keep up with the standard of care. In a multivariable model including hospital structural characteristics, only hospital size independently predicted the presence of one or more hospital initiatives (ethics consult service, OR 6.13, adjusted p=0.02; private conference room in the ICU for family meetings, OR 4.54, adjusted p<0.001).
There is low penetration of hospital practices relevant to quality end-of-life care in Pennsylvania acute care hospitals. Our results may serve to inform the development of future benchmark goals. It is critical establish a strong evidence base for the practices most associated with improved end-of-life care outcomes and to develop quality measures for end-of-life care to complement existing hospital quality measures that primarily focus on life extension.
PMCID: PMC4070305  PMID: 20427307
terminal care; intensive care unit; intensive care; critical care; quality improvement
23.  Trauma triage in the emergency departments of nontrauma centers: An analysis of individual physician caseload on triage patterns 
Treatment at Level I/II trauma centers improves outcomes for patients with severe injuries. Little is known about the role of physicians’ clinical judgment in triage at outlying hospitals. We assessed the association between physician caseload, case mix, and the triage of trauma patients presenting to non-trauma centers.
A retrospective cohort analysis of patients evaluated between January 1, 2007 and December 31, 2010 by emergency physicians working in eight community hospitals in western Pennsylvania. We linked billing records to hospital charts, summarized physicians’ caseloads, and calculated rates of under-triage (proportion of patients with moderate to severe injuries not transferred to a trauma center) and over-triage (proportion of patients transferred with a minor injury). We measured the correlation between physician characteristics, caseload and rates of triage.
29 (58%) of 50 eligible physicians participated in the study. Physicians had 16.8 (SD=10.1) years of post-residency clinical experience; 21 (72%) were board-certified in Emergency Medicine. They evaluated a median of 2,423 patients/year, of whom 148 (6%) were trauma patients and 3 (0.1%) had moderate to severe injuries. The median under-triage rate was 80%; the median over-triage rate was 91%. Physicians’ caseload of patients with moderate to severe injuries was inversely associated with rates of under-triage (correlation coefficient −0.42, p=0.03). Compared to physicians in the lowest quartile, those in the highest quartile under-triaged 31% fewer patients.
Emergency physicians working in non-trauma centers rarely encounter patients with moderate to severe injuries. Caseload was strongly associated with compliance with American College of Surgeons – Committee on Trauma guidelines.
PMCID: PMC3662028  PMID: 23694885
trauma triage; guidelines; volume-outcome
24.  Nighttime Intensivist Staffing and Mortality among Critically Ill Patients 
The New England journal of medicine  2012;366(22):2093-2101.
Hospitals are increasingly adopting 24-hour intensivist physician staffing as a strategy to improve intensive care unit (ICU) outcomes. However, the degree to which nighttime intensivists are associated with improvements in the quality of ICU care is unknown.
We conducted a retrospective cohort study involving ICUs that participated in the Acute Physiology and Chronic Health Evaluation (APACHE) clinical information system from 2009 through 2010, linking a survey of ICU staffing practices with patient-level outcomes data from adult ICU admissions. Multivariate models were used to assess the relationship between nighttime intensivist staffing and in-hospital mortality among ICU patients, with adjustment for daytime intensivist staffing, severity of illness, and case mix. We conducted a confirmatory analysis in a second, population-based cohort of hospitals in Pennsylvania from which less detailed data were available.
The analysis with the use of the APACHE database included 65,752 patients admitted to 49 ICUs in 25 hospitals. In ICUs with low-intensity daytime staffing, nighttime intensivist staffing was associated with a reduction in risk-adjusted in-hospital mortality (adjusted odds ratio for death, 0.62; P = 0.04). Among ICUs with high-intensity daytime staffing, nighttime intensivist staffing conferred no benefit with respect to risk-adjusted in-hospital mortality (odds ratio, 1.08; P = 0.78). In the verification cohort, there was a similar relationship among daytime staffing, nighttime staffing, and in-hospital mortality. The interaction between nighttime staffing and daytime staffing was not significant (P = 0.18), yet the direction of the findings were similar to those in the APACHE cohort.
The addition of nighttime intensivist staffing to a low-intensity daytime staffing model was associated with reduced mortality. However, a reduction in mortality was not seen in ICUs with high-intensity daytime staffing. (Funded by the National Heart, Lung, and Blood Institute.)
PMCID: PMC3979289  PMID: 22612639
25.  Geographic Access to High Capability Severe Acute Respiratory Failure Centers in the United States 
PLoS ONE  2014;9(4):e94057.
Optimal care of adults with severe acute respiratory failure requires specific resources and expertise. We sought to measure geographic access to these centers in the United States.
Cross-sectional analysis of geographic access to high capability severe acute respiratory failure centers in the United States. We defined high capability centers using two criteria: (1) provision of adult extracorporeal membrane oxygenation (ECMO), based on either 2008–2013 Extracorporeal Life Support Organization reporting or provision of ECMO to 2010 Medicare beneficiaries; or (2) high annual hospital mechanical ventilation volume, based 2010 Medicare claims.
Nonfederal acute care hospitals in the United States.
Measurements and Main Results
We defined geographic access as the percentage of the state, region and national population with either direct or hospital-transferred access within one or two hours by air or ground transport. Of 4,822 acute care hospitals, 148 hospitals met our ECMO criteria and 447 hospitals met our mechanical ventilation criteria. Geographic access varied substantially across states and regions in the United States, depending on center criteria. Without interhospital transfer, an estimated 58.5% of the national adult population had geographic access to hospitals performing ECMO and 79.0% had geographic access to hospitals performing a high annual volume of mechanical ventilation. With interhospital transfer and under ideal circumstances, an estimated 96.4% of the national adult population had geographic access to hospitals performing ECMO and 98.6% had geographic access to hospitals performing a high annual volume of mechanical ventilation. However, this degree of geographic access required substantial interhospital transfer of patients, including up to two hours by air.
Geographic access to high capability severe acute respiratory failure centers varies widely across states and regions in the United States. Adequate referral center access in the case of disasters and pandemics will depend highly on local and regional care coordination across political boundaries.
PMCID: PMC3976413  PMID: 24705417

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