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1.  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
2.  Infection Rate and Acute Organ Dysfunction Risk as Explanations for Racial Differences in Severe Sepsis 
Severe sepsis, defined as infection complicated by acute organ dysfunction, occurs more frequently and leads to more deaths in black than in white individuals. The optimal approach to minimize these disparities is unclear.
To determine the extent to which higher severe sepsis rates in black than in white patients are due to higher infection rates or to a higher risk of acute organ dysfunction.
Design, Setting, and Participants
Analysis of infection-related hospitalizations from the 2005 hospital discharge data of 7 US states and infection-related emergency department visits from the 2003-2007 National Hospital Ambulatory Care Survey.
Main Outcome Measure
Age- and sex-standardized severe sepsis and infection hospitalization rates and the risk of acute organ dysfunction.
Of 8 661 227 non–childbirth-related discharges, 2 261 857 were associated with an infection, and of these, 381 787 (16.8%) had severe sepsis. Black patients had a 67% higher age- and sex-standardized severe sepsis rate than did white patients (9.4; 95% confidence interval [CI], 9.3-9.5 vs 5.6; 95% CI, 5.6-5.6 per 1000 population; P<.001) and 80% higher standardized mortality (1.8, 95% CI, 1.8-1.9 vs 1.0, 95% CI, 1.0-1.1 per 1000 population; P<.001). The higher severe sepsis rate was explained by both a higher infection rate in black patients (47.3; 95% CI, 47.1-47.4 vs 34.0; 95% CI, 33.9-34.0 per 1000 population; incidence rate ratio, 1.39; P<.001) and a higher risk of developing acute organ dysfunction (age- and sex-adjusted odds ratio [OR],1.29; 95% CI, 1.27-1.30; P<.001). Differences in infection presented broadly across different sites and etiology of infection and for community- and hospital-acquired infections and occurred despite a lower likelihood of being admitted for infection from the emergency department (adjusted OR, 0.70; 95% CI, 0.64-0.76; P<.001). The higher risk of organ dysfunction persisted but was attenuated after adjusting for age, sex, comorbid conditions, poverty, and hospital effect (OR, 1.14; 95% CI, 1.13-1.16; P<.001). Racial disparities in infection and severe sepsis incidence and mortality rates were largest among younger adults (eg, the proportion of invasive pneumococcal disease occurring in adults <65 years was 73.9% among black patients vs 44.5% among white patients, P<.001).
Racial differences in severe sepsis are explained by both a higher infection rate and a higher risk of acute organ dysfunction in black than in white individuals.
PMCID: PMC3910506  PMID: 20571016
3.  Severe Sepsis in Pre-Hospital Emergency Care 
Rationale: Severe sepsis is common and highly morbid, yet the epidemiology of severe sepsis at the frontier of the health care system—pre-hospital emergency care—is unknown.
Objectives: We examined the epidemiology of pre-hospital severe sepsis among emergency medical services (EMS) encounters, relative to acute myocardial infarction and stroke.
Methods: Retrospective study using a community-based cohort of all nonarrest, nontrauma King County EMS encounters from 2000 to 2009 who were transported to a hospital.
Measurements and Main Results: Overall incidence rate of hospitalization with severe sepsis among EMS encounters, as well as pre-hospital characteristics, admission diagnosis, and outcomes. Among 407,176 EMS encounters, we identified 13,249 hospitalizations for severe sepsis, of whom 2,596 died in the hospital (19.6%). The crude incidence rate of severe sepsis was 3.3 per 100 EMS encounters, greater than for acute myocardial infarction or stroke (2.3 per 100 and 2.2 per 100 EMS encounters, respectively). More than 40% of all severe sepsis hospitalizations arrived at the emergency department after EMS transport, and 80% of cases were diagnosed on admission. Pre-hospital care intervals, on average, exceeded 45 minutes for those hospitalized with severe sepsis. One-half or fewer of patients with severe sepsis were transported by paramedics (n = 7,114; 54%) or received pre-hospital intravenous access (n = 4,842; 37%).
Conclusions: EMS personnel care for a substantial and increasing number of patients with severe sepsis, and spend considerable time on scene and during transport. Given the emphasis on rapid diagnosis and intervention for sepsis, the pre-hospital interval may represent an important opportunity for recognition and care of sepsis.
PMCID: PMC3622444  PMID: 23087028
sepsis; emergency medical services; epidemiology
4.  Access to urban acute care services in high- vs. middle-income countries: an analysis of seven cities 
Intensive Care Medicine  2013;40:342-352.
Cities are expanding rapidly in middle-income countries, but their supply of acute care services is unknown. We measured acute care services supply in seven cities of diverse economic background.
In a cross-sectional study, we compared cities from two high-income (Boston, USA and Paris, France), three upper-middle-income (Bogota, Colombia; Recife, Brazil; and Liaocheng, China), and two lower-middle-income (Chennai, India and Kumasi, Ghana) countries. We collected standardized data on hospital beds, intensive care unit beds, and ambulances. Where possible, information was collected from local authorities. We expressed results per population (from United Nations) and per acute illness deaths (from Global Burden of Disease project).
Supply of hospital beds where intravenous fluids could be delivered varied fourfold from 72.4/100,000 population in Kumasi to 241.5/100,000 in Boston. Intensive care unit (ICU) bed supply varied more than 45-fold from 0.4/100,000 population in Kumasi to 18.8/100,000 in Boston. Ambulance supply varied more than 70-fold. The variation widened when supply was estimated relative to disease burden (e.g., ICU beds varied more than 65-fold from 0.06/100 deaths due to acute illnesses in Kumasi to 4.11/100 in Bogota; ambulance services varied more than 100-fold). Hospital bed per disease burden was associated with gross domestic product (GDP) (R2 = 0.88, p = 0.01), but ICU supply was not (R2 = 0.33, p = 0.18). No city provided all requested data, and only two had ICU data.
Urban acute care services vary substantially across economic regions, only partially due to differences in GDP. Cities were poor sources of information, which may hinder their future planning.
PMCID: PMC3938845  PMID: 24337401
Urban population; Acute care services; Global burden of disease; Hospital beds; Intensive care beds; Ambulances
5.  Epidemiology of severe sepsis 
Virulence  2013;5(1):4-11.
Severe sepsis is a leading cause of death in the United States and the most common cause of death among critically ill patients in non-coronary intensive care units (ICU). Respiratory tract infections, particularly pneumonia, are the most common site of infection, and associated with the highest mortality. The type of organism causing severe sepsis is an important determinant of outcome, and gram-positive organisms as a cause of sepsis have increased in frequency over time and are now more common than gram-negative infections.
Recent studies suggest that acute infections worsen pre-existing chronic diseases or result in new chronic diseases, leading to poor long-term outcomes in acute illness survivors. People of older age, male gender, black race, and preexisting chronic health conditions are particularly prone to develop severe sepsis; hence prevention strategies should be targeted at these vulnerable populations in future studies.
PMCID: PMC3916382  PMID: 24335434
severe sepsis; epidemiology; risk factors; infection; organ dysfunction
6.  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
7.  Do hospitals provide lower quality of care to black patients for pneumonia?* 
Critical care medicine  2010;38(3):759-765.
Recent studies reported lower quality of care for black vs. white patients with community-acquired pneumonia and suggested that disparities persist at the individual hospital level. We examined racial differences in emergency department and intensive care unit care processes to determine whether differences persist after adjusting for case-mix and variation in care across hospitals.
Prospective, observational cohort study.
Twenty-eight U.S. hospitals.
Patients with community-acquired pneumonia: 1738 white and 352 black patients.
We compared care quality based on antibiotic receipt within 4 hrs and adherence to American Thoracic Society antibiotic guidelines, and intensity based on intensive care unit admission and mechanical ventilation use. Using random effects and generalized estimating equations models, we adjusted for case-mix and clustering of racial groups within hospitals and estimated odds ratios for differences in care within and across hospitals.
Main Results
Black patients were less likely to receive antibiotics within 4 hrs (odds ratio, 0.55; 95% confidence interval, 0.43–0.70; p < .001) and less likely to receive guideline-adherent antibiotics (odds ratio, 0.72; 95% confidence interval, 0.57–0.91; p = .006). These differences were attenuated after adjusting for casemix (odds ratio, 0.59; 95% confidence interval; 0.46–0.76 and 0.84; 95% confidence interval, 0.66 –1.09). Within hospitals, black and white patients received similar care quality (odds ratio, 1; 95% confidence interval, 0.97–1.04 and 1; 95% confidence interval, 0.97–1.03). However, hospitals that served a greater proportion of black patients were less likely to provide timely antibiotics (odds ratio, 0.84; 95% confidence interval, 0.78–0.90). Black patients were more likely to receive mechanical ventilation (odds ratio, 1.57; 95% confidence interval, 1.02–2.42; p = .042). Again, within hospitals, black and white subjects were equally likely to receive mechanical ventilation (odds ratio, 1; 95% confidence interval, .94–1.06) and hospitals that served a greater proportion of black patients were more likely to institute mechanical ventilation (odds ratio, 1.13; 95% confidence interval, 1.02–1.25).
Black patients appear to receive lower quality and higher intensity of care in crude analyses. However, these differences were explained by different case-mix and variation in care across hospitals. Within the same hospital, no racial differences in care were observed.
PMCID: PMC3774066  PMID: 20009756
race; disparities; quality of care; community-acquired pneumonia
8.  Is Survival Better at Hospitals With Higher “End-of-Life” Treatment Intensity? 
Medical care  2010;48(2):125-132.
Concern regarding wide variations in spending and intensive care unit use for patients at the end of life hinges on the assumption that such treatment offers little or no survival benefit.
To explore the relationship between hospital “end-of-life” (EOL) treatment intensity and postadmission survival.
Research Design
Retrospective cohort analysis of Pennsylvania Health Care Cost Containment Council discharge data April 2001 to March 2005 linked to vital statistics data through September 2005 using hospital-level correlation, admission-level marginal structural logistic regression, and pooled logistic regression to approximate a Cox survival model.
A total of 1,021,909 patients ≥65 years old, incurring 2,216,815 admissions in 169 Pennsylvania acute care hospitals.
EOL treatment intensity (a summed index of standardized intensive care unit and life-sustaining treatment use among patients with a high predicted probability of dying [PPD] at admission) and 30- and 180-day postadmission mortality.
There was a nonlinear negative relationship between hospital EOL treatment intensity and 30-day mortality among all admissions, although patients with higher PPD derived the greatest benefit. Compared with admission at an average intensity hospital, admission to a hospital 1 standard deviation below versus 1 standard deviation above average intensity resulted in an adjusted odds ratio of mortality for admissions at low PPD of 1.06 (1.04–1.08) versus 0.97 (0.96–0.99); average PPD: 1.06 (1.04–1.09) versus 0.97 (0.96–0.99); and high PPD: 1.09 (1.07–1.11) versus 0.97 (0.95– 0.99), respectively. By 180 days, the benefits to intensity attenuated (low PPD: 1.03 [1.01–1.04] vs. 1.00 [0.98–1.01]; average PPD: 1.03 [1.02–1.05] vs. 1.00 [0.98–1.01]; and high PPD: 1.06 [1.04–1.09] vs. 1.00 [0.98–1.02]), respectively.
Admission to higher EOL treatment intensity hospitals is associated with small gains in postadmission survival. The marginal returns to intensity diminish for admission to hospitals above average EOL treatment intensity and wane with time.
PMCID: PMC3769939  PMID: 20057328
intensive care; terminal care; mortality; hospitals; efficiency; quality
9.  The Adult Respiratory Distress Syndrome Cognitive Outcomes Study 
Rationale: Cognitive and psychiatric morbidity is common and potentially modifiable after acute lung injury (ALI). However, practical measures of neuropsychological function for use in multicenter trials are lacking.
Objectives: To determine whether a validated telephone-based neuropsychological test battery is feasible in a multicenter trial. To determine the frequency and risk factors for long-term neuropsychological impairment.
Methods: As an adjunct study to the Acute Respiratory Distress Syndrome Clinical Trials Network Fluid and Catheter Treatment Trial, we assessed neuropsychological function at 2 and 12 months post–hospital discharge.
Measurements and Main Results: Of 406 eligible survivors, we approached 261 to participate and 213 consented. We tested 122 subjects at least once, including 102 subjects at 12 months. Memory, verbal fluency, and executive function were impaired in 13% (12 of 92), 16% (15 of 96), and 49% (37 of 76) of long-term survivors. Long-term cognitive impairment was present in 41 of the 75 (55%) survivors who completed cognitive testing. Depression, post-traumatic stress disorder, or anxiety was present in 36% (37 of 102), 39% (40 of 102), and 62% (63 of 102) of long-term survivors. Enrollment in a conservative fluid-management strategy (P = 0.005) was associated with cognitive impairment and lower partial pressure of arterial oxygen during the trial was associated with cognitive (P = 0.02) and psychiatric impairment (P = 0.02).
Conclusions: Neuropsychological function can be assessed by telephone in a multicenter trial. Long-term neuropsychological impairment is common in survivors of ALI. Hypoxemia is a risk factor for long-term neuropsychological impairment. Fluid management strategy is a potential risk factor for long-term cognitive impairment; however, given the select population studied and an unclear mechanism, this finding requires confirmation.
PMCID: PMC3381234  PMID: 22492988
acute respiratory distress syndrome; acute lung injury; cognitive function; critical illness
10.  The effects of trauma center care, admission volume, and surgical volume on paralysis following traumatic spinal cord injury 
Annals of surgery  2009;249(1):10-17.
To evaluate compliance with ACS guidelines and whether trauma center designation, hospital TSCI case volume or spinal surgery volume is associated with paralysis. We hypothesized a priori that trauma center care, by contrast to non-trauma center care, is associated with reduced paralysis at discharge.
Summary Background Data
Approximately 11,000 persons incur a traumatic spinal cord injury (TSCI) in the US annually. The American College of Surgeons (ACS) recommends all TSCI patients be taken to a Level I or II Trauma Center.
We studied 4121 patients diagnosed with TSCI by ICD-9-CM criteria in the 2001 hospital discharge files of seven states (FL, MA, NJ, NY, TX, VA, WA), who were treated in 100 trauma centers and 601 non-trauma centers. We performed multivariate analyses, including a propensity score quintile approach, adjusting for differences in case-mix and clustering by hospital and by state. We also studied 3125 patients using the expanded modified Medicare Provider Analysis and Review records for the years 1996, 2001 and 2006 to assess temporal trends in paralysis by trauma center designation.
Mortality was 7.5%, and 16.3% were discharged with paralysis. Only 57.9% (n=2378) received care at a designated trauma center. Trauma centers had a 16-fold higher admission caseload (20.7 vs. 1.3; p<0.001) and 30-fold higher surgical volume (9.6 vs. 0.3; p<0.001). In the multivariate propensity analysis, paralysis was significantly lower at trauma centers (adjusted OR 0.67; 95% CI, 0.53–0.85; p=0.001). Higher surgical volume, not higher admission volume, was associated with lower risk of paralysis. Indeed, at non-trauma centers, higher admission caseload was associated with worse outcome. There was no significant difference in mortality.
Trauma center care is associated with reduced paralysis after TSCI, possibly due to greater use of spinal surgery. National guidelines to triage all such patients to trauma centers are followed little more than half the time.
PMCID: PMC3622042  PMID: 19106669
11.  Determining the optimal approach to improving trauma triage decisions: a cost-effectiveness analysis 
To identify the optimal target of a future intervention to improve physician decision making in trauma triage.
Study Design
A comparison of the incremental cost-effectiveness ratios (ICERs) of current practice versus hypothetical interventions targeting either physicians’ decisional thresholds (attitudes towards transferring patients to trauma centers) or perceptual sensitivity (ability to identify patients who meet guidelines for transfer).
Taking the societal perspective, we constructed a Markov decision model. We drew estimates of triage patterns, mortality, utilities, and costs from the literature. We assumed that an intervention to change decisional threshold would reduce under-triage but also increase over-triage more than an intervention to change perceptual sensitivity. We performed a series of one-way sensitivity analyses, and studied the most influential variables in a Monte Carlo simulation.
The ICER of an intervention to change perceptual sensitivity was $62,799/ quality-adjusted life years (QALY)-gained compared with current practice. The ICER of an intervention to change decisional threshold was $104,975/QALY-gained compared with an intervention to change perceptual sensitivity. These findings were most sensitive to the relative cost of hospitalizing patients with moderate-severe injuries and their relative risk of dying at non-trauma centers. In probabilistic sensitivity analyses, at a willingness-to-pay threshold of $100,000/QALY-gained, there was a 62% likelihood that an intervention to change perceptual sensitivity was the most cost-effective alternative.
Even a minor investment in changing decision making in trauma triage could greatly improve the quality of care provided. The optimal intervention depends on the characteristics of the individual trauma systems.
PMCID: PMC3595173  PMID: 22435966
cost-effectiveness; trauma; triage; clinical practice guidelines; heuristics
12.  Drotrecogin alfa (activated) ... a sad final fizzle to a roller-coaster party 
Critical Care  2012;16(1):107.
Following the failure of PROWESS-SHOCK to demonstrate efficacy, Eli Lilly and Company withdrew drotrecogin alfa (activated) from the worldwide market. Drotrecogin was initially approved after the original trial, PROWESS, was stopped early for overwhelming efficacy. These events prompt consideration of both the initial approval decision and the later decision to withdraw. It is regrettable that the initial decision was made largely on a single trial that was stopped early. However, the decision to approve was within the bounds of normal regulatory practice and was made by many approval bodies around the world. Furthermore, the overall withdrawal rate of approved drugs remains very low. The decision to withdraw was a voluntary decision by Eli Lilly and Company and likely reflected key business considerations. Drotrecogin does have important biologic effects, and it is probable that we do not know how best to select patients who would benefit. Overall, there may still be a small advantage to drotrecogin alfa, even used non-selectively, but the costs of determining such an effect with adequate certainty are likely prohibitive, and the point is now moot. In the future, we should consider ways to make clinical trials easier and quicker so that more information can be available in a timely manner when considering regulatory approval. At the same time, more sophisticated selection of patients seems key if we are to most wisely test agents designed to manipulate the septic host response.
PMCID: PMC3396243  PMID: 22309988
13.  Duration and magnitude of hypotension and monocyte deactivation in patients with community-acquired pneumonia 
Shock (Augusta, Ga.)  2011;36(6):553-559.
To examine the relationship of duration and magnitude of arterial hypotension to subsequent cellular immune suppression and cytokinemia in patients hospitalized with community-acquired pneumonia (CAP).
We studied an observational cohort of 525 subjects hospitalized after presenting to the Emergency Department with radiographic and clinical signs of CAP. We compared the duration and magnitude of hypotension, using the cardiovascular Sequential Organ Failure Assessment subscore (CV SOFA), to day 3 monocyte expression of human leukocyte antigen-DR (mHLA-DR), a previously validated marker of cellular immune suppression.
A significant association of CV SOFA with decreased mHLA-DR expression was present in univariate analysis (p<0.001) and persisted after adjustment for illness severity and other covariates (p=0.01). With CV SOFA separated into components of magnitude and duration, after covariate adjustment only duration was associated with day 3 mHLA-DR expression (p=0.03). Levels of key pro-and anti-inflammatory cytokines (interleukin-6, interleukin-10, tumor necrosis factor) increased with hypotension exposure, and were also associated with mHLA-DR expression.
In patients admitted with CAP, arterial hypotension over the first three days is associated with markers of monocyte deactivation. The duration of exposure to hypotension may be more important than the magnitude, and monocyte deactivation correlates with interleukin-6 and interleukin-10 release. These results suggest that persistent hypotension might contribute to immunosuppression following septic shock.
PMCID: PMC3259126  PMID: 22080961
Septic shock; hypotension; SOFA; flow cytometry; immune suppression; monocyte deactivation; HLA-DR; cytokine
14.  Sources of non-compliance with clinical practice guidelines in trauma triage: a decision science study 
United States trauma system guidelines specify when to triage patients to specialty centers. Nonetheless, many eligible patients are not transferred as per guidelines. One possible reason is emergency physician decision-making. The objective of the study was to characterize sensory and decisional determinants of emergency physician trauma triage decision-making.
We conducted a decision science study using a signal detection theory-informed approach to analyze physician responses to a web-based survey of 30 clinical vignettes of trauma cases. We recruited a national convenience sample of emergency medicine physicians who worked at hospitals without level I/II trauma center certification. Using trauma triage guidelines as our reference standard, we estimated physicians’ perceptual sensitivity (ability to discriminate between patients who did and did not meet guidelines for transfer) and decisional threshold (tolerance for false positive or false negative decisions).
We recruited 280 physicians: 210 logged in to the website (response rate 74%) and 168 (80%) completed the survey. The regression coefficient on American College of Surgeons – Committee on Trauma (ACS-COT) guidelines for transfer (perceptual sensitivity) was 0.77 (p<0.01, 95% CI 0.68 – 0.87) indicating that the probability of transfer weakly increased as the ACS-COT guidelines would recommend transfer. The intercept (decision threshold) was 1.45 (p<0.01, 95% CI 1.27 – 1.63), indicating that participants had a conservative threshold for transfer, erring on the side of not transferring patients. There was significant between-physician variability in perceptual sensitivity and decisional thresholds. No physician demographic characteristics correlated with perceptual sensitivity, but men and physicians working at non-trauma centers without a trauma-center affiliation had higher decisional thresholds.
On a case vignette-based questionnaire, both sensory and decisional elements in emergency physicians’ cognitive processes contributed to the under-triage of trauma patients.
PMCID: PMC3503726  PMID: 23098291
Physician decision making; Clinical guidelines; Compliance; Trauma; Triage; Heuristics; Perceptual sensitivity; Signal detection theory
15.  Revisiting Mars and Venus: understanding gender differences in critical illness 
Critical Care  2011;15(4):180.
Understanding the nature and biological basis of gender-determined differences in risk of and outcome from infection might identify new therapeutic targets, allow more individualised treatment, and facilitate better risk prediction and application of healthcare resources. Gender differences in behaviours, comorbidities, access to healthcare and biology may result in differences in acquiring infection, or in response to infection once acquired. Some studies have reported higher male susceptibility to infection, and higher risk of death with sepsis, but others have found the opposite effect. The explanation for this disagreement is probably that different studies have included patients at different stages on the continuum from infectious agent exposure to death or recovery. Studying sufficient patient numbers to explore this entire continuum while accounting for heterogeneity in type of infection and comorbidity is difficult because of the number of patients required. However, if true gender effects can be identified, examination of their biological or psychosocial causes will be warranted.
PMCID: PMC3387615  PMID: 21888682
16.  Understanding the potential role of statins in pneumonia and sepsis 
Critical care medicine  2011;39(8):1871-1878.
To examine the association of statin use with clinical outcomes and circulating biomarkers in community-acquired pneumonia (CAP) and sepsis.
Multicenter inception cohort study.
Emergency departments of 28 US hospitals.
1895 subjects hospitalized with CAP.
Measurements and Main Results
Our approach consisted of two different comparison cohorts, each reflecting methods used in prior publications in this area. We first compared subjects with prior statin use (prior use cohort), defined as a history of statin use in the week before admission, to those with no prior use. We then compared prior statin users whose statins were continued in-hospital (continued use cohort) to those with either no prior use or no inhospital use. We adjusted for patient characteristics, including demographics, comorbid conditions, and illness severity, and accounted for healthy user effect and indication bias using propensity analysis. We determined risk of severe sepsis and 90-day mortality. We measured markers inflammation (TNF, IL-6, IL-10), coagulation (antithrombin, Factor IX, plasminogen activator inhibitor, D-dimer, thrombin antithrombin complex), and lymphocyte cell surface protein expression during first week of hospitalization. There were no differences in severe sepsis risk between statin users and non-users for prior (30.8% vs. 30.7%, p=0.98) or continued statin use (30.2% vs. 30.8%, p=0.85) in univariate analyses, and after adjusting for patient characteristics and propensity for statin use. Ninety-day mortality was similar in prior statin users (9.2% vs. 12.0%, p=0.11) and lower in continued statin users (7.9% vs. 12.1%, p=0.02). After adjusting for patient characteristics and propensity for statin use, there was no mortality benefit for prior (OR=0.90 (0.63–1.29), p=0.57) or continued statin use (OR=0.73 (0.47–1.13), p=0.15). Only antithrombin activity over time was higher in statin subjects, yet the magnitude of difference was modest. There were no differences in other coagulation, inflammatory, or lymphocyte cell surface markers.
We found no evidence of a protective effect for statin use on clinical outcomes and only modest differences in circulating biomarkers in CAP, perhaps due to healthy user effects and indication bias.
PMCID: PMC3139804  PMID: 21516038
statins; community-acquired pneumonia; sepsis; coagulation; outcomes
17.  Light and the outcome of the critically ill: an observational cohort study 
Critical Care  2012;16(4):R132.
Light before and during acute illness has been associated with both benefit and harm in animal models and small human studies. Our objective was to determine the associations of light duration (photoperiod) and intensity (insolation) before and during critical illness with hospital mortality in ICU patients. Based on the 'winter immunoenhancement' theory, we tested the hypothesis that a shorter photoperiod before critical illness is associated with improved survival.
We analyzed data from 11,439 patients admitted to 8 ICUs at the University of Pittsburgh Medical Center between June 30, 1999 and July 31, 2004. Daily photoperiod and insolation prior to and after ICU admission were estimated for each patient by using data provided by the United States Naval Observatory and National Aeronautics and Space Administration and direct measurement of light gradient from outside to bedside for each ICU room. Our primary outcome was hospital mortality. The association between light and risk of death was analyzed using multivariate analyses, adjusting for potential confounders, including severity of illness, case mix, and ICU type.
The cohort had an average APACHE III of 52.9 and a hospital mortality of 10.7%. In total, 128 ICU beds were analyzed; 108 (84%) had windows. Pre-illness photoperiod ranged from 259 to 421 hours in the prior month. A shorter photoperiod was associated with a reduced risk of death: for each 1-hour decrease, the adjusted OR was 0.997 (0.994 to 0.999, p = 0.03). In the ICU, there was near complete (99.6%) degradation of natural light from outside to the ICU bed. Thus, light exposure once in the ICU approached zero; the 24-hour insolation was 0.005 ± 0.003 kWh/m2 with little diurnal variation. There was no association between ICU photoperiod or insolation and mortality.
Consistent with the winter immunoenhancement theory, a shorter photoperiod in the month before critical illness is associated with a reduced risk of death. Once in the ICU, patients are exposed to near negligible natural light despite the presence of windows. Further studies are warranted to determine the underlying mechanisms and whether manipulating light exposure, before or during ICU admission, can enhance survival.
PMCID: PMC3580717  PMID: 22827924
18.  A randomized trial of the effect of patient race on physician ICU and life-sustaining treatment decisions for an acutely unstable elder with end-stage cancer 
Critical care medicine  2011;39(7):1663-1669.
To test whether hospital-based physicians made different ICU and LST decisions for otherwise identical African American (AA) and European American (EA) patients with end-stage cancer and life-threatening hypoxia.
We conducted a randomized trial of the relationship between patient race and physician treatment decisions using high-fidelity simulation. We counterbalanced the effects of race and case by randomly alternating their order using a table of random permutations. Physicians completed two simulation encounters with AA and EA patient simulators diagnosed with prognostically-identical end-stage gastric or pancreatic cancer and life-threatening hypoxia and hypotension, followed by a self-administered survey of beliefs regarding treatment preferences by race. We conducted within-subjects analysis of each physician’s matched-pair simulation encounters, adjusting for order and case effects, and between-subjects analysis of physicians’ first encounter, adjusting for case.
Peter M. Winter Institute for Simulation Education and Research at the University of Pittsburgh.
33 hospital-based attending physicians, including 12 emergency physicians, 8 hospitalists, and 13 intensivists from Allegheny County, Pennsylvania.
Race of patient simulator.
Measurements and Main Results
Measurements included physician treatment decisions recorded during the simulation and documented in the chart and beliefs about treatment preference by race. When faced with an AA versus a EA patient, physicians did not differ in their elicitation of intubation preferences (within-subject comparison (WS): 28/32 (88%) vs. 28/32 (88%), p=0.589; between-subject comparison (BS): 13/17 (87%) vs. 13/17 (76%), p=0.460), ICU admission (WS: 14/32 (44%) vs. 12/32 (38%), p=0.481; BS: 8/15 (53%) vs. 7/17 (41%), p=0.456), intubation (WS: 5/32 (16%) vs. 4/32 (13%), p=0.567; B: 1/15 (7%) vs. 4/17 (24%), p=0.215) or initiation of comfort measures only (WS: 16/32 (50%) vs. 19/32 (59%), p=0.681; BS: 6/15 (40%) vs. 8/17 (47%), p-0.679). Physicians believed that an AA patient with end-stage cancer was more likely than a similar EA patient to prefer potentially-life prolonging chemotherapy over treatment focused on palliation (67% vs. 64%, z= − 1.79, p=.07) and to want mechanical ventilation for 1 weeks’ life extension (43% vs. 34%, z= − 2.93, p=.003), and less likely to want a DNR order if hospitalized (51% vs. 60%, z= 3.03, p=.003).
In this exploratory study, hospital-based physicians did not make different treatment decisions for otherwise identical terminally ill AA and EA elders despite believing that AA patients are more likely to prefer intensive, life-sustaining treatment, and they grossly overestimated the preference for intensive treatment for both races.
PMCID: PMC3119368  PMID: 21460710
terminal care; intensive care; physician decision making; cancer; acute respiratory failure; palliative care; simulation
19.  The International Community-Acquired Pneumonia (CAP) Collaboration Cohort (ICCC) study: rationale, design and description of study cohorts and patients 
BMJ Open  2012;2(3):e001030.
To improve the understanding of the determinants of prognosis and accurate risk stratification in community-acquired pneumonia (CAP).
Multicentre collaboration of prospective cohorts.
6 cohorts from the USA, Canada, Hong Kong and Spain.
From a published meta-analysis of risk stratification studies in CAP, the authors identified and pooled individual patient-level data from six prospective cohort studies of CAP (three from the USA, one each from Canada, Hong Kong and Spain) to create the International CAP Collaboration Cohort. Initial essential inclusion criteria of meta-analysis were (1) prospective design, (2) in English language, (3) reported 30-day mortality and transfer to an intensive or high dependency care and (4) minimum 1000 participants. Common baseline patient characteristics included demographics, history and physical examination findings, comorbidities and laboratory and radiographic findings.
Primary and secondary outcome measures
This paper reports the rationale, hypotheses and analytical framework and also describes study cohorts and patients. The authors aim to (1) compare the prognostic accuracy of existing CAP risk stratification tools, (2) assess patient-level determinants of prognosis, (3) improve risk stratification by combined use of scoring systems and (4) understand prognostic factors for specific patient groups.
The six cohorts assembled from 1991 to 2007 included 13 784 patients (median age 71 years, 54% men). Aside from one randomised controlled study, the remaining five were cohort studies, but all had similar inclusion criteria. Overall, there was 0%–6% missing data. A total of 6159 (44%) had severe pneumonia by Pneumonia Severity Index class IV/V. Mortality at 30 days was 8% (1036). Admission to intensive care or high dependency unit was also 8% (1059).
International CAP Collaboration Cohort provides a pooled multicentre data set of patients with CAP, which will help us to better understand the prognosis of CAP.
Article summary
Article focus
This paper reports the rationale, hypotheses and analytical framework and also describes study cohorts and patients. We aim to
compare the prognostic accuracy of existing CAP risk stratification tools;
assess patient-level determinants of prognosis;
improve risk stratification by combined use of scoring systems;
understand prognostic factors for specific patient groups.
Key messages
The International CAP Collaboration Cohort (ICCC) as described in this report will be able to provide better understanding of determinants of outcomes in CAP. Examples of such development include comparison of commonly and less commonly known CAP severity scoring systems and identification of characteristics of CAP patients with poor outcome (30-day mortality) despite non-severe status of severity score.
In view of the large sample size, the ICCC cohort will be able to provide the determinants of outcomes in patient groups with specific conditions such as cardiovascular and respiratory diseases taking into account case mix and individual prognostic indicators.
The ICCC cohort will be of benefit to the CAP research community and help define a future agenda for research, as well as helping clinicians make better clinical decisions for patients with CAP.
Strengths and limitations of this study
The ICCC is a multicentre/multiethnic cohort where all collaborating groups defined pneumonia based on clinical features and the presence of CXR evidence of pneumonia. The major strengths of ICCC are prospective study design, inclusion of CAP patients spanning across wide age range, ethnicity, different healthcare settings and large sample size. Potential areas of improvement in assessment of CAP might be identification of at-risk patients with pneumonia who have been initially assessed as non-severe CAP. With large sample size, ICCC may provide an opportunity to identify characteristics of such individuals. Based on this work, risk assessment may be applied at more than one point in time in order to observe temporal trends in recovery or deterioration in future CAP research and clinical practice.
There were multiple observers and data collections across several centres. However, all cohorts followed the strict criteria in data collection as described in table 1. Furthermore, the data collected were objective measures such as age and urea level, thereby ruling out potential observer bias. The process of care between hospitals may be variable. There may be a variation in clinical management between different hospitals and in different healthcare setting between the various countries such as there may be important variations in antibiotic use, patterns of infective micro-organisms, care protocols and treatment guidelines. Other limitations to consider are biomarkers, healthcare provider and site characteristics. The patients were enrolled into the study at different time periods. However, this presents an opportunity to compare and contrast different healthcare systems to better understand the variation in healthcare setting and outcomes. Since all six studies used the Pneumonia Severity Index (PSI) for risk stratification, this can have implications, for example, patients who scored non-severe at initial assessment (low PSI) but might have had worse outcome are under-represented if such patients were sent home. This could contribute to attenuation of estimates in low PSI group. Nevertheless, it is possible that these patients would have presented again to the medical centre if/when deterioration occurred. Cohorts that only had data on CURB-related variables and cohorts with smaller sample sizes were not included in the ICCC, and this may introduce some degree of selection bias. Nevertheless, this should not have any effect on the internal relationship between the predictors and outcomes of interest.
PMCID: PMC3358618  PMID: 22614174
20.  Disability among Elderly Survivors of Mechanical Ventilation 
Rationale: Studies of long-term functional outcomes of elderly survivors of mechanical ventilation (MV) are limited to local samples and biased retrospective, proxy-reported preadmission functional status.
Objectives: To assess the impact on disability of hospitalization with MV, compared with hospitalization without MV, accounting for prospectively assessed prior functional status.
Methods: Retrospective population-based longitudinal cohort study of Medicare beneficiaries age 65 and older enrolled in the Medicare Current Beneficiary Survey, 1996–2003.
Measurements and Main Results: Premeasures and postmeasures of disability included mobility difficulty and weighted activities of daily living disability scores ranging from 0 (not disabled) to 100 (completely disabled) based on self-reported health and functional status collected 1 year apart. Among 54,771 person-years (PY) of observation over 7 calendar years of data, 42,890 PY involved no hospitalization, 11,347 PY involved a hospitalization without MV, and 534 PY included a hospitalization with MV. Mortality at 1 year was 8.9%, 23.9%, and 72.5%, respectively. The level of disability at the postassessment was substantially higher for a prototypical patient who survived after hospitalization with MV (adjusted activities of daily living disability score [95% confidence interval] 14.9 [12.2–17.7]; adjusted mobility difficulty score [95% confidence interval] 25.4 [22.4–28.4]) compared with an otherwise identical patient who survived hospitalization without MV (11.5 [11.1–11.9] and 22.3 [21.8–22.9]) or who was not hospitalized (8.0 [7.9–8.1] and 13.4 [13.3–13.6]).
Conclusions: The greater marginal increase in disability among survivors of MV compared with survivors of hospitalization without MV is larger than would be predicted from prior functional status.
PMCID: PMC3159078  PMID: 21057004
Medicare; intensive care; mechanical ventilation; quality of life; functional status
21.  Variability of Intensive Care Admission Decisions for the Very Elderly 
PLoS ONE  2012;7(4):e34387.
Although increasing numbers of very elderly patients are requiring intensive care, few large sample studies have investigated ICU admission of very elderly patients. Data on pre triage by physicians from other specialities is limited. This observational cohort study aims at examining inter-hospital variability of ICU admission rates and its association with patients' outcomes. All patients over 80 years possibly qualifying for ICU admission who presented to the emergency departments (ED) of 15 hospitals in the Paris (France) area during a one-year period were prospectively included in the study. Main outcome measures were ICU eligibility, as assessed by the ED and ICU physicians; in-hospital mortality; and vital and functional status 6 months after the ED visit. 2646 patients (median age 86; interquartile range 83–91) were included in the study. 94% of participants completed follow-up (n = 2495). 12.4% (n = 329) of participants were deemed eligible for ICU admission by ED physicians and intensivists. The overall in-hospital and 6-month mortality rates were respectively 27.2% (n = 717) and 50.7% (n = 1264). At six months, 57.5% (n = 1433) of patients had died or had a functional deterioration. Rates of patients deemed eligible for ICU admission ranged from 5.6% to 38.8% across the participating centers, and this variability persisted after adjustment for patients' characteristics. Despite this variability, we found no association between level of ICU eligibility and either in-hospital death or six-month death or functional deterioration. In France, the likelihood that a very elderly person will be admitted to an ICU varies widely from one hospital to another. Influence of intensive care admission on patients' outcome remains unclear.
Trial Registration NCT00912600
PMCID: PMC3324496  PMID: 22509296
22.  The effect of light on critical illness 
Critical Care  2011;15(2):218.
PMCID: PMC3219304  PMID: 21457502
23.  The influence of pre-existing diabetes mellitus on the host immune response and outcome of pneumonia: analysis of two multicenter cohort studies 
Thorax  2010;65(10):870-877.
Although diabetes mellitus is implicated in susceptibility to infection, the association of diabetes with the subsequent course and outcome is unclear.
Design and setting
Retrospective analysis of two multicenter cohorts. We determined the association of pre-existing diabetes on the host immune response, acute organ function, and mortality in patients hospitalized with community-acquired pneumonia (CAP) in the GenIMS study (n=1895) and on mortality following either CAP or non-infectious hospitalizations in the population-based cohort study, Health ABC (n=1639).
Mortality rate within first year, risk of organ dysfunction, and immune responses, including circulating inflammatory (tumor necrosis factor, interleukin-6, interleukin-10), coagulation (Factor IX, thrombin-antithrombin complexes, antithrombin), fibrinolysis (plasminogen-activator inhibitor-1, and D-dimer), and cell-surface markers (CD120a, CD120b, HLA-DR, TLR-2 and TLR-4).
In GenIMS, diabetes increased mortality rate within first year after CAP (unadjusted hazard ratio [HR]=1.41, 95% confidence interval [CI]=1.12–1.76, p=0.002), even after adjusting for pre-existing cardiovascular and renal disease (adjusted HR=1.3, CI=1.03–1.65, p=0.02). In Health ABC, diabetes increased mortality rate within first year following CAP hospitalization, but not after hospitalization for non-infectious illnesses (significant interaction for diabetes and reason for hospitalization [p=0.04]; HR for diabetes on mortality over first year after CAP 1.87, CI=0.76–4.6, p=0.16 and after non-infectious hospitalization=1.16, CI=0.8–1.6, p=0.37). In GenIMS, immediate immune response was similar, as evidenced by similar circulating immune marker levels in the emergency department and during the first week. Those with diabetes had higher risk of acute kidney injury during hospitalization (39.3% vs. 31.7%, p=0.005) and they were more likely to die due to cardiovascular and kidney disease (34.4% vs. 26.8% and 10.4% vs. 4.5%, p=0.03).
Pre-existing diabetes was associated with a higher risk of death following CAP. The mechanism is not due to an altered immune response, at least as measured by a broad panel of circulating and cell surface markers, but may be due to worsening of pre-existing cardiovascular and kidney disease.
PMCID: PMC3306240  PMID: 20861291
24.  Learning Patient-Specific Predictive Models from Clinical Data 
Journal of biomedical informatics  2010;43(5):669-685.
We introduce an algorithm for learning patient-specific models from clinical data to predict outcomes. Patient-specific models are influenced by the particular history, symptoms, laboratory results, and other features of the patient case at hand, in contrast to the commonly used population-wide models that are constructed to perform well on average on all future cases. The patient-specific algorithm uses Markov blanket (MB) models, carries out Bayesian model averaging over a set of models to predict the outcome for the patient case at hand, and employs a patient-specific heuristic to locate a set of suitable models to average over. We evaluate the utility of using a local structure representation for the conditional probability distributions in the MB models that captures additional independence relations among the variables compared to the typically used representation that captures only the global structure among the variables. In addition, we compare the performance of Bayesian model averaging to that of model selection. The patient-specific algorithm and its variants were evaluated on two clinical datasets for two outcomes. Our results provide support that the performance of an algorithm for learning patient-specific models can be improved by using a local structure representation for MB models and by performing Bayesian model averaging.
PMCID: PMC2933959  PMID: 20450985
patient-specific; population-wide; Bayesian networks; Markov blanket; Bayesian model averaging; prediction; algorithm
25.  The challenge of admitting the very elderly to intensive care 
The aging of the population has increased the demand for healthcare resources. The number of patients aged 80 years and older admitted to the intensive care unit (ICU) increased during the past decade, as has the intensity of care for such patients. Yet, many physicians remain reluctant to admit the oldest, arguing a "squandering" of societal resources, that ICU care could be deleterious, or that ICU care may not actually be what the patient or family wants in this instance. Other ICU physicians are strong advocates for admission of a selected elderly population. These discrepant opinions may partly be explained by the current lack of validated criteria to select accurately the patients (of any age) who will benefit most from ICU hospitalization. This review describes the epidemiology of the elderly aged 80 years and older admitted in the ICU, their long-term outcomes, and to discuss some of the solutions to cope with the burden of an aging population receiving acute care hospitalization.
PMCID: PMC3224497  PMID: 21906383

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